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`21
`
`The
`liquid.
`or
`suspension
`capsule,
`tablet,
`in the
`pharmaceutical composition is preferably made
`form of a dosage unit containing a particular amount of
`the active ingredient.
`Examples of such dosage units
`are
`capsules,
`tablets,
`powders,
`granules
`or
`a
`suspension, with conventional additives such as lactose,
`mannitol,
`corn starch or potato starch; with binders
`such as crystalline cellulose, cellulose derivatives,
`acacia,
`corn starch or gelatins; with disintegrators
`as
`such
`corm
`starch,
`potato
`starch
`or
`sodium
`carboxymethyl-celliulose;
`and with lubricants
`such as
`talc or magnesium stearate.
`The active ingredient may
`also be
`administered by
`injection as
`a
`composition
`wherein,
`for example, saline, dextrose or water may be
`
`10
`
`15
`
`used as a suitable carrier.
`For
`intravenous,
`intramuscular,
`
`subcutaneous,
`
`or
`
`intraperitoneal
`
`administration,
`
`the
`
`compound may be
`
`20
`
`is
`solution which
`sterile aqueous
`combined with a
`preferably isotonic with the blood of
`the recipient.
`Such formulations may be prepared by dissolving solid
`active ingredient
`in water containing physiologically
`compatible substances such as sodium chloride, glycine,
`
`and having a buffered pH compatible with
`and the like,
`physiological conditions to produce an aqueous Solution,
`
`25
`
`and rendering said solution sterile. The
`
`formulations
`
`may be present in unit or muiti-dose containers such as
`
`sealed ampoules or vials.
`tract,
`If the neoplasia is localized in the G.I.
`the compound may be formulated with acid-stable, base-
`
`30
`
`labile coatings known in the art which begin to dissolve
`
`in the high pH small
`
`intestine. Formulation to enhance
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`
`The
`liquid.
`or
`suspension
`capsule,
`tablet,
`in the
`pharmaceutical composition is preferably made
`form of a dosage unit containing a particular amount of
`the active ingredient.
`Examples of such dosage units
`are
`capsules,
`tablets,
`powders,
`granules
`or
`a
`suspension, with conventional additives such as lactose,
`mannitol,
`corn starch or potato starch; with binders
`such as crystalline cellulose, cellulose derivatives,
`acacia,
`corn starch or gelatins; with disintegrators
`as
`such
`corm
`starch,
`potato
`starch
`or
`sodium
`carboxymethyl-celliulose;
`and with lubricants
`such as
`talc or magnesium stearate.
`The active ingredient may
`also be
`administered by
`injection as
`a
`composition
`wherein,
`for example, saline, dextrose or water may be
`
`10
`
`15
`
`used as a suitable carrier.
`For
`intravenous,
`intramuscular,
`
`subcutaneous,
`
`or
`
`intraperitoneal
`
`administration,
`
`the
`
`compound may be
`
`20
`
`is
`solution which
`sterile aqueous
`combined with a
`preferably isotonic with the blood of
`the recipient.
`Such formulations may be prepared by dissolving solid
`active ingredient
`in water containing physiologically
`compatible substances such as sodium chloride, glycine,
`
`and having a buffered pH compatible with
`and the like,
`physiological conditions to produce an aqueous Solution,
`
`25
`
`and rendering said solution sterile. The
`
`formulations
`
`may be present in unit or muiti-dose containers such as
`
`sealed ampoules or vials.
`tract,
`If the neoplasia is localized in the G.I.
`the compound may be formulated with acid-stable, base-
`
`30
`
`labile coatings known in the art which begin to dissolve
`
`in the high pH small
`
`intestine. Formulation to enhance
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`PCT/US02/03201
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`local pharmacologic effects and reduce systemic uptake
`
`are preferred.
`
`Formulations suitable for parenteral administration
`
`conveniently comprise a sterile aqueous preparation of
`
`the active compound which is preferably made isotonic.
`
`Preparations for
`
`injections may also be
`
`formulated by
`
`suspending or emulsifying the compounds
`
`in non-aqueous
`
`solvent,
`
`such as vegetable oil, synthetic aliphatic acid
`
`gliycerides,
`
`esters
`
`of
`
`higher aliphatic
`
`acids
`
`or
`
`10
`
`propylene glycol.
`
`.
`
`Formulations
`
`for
`
`topical use include known gels,
`
`creams, oils,
`
`and the like. For aerosol delivery,
`
`the
`
`compounds
`exipients,
`
`may
`be
`formulated with
`known
`aerosol
`such as saline,
`and
`administered using
`
`15
`
`commercially
`
`available nebulizers.
`
`Formulation
`
`in a
`
`fatty
`
`acid
`
`source
`
`may
`
`be
`
`used
`
`to
`
`enhance
`
`biocompatibility. Berosol delivery is
`
`the preferred
`
`method of delivery for epithelial neoplasias of the lung
`
`20
`
`for prevention application.
`For
`rectal administration,
`the active ingredient
`may be formulated into suppositories using bases which
`are solid at
`room temperature and melt or dissolve at
`
`coca
`include
`Commonly used bases
`temperature.
`body
`butter,
`glycerinated gelatin,
`hydrogenated vegetable
`
`25
`
`oll, polyethylene glycols of various molecular weights,
`
`and fatty esters of polyethylene stearate.
`
`form and
`dosage
`The
`reference
`established
`by
`prophylactic regiments. The
`
`can
`amount
`to
`known
`amount of
`
`readily
`be
`treatment
`or
`therapeutically
`
`30
`
`active compound
`
`that
`
`is administered and the dosage
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`PCT/U802/03201
`
`condition with the
`treating a disease
`for
`regimen
`compounds and/or compositions of this invention depends
`on a variety of factors,
`including the age, weight,
`sex
`and medical condition of
`the subject,
`the severity of
`the disease,
`the route and frequency of administration,
`and the particular compound employed,
`the location of
`the neoplasia, as well as the pharmacokinetic properties
`of
`the individual
`treated,
`and thus may vary widely.
`The dosage will generally be lower if the compounds are
`administered locally rather than systemically,
`and for
`prevention rather
`than for
`treatment. Such treatments
`may be administered as often as necessary and for the
`period
`of
`time
`judged
`necessary
`by
`the
`treating
`physician. One of skill in the art will appreciate that
`the dosage regime or therapeutically effective amount of
`the
`inhibitor
`to be
`administrated may
`need
`to be
`optimized
`for
`each
`individual.
`The
`pharmaceutical
`compositions may contain active ingredient
`in the range
`of about 0.1 to 2000 mg, preferably in the range of
`about 0.5 to 500 mg and most preferably between about 1
`and 200 mg. A daily dose of about 0.01 to 100 mg/kg body
`weight, preferably between about 0.1 and about 50 mg/kg
`body weight and most preferably from about
`1 to 20 mg/kg
`body weight, may be appropriate. The daily dose can be
`administered in one to four doses per day.
`Human uroguanylin cDNA has been cloned in bacteria,
`chemically synthesized by
`solid phase peptide
`and
`synthesis.
`Uroguanylin peptide
`can
`be
`chemically
`synthesized by using the procedure as described in U.S.
`patent number 5,489,670 Human Uroguanylin and in U.S.
`patent
`number
`5,140,102
`Pentadecapeptide,
`guanylin,
`which stimulates intestinal guanylate cyclase. Peptides
`similar to uroguanylin peptides have been identified in
`mouse,
`rat,
`porcine,
`and
`bovine
`species.
`The
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`
`functionally active domain in most of these peptides are
`highly
`conserved.
`Therefore,
`the
`physiological
`functions of
`these peptides may be similar,
`and these
`peptides may be used as
`intestinal cancer preventative
`agents as well. Thus, as long as the functionally active
`domains of
`these peptides are conserved,
`substitutions
`in the non-active domains may be achieved with no change
`in the activity of the peptides.
`the combination of any
`In the present
`invention,
`one or more of
`the following peptides; wuroguanylin,
`human
`uroguanylin,
`pro-uroguanylin,
`and
`human pro-
`uroguanylin, guanylin,
`lymphoguanylin, prolymphoguanylin
`and heat stable enterotoxin, with any one of more of
`naturally occurring,
`oer
`an
`extract
`of
`a natural
`occurring, or a chemically synthesized cyclooxygenase-2
`inhibitor,
`preferably
`a
`selective
`cyclooxygenase-2
`inhibitor:-or inhibitors is disclosed for the prevention,
`inhibition, or
`treatment of cancer
`in the intestinal
`
`tract by administration of an effective amount of such a
`combination to a subject in need of such treatment.
`In such a combination,
`the cyclooxygenase inhibitor
`can be,
`by way
`of
`example,
`a
`COX-2
`nonselective
`inhibitor or a COX-2 selective inhibitor.
`Examples of
`
`the well-known
`COX-2 nonselective inhibitors
`include
`|
`compounds
`‘ aspirin,
`acetaminophen,
`indomethacin,
`sulindac, etodolac, mefenamic acid,
`tolmetin, ketorolac,
`
`fenoprofen, ketoprofen,
`ibuprofen, naproxen,
`diclofenac,
`piroxicam,
`tenoxicam,
`flurbiprofen,
`oxaprozin,
`or
`nimesulide
`or
`a
`phenylbutazone,
`apazone,
`salt
`or
`derivative or
`pharmaceutically
`acceptable
`prodrug thereof.
`In a preferred embodiment of
`the
`invention the COX-2 nonselective inhibitor is selected
`
`aspirin,
`comprising
`group
`from the
`indomethacin,
`ibuprofen, or naproxen.
`
`acetaminophen,
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`
`the cyclooxygenase-2
`In the preferred embodiments,
`inhibitor is selected from compounds of Formula I
`
`O
`R24
`
`Ri:ee
`
`R3
`
`7
`
`wherein A is
`
`a
`
`substituent
`
`selected from
`
`partially unsaturated or unsaturated heterocyclyl
`and
`partially
`unsaturated
`or
`unsaturated
`carbocyclic rings;
`wherein
`Rt
`
`one
`
`substituent
`
`is
`
`at
`
`least
`
`cycloalkyl,
`heterocyclyl,
`from
`selected
`is optionally
`and aryl, wherein R!
`cycloalkenyl
`substituted at a substitutable position with one or
`more
`radicals
`selected from alkyl,
`haloalkyl,
`cyano,
`carboxyl,
`“alkoxycarbonyl,
`hydroxyl,
`hydroxyalkyl,
`haloalkoxy,
`amino,
`alkylamino,
`arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo,
`alkoxy and alkylthio;
`wherein R2 is methyl or amino; and
`wherein R3 is a radical selected from hydrido,
`alkyl,
`alkenyl,
`alkynyl,
`OXO,
`cyano,
`halo,
`carboxyl,
`cyanoalkyl,
`heterocyclyloxy,
`-alkyloxy,
`alkylthio,
`alkylcarbonyl,
`cycloalkyl,
`aryl,
`haloalkyl,
`heterocyclyl,
`cycloalkenyl,
`aralkyl,
`heterocyclylalkyl,
`acyl,
`alkylthioalkyl,
`hydroxyalkyl,
`alkoxycarbonyl,
`arylcarbonyl,
`aralkylcarbonyl,
`aralkenyl,
`alkoxyalkyl,
`aryithioalkyl,
`aryloxyalkyl,
`aralkyithioalkyl,
`aralkoxyalkyl,
`alkoxyaralkoxyalkyl,
`alkoxycarbonylalkyl,
`aminocarbonyl,
`aminocarbonylalkyl,
`alkylaminocarbonyl,
`N-
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`
`N-alkyl-N~-arylaminocarbonyl,
`arylaminocarbonyl,
`alkylaminocarbonylalkyl, carboxyalkyl,
`alkylamino,
`N-arylamino,
`N-aralkylamino,
`N-alky1-N-
`aralkylamino,
`N-alkyl-N-arylamino,
`aminoalkyl,
`alkylaminoalkyl,
`N-arylaminoalkyl,
`N-
`aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl, N-
`alkyl~-N-arylaminoalkyl,
`aryloxy,
`aralkoxy,
`arylthio,
`aralkylthio,
`alkylsulfinyl,
`alkylsulfonyl,
`aminosulfonyl,
`alkylaminosulfonyl,
`N-arylaminosulfonyl,
`arylsulfonyl,
`N-alkyl-N-
`arylaminosulfonyl;
`or
`a
`pharmaceutically—
`acceptable salt thereof.
`A preferred class of compounds which inhibit
`cyclooxygenase-2 consists of compounds of Formula I
`wherein A is selected from 5- or 6-member partially
`
`heterocyclyl,
`unsaturated
`heterocyclyl,
`unsaturated
`condensed
`unsaturated
`cycloalkenyl and phenyl;
`from 5-
`and
`6-membered
`
`6-member
`or
`5
`10-member
`or
`9-
`lower
`heterocyclyl,
`wherein R!
`is. selected
`heterocyclyl,
`lower
`
`and aryl selected
`lower cycloalkenyl
`cycloalkyl,
`from phenyl, biphenyl and naphthyl, wherein RI
`is
`optionally substituted at a substitutable position
`with one or more
`radicals
`selected from lower
`alkyl,
`lower haloalkyl,
`cyano,
`carboxyl,
`lower
`alkoxycarbonyl, hydroxyl,
`lower hydroxyalkyl,
`lower
`haloalkoxy,
`amino,
`lower alkylamino,
`-phenylamino,
`lower alkoxyalkyl,
`lower alkylsulfinyl, halo,
`lower
`alkoxy and lower alkylthio; wherein R2 is methyl or
`amino; amd wherein R?
`is a radical selected from
`hydrido,
`OXO,
`cyano,
`carboxyl,
`lower
`alkoxycarbonyl,
`lower
`carboxyalkyl,
`lower
`cyanoalkyl,
`halo,
`lower
`alkyl,
`lower
`alkyloxy,
`lower cycloalkyl, phenyl,
`lower haloalkyl, 5- or 6-
`
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`
`lower
`lower hydroxylalkyl,
`membered heterocyclyl,
`aralkyl,
`acyl, phenylcarbonyl,
`lower alkoxyalkyl,
`5-
`or
`6-membered heteroaryloxy,
`aminocarbonyl,
`lower alkylaminocarbonyl,
`lower alkylamino,
`lower
`aminoalkyl,
`lower alkylaminoalkyl, phenyloxy,
`and
`lower aralkoxy;
`or
`a pharmacentically-acceptable
`salt thereof.
`
`compounds which
`A more preferred class of
`inhibit cyclooxygenase-2 consists of compounds of
`Formula
`I wherein A is selected from oxazolyl,
`isoxazolyl, furyl,
`thienyl, dihydrofuryl, pyrrolyl,
`pyrazolyl,
`thiazolyl,
`imidazolyl,
`isothiazolyl,
`benzofuryl,
`cyclopentenyl,
`cyclopentadienyl,
`phenyl,
`and pyridyl; wherein Ri
`is selected from
`pyridyl optionally substituted at a substitutable
`position with one. or more methyl
`radicals,
`and
`phenyl optionally substituted at
`a substitutable
`position with one or more
`radicals selected from
`methyl,
`ethyl,
`isopropyl,
`butyl,
`tert-butyl,
`isobutyl,
`pentyl,
`hexyl,
`fluoromethyl,
`difluoromethyl,
`trifluoromethyl,
`cyano,
`carboxyl,
`methoxycarbonyl,
`ethoxycarbonyl,
`hydroxyl,
`hydroxymethyl,
`trifluoromethoxy,
`amino,
`N-
`methylamino, N,N-dimethylamino, N-ethylamino, N,N-
`dipropylamino, N-butylamino, N-methyl-N-ethylamino,
`phenylamino, methoxymethyl, methylsulfinyl,
`fluoro,
`chloro, bromo, methoxy, ethoxy, propoxy, n-butoxy,
`pentoxy,
`and methylthio; wherein R2
`is methyl or
`amino;
`and wherein R3
`is a radical selected from
`hydrido,
`oxo,
`cyano,
`carboxyl, methoxycarbonyl,
`ethoxycarbonyl,
`carboxypropyl,
`carboxymethyl,
`carboxyethyl,
`cyanomethyl,
`fluoro, chloro,
`bromo,
`methyl,
`ethyl,
`isopropyl,
`butyl,
`tert-butyl,
`isobutyl,
`pentyl,
`hexyl,
`difluoromethyl,
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`
`pentafluoroethyl,
`trifluoromethyl,
`difluoropropyl,
`difluoroethyl,
`heptafluoropropyl,
`propoxy,
`n-butoxy,
`pentoxy,
`methoxy,
`ethoxy,
`cyclohexyl, phenyl, pyridyl,
`thienyl,
`thiazolyl,
`oxazolyl,
`furyl,
`pyrazinyl,
`hydroxylmethyl,
`hydroxylpropyl,
`benzyl,
`formyl,
`phenylcarbonyl,
`methoxymethyl,
`furylmethyloxy,
`aminocarbonyl, N-
`methylaminocarbonyl,
`N, N-dimethylaminocarbonyl,
`N,N-dimethylamino, N-eethylamino, N,N-dipropylamino,
`N-butylamino, N-methyl-N-ethylamino,
`aminomethyl,
`N,N-dimethylaminomethyl,
`‘N-methyl-N-
`ethylaminomethyl, benzyloxy,
`and phenyloxy; or
`a
`pharmaceutically-acceptable salt thereof.
`A family of specific compounds of particular
`interest within Formula I consists of
`compounds
`and pharmaceutically-acceptable salts thereof as
`follows:
`
`5- (4-fluorophenyl)—-1-[4- (methylsulfonyl) phenyl] -3-
`(trifluoromethyl) pyrazole;
`4- (4~fluorophenyl) —5-[4- (methylsulfonyl) phenyl] -1-
`phenyi-3- (trifluoromethyl) pyrazole;
`4-(5-(4-chlorophenyl) ~3- (4-methoxyphenyl1) -1H-
`pyrazol-1~-y1) benzenesulfonamide
`4-(3,5-bis (4-methylphenyl1) -lH-pyrazol-1-
`
`yil)benzenesulfonamide;
`4- (5-(4-chlorophenyl) -3-phenyl-lH-pyrazol-1-
`
`yl) benzenesulfonamide;
`4-(3,5-bis (4-methoxyphenyl)~1lH-pyrazol-1-
`yl) benzenesulfonamide;
`4- (5-(4-chloropheny]1) -3- (4-methylphenyl1) -1H-pyrazol-
`1-yl) benzenesulfonamide;
`4-(5- (4—chlorophenyl1) ~3- (4-nitrophenyl) -1H-pyrazol-
`1-yl) benzenesulfonamide;
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`
`4~ (5- (4-chlorophenyl) -3- (5-chloro-2~thieny1l) -15-
`pyrazol-1-yl) benzenesulfonamide;
`4-(4-chloro-3, 5-diphenyl-1H-pyrazol-1-
`
`. yl) benzenesulfonamide
`4-[5- (4-chlorophenyl) -3- (trifluoromethyl) -1H-
`pyrazol-1-yl]benzenesulfonamide;
`4~[5-phenyl-3- (trifluoromethyl) -1H-pyrazol-1-
`yiljbenzenesulfonamide;
`4~[5- (4-fluorophenyl) -3- (trifluoromethyl) -1H-
`pyrazol-1~yl]benzenesulfonamide;
`4-[5- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-
`pyrazol—-l1-yl]benzenesulfonamide;-
`4-[5- (4-chlorophenyl1) -3- (difluoromethyl) -1H-pyrazol-
`1-yl]benzenesulfonamide;
`4-[5- (4-methylpheny1) ~3- (trifluoromethyl) -1H-
`pyrazol-i-yl] benzenesulfonamide;
`4-[4-chloro-5- (4-chloropheny1) -3- (trifluoromethyl1) -
`1lH-pyrazol-i-yl]benzenesulfonamide;
`4-[(3- (difluoromethyl) -5- (4-methylphenyl) -1lH-pyrazol-
`
`1l-yl]benzenesulfonamide;
`4-[3-(difluoromethyl) -5-phenyl-1H-pyrazol-1-
`
`yljbenzenesulfonamide;
`
`4-[(3- (difluoromethyl) -5- (4-methoxyphenyl1) -1H-
`pyrazol-1-yl] benzenesulfonamide;
`4-[3-cyano-5- (4-fluorophenyl) -1H-pyrazol-1-
`
`yljbenzenesulfonamide;
`
`.
`
`.
`
`.
`
`4—-[3- (difluoromethyl1) ~5- (3-fluoro-4-methoxyphenyl) -
`1H-pyrazol-1l-yl]benzenesul fonamide;
`4-[(5- (3-fluocro-4-methoxyphenyl) -3- (trifluoromethyl) -
`1H-pyrazol~-1~-yl]benzenesulfonamide;
`
`4-[4-chloro~-5-phenyl-1H-pyrazol-1-
`
`ylj]benzenesulfonamide;
`4-[5- (4-chlorophenyl) ~3- (hydroxymethyl) -LH-pyrazol-
`l-ylj]benzenesulfonamide;
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`4-[5- (4-(N,N-dimethylamino) phenyl) -3-
`(trifluoromethyl) -1lH-pyrazol-1-
`yi)benzenesulfonamide;
`
`5- (4-fluorophenyl)-6-[4-
`(methylsulfonyl) phenyl] spiro[2.4]hept-5-ene;
`4-(6- (4-fluorophenyl) spiro[2.4]hept-5-en-5-
`
`yl] benzenesulfonamide;
`
`6~ (4-fluocrophenyl)-7-[4-
`
`(methylisulfonyl) phenyl] spiro[3.4]oct—6-ene;
`
`5- (3-chloro-4-methoxyphenyl) -6-[4-
`(methylsulfonyl) phenyl] spiro[2.4]hept-—5-ene;
`4-[6- (3-chloro-4-methoxyphenyl) spiro[2.4]hept-5-en-
`5-yl]benzenesulfonamide;
`5- (3, 5-dichloro-4-methoxyphenyl) -6-[4-
`(methylsulfonyl) phenyl] spiro[2.4]hept—5-ene;
`5~ (3-chloro-4-flucrophenyl) -6-[4-
`.
`(methylsulfonyl) phenyl] spiro[2.4]hept~5-ene;.
`4-[6- (3, 4-dichlorophenyl) spiro[2.4]hept~5-en-5-
`yl]benzenesulfonamide;
`2- (3-chloro~4-fluorophenyl) -4- (4-fluorophenyl)-5- (4-
`methylsulfonylphenyl) thiazole;
`2- (2~chlorophenyl) -4~- (4~fluorophenyl) ~5- (4-
`methylsulfonylphenyl) thiazole;
`5- (4~fluorophenyl) -4~ (4-methylsulfonylphenyl) -2-
`methylthiazole;
`‘
`‘
`4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl1) -2-
`trifluoromethyithiazole;
`4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -2- (2-
`thienyl) thiazole;
`4- (4-fluocrophenyl) -5- (4-methylsulfonylphenyl) -2-
`benzylaminothiazole;
`,
`4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -2~(1-
`propylamino) thiazole;
`
`10
`
`15
`
`20
`
`25
`
`30
`
`1792
`
`1792
`
`
`
`WO 02/062369
`
`31
`
`PCT/US02/03201
`
`2-[ (3, 5-dichlorophenoxy) methyl) -—4- (4-fluorophenyl1) -
`5-[4-(methylsulfonyl) phenyl] thiazole;
`5~- (4-fluorophenyl)—-4- (4-methylsulfonyiphenyl) -2-
`
`trifluoromethylthiazole;
`
`l~methylsulfonyl-4-[1,1-dimethyl-4-(4-
`fluorophenyl) cyclopenta-2, 4~dien~-3-yl] benzene;
`4~[(4—(4-fluorophenyl)-1,1-dimethylcyclopenta-2, 4-
`dien-3-yl]benzenesulfonamide;
`
`5- (4-fluorophenyl) -6- [4-
`(methylsulfonyl) phenyl] spiro[2.4]hepta-4, 6~diene;
`4-(6- (4~fluorophenyl) spiro[2.4]hepta-4, 6-dien-5-
`
`yljJbenzenesulfonamide;
`
`6- (4~fluorophenyl) -2-methoxy~5- [4-
`(methylsulfonyl) phenyl]-pyridine-3-carbonitrile;
`2-bromo-6~ (4-fluorophenyl) -5-[4-
`(methylsulfonyl) phenyl]-pyridine-3-carbonitrile;
`6- (4-fluorophenyl) —-5~-[4- (methyl sulfonyl) phenyl] -2-
`phenyl-pyridine-3-carbonitrile;
`4-[2- (4-methylpyridin-2-yl) -4- (trifluoromethyl) -1H-
`imidazol-1-yl]benzenesulfonamide;
`4-[2- (5-methylpyridin-3-yl) -4- (trifluoromethyl) -1H-
`imidazol-l-yl]benzenesulfonamide;
`4-[2-(2-methylpyridin-3~yl) -4- (trifluoromethyl) -1H-
`imidazol-1-yl]benzenesulfonamide;
`3-[1-[4-(methylsulfonyl) phenyl] —4- (trifluoromethy))
`1H-imidazol-2-yl] pyridine;
`2-[1-[4- (methylsulfonyl) phenyl-4- (trifluoromethyl) -
`- LH-imidazol~2-yl]pyridine;
`
`2-methyl-4-[1-[4- (methylsulfonyl) phenyl-4-
`(trifluoromethyl) -1H-imidazol—2-yl] pyridine;
`2-methyl-6- [1-[4- (methylsulfonyl) phenyl-4-
`(trifluoromethyl) ~1H-imidazol-2-yl] pyridine;
`4-—[2-(6-methylpyridin-3-yl) -4- (trifluoromethyl) -1H-
`imidazol-i-yl]benzenesulfonamide;
`
`10
`
`15
`
`20
`
`25
`
`30
`
`1793
`
`1793
`
`
`
`WO 02/062369
`
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`
`PCT/US02/03201
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`2- (3, 4-difluorophenyl) -1- [4- (methylsulfonyl) phenyl} -
`4~ (trifluoromethyl) -1H-imidazole;
`4-[{2-(4-methylphenyl) ~4- (trifluoromethyl) -1H-
`imidazol-l-ylj]benzenesulfonamide;
`2- (4~chlorophenyl) -1~[4~- (methylsulifonyl) phenyl] -4-
`methyl-1lH-imidazole;
`2- (4-chlorophenyl) -1-[4- (methylsulfony1) phenyl] -4-
`phenyl~1H-imidazole;
`2~ (4~chlorophenyl) -4~ (4-fluorophenyl)-1-[4-
`(methylsulfonyl) phenyl]-1H-imidazole;
`2- (3-fluoro-4-methoxyphenyl) -1-[4-
`(methylsulfonyl) phenyl-4- (trifluoromethyl) ~1H-
`imidazole;
`1-[4- (methylsulfonyl) phenyl] -2-phenyl-4-
`trifluoromethyl-1H-imidazole;
`2- (4-methylphenyl) -1~-[4- (methylsulfonyl) phenyl] -4-
`trifluoromethyl-1H-imidazole;
`4- [2-—(3-chloro-4-methylphenyl) -4- (trifluoromethyl) -
`1LH-imidazol-1-yl]benzenesulfonamide;
`2-(3-fluocro-5-methylphenyl) -1-[4-
`(methylsulfonyl) phenyl ]-4- (trifluoromethyl) -1H-
`imidazole;
`4-[2-(3-fluoro-5-methylphenyl) ~—4- (trifluoromethyl) -
`1H-imidazol-1-yl]benzenesulfonamide;
`2- (3-methylphenyl)-1-[4- (methylsulfonyl) phenyl] -4-
`trifluoromethyl-1H-imidazole;
`4— [2- (3-methylphenyl) -4-trifluoromethyl-1H-imidazol-
`L~yl]lbenzenesulfonamide;
`1-[4-(methylsulfonyl) phenyl] ~-2- (3-chlorophenyl1) -4-
`trifluoromethyl-1lH-imidazole;
`4-[2- (3-chlorophenyl) -4-trifluoromethy1-1H-imidazol-
`1-yl]benzenesulfonamide;
`4~[2-phenyl-4-trifluoromethyl-1H-imidazol-1-
`yl]benzenesulfonamide;
`
`1794
`
`1794
`
`
`
`WO 02/062369
`
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`
`33
`
`4-[2- (4-methoxy-3-chlorophenyl) ~4-trifluoromethyl-
`1JH-imidazol-1-yl)benzenesulfonamide;
`l-allyl-4~- (4-fluorophenyl) -3-[4-
`(methylsulfonyl) phenyl]-5- (trifluoromethyl) -1H-
`
`pyrazole;
`4-[{1l-ethyl1-4- (4-fluorophenyl]) -5~ (trifluoromethyl) -:
`LH-pyrazol-3-yl]benzenesulfonamide;
`N-phenyl-[4- (4-luorophenyl) -3-[4-
`(methylsulfonyl) phenyl1]-5- (trifluoromethyl) -1H-
`pyrazol-l-yl]acetamide;
`[4- (4-fluorophenyl) -3-[4-
`ethyl
`(methylsulfonyl) phenyl]-5- (trifluoromethyl) -1H-
`pyrazol-l-yljacetate;
`4- (4-fluoropheny!]) ~3~[4-(methylsulfonyl) phenylj-1i-
`(2-phenylethyl) -1H-pyrazole;
`4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl]-1-
`(2-phenylethyl) -5- (trifluoromethyl!) pyrazole;
`l-ethyl-4- (4~fluorophenyl1) -3-[4-
`(methylsulfonyl) phenyl] -5- (trifluoromethyl) -1H-
`pyrazole;
`5- (4-fluorophenyl)-4- (4~methylsulfonylphenyl) -2-
`trifluoromethyl-1H-imidazole;
`4-[4- (methylsulfonyl) phenyl}]-5- (2-thiophenyl) -2-
`(trifluoromethyl) -1H-imidazole;
`5- (4-fluorophenyl) -2-methoxy-4- [4-
`(methylsulfonyl) phenyl] -6-
`(trifluoromethyl) pyridine;
`2-ethoxy-5- (4-fluorophenyl) -4-[4-
`(methylsulfonyl) phenyl] -6-
`(trifluoromethyl) pyridine;
`5- (4-—fluorophenyl) -4-[4- (methylsul fonyl) phenyl]-2-
`(2-propynyloxy) -6- (trifluoromethyl) pyridine;
`
`10
`
`15
`
`20
`
`25
`
`30
`
`1795
`
`1795
`
`
`
`WO 02/062369
`
`PCT/US802/03201
`
`34
`
`5
`
`10
`
`1S
`
`20
`
`25
`
`30
`
`2-bromo-5- (4~-fluorophenyl) ~4- [4-
`(methyisulfonyl) phenyl] -6-
`(trifluoromethyl) pyridine;
`4-[2-(3-chloro-4-methoxyphenyl) -4, 5-
`difluorophenyl)]benzenesulfonamide;
`1- (4~-fluorophenyl) -2-[4-
`(methylsulfonyl) phenyl] benzene;
`5-difluoromethyl-4- (4-methylsulfonylphenyl)-3-
`phenylisoxazole;
`
`4- [(3-ethyl~—5-phenylisoxazol-4-yl] benzenesulfonamide;
`4-[5-difluoromethyl-3-phenylisoxazol-4-
`ylilbenzenesulfonamide;
`
`4- [5-hydroxymethyl-3-phenylisoxazol-4-
`yljbenzenesulfonamide;
`4-[{5-methyl-3-phenyl-isoxazol-4-
`yl] benzenesul fonamide;
`
`1-[2-(4~—-fluorophenyl) cyclopenten-1-yl]-4-
`(methylsulfonyl) benzene;
`1-[2- (4-flucro-2-methylphenyl) cyclopenten-1-yl1]~-4-
`(methylsulfonyl) benzene;
`1-[2-(4-chliorophenyl) cyclopenten-1-yl]~4-
`(methylsulfonyl) benzene;
`1-{2-(2, 4-dichlorophenyl) cyclopenten~-i1+yl]-4-
`(methylsulfonyl) benzene;
`1-[2- (4-trifluoromethylphenyl) cyclopenten-1-yl]-4-
`(methylsulfonyl) benzene;
`1-[2-(4-methylthiophenyl) cyclopenten-1-yl1]-4-
`(methylsulfonyl) benzene;
`1-[2- (4~fluorophenyl) -4, 4-dimethylcyclopenten-1-yl]-
`4-(methylsulfonyl) benzene;
`4-[2-(4-fluorophenyl)-4, 4-dimethylcyclopenten-1-
`yl])benzenesulfonamide;
`
`1-[2-(4-chlorophenyl) -4, 4-dimethylcyclopenten-1-yl1]-
`4-(methylsulfonyl) benzene;
`
`1796
`
`1796
`
`
`
`WO 02/062369
`
`35
`
`PCT/US02/03201
`
`4-[2-(4-chlorophenyl1) -4, 4-dimethylcyclopenten-1i-
`
`yijJbenzenesulfonamide;
`4-[2- (4-fluorophenyl) cyclopenten-1-
`yl]benzenesulfonamide;
`4~[2-(4-chlorophenyl) cyclopenten-1-
`ylj]benzenesulfonamide;
`1-[2- (4-methoxyphenyl) cyclopenten~1-y1]-4-
`
`(methylsulfonyl) benzene;
`1-[2- (2, 3-difluorophenyl) cyclopenten-1-y1]-4-
`
`10
`
`(methylsulfonyl) benzene;
`4~[2~ (3-fluoro-4-methoxyphenyl) cyclopenten-1-
`ylj]benzenesulfonamide;
`1-[2- (3-chloro-4-methoxyphenyl) cyclopenten-1-yl] -4-
`
`(methylsulfonyl) benzene;
`4-[2-(3-chloro-4-fluorophenyl) cyclopenten-1-
`
`15
`
`20
`
`25
`
`30
`
`yilbenzenesulfonamide;
`
`4-[2- (2-methylpyridin~5-yl) cyclopenten-1-
`yl]benzenesulfonamide;
`ethyl
`2-~[4- (4~fluorophenyl)-5-[4- (methylsulfonyl)
`phenyl] 0xazol-2-yl]~-2-benzyl-acetate;
`2-[(4-(4~-fluorophenyl) -5-[4-
`(methylsulfonyl) phenyl] oxazol-2-yljacetic acid;
`2- (tert-butyl) -4- (4-fluorophenyl) -5- [4-
`(methylsulfonyl) phenyl ]oxazole;
`4-(4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -2-
`phenyloxazole;
`4-(4-fluocrophenyl) -2-methy1-5- [4-
`(methylsulfonyl) phenylj]oxazole; and
`4-[5- (3-fluoro-4-methoxyphenyl) -2-trifluoromethyl-4-
`oxazolylibenzenesulfonamide.
`of more
`compounds
`A family of
`specific
`particular interest within Formula I consists of
`compounds
`and pharmaceutically-acceptable
`salts
`thereof as follows:
`
`1797
`
`1797
`
`
`
`WO 02/062369
`
`PCT/US02/03201
`
`36
`
`4-[5- (4-chloropheny]1)-3- (trifluoromethyl) -1H-
`
`pyrazol-1-yl]benzenesulfonamide;
`
`4-[5- (4-methylphenyl) -3- (trifluoromethyl) -1H-
`
`pyrazol-1-yl]benzenesulfonamide;
`4-[5- (3-fluoro-4-methoxyphenyl) -—3- (difluoromethyl) -
`lH-pyrazol-1l-yljbenzenesulfonamide;
`3-[1- [4- (methylsulfonyl) phenyl]-4-trifluoromethyl-
`1H-imidazol-2~-yl]pyridine;
`2-methy1l-5-[1-[4- (methylsulfonyl) phenyl1]-4-
`trifluoromethyl-1H-imidazol-2-yl]pyridine;
`4~[2- (5-methylpyridin-3-yl1) -4- (trifluoromethyl) -1H-
`imidazol-1-yl]benzenesulfonamide;
`
`4-[5-methyl-3-phenylisoxazol-4-
`
`ylj]benzenesul fonamide;
`
`4-[S5-hydroxymethyl-3-phenylisoxazol-4-
`yl] benzenesyl fonamide;
`
`[2-trifluoromethyl-5- (3, 4-difluorophenyl) -4-
`oxazolyl]benzenesulfonamide;
`4-[2-methyl-4-phenyl-5-oxazolyl]benzenesulfonamide;
`and
`4~[(5- (3-fluoro-4-methoxyphenyl-2-trifluoromethyl)-
`
`4-oxazolyl]benzenesulfonamide.
`
`A
`
`subclass
`
`of
`
`cyclooxygenase-2
`
`inhibitors
`
`is
`
`selected from compounds of Formula II
`
`10
`
`15
`
`20
`
`25
`
`HON
`
`2 \,
`o*ii
`
`R®
`
`we
`
`\
`
`5
`
`R
`
`RB!
`
`It
`
`1798
`
`1798
`
`
`
`WO 02/062369
`
`37
`
`PCT/US02/03201
`
`wherein
`
`R4
`
`is
`
`selected
`
`from hydrido,
`
`alkyl,
`
`haloalkyl, alkoxycarbonyl, cyano, cyanoalkyl, carboxyl,
`
`aminocarbonyl,
`
`cycloalkylaminocarbonyl,
`
`alkylaminocarbonyl,
`
`arylaminocarbonyl,
`
`carboxyalkylaminocarbonyl,
`
`carboxyalkyl,
`
`aralkoxycarbonylalkylaminocarbonyl,
`
`aminocarbonylalkyl,
`
`alkoxycarbonylcyanoalkenyl and hydroxyalkyl;
`
`wherein R° is selected from hydrido, alkyl, cyano,
`
`hydroxyalkyl, cycloalkyl, alkylsulfonyl and halo; and
`
`10
`
`wherein
`
`R&
`
`is
`
`selected from aralkenyl,
`
`aryl,
`
`cycloalkyl, cycloalkenyl and heterocyclic; wherein R4 is
`optionally substituted at a substitutable position with
`
`one or more
`
`radicals
`
`selected from halo,
`
`alkylthio,
`
`alkylsulfonyl, cyano, nitro, haloalkyl, alkyl, hydroxyl,
`alkenyl, hydroxyalkyl, carboxyl, cycloalkyl, alkylamino,
`
`15
`
`dialkylamino,
`alkoxycarbonyl,
`aminocarbonyl,
`haloalkoxy, sulfamyl, heterocyclic and amino;
`or
`a
`pharmaceutically-acceptable
`salt
`
`alkoxy,
`
`or
`
`derivative thereof.
`
`20
`
`25
`
`30
`
`interest
`of particular
`compounds
`of
`class
`A
`consists of those compounds of Formula I. wherein R4 is
`selected from hydrido,
`lower alkyl,
`lower haloalkyl,
`lower alkoxycarbonyl, cyano,
`lower cyanoalkyl, carboxyl,
`aminocarbonyl,
`lower
`alkylaminocarbonyl,
`lower
`cycloalkylaminocarbonyl,
`arylaminocarbonyl,
`lower
`carboxyalkylaminocarbonyl,
`lower
`aminocarbonylalkyl,
`lower
`aralkoxycarbonylalkylaminocarbonyl,
`lower
`carboxyalkyl,
`lower
`alkoxycarbonylcyanoalkenyl
`and
`lower hydroxyalkyl; wherein RY is selected from hydrido,
`lower
`alkyl,
`cyano,
`lower
`hydroxyalkyl,
`lower
`
`1799
`
`1799
`
`
`
`WO 02/062369
`
`PCT/US02/03201
`
`38
`
`lower alkylsulfonyl and halo; and wherein RO
`cycloalkyl,
`is
`selected
`from
`aralkenyl,
`aryl,
`cycloalkyl,
`cycloalkenyl and heterocyclic; wherein R4 is optionally
`substituted at
`a substitutable position with one or
`
`lower
`more radicals selected from halo,
`lower alkylthio,
`lower
`alkylsulfonyl,
`cyano, nitro,
`lower haloalkyl,
`alkyl,
`hydroxyl,
`lower
`alkenyl,
`lower hydroxyalkyl,
`carboxyl,
`lower
`cycloalkyl,
`lower
`alkylamino,
`lower
`dialkylamino,
`lower alkoxycarbonyl, aminocarbonyl,
`lower
`alkoxy,
`lower haloalkoxy, sulfamyl,
`five or six membered
`heterocyclic and amino; or a pharmaceutically-acceptable
`salt or derivative thereof.
`
`of
`
`family
`A
`of particular
`compounds
`specific
`interest within
`of
`compounds,
`consists
`Formula
`I
`derivatives
`and
`pharmaceutically-acceptable
`salts
`thereof as follows:
`.
`4-[5~ (4~chloropheny1) -3- (trifluoromethyl) -1H-pyrazol-1-
`ylibenzenesulfonamide;
`4~{5-phenyl-3- (trifluoromethyl) -1H-pyrazol-1-
`yl]benzenesulfonamide;
`4-[5- (4-fluoropheny!) -3- (trifluoromethyl) -1H-pyrazol-1-
`yljbenzenesulfonamide;
`4-[5-(4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-
`yi]benzenesulfonamide;
`4-[5- (4-chloropheny1) -3- (difluoromethyl) -lH-pyrazol-1-
`
`yijbenzenesul fonamide;
`4-[5- (4-methylipheny1) -3- (trifluoromethyl) -1H-pyrazol-1-
`
`yljbenzenesul fonamide;
`4~[4-chloro-5- (4-chlorophenyl) -3- (trifluoromethyl) -1H-
`pyrazol-1-yl]benzenesulfonamide;
`4-[3+- (difluoromethyl)-5- (4-methylphenyl) -1H-pyrazol-1l-
`
`ylj]benzenesulfonamide;
`4-[3-(difluoromethy1)-5-phenyl-1H-pyrazol~1-
`
`yiljbenzenesulfonamide;
`
`10
`
`15
`
`20
`
`25
`
`30
`
`1800
`
`1800
`
`
`
`WO 02/062369
`
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`
`39
`
`4-[(3- (difluoromethyl) -5- (4-methoxyphenyl) -l1H-pyrazol-1-
`yl]benzenesulfonamide;
`
`4-[3-cyano-5- (4-fluorophenyl) -1H-pyrazol-1-
`
`yilbenzenesulfonamide;
`4-[3-(difluoromethyl) -—5- (3-fluoro-4-methoxyphenyl) -1H-
`
`pyrazol-i-yl]benzenesulfonamide;
`4-[5- (3-fluoro-4-methoxyphenyl) -3- (trifluoromethyl) -1H-
`
`pyrazol-li-yl]benzenesulfonamide;
`4- [4~chloro-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
`4-[5- (4-chlorophenyl) -3- (hydroxymethyl) -1H~pyrazol-1-
`
`ylibenzenesulfonamide; and
`
`4-[5-(4-(N,N-dimethylamino) phenyl) -3- (trifluoromethyl) -
`1H-pyrazol-l1-yl]benzenesul fonamide.
`
`A family of specific compounds of more particular
`interest within Formula
`I consists of
`compounds
`and
`
`pharmaceutically-acceptable salts or derivatives thereof
`as follows:
`
`10
`
`15
`
`20
`
`4-[5- (4-methylphenyl) -3- (trifluoromethyl) ~1H~pyrazol-1-
`
`yljbenzenesulfonamide;
`
`4-[5- (4-chlorophenyl) -3- (difluoromethyl) -1H-pyrazol-1-
`
`yljbenzenesulfonamide; and
`
`4-[5-(3-fluoro-4-methoxyphenyl) -3- (difluoromethyl) -1H-
`
`25
`
`pyrazol-1-yl]benzenesulfonamide.
`
`Derivatives are intended to encompass any compounds
`
`which are structurally related to the cyclooxygenase-2
`
`inhibitors or which possess the substantially equivalent
`biologic activity. By way of example,
`such inhibitors
`may include, but are not limited to, prodrugs thereof.
`
`30
`
`The term "hydrido" denotes a single hydrogen
`atom (H).
`This hydrido radical may be attached,
`
`1801
`
`1801
`
`
`
`WO 02/062369
`
`PCT/US02/03201
`
`40
`
`to an oxygen atom to form a hydroxyl
`for example,
`two hydrido radicals may be attached
`radical or
`to a
`carbon atom to form a methylene
`(-CH2-)
`
`radical.
`
`Where used,
`
`either
`
`alone or within
`
`other terms such as "haloalkyl", "alkyisulfonyl",
`"alkoxyalkyl"
`and
`"hydroxyalkyl",
`the
`term
`"alkyl"
`embraces
`linear
`or
`branched
`radicals
`
`twenty carbon atoms or,
`to about
`one
`having
`one
`to about
`twelve
`carbon atoms.
`preferably,
`More preferred alkyl
`radicals are "lower alkyl"
`
`ten carbon atoms.
`to about
`radicals having one
`Most preferred are lower alkyl
`radicals having
`one to about six carbon atoms.
`Examples of such
`
`ethyl,
`n-propyl,
`include methyl,
`radicals
`sec-butyl,
`n-butyl,
`isopropyl,
`isobutyl,
`tert-
`butyl, pentyl,
`iso-amyl, hexyl and the like.
`The
`term "“alkenyi"
`embraces
`linear
`or
`branched
`radicals having at least one carbon-carbon double
`
`bond of
`
`two to about
`
`twenty carbon atoms or,
`
`10
`
`15
`
`20
`
`preferably,
`
`two
`
`to about
`
`twelve
`
`carbon atoms.
`
`More preferred alkyl radicals are "lower alkenyl”
`radicals having two to about six carbon atoms.
`Examples of
`alkenyl
`radicals
`include
`ethenyl,
`propenyl,
`allyl,
`propenyl,
`butenyl
`and
`4-
`methylbutenyl.
`The term "alkynyl" denotes linear
`or branched radicals having two to about
`twenty
`
`twelve
`two to about
`carbon atoms or, preferably,
`carbon atoms. More preferred alkynyl radicals are
`
`25
`
`ten
`"lower alkynyl" radicals:having two to about
`carbon atoms. Most preferred are lower alkynyl
`
`30
`
`radicals having two to about six carbon atoms.
`
`such
`of
`Examples
`and the
`butynyl,
`"lower alkenyl",
`
`include propargyl,
`radicals
`like.
`The
`terms
`"alkenyl",
`embrace
`radicals having "cis"
`
`1802
`
`1802
`
`
`
`WO 02/062369
`
`PCT/US02/03201
`
`41
`
`"BR"
`and "trans" orientations, or alternatively,
`and
`"2" orientations.
`The
`term "cycloalkyl"
`embraces
`saturated carbocyclic radicals
`having
`
`More preferred
`carbon atoms.
`three to twelve
`cycloalkyl
`radicals
`are
`"lower
`cycloalkyl"
`radicals
`having
`three
`to
`about
`eight
`carbon
`atoms.
`Examples
`of
`such
`radicals
`include
`cyclopropyl,
`cyclobutyl,
`cyclopentyl
`and
`
`embraces
`term "cycloalkenyl"
`The
`cyclohexyl.
`partially unsaturated carbocyclic radicals having
`three to twelve
`carbon atoms.
`More preferred
`
`cycloalkenyl"
`"Lower
`are
`radicals
`cycloalkenyl
`radicals having four to about eight carbon atoms.
`Examples of
`such radicals include cyclobutenyl,
`cyclopentenyl,
`cyclopentadienyl,
`and
`The
`cyclohexenyl.
`term "halo" means halogens
`such as
`fluorine,
`chlorine,
`bromine or
`iodine.
`
`The
`
`term "haloalkyl"
`
`embraces
`
`radicals wherein
`
`any one or more of
`
`the alkyl carbon atoms
`
`is
`
`10
`
`15
`
`20
`
`substituted
`
`with
`
`halo
`
`as
`
`defined
`
`above.
`
`25
`
`30
`
`Specifically
`dihaloalkyl
`
`are
`embraced
`and
`polyhaloalkyl
`
`monohaloalikyl,
`radicals.
`A
`
`for one example, may have
`monohaloalkyl radical,
`either
`an
`iodo,
`bromo,
`chloro or
`fluoro atom
`within the radical.
`Dihalo and polyhaloalkyl
`radicals may have two or more of
`the same halo
`atoms
`or
`a
`combination
`of
`aifferent
`halo
`
`radicals
`embraces
`"Lower haloalkyl"
`radicals.
`having 1-6 carbon atoms.
`Examples of haloalkyl
`radicals
`include
`fluoromethyl,
`difluoromethyl,
`trifluoromethyl,
`chioromethyl,
`dichloromethyl,
`trichloromethyl,
`trichloromethyl,
`pentafluoroethyil,
`heptafluoropropyl,
`difluorochloromethyl,
`dichlorofluoromethyl,
`
`1803
`
`1803
`
`
`
`WO02/062369
`
`PCT/US02/03201
`
`42
`
`Gifluoroethyl, difluoropropyl, dichloroethyl and
`dichloropropyl.
`The term "hydroxyalkyl" embraces
`linear or branched alkyl radicals having one to
`about
`ten carbon atoms any one of which may be
`
`substituted with one or more hydroxyl
`radicals.
`More preferred hydroxyalkyl
`radicals are "lower
`hydroxyalkyl" radicals having one to six carbon
`atoms
`and
`one
`or more
`hydroxyl
`radicals.
`Examples of
`such radicals include hydroxymethyl,
`hydroxyethyl,
`hydroxypropyl,
`hydroxybutyl
`and
`hydroxyhexyl.
`The terms "alkoxy" and "alkyloxy"
`embrace
`linear
`or
`branched
`oxy-containing
`radicals
`each having alkyl portions of
`one
`to
`about
`ten carbon atoms.
`More preferred alkoxy
`radicals are "lower alkoxy" radicals having one
`to six carbon atoms. Examples of such radicals
`include methoxy,
`ethoxy,
`PLOPORy,
`bu
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