EP 0 831 799 B1
`
`Table 2
`
`Structuza
`
`compound
`
`aad
`
`cherapout .1. c
`
`blocker: coronary
`vasodilacor
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 1501
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 1501
`
`

`
`EP 0 831 799 B1
`
`_pnen:.ra:n.1.ne
`( antihistamine )
`
`chlorpheniramine
`
`(antihistamine)
`
`brompheniramine
`
`(antihistamine)
`
`diphenhydraznine
`(antihistamine)
`
`doxylamine
`
`(antihistamine:
`
`hypnotic)
`
`chlozcyclizine
`
`(antihistamine)
`
`cyclizine
`
`(antiemetic)
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`55
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 1502
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 1502
`
`

`
`EP 0 831 799 B1
`
`nor-cyclzzine
`(pharmaceutical
`
`intermediate )
`
`desipramine
`
`(antidepressant)
`
`protriptyline
`
`(antidepressant)
`
`lidoflazine
`
`(calcium channel
`
`blocker; coronary
`
`vasodilator)
`
`pimczide
`
`( antipsycho tic )
`
`.- disopyramide
`
`(antiarrhythmic )
`
`isopropamide
`
`(ancicholinergic)
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`56
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 1503
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 1503
`
`

`
`EP 0 831 799 B1
`
`pridinol
`(anticholinergic:
`
`antiparkinsonian)
`
`lchloropyramine
`(antihistamine)
`
`trihexyphenidyl
`
`tanticholinergic;
`
`antiparkinsenien)
`
`fluoxetine
`
`(antidepressant)
`
`zimeldine
`
`(antidepressant)
`
`methadone
`
`(opiate analgesic)
`
`Astra compoundb
`
`(ant;depressant)
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`.
`
`not tested
`
`57
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 1504
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 1504
`
`

`
`
`
`
`Nova-Nordisk
`
`compounds:
`
`(calcium channel
`
`blocker:
`
`
`
`neuroprocectant)
`
`EP 0 831 799 B1
`
`(“*3
`©\/\»N\/\,‘CHa
`
`O
`
`I act tested
`
`'
`
`.
`
`F50
`
`
`
`Nova-Ncrdisk
`
`N
`
`(EH:
`Kc”:
`
`
`
`
`
`
`23.3
`
`not tested
`
`
`
`(xnonoamine uptake
`
`inhibitor:
`
`antidepressant)
`
`cerodiline
`
`(calcium channel
`
`
`
`blocker:
`
`ancicholinergic;
`
`vasodilator)
`
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`58
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 1505
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 1505
`
`

`
`EP 0 831 799 B1
`
`"Inhibition of NMDA/glycine-induced increases in intracellular
`
`calcium in cultured rat cerebellar granule cells (RCGC's)
`Example 1).
`-
`
`(see
`
`":Disc1osed as compound 2 in Table 4
`
`in Marcusson er: al.,
`
`Inhibition of Pfllparoxetine binding by various serotonin
`uptake inhibitors: struccure—activity relationships. Europ. J.
`Pharinacol. 215: 1912198. 1992.
`
`° : Disclosed
`
`as
`
`compound
`
`1 7
`
`in
`
`Jakobsen
`
`e t
`
`al . ,
`
`Aryloxy-phenylpropylamines and their calcium overload blocking
`
`compositions and methods of use. U.s. Patent No. 5,310,756,
`
`May 10.
`
`.1994.
`
`Mbisclosed
`
`as
`
`compound
`
`25.
`
`in
`
`Jakobsen
`
`ex:
`
`.31.,
`
`Aryloxy-plhzenylpropylamines and their calcium overload blocking
`
`compositions and methods of use. U.s. Patent: No. 5,310,756,
`
`may 10, 1994.
`
`'
`
`Structure-activity relationship studies were initiated using Compound 19 (Reference compound) as the lead
`[0337]
`structure. An examination of the side chain demonstrated that the propyl side chain was optimal for NMDA receptor
`antagonist potency (Table 3).
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
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`55
`
`59
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`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 1506
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 1506
`
`

`
`EP 0 831 799 B1
`
`Strufitura
`
`2 , 2-diplienylechylamine
`
`3,3-diphenyhprqpylamine
`
`(compound 19)
`
`454-diphenjlbutylamine
`(compound 70)
`
`.
`
`1.7
`
`S . S-diphenylpentylamine
`
`(compuund 71)
`
`2.2-hist3-fluoruphenyli'1-
`
`ethyianine
`
`(compound 98)
`
`4 , 6-bistl-£1uoroPh9nY1) -1-
`
`hutykmfine
`
`‘tcampound 100)
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`-: Inhibition
`
`pf
`
`NMDA/Qlycine-induced
`
`‘increases
`
`in
`
`intracellular calcium in cultured rat cerebellar granule cells
`
`-(‘RCGC's)
`
`(see Example 1).
`
`[0338]
`
`Further SAR studies examined the optimal pattern of phenyl ring substitution. Initial studies demonstrated
`
`60
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 1507
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 1507
`
`

`
`EP 0 831 799 B1
`
`that substitution of a halogen group (fluoro or chloro) at the meta position was optimal for NMDA receptor antagonist
`potency (Table 4). Increasing the number of fluoro substituents led to an apparent decrease in potency (Table 4).
`
`4
`
`compound
`
`Structure
`
`-.r:a:n1'e
`
`
` 3', 3-diphenyl-1-prapylamine
`(Compound -19)
`
`
`
`
` . 3—(2-£1uazo_oheny1);3—¢4_-
`
`£1uorophe§y'l)—1-
`propy1an;ne'
`(Compound 76)
`
`-
`
`' 3 . 3'-bis (4—£.'l.uoro’phe.ny1)-1-‘
`
`
`
`{Compound 77)
`
`(3-f1uarophe.ny1)~1-
`
` 3-(3.s-d5.£1uo:opha:y1)-3-
`
`d .
`
`Hcauapcixncl sis)’
`
`
`
`
`bis (3. 5.d.'i.£1uorophenyJ.)-1-
`
`
`prapylanine
`
`(Compound .97)
`
` 3 ,3— ,
`
`
`
`( tri£1u.oromet:hy1)pheny1] -
`
` 3 . 3-1515 [3-
`
`
`1-propylamine
`
`.
`’ mampound vs)
`
`
`61
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 1508
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 1508
`
`

`
`EP 0 831 799 B1
`
`in
`increaees‘
`.NMDA/glycine-induced
`'of
`':Iafiibition
`intracellular calcium in cultured rat cerebellar granule cells
`
`(RCGC's)
`
`(see Example 1) .
`
`[0339] Replacement of one of the fluoro groups on one phenyl ring with a methyl, methoxy or hydroxy group led to
`no change or a decrease in the in vitro NMDA receptor antagonist potency. The ortho position was optimal for this
`methyl, methoxy or hydroxy group, and the rank order of potency for this substitution was methyl > methoxy > hydroxy
`(Table 5). Also illustrated in Table 5 are those compounds possessing the 3.3-bis(3-fluorophenyl) moiety with additional
`methyl or methoxy substitutions on the phenyl rings, often leading to an increase in NMDA receptor antagonist potency.
`Table 5 also illustrates those compounds possessing the 3,3-bis(2-methylphenyl) or 3,3-bis(2-methoxyphenyl) moiety
`in place of the 3,3-bis(3-fluorophenyl) moiety; these substitutions are acceptable. although a decrease in potency is
`noted.
`
`3- (2-metho:=ypbe-nY1l43-
`phenyl-1 -_pray'y1am:i.ne
`(Compound 97)
`
`3~t3—hyd:¢°=215henY1l -3-‘3-
`. fluorophenylt -1-
`
`[Cumpound 101)
`
`3-(3-fluoéophenyli-3-(2-
`methy1—3-flunrophenyll -1-
`
`propyianiine
`rccnipouna 5;),
`
`'
`
`3-i3—£1uo:ophe$y1)r3-(3-
`f1uoro- 6-methylphenyl) -1-
`
`propylamine
`
`tcampound 57)
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`62
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 1509
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 1509
`
`

`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`EP 0 831 799 B1
`
`3,3-bis(3-£luorc—6-
`
`mechylphenyl ) - 1 -
`
`propylamine
`icompound 5st‘
`
`3- (3—f1uorophenyl) -3- (3'-
`
`fluoro-S-methoxyphenyl) -1-
`propylamine
`
`.
`
`(compound ‘ 61) .
`
`3 , 3 —bis (2-methylphenyl) -1-
`
`propylamine
`I (Compound 65)
`
`3 . 3—bis (2-methoxyphenyl) -
`
`'
`
`1-piropylamine
`
`(Compound.€2)
`
`3 , 3 -his (3-methoxyphenyll -
`V
`1-propylamine
`
`(compound 11.5)
`
`.
`
`':Inhibition
`
`'NM®A/glycine-induced
`of
`increases .
`in
`' intracellular calcium in. cultured rat cerebellar. granule cells
`
`(RCGC's)
`
`(see Example 1);
`
`[0340] The next series of SAR experiments investigated the effect of alkyl chain substitutions (branching patterns)
`on NMDA receptor antagonist potency in vitro. The addition of a methyl group on eitherthe a or [3 carbon on the propyl
`side chain led to a decrease or no change in potency. respectively (Table 6).
`
`63
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 1510
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 1510
`
`

`
`EP 0 831 799 B1
`
`3,3-hists-sluoeophenyli-2-
`ethyl-1-piupyiamine
`
`(campbma 55)
`
`tcamiaoxmfi S4)
`
`ethyl-1-.-propylamine
`
`
`
`3 . 3-his (3-fluorcphenyl) -
`2 . 2-diethyl-1-propylamina
`
`
`
`{CDmpO1.:.nd 80)
`
`
`
`~ Inhibition
`
`of
`
`NMDAI glycine - induced
`
`A
`
`increases
`
`in
`
`intracellular calcium in cultured rat cerebellar granule cells
`
`(RCGC's)
`
`(see Example 1).
`
`[0341] The next series of SAR experiments investigated the effect of incorporation of a double bond within the propyl
`chain on HMDA receptor antagonist potency in vitro (Table 7). As can be seen in Table 7. the incorporation of a double
`bond decreased potency in a consistent manner.
`
`64
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 1511
`
`
`
`3 , 3-b:i.s(3-£luu':-:cphe:ny1)-3-
`
`tconipouznd 82)
`
`10
`
`20
`
`25
`
`30
`
`45
`
`50
`
`55
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 1511
`
`

`
`3 , 3 -diphen}-1-1-prdpylamine
`
`(Cémpound 19) '
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`3 . 3-sis (3-flu
`
`prcp-2-ene-1-amine
`
`(Cmipaund 139)
`
`
`
`EP 0 831 799 B1
`
`65
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 1512
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 1512
`
`

`
`10
`
`20
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`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`EP 0 831 799 B1
`
`3 , 3 -d1phenyl—prap-2-ene-1-
`
`amine
`
`(Compound 5:.)
`
`.
`
`3-(3-£1u.o:copheny1)-3- '
`phenyli-{atop-2'-ene-1-amine
`
`(compound 107)
`
`1-propylamine
`
`(Compound 115)
`
`3 , 3-bis(3-met.hoxyp1:tenyl)-
`prob-2-ene-1-amine
`(Compound 116)
`
`13:11.-fizibition .
`
`of
`
`Mt/IDA/glycine- indticed
`intracellular calcium in cultured-rat: cerebellar granuie ce1_1s
`(RCGC's)
`(see_Example 1) .
`
`increases
`
`in
`
`[0342] The next series of SAR experiments investigated the effect of incorporation of the propylamine chain into a
`ring structure on NMDA receptor antagonist potency in vitro (Table 8).
`
`66
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 1513
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 1513
`
`

`
`EP 0 831 799 B1
`
`‘£31313 '8
`
`-Compound
`
`
`
` _.____:%. _._..:_.j_..:.
`
`3 , 3 -his (3-fluorophenyl) -1.-
`
`propylamine
`
`(Compound 20)
`
`Compound 63
`
`compound 102
`
`Compotmd 112
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`67
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 1514
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 1514
`
`

`
`EP 0 831 799 B1
`
`of
`‘:Inhibition
`NMDA/glycine-induced
`intrace1lu_1ar calcium in cultured rat cerebellar gfanule cells
`
`increases
`
`in
`
`(RCGC's)
`
`tsee.Examp1e 1).
`
`[0343] The next series of SAR experiments investigated the effect of simple alkyl substitution on the nitrogen on
`NMDA receptor antagonist potency in vitro (Table 9).
`
`'
`
`'1.'_a.h1a 9
`
`3,3-bmauorophenyli-1~
`propylemine
`
`(Compound 20')
`
`n-med.-.yJ.-3",. 3-2315 (:4- '
`fluorophenyl) -1-
`- grapylamine
`
`N-ethyl-3 . 3 -bis (3-
`
`n, H-dinethyl-3 .3—15is (3-
`fluoruphenyll -1-
`
`(ceiapozmd 133)
`
`3 . 3-diphenylpropylanfine
`
`[compound 19)
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`68
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 1515
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 1515
`
`

`
`10
`
`15
`
`20
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`25
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`30
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`35
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`40
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`45
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`55
`
`EP 0 831 799 B1
`
`N-methyl-3 , 3-
`diphenylpropylamine
`
`(Compound 67)_ "
`
`diphenylprcpylamine
`
`(Compound 68)
`
`N.N-dimet:.hy1—3 . 3-
`
`-giphenylpropylamine
`(Compound 73)
`
`N-isopropyl-3 , 3-
`
`dipheuylpropylamine
`(compound 72)
`
`N:
`
`I 3 -
`
`diphenylpropylamine
`‘
`(coxnpci:'.nd'
`'74)
`
`H
`
`in
`increases
`NMDA/glycine-induced
`of
`“zlnbibition
`intracellular calcium in cultured rat: cerebellar granule cells‘
`
`(RCGC'sl
`
`(see Example 1).
`
`[0344] Certain simplified arylalkylamine compounds were selected for evaluation of activity in a battery of neuro-
`transmitter receptor binding assays, and for activity against the L-type calcium channel and delayed rectifier potassium
`channel. The compounds were inactive (less than 50% inhibition at concentrations up to 10 ).M) in the following assays:
`nonselective a2 adrenergic receptor ([3H]RX 821002 binding in rat cortex). H1 histamine receptor ([3H]pyrilamine bind-
`ing in bovine cerebellum), nonselective sigma receptor ([3H]DTG binding in guinea pig brain), nonselective opiate
`receptor ([3H]naloxone binding in rat forebrain), monoamine oxidase (MAO) activity, both MAO-A ([140] serotonin me-
`tabolism in rat liver mitochondria) and MAO-B ([14C]phenylethylamine metabolism in rat liver mitochondria).
`[0345] As can be seen in Table 10, activity was noted for several compounds at concentrations below 10 pM in the
`following assays: L-type calcium channel. delayed rectifier potassium channel, central muscarinic cholinergic receptor
`binding, and monoamine (dopamine, norepinephrine, and serotonin) uptake binding assays. This profile of activity in
`the central muscarinic cholinergic receptor and monoamine uptake binding assays is not unexpected, given the chem-
`ical structures of our simplified arylalkylamines (refer to Table 2 above). With the exceptions, however. of the activity
`
`69
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 1516
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 1516
`
`

`
`EP 0 831 799 B1
`
`of Compounds 63 and 64 in the dopamine uptake binding assay, and the activity of Compound 60 in the dopamine
`and serotonin uptake binding assays. the simplified arylalkylamine compounds were most potent at the NMDA receptor.
`
`Table 10
`
`Compound
`
`lC50 (pM) vs.
`NMDAB
`
`L-type calcium
`channel”
`
`Compound 63
`
`0.093
`
`Delayed
`rectifier
`
`potassium
`channelc
`
`not tested
`
`Central
`miscarinic
`
`cholinergic
`receptor“
`
`11 % at 0:1 B1 % at
`10
`
`Compound 64
`
`0.309
`
`not tested
`
`not tested
`
`11% at 0.183% at
`10
`
`Compound 58
`
`0.028
`
`1.6
`
`'
`
`not tested
`
`1% at 0.148% at
`10
`
`Compound 59
`
`0.272
`
`not tested
`
`not tested
`
`9% at 0.187% at
`10
`
`Compound 60
`
`0.416
`
`2.3
`
`not tested
`
`13% at 0.193% at
`10
`
`Monoamine
`
`uptake binding
`assays‘’
`
`64% at 0.11980/o
`at 10'7% at
`0.1976"/o at
`10913% at
`0.1“85% at 10"
`
`50% at 0.199%
`at 10f 8% at
`0.1965% at
`10929% at
`0.1"68% at 10"
`
`0% at 0.1f45°/o at
`1011 "/0 at
`0.1967% at
`10927% at
`0.1h95% at 10“
`
`2% at0.1‘78% at
`10‘7% at
`0.1951"/o at
`10914% at
`0.1h86% at 10"
`
`0.914'16% at
`O.1964% at 109
`0.068“
`
`azlnhibition of NMDA/glycine-induced increases in intracellular calcium in cultured rat cerebellar granule cells (RCGC's) (see Example 1).
`bzlnhibition of KCl depolarization-induced increases in intracellular calcium in cultured rat cerebellar granule cells (RCGCs); estimated IC50 value
`in pM.
`
`czlnhibition of delayed rectifier potassium channel in cultured N1E-115 neuroblastoma cells; estimated lC50 value in pM.
`dzlnhibition of the binding of [3H]quinuclidinylbenzilate (QNB) to rat cortical membranes; percent block at indicated concentration in p.M.
`ezlnhibition of the binding of [3H]WlN-35,428 to guineafig striatal membranes (dopamine uptake binding assay), [3H]desipramine to rat cortical
`membranes (norepinephrine uptake binding assay). or [ Hlcitalopram to rat forebrain membranes (serotonin uptake binding assay); percent block
`at indicated concentration in 11M, or |C50 when available.
`~
`fzdopamine uptake binding assay
`Qznorepinephrine uptake binding assay
`hzserotonin uptake binding assay
`
`[0346] Advantageous properties of the arylalkylamine compounds of the present invention are illustrated by the fact
`that concentrations which suppress NMDA receptor-mediated synaptic transmission fail to inhibit LTP.
`
`Formulation and Administration
`
`[0347] As demonstrated herein, useful compounds of this invention and their pharmaceutically acceptable salts may
`be used to treat neurological disorders or diseases. While these compounds will typically be used in therapy for human
`patients, they may also be used to treat similar or identical diseases in other vertebrates such as other primates, farm
`animals such as swine, cattle and poultry. and sports animals and pets such as horses, dogs and cats.
`[0348]
`In therapeutic and/or diagnostic applications, the compounds of the invention can be formulated for a variety
`of modes of administration, including systemic and topical or localized administration. Techniques and formulations
`generally may be found in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton PA.
`[0349]
`Pharmaceutically acceptable salts are generally well known to those of ordinary skill in the art, and may
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`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 1517
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`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 1517
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`

`
`EP 0 831 799 B1
`
`include, by way of example but not limitation, acetate, benzenesulfonate, besylate, benzoate, bicarbonate, bitarcrace,
`calcium edetate, camsylate, carbonate, citrate, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate,
`glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, io-
`dide, isethionate, lactate, lactobionace, malate, maleate, mandelate, mesylate, mucate, napsylate, nitrate, pamoate
`(embonate), pantothenate, phosphate/disphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate,
`sulfate, tannate, tartrate, or teoclate. Other pharmaceutically acceptable salts may be found in, for example, Reming-
`ton's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA (18th ed, 1990).
`[0350] Preferred pharmaceutically acceptable salts include, for example, acetate, benzoate, bromide, carbonate,
`citrate, gluconate, hydrobromide, hydrochloride, maleate, mesylate, napsylate pamoate (embonate), phosphate, sal-
`icylate, succinate, sulfate, or tartrate.
`[0351] The useful compounds of this invention may also be in the form of pharmaceutically acceptable complexes.
`Pharmaceutically acceptable complexes are known to those of ordinary skill in the art and include, by way of example
`but not limitation, B-chlorotheophyllinate (teoclate).
`[0352] The exact formulation, route of administration and dosage can be chosen by the individual physician in view
`of the patient's condition. (See gg_. Fingl et al., in The Pharmacological Basis of Therapeutics, 1975, Ch. 1 p. 1).
`[0353]
`It should be noted that the attending physician would know how and when to terminate, interrupt, or adjust
`administration due to toxicity or organ dysfunction. Conversely, the attending physician would also know to adjust
`treatment to higher levels if the clinical responses were not adequate (precluding toxicity). The magnitude of an ad-
`ministered dose in the management of the disorder of interest will vary with the severity of the condition to be treated
`and to the route of administration. The severity of the condition may, for example, be evaluated in part, by standard
`prognostic evaluation methods. Further, the dose and perhaps dose frequency, will also vary according to the age,
`body weight, and response of the individual patient. A program comparable to that discussed above may be used in
`veterinary medicine.
`[0354] Depending on the specific conditions being treated, such agents may be formulated into liquid or solid dosage
`fonns and administered systemically or locally. The agents may be delivered, for example, in a timed or sustained-
`release form as is known to those skilled in the art. Techniques for formulation and administration may be found in
`Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA. Suitable routes may include oral, buccal,
`sublingual, rectal, transdermal, vaginal, transmucosal, nasal or intestinal administration; parenteral delivery, including
`intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, in-
`traperitoneal, intranasal, or intraocular injections, just to name a few.
`[0355]
`For injection, the agents of the invention may be formulated in aqueous solutions, preferably in physiologically
`compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. For such transmucosal
`administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are
`generally known in the art.
`[0356] Use of pharmaceutically acceptable carriers to formulate the compounds herein disclosed for the practice of
`the invention into dosages suitable for systemic administration is within the scope of the invention. With proper choice
`of carrier and suitable manufacturing practice, the compositions of the present invention, in particular, those formulated
`as solutions, may be administered parenterally, such as by intravenous injection. The compounds can be formulated
`readily using pharmaceutically acceptable carriers well known in the art into dosages suitable for oral administration.
`Such carriers enable the compounds of the invention to be formulated as tablets, pills, capsules, liquids, gels, syrups,
`slurries, suspensions and the like, for oral ingestion by a patient to be treated.
`[0357] Agents intended to be administered intracellularly may be administered using techniques well known to those
`of ordinary skill in the art. For example, such agents may be encapsulated into liposomes, then administered as de-
`scribed above. Liposomes are spherical lipid bilayers with aqueous interiors. All molecules present in an aqueous
`solution at the time of liposome formation are incorporated into the aqueous interior. The liposomal contents are both
`protected from the external microenvironment and, because liposomes fuse with cell membranes, are efficiently de-
`livered into the cell cytoplasm. Additionally, due to their hydrophobicity, small organic molecules may be directly ad-
`ministered intracellularly.
`[0358] Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active
`ingredients are contained in an effective amount to achieve its intended purpose. Determination of the effective amounts
`is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
`[0359]
`In addition to the active ingredients, these pharmaceutical compositions may contain suitable pharmaceuti- -
`cally acceptable carriers comprising excipiencs and auxiliaries which facilitate processing of the active compounds
`into preparations which can be used pharmaceutically. The preparations formulated for oral administration may be in
`the form of tablets, dragees, capsules, or solutions.
`[0360] The pharmaceutical compositions of the present invention may be manufactured in a manner that is itself
`known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encap-
`sulating, entrapping or lyophilizing processes.
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`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 1518
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`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 1518
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`

`
`EP 0 831 799 B1
`
`Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds
`[0361]
`in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection
`suspension. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid ester,
`such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which
`increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the
`suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for
`the preparation of highly concentrated solutions.
`[0362]
`Pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid
`excipients, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxil-
`iaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including
`lactose, sucrose, mannitol, or sorbitol; cellulose preparations, for example, maize starch, wheat starch, rice starch,
`potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellu-
`lose (CMC), and/or polyvinylpyrrolidone (PVP: povidone). If desired, disintegrating agents may be added, such as the
`cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
`[0363] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be
`used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol (PEG.,
`and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dye-stuffs or pigments
`may be added to the tablets or dragee coatings for identification or to characterize different combinations of active
`compound doses.
`[0364]
`Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as
`soft, sealed capsules made of gelatin, and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain
`the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc
`or magnesium stearate and, optionally, stabilizers. in soft capsules, the active compounds may be dissolved or sus-
`pended in suitable, liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols (PEGS). In addition, stabilizers
`may be added.
`[0365] Other embodiments are within the following claims.
`
`Claims
`
`1. Use of a compound which is selected from the group consisting of
`
`0-H
`
`
`
`’ Compound 5%
`
`
`
`Compcund 55
`
`
`
`Compound -'56
`
`Conrpounfi S 7
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`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 1519
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`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 1519
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`

`
`EP 0 831 799 B1
`
`
`
`
`.u\'.,_CH;.'
`
`‘O
`Q
`
`Compound 55
`
`CH; .
`
`NH;
`
`0
`
`0 F
`
`F
`
`Compound 5
`
`8
`
`
`
`Comgaund 64
`
`. :1
`
`‘ca;
`
`O
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`Cpmpound 67
`
`Cflffipound ‘6a_
`
`Compcund 69
`
`73
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`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 1520
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`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 1520
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`

`
`C<=mpauna_ 72
`
`C°mPcund 75 '
`
`cg. G ma"
`0
`
`ca
`
`Compougd 73
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`EP 0 831 799 B1
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`Compound 76
`
`~ Compound 77
`
`NH;
`
`Ix \'
`
`/
`
`F
`
`Compeuni 73
`
`74
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 1521
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`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 1521
`
`

`
`0 NH
`OH
`
`F
`
`Compound '84
`
`
`
`C°mP_ou.nc7. 97
`
`EP 0 831 799 B1
`
`
`
`Compound 85
`
`(m.ixcu.re of 2
`
`.coq:pou1ids)
`
`O °~’—‘NH;
`0
`
`F
`
`'
`
`N}-I1.’
`
`NH '
`
`O '
`
`‘ F
`
`NH:
`
`5 /
`
`F
`
`Cor-npound 88.
`
`Compound -'89 _
`
`Campouhd E _O
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`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 1522
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`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 1522
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`

`
`EP0831799B1
`
`Compound ‘S1 '
`
` Cmnpound _92
`
`
`
`Compound 57
`
`Congound S 8
`
`
`
`
`
`Compcund 100
`
`Compéund 101'
`
`'Compau_.nd 102
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`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 1523
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`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 1523
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`

`
`EP 0 831 799 B1
`
`
`
`Compound 103
`
`
`
`.Cofipoupd 105
`
`
`
`Compound 106
`
`
`
`Campouni lbs
`
`Cpmpound 107
`
`(mixture of 2
`
`compounds)
`
`
`
`,qémpound 109~
`
`
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`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 1524
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`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 1524
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`

`
`EP 0 831 799 B1
`
`
`
`Comlaounci 114
`
`
`
`
`
`H:CO
`
`Compouna 115
`
`Compound 116
`
`Compound 117
`
`compouzid .118
`
`' Compound. 119
`
`C.c>mpo'un'd 1&0
`
`g©Yw
`Q.
`'
`
`/
`
`GEM
`Compoufié 121
`
`‘El
`
`cbfipouné 122
`
`Compound 123
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`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 1525
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`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 1525
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`

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`EP 0 831 799 B1
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`NH;
`
`.
`F“
`
`Compound 124
`
`
`
`‘ 0
`
`I8
`
`NH: '
`
`Compound 12?
`
`Compound 12,8
`
`
`
`
`
`E.-ampouna 130
`
`Cdmpouna 131:
`
`©.
`Corqppnn-.iéI 132
`
`Na:
`
`C1
`
`écmpounfi 13 3
`
`.
`
`Ccmpozmd 1.32
`
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`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 1526
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`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 1526
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`

`
`EP 0 831 799 B1
`
`
`
`_Cam-pound 135
`
`Campound 1_37.
`
`
`
`camnouné 1&5 .
`
`Couaound 143
`
`
`
`H:
`
`‘
`
`CORDOUJEE 141
`
`0
`
`Compound ‘Lu
`
`CF
`
`cawafind 14; '
`
`cor»-‘pound 1.1.5
`
`80
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 1527
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`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 1527
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`

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`
`c/©\,/\z""'2
`c.\©,°
`,-
`Compound 149p
`
`.-.
`
`-.
`
`EP 0 831 799 B1
`
`-0,
`
`Corxpouad 143
`
`_ ~©/
`
`—
`
`Ccnqadund 150- '
`
`, and pharmaceutically acceptable salts and complexes thereof for the preparation of a pharmaceutical com-
`position for the treatment of a neurological disease or disorder.
`
`The use according to claim 1, wherein the compound is selected from the group consisting of compounds 54-66,
`68-71,75,76,78,79,81-90,92-98,100,101,103,105,106,108,109,111,114-122,124-136,138,139,141-144,
`148-150, and pharmaceutically acceptable salts and complexes thereof.
`
`The use according to claim 1. wherein the compound is selected from the group consisting of compounds 54-66,
`69, 70, 75,76, 81-83, 85-97, 100- 103, 105, 106, 108, 109, 111, 115, 118-122, 125-133,135-139, 142, 144-150,
`and pharmaceutically acceptable salts and complexes thereof.
`
`The use according to claim 1, wherein the compound is selected from the group consisting of compounds 54-66,
`69, 70, 75, 76, 81-83, 85-90, 92-97, 100, 101, 103, 105, 106, 108, 109, 111, 115, 118-122, 125-133, 135, 136, 138,
`139, 142, 144, 148-150, and pharmaceutically acceptable salts and complexes thereof.
`
`The use according to claim 1, wherein the compound is selected from the group consisting of compounds 54-66,
`69, 82, 83, 89-97, 103, 111, 118-120, 122, 126, 135-138, 142, 144, 145, 147-150, and pharmaceutically acceptable
`salts and complexes thereof.
`
`The use according to claim 1, wherein the compound is selected from the group consisting of compounds 54-66.
`69, 82, 83, 89-90, 92-97, 103, 111, 118-120, 122, 126, 135, 136, 138, 142, 144, 148-150, and pharmaceutically
`acceptable salts and complexes thereof.
`
`The use according to claim 1, wherein the compound is selected from the group consisting of compounds 60, 66,
`69, 103, 111, 118-120, 122, 136, 138, 142, 144, 148-150, and pharmaceutically acceptable salts and complexes
`thereof.
`
`The use according to claim 1, wherein the compound is selected from the group consisting of compounds 118-122.
`137, 145, 148-150, and pharmaceutically acceptable salts and complexes thereof.
`
`The use according to claim 1, wherein the compound is selected from the group consisting of compounds 118-122,
`148-150, and pharmaceutically acceptable salts and complexes thereof.
`
`81
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`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 1528
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`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 1528
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`

`
`EP 0 831 799 B1
`
`10. The use according to claim 1, wherein the compound is selected from the group consisting of compounds 63 and
`64 and pharmaceutically acceptable salts and complexes thereof.
`
`11. The use according to claim 1. wherein the compound is selected from compound 119. and pharmaceutically ac-
`ceptable salts and complexes thereof.
`‘
`
`12. The use according to claim 1, wherein the compound is selected from compound 144. and pharmaceutically ac-
`ceptable salts and complexes thereof.
`
`13. The use of compound 60, and pharmaceutically acceptable salts and complexes thereof for the preparation of a
`pharmaceutical composition for the treatment of a neurological disease or disorder.
`
`14. Use of a compound having the formula:
`
`
`
`wherein:
`
`X is independently selected from the group consisting of -Br, -Cl, -F, -l,-CF3, alkyl, -OH, -OCF3, -O-alkyl, and
`-O-acyl;
`R1 is independently selected from the group consisting of -H, C1-C4 alkyl, and -O-acyl;
`R2 is independently selected from the group consisting of -H, alkyl, and hydroxyalkyl, or both R23 together are
`mine;
`
`R4 is phenoxy which is optionally substituted with -F, -Cl, -Br, -I, -CF3, alkyl, -OH,- OCF3-O-alkyl, or -O-acyl; and
`m is independently an integer from 0 to 5; and pharmaceutically acceptable salts and complexes thereof pro-
`vided that said compound is not:
`3-(p-isopropoxyphenoxy)-3-phenylpropylamine
`3-(2'-methyl-4',5'-dichlorophenoxy)-3—phenylpropylamine
`3-(p-t-butylphenoxy)-3-phenylpropylamine
`3-(2',4‘-dichlorophenoxy)-3-phenyl-2-methyl propylamine
`3—(o-ethylphenoxy)-3-phenylpropylamine
`3-(o—methoxyphenoxy)-3-phenylpropylamine
`3-phenoxy-3-phenylpropylamine
`
`for the preparation of a pharmaceutical composition for the treatment of a neurological disease or disorder.
`
`15. Use of a compound having the formula
`
`wherein:
`
`
`
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`Patent Owner, UCB Pharma GmbH — Exhibit 2011 - 1529
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`Patent Owner, UCB Pharma GmbH – Exhibit 2011 - 1529
`
`

`
`EP 0 831 799 81
`
`X is independently selected from the group consisting of-F, -CI, -Br, -I. -CF3 alkyl, -OH. -OCF3. -O-alkyl, and
`-O-acylz
`R, is independently selected from the group consisting of -H, C1-C4 alkyl, and -O-acyl;
`R2 is independently selected from the group consisting of -H, C1-C4 alkyl, and hydroxyalkyl, or both Rzs to-
`gether are imino;
`'
`-
`R3 is selected from the group consisting of methyl and ethyl;
`R4 is phenoxy which is optionally substituted with -F, -Cl. -Br, —I, -CF3, alkyl, -OH, —OCF3. -O-alkyl, or -O-acyl;
`and m is independently an integer from 0 to 5; and pharmaceutically acceptable salts and complexes thereof
`provided that said compound is not
`N-methyl 3-(o-chIoro-p-tolyloxy)-3-phenyl—1—methylpropy|amine
`N-methyl 3-(p-to|y|oxy)-3-phenylpropylamine
`N-methyl 3-(o-ch|oro-p-isopropylphenoxy)-3-phenyl-2-methylpropylamine
`N-methyl 3-(p-iodophenoxy)-3-phenyl-propylamine
`N-methyl 3-(3-n propylphenoxy