w
`
`AnntxUS.II, Page 1
`
`PCTApplicant'sGuide524R GSUPCTIPIO2 8 SEP 1999
`
`‘
`
`
`
`
`FORM PTO-1390
`{REV 10-95)
`
`U §. DEPARTMENTOF COMMERCE PATENT AND TRADEMARK. OFFICE
`
`TRANSMITTAL LETTER TO THE UNITED STATES
`PATENT AND TRADEMARK OFFICE
`
`DESIGNATED/ELECTED OFFICE (DO/EO/US)
`CONCERNINGA FILING UNDER35 U.S.C. 371
`
`PCT/IB98/01813
`TITLE OF INVENTION
`
`
`INTERNATIONALFILING DATE
`November 13, 1998 (11.13.1998
`
`PRIORITY DATE CLAIMED
`December 31, 1997 (12.31.1997
`
`
`ATTORNEY’S DOCKET NUMBER
`
`
`PC10030A
`
`vsad IONNO.O36j¢ 1.5)
`0 > / 4
`
`
`
`HOW
`XIXI
`
`XO
`
`ARYL FUSED AZAPOLYCYCLIC COMPOUNDS
`APPLICANT(S) FOR DO/EO/US
`Jotham Wadsworth COEand Paige Roanne Palmer BROOKS
`Applicant herewith submits to the United States Designated/Elected Office (DO/EO/US)the following items and other information:
`1.
`This is the FIRST submission of items concerninga filing under 35 U.S.C. 371.
`2.
`This is the SECOND or SUBSEQUENTsubmission ofitems concerning a filing under 35 U.S.C. 371.
`3.
`This express request to begin national examination procedures (35 U.S.C. 371(f)) at any timerather than delay
`examination until the expiration ofthe applicable time limit set in 35 U.S.C. 371(b) and PCT Articles 22 and 39(1).
`A proper Demandfor International Preliminary Examination was made by the 19" month from the earliest claimed priority date.
`A copy ofthe International Application as filed (35 U.S.C. 371(c)(2))
`a.
`XX
`is transmitted herewith (required only if not transmitted by the International Bureau).
`b.
`Cl
`has been transmitted by the International Bureau.
`c.
`O
`is not required, as the application was filed in the United States Receiving Office (RO/US).
`A translation ofthe International Application into English (35 U.S.C. 371(c)(2)).
`Amendmentsto the claims of the International Application under PCT Article 19 (35 U.S.C. 371(c)(3))
`a.
`|
`are transmitted herewith (required only ifnot transmitted by the International Bureau).
`b.
`C
`have beentransmitted by the International Bureau.
`c.
`oO
`have not been made; however, the time limit for making such amendments has NOT expired.
`d.
`RX
`have not been made and will not be made.
`8. [1]Atranslation ofthe amendmentsto the claims under PCT Article 19 (35 U.S.C. 371(c)(3)).
`
`9.
`[J An oath or declaration ofthe inventor(s) (35 U.S.C. 371(c)(4)).
`
`10. (1Atranslation ofthe annexesto the International Preliminary Examination Report under PCT Article 36
`(35 U.S.C. 371(c)(5)).
`
` Items 11. To 16. Below concern other documents(s) or information included:
`
`11.
`12
`13.
`
`14.
`15.
`16.
`
`EK] An Information Disclosure Statement under 37 C.F.R. 1.97 and 1.98.
`[1 Anassignment documentfor recording. A separate cover sheet in compliance with 37 C.F.R. 3.28 and 3.31 is included.
`[] A FIRSTpreliminary amendment.
`[] ASECONDor SUBSEQUENT preliminary amendment.
`(A substitute specification.
`[1 A changeof powerof attorney and/or addressletter.
`(J
`Otheritemsor information:
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`
`Bye ae —
`ve
`2
`-
`; EXPRESS MAIC NCZLYPTSS Od |
`
`TRANSMITTAL LETTER UNDER35 U.S.C. 371 PTO 1390, 3/99
`
`Apotex Exhibit 1007.001
`
`Apotex Exhibit 1007.001
`
`

`

`Search Report has been prepared by the EPO or IPO...ceccccssessesercenerseeesene eee840,00 International preliminary examination fee paid to USPTO (37CFR 1.482)...,.......... 3670.00
`
`Paul H. Ginsburg
`Pfizer Inc
`235 East 42nd Street
`New York, NY 10017-5755
`
`
`
`Sighature
`Karen DeBenedictis
`Name
`32,977
`Registration Number
`
`¥
`
`>
`
`.
`
`° AnnkxUS.H,Page2
`'( WSTAPPLICATION NO, (ifknown, see 37.CFR 15
`Notyetassigneff } g fAUEU 4 0
`. cEaS
`
`PCTApplicant's Guide - Vetus14RecdPCT(PTO 2 8 SEP 1999
`
`17.
`
`The following fees are submitted
`
`BASIC NATIONALFEE(37 CFR1.492 (a)(1)-(5)):
`ba
`
`Nointemational preliminary examination fee paid to USPTO (37 CFR 1.482)
`but international search fee paid te USPTO (37 CFR 1.445(a)(Q)) 0. ee sess seseeseeneeee 760.00
`
`Neither international preliminary examination fee (37 CFR 1.482) nor
`international search fee (37 CFR. 1.445(a)(2)) paid to USPTO wooa.ssessseesscscssssseessees 9970.00
`
`0 O O
`
`O International preliminary examination fee paid to USPTO (37 CFR 1.482) and
`all claimssatisfied provisions of PCT Asticle 33(2)-(4) ....csecsssccsssceessseertsserseseeereeed 96,00
`ENTER APPROPRIATE BASIC FEE AMOUNT =
`
`Surcharge of $130.00 for furnishing the oath or declaration later than {_] 20 L] 30 months
`from the earliest claimed priority
`date (37 CFR 1.492(e)).
`
`CLAIMS
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`NUMBER EXTRA
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`Independent
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`-35
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`TOTAL OF ABOVE CALCULATIONS=
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`Reduction by % forfiling by small entity, if applicable. Verified Small Entity Statement
`must also befiled. (Note: 37 CFR 1.9, 1.27, 1.28
`
`Processing fee of$130.00for furnishing the English translation later than {_} 20 [[] 30
`months from the earliest claimedpriori
`.
`
`Fee for recording the enclosed assignment (37 CFR 1.21(h)). The assignment must be
`accompanied by an appropriate cover sheet (37 CFR 3.28, 3.31). $40.00
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`| Please charge my Deposit Account No. 16-1445 in the amountof $ 918 to cover the above fees.
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`NOTE: Where an appropriate time limit under 37 CFR 1.494 or 1.495 has not been met, a petition to revive (37 CFR
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`EXPRESS MAIL NO.CIMPPERS2Q0¢/
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`TRANSMITTAL LETTER UNDER35 U.S.C. 371 PTO 1390, 3/99
`
`Apotex Exhibit 1007 .002
`
`Apotex Exhibit 1007.002
`
`

`

`eo
`
`;
`
`PC10030A
`
`514 Recd PCTIPTO 2 8 sep 999
`
`“4.
`
`5
`
`10
`
`,
`
`- ARYL FUSED AZAPOLYCYCLIC COMPOUNDS
`Background of the invention
`
`This invention relates to aryl
`
`fused azapolycyclic compounds, as defined more
`
`specifically by formula | below. Compounds of formula | bind to neuronal nicotinic acetyicholine
`
`specific receptor sites and are useful in modulating cholinergic function. Such compounds are
`useful in the treatment of infammatory bowel disease (inciuding but not limited to ulcerative
`calitis, 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
`
`15
`
`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-compuisive disorder, psychosis,
`
`Huntington's Chorea,
`
`tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct
`
`20
`
`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
`
`cisorder (ADHD) and Tourette's Syndrome.
`
`The compounds of
`
`this
`
`invention may also be used in
`
`combination with an
`
`antidepressant such as, for example, a tricyclic antidepressant or a serotonin reuptake inhibiting
`
`25
`
`antidepressant (SRI). in order to treat bath the cognitive decline and depression associated with
`
`AD, PD. stroke, Huntington's Chorea or traumatic brain injury (TBE):
`
`in combination with
`
`muscarinic agonists in order to strmulate both central muscannic 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
`
`
`
`30=order to maximize cholinergic enhancement for 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 antunflammatory
`agents and estrogen-like therapy
`
`EXPRESS WAIL NO,EYPEIg/
`
`Apotex Exhibit 1007.003
`
`Apotex Exhibit 1007.003
`
`

`

`
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`-2-
`
`Other compoundsthat bind to neuronal nicotinic receptor sites 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 ts incorporated herein by
`reference in its entirety.
`
`Summary of the Invention
`This invention relates to aryl fused azapolycyclic compoundsof the formula
`
`R2
`
`R?
`
`NR’
`
`(1)
`
`(C,-Ce)alkyl, unconjugated (C3-C,)alkenyl, benzyl, XC(=O)R'* or
`
`is hydrogen,
`R'
`-CH,CH,-O-(C,-C,)alkyl:
`R’ and R® are selected, independently, from hydrogen, (C,-C,)alkenyl, (Co-Ce)alkynyi,
`nitro, amino, halo,
`cyano,
`-SO,(C,-Ce)alkyl wherein q
`is zero, one or
`two,
`hydroxy,
`(C,.Cg)alkylamino-,
`[(C,-Cg)alkylamino-,
`-CO,R*,
`-CONR®R®,
`-SO,NR’R®,
`-c(=0)R",
`-XC(=O)R"?, aryl-(Co -C,)alkyl- or aryl-(Cy-C,)alkyl-O-, wherein said aryl is selected from phenyl
`and naphthyl, heteroaryl-(Cp-C,)alkyl- or heteroaryl-(C,-C,)alkyl-O-, wherein said heteroary! is
`selected from five to seven membered aromatic rings containing from one to four heteroatoms
`selected from oxygen, nitrogen and sulfur, and X7(Co-Cg)alkoxy-(Co-C,)alkyl-, wherein X? is
`absent or X? is (C,-C.)alkylamino- or [(C,-C,)alkyl],amino-, and wherein the (Co-C,)alkoxy-(C,-
`C.)alky!- moiety of said X*(Co-C,)alkoxy-(Co-Ce)alkyl- contains at least one carbon atom, and
`wherein from one to three of the carbon atoms of said (Co-C,)alkoxy-(C-C,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 (C,Cg)alkoxy-(Cp-Ce)alkyl- may be optionally substituted with from two to seven
`fluonne atoms, and wherein one of the carbon atomsof each of the alkyl moieties of said aryi-
`(Cy-C,)alkyl- and said heteroaryl-(C.-C,)alkyl- may optionally be replaced by an oxygen, nitrogen
`or sulfur atom, and wherein each of 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,-Cg)alkyl optionally substituted with from one to seven fluonne
`atoms. (C,-C,)alkoxy optionally substituted with from two to seven fluorine atoms, halo ({ e.g.,
`chloro fluoro, bramo or todo), (C,-C,)aikeny!, (C2-C,)alkynyl, hydroxy, nitro, cyano, amino, (C,-
`
`Apotex Exhibit 1007 .004
`
`Apotex Exhibit 1007.004
`
`

`

`-3-
`
`5
`
`10
`
`15
`
`20
`
`-SO,NR’R®,
`
`-C(=0)R™ and -
`
`[(C,-Cs) alkyl],amino-,
`
`-CO,R*.
`
`-CONR°R®,
`
`Ce)alkylamino-,
`XC(=O)R™,
`or R? and R®, together with the carbons to which they are attached, form a four to seven
`membered monocyclic, or a ten to fourteen membered bicyclic, carbocyclic nng 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 atoms ofsaid bicyclic nngs that are not part
`of the benzo ring shown in formuia |, 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 (Cy -C,)alkoxy-(Cy-C,)alkyl-, wherein the total numberof carbon atoms does
`not exceed six and wherein anyof the alky! moieties may optionally be substituted with from one
`to seven fluorine atoms; nitro. oxo, cyano, halo, (C2-Ce)alkenyl, (C;-C,)alkynyl, hydroxy, amino,
`(C,-Ce)alkylamino-,
`[(C,-Ce)atkyl],amino-, -CO,R*,
`-CONR®R®,
`-SO,NR’R®,
`-C(=O)R™. and -
`XC(=O)R™,
`each R*, R®,R®R’, R® and R'is selected, independently, from hydrogen and (C, -C.)
`alkyl, or R° and R°, or R’ and R® together with the nitrogen to which they are attached, form a
`pyrrolidine,
`piperidine, morpholine,
`azetidine,
`piperzine,
`-N-(C ,-Cg)alkylpipenzine
`or
`thiomorpholinering, or a thiomorphoiine mng wherein the ring sulfur is replaced with a sulfoxide
`ar sulfone; and
`
`
`
`
`
`25 eachXis, 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 methy! or hydrogen:
`and the pharmaceutically acceptable salts of such compounds.
`Examplesof heteroaryl groups that each of R® and R® can be are thefollowing:
`thienyi, oxazoyl,
`isoxazolyl,
`pyridyl, pynmidyl,
`thiazolyl,
`tetrazolyl,
`isothiazolyl,
`imidazalyl, tetrazoly!, pyrroyl and the following groups
`
`30
`
`triazolyl,
`
`Apotex Exhibit 1007.005
`
`Apotex Exhibit 1007.005
`
`

`

`oR
`O-N
`/
`
`R
`
`N
`YS
`SR
`
`oO
`R&
`|
`|
`a R®
`
`N——N
`
`NN
`
`&
`NNpe
`
`R
`
`5
`
`Rie
`wherein one of R°® and R™is hydrogen or (C,-C,)alkyl, and the other is a bondto the
`
`3
`
`Rp’
`One
`N=
`
`8 N~
`
`K =N
`\ atN
`
`
`
`benzo nng of formula |.
`
`Examples of compounds of this invention are compounds of the formula |, and their
`pharmaceutically acceptable salts, wherein R? and R°*, together with the benzo ring of formula |,
`
`10
`
`form a bicyclic ring system selected from the following:
`
`N
`
`S—R™
`
`N
`R’
`
`N
`
`Sr"
`
`O
`
`N_R®
`
`(OTLen
`
`N
`
`Oo
`
`N
`
`Col
`
`Re?
`
`1
`
`3
`
`S
`
`or prN
`
`wherein R' and R" are selected,
`
`independently,
`
`from (Co-C,)alkoxy-(Co-C,)alkyl-
`
`wherein the total number of carbon atoms does not exceed six and wherein any of the alky!
`
`15
`
`20
`
`moieties may optionally be substituted with from one to seven fluorine atoms: nitro, cyano, halo,
`amino, (C,-Cz)alkylamino-, [(C,-C,) alkyl],amino-, -CO,R*, -CONR®R®, -SO,NR’R®, -C(=O)R™
`-XC(=O)R", phenyl and monocyclic heteroaryl wherein said heteroarylis defined as R* and R?
`are defined in the definition of compoundsof the formula | above;
`
`Other embodiments of this invention relate to compounds of the formula |, and thetr
`pharmaceutically acceptable salts, wherein R? and R’®, together with the benzo ring of formula I,
`form a bicyclic or tneyclic ring system selected from the following:
`
`Apotex Exhibit 1007.006
`
`Apotex Exhibit 1007.006
`
`

`

`-5-
`
`R10
`
`Ss.
`
`NCOL
`
`R10
`17
`
`R's
`
`N
`
`N
`
`RV
`
`Ri?
`
`R
`
`N
`
`R’
`10
`R
`
`oO
`
`)
`
`"
`
`47
`
`R
`
`CNCre
`
`R
`
`Re
`
`7
`
`"
`
`1
`
`aN,
`O— /
`N
`
`Rt?
`os
`N
`L
`
`N
`
`\
`
`R
`N
`
`0
`OooeN
`
`Ri?
`wherein R" and R"” are defined as above and m is zero, one or two, and wherein one of
`the carbon atomsof ring A can optionally be repiaced with oxygen or -N(C ,-Ce)alkyl.
`Other embodiments of this invention relate to compounds of the formula 1, and their
`pharmaceutically acceptable salts, wherein neither R? nor R® is attached to the benzo ring of
`formula | via an oxygen atom.
`
`Other embodiments of this invention relate to compoundsof the formula | wherein R' 1s
`not methyl
`
`Examplesof specific compounds ofthe formula | are the following:
`6-methyl-5,7-dioxo-6,13-diazatetracycio[9 3.1.07 '° of *|pentadeca-2(10),3,8-trene
`hydrochioride:;
`
`Apotex Exhibit 1007.007
`
`
`
`5
`
`10
`
`15
`
`Apotex Exhibit 1007.007
`
`

`

`6-
`
`6-methy!-5-oxo-6, 13-diazatetracyclo[9.3 1 0*'° 0**}pentadeca-2(10),3,8-triene
`hydrochioride;
`
`5,7-dimethy|-6-oxo-5,7,13-trazatetracyclo[9 3.1.07"° 0**}pentadeca-2(10),3,8-tnene
`hydrochloride;
`
`5,7-dioxo-6, 13-diazatetracyclo[9.3.1.07'"0*"|pentadeca-2(10),3,8-triene
`hydrochloride;
`5-0x0-6, 13-diazatetracycio[9.3.1.0°"° 0**}pentadeca-2(10),3,8-triene hydrochloride:
`6-0xo-5,7,13-trazatetracycio[9.3.1.07'° 94 *Ipentadeca-2( 10),3,8-triene hydrochloride:
`4,5-difluoro-10-aza-tricyclo[6.3.1.0°"]dodeca-2(7),3.5-triene hydrochlonde:
`S-fluoro-10-aza-tricyclo[6.3.1.0°’|dodeca-2(7),3,5-triene-4-carbontrile hydrochioride:
`4-ethynyl-5-fluoro-10-aza-tricyclo[6.3.1.0 “Jdodeca-2(7),3,5-triene hydrochioride;
`S-ethyny!-10-aza-tricyclo[6.3.1.0°’}dodeca-2(7),3,5-triene-4-carbonitrile hydrochloride:
`5-chloro-10-aza-tricyclo[6.3.1.0°”}dodeca-2(7),3,5-triene-4-carbonitrile hydrochioride:
`4-ethyny|-5-chioro-10-aza-tricyclo[6.3.1.0° "|\dodeca-2(7),3.5-triene hydrochioride:
`5-oxa-7-methy|-6-oxo-7, 13-diazatetracyclo[9.3.1 07° 0* "Jpentadeca-2(10),3,8-tnene
`hydrochloride;
`
`4-fluoro-5-trifluoromethy|-1 O-aza-tricyclo[6.3.1 0? "]dodeca-2(7),3,5-triene
`hydrochloride;
`
`4-chloro-5-trifluoromethy!-10-aza-tricyclo[6.3.1.0°Jdodeca-2(7),3,5-triene
`hydrochionde;
`
`5-trifluoromethyl-10-aza-tnicyclo[6 3 1 0°"]dodeca-2(7),3,5-triene-4-carbonitrile
`hydrochioride;
`
`4-ethyny|-5-trifluoromethyl-10-aza-tricyclo[6 3 4 0*}dodeca-2(7),3,5-tnene
`hydrochloride,
`
`10
`
`15
`
`20
`
`25
`
`30
`
`6-methy|-5-thia-5-dioxa-6, 13-Diazatetracycio[9.3 1.0 ° 0* Ypentadeca-2(10),3 8-
`tnene hydrochloride:
`
`7-dimethylamino-5-thia-5-dioxa-6, 13-Diazatetracyclo[9.3.1.0? '° 0* "Jpentadeca-
`2(10),3,8-triene hydrochloride;
`6,7-dioxa-5,8, 14-triazatetracyclo[10.3.1 0° *' 0* Jnexadeca-2(11),3,9-triene
`hydrochioride; and
`5,8-dimethyl-6,7-dioxa-5,8,14-trazatetracyclo[10 3 1 0? '' 0* Yhexadeca-2(11).3.9-
`tnene hydrochloride
`
`35
`
`This invention also retates to compounds of the formula
`
`
`
`Apotex Exhibit 1007.008
`
`Apotex Exhibit 1007.008
`
`

`

`
`
`
`Ri4
`
`R15
`
`wherein P is hydrogen, methyi, COOR™ wherein R™ ts (C,-Ce)alkyl,ally!, 2,2,2-trichioroethy!
`or (Cy-Ce)alkyl; -C(=O)NR°R® wherein R° and R® are defined as in formula | above: -C(=O)H,
`-C(=O)(C,-Ce)aikyl wherein the alkyl moiety may optionally be substituted with from 1
`to 3
`
`10
`
`15
`
`halo atoms, preferably with from 1 to 3 fluoro or chioro atoms; benzy! or t-butoxycarbony! (t-
`Boc); and R'* and R"* are selected,
`independently, from hydrogen, (C,-C,}alky! optionally
`substituted with from one to seven fluorine atoms, -C(=O)(C,-Cg)alkyl, cyano, hydroxy, nitro,
`amino, -O(C,-C,)alky! or halo, with the proviso that R' and R' can not both be hydrogen
`when P is hydrogen or methyl. Such compounds are useful as intermediates in the synthesis
`of compoundsof the formula t.
`Unless otherwise indicated,
`bramo and todo.
`
`the term "halo", as used herein,
`
`includes fluoro, chloro,
`
`Uniess otherwise indicated, the term “alky!”,as used herein. includes straight, branched
`
`or cyclic, and may include straight and cyclic alkyl moreties as well as branched and cyclic
`moteties.
`
`20
`
`The term “alkoxy”, as used herein, means “alkyi-O-", wherein “alkyl” is defined as
`
`above
`
`The term “alkylene, as used herein, means an alkyl radical having two available bonding
`
`sites (1@., -alkyl-), wherein “alkyl” is defined as above.
`Unless otherwise indicated, the term “one or more substituents", as used herein, refers
`
`25
`
`‘to from one to the maximum numberof substituents possibile based on the numberof available
`
`bonding sites.
`
`The term “treatment", as used herein, refers to reversing. alleviating,
`
`inhibiting the
`
`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” 1s defined immediately above.
`
`The compounds of forrnula | may have optical centers and therefore may occur in
`
`different enantiomenc configurations. The invention includes all enantiomers, diastereomers, and
`
`Apotex Exhibit 1007.009
`
`Apotex Exhibit 1007.009
`
`

`

`5_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 compoundsof the
`
`formulae |. Preferred radiolabelled compoundsof formula | are those wherein the radiolabets are
`selected from as °H,
`'"'C, “C,
`‘°F,
`423,
`425)
`
`Such radiolabelled compounds are useful as
`
`1 and
`
`
`
`10
`
`research and diagnostic tools in metabolism pharmacokinetics studies and in binding assaysin
`both animals and man.
`
`The present invention also relates to a pharmaceutical composition for use in reducing
`
`nicotine addiction or aiding in the cessation or lessening of tabacco use in a mammal, including
`
`a human, comprising an amount of a compound of the formula !, or a pharmaceutically
`
`15
`
`acceptable salt thereof, that is effective in reducing nicotine addiction or 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 formula |, or a pharmaceutically
`
`20
`
`acceptable salt thereof, that ts 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 disarder or condition
`
`selected from inflammatory bowel disease (including but not
`
`limited to ulcerative colitis,
`
`pyoderma gangrenosum and Crohn's disease),
`
`irmtable bowel syndrome, spastic dystoma,
`
`25
`
`chronic pain, acute pain, celac sprue, pouchitis. vasoconstriction, anxety, panic disorder,
`
`depression, bipolar disorder, autism, steep disorders, jet lag, amylotropic lateral sclerosis (ALS),
`
`cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastnc acid
`
`hypersecretion,
`
`ulcers, pheochromocytoma, progressive
`
`supramuscular palsy,
`
`chemical
`
`dependencies and addictions (e.g, dependencies on, or addictions to nicotine (and/or tobacco
`
`30
`
`products), alcohol, benzodiazepines, barbituates, opioids or cocaine), headache,
`
`stroke,
`
`traumatic brain injury (TBI), psychosis, Huntington's Chorea, tardive dyskinesia, hyperkinesia,
`
`dysiexia, schizophrenia, multi-infarct dernentia, age related cognitive decline, epilepsy, including
`
`petit mai 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,
`
`35
`
`comprising administering to a mammal in need of such treatment an amount of a compound of
`
`the formula |, or a pharmaceuticaily acceptable salt thereof, that is effective in treating such
`disorder or condition.
`
`Apotex Exhibit 1007.010
`
`Apotex Exhibit 1007.010
`
`

`

`
`
`
`
`
`5
`
`The present
`
`invention also relates to a pharmaceutical composition for treating a
`
`disorder or condition selected from inflammatory Dowel disease (including but not limited to
`
`ulcerative colitis, pyoderma gangrencsum and Crohn's disease),
`
`imtable 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
`
`10
`
`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, opicids or cocaine),
`
`headache,
`
`stroke,
`
`traumatic brain injury (TBI), psychosis, Huntington’s Chorea,
`
`tardive
`
`15
`
`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.
`
`20
`
`The present invention also relates ta a method for reducing nicotine addiction or aiding
`
`in the cessation or lessening of tobacco use in a mammal, comprising administering to said
`
`mammal an amount of a compound comprising an amount of a compoundof the formula
`
`S:
`
`LA
`
`NH
`
`or a pharmaceutically acceptable salt thereof,
`
`that
`
`is effective in reducing nicotine
`
`25
`
`addiction or aiding in the cessation or lessening of tobacco use
`
`The present invention aiso 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),
`
`irmtable bowel syndrome, spastic dystonia,
`
`chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panic disorder,
`
`30
`
`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, mult-infarct dementia, age related cognitive decline. epilepsy, including
`
`35
`
`Apotex Exhibit 1007.011
`
`Apotex Exhibit 1007.011
`
`

`

`-10-
`
`5
`
`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.
`
`15
`
`This invention also reiates to the pharmaceutically acceptable acid addition salts of the
`compounds of formula |. Examples of pharmaceutically acceptable acid addition salts of the
`compoundsof formula | are the salts of hydrochloric acid, p-toluenesulfonic acid, fumanc acid,
`cite acid,
`succinic acid,
`salicylic acid, oxalic acid. hydrobromic acid, phosphoric acid,
`methanesulfonic acid, tartaric acid, malate, di-p-toluoy! tartaric 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 thatfollow are defined as above.
`
`
`
`Apotex Exhibit 1007.012
`
`Apotex Exhibit 1007.012
`
`

`

`-14-
`
`Scheme 1
`
`II]
`
`HA
`
`
`
`Apotex Exhibit 1007.013
`
`Apotex Exhibit 1007.013
`
`

`

`Scheme 2
`
`O
`
`N
`
`CF,
`
`IA
`
`5
`
`ON
`
`O,N
`
`ON
`
`O,N
`
`HN
`
`H,N
`
`
`
`Apotex Exhibit 1007.014
`
`Apotex Exhibit 1007.014
`
`

`

`5
`
`Scheme 2 continued
`
`VIB
`
`5
`
`1R- \ TD Vu
`
`N
`
`N
`
`
`
`i
`1RoTe vit
`JN
`
`>
`
`N
`
`H
`
`
`
`R'2 N—\
`
`N
`
`NH
`
`lA
`
`17
`
`N
`
`N
`
`IB
`
`Apotex Exhibit 1007.015
`
`Apotex Exhibit 1007.015
`
`

`

`5
`
`-14-
`
`Scheme 3
`
`O,N
`
`ON2
`
`17
`
`R
`
`HN
`
`O,N
`
`R'’HN
`
`Lee
`
`H,
`
`
`
`VIA
`
`XXII
`
`XXIV
`
`Apotex Exhibit 1007.016
`
`Apotex Exhibit 1007.016
`
`

`

`Scheme 4
`
`HN
`
`HN2
`
`Re
`
`RV
`
`Nae
`
`Sn
`
`,
`
`
`
`Apotex Exhibit 1007.017
`
`Apotex Exhibit 1007.017
`
`

`

`-16-
`
`Scheme 5
`
`Y
`
`I
`OLDer,
`
`O,N
`
`Xxil
`
`
`
`HO
`
`O,N
`
`7
`
`OROKCl
`
`N
`
`IE
`
`Apotex Exhibit 1007.018
`
`Apotex Exhibit 1007.018
`
`

`

`Scheme 6
`
`
`
`Xl
`
`Apotex Exhibit 1007.019
`
`Apotex Exhibit 1007.019
`
`

`

`-18-
`
`Scheme 6 continued
`
`i
`
`NH
`
`H
`
`NN
`
`s
`
`R'X—<
`|
`
`IF
`
` a
`
`Apotex Exhibit 1007.020
`
`Apotex Exhibit 1007.020
`
`

`

`-19-
`
`Scheme7
`
`
`
`(ring A = present or
`absent)
`Xll
`
`(ring A = present or absent)
`XI
`
`CCI.
`
`(ring A= present or absent)
`XIHA
`
`ec”
`
`(ring A = present or absent)
`XIV
`
`|
`
`IG:
`
`(R* and R? form ring A)
`
`Ii:
`
`(ring A = absent)
`
`
`
`Apotex Exhibit 1007.021
`
`Apotex Exhibit 1007.021
`
`

`

`5
`
`Rie
`
`/ . ~F
`
`-20-
`
`Scheme 8
`
`Ris
`
`|
`
`° F
`
`Rs
`
`
`
`XV
`
`XVI
`
`XVII
`
`(R*8 = F or (C,-C,)alkoxy)
`
`Rte
`
`A
`A
`
`XIX
`
`Re
`
`IH
`
`N——~
`
`Ri
`——
`CH, — i
`
`on
`
`OH
`
`—-
`
`NH
`
`XVIH
`
`Ris
`
`XX
`
`|
`
`R's
`
`XXI
`
`Oo
`
`yd
`CF,
`
`N
`
`6
`
`CF,
`
`O,N
`
`Apotex Exhibit 1007.022
`
`Apotex Exhibit 1007.022
`
`

`

`
`
`5
`
`Scheme 9
`
`I>»
`
`R’R°NO,S
`
`IJ
`
`Ox
`
`CF
`os
`
`NQ —So
`
`IK
`
`NH
`
`Apotex Exhibit 1007.023
`
`Apotex Exhibit 1007.023
`
`

`

`NC
`O._CF,
`|_eee
`N
`
`Co
`
`
`
`-22.
`
`5
`
`Scheme 10
`
`1ea),
`
`Cl
`
`IM
`
`IN
`
`NH, ae SOL
`
`HN
`
`ix’
`
`Apotex Exhibit 1007.024
`
`Apotex Exhibit 1007.024
`
`

`

`-23-
`
`5
`
`Scheme 1-10 illustrate methods of synthesizing compoundsof the formula |.
`
`Referring to Scheme1, the starting material of formula Ill 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 0°C to about room
`
`temperature.
`
`10
`
`The compound of formula IV is then converted into the dinitro derivative of formula IIA
`
`by the following process. The compound ofthe formula IV is added to a mixture of 4 or more
`
`equivalents oftrifluoromethanesulfonic acid (CF;50,0H) 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 of the foregoing
`reactions are generally conducted at a temperature ranging from about -78°C to about O°C for
`
`15
`
`about 2 hours, and then allowed to warm to room temperature for the remaining time.
`
`Reduction of the compound offormuia IIA, using methods well known to thoseofskill in
`
`the art. yields the compound of formula IIB This reduction can be accampiished, for example,
`
`using hydrogen and a palladium catalyst such as palladium hydroxide and running the reaction
`in methanol at about room temperature.
`
`20
`
`Referring ta Scheme 2, the compoundof formula IIA is converted into the corresponding
`compound wherein the tnfluoroacety! protecting group !s replaced by a t-Boc protecting group
`(VIA) by reacting it 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
`
`25
`
`or carbonate ts generally carned 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 1s preferably carned out in a
`
`
`
`30=solvent such as THF, dioxane or methylene chloride at a ternperature from about 0°C to about
`
`raom 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 base is preferred The resuiting 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 JIA into the
`
`35
`
`corresponding diamino compound of formuia IIB.
`
`The conversion of the compound of formula VIB into the desired compound of the
`formula Vil can be accomplished by reacting the compoundof formula VIB with a compound of
`the formula
`
`Apotex Exhibit 1007.025
`
`Apotex Exhibit 1007.025
`
`

`

`
`
`-24-
`
`H,C,0,C
`
`CO,C,H,
`
`XXIA
`
`10
`
`R
`
`OC.H,
`
`10
`
`15
`
`20
`
`25
`
`30
`
`wherein R® is hydrogen, (C,-C.)alkyl optionally substituted with from one to seven fiuorine
`atoms, aryl-(Co -C,)alkyl wherein said aryl is selected from pheny! and naphthyl, or heteroaryl-
`(Cy -C,)alkyl wherein said heteroaryl is selected from five to seven membered aromatic rings
`containing from one to four heteratoms selected from oxygen, nitrogen and sulfur, and wherein
`each of the foregoing aryl and heteroryi groups may optionally be substituted with one or more
`substituents, preferably from zero to two substituents, independently selected from (C, -Ce)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 ethanotacetic 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, ortrifluoroacetic acid, preferably hydrochloric acid in ethy! 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.
`