(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).
`
`(74) Agents: SPIEGEL, Allen, J. et al.; Pfizer Inc., 235 East 42nd
`Street, New York, NY 10017 (US).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(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, [(2,
`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).
`
`Published
`With international search report.
`
`PCT
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`
`
`(51) International Patent Classification 6 :
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
` WO 99/35131
`
`(11) International Publication Number:
`
`C07D 221/22, A61K 31/435, C07D
`(43) International Publication Date:
`15 July 1999 (15.07.99)
`
`
`471/08, 498/08, 513/08
`
`
`
`PCT/IB98/01813
`(21) International Application Number:
`
`(22) International Filing Date:
`13 November 1998 (13.11.98)
`
`
`
`
`
`
`
`
`
`(54) Title: ARYL FUSED AZAPOLYCYCLIC COMPOUNDS
`
`R2
`
`R3
`
`(I)
`
`(57) Abstract
`
`Compounds of formula (I) and their pharmaceutically acceptable salts, wherein R1, R2, R3 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
`
`

`

`Singapore
`
`Albania
`Armenia
`Austria
`Australia
`Azerbaijan
`Bosnia and Herzegovina
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`care d‘Ivoire
`Cameroon
`China
`Cuba
`Czech Republic
`Germany
`Denmark
`Estonia
`
`ES
`FI
`FR
`GA
`GB
`GE
`GH
`GN
`GR
`HU
`IE
`IL
`[S
`[T
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LC
`LI
`LK
`LR
`
`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
`
`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
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`N0
`NZ
`PL
`PT
`R0
`RU
`SD
`SE
`SG
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT
`
`51
`SK
`SN
`SZ
`TD
`TG
`TJ
`TM
`TR
`TT
`UA
`UG
`US
`UZ
`VN
`YU
`ZW
`
`Slovenia
`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
`
`Apotex Exhibit 1005.002
`
`

`

`WO 99/35131
`
`PCT/IB98/01813
`
`ARYL FUSED AZAPOLYCYCLIC COMPOUNDS
`
`Background of the Invention
`
`1O
`
`15
`
`20
`
`25
`
`30
`
`This
`
`invention relates to aryl
`
`fused azapolycyclic compounds, as defined more
`
`specifically by formula I below. Compounds of formula I 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 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 (eg, dependencies on, or addictions to nicotine
`
`(and/or
`
`tobacco products),
`
`alcohol, benzodiazepines, barbituates, opioids or cocaine),
`
`headache, stroke,
`
`traumatic brain injury (TBl), 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.
`
`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
`
`antidepressant (SRI), in order to treat both the cognitive decline and depression associated with
`
`AD, PD, stroke, Huntington’s Chorea or traumatic brain injury (TBl),
`
`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 enhancement for the treatment, for example, of ALS, cognitive
`
`dysfunction, age related cognitive decline, AD, PD stroke, Huntington’s Chorea and TBl, or in
`
`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.
`
`Apotex Exhibit 1005.003
`
`Apotex Exhibit 1005.003
`
`

`

`W0 99/3513]
`
`PCT/IB98/01813
`
`5
`
`Other compounds that 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 is incorporated herein by
`reference in its entirety.
`
`10
`
`This invention relates to aryl fused azapoiycyciic compounds of the formula
`
`Summary of the invention
`
`R2
`
`R3
`
`NR1
`
`(I)
`
`is hydrogen,
`R1
`-CH2CH2-O-(C1-C4)alkyi;
`
`(C1-C6)aikyi, unconjugated (C3-C6)aikenyi, benzyi, xc(=0)R13 or
`
`15
`
`hydroxy,
`
`R2 and R3 are selected, independently, from hydrogen, (C2—C6)alkenyi, (CZ-C6)aikynyi,
`nitro,
`amino, halo, cyano,
`-SOq(C1-C6)aikyi wherein q
`is zero, one or
`two,
`
`-C(=O)R13,
`-SOZNR7R8,
`-CONR5R5,
`-C02R4,
`[(C1-Ce)alkyi]2amino-,
`(C1_Ce)alkylamino-,
`-XC(=O)R13, aryl-(Co-C3)ali<yi- or aryl-(Co-C3)alkyl—O-, wherein said aryl is selected from phenyl
`
`and naphthyl, heteroaryl-(Co-Cs)alkyi- or heteroaryl-(CO-Ca)aikyl-O-, wherein said heteroaryl is
`
`selected from five to seven membered aromatic rings containing from one to four heteroatoms
`
`20
`
`selected from oxygen, nitrogen and sulfur, and X2(CO—Cs)alkoxy-(Co-Ce)alkyl—, wherein X2 is
`absent or X2 is (C1-C6)aiky|amino- or [(C1—Cs)alkyl]2amino-, and wherein the (C0-C6)alkoxy-(Co-
`C6)alky|- moiety of said X2(Co-C6)alkoxy-(Co-C6)aikyi- contains at least one carbon atom, and
`
`wherein from one to three of the carbon atoms of said (Co-C6)alkoxy-(Co-C5)alkyl- moiety may
`
`optionally be replaced by an oxygen, nitrogen or sulfur atom, with the proviso that any two such
`
`25
`
`heteroatoms must be separated by at least two carbon atoms, and wherein any of the alkyl
`
`moieties of said (COC5)a|koxy-(CO—Ce)aikyl- may be optionally substituted with from two to seven
`
`fluorine atoms, and wherein one of the carbon atoms of each of the alkyl moieties of said aryl-
`
`(Co-C3)alkyi- and said heteroaryl—(Co-C3)aikyi- may optionally be replaced by an oxygen, nitrogen
`
`or sulfur atom, and wherein each of the foregoing aryl and heteroaryl groups may optionally be
`
`30
`
`substituted with one or more substituents, preferably from zero to two substituents,
`
`independently selected from (C1-C6)alkyl optionally substituted with from one to seven fluorine
`
`atoms, (C1-Cs)alkoxy optionally substituted with from two to seven fluorine atoms, halo (39;
`
`chloro, fluoro, bromo or iodo), (CZ-Cs)alkenyi, (CZ—Cs)alkynyi, hydroxy, nitro, cyano, amino, (C1-
`
`Apotex Exhibit 1005.004
`
`Apotex Exhibit 1005.004
`
`

`

`W0 99/3513]
`
`PCT/IB98/01813
`
`5
`
`C6)alkylamino-,
`XC(=O)R13;
`
`[(C1-C6) alkyllzamino-, —c02R4,
`
`-CONR5R6,
`
`-SOZNR7R8, —C(=O)R13 and -
`
`or R2 and R3, together with the carbons to which they are attached, form a four to seven
`
`membered monocyciic, or a ten to fourteen membered bicyclic, carbocyciic ring that can be
`
`saturated or unsaturated. wherein from one to three of the nonfused carbon atoms of said
`
`monocyciic rings, and from one to five of the carbon atoms of said bicyclic rings that are not part
`of the benzo ring shown in formula 1, may optionally and independently be replaced by a
`nitrogen, owgen or sulfur, and wherein said monocyciic and bicyclic rings may optionally be
`
`substituted with one or more substituents, preferably from zero to two substituents for the
`
`monocyciic rings and from zero to three substituents for the bicyclic rings, that are selected,
`
`independently, from (C0-C5)alkoxy-(CD-Ce)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, (C2-C6)alkenyl, (C2-C6)alkynyl, hydroxy, amino,
`(C1—C6)alkylamino-,
`[(C1~C5)alkyl}2amino-,
`-C02R4,
`-CONR5R6,
`-SOZNR7R5,
`-C(=O)R13, and -
`XC(=O)R13;
`
`each R“, R5, R6, R7, R8 and R13 is selected, independently, from hydrogen and (C1-Ce)
`alkyl, or R5 and R6, or R7 and R8 together with the nitrogen to which they are attached, form a
`
`pyrrolidine,
`
`piperidine, morpholine,
`
`azetidine,
`
`piperizine,
`
`-N—(C1-Ce)aikylpiperizine
`
`or
`
`thiomorpholine ring, or a thiomorpholine ring wherein the ring sulfur is replaced with a sulfoxide
`or sulfone; and
`
`each X is, independently, (C1-C5)alkylene;
`
`with the proviso that: (a) at least one of R1, R2 and R3 must be the other than hydrogen,
`and (b) when R2 and R3 are hydrogen, R1 cannot be methyl or hydrogen;
`
`and the pharmaceutically acceptable salts of such compounds.
`
`Examples of heteroaryl groups that each of R2 and R3 can be are the following:
`
`thienyl, oxazoyl,
`
`isoxazolyi,
`
`pyridyl,
`
`pyrimidyl,
`
`thiazolyl,
`
`tetrazolyl,
`
`isothiazolyl,
`
`triazolyi,
`
`imidazolyl, tetrazolyl, pyrroyl and the following groups:
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Apotex Exhibit 1005.005
`
`Apotex Exhibit 1005.005
`
`

`

`WO 99/35131
`
`PCT/IB98/Ol8l3
`
`R9
`
`18
`
`RYO R9
`l T
`N———N
`
`N
`
`\
`
`‘0
`
`\”
`
`18
`
`18
`
`R
`
`9
`
`R18
`
`Y/ R
`
`N
`/
`
`O—N
`
`{If
`R18
`N\R9
`
`5
`
`R KN’RQ
`N:_/
`
`R9 NQN
`N\ /
`N
`
`R18
`
`wherein one of R9 and R18 is hydrogen or (C1-Cs)alkyl, and the other is a bond to the
`benzo ring of formula I.
`
`Examples of compounds of this invention are compounds of the formula I, and their
`
`pharmaceutically acceptable salts, wherein R2 and R3, together with the benzo ring of formula I,
`
`10
`
`form a bicyclic ring system selected from the following:
`
`N
`
`\>~R10
`
`N
`
`N
`
`\>_R1o
`
`N R10
`R17
`
`N
`
`O\
`
`(Opt!
`
`R10
`
`10
`
`S
`
`@D—RN
`
`wherein R1“ and R” are selected.
`
`independently,
`
`from (CO-C6)alkoxy-(Co-Ce)alkyl—
`
`wherein the total number of carbon atoms does not exceed six and wherein any of the alkyl
`
`15
`
`moieties may optionally be substituted with from one to seven fluorine atoms; nitro, cyano, halo,
`
`amino, (C1-Cs)alkylamino-, [(c1-ce) alkyllzaminoq -COZR4, -CONR5R6, -SOZNR7R8, -C(=O)R13,
`
`-XC(=O)R13, phenyl and monocyclic heteroaryl wherein said heteroaryl is defined as R2 and R3
`
`are defined in the definition of compounds of the formula I above;
`
`Other embodiments of this invention relate to compounds of the formula I, and their
`
`20
`
`pharmaceutically acceptable salts, wherein R2 and R3, together with the benzo ring of formula I,
`
`form a bicyclic or tricyclic ring system selected from the following:
`
`Apotex Exhibit 1005.006
`
`Apotex Exhibit 1005.006
`
`

`

`wo 99/35131
`
`PCT/IB98/01813
`
`/
`N
`
`S \
`
`@Q/
`
`10
`
`R
`
`R10
`
`R17
`
`5
`
`R10
`
`N
`
`R17
`
`N
`
`R17
`
`N
`E10
`
`)m
`
`R17
`
`CN
`
`N
`”Rio
`
`R10
`
`R17
`
`N
`
`N
`\
`N A
`
`/ \
`
`\ /
`
`17
`
`m/Zx
`
`10
`
`R10
`N
`,1]
`R17
`
`wherein R10 and R17 are defined as above and m is zero, one or two‘ and wherein one of
`
`the carbon atoms of ring A can optionally be replaced with oxygen or -N(C1-C6)alkyl.
`
`Other embodiments of this invention relate to compounds of the formula I, and their
`
`10
`
`pharmaceutically acceptable salts, wherein neither R2 nor R3 is attached to the benzo ring of
`formula l via an oxygen atom.
`
`Other embodiments of this invention relate to compounds of the formula l wherein R1 is
`
`not methyl.
`
`Examples of specific compounds of the formula I are the following:
`
`15
`
`6-methyl—5,7—dioxo-6,13-diazatetracyclo[9r3.1.02'1D.04'3]pentadeca—2(10),3,8—triene
`
`hydrochloride;
`
`Apotex Exhibit 1005.007
`
`Apotex Exhibit 1005.007
`
`

`

`WO 99/35131
`
`PCT/IB98/01813
`
`5
`
`6—methyI-5-oxo-6,13-diazatetracyclo[9.3.1.02'1°.O4'B]pentadeca-2(1O),3,8—triene
`hydrochloride;
`
`5,7-dimethyl-6—oxo-5,7,13-triazatetracyclo[9.3.1.02'1°.04‘8]pentadeca-2(10),3,8-triene
`hydrochloride;
`
`5,7—dioxo—6,13-diazatetracyclo[9.3.1.02'10.04'8]pentadeca-2(1O),3,8—triene
`
`10
`
`hydrochloride;
`
`15
`
`5-oxo-6,13—diazatetracyclo[9.3.1.02'1°.O4'8]pentadeca-2(1O),3,8-triene hydrochloride;
`
`6-oxo-5,7,13-triazatetracyclol9.3.1.02'1°.04'8]pentadeca-2(10),3,8—triene hydrochloride;
`4,5-difluoro—10-aza—tricyclo[6.3.1.02'7]dodeca-2(7),3,5—triene hydrochloride;
`
`5-fluoro—10-aza—tricyclo[6.3.1.02'7]dodeca-2(7),3,5-triene—4-carbonitrile hydrochloride;
`
`4-ethynyl-5-fluoro-10-aza-tricyclo[6.3.1.02'71dodeca-2(7),3,5-triene hydrochloride;
`5-ethynyI-1 O-aza-tricyclo[6. 3.1 .02‘7ldodeca—2(7),3,5-triene-4—carbonitrile hydrochloride;
`5-chloro-10-aza-tricyclo[6.3.1.02‘7]dodeca-2(7);3,5-triene-4-carbonitrile hydrochloride;
`
`4-ethynyl-5-chloro-1O-aza-tricyclo[6.3.1.02'7]dodeca-2(7),3,5-triene hydrochloride;
`
`5-oxa-7-methyI-6-oxo-7,13-diazatetracyclo[9.3.1.02'1°.O"B]pentadeca-2(1O),3,8—triene
`hydrochloride;
`
`20
`
`4—fluoro-5—trifluoromethyl-10-aza-tricyclo[6.3.1.02‘7]dodeca-2(7).3,5-triene
`
`hydrochloride;
`
`4-chloro-5-trifluoromethyI-10-aza-tricyclo[6.3.1.02'7]dodeca-2(7),3,5-triene
`
`hydrochloride;
`
`25
`
`5—trifluoromethyi-10—aza-tricyclo[6.3.1.02'7]dodeca-2(7),3,5-triene-4-carbonitrile
`
`hydrochloride;
`
`4-ethynyI-5-trifluoromethyI-10-aza-tricyclo[6.3.1.02‘7]dodeca-2(7),3,5-triene
`
`hydrochloride;
`
`6-methyI-5-thia-5-dioxa—6,13-Diazatetracyclo[9.3.1.02'1°.04'8]pentadeca-2(10),3,8-
`
`30
`
`triene hydrochloride;
`
`7-dimethylamino—S—thia—5-dioxa—6,13-Diazatetracyclo[9.3.1 .02'1°.04‘8]pentadeca-
`
`2(10).3,8-triene hydrochloride;
`
`6,7-dioxa-5,8,14-triazatetracyclo[10.3.1.02'”.O4‘9]hexadeca—2(11),3,9-triene
`
`hydrochloride; and
`
`35
`
`5,8-dimethyI-6,7-dioxa-5,8,14-triazatetracyclo[10.3.1.02'“.04‘9]hexadeca-2(11).3,9—
`
`triene hydrochloride.
`
`This invention also relates to compounds of the formula
`
`Apotex Exhibit 1005.008
`
`Apotex Exhibit 1005.008
`
`

`

`WO 99/35131
`
`PCT/IB98/01813
`
`Z—"U
`
`R14
`
`R15
`
`wherein P is hydrogen, methyl, COOR16 wherein R16 is (C1-C6)alkyl, allyl, 2,2,2-trichloroethyl
`or (C1—C6)alkyl; -C(=O)NR5R6 wherein R5 and R6 are defined as in formula I above; —C(=O)H,
`
`-C(=O)(C1-C6)alkyl wherein the alkyl moiety may optionally be substituted with from 1
`
`to 3
`
`10
`
`halo atoms, preferably with from 1 to 3 fluoro or chloro atoms; benzyl or t—butoxycarbonyl (t-
`Boc); and R14 and R15 are selected,
`independently, from hydrogen, (C1-Ce)alkyl optionally
`
`substituted with from one to seven fluorine atoms; ~C(=O)(C1—Ce)alkyl, cyano, hydroxy, nitro,
`
`amino, —O(C1-Cs)alkyl or halo; with the proviso that R” and R15 can not both be hydrogen
`
`when P is hydrogen or methyl. Such compounds are useful as intermediates in the synthesis
`of compounds of the formula I.
`
`Unless othenivise indicated,
`bromo and iodo.
`
`the term "halo", as used herein,
`
`includes fluoro, chloro,
`
`Unless othenNise 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 "aikoxy", as used herein, means “alkyl-O-", wherein “alkyl" is defined as
`
`above.
`
`The term "alkylene, as used herein, means an alkyl radical having two available bonding
`
`sites (ii, -aIkyl-), 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 number of substituents possible based on the number of 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
`
`of treating, as “treating” is defined immediately above.
`
`The compounds of formula I may have optical centers and therefore may occur in
`
`different enantiomeric configurations. The invention includes all enantiomers, diastereomers, and
`
`15
`
`20
`
`25
`
`30
`
`Apotex Exhibit 1005.009
`
`Apotex Exhibit 1005.009
`
`

`

`W0 99/3513]
`
`PCT/IB98/01813
`
`other stereoisomers of such compounds of formula I, as well as racemic and other mixtures
`thereof.
`
`The present invention also relates to all radiolabelled forms of the compounds of the
`
`formulae I. Preferred radiolabelled compounds of formula l are those wherein the radiolabels are
`
`selected from as 3H. 11C, 1“C, 18F, 123| and 125l. Such radiolabelled compounds are useful as
`
`research and diagnostic tools in metabolism pharmacokinetics studies and in binding assays in
`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 tobacco use in a mammal, including
`a human, comprising an amount of a compound of the formula I, 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 compound of the formula I, 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 mammal in need of such treatment an amount of a compound of
`
`the formula I, or a pharmaceutically acceptable salt thereof, that is effective in treating such
`disorder or condition.
`
`1O
`
`15
`
`20
`
`25
`
`30
`
`35
`
`ApoteX Exhibit 1005.010
`
`Apotex Exhibit 1005.010
`
`

`

`W0 99/3513]
`
`PCT/IB98/01813
`
`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 1, 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
`
`mammal an amount of a compound comprising an amount of a compound of the formula
`
`NH
`
`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 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 (TBl), psychosis, Huntington’s Chorea, tardive dyskinesia, hyperkinesia,
`
`dyslexia, schizophrenia, multi-infarct dementia, age related cognitive decline, epilepsy, including
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`ApoteX Exhibit 1005.011
`
`Apotex Exhibit 1005.011
`
`

`

`WO 99/35131
`
`PCT/IB98/01813
`
`-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
`
`‘15
`
`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
`
`compounds of formula 1. Examples of pharmaceutically acceptable acid addition salts of the
`
`compounds of formula I are the salts of hydrochloric acid, p-toiuenesulfonic acid, fumaric acid,
`
`citric acid, succinic acid,
`
`salicylic acid, oxalic acid. hydrobromic acid, phosphoric acid,
`
`methanesulfonic acid, tartaric acid, malate, di-p-toiuoyl tartaric acid, and mandelic acid.
`
`Except where otherwise stated, R1 through R”, m and P, and structural formula I in the
`
`reaction schemes and discussion that follow are defined as above.
`
`Detailed Description of the Invention
`
`ApoteX Exhibit 1005.012
`
`Apotex Exhibit 1005.012
`
`

`

`W0 99/3513]
`
`PCT/IB98/01813
`
`-11-
`
`Scheme 1
`
`IV
`
`HA
`
`IIB
`
`ApoteX Exhibit 1005.013
`
`Apotex Exhibit 1005.013
`
`

`

`W0 99/3513]
`
`PCT/IB98/01813
`
`-12_
`
`
`
`IIA
`
`VIA
`
`VIB
`
`ApoteX Exhibit 1005.014
`
`Apotex Exhibit 1005.014
`
`

`

`WO 99/35131
`
`PCT/[B98/01813
`
`5
`
`-13-
`
`Scheme 2 continued
`
`VIB
`
`V“
`
`H N
`
`R10—<\ mN—tBoc
`
`N
`
`17
`
`T
`N
`R10
`—<\
`N
`
`H
`
`N
`R10
`‘<\
`N
`
`N~tBoc
`
`I
`
`vn
`
`NH
`
`IA
`
`IB
`
`ApoteX Exhibit 1005.015
`
`R17
`
`1 N
`
`H mmN
`
`Apotex Exhibit 1005.015
`
`

`

`WO 99/3513]
`
`PCT/IB98/01813
`
`_14-
`
`
`Scheme 3
`
`094
`
`c%N
`
`:]::::1:::E:>u—130c
`
`RWHN
`
`C)N
`
`mN—tBoc
`
`VIA
`
`XXIII
`
`RWHN
`
`A’j£:I$N—t800
`
`H2
`
`XXIV
`
`Z—JU
`R1q__<$ ::[::::I:::§E:>v—¢Boc
`
`N
`
`17
`
`I
`
`N
`
`RQ__<\:I:::]::>E>NH
`
`N
`
`XXV
`
`IB
`
`ApoteX Exhibit 1005.016
`
`Apotex Exhibit 1005.016
`
`

`

`WO 99/35131
`
`PCT/lB98/01813
`
`5
`
`-15-
`
`
`Scheme 4
`
`H2N
`
`HZN
`
`mN—tBoc
`
`VIB
`
`R10
`
`N/
`
`I mm to
`
`R17
`
`\N
`
`ApoteX Exhibit 1005.017
`
`Apotex Exhibit 1005.017
`
`

`

`WO 99/35131
`
`PCT/IB98/01813
`
`Scheme 5
`
`02N
`
`O
`
`HO
`
`H1334
`
`ON
`
`0
`
`R1°—<\ mmN
`
`XXII
`
`V|||
`
`IE
`
`ApoteX Exhibit 1005.018
`
`Apotex Exhibit 1005.018
`
`

`

`WO 99/3513]
`
`PCT/IB98/01813
`
`-17-
`
`Scheme 6
`
`IX
`
`IX
`
`XI
`
`ApoteX Exhibit 1005.019
`
`Apotex Exhibit 1005.019
`
`

`

`WO 99/35131
`
`PCT/IB98/01813
`
`-18-
`
`5
`
`Scheme 6 continued
`
`H
`
`R10\H/N
`
`i
`
`s
`
`10R (\wa
`
`IF
`
`ApoteX Exhibit 1005.020
`
`Apotex Exhibit 1005.020
`
`

`

`WO 99/3513]
`
`PCT/IB98/01813
`
`5
`
`-19-
`
`
`Scheme 7
`
`X1
`
`00 2
`
`X
`
`
`
`A O.)
`
`(ring A = present or
`
`(ring A = present or absent)
`
`XII
`
`/X||I
`absent)
`00.):
`
`(ring A= present or absent)
`XIIIA
`
`00.
`
`(ring A = present or absent)
`XIV
`
`I
`
`00. NH
`
`IG:
`
`(R2 and R3 form ring A)
`
`III:
`
`(ring A = absent)
`
`ApoteX Exhibit 1005.021
`
`Apotex Exhibit 1005.021
`
`

`

`WO 99/35131
`
`PCT/IB98/01813
`
`-20-
`
`Scheme 8
`
`R18
`
`1
`
`R18
`
`l
`
`I a
`
`F
`
`F
`
`5
`
`18
`
`R
`
`I
`
`xv
`
`XVI
`
`XVII
`
`(R15 = F or (C1-Ce)alkoxy)
`
`R18
`
`L
`
`R18
`
`N
`
`mm «—— (iii OH
`
`OH
`
`XIX
`
`R18
`
`IH
`
`NH
`
`XVHI
`
`18
`
`R
`
`—~ @EE 4)N
`
`CF3
`
`ON
`
`XX
`
`J
`
`R18
`
`XXI
`
`0
`N4
`
`CF3
`
`ApoteX Exhibit 1005.022
`
`Apotex Exhibit 1005.022
`
`

`

`W0 99/3513]
`
`PCT/IB98/01813
`
`5
`
`Scheme 9
`
`gm
`
`R7R8NOZS
`
`IJ
`
`CF
`
`CY 3
`
`N
`
`CI
`
`-—~» mm
`
`IK
`
`IV
`
`R13
`
`NH
`
`|L
`
`ApoteX Exhibit 1005.023
`
`Apotex Exhibit 1005.023
`
`

`

`W0 99/3513]
`
`PCT/IB98/01813
`
`-22-
`
`5
`
`Scheme 10
`
`mmCI
`
`IM
`
`CF3
`
`j: /
`
`mmNC
`
`IX'
`
`H N
`2
`
`RBJLN
`
`IN
`
`IP
`
`IQ
`
`ApoteX Exhibit 1005.024
`
`Apotex Exhibit 1005.024
`
`

`

`W0 99/3513]
`
`PCT/IB98/018l3
`
`-23-
`
`Scheme 1—10 illustrate methods of synthesizing compounds of the formula I
`
`.
`
`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 W. This reaction is
`
`typically conducted in methylene chloride at a temperature from about 0°C to about room
`
`temperature.
`
`The compound of formula IV is then converted into the dinitro derivative of formula ”A
`
`by the following process. The compound of the formula W is added to a mixture of 4 or more
`
`equivalents of trifluoromethanesulfonic acid (CF 3SOZOH) and 2 to 3 equivalents of nitric 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 0°C for
`
`about 2 hours, and then allowed to warm to room temperature for the remaining time.
`
`Reduction of the compound of formula “A, using methods well known to those of skill 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 of formula HA is converted into the corresponding
`
`compound wherein the trifluoroacetyl protecting group is 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
`
`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—butyidicarbonate is preferably carried out in a
`
`solvent such as THF, dioxane or methylene chloride 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.
`
`When the reactant is a salt of the amine, use of a base is 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 compound of formula MB.
`
`The conversion of the compound of formula VIB into the desired compound of the
`
`formula Vll can be accomplished by reacting the compound of formula VIB with a compound of
`the formula
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`ApoteX Exhibit 1005.025
`
`Apotex Exhibit 1005.025
`
`

`

`WO 99/35131
`
`PCT/lB98/01813
`
`-24-
`
`HSCZOZC
`
`COZCZH5
`
`xqu
`
`R10
`
`ocZH5
`
`1O
`
`15
`
`20
`
`wherein R10
`
`is hydrogen, (C1-CE)alkyl optionally substituted with from one to seven fluorine
`
`atoms, aryl—(C0 -Cs)alkyl wherein said aryl is selected from phenyl and naphthyl, or heteroaryl—
`
`(C0 -C3)alky| 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 heteroryl groups may optionally be substituted with one or more
`
`substituents, preferably from zero to two substituents, independently selected from (C1 -Cs)alkyl
`
`optionally substituted with from one to seven fluorine atoms. (C1—Cs)alkoxy optionally substituted
`
`with from one to seven fluorine atoms and cyano. The preferred solvent for this reaction is a
`
`10:1 mixture of ethanolzacetic 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.
`
`Alternate methods of preparing compounds of the formula Vll
`
`the compound of
`
`formula VIB are described by Segelstein eta_l., Tetrahedron Lett., 1993, 33:, 1897.
`
`Removal of the t-Boc protecting group from the compound of formula Vll yields
`
`corresponding compound of 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 V“ 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.
`
`25
`
`The compound of formula V” can be converted into the corresponding compound of
`
`formula IB by reacting it with a compound of the formula R172, wherein R17 is defined as R10 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
`
`30
`
`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 R172 is generally
`
`carried out at a temperature from about room temperature to about 100°C, preferably at about
`50°C, for about five hours.
`
`ApoteX Exhibit 1005.026
`
`Apotex Exhibit 1005.026
`
`

`

`WO 99/35131
`
`PCT/IB98/01813
`
`-25-
`
`Scheme 3 illustrates 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 R17 is a bulky group such as an aryl or heteroaryl
`containing group, or when R17 can not be attached, as illlustrated in Scheme 2, by alkylation
`
`or aryl substitution methods. Referring to Scheme 3, the compound of