PCT
`
`WORLD INTELLECTUAL, PROPERTY ORGANIZATION
`International Bureau
`
`
`
`(22) International Filing Date:
`
`13 November 1998 (13.11.98)
`
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`
`
`(51) International Patent Classification 6;
`WO 99/35131
`(11) International Publication Number:
`CO7D 221/22, A6G1K 31/435, C07D
`
`
`
`(43) International Publication Date:
`15 July 1999 (15.07.99)
`471/08, 498/08, 513/08
`
`
`
`(21) International Application Number: PCT/IB98/01813|(81) Designated States: AL, AM, AT, AU, AZ, BA, BB, BG, BR,
`
`BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE,
`
`
`GH, GM, HR, HU,ID,IL, IS, JP, KE, KG, KP, KR, KZ,
`LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, Mw,
`MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL,
`
`TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW, ARIPO
`patent (GH, GM,KE, LS, MW,SD,SZ, UG, ZW), Eurasian
`patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European
`patent (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR,
`IE, IT, LU, MC, NL, PT, SE), OAPI patent (BF, BJ, CF,
`CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG).
`
`(30) Priority Data:
`60/070,245
`
`31 December 1997 (31.12.97)
`
`US
`
`PFIZER
`(71) Applicant (for all designated States except US):
`PRODUCTS INC. [US/US]; Eastern Point Road, Groton,
`CT 06340 (US).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): COE, Jotham, Wadsworth
`[US/US]; 8 Bush Hill Drive, Niantic, CT 06357 (US).
`BROOKS, Paige, Roanne, Palmer [US/US]; 9 Wyassup
`Road, North Stonington, CT 06359 (US).
`
`Published
`With international search report.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(74) Agents: SPIEGEL, Allen, J. et al.; Pfizer Inc., 235 East 42nd
`Street, New York, NY 10017 (US).
`
`
`
`(54) Titles ARYL FUSED AZAPOLYCYCLIC COMPOUNDS
`
`R?
`
`R°
`
`R’
`
`()
`
`(57) Abstract
`
`Compounds of formula (1) and their pharmaceutically acceptable salts, wherein R!, R2, R? and n are defined as in the specification,
`intermediates in the synthesis of such compounds, pharmaceutical compositions containing such compounds and methods of using such
`compounds in the treatment of neurological and psychological disorders are claimed.
`
`Apotex Exhibit 1005.001
`
`Apotex Exhibit 1005.001
`
`

`

`Zw Slovenia
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`ES
`Albania
`FI
`Armenia
`FR
`Austria
`Australia
`GA
`GB
`Azerbaijan
`GE
`Bosnia and Herzegovina
`Barbados
`GH
`GN
`Belgium
`Burkina Faso
`GR
`HU
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`Céte d’Ivoire
`Cameroon
`China
`Cuba
`Czech Republic
`Germany
`Denmark
`Estonia
`
`SI
`sk
`SN
`8Z
`TD
`TG
`TJ
`TM
`TR
`TT
`UA
`UG
`us
`UZ
`VN
`YU
`
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Turkmenistan
`Turkey
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`Viet Nam
`Yugoslavia
`Zimbabwe
`
`Apotex Exhibit 1005.002
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democratic People’s
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SG
`
`Lesotho
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`The former Yugoslav
`Republic of Macedonia
`Mali
`Mongolia
`Mauritania
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`
`Apotex Exhibit 1005.002
`
`

`

`WO 99/35131
`
`PCT/IB98/01813
`
`ARYL FUSED AZAPOLYCYCLIC COMPOUNDS
`
`Background of the Invention
`invention relates to aryl
`fused azapolycyclic compounds, as defined more
`This
`specifically by formula | below. Compoundsof formula | bind to neuronal nicotinic acetylcholine
`specific receptor sites and are useful in modulating cholinergic function. Such compounds are
`useful in the treatment of inflammatory bowel disease (including but notlimited to ulcerative
`colitis, pyoderma gangrenosum and Crohn's disease),
`irritable bowel syndrome, spastic
`dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panic
`disorder, depression, bipolar disorder, autism, sleep disorders,
`jet
`lag, amylotropic lateral
`sclerosis
`(ALS), cognitive dysfunction, hypertension, bulimia,
`anorexia, obesity, cardiac
`arrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supramuscular
`palsy, chemical dependencies and addictions (e.g., dependencies on, or addictions to nicotine
`(and/or
`tobacco products),
`alcohol, benzodiazepines, barbituates, opioids or cocaine),
`headache, stroke,
`traumatic brain injury (TBI), obsessive-compulsive disorder, psychosis,
`Huntington's Chorea,
`tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct
`dementia, age related cognitive decline, epilepsy,
`including petit mal absence epilepsy, senile
`dementia of the Alzheimer's type (AD), Parkinson's disease (PD), attention deficit hyperactivity
`disorder (ADHD) and Tourette’s Syndrome.
`
`invention may also be used in combination with an
`this
`The compounds of
`antidepressant such as, for example,a tricyclic antidepressant or a serotonin reuptake inhibiting
`antidepressant(SRI), in orderto treat both the cognitive decline and depression associated with
`AD, PD, stroke, Huntington’s Chorea or traumatic brain injury (TBI);
`in combination with
`muscarinic agonists in order to stimulate both central muscarinic and nicotinic receptors for the
`treatment, for example, of ALS, cognitive dysfunction, age related cognitive decline, AD, PD,
`Stroke, Huntington’s Chorea and TBI; in combination with neurotrophic factors such as NGF in
`order to maximize cholinergic enhancementfor the treatment, for example, of ALS, cognitive
`dysfunction, age related cognitive decline, AD, PD stroke, Huntington's Chorea and TBI: orin
`combination with agents that slow or arrest AD such as cognition enhancers, amyloid
`aggregation inhibitors, secretase inhibitors,
`tau kinase inhibitors, neuronal antiinflammatory
`agents and estrogen-like therapy.
`
`10
`
`20
`
`25
`
`30
`
`Apotex Exhibit 1005.003
`
`Apotex Exhibit 1005.003
`
`

`

`WO 99/35131
`
`PCT/AB98/01813
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Other compoundsthat bind to neuronalnicotinic receptorsites are referred to in United
`States Patent Application 08/963,852, which was filed on November 4, 1997. The foregoing
`application is owned in common with the present application, and is incorporated herein by
`referencein its entirety.
`
`Summary of the invention
`This invention relates to aryl fused azapolycyclic compoundsofthe formula
`
`R2
`
`R3
`
`NR’
`
`(1)
`
`(C;-Cg)alkyl, unconjugated (C,-C,)alkenyl, benzyl, XC(=O)R™ or
`
`is hydrogen,
`R'
`-CH,CH,-0-(C,-C,)alkyl:
`R® and R® are selected, independently, from hydrogen, (C>-Ce)alkenyl, (Co-C,)alkynyl,
`nitro,
`amino, halo, cyano,
`-SO,(C,-C,)alkyl wherein q
`is zero, one or
`two,
`hydroxy,
`(C,.Ce)alkylamino-,
`[(C,-Cg)alkyl],amino-,
`-CO,R*,
`-CONR®R®,
`-SO,NR’R®,
`-C(=0)R™,
`-XC(=O)R™, aryl(Co -Ca)alkyl- or aryl-(Cy-C,)alkyl-O-, wherein said aryl is selected from pheny!
`and naphthyl, heteroaryl-(Co-Cz)alkyl- or heteroaryl-(C,-C,)alkyl-O-, wherein said heteroaryl is
`selected from five to seven membered aromatic rings containing from one to four heteroatoms
`selected from oxygen, nitrogen and sulfur, and X?(Cy-Cz)alkoxy-(Cy-Ce)alkyl-, wherein X? is
`absentor X? is (C,-C,)alkylamino- or [(C,-Ce)aikyl],amino-, and wherein the (Co-C,)alkoxy-(Co-
`C,)alkyl- moiety of said X*(Co-Cg)alkoxy-(Co-Ce)alkyl- contains at least one carbon atom, and
`wherein from one to three of the carbon atoms of said (Co-Ce)alkoxy-(Co-Ce)alkyl- moiety may
`optionally be replaced by an oxygen,nitrogen or sulfur atom, with the proviso that any two such
`heteroatoms must be separated by at least two carbon atoms, and wherein any of the alkyl
`moieties of said (Co.C,)alkoxy(Cp-C,)alkyl- may be optionally substituted with from two to seven
`fluorine atoms, and wherein one of the carbon atomsof each ofthe alkyl moieties of said aryl-
`(Co-C)alky!- and said heteroaryl-(C-C,)alkyl- may optionally be replaced by an oxygen, nitrogen
`or sulfur atom, and wherein eachof the foregoing aryl and heteroaryl groups may optionally be
`substituted with one or more substituents, preferably from zero to two substituents,
`independently selected from (C,-C,)alkyl optionally substituted with from one to seven fluorine
`atoms, (C,-C,)alkoxy optionally substituted with from two to seven fluorine atoms, halo ( e.g.
`chloro, fluoro, bromo oriodo), (C,-C,)alkenyl, (C2-C,)alkynyl, hydroxy, nitro, cyano, amino, (C,-
`
`Apotex Exhibit 1005.004
`
`Apotex Exhibit 1005.004
`
`

`

`WO 99/35131
`
`PCT/IB98/01813
`
`[(Cy-C,) alkyl},amino-,
`
`-CO,R*,
`
`-CONR®R®,
`
`-SO,NR’R®,
`
`-C(=0)R™ and -
`
`C,)alkylamino-,
`XC(=O)R™;
`or R’ and R®, togetherwith the carbonsto which they are attached, form a four to seven
`membered monocyclic, or a ten to fourteen membered bicyclic, carbocyclic ring that can be
`saturated or unsaturated, wherein from one to three of the nonfused carbon atoms of said
`monocyclic rings, and from onetofive of the carbon atomsof said bicyclic rings that are not part
`of the benzo ring shown in formula |, may optionally and independently be replaced by a
`nitrogen, oxygen or sulfur, and wherein said monocyclic and bicyclic rings may optionally be
`substituted with one or more substituents, preferably from zero to two substituents for the
`monocyclic rings and from zero to three substituents for the bicyclic rings, that are selected,
`independently, from (Cp -C,)alkoxy-(C,-Cg)alkyl-, wherein the total number of carbon atoms does
`not exceed six and wherein any of the alkyl moieties may optionally be substituted with from one
`to seven fluorine atoms; nitro, oxo, cyano, halo, (Cz-Ce)alkenyl, (C2-Ce)alkynyl, hydroxy, amino,
`(Cy-Ce)alkylamino-,
`[(C1-Ce)alkyl],amino-,
`-CO,R*,
`-CONR®R®,
`-SO,NR’R®, -C(=0)R",
`and-
`XC(=O)R™
`each R®, R’, R®,R’, R® and R™is selected, independently, from hydrogen and (C, -Cz)
`alkyl, or R° and R®, or R’ and R®togetherwith the nitrogen to which they are attached, form a
`
`
`
`pyrrolidine, azetidine,_piperizine,piperidine, morpholine, -N-(C ,-Cg)alkylpiperizine or
`
`thiomorpholine ring, or a thiomorpholine ring wherein the ring sulfuris replaced with a sulfoxide
`or sulfone; and
`
`10
`
`20
`
`25
`
`30
`
`eachX is, independently, (C,-C,)alkylene:
`with the proviso that: (a) at least one of R', R? and R® must be the other than hydrogen,
`and (b) when R’ and R®are hydrogen, R' cannot be methyl or hydrogen;
`and the pharmaceutically acceptable salts of such compounds.
`Examplesof heteroary! groups that each of R* and R® can bearethefollowing:
`thienyl, oxazoyl,
`isoxazoly!,
`pyridyl,
`pyrimidyl,
`thiazolyl,
`tetrazolyl,
`isothiazoly!,
`imidazolyl, tetrazolyl, pyrroyl and the following groups:
`
`triazolyl,
`
`Apotex Exhibit 1005.005
`
`Apotex Exhibit 1005.005
`
`

`

`WO 99/35131
`
`PCT/IB98/01813
`
`-4-
`
`R'e
`
`N
`O 7 9
`bN "
`
`rR’
`
`N
`( yr
`N—O
`
`18
`" yor
`
`N—N
`
`or
`R'® Ne
`
`Ri Ney
`N —
`Ris
`N
`wherein one of R® and R™is hydrogen or (C,-C,)alkyl, and the other is a bond to the
`benzoring of formula |.
`
`18
`
`"OOyeR?
`N=/
`
`Examples of compoundsofthis invention are compounds of the formula |, and their
`pharmaceutically acceptable salts, wherein R* and R®, together with the benzoring of formula |,
`form a bicyclic ring system selected from the following:
`
`10
`
`N
`
`SR"
`
`S—R"
`
`N
`
`O
`
`N R10
`Rv
`
`N
`
`O
`
`js
`
`.
`
`s
`
`oF
`
`Y—R
`
`10
`
`from (Cg-C,)alkoxy-(Cy-Ce)alky!-
`independently,
`wherein R™ and R" are selected,
`wherein the total number of carbon atoms does not exceed six and wherein any of the alky!
`moieties may optionally be substituted with from one to sevenfluorine atoms;nitro, cyano, halo,
`amino, (C,-C,)alkylamino-, [(C4-C,) alkyl],amino-, -CO,R*, -CONR®R®, -SO,NR’R®, -C(=O)R™,
`-XC(=O)R™, phenyl and monocyclic heteroary! wherein said heteroarylis defined as R? and R®
`are defined in the definition of compoundsofthe formula | above:
`
`Other embodiments of this invention relate to compounds of the formula |, and their
`pharmaceutically acceptable salts, wherein R? and R°, together with the benzo ring of formulaI,
`form a bicyclic ortricyclic ring system selected from thefollowing:
`
`15
`
`20
`
`Apotex Exhibit 1005.006
`
`Apotex Exhibit 1005.006
`
`

`

`WO 99/35131
`
`PCT/IB98/01813
`
`N 1
`
`/
`
`N\R
`
`0
`
`S.Cory
`
`N R
`
`10
`
`27
`n-=~
`
`10
`
`R'°
`
`N| NR
`
`10
`
`R
`
`7
`
`R'
`
`Ou
`
`N
`
`CN
`
`7
`
`R!
`
`Ory
`
`hR
`
`10
`
`R
`
`17
`
`R
`
`N
`
`N
`\
`
`N
`
`t
`wherein R™ and R’” are defined as above and mis zero, one or two, and wherein oneof
`the carbon atomsof ring A can optionally be replaced with oxygen or -N(C ,-C,)alkyl.
`Other embodiments of this invention relate to compounds of the formula |, and their
`pharmaceutically acceptable salts, wherein neither R* nor R° is attached to the benzo ring of
`formula | via an oxygen atom.
`
`Other embodimentsof this invention relate to compoundsofthe formula | wherein R' is
`
`not methyl.
`
`Examples of specific compoundsof the formula | are the following:
`6-methyl-5,7-dioxo-6,13-diazatetracyclo[9.3. 1.07"°.0**]pentadeca-2(10),3,8-triene
`hydrochloride;
`
`Apotex Exhibit 1005.007
`
`10
`
`15
`
`Apotex Exhibit 1005.007
`
`

`

`WO 99/35131
`
`PCT/IB98/01813
`
`6-methy|-5-oxo-6, 13-diazatetracyclo[9.3.1.07"°. 0*"Ipentadeca-2( 10),3,8-triene
`hydrochloride;
`5,7-dimethy!-6-oxo-5,7, 13-triazatetracyclo[9.3.1.07"°.0**]pentadeca-2(10),3,8-triene
`hydrochloride;
`5,7-dioxo-6, 13-diazatetracyclo[9.3.1.0°"°.0**Jpentadeca-2(10),3,8-triene
`hydrochloride;
`5-0x0-6, 13-diazatetracyclo[9.3.1.07'°.0**|pentadeca-2(10),3,8-triene hydrochloride;
`6-oxo-5,7,13-triazatetracyclo[9.3.1.07'°.0**]pentadeca-2(10),3,8-triene hydrochloride;
`4,5-difluoro-10-aza-tricyclo[6.3.1 .0?"Jdodeca-2(7),3,5-triene hydrochloride;
`5-fluoro-10-aza-tricyclo[6.3.1.0°”|dodeca-2(7),3,5-triene-4-carbonitrile hydrochloride;
`4-ethyny-5-fluoro-10-aza-tricyclo[6.3.1 .0”Idodeca-2(7),3,5-triene hydrochloride;
`5-ethynyl-10-aza-tricyclo[6.3. 1.0°”|dodeca-2(7),3,5-triene-4-carbonitrile hydrochloride:
`5-chloro-10-aza-tricyclo[6.3.1.07Jdodeca-2(7),3,5-triene-4-carbonitrile hydrochloride:
`4-ethynyl-5-chloro-10-aza-tricyclo[6.3.1.0”"|dodeca-2(7),3,5-triene hydrochloride:
`5-oxa-7-methyl-6-oxo-7,13-diazatetracyclo[9.3.1.07'°.0**|pentadeca-2(10),3,8-triene
`hydrochloride;
`4-fluoro-5-trifluoromethy|-10-aza-tricyclo[6.3.1 .0?"|dodeca-2(7),3,5-triene
`hydrochloride;
`4-chloro-5-trifluoromethyl-10-aza-tricyclo[6.3.1.0]dodeca-2(7),3,5-triene
`hydrochloride;
`5-trifluoromethy|-10-aza-tricyclo[6.3.1 0”"|dodeca-2(7),3,5-triene-4-carbonitrile
`hydrochloride;
`4-ethynyl-5-trifluoromethyl-10-aza-tricyclo[6.3.1 .0*"Idodeca-2(7),3,5-triene
`hydrochloride;
`6-methy|-5-thia-5-dioxa-6,13-Diazatetracyclo[9.3. 1.0°"°.0**]pentadeca-2(10),3,8-
`triene hydrochioride;
`7-dimethylamino-5-thia-5-dioxa-6, 13-Diazatetracyclo[9.3.1.07'°.0**}pentadeca-
`2(10),3,8-triene hydrochloride;
`6,7-dioxa-5,8, 14-triazatetracyclo[10.3.1.07'".0**|hexadeca-2(11),3,9-triene
`hydrochloride; and
`5,8-dimethyl-6,7-dioxa-5,8, 14-triazatetracyclo[10.3.1.07'.0**}hexadeca-2(11),3,9-
`triene hydrochloride.
`
`This invention also relates to compoundsof the formula
`
`= 0
`
`15
`
`20
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`25
`
`30
`
`35
`
`Apotex Exhibit 1005.008
`
`Apotex Exhibit 1005.008
`
`

`

`WO 99/35131
`
`PCT/1IB98/01813
`
`Ri4
`
`R15
`
`wherein P is hydrogen, methyl, COOR™wherein R"is (C,-C,)alkyl, allyl, 2,2,2-trichloroethy!
`or (C,-Ce)alkyl; -C(=O)NR°R® wherein R® and R° are defined as in formula | above: -C(=O)H,
`-C(=0)(C,-Ce)alkyl wherein the alky| moiety may optionally be substituted with from 1
`to 3
`halo atoms, preferably with from 1 to 3 fluoro or chloro atoms; benzyl or t-butoxycarbony| (t-
`Boc), and R™ and R'° are selected,
`independently, from hydrogen, (C,-C,)alky! optionally
`Substituted with from one to sevenfluorine atoms; -C(=O)(C,-Cg)alkyl, cyano, hydroxy, nitro,
`amino, -O(C;-Ce)alkyl or halo; with the proviso that R'* and R"® can not both be hydrogen
`when P is hydrogen or methyl. Such compoundsare useful as intermediates in the synthesis
`of compounds of the formulaI.
`
`Unless otherwise indicated,
`bromo and iodo.
`
`the term “halo”, as used herein,
`
`includes fluoro, chloro,
`
`Unless otherwise indicated, the term "alkyl", as used herein, includes straight, branched
`or cyclic, and may include straight and cyclic alkyl moieties as well as branched and cyclic
`moieties.
`
`The term “alkoxy", as used herein, means “alkyl-O-”, wherein “alkyl” is defined as
`
`above.
`
`15
`
`20
`
`The term “alkylene, as used herein, means analky! radical having two available bonding
`sites (i.e., -alkyl-), wherein “alkyl”is defined as above.
`
`Unless otherwise indicated, the term “one or more substituents", as used herein, refers
`to from one to the maximum numberof substituents possible based on the numberof available
`
`25
`
`bonding sites.
`
`inhibiting the
`The term “treatment’, as used herein, refers to reversing, alleviating,
`progress of, or preventing the disorder or condition to which such term applies, or one or more
`symptoms of such condition or disorder. The term “treatment”, as used herein, refers to the act
`
`30
`
`of treating, as “treating” is defined immediately above.
`
`The compounds of formula | may have optical centers and therefore may occur in
`different enantiomeric configurations. The invention includes all enantiomers, diastereomers, and
`
`Apotex Exhibit 1005.009
`
`Apotex Exhibit 1005.009
`
`

`

`WO 99/35131
`
`PCT/IB98/01813
`
`other stereoisomers of such compounds of formula |, as well as racemic and other mixtures
`thereof.
`
`The present invention also relates to all radiolabelled forms of the compounds ofthe
`formulae |. Preferred radiolabelled compoundsof formula | are those wherein the radiolabels are
`selected from as °H, "'C, ““c, "°F, "*1 and I. Such radiolabelled compoundsare useful as
`research and diagnostic tools in metabolism pharmacokinetics studies and in binding assaysin
`both animals and man.
`
`The presentinvention also relates to a pharmaceutical composition for use in reducing
`nicotine addiction oraiding in the cessation or lessening of tobacco use in a mammal, including
`a human, comprising an amount of a compound of the formula |, or a pharmaceutically
`acceptable salt thereof, that is effective in reducing nicotine addictionor aiding in the cessation
`or lessening of tobacco use and a pharmaceutically acceptable carrier.
`The present invention also relates to a method for reducing nicotine addiction or aiding
`in the cessation or lessening of tobacco use in a mammal,
`including a human, comprising
`administering to said mammal an amount of a compoundofthe formulaI, or a pharmaceutically
`acceptable salt thereof, that is effective in reducing nicotine addiction or aiding in the cessation
`or lessening of tobacco use.
`
`The present invention also relates to a method of treating a disorder or condition
`selected from inflammatory bowel disease (including but not
`limited to ulcerative colitis,
`pyoderma gangrenosum and Crohn's disease),
`irritable bowel syndrome, spastic dystonia,
`chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panic disorder,
`depression, bipolar disorder, autism, sleep disorders,jet lag, amylotropic lateral sclerosis (ALS),
`cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastric acid
`hypersecretion,
`ulcers, pheochromocytoma,
`progressive
`supramuscular palsy,
`chemical
`dependencies and addictions (e.g., dependencies on, or addictions to nicotine (and/or tobacco
`products), alcohol, benzodiazepines, barbituates, opioids or cocaine), headache,
`stroke,
`traumatic brain injury (TBI), psychosis, Huntington’s Chorea, tardive dyskinesia, hyperkinesia,
`dyslexia, schizophrenia, multi-infarct dementia, age related cognitive decline, epilepsy, including
`petit mal absence epilepsy, senile dementia of the Alzheimer's type (AD), Parkinson's disease
`(PD), attention deficit hyperactivity disorder (ADHD) and Tourette’s Syndrome in a mammal,
`comprising administering to a mammalin need of such treatment an amount of a compound of
`the formula |, or a pharmaceutically acceptable salt thereof, that is effective in treating such
`disorder or condition.
`
`15
`
`20
`
`25
`
`30
`
`35
`
`Apotex Exhibit 1005.010
`
`Apotex Exhibit 1005.010
`
`

`

`WO 99/35131
`
`PCT/IB98/01813
`
`-9-
`
`The present invention also relates to a pharmaceutical composition for treating a
`disorder or condition selected from inflammatory bowel disease (including but not limited to
`ulcerative colitis, pyoderma gangrenosum and Crohn’s disease),
`irritable bowel syndrome,
`spastic dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety,
`panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amylotropic lateral
`sclerosis
`(ALS),
`cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac
`arrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supramuscular
`palsy, chemical dependencies and addictions (e.g., dependencies on, or addictions to nicotine
`(and/or
`tobacco products),
`alcohol, benzodiazepines, barbituates, opioids or cocaine),
`headache,
`stroke,
`traumatic brain injury (TBI), psychosis, Huntington's Chorea,
`tardive
`dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, age related cognitive
`decline, epilepsy, including petit mal absence epilepsy, senile dementia of the Alzheimer's type
`(AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette's
`Syndrome in a mammal, comprising an amount of a compound of the formula |, or a
`pharmaceutically accepable salt thereof, and a pharmaceutically acceptable carrier.
`The present invention also relates to a method for reducing nicotine addiction or aiding
`in the cessation or lessening of tobacco use in a mammal, comprising administering to said
`marnmai an amount of a compound comprising an amount of a compoundof the formula
`
`15
`
`20
`
`NH
`
`that
`or a pharmaceutically acceptable salt thereof,
`addiction or aiding in the cessation or lessening of tobacco use.
`
`25
`
`is effective in reducing nicotine
`
`The present invention also relates to a method for treating a disorder or condition
`selected from inflammatory bowel disease (including but not
`limited to ulcerative colitis,
`pyoderma gangrenosum and Crohn's disease),
`irritable bowel syndrome, spastic dystonia,
`chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panic disorder,
`depression, bipolar disorder, autism, sleep disorders,jet lag, amylotropic lateral sclerosis (ALS),
`cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastric acid
`hypersecretion, ulcers, pheochromocytoma, progressive
`supramuscular palsy,
`chemical
`dependencies and addictions (¢.g., dependencies on, or addictions to nicotine (and/or tobacco
`products), alcohol, benzodiazepines, barbituates, opioids or cocaine), headache,
`stroke,
`traumatic brain injury (TBI), psychosis, Huntington’s Chorea, tardive dyskinesia, hyperkinesia,
`dyslexia, schizophrenia, multi-infarct dementia, age related cognitive decline, epilepsy, including
`
`30
`
`35
`
`Apotex Exhibit 1005.011
`
`Apotex Exhibit 1005.011
`
`

`

`WO 99/35131
`
`PCT/1B98/01813
`
`-10-
`
`petit mal absence epilepsy, senile dementia of the Alzheimer's type (AD), Parkinson's disease
`(PD), attention deficit hyperactivity disorder (ADHD) and Tourette’s Syndrome in a mammal,
`comprising administering to a mammal in need of such treatment an amount of a compound of
`the formula
`
`NH
`
`10
`
`or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder
`or condition.
`
`This invention also relates to the pharmaceutically acceptable acid addition salts of the
`compoundsof formula |. Examples of pharmaceutically acceptable acid addition salts of the
`compounds of formula | are the salts of hydrochloric acid, p-toluenesulfonic acid, fumaric acid,
`citric acid, succinic acid,
`salicylic acid, oxalic acid, hydrobromic acid, phosphoric acid,
`methanesulfonic acid, tartaric acid, malate, di-p-toluoyltartaric acid, and mandelic acid.
`
`Detailed Description of the Invention
`Except where otherwise stated, R' through R', m and P, and structural formula | in the
`
`reaction schemes and discussion that follow are defined as above.
`
`Apotex Exhibit 1005.012
`
`Apotex Exhibit 1005.012
`
`

`

`WO 99/35131
`
`PCT/1B98/01813
`
`-11-
`
`Scheme 1
`
`HA
`
`NB
`
`De.
`
`H.N
`
`HN
`
`Apotex Exhibit 1005.013
`
`Apotex Exhibit 1005.013
`
`

`

`WO 99/35131
`
`PCT/1B98/01813
`
`-12-
`
`O.N
`
`ON
`
`N
`
`CF,
`
`IIA
`
`O,NLO»—tBoc
`
`ON
`
`VIA
`
`H,N
`
`H,N
`
`Apotex Exhibit 1005.014
`
`Apotex Exhibit 1005.014
`
`

`

`WO 99/35131
`
`PCT/1B98/01813
`
`-13-
`
`5
`
`Scheme2 continued
`
`N—tBoc
`
`VII
`
`VIB
`
`. N
`
`10
`R-\
`N
`
`Rio
`
`N-tBoc
`
`VII
`
`N
`
`10<<.
`
`N
`
`Ri?
`|
`
`10
`
`NClN
`
`IB
`
`Apotex Exhibit 1005.015
`
`Apotex Exhibit 1005.015
`
`

`

`WO 99/35131
`
`PCT/IB98/01813
`
`5
`
`-14-
`
`Scheme 3
`
`O,NTeO,N
`
`VIA
`
`XXlll
`
`XXIV
`
`Apotex Exhibit 1005.016
`
`Apotex Exhibit 1005.016
`
`

`

`WO 99/35131
`
`PCT/1B98/01813
`
`-15-
`
`5
`
`Scheme 4
`
`HNTOD VIB
`
`H,N
`
`Re
`
`N
`
`“aIeRU
`
`Sn
`
`Apotex Exhibit 1005.017
`
`Apotex Exhibit 1005.017
`
`

`

`WO 99/35131
`
`PCT/1B98/01813
`
`-16-
`
`5
`
`Scheme 5
`
`Y
`
`|OL
`
`O,N
`
`O
`
`|Oe.
`
`HO
`
`O.N
`
`Oem TOLD
`
`N
`
`XXll
`
`VIII
`
`Apotex Exhibit 1005.018
`
`Apotex Exhibit 1005.018
`
`

`

`WO 99/35131
`
`PCT/1B98/01813
`
`5
`
`-17-
`
`Scheme 6
`
`>
`
`Xl
`
`Apotex Exhibit 1005.019
`
`Apotex Exhibit 1005.019
`
`

`

`WO 99/35131
`
`PCT/1B98/01813
`
`-18-
`
`5
`
`Scheme 6 continued
`
`H
`
`;
`NS
`60)-—.
`
`Xl
`
`SmIN
`
`Apotex Exhibit 1005.020
`
`Apotex Exhibit 1005.020
`
`

`

`WO 99/35131
`
`PCT/1B98/01813
`
`-19-
`
`5
`
`Scheme 7
`
`
`
`x"Ol x
`(OI
`yn
`absent)
`COO,
`(ring A = present orvaesen)
`
`(ring A = present or
`
`(ring A = present or absent)
`
`Xi
`
`XINA
`
`LTO
`
`(ring A = present or absent)
`XIV
`
`|
`CTT
`
`IG:
`
`(R? and R? form ring A)
`
`Ill:
`
`(ring A = absent)
`
`Apotex Exhibit 1005.021
`
`Apotex Exhibit 1005.021
`
`

`

`WO 99/35131
`
`PCT/1B98/01813
`
`5
`
`18
`
`R
`
`F
`
`-20-
`
`Scheme 8
`
`R's
`
`|
`
`F
`
`Re
`
`XV
`
`XVI
`
`XVII
`
`(R18 = F or (C,-C,)alkoxy)
`
`R'®
`
`|
`
`.
`
`XIX
`
`Re
`
`IH
`
`“on = CID OH
`
`OH
`
`Ri
`
`_
`
`NH
`
`XVIII
`
`18
`
`R
`
`XX
`
`|
`
`rR’
`
`O
`
`nt
`CF,
`
`O,N
`2
`
`XXI
`
`O
`
`i,
`
`CF,
`
`Apotex Exhibit 1005.022
`
`Apotex Exhibit 1005.022
`
`

`

`PCT/IB98/01813
`
`Scheme 9
`
`OD
`
`R’R'NO,S
`
`IJ
`
`OxCF
`
`N
`
`IV
`
`Cl— Sos
`
`Cl
`
`IK
`
`IL
`
`NH
`
`Ri
`
`O
`
`Apotex Exhibit 1005.023
`
`Apotex Exhibit 1005.023
`
`

`

`WO 99/35131
`
`PCT/1B98/01813
`
`-22-
`
`5
`
`Scheme 10
`
`SID»
`
`Cl
`
`Apotex Exhibit 1005.024
`
`Apotex Exhibit 1005.024
`
`

`

`WO 99/35131
`
`PCT/1B98/01813
`
`-23-
`
`.
`Scheme 1-10 illustrate methods of synthesizing compoundsofthe formula |
`Referring to Scheme 1, the starting material of formula III is reacted with trifluoroacetic
`anhydride,
`in the presence of pyridine, to form the compound of formula IV. This reaction is
`typically conducted in methylene chloride at a temperature from about O°C to about room
`
`temperature.
`
`10
`
`The compoundof formula IV is then converted into the dinitro derivative of formula IIA
`
`by the following process. The compound of the formula IV is added to a mixture of 4 or more
`equivalents oftrifluoromethanesulfonic acid (CF ;SO0,OH) and 2 to 3 equivalents ofnitric acid, in
`a chlorinated hydrocarbon solvent such as chloroform, dichoroethane (DCE) or methylene
`chloride. The resulting mixture is allowed to react for about 5 to 24 hours. Both ofthe foregoing
`reactions are generally conducted at a temperature ranging from about -78°C to about 0°C for
`about 2 hours, and then allowed to warm to room temperature for the remaining time.
`Reduction of the compoundofformula tA, using methods well knownto those ofskill in
`the art, yields the compound of formula IIB. This reduction can be accomplished,for example,
`using hydrogen and a palladium catalyst such as palladium hydroxide and running the reaction
`in methanol at about room temperature.
`Referring to Scheme 2, the compound offormulaIIA is converted into the corresponding
`compound wherein the trifluoroacetyl protecting group is replaced by a t-Bocprotecting group
`(VIA) by reactingit first with an alkali metal or alkaline earth metal (or ammonium) hydroxide or
`carbonate, and then reacting the isolated product
`from the foregoing reaction with di-t-
`butyldicarbonate. The reaction with the alkali or alkaline earth metal (or ammonium) hydroxide
`or carbonate is generally carried out in an aqueous alcohol, dioxane or tetrahydrofuran (THF)at
`a temperature from about room temperature to about 70°C, preferably at about 70°C, for about
`one to about 24 hours. The reaction of the isolated, unprotected amine or an acid addition salt of
`such amine, from the above reaction with di-t-butyldicarbonate is preferably carried out in a
`solvent such as THF, dioxane or methylene chtoride at a temperature from about 0°C to about
`room temperature. This reaction may or may not be conducted in the presence of a base.
`Whenthe reactantis a salt of the amine, use of a baseis preferred. The resulting compound of
`formula VIA can be converted into the corresponding diamino derivative of formula VIB using the
`procedure described above for converting the dinitro compound of formula IIA into the
`corresponding diamino compoundofformulaIIB.
`
`The conversion of the compound of formula VIB into the desired compound of the
`formula VII can be accomplished by reacting the compound of formula VIB with a compound of
`the formula
`
`20
`
`25
`
`30
`
`35
`
`Apotex Exhibit 1005.025
`
`Apotex Exhibit 1005.025
`
`

`

`WO 99/35131
`
`PCT/1B98/01813
`
`-24-
`
`H,C,0,C
`
`CO,C,H,
`
`XXIIA
`
`OC,H,
`R™
`wherein R™ is hydrogen, (C,-C,)alky! optionally substituted with from one to seven fluorine
`atoms, aryl-(Cy -C;)alkyl wherein said aryl is selected from phenyl and naphthyl, or heteroaryl-
`(Co -Cs)alkyl wherein said heteroaryl is selected from five to seven membered aromatic rings
`containing from oneto four heteratoms selected from oxygen, nitrogen and sulfur, and wherein
`each of the foregoing aryl and heteroryl groups may optionally be substituted with one or more
`substituents, preferably from zero to two substituents, independently selected from (C, -C,)alky]
`optionally substituted with from one to seven fluorine atoms, (C , -C,)alkoxy optionally substituted
`with from one to seven fluorine atoms and cyano. The preferred solvent for this reaction is a
`10:1 mixture of ethanol:acetic acid. The reaction temperature can range from about 40°C to
`about 100°C.
`It
`is preferably about 60°C. Other appropriate solvents include acetic acid,
`ethanol and isopropanol.
`
`the compound of
`Alternate methods of preparing compounds of the formula VII
`formula VIB are described by Segelstein et al., Tetrahedron Lett., 1993, 34, 1897.
`Removal of the t-Boc protecting group from the compound of formula VII yields
`corresponding compoundof formula IA. The protecting group can be removed using methods
`well known to those of skill
`in the art. For example, the compound of formula VII can be
`treated with an anhydrous acid such as hydrochloric acid, hydrobromic acid, methanesulfonic
`acid, or trifluoroacetic acid, preferably hydrochloric acid in ethyl acetate, at a temperature from
`about 0°C to about 100°C, preferably from about room temperature to about 70°C, for about
`one to 24 hours.
`
`The compound of formula VIl can be converted into the corresponding compound of
`formula IB by reacting it with a compoundof the formula RZ, wherein R" is defined as R” is
`defined above, and Z is a leaving group such as a halo or sulfonate (e.g., chloro, bromo,
`mesylate or tosylate), in the presence of a base such as an alkali metal hydride, hydroxide or
`carbonate,
`preferably
`potassium hydroxide,
`in
`a
`polar
`solvent
`such
`as_ water,
`dimethylsulfoxide (DMSO), THF or DMF, preferably a mixture of DMSO and water, and then
`removing the protecting group as described above. The reaction with R'’Z is generally
`carried out at a temperature from about room temperature to about 100°C, preferably at about
`50°C, for about five hours.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Apotex Exhibit 1005.026
`
`Apotex Exhibit 1005.026
`
`

`

`WO 99/35131
`
`PCT/IB98/01813
`
`-25-
`
`Scheme3illustrates an alternate method of preparing compounds of the formula IB
`from the compound of formula VIA.
`This method is the preferred method of making
`compounds of the formula IB wherein R'’ is a bulky group such as an aryl or heteroaryl
`containing group, or when R"’ can not be attached, asililustrated in Scheme 2, by alkylation
`or aryl substitution methods. Referring to Scheme 3, the compound of formula VIA is reacted
`with the appropriate compound of formula R'’NH,in a polar solvent such as THF, DMF or
`DMSO, preferabiy THF, at a temperature from about room temperature to about 100°C,
`preferably at the reflux temperature, for about four to eighteen hours. The resulting compound
`of formula XXIII is then converted into the corresponding compound of the formula XXIV by
`reducing the nitro group to an amino group using methods well known to thoseof skill in the
`art. Such methods are referred to abovefor the conversion of the compoundsof the formula
`IA into a compoundof the formula IIB in Scheme 1, and exemplied in experimental Examples
`12B and 18B. Closure of the imidazole ring to form the corresponding compound of formula
`XXV can then be accomplished by reacting the compound