(12) United States Patent
`Coe et al.
`
`I 1111111111111111 11111 111111111111111 IIIII 111111111111111 1111111111 11111111
`US006410550Bl
`US 6,410,550 Bl
`Jun.25,2002
`
`(10) Patent No.:
`(45) Date of Patent:
`
`(54) ARYL FUSED AZAPOLYCYCLIC
`COMPOUNDS
`
`(75)
`
`Inventors: Jotham Wadsworth Coe, Niantic;
`Paige Roanne Palmer Brooks, North
`Stonington, both of CT (US)
`
`(73) Assignee: Pfizer INC, New York, NY (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by O days.
`
`(21) Appl. No.:
`
`09/402,010
`
`(22) PCT Filed:
`
`Nov. 13, 1998
`
`(86) PCT No.:
`
`PCT/IB98/01813
`
`§ 371 (c)(l),
`(2), ( 4) Date:
`
`Sep. 28, 1999
`
`(87) PCT Pub. No.: WO99/35131
`
`PCT Pub. Date: Jul. 15, 1999
`
`(51)
`
`Related U.S. Application Data
`(60) Provisional application No. 60/070,245, filed on Dec. 31,
`1997.
`Int. Cl.7 ...................... A61K 31/44; A61K 31/505;
`C07D 221/22; C07D 413/00; A61P 1/00
`(52) U.S. Cl. ............... 514/289; 514/210.21; 514/228.2;
`514/232.8; 514/253.02; 514/253.03; 514/256;
`514/281; 514/295; 546/43; 546/74; 546/97;
`544/58.2; 544/60; 544/125; 544/126; 544/242;
`544/361
`(58) Field of Search .............................. 546/43, 74, 97;
`544/58.2, 60, 125, 126, 242, 361; 514/210.21,
`228.2, 232.8, 253.02, 253.03, 256, 281,
`289,295
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`3,471,503 A * 10/1969 Carson .................... 260/294.7
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`EP
`WO
`WO
`WO
`
`0 955 301
`1 078 637
`WO 99/55680
`WO 00/44755
`WO 00/45846
`
`* 11/1999
`* 2/2001
`* 11/1999
`* 8/2000
`* 8/2000
`
`OTHER PUBLICATIONS
`
`Mazzocchi et al., Synthesis and Pharmacological Activity of
`2,3,4,5-Tetrahydrol,5 methano-lH-3-benzazepines, lour-
`nal of Medicinal Chemistry, vol. 22, No. 4, pp. 455-457,
`1979.*
`
`* cited by examiner
`
`Primary Examiner-Brenda Coleman
`(74) Attorney, Agent, or Firm-Peter C. Richardson; Paul
`H. Ginsburg; Roy F. Waldron
`
`(57)
`
`ABSTRACT
`
`Compounds of the formula
`
`(I)
`
`, R 2
`and their pharmaceutically acceptable salts, wherein R 1
`,
`and R 3 are defined as in the specification, intermediates in
`the synthesis of such compounds. pharmaceutical composi(cid:173)
`tions containing such compounds and methods of using such
`compounds, in the treatment of neurological and psycho(cid:173)
`logical disorders.
`
`15 Claims, No Drawings
`
`Apotex Exhibit 1006.001
`
`

`

`US 6,410,550 Bl
`
`1
`ARYL FUSED AZAPOLYCYCLIC
`COMPOUNDS
`
`2
`SUMMARY OF IBE INVENTION
`This invention relates to aryl fused azapolycyclic com(cid:173)
`pounds of the formula
`
`This application is a national stage entry under 35 U.S.C. 5
`§371 of PCT/IB98/01813, filed Nov. 13, 1998 which claims
`the benefit of U.S. Provisional Application Ser. No. 60/070,
`245, filed Dec. 31, 1997.
`
`BACKGROUND OF THE INVENTION
`
`10
`
`(I)
`
`15
`
`This invention relates to aryl fused azapolycyclic
`compounds, as defined more specifically by formula I below.
`Compounds of formula I bind to neuronal nicotinic acetyl-
`choline 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 20
`dystonia, chronic pain, acute pain, celiac sprue, pouchitis,
`vasoconstriction, anxiety, panic disorder, depression, bipolar
`disorder, autism, sleep disorders, jet lag, amyotrophic lateral
`sclerosis (ALS), cognitive dysfunction, hypertension,
`bulimia, anorexia, obesity, cardiac, arrythmias, gastric acid
`hypersecretion, ulcers, pheochromocytoma, progressive
`supranuclear palsy, chemical dependencies and addictions
`(e.g., dependencies on, or addictions to nicotine (and/or
`tobacco products), alcohol, benzodiazepines, barbiturates, 30
`opioids or cocaine), headache, stroke, traumatic brain injury
`(TEI), obsessive-compulsive disorder, psychosis, Hunting(cid:173)
`ton's Chorea, tardive dyskinesia, hyperkinesia, dyslexia,
`schizophrenia, multi-infarct dementia, age related cognitive
`decline, epilepsy, including petit mal absence epilepsy, 35
`senile dementia of the Alzheimer's type (AD), Parkinson's
`disease (PD), attention deficit hyperactivity disorder
`(ADHD) and Tourette's Syndrome.
`
`25
`
`40
`
`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, 45
`Huntington's Chorea or traumatic brain injury (TEI): 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 50
`Chorea and TEI; 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, 55
`Huntington's Chorea and TEI; 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.
`
`60
`
`Other compounds that bind to neuronal nicotinic receptor
`sites are referred to in U.S. patent application Ser. No.
`08/963,852, which was filed on Nov. 4, 1997 now U.S. Pat.
`No. 6,020,335. The foregoing application is owned in com- 65
`mon with the present application, and is incorporated herein
`by reference in its entirety.
`
`R1
`is hydrogen, (CcC6)alkyl, unconjugated (C3-C6)
`alkenyl, benzyl, XC(=O)R13 or -CH2 CH2-O(cid:173)
`(CcC4)alkyl;
`R2 and R3 are selected, independently, from hydrogen,
`(C 2-C 6)alkenyl, (C 2-C6)alkynyl, hydroxy, nitro,
`amino, halo, cyano, -SOq(C1-C6)alkyl wherein q is
`zero, one or two, (C1-C6)alkylamino-, [(C1-C6)alkyl]
`, -SO 2 NR7 R8
`2 amino-, -CO 2 R4, -CONR 5 R 6
`,
`-C(=O)R13 -XC(=O)R13
`, aryl-(C0-C3)alkyl- or
`aryl-(C0-C3)alkyl-O-, wherein said aryl is selected
`from phenyl and naphthyl, heteroaryl-(C0-C3)alkyl- or
`heteroaryl-(C0-C3)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 X2(C0-C6)alkoxy(cid:173)
`(C0-C6)alkyl-, wherein X2 is absent or X2 is (C1-C6)
`alkylamino- or [(CcC6)alkyl]2amino-, and wherein the
`(C 0-C 6)alkoxy-(C 0-C 6)alkyl- moiety of said
`X2(C0-C6)alkoxy-(C0-C6)alkyl- contains at least one
`carbon atom, and wherein from one to three of the
`carbon atoms of said (C0-C6)alkoxy-(C0-C6)alkyl(cid:173)
`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 (C0-C6)alkoxy-(C0-C6)alkyl- may be optionally
`substituted with from two to seven fluonne atoms, and
`wherein one of the carbon atoms of each of the alkyl
`moieties of said aryl-(C0-C3)alkyl- and said heteroaryl(cid:173)
`(C0-C3)alkyl- may optionally be replaced by an
`oxygen, nitrogen or sulfur atom, and wherein each of
`the foregoing aryl and heteroaryl groups may option(cid:173)
`ally be substituted with one or more substituents,
`preferably from zero to two substituents, independently
`selected from (CcC6)alkyl optionally substituted with
`from one to seven fluonne atoms, (CcC6)alkoxy
`optionally substituted with from two to seven fluorine
`atoms, halo (e.g., chloro, fluoro, bromo or iodo),
`(C 2-C 6)alkenyl, (C 2-C6)alkynyl, hydroxy, nitro,
`cyano, amino, (CcC6)-, [(CcC6)alkyl] 2 amino-,
`-CO2 R4, -CONR5R6, -SO2 NR7R8
`, -C(=O)R13
`and -XC(=O)R13
`;
`or R2 and R3
`, together with the carbons to 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 one to five of the carbon
`atoms of said bicyclic rings that are not part of the
`benzo ring shown in formula I, 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 sub(cid:173)
`stituents for the bicyclic rings, that are selected,
`independently, from (C0-C6)alkoxy-(C0-C6)alkyl-,
`wherein the total number of carbon atoms does not
`
`Apotex Exhibit 1006.002
`
`

`

`US 6,410,550 Bl
`
`4
`alkylamino-, [(C 1 -C 6 ) alkyl] 2 amino-, -CO 2 R 4
`-CONRsR6
`, -SO2 NR7Rs, -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 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:
`
`,
`
`3
`exceed six and wherein any of the alkyl moieties may
`optionally be substituted with from one to seven fluo(cid:173)
`rine atoms; nitro, oxo, cyano, halo, (C2-C6)alkenyl,
`(C2-C6)alkynyl, hydroxy, amino, (C1-C6)alkylamino-,
`, -CONRsR 6
`[(CcC 6)alkyl] 2 amino-, -CO 2 R4
`,
`, and -XC(=O)R13
`-SO2 NR7Rs, -C(=O)R13
`;
`, R7
`each R4, Rs, R6
`, Rs and R13 is selected, independently,
`from hydrogen and (C1-C6) alkyl, or Rs and R6
`, or R7
`and Rs together with the nitrogen to which they are
`attached, form a pyrrolidine, piperidine, morpholine, 10
`azetidine, piperazine, -N-(CcC6)alkylpiperazine or
`thiomorpholine ring, or a thiomorpholine ring wherein
`the ring sulfur is replaced with a sulfoxide or sulfone;
`and
`each Xis, independently, (C1-C6)alkylene:
`, R2 and R3
`with the proviso that: (a) at least one of R1
`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 com(cid:173)
`pounds.
`Examples of heteroaryl groups that each of R2 and R3 can
`be are the following: thienyl, oxazoyl, isoxazolyl, pyridyl,
`pyrimidyl, thiazolyl, tetrazolyl, isothiazolyl, triazolyl,
`imidazolyl, tetrazolyl, pyrroyl and the following groups:
`
`5
`
`15
`
`20
`
`25
`
`30
`
`35
`
`0 00'·dbi
`
`wherein one of R9 and R 18 is hydrogen or (CcC6)alkyl, and 40
`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, form a bicyclic ring system selected from the following: 45
`
`55
`
`wherein R 10 and R 17 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(CcC6)alkyl.
`Other embodiments of this invention relate to compounds
`of the formula I, and their pharmaceutically acceptable salts,
`wherein neither R2 nor R3 is attached to the benzo ring of
`50 formula I via an oxygen atom.
`Other embodiments of this invention relate to compounds
`of the formula I, and their pharmaceutically acceptable salts,
`wherein R2 and R3 do not, together with the benzo ring of
`formula I, form a bicyclic or tricyclic ring system.
`Other embodiments of this invention relate to compounds
`of the formula I wherein one or both of R2 and R3 are
`, wherein R 13 is (CcC 6)alkyl. Further
`-C(=O)R13
`embodiments of this invention relate to compounds of the
`formula I wherein one or both of R2 and R3 are -C(=O)
`60 R13
`, wherein R13 is (CcC 6)alkyl or (CcC3)alkyl optionally
`substituted with from one to seven fluorine atoms. Other
`embodiments relate to compounds of the formula I wherein
`one of R2 and R3 is CF3 , fluoro, cyano or C2Fs.
`Other embodiments of this invention relate to compounds
`65 of the formula I wherein R1 is not methyl.
`Examples of specific compounds of the formula I are the
`following:
`
`ocOR"~N RIO
`0)--R'°
`
`wherein R10 and R17 are selected, independently, from
`(C0-C6)alkoxy-(C0-C6)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, cyano, halo, amino, (CcC 6)
`
`Apotex Exhibit 1006.003
`
`

`

`US 6,410,550 Bl
`
`5
`
`6
`(CcC6)alkyl optionally substituted with from one to seven
`fluorine atoms; -C(=O)(CcC6)alkyl, cyano, hydroxy,
`nitro, amino, -O(CcC6)alkyl or halo: with the proviso that
`R 14 and R 15 can not both be hydrogen when P is hydrogen
`5 or methyl. Such compounds are useful as intermediates in
`the synthesis of compounds of the formula I.
`The invention also relates to a compound of the formula
`
`]
`
`]
`
`]
`
`R~~
`(~NP'.
`
`R3
`
`(!')
`
`(!')
`
`15
`
`25
`
`35
`
`40
`
`wherein R2 and R3 are defined above; and P' is COOR16
`wherein R16 is allyl, 2,2,2-trichloroethyl or (C1-C6)alkyl;
`-C(=O)NR5R6 wherein R5 and R6 are defined as in claim
`2; -C(=O)H, -C(=O)(C1-C6)alkyl wherein the alkyl
`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-butoxycarbonyl (t-Boc).
`Unless otherwise indicated, the term "halo", as used
`herein, includes fluoro, chloro, bromo and iodo.
`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-0-",
`wherein "alkyl" is defined as above.
`The term "alkylene, as used herein, means an alkyl 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 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
`50 "treating" is defined immediately above.
`The compounds of formula I may have optical centers and
`therefore may occur in different enantiomeric configura(cid:173)
`tions. The invention includes all enantiomers, diastereomers,
`and other stereoisomers of such compounds of formula I, as
`55 well as racemic and other mixtures thereof.
`The present invention also relates to all radiolabeled
`forms of the compounds of the formula I. Preferred radio(cid:173)
`labeled compounds of formula I are those wherein the
`radiolabels are selected from as 3H, 11C, 14C, 18F, 123I and
`60 1251. Such radiolabeled 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
`65 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,
`
`6-methyl-5, 7-dioxo-6,13-diazatetracyclo[9 .3 1.02·10 .04·8
`pentadeca-2(10),3,8-triene hydrochloride;
`6-methy l-5-oxo-6,13-diazatetracyclo[9 .3.1.02·10 .04·8
`pentadeca-2(10),3,8-triene hydrochloride;
`5, 7-dimethyl-6-oxo-5, 7, 13-triazatetracyclo[9 .3 .1. 02·10 .04·8
`pentadeca-2(10),3,8-triene hydrochloride;
`5, 7-dioxo-6, 13-diazatetracyclo[ 9 .3 .1. 02·10 .O4·8 ]pentadeca-2
`(10),3,8-triene hydrochloride;
`5-oxo-6,13-diazatetracyclo[9 .3 .1.02·10 .O4' 8 ]pentadeca-2 10
`(10),3,8-triene hydrochloride:
`6-oxo-5, 7 ,13-triazatetracyclo[9 .3 .1.02·10 .O4·8 ]pentadeca-2
`(10),3,8-triene hydrochloride;
`4,5-difluoro- l O-aza-tricyclo[ 6 .3 .1.02· 7 ]dodeca-2(7),3,5-
`triene hydrochloride;
`5-fluoro-10-aza-tricyclo[ 6 .3 .l .O2·7 ]dodeca-2(7),3,5-triene-
`4-carbonitrile hydrochloride;
`4-ethynyl-5-fluoro-10-aza-tricyclo[ 6.3 .1.02· 7 ]dodeca-2(7),
`3,5-triene hydrochloride;
`5-ethynyl-10-aza-tricyclo[ 6.3.l .O2·7 ]dodeca-2(7),3,5-triene- 20
`4-carbonitrile hydrochloride;
`4-ethynyl-5-chloro-10-aza-tricyclo[ 6.3.1.02· 7 ]dodeca-2(7),
`3,5-triene-4-carbonitrile hydrochloride;
`4-ethynyl-5-chloro-10-aza-tricyclo[ 6.3.1.02· 7 ]dodeca-2(7),
`3,5-triene hydrochloride.
`5-oxa-7-methyl-6-oxo-7,13-diazatetracyclo[9 .3.1.02·10 .04·8
`pentadeca-2(10),3,8-triene hydrochloride;
`4-fluoro-5-trifluoromethyl-1O-aza-tricyclo[ 6 .3 .1.02· 7
`dodeca-2(7),3,5-triene hydrochloride;
`4-chloro-5-trifluoromethy 1-10-aza-tricyclo[ 6 .3 .1.02· 7
`] 30
`dodeca-2(7),3,5-triene hydrochloride;
`5-trifluoromethyl-10-aza-tricyclo[ 6.3.1.02· 7 ]dodeca-2(7),3,
`5-triene-4-carbonitrile hydrochloride:
`4-eth yny 1-5-trifl uoromethy 1-10-aza-tricyclo[ 6 .3 .1.02· 7
`dodeca-2(7),3,5-triene hydrochloride.
`6-methy l-5-thia-5-dioxa-6,13-Diazatetracyclo[ 9 .3 .1.02·
`10.O4·8]pentadeca-2(10),3,8-triene hydrochloride;
`7 -dime thy lamino-5-thia-5-dioxa-6, 13-Diaz a tetr acyclo
`[9 .3.1.02·10 .O4·8 ]pentadeca-2(10),3,8-triene hydrochlo-
`ride;
`6, 7-dioxa-5 ,8, 14-triaza te tracyclo[ 10. 3 .1.0 2·11 .0 4·9
`hexadeca-2(11),3,9-triene hydrochloride; and
`5 ,8-dimethy 1-6, 7-dioxa-5 ,8,14-triazatetracyclo[l 0.3 .1.02·
`11.O4·9 ]hexadeca -2( 11 ),3,9-triene hydrochloride.
`
`]
`
`]
`
`]
`
`]
`
`45
`
`This invention also relates to compounds of the formula
`
`wherein P is hydrogen, methyl, COOR16 wherein R16 is
`(C1-C6)alkyl, allyl, 22·2·2-trichloroethyl or (C1-C6)alkyl;
`-C(=O)NR5R6 wherein R5 and R6 are defined as in
`formula I above; -C(=O)H, -C(=O)(CcC6)alkyl
`wherein the alkyl 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-butoxycarbonyl (t-Boc); and
`R 14 and R 15 are selected, independently, from hydrogen,
`
`Apotex Exhibit 1006.004
`
`

`

`US 6,410,550 Bl
`
`10
`
`25
`
`7
`that is effective in reducing nicotine addiction or aiding in
`the cessation or lessening of tobacco use and a pharmaceu(cid:173)
`tically acceptable carrier.
`The present invention also relates to a method for reduc(cid:173)
`ing nicotine addiction or aiding in the cessation or lessening 5
`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, pyo(cid:173)
`derma gangrenosum and Crohn's disease), irritable bowel 15
`syndrome, spastic dystonia, chronic pain, acute pain, celiac
`sprue, pouchitis, vasoconstriction, anxiety, panic disorder,
`depression, bipolar disorder, autism, sleep disorders, jet lag,
`amyotrophic lateral sclerosis (ALS), cognitive dysfunction,
`hypertension, bulimia, anorexia, obesity, cardiac arrythmias, 20
`gastric acid hypersecretion, ulcers, pheochromocytoma, pro(cid:173)
`gressive supranuclear, palsy, chemical dependencies and
`addictions (e.g., dependencies on, or addictions to nicotine
`( and/or tobacco products), alcohol, benzodiazepines,
`barbiturates, opioids or cocaine), headache, stroke, trau-
`matic brain injury (TEI), obsessive-compulsive disorder
`(OCD), psychosis, Huntingon's Chorea, tardive dyskinesia,
`hyperkinesia, dyslexia, schizophrenia, multi-infarct
`dementia, age related cognitive decline, epilepsy, including 30
`petit mal absence epilepsy, senile dementia of the Alzhe(cid:173)
`imer'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 35
`I, or a pharmaceutically acceptable salt thereof, that is
`effective in treating such disorder or condition.
`The present invention also relates to a pharmaceutical
`composition for treating a disorder or condition selected
`from inflammatory bowel disease (including but not limited 40
`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, amyotropic lateral sclerosis (ALS), 45
`cognitive dysfunction, hypertension, bulimia, anorexia,
`obesity, cardiac arrythmias, gastric acid hypersecretion,
`ulcers, pheochromocytoma, progressive supranuclear palsy,
`chemical dependencies and addictions (e.g., dependencies
`on, or addictions to nicotine (and/or tobacco products), 50
`alcohol, benzodiazepines, barbiturates, opioids or cocaine),
`headache, stroke, traumatic brain injury (TEI) obsessive(cid:173)
`compulsive disorder (OCD), 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 I, or a pharma- 60
`ceutically acceptable salt thereof, and a pharmaceutically
`acceptable carrier.
`The present invention also relates to a method for reduc(cid:173)
`ing nicotine addiction or aiding in the cessation or lessening
`of tobacco use in a mammal, comprising administering to 65
`said mammal an amount of a compound comprising an
`amount of a compound of the formula
`
`8
`
`or a pharmaceutically acceptable salt thereof, that is effec(cid:173)
`tive 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, pyo(cid:173)
`derma 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,
`amyotrophic latera sclerosis (ALS), cognitive dysfunction,
`hypertension, bulimia, anorexia, obesity, cardiac arrythmias,
`gastric acid hypersecretion, ulcers, pheochromocytoma, pro(cid:173)
`gressive supranuclear 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 (TEI) obsessive-compulsive disorder (OCD),
`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 Alzhe(cid:173)
`imer'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
`
`or a pharmaceutically acceptable salt thereof, that is effec(cid:173)
`tive in treating such disorder or condition.
`This invention also relates to the pharmaceutically accept(cid:173)
`able acid addition salts of the compounds of formula I.
`Examples of pharmaceutically acceptable acid addition salts
`of the compounds of formula I are the salts of hydrochlonc
`acid, p-toluenesulfonic acid, fumaric acid, citric acid, suc(cid:173)
`cinic acid, salicylic acid, oxalic acid, hydrobromic acid,
`phosphoric acid, methanesulfonic acid, tartaric acid, malate,
`di-p-toluoyl tartaric acid, and mandelic acid.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`Except where otherwise stated, R 1 through R 18
`, m and P,
`55 and structural formula I in the reaction schemes and discus-
`sion that follow are defined as above.
`
`Scheme 1
`
`III
`
`Apotex Exhibit 1006.005
`
`

`

`9
`
`-continued
`
`US 6,410,550 Bl
`
`10
`-continued
`
`IA
`
`R17
`
`I N:(XI)
`
`10
`
`R
`
`- { I
`
`N
`
`NH
`
`#
`
`Scheme 3
`
`VIA
`
`R17
`
`I
`
`R 10- {N~N - tBo c XXV
`
`N--1LJ-L__;
`!
`
`VIE
`
`IV
`
`IIA
`
`IIB
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Apotex Exhibit 1006.006
`
`

`

`US 6,410,550 Bl
`
`IC
`
`R
`
`11
`-continued
`
`Scheme 5
`
`IE
`
`Scheme 6
`
`12
`-continued
`
`SD})
`10----<
`
`I
`N ~
`
`NH
`
`IF
`
`Scheme 7
`
`~X l
`
`~x2
`(ring A= present or absent)
`
`XII
`
`(ring A= present of
`absent)
`XIII
`
`I
`GX)}(on
`
`(ring A= present or absent) OH
`
`XIIIA
`
`(ring A= present or absent)
`
`XIV
`
`IG: (R2 and R3 form ring A)
`III: (ring A= absent)
`
`Scheme 8
`
`R1s
`
`R1s
`
`R1s
`
`Q~CC· (X]
`-
`
`F
`
`#
`
`F
`
`xv
`R18 =For C1-C6)alkoxy)
`
`XVI
`
`XVII
`
`!
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Apotex Exhibit 1006.007
`
`

`

`US 6,410,550 Bl
`
`13
`-continued
`
`R1s
`
`R1s
`
`~ oa(on
`
`N \ -
`C6Hs
`
`XIX
`
`XVIII
`
`OH
`
`R1s
`
`R1s
`
`~m, 03--<o
`-
`!
`
`1H
`
`xx
`
`N
`
`CF3
`
`5
`
`10
`
`15
`
`20
`
`25
`
`/
`
`OYCF3
`
`N
`
`/
`
`NH2
`
`IX'
`
`"'-
`
`14
`
`Scheme 10
`
`~m ,
`Cl ~
`
`IM
`
`~m ,
`
`NC
`
`IN
`
`IP
`
`IQ
`
`0 } }
`~ H2N
`o ,O::I)m,
`R13) lN ~
`
`30
`
`Scheme 1-10 illustrate methods of synthesizing com(cid:173)
`pounds 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 IV. This reaction
`is typically conducted in methylene chloride at a tempera(cid:173)
`ture from about 0° C. to about room temperature.
`
`35
`
`40
`
`The compound of 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
`45 or more equivalents of trifluoromethanesulfonic acid
`(CF3 SO2 OH) and 2 to 3 equivalents of nitric acid, in a
`chlorinated hydrocarbon solvent such as chloroform, dichlo(cid:173)
`roethane (DCE) or methylene chloride. The resulting mix(cid:173)
`ture is allowed to react for about 5 to 24 hours. Both of the
`50 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.
`
`55
`
`Reduction of the compound of formula IIA, using meth(cid:173)
`ods well known to those of skill in the art, yields the
`compound of formula IIB. This reduction can be
`60 accomplished, for example, using hydrogen and a palladium
`catalyst such as palladium hydroxide and running the reac(cid:173)
`tion in methanol at about room temperature.
`
`65
`
`Referring to Scheme 2, the compound of formula IIA is
`converted into the corresponding compound wherein the
`
`XXI
`
`Scheme 9
`
`[J Cl::ox
`
`I
`Cl ~
`
`NH
`
`IV
`
`IK
`
`IL
`
`0
`
`Apotex Exhibit 1006.008
`
`

`

`US 6,410,550 Bl
`
`15
`trifluoroacetyl protecting group is replaced by a t-Boc pro(cid:173)
`tecting 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 aque(cid:173)
`ous alcohol, dioxane or tetrahydrofuran (IBF) at a tempera(cid:173)
`ture from about room temperature to about 70° C., prefer(cid:173)
`ably 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 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 VIE using the procedure described above for con(cid:173)
`verting the dinitro compound of formula IIA into the cor(cid:173)
`responding diamino compound of formula IIB.
`The conversion of the compound of formula VIE into the
`desired compound of the formula VII can be accomplished
`by reacting the compound of formula VIE with a compound
`of the formula
`
`XXIIA
`
`10
`
`16
`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),
`5 THF or DMF, preferably a mixture of DMSO and water, and
`then removing the protecting group as described above. The
`reaction with R 17Z is generally carried out at a temperature
`from about room temperature to about 100° C., preferably at
`about 50° C., for about five hours.
`Scheme 3 illustrates an alternate method of preparing
`compounds of the formula IE from the compound of for(cid:173)
`mula VIA This method is the preferred method of making
`compounds of the formula IE wherein R 17 is a bulky group
`such as an aryl or heteroaryl containing group, or when R17
`can not be attached, as illustrated in Scheme 2, by alkylation
`15 or aryl substitution methods. Referring to Scheme 3, the
`compound of formula VIA is reacted with the appropriate
`compound of formula R 17NH2 in a polar solvent such as
`THF, DMF or DMSO, preferably THF, at a temperature
`from about room temperature to about 100° C., preferably at
`20 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 those of skill in the art. Such methods are
`referred to above for the conversion of the compounds of the
`formula IIA into a compound of the formula IIB in Scheme
`1, and exemplified in experimental Examples 12B and 18B.
`Closure of the imidazole ring to form the corresponding
`compound of formula XXV can then be accomplished by
`30 reacting the compound of formula XXIV from the above
`reaction with a compound of the formula
`
`25
`
`XXIIA
`
`wherein R 10 is defined as above, as described above for
`converting compounds of the formula VIE into those of the
`formula VII.
`Removal of the protecting group from the compound of
`formula XXV yields the corresponding compound of for(cid:173)
`mula IE. This can be accomplished using methods well
`known in the art, for example, as described above for
`forming compounds of the formula IA from the correspond(cid:173)
`ing compounds of the formula VII.
`Scheme 4 illustrates a method of preparing compounds of
`50 the formula IC, wherein R10 and R17 are as defined above.
`Referring to Scheme 4, the compound of formula VIE is
`reacted with a compound of the formula
`
`wherein R10 is hydrogen, (C1-C6)alkyl optionally substi(cid:173)
`tuted with from one to seven fluorine atoms, aryl-(C0-C3 ) 35
`alkyl wherein said aryl is selected from phenyl and naphthyl,
`or heteroaryl-(C0-C3 )alkyl wherein said heteroaryl is
`selected from five to seven membered aromatic rings con(cid:173)
`taining from one to four heteroatoms selected from oxygen,
`nitrogen and sulfur, and wherein each of the foregoing aryl 40
`and heteroaryl groups may optionally be substituted with
`one or more substituents, preferably from zero to two
`substituents, independently selected from (CcC 6)alkyl
`optionally substituted with from one to seven fluorine atoms,
`(C1-C6)alkoxy optionally substituted with from one to 45
`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.
`Alternate methods of preparing compounds of the formula
`VII the compound of formula VIE are described by Segel(cid:173)
`stein et al., Tetrahedron Lett., 1993, 34, 1897.
`Removal of the t-Boc protecting group from the com(cid:173)
`pound of formula VII yields corresponding compound of 55
`formula IA The protecting group can be removed using
`methods well known to thos