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`EP 019 358 81
`
`R3
`
`R2
`
`R4
`
`R5
`
`Rla
`6
`lc:H—_cH2—cI~12—N/\R7
`
`R
`
`Ar
`
`dans laquelle R2 3 R7 et Ar son! tels que définis dans la revendication 1, et R‘a est carboxyl ou alkoxy, la
`conversion de R‘a en hydroxy, on
`
`f) dans un composé de Formule VII
`
`FormuleVI
`
`2
`R}, Rb
`
`R1
`
`kg /c1~1.c:H2—cH2-N/\R7
`
`Ar
`
`.
`
`R6
`
`Fon:nuleVII
`
`dans Iaquefle R‘, R5, R7 et Ar sont tels que définis dans la revendication 1. et un des éléments Rzb é R5b est
`alkyléne et Ies autres sont tels que définis dans la revendication 1 pour R2 2‘: R5, la réduction de I'alky|éne en
`alkyle, hydroxyalkyle ou dihydroxyalkyle, on
`
`g) dans un composé de Formule I tel que défini dans la revendication 1, la conversion d'un ou plusieurs des
`groupes R‘ :31 R5 en un autre groupe ou en d'autres groupes R‘ 2‘: R5, ou
`
`h) Ia réaction d'un composé de Fonnule VIII
`
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`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 0501
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`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 0501
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`

`
`EP 1 019 358 B1
`
`R3
`
`R2
`
`R4
`
`R1
`
`R5
`
`R6
`CH-CH2-— CH2-N< R7
`
`¢x
`
`~
`
`‘CH2
`
`dans laquelle R‘ a R7 sont Iels que définis dans Ia revendication 1. et X est oxygéne
`ou soufre, avec un composé de Fonnule IX
`
`Formulc VIII
`
`CH3N=C :
`
`formule IX
`
`pour former un composé de Forrnule Ia
`
`R3
`
`R2
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`15
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`20
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`25
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`_30
`
`R4
`
`R1
`
`Formule Ia
`
`R6
`CH-CH2—CH2-N<R7
`
`R5
`
`x \
`
`=
`
`dans laquelle R1 é R7 et X sont tels que définis ci—dessus. ou
`
`I) la réaction d'un composé de Formule VIII défini ci—dessus. dans Iequel X est oxygéne, avec un composé de
`Fonnule X
`
`OH
`
` NI-I2
`
`pour former un composé de Formule lb
`
`For-mule X
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`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 0502
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`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 0502
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`

`
`EP 1 019 358 B1
`
`R3
`
`R2
`
`R“
`
`RI
`
`R5
`
`(bu-1- CH2—CH2-N/\R7
`
`R6
`
`dans laquelle R‘ :21 R7 sont tels qué définis dans la revendication 1, ou
`
`j) Ia conversion d'un composé de Formule XI
`
`Formule Ib
`
`dans laquelle R‘ a R7 sont tels que définis dans la revendication 1, en un composé de Formule XII
`
`Formule XI
`
`R3
`
`R2
`
`R5
`
`/ R
`CH— CH 2-CH2_N 7
`
`6
`
`dans laquelle R‘ a R7 sont tels que définis dans la revendication 1, ou
`
`k) Ia conversion d'_un composé de Formule XIII
`
`Formule XH
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`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 0503
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`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 0503
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`

`
`EP 1 019 358 B1
`
`R3
`
`R2
`
`R4
`
`R1
`
`.
`
`R6
`
`R5
`
`cii—c:H2—cH2_N(R.,
`Hzbf \ X
`
`dans Iaquelle R‘ é R7 sont tels que définis dans la revendication 1, et X est oxygene ou soufre, en un composé
`de Fonnule XIV
`
`Formule XIII
`
`Fonnule XIV
`
`dans Iaquelle R‘ é R7 et X sont tels que définis ci-dessus. et R3 et R9 sont indépendamment hydrogéne ou alkyl, et
`
`(i) si nécessaire, la séparation des groupes de protection des éléments hydroxy dans les composés obtenus.
`(ii) si désiré, Ia conversion des bases de Formula I obtenues en leurs sels avec des acides physiologiquement
`acceptables, ou vice versa, et/ou
`(iii) si désiré, ia séparation d'un mélange obtenu d'isoméres optiques en énantioméres individuels.
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`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 0504
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`

`
`Européiisches Patentamt
`
`(19)
`
`.0)
`
`European Patent Office
`Office européen des brevets
`
`llllllilllllillllllllllilllillllllllllllilllllllllllllillli
`
`(11)
`
`EP 1 077 912 B1
`
`(12)
`
`' EUROPEAN PATENT SPECIFICATION
`
`(45) Date of publication and mention
`of the grant of the patent:
`03.07.2002 Bulletin 2002/27
`
`(21) Application number: 99924929.5
`
`(22) Date offiling: 11.05.1999
`
`(51) |ntC|.7: C07C.1/00, C07C 217/62,
`CO7C 217/48, C07C 219/28,
`CO7C 219/22, C07D 207/06,
`C07D 295/06, C07C 271/08.
`C07F 7/18, C07C 307/02,
`A61 K 31/135, A61K 31/325,
`A61 K 31/40, A61 K 31/435
`
`(86) lntemational application number:
`PCT/EP99/03212
`
`(87) International publication number:
`WO 99I58478 (18.11.1999 Gazette 1999/46)
`
`(54) NOVEL DERIV-ATIVES OF 3,3-DlPHENYLPROPYLAM|NES
`3,3-DIPHENYLPROPYLAMINDERIVATE
`
`NOUVEAUX DERIVES DE 3,3-DIPHENYLPROPYLAMINES
`
`
`
`- SPARF, Bengt
`S-142 65 Tr ngsund (SE)
`
`(84) Designated Contracting States:
`AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU
`MC NL PT SE
`
`Designated Extension States:
`_ AL LT LV MK RO SI
`
`(30) Priority: 12.05.1998 EP 98108608
`
`(74) Representative: Albrecht, Thomas, Dr.
`Kraus 8. Weisert,
`Thomas-Wimmer-Ring 1 5
`80539 Mi1nchen(DE)
`
`(43) Date of publication of application:
`28.02.2001 Bulletin 2001/09
`
`(56) References cited:
`W0-A-89/06644
`
`W0-A-94I11337
`
`
`
`(73) Proprietor: SCHWARZ PHARMA AG
`D-40789 MonheimIRhld. (DE)
`
`(72) Inventors:
`- MEESE, Claus
`D-40789 Monheim (DE)
`
`- LISBETH NILVEBRANT ET AL.: "Tolterodine - a
`
`new bladder-selective antimuscarinic agent"
`EUROPEAN JOURNAL OF PHARMACOLOGY,
`vol. 327, 1997, pages 195-207, XP002079629
`cited in the application
`
`EP1077912B1
`
`Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give
`notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in
`a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Arl.
`99(1) European Patent Convention).
`
`Printed by Jouve. 75001 PARIS (FR)
`
`Patent Owner, UCB Pharma GmbH Exhibit 2011 - 0505
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 0505
`
`

`
`Description
`
`EP 1 077 912 B1
`
`[0001] The present invention relates to novel derivatives of 3,3-diphenylpropylamines, methods for their preparation,
`pharmaceutical compositions containing the novel compounds, and the use of the compounds for preparing drugs.
`[0002]
`In man, normal urinary bladder contractions are mediated mainly through cholinergic muscarinic receptor
`stimulation. There is reason to believe that muscarinic receptors mediate not only normal bladder contractions, but
`also the main part of the contractions in the overactive bladder resulting in symptoms such as urinary frequency, urgency
`and urge incontinence. For this reason, antimuscarinic drugs have been proposed for the treatment of bladder over-
`activity.
`[0003]- Among the antimuscarinic drugs available on the market. oxybutynin is currently regarded as the gold standard
`for pharmacological treatment of urge incontinence and other symptoms related to bladder overactivity. The effective-
`ness of oxybutynin has been demonstrated in several clinical studies, but the clinical usefulness of oxybutynin is limited
`due to antimuscarinic side effects. Dryness of the mouth is the most common experienced side effect which may be
`severe enough to result in poor compliance or discontinuation of treatment (Andersson, K.-E., 1988, Current concepts
`in the treatment of disorders of micturition, Drugs 35, 477-494; Kelleher et al. 1994).
`[0004] Tolterodine is a new, potent and competitive, muscarinic receptor antagonist intended for the treatment of
`urinary urge incontinence and detrusor hyperactivity. Preclinical pharmacological data show that tolterodine exhibits a
`favourable tissue selectivity in vivo for the urinary bladder over the effect on the salivation (Nilvebrant et al., 1997,
`Tolterodine - a new bladder-selective antimuscarinic agent, Eur. J. Pharmacol. 327 (1997), 195-207), whereas oxybu-
`tynin exhibits the reversed selectivity. Tolterodine is equipotent to oxybutynin at urinary bladder muscarinic receptors
`and the favourable tissue selectivity of tolterodine demonstrated in the preclinical studies has been confirmed in clinical
`studies. Thus a good clinical efficacy has been combined with a very low number of incidences of dry mouth and
`antimuscarinic side effects.
`
`[0005] A major metabolite of tolterodine, the 5-hydroxymethyl derivative is also a potent muscarinic receptor antag-
`onist and the pharmacological in vitro and in vivo profiles of this metabolite are almost identical to those of tolterodine
`(Nilvebrant et al., 1997, Eur. J. Pharmacol. 327 (1997), 195-207). Combined phannacological and phannacokinetic
`data indicate that it is most likely that the metabolite gives a major contribution to the clinical effect in most patients.
`[0006] WO 94111337 proposes the active metabolite of tolterodine as a new dmg for urge incontinence. Administration
`of the active metabolite directly to patients has the advantage compared to tolterodine that only one active principle
`(compound) has to be handled by the patient which normally should result in a lower variation in efficacy and side
`effects between patients and lower risk of interaction with other dmgs.
`[0007] However, the introduction of an additional hydroxy group in the tolterodine results in an increased hydrophilic
`property of the new compounds (3,3-diphenylpropylamines) compared to the parent compounds which normally results
`in a lower absorption/bioavailability, leading to pre-systemic side effects or interactions due to non-absorbed antimus-
`carinic drug. in a method to circumvent this disadvantage, different prodrugs of the metabolite have been synthesized
`and tested for their antimuscarinic activity, potential absorption through biological membranes and enzymatic cleavage.
`[0008]
`it is an object of the present invention to provide novel derivatives of 3,3-diphenylpropylamines. It is a further
`object of the present invention to provide new- derivatives of 3.3-diphenylpropylamines which will be more useful as
`prodrugs for treatment of urinary incontinence and other spasmogenic conditions that are caused by muscarinic mech-
`anisms while avoiding the disadvantage of a too low absorption through biological membranes of the drugs or an
`unfavourable metabolism.
`
`[0009] A further object of the invention is to provide novel prodrugs of antimuscarinic agencs with superior pharma-
`cokinetic properties compared to present drugs as oxybutynin and tolterodine, methods for preparing thereof, phar-
`maceutical compositions containing them, a method of using said compounds and compositions for the treatment of
`urinary incontinence, gastrointestinal hyperactivity (irritable bowel syndrome) and other smooth muscle contractile
`conditions.
`‘
`[0010] According to the present invention, novel 3,3-diphenylpropylamines are provided, which are represented by
`the general formulae l and VII‘
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`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 0506
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`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 0506
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`

`
`EP 1 077 912 B1
`
`
`
`
`
`Formula VIl'
`
`wherein R and R’ are independently selected from
`
`a) hydrogen, C1-C6 alkyl, C3-C16 cycloalkyl, substituted or unsubstituted benzyl, allyl or carbohydrate; or
`
`b) formyl, C1-C6 alkylcarbonyl, cycloalkylcarbonyl, substituted or unsubstituted arylcarbonyl, preferably benzoyl; or
`
`c) C1-C6 alkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, benzoylacyl, benzoylglycyl, a substituted
`or unsubstituted amino acid residue; or
`
`d)
`
`R‘
`\
`RF’
`
`N-CG
`
`wherein R4 and R5 independently represent hydrogen. C1-C6 alkyl, substituted or unsubstituted aryl, preferably
`substituted or unsubstituted phenyl, benzyl or phenoxyalkyl wherein the alkyl residue has 1 to 4 carbon atoms and
`wherein R4 and R5 may form .a ring together with the amine nitrogen; or
`
`e)
`
`R‘
`R
`117/
`
`Na-502'
`
`wherein R5 and R7 independently represent C1-C6 alkyl, substituted or unstubstituted aryl, preferably substituted
`or unsubstituted phenyl. benzyl or phenoxyalkyl wherein the alkyl residue has 1 to 6 carbon atoms; or
`
`0 an ester moiety of inorganic acids,
`
`g) -SiRaR1,Rc, wherein Ra, R1,, R6 are independently selected from C1-C1 alkyl or aryl, preferably phenyl,
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`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 0507
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`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 0507
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`

`
`EP 1 077 912 B1
`
`with the proviso that R’ is not hydrogen. methyl or benzyl if R is hydrogen. R is not ethyl if R‘ is hydrogen,
`X represents a tertiary amino group of formula la
`
`/5!‘
`....N\\R'
`
`Furmulala
`
`wherein R3 and R9 represent non-aromatic hydrocarbyl groups, which may be the same or different and which together
`contain at least three carbon atoms. and wherein R9 and R9 may form a ring together with the amine nitrogen,
`Y and Z independently represent a single bond between the (CH2),, group and the carbonyl group, O, S or NH,
`A represents hydrogen (‘H) or deuterium (ZH),
`n is 0 to 12
`and
`
`their salts with physiologically acceptable acids. their free bases and. when the compounds can be in the form of optical
`isomers, the racemic mixture and the individual enantiomers.
`[0011] The aforementioned compounds can form salts with physiologically acceptable organic and inorganic acids.
`Furthennore, the aforementioned compounds comprise the free bases as well as the salts thereof. Examples of such
`acid addition salts include the hydrochloride and hydrobromide.
`[0012] When the novel compounds are in the form of optical isomers. the invention comprises the racemic mixture
`as well as the individual isomers as such.
`
`Preferably each of R9 and R9 independently signifies a saturated hydrocarbyl group. especially saturated
`[0013]
`aliphatic hydrocarbyl groups such as C1 _8-alkyl. especially C1_6-alkyl, or adamantyl, R3 and R9 together comprising at
`- least three, preferably at least four carbon atoms.
`[0014] According to another embodiment of the invention, at least one of R3 and R9 comprises a branched carbon
`chain.
`
`[0015] Presently preferred tertiary amino groups X in formula I include the following groups a) to h):
`
`a)
`
`‘--N<
`
`CH(CI-I )
`3 2
`CH<‘-‘Kala
`
`b)
`
`-—-N<
`
`c1-:
`
`3
`C(CH3):3
`
`<2)
`
`/CH3
`--N\
`
`C(CH3)gCH2CH3
`
`d)
`
`H r:
`a
`--N-
`
`ca
`
`3
`
`Bgc
`
`CH3
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`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 0508
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`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 0508
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`
`EP 1 077 912 B1
`
`Hgc
`--II?
`H30
`
`cl
`
`ca,
`
`(‘:1-13
`—-N"
`
`f)
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`g)
`
`__ C’
`
`11)
`
`._..i ..
`
`Group a) is particularly preferred.
`[0016] The aforementioned tertiary amino groups X are described in WO 94/11337 and the compounds according
`to the present invention can be obtained by using the corresponding starting compounds.
`[0017]
`in the compounds according to the present invention. the term "alkyI" preferably represents a straight-chain
`or branched-chain hydrocarbon group having 1 to 6 carbon atoms. Such hydrocarbon groups may be selected from
`methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and hexyl. The term "cycloalkyl' denotes a cyclic hydrocarbon
`group having 3 to 10 carbon atoms which may be substituted conveniently.
`[0018] The term ‘substituted or unsubstituted benzyl‘ denotes a benyl group -CH2-CSH5 which is optionally substi-
`tuted by one or more substituents on the phenyl ring. Suitable substituents are selected from alkyl, alkoxy, halogen
`and nitro. Suitable halogen atoms are fluorine. chlorine and iodine atoms. Preferred substituted benzyl groups are
`4-methylbenzyl, 2-methylbenzyl, 4-methoxybenzyl. 2-methoxybenzyl, 4-nitrobenzyl. 2-nitrobenzyl, 4—ch|orobenzy| and
`2-chlorobenzyl.
`[0019]
`In the compounds according to the present invention the term "C1-C6 alkylcarbonyl‘ denotes a group R-C
`(=0)- wherein R is an alkyl group as defined hereinbefore. Preferred C1-C5 alkylcarbonyl groups are selected from
`acetyl. propionyl, isobutyryl, butyryl, valeroyl and pivaloyl. Thegterm "cycloalkylcarbonyl" denotes a group R-C(=O)-
`wherein R is a cyclic hydrocarbon group as defined hereinbefore. The same counts to the selected carbonyl groups.
`[0020] The term ‘aryl’ denotes an aromatic hydrocarbon group such as phenyl- (C5H5-), naphthyl- (C10H7-) and
`anthryl- (C14H9—).'Preferred aryl groups according to the present invention are phenyl and naphthyl with phenyl being
`particularly preferred.
`[0021] The term "benzoyl' denotes an acyl group of the formula -CO-C6H5 wherein the phenyl ring may have one
`or more substituents.
`
`[0022] Preferred substituents of the aryl group and in particular of the phenyl group are selected from alkyl, alkoxy,
`halogen and nitro. As substituted benzoyl groups 4-methylbenzoyl, 2-methylbenzoyl, 4—methoxybenzoyl, 2-methoxy-
`benzoyl, 4-chlorobenzoyl, 2-chlorobenzoyl, 4-nitrobenzoyl and 2-nitrobenzoyl may be mentioned.
`[0023] The term ‘C1-C5 alkoxycarbonyl" refers to a group ROC(=O)-wherein R is an alkyl group as defined herein-
`before. Preferred C1-C5 alkoxycarbonyl groups are selected from CH3OC(=O)-, CZH5-OC(=O)-, C3H7OC(=0)- and
`(CH3)3COC(=O)- and alicyclic alkyloxycarbonyl._
`[0024] The term ‘amino acid residue‘ denotes the residue of a naturally occurring or synthetic amino acid. Particularly
`preferred amino acid residues are selected from the group consisting of glycyl; valyl, leucyl, isoleucyl, phenylalanyl,
`prolyl, seryl, threonyl, methionyl, hydroxyprolyl.
`[0025] The amino acid residue may be substituted by a suitable group and as substituted amino acid residues.
`benzoylglycyl and N—acetylglycyl may be mentioned.
`[0026] The term "carbohydrate" denotes the residue of a polyhydroxy aldehyde or polyhydroxy ketone of the formula
`C,,H2nO,, or Cn(H2O)n and corresponding carbohydrate groups are, for example, described in Aspinal. The Polysac-
`charides. New York: Academic Press 1982. 1983. A preferred carbohydrate group in the compounds according to the
`present invention is a glucuronosyl group, in particular a 1|}-D-glucuronosyl group.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 0509
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 0509
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`

`
`EP 1 077 912 B1
`
`[0027] The term ‘LG’ as used herein denotes a leaving group selected from halogenides, carboxylates and imida-
`zolides.
`
`[0028] The term 'Bn" as used herein denotes a benzyl group.
`[0029]
`Suitable ester moieties of inorganic acids may be derived from inorganic acids such as sulfuric acid and
`phosphoric acid.
`[0030] Preferred compounds according to the present invention are:
`
`A) Phenolic monoesters represented by the general formulae ii and II‘
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`
`
`wherein R‘ represents hydrogen. C1-C5 alkyl or phenyl.
`Particularly preferred phenolic monoesters are listed below:
`
`(t)-formic acid 2—(3-diisopropylamino-1-phenylpropyl)-4—hydroxymethylphenyI ester,
`(i)-acetic acid 2—(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,
`(:)-propionic acid 2—(3-diisopropylamino-1-phenylpropyl)—4-hydroxymethylphenyl ester,
`(i)-n—butyric acid 2-(3-diisopropylamino—1-phenylpropyl)-4-hydroxymethylphenyl ester,
`(i)-isobutyric acid 2—(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,
`R-(+)-isobutyric acid 2—(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester.
`(;i:)-2,2-dimethylpropionic acid 2-(3-diisopropy|amino-1-phenylpropyl)-4-hydroxymethylphenyl ester,
`(i)~2-acetamidoacetic acid 2—(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,
`(i)-cyclopentanecarboxylic acid 2—(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,
`(t)-cyclohexanecarboxylic acid 2—(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,
`(i)-benzoic acid 2—(3-diisopropylamino-1-phenylpropyl)—4-hydroxymethylphenyl ester,
`R-(+)-benzoic acid 2—(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,
`(-L)-4-methylbenzoic acid 2—(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,
`(i)—2-methylbenzoic acid 2—(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,
`(i)-2-acetoxybenzoic acid 2—(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,
`(1)-1-naphthoic acid 2—(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester.
`(i)—2-naphthoic acid 2—(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,
`(i)-4—chlorobenzoic acid 2—(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,
`(zt)-4-methoxybenzoic acid 2—(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,
`(i)—2-methoxybenzoic acid 2-(3-diisopropylamino-1-phenylpropyl)—4-hydroxymethylphenyl ester,
`(i)-4-nitrobenzoic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,
`(J_r)—2-nitrobenzoic acid 2—(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,
`(1)-malonic acid bis-[2-(3-diisopropylamino-1-phenylpropyl)—4-hydroxymethyl-phenyl] ester,
`(i)-succinic acid bis-[2—(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethyl-phenyllester,
`(i)-pentanedioic acid bis- [2- (3~diisopropylamino-1-phenylpropyl)-4-hydroxymethyl-pheny|]ester,
`(i)-hexanedioic acid bis-[2-(3—diisopropylamino-1-phenylpropyl)-4-hydroxymethyl-phenyllester.
`
`8) identical diesters represented by the general formula III
`
`6
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 0510
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`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 0510
`
`

`
`EP 1 077 912 B1
`
`
`
`wherein R‘ is as defined above.
`
`Particularly preferred identical diesters are listed below:
`
`'
`
`(:l:)-formic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-forrnyloxymethylphenyl ester,
`(1)-acetic acid 4-acetoxy-3-(3-diisopropylamino-1-phenylpropyl)~benzyl ester,
`(t)-propionic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-propionyloxymethylphenyl ester.
`(t)-n-butyric acid 4-n-butyryloxymethyl-2-(3-diisopropylamino-1-phenylpropyl)-phenyl ester,
`(t)-isobutync acid 2-(3-diisopropylamino-1-phenylpropyl)-4-isobutyryloxymethylphenyl ester,
`(;l:)—2,2-dimethylpropionic acid 3-(3-diisopropylamino-1-phenylpropyl)-4-(2.2-dimethyl-propionyloxy)-benzyl
`ester,
`(1)-benzoic acid 4-benzoyloxymethyl-2-(3-diisopropy|amino-1-phenylpropyl)—phenyl ester,
`R-(+)-benzoic acid 4-benzoyloxymethyl-2-(3—diisopropylamino-1-phenylpropyl)-phenyl ester,
`(i)-pent-4-enoic acid 2-(3-diisopropylamino-1-phenylpropyl)—4-(pent-4-enoyloxymethyl)-phenyl ester,
`cyclic oct-4-ene-1.8-dioate of Intermediate B,
`cyclic octane-1.8-dioate of lnterrnediate B.
`poly-co-DL-Iactides of lnterrnediate B.
`
`0) Mixed diesters represented by the general formula IV
`
`Fan-nu: iv
`
`R2
`
`O
`
`e
`
`wherein R‘ is as defined above
`and
`
`R2 represents hydrogen, C,-C6 alkyl or phenyl
`with the proviso that R‘ and R2 are not identical.
`Particularly preferred mixed diesters are listed below:
`
`(1)-acetic acid-5-(3-diisopropylamino-1-phenylpropyl)-4-formyloxymethylphenyl ester,-
`(at)-benzoic acid 2-(3-diisopropylamino-1-phenylpropyl)—4-formyloxymethylphenyl ester,
`(i)—benzoic acid 2-(3-diisopropylamino-1~phenylpropyl)-4-acetoxymethylphenyl ester,
`R-(+)-benzoic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-acetoxymethylphenyl ester,
`(1)-isobutyric acid 4-acetoxymethy|-2—(3-diisopropylamino-1-phenylpropyl)-phenyl ester,
`R-(+)-isobutyric acid 4-acetoxymethyl-2-(3-diisopropylamino-1-phenylpropyl)—phenyl ester,
`(i:)—2.2-dimethylpropionic acid 4-acetoxy-3-‘(3-diisopropylamino-1-phenylpropyl)—benzyl ester,
`(i)-2.2-dimethylpropionic acid 4-acetoxymethyl-2-(3-diisopropylamino-1-phenylpropyl)-phenyl ester,
`(i)-benzoic acid 4-benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-benzyl ester.
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`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 0511
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`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 0511
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`

`
`D) Benzylic monoesters represented by the general formula V
`
`EP 1 077 912 B1
`
`Farrmda V
`
`wherein R1 is as defined above.
`Particularly preferred benzylic monoesters are listed below:
`
`(i)-formic acid 3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzyl ester,
`(t)-acetic acid 3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzyl ester,
`(zt)-propionic acid 3-(3-diisopropylamino-1-pheny|propyl)—4-hydroxybenzyl ester,
`(:l:)-butyric acid 3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzyl ester,
`(i:)-isobutyn'c acid 3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzyl ester.
`(i)-2.2-dimethylpropionic acid 3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzyl ester,
`(4.-)-benzoic acid 3- (3-diisopropylamino-1-phenylpropyl)—4-hydroxybenzyl ester.
`
`E) Ethers and silyl ethers represented by the general formula VI ~
`
` Fan-mla Vi
`
`wherein at least one of R10 and R“ is selected from C1-C6 alkyl, benzyl or -SAiRaRbRc asvdefined above and the
`other one of R10 and R“ may additionally represent hydrogen, C1-C5 alkylcarbonyl or benzoyl.
`Particularly preferred ethers and silyl ethers are listed below:
`
`(i)-2—(3—diisopropylamino-1-phenylpropyl)-4-methoxymethylphenol,
`(i)—2—(3-diisopropylamino-1-phenylpropyl)-4—ethoxymethylphenol.
`(+) -2-(3-diisopropylamino-1-phenylpropyl)-4~propoxymethylphenoI.
`(t) -2- (3-diisopropylamino-1 -phenylpropyl)-4-isopropoxymethylphenol,
`(i)-2-(3-diisopropylamino-1-phenylpropyl)-4-butoxymethylphenol,
`(1)-acetic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-melhoxymethylphenyl ester,
`' (t)-acetic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-ethoxymethylphenyl ester.
`‘
`(1)-2-(3-diisopropylamino-1-phenylpropyl)-4-trirnethylsilanyloxymethylphenol,
`(1)-diisopropy|-[3-phenyl-3-(2-trimethylsilanyloxy-5-trimethylsilanyloxymethylphenyl)-propyl]-amine,
`(1)-[3-(3-diisopropylamino-1-phenylpropyl)-4-trimethylsilanyloxyphenyl]-methanol.
`(:t)-diisopropyl—[3~(5-methoxymethyl-2-trimethylsilanyloxyphenyl)-3-phenylpropylamine.
`(zt)-diisopropyl-[3-(5-ethoxymethyl-2-trimethylsilanyloxyphenyt)-3-phenylpropylamine,
`(;t)-[4-(terl.—butyI-dimethylsilanyloxy)-3-(3-diisopropylamino-1-phenylpropyl)~phenyl]-methanol,
`(t)-acetic acid 4-(tert. -butyl—dimethylsilanyloxy)-3—(3-diisopropylamino-1-phenylpropyl)-benzyl ester,
`(zt)-4-(tert.-butyl-dimethylsilanyloxy)-3-(3-diisopropylamino-1-phenylpropyl)—phenol.
`(1)-acetic acid 4-(tert.—butyl-dimethylsiIanyloxy)-2-(3-diisopropylamino-1-phenylpropyl)-phenyl ester.
`(i)-{3—[2-(tert.-butyi—dimethylsilanyloxy)-5-(tert.-butyl—dimethylsilanyloxymethyl)—pheny|]-3-pheny|propy|}—di-
`isopropylamine,
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`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 0512
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`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 0512
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`

`
`EP 1 077 912 B1
`
`(zt)-[4—(tert.-butyl-diphenylsilanyloxy)-3-(3-diisopropylamino-1-phenyIpropy|)—phenyl]-methanol,
`(i)—acetic acid 4-(tert.-b‘utyI—diphenylsilanyloxymethyl)-2-(3-diisopropylamino-1-phenylpropyl)-phenyl ester,
`(1-)-4-(tert.-butyl-diphenylsilanyloxymethyl)-2-(3-diisopropylamino—1-phenylpropyl )-phenol.
`(t)-{3-[2-(ten.-butyl-diphenylsilanyloxy)-5-(tert.-butyl-diphenylsilanyloxymethyl)-phenyl]-2-phenylpropyl}-di-
`isopropylamine,
`(i)-acetic acid 4-benzy|oxy—3-(3-diisopropylamino-1-phenylpropyl)-benzyl ester,
`(1)-benzoic acid 4-benzyloxy—3-(3-diisopropylamino-1-phenylpropy|)¢benzy| ester,
`(i)-isobutyric acid 4-benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-benzyl ester,
`(iz)-2-(3-diisopropylamino—1-phenylpropyl)-4-(1B-D—gIucuronosyIoxymethyI)-phenol.
`
`F) Carbonates and carbamates represented by the general formulae VII and VIII
`
` 0
`
`Z
`
`.0 Y‘
`
`F-‘lonmjaVII
`
`‘T
`
`@
`
`Fomiula-VIII
`
`wherein Y, Z and n are as defined above and wherein R12 and R‘3 represent a C1-C6 alkoxycarbonyl group or
`
`V
`wherein R4 and R5 are as defined above.
`Particularly preferred carbonates and carbamates are listed below:
`
`(t)-N-ethylcarbamic acid 2-(3-diisopropylamino-1-phenylpropyl)—4-hydroxymethylphenyl ester,
`(i)-N.N—dimethyIcarbamic acid 2-(3-diisopropylamino-1-phenylpropyl)—4-hydroxymethylphenyl ester.
`(w_*)~N,N-diethylcarbamic acid 2-(3-diisopropylamino-1-phenylpropyi)-4~hydroxymethy|phenyl ester,
`(t)-N-phenylcarbarnic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester.
`(1-)-[2-(3-DiisopropyIamino-1-phenylpropyl)-4-hydroxymethyl-phenoxycarbonylaminolacetic acid ethyl ester
`hydrochloride,
`(1)-N-ethylcarbamic acid 3-(3-diisopropyiamino-1-phenylpropyl)-4-N-ethylcarbamoyloxybenzyl ester,
`(j:)—N.N-dimethylcarbamic acid 3-(3-diisopropylamino-1-phenylpropyl)-4-N,N-dimethylcarbamoyloxybenzyl
`ester,
`(1)-N,N-diethylcarbamic acid 3-(3»diisopropy|amino-1—pheny|propy|)—4-N,N-diethylcarbamoyloxybenzyl ester.
`(t)-N-phenylcarbamic acid 3-(3-diisopropylamino-1-phenylpropyl)—4-N-phenylcarbamoyloxybenzyl ester,
`(t)-{4- [2- (3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenoxycarbonylaminol-butyl}-carbamic ac-
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 0513
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`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 0513
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`-EP1077 912 B1
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`id 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,
`(i)-carbonic acid 2-(3-diisopropylamino-1-phenylpropyl )-4-hydroxymethylphenyl ester ethyl ester.
`(zt)-carbonic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester phenyl ester.
`(:)-carbonic acid 2-(3-diisopropylamino-1-phenylpropyl)—4-ethoxycarbonyloxymethylphenyl ester ethyl ester.
`(:l:)-carbonic acid 2-(3-diisopropylamino-1-phenylpropyl)-4~phenoxycaibonyloxymethylphenyl ester phenyl es-
`ter.
`
`G) 3.3-Diphenylpropylamines selected from
`
`(i) compounds of the formulae IX and IX‘
`
`
`at
`
`/\
`
`Formula lX'
`
`wherein o and p are the same or different and represent the number of methylene units ( CH2 } and may range
`from 0 to 6,
`
`(ii) (t)-Benzoic acid 2-(3-diisopropylamino-1-phenylpropyl)—4-sulphooxymethyl-phenyl ester
`
`(iii) Poly-co-DL-lactides of 2-(3-diisopropylaminophenylpropyl)-4-hydroxymethyl-phenol
`
`(iv) (:l:)-,2-(3-Diisopropylamino-1-phenylpropy|)—4-(15-D-glucuronosyloxymethyl)-phenol having the formula
`
`
`
`and
`
`their salts with physiologically acceptable acids. their free bases and. when the compounds can be in the form
`of optical isomers. the racemic mixture and the individual enantiomers.
`
`[0031] The present invention, moreover, relates to processes for the preparation of the aforementioned compounds.
`In particular, according to the present invention, the following processes are provided:
`[0032] A process for the production of phenolic monoesters represented by the general fonnula ll
`
`10
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`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 0514
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`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 0514
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`

`
`EP 1 077 912 B1
`
`HO
`A
`
`/
`
`A
`
`N
`
`'
`
`\|/
`
`’ l
`\/
`
`Fcmuiall
`
`as defined above, which comprises treatment of a compound of the formula
`
`with an equivalent of an acylating agent selected from
`
`0 l
`
`l
`R‘-C—Lo
`
`wherein LG represents a leaving group selected from halogenide, carboxylate and imidazolide and R‘ is as defined
`above. in an inert solvent in the presence of a condensating agent.
`[0033]
`Preferably, the acylating agent is selected from
`
`O
`
`O
`
`O
`
`1 U
`R -C—Hal
`
`or
`
`u
`u
`‘
`R‘-c—o-C-R‘,
`
`wherein Hal represents a halogen atom, preferably a chlorine. atom, and R‘ is as defined above.
`[0034] A process for the production of phenolic monoesters represented by the general formula II’
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`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 0515
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`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 0515
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`EP 1 077 912 B1
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`0
`
`(ca,
`
`:3
`
` Fcmua II‘
`
`as defined above, which comprises treatment of two equivalents of a compound of the formula
`
`H0
`
`A
`
`/
`
`A
`
`with an acylating agent selected from
`
`O
`0
`II
`H
`Hal—C- (CI-I3),-C-Hal
`
`O
`O
`._U
`-
`ll
`C- (CH,)n'C
`
`or
`
`wherein Hal represents a halogen atom. preferably a chlorine atom.
`[0035] Hence. in these processes. an lntennediate B having the formula
`
`"Y
`
`is treated with an-equivalent of an acylating agent (e.g. an acyl halogenite or acyl anhydride) in an inert solvent and in
`the presence of a condensating agent (e.g. amine) to provide phenolic monoesters of formula II or formula II‘ (wherein
`n is 0-12), respectively, if polyfunctional acylating agents (e.g. acid halides, preferably acid chlorides of dicarboxylic
`acids) are used.
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`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 0516
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`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 0516
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`

`
`-EP 1 077 912 B1
`
`[0036] The lntennediate B as used in the processes for the production of the 3,3-diphenylpropylamines according
`to the present invention can be in the form of a racemic mixture or of optically active compounds in accordance with
`the fonnulae shown below:
`
`
`
`Intermediate RS
`
`lnfeflnediafe R‘(+)
`
`intermediate S-(-)
`
`[0037] Alternatively, structures of formula II or II' may be obtained by regioselective deprotection of a protected ben-
`zylic hydroxy group (chemically or enzymaticallyz T. W. Greene. P. G. M. Wuts. ‘Protective Groups in Organic Chem-
`istry", 2nd Ed., J. Wily & Sons. New York 1991).
`[0038] The identical diesters represented by the general fonnula Ill
`
`
`
`with at least two equivalents of the acylating agent R‘-C(=O)-LG as defined above.
`[0039] Thus, the aforementioned di-acyl compounds are readily accessible if an at least two-molar excess of an
`acylating agent is used in the above-mentioned conversion of lnterrnediate B or. more general, on treatment of com-
`pounds of formula I with acylating agents in the presence of suitable catalysts. In the above process, the following
`Intermediate A
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`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 0517
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`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 0517
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`

`
`EP1077 912 B1
`
`
`
`wherein R‘ denotes a benzyl group can be used instead of Intennediate B. The lntennediate A can be used in the form
`of a racemic mixture or of optically active compounds (similar to lnterrnediate B).
`[0040] Benzylic monoesters represented by th