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`interactions, hydrogen bonds, dipole-dipole interactions, and steric interactions to achieve
`chiral recognition. To be resolved on a Type I column, analyte enantiomers must contain
`functionality complementary to that of the CSP so that the analyte undergoes essential
`
`interactions with the CSP. The sample should preferably contain one of the following
`
`fimctional groups: p-acid or p-base, hydrogen bond donor and/or acceptor, or an amide
`
`dipole. Derivatization is sometimes used to add the interactive sites to those compounds
`
`lacking them. The most common derivatives involve the formation of amides from
`
`amines and carboxylic acids.
`
`The MetaChiral ODMTM is a type II CSP. The primary mechanisms for the
`
`formation of solute-CSP complexes is through attractive interactions, but inclusion
`
`complexes also play an important role. Hydrogen bonding, pi-pi, and dipole stacking are
`
`important for chiral resolution on the MetaChiralTM ODM. Derivatization is often
`
`necessary when the solute molecule does not contain the groups required for solute-
`
`column interactions. Derivatization, usually to benzylarnides, is also required of some‘
`
`strongly polar molecules like amines and carboxylic acids, which would otherwise
`
`interact too strongly with the stationary phase through non-stereo- specific interactions.
`
`The invention provides compounds of formula I as set forth above.
`
`In certain embodiments, formulal set forth above may include a proviso that
`
`excludes compounds represented by the generic formula disclosed in US 643 6964.
`
`In certain embodiments, formula I set forth above may include a proviso that
`
`excludes compounds represented by the generic formula disclosed in US 5585374.
`
`In certain embodiments, formula I set forth above may include a proviso that
`
`excludes compounds represented by the generic formulas disclosed in both US 6436964
`
`and US 5585374.
`
`Compounds of formula I can be separated into diastereomeric pairs by, for
`
`example, by separation by TLC.These diastereomeric pairs are referred to herein as
`diastereoisomer with upper TLC Rf; and diastereoisomer with lower TLC Rf. The
`
`diastereoisomers can further be enriched for a particular enantiomer or resolved into a
`
`single enantiomer using methods well known in the art , such as those described herein.
`
`SYNTHESIS OF THE COMPOUNDS OF THE INVENTION
`
`The compounds of the invention are generally prepared according to the following
`
`schemes :
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 2001
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 2001
`
`

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`0
`
`IAK
`
`R3
`
`j__>_
`
`R W
`
`Scheme1
`
`0
`
`R3
`
`»
`——-——-—> CHO + HR§—R4
`
`Re
`
`(2)
`
`R (3)
`
`(4)
`
`HO
`
`I/x
`
`R
`
`R3
`
`R
`R: 4
`
`(I,R2=H)
`
`Group R is the same as (R+ R1 ) as given in the general formula I. A, R2, R3, R4
`
`and R5 have the same meanings as given in the general formula I and R3 is a lower alkyl
`
`group.
`
`Starting material (1) is treated with a base, preferably potassium tert-butoxide,
`
`followed by alkylation with 2-bromoacetaldehyde dialkyl acetal or other carbonyl
`
`protected 2-haloacetaldehyde ( e.g., the R, alkyl groups can also be joined in a cycle to
`
`give a dioxolane or dioxane ring). Other alternative and appropriate bases to carry out the
`
`condensation include lithium amides, sodium hydride, sodium hydroxide, potassium
`
`hydroxide, potassium carbonate, cesium carbonate and the like with the aid or not of
`
`phase transfer catalysts. The reaction is preferably carried out in a solvent such as
`
`dimethyl sulfoxide or toluene at a temperature of 0°C to reflux.
`
`The use of 3-bromopropionaldehyde dialkyl acetal or other carbonyl protected 3-
`
`halopropionaldehyde allow to obtain, by following the same reaction conditions described
`
`above in Scheme 1, compound I having in = 2 as foreseen in the general formula.
`Treatment of (2) with an acid, such as hydrochloric acid or p-toluenesulfonic acid
`
`or trifluoroacetic acid in a suitable organic solvent, achieves aldehyde (3). Generally, the
`
`reaction is conducted in a protic solvent, such a mixture of aqueous acid and acetone or
`
`tetrahydrofuran, at temperatures of 5°C to 75°C, preferably at ambient temperature. A
`
`preferred similar method consists of carrying out the reaction in a mixture of aqueous
`
`trifluoroacetic acid in a chlorinated solvent at r.t.
`
`Aldehyde (3) is coupled with the desired amine (4) by reductive amination
`
`procedure to prepare (5). The reaction is preferably carried out at ambient temperature in
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 2002
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 2002
`
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`a chlorinated solvent such as dichloroethane or methylene chloride or chloroform in the
`
`presence of sodium tziacetoxyborohydride and is substantially complete in one to 24
`
`hours (see for example A. F. Abdel-Magid et al., J Org. Chem., _6_L 3849 (1996)) or can
`
`be carried out in a prot:ic solvent (e.g., methanol) with the aid of sodium
`
`cyanoborohydride, optionally in the presence of molecular sieves.
`Reduction of (5) to the alcohol (I) is readily accomplished using a reducing agent
`
`such as sodium borohydride or diisobutylaluminum hydride or other aluminum or boron
`
`hydride or other reduction method to carry out the conversion ketone to alcohol, well
`
`known to those skilled in the art, to prepare the hydroxy compound (I). The reaction is
`
`preferably carried out in an organic solvent such as methanol or methylene chloride or
`
`tetrahydrofuran at temperatures of -20°C to 0°C - ambient temperature.
`
`O
`/[L
`
`R,
`
`(6)
`
`H3C\N
`,6
`
`“a0
`
`Scheme 2
`
`R
`+ Fjym _______,
`A
`
`(7)
`
`.
`
`(1)
`
`Starting material (1) is either commercially available or can be prepared by
`
`coupling the appropriate Weinreb amide (6) (See Nahm et al., Tetrahedron Lett., Q,
`
`3815, (1981)) with (7), as described in Scheme 2 above, where M is a metallic salt, such
`
`as lithium or magnesium halide. The reaction is preferably carried out under nitrogen
`
`atmosphere, in an aprotic solvent, such as tetrahydrofuran, at ambient or lower
`
`temperatures down to -78°C.
`
`Alternatively, an ester of structure R3CO0alkyl can be treated with a substituted
`
`benzylmagnesium chloride or benzylmagnesium bromide or lithium derivative under
`
`standard conditions well known in the art to provide the ketone of structure (1).
`
`V
`
`An alternative route to obtain compounds (1) consists of reacting the appropriate
`
`arylaldehyde with an allcylnitro derivative in a nitroaldol fashion, dehydration of the nitro
`
`alcohol thus obtained, followed by double bond reduction afford a 2-nitro(2—
`
`Ak)phenethyl derivative, which can undergo Nef reaction to yield the wished keto
`
`derivative 1. This kind of pathway is well documented in the experimental part and in the
`
`literature.
`
`A preferred_si1ni1ar way of synthesis of (1) is the palladium catalysed coupling of
`an acyl halide with a compound (7) where lvl is Zn halide. More specifically, the
`compounds of formula (5) can be prepared following the procedure described in Scheme
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 2003
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 2003
`
`

`

`W0 03/106421
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`3. All substituents, unless otherwise indicated, are as defined previously. The reagents
`
`and starting materials are readily available to one of ordinary skill in the art.
`
`Scheme 3
`
`
`
`(10)
`
`(5)
`
`In Scheme 3, step A, for example, cyclohexanecarbonyl chloride is added to a
`mixture ofthe suitable benzylzinc chloride(bromide) and an appropriate palladium
`
`catalyst, e.g., dichlorobis(tripheny1phosph.ine)palladium (II) stirred at 0°C in a solvent
`
`such as tetrahydrofuran. Afterwards, stirring is continued at r.t. for 4-24 h. Then the
`
`reaction is quenched for example with an aqueous saturated solution of ammonium
`
`chloride. Typical work-up procedure by extraction provides the ketone (8). Ketone (8)
`can be purified by techniques well known in the art, such as flash chromatography on
`
`silica gel with a suitable eluent, such as ethyl acetate/hexane to provide the purified
`
`material. Alternatively, the crude ketone (8) can be used in step B without purification.
`
`In Scheme 3, step B, ketone (8) is alkylated with bromoacetaldehyde diethyl
`
`acetal under conditions well known in the art to provide compound of structure (9). For
`
`example, ketone (8) is dissolved in a suitable organic solvent, such as dimethyl sulfoxide
`
`or toluene and treated with a slight excess of a suitable base, such as potassium tert-
`
`butoxide. The reaction is stirred for about 15 to 30 minutes at a temperature of between
`
`0°C and the reflux temp. of the solvent and bromoacetaldehyde diethyl acetal is added
`
`dropwise to the reaction. One of ordinary skill in the art would readily appreciate that
`
`bromoacetaldehyde dimethyl acetal, bromoacetaldehyde ethylene acetal and the like may
`
`be used in place of the corresponding diethyl acetal.
`
`In Scheme 3, step C, compound (9) is hydrolyzed under acidic conditions to
`
`provide aldehyde (10) in a manner analogous to the procedure described in Scheme 1.
`
`More specifically, for example, compound (9) is dissolved in a suitable organic solvent,
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 2004
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 2004
`
`

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`' W0 03/106421
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`such as dichloromethane and treated with a suitable acid, such as aq. trifluoroacetic acid.
`The reaction mixture is stirred for about 1 to 6 hours at room temperature. The reaction
`
`mixture is then diluted with the same solvent, washed with brine; the organic layer is
`
`separated, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum
`to provide aldehyde ‘(10). Aldehyde (10) can be purified by techniques well known in the
`
`art, such as flash chromatography on silica gel with a suitable eluent, such as ethyl
`
`acetate/hexane. Alternatively, crude aldehyde (10) can be used directly in step D.
`
`In Scheme 3, step D, aldehyde (10) is reductively aminated, under conditions well
`known in the art, with amine (4) to provide the ketone (5) in a manner analogous to the
`
`procedure described in Scheme 1. Morespecifically, for example, aldehyde (10) is
`dissolved in a suitable organic solvent, such as methylene chloride. To this solution is
`
`added about 1.05 or more equivalents of amine (4). Acetic acid may optionally be added
`
`to aid in dissolution of the amine (4). Then about 1.4 to 1.5 equivalents of sodium
`
`triacetoxyborohydride is added and the reaction is stirred at room temperature for about 3
`
`to 5 hours. The reaction is then quenched by addition of a suitable base, such as aqueous
`
`sodium carbonate or hydroxide to provide a pH fiom 8 to about 12. The quenched
`
`reaction is then extracted with a suitable organic solvent, such as methylene chloride. The
`organic extracts are combined, washed with brine, dried, filtered and concentrated under
`
`vacuum to provide the compound of formula (5). This material can then be purified by
`
`techniques well known in the art, such as flash chromatography on silica gel with a
`
`suitable eluent, such as ethyl acetate/petroleum ether or hexane.
`
`O
`
`H
`
`HO
`
`R,
`
`O .Ra
`
`Scheme 4
`
`St A
`
`3
`(12)
`
`(11) R
`
`R (13)
`
`St
`
`B
`
`K
`
`R (1)
`
`X/F: lstepc
`
`
`R3
`
`StepD
`
`R
`
`(5)
`
`I
`
`H—R5—R4
`(4)
`
`CHO
`(3)
`
`R
`
`0
`[AK
`
`R
`
`3
`
`\
`
`R
`
`(14)
`
`Alternatively, compounds of structure (5) can be prepared following the procedure
`
`described in Scheme 4. All substituents, unless otherwise indicated, are previously
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 2005
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 2005
`
`

`

`' W0 03/106421
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`defined. The reagents and starting materials are readily available to one of ordinary skill
`in the art.
`
`In Scheme 4, step A, aldehyde (11) is combined with a suitable organometallic
`reagent (12) under conditions well known in the art to provide alcohol (13). Examples of
`
`suitable organometallic reagents include Grignard Reagents, alkyl lithium reagents, alkyl
`
`zinc reagents, and the like. Grignard Reagents are preferred. For examples of typical
`
`Grignard Reagents and reaction conditions, see I. March, "Advanced Organic Chemistry:
`
`Reactions, Mechanisms, and Structure", 2nd Edition, McG:raw-Hill, pages 836-841
`
`(1977). More specifically, aldehyde (11) is dissolved in a suitable organic solvent, such as
`
`tetrahydrofuran or toluene, cooled to about
`
`-5°C and treated with about 1.1 to 1.2
`
`equivalents of a Grignard reagent of formula (12) wherein M is MgCl or MgBr. The
`
`reaction is stirred for about 0.5 to 6 hours, then quenched, and alcohol (13) is isolated by
`
`well-known work—up procedure.
`
`_
`
`In Scheme 4, step B, alcohol (13) is oxidized under standard conditions well know
`
`in the art, such as those described by J. March, "Advanced Organic Chemistry: Reactions,
`
`Mechanisms, and Structure", 2nd Edition, McGraw-Hill, pages 1082-1084 (1977), to
`
`provide ketone (1). (Ketone (1) is the starting’ material used in Scheme 1 above.)
`
`. For example, the above oxidation is also performed using standard Swem
`Oxidation conditions which are well known to one of ordinary skill in the‘ art, or the
`
`alcohol (13) is dissolved in a suitable organic solvent, such as methylene chloride, the
`
`solution cooled with a wet ice-acetone bath, and treated with 2.5 to 3.0 equivalents of
`
`dimethyl sulfoxide. After stirring for about 30 minutes, the reaction is then treated with
`
`about 1.8 equivalent_s of P205. The reaction is stirred for about 3 hours and then,
`
`preferably, treated over about 30 minutes with about 3.5 equivalents of a suitable amine,
`
`such as triethylamine. The cooling bath is then removed and the reaction is stirred for
`
`about 8 to 16 hours. The ketone (1) is then isolated by standard extraction techniques well
`
`known in the art.
`
`In Scheme 4, step C, ketone (1) is treated with a suitable base followed by
`
`addition of the alkene (15), wherein X is a suitable leaving group, to provide compound
`
`(14). For example, ketone (1) is combined with an excess of alkene (15) in a suitable
`
`organic solvent, such as tetrahydrofuran, and cooled with a Wet ice acetone bath.
`
`Examples of suitable leaving groups are Cl, Br, I, tosylate, mesylate, and the like.
`
`Preferred leaving groups are Cl and Br. About 1.1 equivalents of a suitable base are added
`
`and the reaction is allowed to stir for about 2 hours at room temperature. Examples of
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 2006
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 2006
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`

`

`wo 03/106421
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`_1,/_
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`PCT/EP03/06290
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`suitable bases are potassium tert-butoxide, sodium hydride, NaN(Si(CH3)3)2, LI)A,
`
`KN(Si(CH3)3)2, NaN'l-I2, sodium ethoxide, sodium methoxide and the like. Potassium tert-
`
`butoxide is the preferred suitable base. The reaction is then quenched wifli aqueous acid
`
`and compound (14) is isolated by usual work—up procedure.
`
`In Scheme 4, step D, compound (14) is treated with a suitable oxidizing agent to
`provide aldehyde (3). (Aldehyde (3) is also prepared in Scheme 1.) Examples of suitable
`
`oxidizing agents are ozone, NaIO4 /Osmium catalyst, and the like. Ozone is the preferred
`
`oxidizing agent. Examples of suitable oxidizing reagents and conditions are described by
`
`J. March, "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 2nd
`
`Edition, McGraw—I-Iill, pages 1090-1096 (1977).
`
`For example, compound (14) is dissolved in a suitable organic solvent, such as
`
`methanol, a small amount of Sudan III is added, and the solution is cooled to about -20°C.
`
`Ozone is bubbled into the solution for about 4 hours until the pink color turns to a pale
`
`yellow color. Then a reducing agent such as Me2S or tributylphosphine is added.
`
`Concentration provides the intermediate dimethyl acetal ofaldehyde (3). This dimethyl
`
`acetal is readily hydrolyzed under standard acidic conditions to provide aldehyde (3).
`
`Alternatively, direct acidic work-up of the cmde reaction mixture provides aldehyde (3).
`
`Alternatively, aldehyde (3) can be obtained directly by ozonolysis of (14) in a non-acetal
`
`fonning solvent, such as methylene chloride.
`
`In Scheme 4, step E, aldehyde (3) is reductively aminated under conditions
`
`analogous to those described above in Scheme 3, step D, to provide compound (5).
`
`(Compound 5 is also prepared in Scheme 1.)
`
` /CH0 StepA
`
` (5)
`
`
`H—R5—R4
`(4)
`
`0 R.
`
`i
`
`R
`
`(3)
`
`Scheme 5 provides an alternative synthesis for the preparation of ketone (5). All
`
`substituents, unless otherwise indicated, are previously defined. The reagents and starting
`
`materials are readily available to one of ordinary skill in the art.
`
`In Scheme 5, step A, aldehyde (3) is condensed with amine (4) under standard
`
`conditions well known in the art to provide the enamine (16). For example, about 1.05
`
`equivalents of aldehyde (3) dissolved in a suitable organic solvent, such as isopropyl
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 2007
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 2007
`
`

`

`wo 03/10642]
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`_13_
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`
`acetate or isopropanol, is added to neat amine (4), lies base. Additional organic solvent is
`added to produce a slurry and the reaction is stirred for about 1 to 2 hours. The enamine
`
`(16) is then isolated by standard techniques, such as collection by filtration. '
`
`In Scheme 5, step B, the enamine (16) is hydrogenated under conditions well
`
`known to one of ordinary skill in the art to provide compound (5). For example, enamine
`
`(16) is combined with a suitable organic solvent, such as isopropyl alcohol and a catalytic
`
`amount of 5% palladium on carbon in a Parr bottle. The mixture is placed under 50 psi of
`
`hydrogen and shaken for about 2 days at room temperature. The slurry is then filtered to
`
`remove catalyst and the filtrate is concentrated to provide compound (5).
`Scheme6
`
`0 R3
`A‘
`
`R 0.
`
`I
`
`A-IO
`-—>—| \
`O\
`R‘
`Re (2)
`
`Ra
`
`R:-\0
`0———>-I
`‘R
`E
`(17)
`
`R
`
`Re
`
`R O‘
`
`R3
`O
`
`R2/o R, +
`v°’”’ ’\
`CHO
`l
`\Ra
`‘Re
`(18)
`
`R
`
`(19)
`
`H\R/R4
`5
`(4)
`
`R2/o R,
`AK
`
`I
`
`R5__R4
`
`R
`
`I(R, notH)
`
`For the synthesis of(compounds I where R2 is different than H, the method given
`
`in Scheme 6 is used. Intermediate ketone (2) is reduced with the same reduction methods
`
`used above in scheme 1 for compound (5) affording intennediate (17), which is etherified
`
`by reaction with a base, for example NaH or potassium tert-butoxide or NaNH2 or LiNI-I2
`
`or others in a suitable solvent e.g. tetrahydrofuran, aflbrding the alkoxide, which is then
`
`reacted in situ with the appropriate R2-X with X leaving group (halogen or mesylate or
`
`tosylate) at a temperature of from 0°C to the reflux temperature. The so obtained
`
`compounds (18) can undergo the same reactions described in scheme 1 affording product
`
`I with R2 is not H.
`
`Alternatively, compounds of formula I where R; is not a hydrogen atom, can be
`
`obtained by alkylating compounds of formula I where R; = H with the same methods
`
`described above for alkylating compound 17, limiting this procedure to the alkylation
`
`with very reactive halogenide or mesylate/tosylate (e.g., benzyl bromides) which can
`
`react under time/temperature controlled reaction condition, preferably at r.t.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 2008
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 2008
`
`

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`Scheme 7 describes a double fimctionalization approach to the synthesis of
`
`Compound (I). This kind of approach can be usefiil for the synthesis of libraries of
`. compounds (I) introducing different amine moieties and diflerent R3 goups at the same
`time.
`
`Scheme 7
`
`
`
`(20)
`
`In scheme 7 R3 is a lower alkyl group or the two Ra groups are linked forming a
`
`1,3-dioxolanyl or 1,3-dioxanyl group. An appropriate commercial benzyl derivative
`
`(with X = halogen or rnethanesulphonyloxy or p-toluenesulphonyloxy groups) can be .
`
`reacted, as very well known to those skilled in the art, to afford the benzyl cyanide (20).
`
`These reactants can be converted following known alkylation methods into compounds
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 2009
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 2009
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`(21) or (27) respectively reacting them with allyl halogenides (or allyl mesylatese or
`
`tosylates) or haloalkylaldehydes in their carbonyl protected form (acetals or dioxolanyl
`
`derivatives or other).
`
`'
`
`These alkylation reactions can be carried out by the use of bases to generate the
`
`reactive benzyl carbanions. Example of used bases are lithium diisopropylamide (LDA)
`
`or tert-Butyl lithium or NaH or potassium tert-butoxide or sodium amide or potassium
`
`amide or others in an appropriate solvent such as TI-IF or Et2O or DMF or other at a
`temperature ranging from —78°C to the reflux temperature. A preferred method of
`
`alkylation include the use of hindered bases such as LDA in the presence of hexamethyl
`
`phosphorous triamide or DMPU at -78 °C — r.t.
`
`Compounds (21) can be in turn reduced by the use of diisobutylaluminum hydride
`
`(DIBAL-H) in an appropriate solvent (toluene, DMF, CH2Cl2 or other) at a temperature
`
`ranging from —78°C to the reflux of the solvent. The so obtained aldehydes (22) are then
`
`carbonyl protected following methods very well known to those skilled in the art to give
`
`compounds (23), which can be catalytically osmilated (C. P. Forbes .I.C.S'. Perkin Trans I
`
`I 1979, 906-910) or undergo ozonolysis to afford compounds (24). Compounds (24) can be
`
`reductively aminated as described above to afford compounds (25). Deprotection by
`
`common methods leads to the aldehydes (26).
`
`Compounds (26) can be alternatively obtained from compounds (21) applying the
`
`osmilation or ozonolysis procedure on them. The so obtained cyanopropionaldehydes
`
`(27) are then reductively aminated to compound (28). Repeating the DIBAL-H reduction
`
`described above on these compounds affords the aldehydes (26).
`
`Compounds (27) are also easily obtained from compounds (29) by simple
`
`deprotection of the carbonyl functionality. The reaction of R3-M (where M is a metallic
`
`salt, such as lithium or magnesium halide) with compoimds (26) afford compounds (I). A
`
`large number of organometallics such as litium or magnesium derivatives are
`
`commercially available or easily prepared and can be reacted in an appropriate solvent
`
`such as THF or Et2O or others at —78°C — reflux.
`
`Stereoclz emistm
`
`In Schemes 1, 6 and 7 compounds I are obtained in syn/anti mixture of
`
`diastereoisomers with ratio depending on the reaction condition used. The
`
`diastereoisomers can be separated by usual tecniques known to those skilled in the art
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 2010
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 2010
`
`

`

`wo 03/106421
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`-21-
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`
`including fractional crystallization of the bases or their salts or chromatografic tecniques
`
`such as LC or flash chromatography. For both the diastereoisomers, the (+) enantiomer of
`.formula Ia can be separated from the (-) enantiomer using techniques and procedures well
`known in the art, such as that described by J. Jacques, et al., "Enantiomers, Racemates,
`
`and Resolutions", John Wiley and Sons, Inc., 1981. For example, chiral chromatography
`
`with a suitable organic solvent, such as ethanol/acetonitrile and Chiralpak AD packing, 20
`
`micron can also be utilized to effect separation of the enantiomers.
`
`The free bases of formula 1, their diastereoisomers or enantiomers can be
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`converted to the corresponding pharmaceutically acceptable salts under standard
`
`conditions well known in the art. For example, the free base of fonnula I is dissolved in a
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`suitable organic solvent, such as methanol, treated with one equivalent of maleic or oxalic
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`acid for example, one or two equivalents of hydrochloric acid or methanesulphonic acid
`
`for example, and then concentrated under vacuum to provide the corresponding
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`pharmaceutically acceptable salt. The residue can then be purified by recrystallization
`
`from a suitable organic solvent or organic solvent mixture, such as methanol/diethyl
`ether.
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`Combination treatments
`
`In certain embodiments, disorders of the urinary tract are treated by administering
`
`a compound of formula I in combination with an additional 5-HT1,s_ antagonist or an
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`antagonist of one or more additional class of receptors. In preferred embodiments a
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`compound of formula I is administered in combination with an antagonist of an oil-
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`adrenergic, or muscarinic receptor.
`
`In further embodiments, lower urinary tract disease is treated by administering a
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`compound of formula I in combination with one or more inhibitor of the cyclooxygenase
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`enzyme, which may inhibit both COX1 and COX2 isozymes or which may, alternatively,
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`be selective for COX2 isozyme, and NO donor derivatives thereof.
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`Examples of antimuscarinic drugs for administration in combination with a
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`compound of formulal are oxybutynin, tolterodine, darifenacin, and temiverine.
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`A compound of formulal may be administered in combination with oLl-adrenergic
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`antagonists, for the therapy of lower urinary tract symptoms, whether or not these are
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`associated with BPH. Preferred otl-adrenergic antagonists suitable for administration in
`
`combination with a compound of formula I are, for example, prazosin, doxazosin,
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 2011
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`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 2011
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`terazosin, alfuzosin, and tamsulosin. Additional ocl-adrenergic antagonists suitable for
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`administration in combination with a compound of formula I are described in U.S. Patents
`
`No. 5,798,362, 5,990,114; 6,306,861; 6,365,591; 6,387,909; and 6,403,594.
`Examples of 5-HT“ antagonists that may be administered in combination with a
`
`compound of formula I are found in Leonardi et al., J Pharmacol. Exp. Iher. _2_92: 1027-
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`1037, 2001 (e.g., Rec 15/3079), U.S. Patent No. 6,071,920, other phenylpiperazine
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`derivatives described in W0 99/063 83 and pending U.S. Patent Applications Serial No.
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`10/266,088 and 10/266,104 filed on October 7, 2002. Additional 5-HT1A antagonists
`
`include DU-125530 and related compounds described in U.S. Patent No. 5,462,942 and
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`robalzotan and related compounds described in W0 95/1 1891.
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`Examples of selective COX2 inhibitors that may be administered in combination
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`with a compound of fonn11laI are, without limitation, nimesulide, meloxicam, rofecoxib,
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`celecoxib, parecoxib and valdecoxib. Additional examples of selective COX2 inhibitors
`
`are described, without limitation, in US 6,440,963. Examples of non-selective COX1-
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`COX2 inhibitors are, without limitation, acetylsalicylic acid, niflumic acid, flufenamic
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`acid, enfenamic acid, meclofenamic acid, tolfenamic acid, thiaprophenic acid, ibuprofen,
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`naproxen, ketoprofen, flurbiprofen, furprofen, indomethacin, acemethacin,
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`proglumethacin, ketorolac, diclofenac, etodolac, sulindac, fentiazac, tenoxicam,
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`lomoxicam, cynnoxicam, ibuproxam, nabumetone, tolmetin, amtolmetin. Accordingly,
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`each ofthe foregoing are non-limiting examples of COX inhibitors that may be
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`administered in combination with a compound of formula 1.
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`Examples of derivatives of COX inhibitors that may be administered in
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`combination with a compound of formula I are derivatives of COX inhibitors bearing
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`nitrate (nitrooxy) or nitrite groups, such as those‘ given , for example, in WO 98/09948,
`able to release NO in vivo.
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`Pharmaceutical Compositions
`
`The invention further provides pharmaceutical compositions comprising a
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`compound of formula I or an enantiomer, diastereomer, N-oxide, crystalline form,
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`hydrate, solvate, active metabolite or pharmaceutically acceptable salt of the compound.
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`The pharmaceutical composition may also include optional additives, such as a
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`pharmaceutically acceptable carrier or diluent, a flavouring, a sweetener, a preservative, a
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`dye, a binder, a suspending agent, a dispersing agent, a colorant, a disintegrator, an
`
`excipient, a diluent, a lubricant, an absorption enhancer, a bactericide and the like, a
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 2012
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`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 2012
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`stabiliser, a plasticizer, an edible oil, or any combination oftwo or more of said additives.
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`Suitable pharmaceutically acceptable carriers or diluents include, but are not
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`limited to, ethanol, water, glycerol, aloe vera gel, allarrtoin, glycerine, vitamin-A and E
`oils, mineral oil, phosphate buffered saline, .PPG2 myristyl propionate, magnesium
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`carbonate, potassium phosphate, vegetable oil, animal oil and solketal.
`
`Suitable binders include, but are not limited to, starch, gelatine, natural sugars
`such as glucose, sucrose and lactose, corn sweeteners, natural and synthetic gums such as
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`acacia, tragacanth, vegetable gum, sodium alginate, carboxymethylcellulose, polyethylene
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`glycol, waxes and the like.
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`Suitable disintegrators include, but are not limited to, starch such as corn starch,
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`"methyl cellulose, agar, bentonite, xanthan gum and the like.
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`Suitable lubricants include, but are not limited to, sodium oleate, sodium stearate,
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`magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
`Suitable suspending agents include, but are not limited to, bentonite.
`Suitable dispersing and suspending agents include, but are not limited to, synthetic
`
`and natural gums such as vegetable gum, tragacanth, acacia, alginate, dextran, sodium
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`carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone and gelatine.
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`Suitable edible oils include, but are not limited to, cottonseed oil, sesame oil,
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`coconut oil and peanut oil.
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`Examples of additional additives include, but are not limited to, sorbitol, talc,
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`stearic acid and dicalcium phosphate.
`‘ Unit Dosage Form
`
`The pharmaceutical composition may be formulated as unit dosage forms, such as
`
`tablets, pills, capsules, boluses, powders, granules, sterile parenteral solutions, sterile
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`parenteral suspensions, sterile parenteral emulsions, elixirs, tinctures, metered aerosol or
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`liquid sprays, drops, ampoules, autoinjector devices or suppositories. The unit dosage
`
`forms may be used for oral, parenteral, intranasal, sublingual or rectal administration, or
`for administration by inhalation or insufflation, transdermal patches, and a lyophflized A
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`composition. In general, any delivery of active ingredients that results in systemic
`
`availability of such ingredients can be used. Preferably the unit dosage form is an oral
`
`dosage form, most preferably a solid oral dosage; therefore the preferred dosage forms are
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`tablets, pills and capsules. However, parenteral preparations are preferred too.
`
`Solid unit dosage fonns may be prepared by mixing the active agents of the
`
`present invention with a pharmaceutically acceptable carrier and any other desired
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`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 2013
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`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 2013
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`wo 03/10642]
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`additives as described above. The mixture is typically mixed until a homogeneous
`
`mixture ofthe active agents of the present invention is obtained and the carrier and any
`
`other desired additives are formed, i.e. the active agents are dispersed evenly throughout
`the composition. In this case, the composition can be fonned as dry or moist granules.
`
`Dosage forms can be formulated as, for example, "immediate release" dosage
`
`forms. "Immediate release" dosage forms are typically formulated as tablets that release
`
`at least 60%-90% of the active ingredient within 30-60 min when tested in a drug
`dissolution test, e.g., U.S. Pharmacopeia standard <711>. In a preferred embodiment,
`
`immediate dosage forms release at 75% of active ingredient within about 45 min.
`
`Dosage forms can also be formulated as, for example, "controlled release" dosage
`
`forms. "Controlled," "sustained," "extended" or "time release" dosage forms are
`
`equivalent terms that describe the type of active agent delivery that occurs when the
`
`active agent is released fiom a delivery vehicle at an ascertainable and manipulatable rate
`
`- over a period of time, which is generally on the order of minutes, hours or days, typically
`
`ranging from about sixty minutes to about 3 days, rather than being dispersed
`
`immediately upon entry into the digestive tract or upon contact with gastric fluid. A
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`controlled release rate can vary as a function of a multiplicity of factors. Factors.
`
`influencing the rate of delivery in controlled release include the particle size,
`
`composition, porosity, charge structure, and degree of hydration of the delivery vehicle
`
`and the active ingredient(s), the acidity of the environment (either internal or external to
`
`the delivery vehicle), and the solubility of the active agent in the physiological
`
`environment, i.e., the particular location along the digestive tract. Typica