"1
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`EP 1 078 637 A2 ~
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`12
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`9-bromo-1 ,2,3,4,5,6-hexahydro-1,5-methano-pyri-
`do[1,2-a][1, 5]jdiazocin-8-one;
`9-chloro-1,2,3,4,5,6-hexahydro-1,5-methano-pyri-
`do[1.2-a][1,5]diazocin-8-one:
`9-fluoro-1,2,3,4,5,6-hexahyero-1,5-methano-pyri-
`do[1,2-a][1,5]diazocin-8-one;
`9-acetyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyri-
`do[1,2a][1,5]diazocin-8-one;
`9-iodo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido
`[1,2a][1 5}diazocin-8-one:
`9-cyano-1,2,3,4.5,6-hexahydro-1,5-methano-pyri-
`do[1,2a][1,5}diazocin-8-one;
`9-carbomethoxy-1 ,2,3,4,5,6-hexahydro-1,5-meth-
`ano-pyrido[1,2a][1,5]diazocin-8-one;
`9-carboxyaldehyde-1,2,3.4,5,6-hexahydro-
`1,5-methano-pyrido[1,2a][1,5}diazocin-8-one;
`9-(2,6-difluoropheny!)-1,2,3,4,5,6-hexahydro-
`1,5-methano-pyrido[1 ,2a][1, 5]diazocin-8-one;
`9-phenyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyri-
`do[1,2a][1,5]diazocin-8-one;
`9-(2-fluoropheny!)-1,2,3,4,5,6-hexahydro-
`1,5-methano-pyrido[1 ,2a][1,5]diazocin-8-one;
`6-methyl-5-thia-5-dioxa-6, 13-diazatetracyclo
`[9.3.1.02:19.04-8]pentadeca-2(10),3,8-triene;
`4-fluoro-10-aza-tricyclo[6.3. 1.02-7]dodeca-2(7),
`3,5-triene;
`4-trifluoromethy|-10-aza-tricyclo[6.3. 1.02-7]do-
`deca-2(7),3,5-triene;
`4-nitro-10-azatricyclo[6. 3. 1.02-7]Jdodeca-2(7),
`3,5-triene;
`6-methyI-5, 7, 13-triazatetracyclo[9.3. 1.02-1994.8]
`pentadeca-2(10),3,5,8-tetraene;
`6,7-dimethyl-5,8, 14-triazatetracyclo[ 10.3. 1.02.1.
`04-9|nexadeca-2(11),3.5,7,9-pentaene;
`5,8,14-triazatetracyclo[10.3.1.02-11.04-9Jnexadeca-
`2(11),3,5,7,9-pentaene;
`5-oxa-7,13-diazatetracyclo[9.3.1.02-19.04-8)jpenta-
`deca-2(10),3,6,8-tetraene;
`6-methyl-5-oxa-7, 13-diazatetracyclo[9.3.1.02-10,
`04.8|]pentadeca-2(10),3,6,8-tetraene;
`10-azatricyclo[6.3.1.02-7]dodeca-2(7),3,5-trien-
`4-yl cyanide;
`1-(10-azatricyclo[6.3. 1.0*-7]dodeca-2(7),3,5-trien-
`4-yl)-1-ethanone;
`11 -azatricyclo[7.3. 1.02-7]trideca-2(7),3,5-triene-
`§-carbonitrile;
`1-[11-azatricyclo[7.3. 1.02.7}trideca-2(7),3,5-trien-
`5-yl]-1-ethanone;
`1-[11-azatricyclo[7.3. 1.02-7}trideca-2(7),3,5-trien-
`5-yl]-1-propanone;
`4-fluoro-11 -azatricyclo[7.3. 1.0?-7}trideca-2(7),
`3,5-triene-5-carbonitrile;
`5-fluoro-11 -azatricyclof7 .3. 1.02-7]trideca-2(7),
`3,5-triene-4-carbonitrile;
`6-methyl-7-thia-5, 14-diazatetracyclo[10.3.1.0210
`04.8|hexadeca-2(10),3,5,8-tetraene;
`6-methyl-5,7, 14-triazatetracyclo{10.3.1.02-10 04.8]
`hexadeca-2(10),3,5,8-tetraene;
`
`6,7-dimethy!-5,7, 14-triazatetracyclof 10.3. 1.02-10,
`04-8]hexadeca-2(10),3,5,8-tetraene:
`6-methyl-7-oxa-5,14-diazatetracyclo[10.3. 1.02.10.
`04.8}hexadeca-2(10),3,5,8-tetraene:
`6-methyl-5-oxa-7, 14-diazatetracyclo[10.3. 1.02.10.
`04-8]hexadeca-2(10),3,6,8-tetraene;
`' 5,6-difluoro-11 -aza-tricycio[7.3.1.07-"}trideca-
`2,4,6-triene;
`6-triftuoromethy!-11-aza-tricyclo[7.3. 1.02.“trideca-
`2,4,6-triene;
`6-methoxy-11-aza-tricycio[7.3.1.02-"Iideca“27),
`3,5-triene;
`6-fluoro-11 -aza-tricyclo[7.3.1 027prideca-2(7),
`3,5-triene; and
`11-aza-tricyclo{7 3, 1.0-"]trideca-2(7),3,5-trien-
`5-ol and the pharmaceutically acceptable salts and
`optical isomers of the foregoing compounds.
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`In another more specific embodiment, the anti-
`[0014]
`20 depressant is selected from amitriptyline, imipramine,
`sertraline, paroxetine, fluoxetine, bupropion, nefazo-
`done, phenelzine, tranyicypromine, moclobemide, ven-
`lafaxine, and the pharmaceutically acceptable saits and
`optical isomers isomers. A preferred anti- depressants
`buproprion hydrochloride or oneof its optical isoniérs.
`[0015] The anxiolytic agent can be a benzodiazepine
`or a non-benzodiazepine and are selected from di-
`azepam,alprazolam, chlordiazepoxide, buspirone, hy-
`droxyzine or doxepin or a pharmaceutically acceptable ~
`galt or their optical isomers thereof.
`[0016] A preferable anxiolytic agent is doxepin. The
`nicotine receptor partial agonist and the anti-depressant
`or anxiolytic agent can be administered substantially si-
`multaneously.
`[0017] The method also comprises administering toa
`mammala nicotine receptor partial agonist or a phar-
`maceutically acceptable salt in amounts that render the
`composition effective in the treatment of tobacco or nic-
`otine addiction, nicotine withdrawal symptoms,alcohol
`- 40 dependence or cocaine or other substance addiction.
`The nicotine partial receptor agonist is selected from
`
`35
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`9-bromo-1 ,2,3,4,5,6-hexahydro-1,.5-methano-pyri-
`do{1,2-a][1,5]diazocin-8-one;
`9-chloro-1 ,2,3,4,5,6-hexahydro-1 ,5-methano-pyri-
`dof{i ,2-a][1,5]diazocin-8-one;
`9-fluoro-1,2,3,4,5,6-hexahydro-1,5-methano-pyri-
`_ do[t ,2-a][1 ,S]diazocin-8-one;
`9-ethyl-1,2,3,4,5,6-hexahydro-1 ,5-methano-pyrido
`[1,2-a][1,5]diazocin-8-one;
`9-methyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyri-
`do[1,2-a][1,5]diazocin-8-one;
`9-phenyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyri-
`do[1,2-a]{1,5]diazocin-B-one;
`9-vinyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido
`[1,2-a][1, 5]diazocin-8-one;
`9-bromo-3-methyl-1,2,3,4,5,6-hexahydro-
`1,5-methano-pyrido[ 1, 2-a][1, 5}diazocin-8-one;
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`BNSDOCID: <EP__1078637A2_I_>
`
`Apotex Exhibit 1007.459
`
`Apotex Exhibit 1007.459
`
`

`

`13
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`EP 1 078 637 A2
`
`14
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`3-benzyl-9-bromo-1,2,3,4,5,6-hexahydro-
`4,5-methano-pyrido[1 ,2-a][1.5]diazocin-8-one;
`3-benzyl-9-chloro-1,2,3,4,5,6-hexahydro-
`1,5-methano-pyridof[1,2-a][1.5]diazocin-8-one:
`9-acetyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyri-
`dof 1, 2a]{1,5]diazocin-8-one;
`9-iodo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido
`(1,2a]{1, 5]jdiazocin-8-one:
`9-cyano-1,2,3,4,5,6-hexahydro-1,5-methano-pyri-
`do[1, 2a][1,5]diazocin-8-one;
`9-ethynyl-1,2,3,4,5.6-hexahydro-1,5-methano-py-
`rido[1,2a]{1,5]diazocin-8-one;
`9-(2-propenyl)-1,2,3,4,5,6-hexahydro-1,5-meth-
`ano-pyrido[1,2a][ 1 ,5]diazocin-8-one;
`9-(2-propyl)-1,2,3,4,5,6-hexahydro- 1,5-methano-
`pyrido[1,2a][1,5]diazocin-8-one;
`9-carbomethoxy-1,2,3,4,5,6-hexahydro-1,5-meth-
`ano-pyrido[1,2a][1,5]diazocin-8-one;
`9-carboxyaldehyde-1,2,3.4,5,6 hexahydro-
`1,5-methano-pyrido[1 ,2a][ 7 ,5]diazocin-8-one;
`9-(2,6-difluoropheny!)-1,2,3,4,5,6-hexahydro-
`1,5-methano-pyrido[1 ,2a][1,5]diazocin-8-ons;
`9-pheny!-1,2,3,4,5,6-hexahydro-1 ,5-methano-pyri-
`do{1,2a][1,5]diazocin-8-one;
`9-(2-fluoropheny!)-1,2,3,4,5,6-hexahydro-
`1,5-methano-pyrido[1 ,2a][1,5]diazocin-8-one;
`9-(4-fluorophenyl)-1 .2,3,4,5,6-hexahydro-
`1,5-methano-pyrido[1 ,2a][1,5]diazocin-8-one;
`9-(3-fluoropheny!l)-1,2,3,4,5,6-hexahydro-
`1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
`9-(3,5-difluorophenyl)-1,2,3,4,5.6-hexahydro-
`1,5-methano-pyrido/1,2a][1 ,5}diazocin-8-one;
`9-(2,4-difluoropheny])-1,2,3,4,5,6-hexahydro-
`1,5-methano-pyridof{1 ,2a][1,5]diazocin-8-one;
`9-(2,5-difluorophenyl)-1,2,3,4,5,6-hexahydro-
`1,5-methano-pyrido[1 ,2a][1,5]diazocin-8-one;
`6-methyl-5-oxo-6, 13-diazatetracyclof[9.3.1.02-10.
`04-8)}pentadeca-2(10),3,8-triene;
`5-0xo-6, 13-diazatetracyclo[9.3.1.02-19.04-8}penta-
`deca-2(10),3,8-triene;
`6-0x0-5,7,13-triazatetracyclo[9.3. 1.0219.04-8]pen-
`tadeca-2(10),3,8-triene;
`4,5-difluoro- 10-aza-tricyclo[6.3, 1.0?-7)\dodeca-2(7),
`3,5-triene;
`5-fluoro-10-aza-tricyclo[6.3. 1.02:7|dodeca-2(7),
`3,5-triene-4-carbonitrile;
`4-ethynyl-5-fluoro-10-aza-tricyclo[6.3.1.02-7}do-
`deca-2(7),3,5-triene;
`5-ethynyl-10-aza-tricyclo[6.3. 1.0?-7]Jdodeca-2(7),
`3,5-triene-4-carbonitrile;
`6-methyI-5-thia-5-dioxa-6,13-diazatetracyclo
`[9.3.1.02-19.04.8ipentadeca-2(10),3,8-triene;
`10-aza-tricyclo[6.3.1.02-7]dodeca-2(7},3,5-triene;
`4-fluoro-10-aza-tricyclof[6.3. 1.02-7}Jdodeca-2(7),
`3,5-triene;
`4-methyl-10-aza-tricyclo[6.3.1.02-7|dodeca-2(7),
`3,5-iriene:;
`4-trifluoromethyl-10-aza-tricyclo[6.3. 1.02-7}do-
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`deca-2(7),3,5-triene;
`4-nitro- 10-azatricyclo[6.3.1.02-7]dodeca-2(7),
`3,5-triene;
`7-methyl-5,7, 13-triazatetracyclo[9.3.1.02-10 94.8}
`pentadeca-2(10),3,5,8-tetraene:
`6-methyl-5,7, 13-triazatetracyclo[9.3.1.02-19.04.8}
`pentadeca-2(10),3,5,8-tetraene;
`6,7-dimethyl-5,7,13-triazatetracycio[9.3.1.02-10,
`048}pentadeca-2(10),3,5,8-tetraene;
`6-methyl-7-phenyl-5,7,13-triazatetracyclo
`[9.3.1.02.10 04 8]pentadeca-2(10),3,5,8-tetraene;
`6,7-dimethyI-5,8, 14-triazatetracycio[ 10.3. 1.02.11,
`04-9Jhexadeca-2(11),3,5,7,9-pentaene;
`5,8, 14-triazatetracyclo[ 10.3. 1.02.1) _04-9]hexadeca-
`2(11),3,5,7,9-pentaene;
`14-methyl-5.8, 14-triazatetracyclo[10.3. 1.02-1! 04.9]
`hexadeca-2(11),3,5,7,9-pentaene;
`5-0xa-7, 13-diazatetracycio[9. 3. 1.02-19.04.8)penta-
`deca-2(10),3,6,8-tetraene;
`6-methy!-5-oxa-7, 13-diazatetracyclo[9.3. 1.02-19.
`04 8]pentadeca-2(10),3,6,8-tetraene;
`4-chloro-10-azatricyclo[6.3.1.02-7]Jdodeca-2(7),
`3,5-triene;
`10-azatricyclo[6.3.1.02-7)dodeca-2(7),3,5-trien-
`4-yl cyanide;
`1-(10-azatricyclo[6.3.1.02-7|dodeca-2(7),3,5-trien-
`4-yl)-1-ethanone;
`10-azatricyclo[6. 3. 1.02-7|dodeca-2(7),3,5-trien-
`4-ol:
`7-methyl-5-oxa-6,13-diazatetracyclo[9.3. 1.02.10.
`0*8]pentadeca-2, 4(8),6,9-tetraene;
`4,5-dichloro-10-azatricyclo6.3. 1.02-7|dodeca-2(7),
`3,5-triene;
`11 -azatricyclo{7.3.1 02-7}trideca-2(7),3,5-triene-
`5-carbonitrile;
`1-[11-azatricyclof[7.3. 1.02-7}trideca-2(7),3,5-trien-
`§-yl]-1-ethanone;
`1-[11-azatricyclof7.3.1.02-7}trideca-2(7),3,5-trien-
`5-yl]-1-propanone;
`4-fluoro-11 -azatricyclo[7.3.1.0?-7]trideca-2(7),
`3,5-triane-S-carbonitrile;
`5-fluoro-11 -azatricyclo[7. 3. 1.02-7]trideca-2(7),
`3,5-triene-4-carbonitrile;
`6-methyl-7-thia-5, 14-diazatetracyclo[10.3. 1.02.19.
`04jhexadeca-2(10),3,5,8-tetraene;
`6-methylI-5,7,14-triazatetracyclo[ 10.3. 1.02-1004.8)
`nexadeca-2(10),3,5,8-tetraene;
`6,7-dimethyI-5,7,14-triazatetracyclo[10.3.1.02-19.
`04 8]nhexadeca-2(10),3,5,8-tetraene;
`5,7, 14-triazatetracyclo[ 10.3. 1.02-19.04.8]hexadeca-
`2(10),3,5,8-tetraene;
`5,6-dimethyI-5,7,14-triazatetracydo[10.3. 1.02.10
`04.8]hexadeca-2(10),3,6,8-tetraene;
`5-methyl-5,7, 14-triazatetracyclof 10.3. 1.02.10 94.8]
`hexadeca-2(10),3,6,8-tetraene;
`6-(trifluoromethyl)-7-thia-5, 14-diazatetracyclo
`(10.3. 1.02-1004.8]hexadeca-2(10),3,5,8-tetraene;
`5,8, 15-triazatetracyclo{11.3. 1.02.11 04-9]heptade-
`
`SNSDOCID: <EP__1076637A2_I_>
`
`Apotex Exhibit 1007.460
`
`Apotex Exhibit 1007.460
`
`

`

`15
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`EP 1 078 637 A2
`
`16
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`ca-2(11),3,5,7,9-pentaene;
`7-methyl-5,8, 15-triazatetracyclo[11.3.1.02-11 94.9]
`heptadeca-2(11),3,5,7,9-pentaene;
`6-methyt-5,8, 15-triazatetracyclo[11.3.1.02-11.04.9]
`heptadeca-2(11),3,5,7,9-pentaene:
`6,7-dimethyl-5,8, 15-triazatetracyclo[11.3.1.02-11.
`04-9}heptadeca-2(11),3,5,7,9-pentaene;
`7-oxa-5, 14-diazatetracydo[10,3, 1,02-19.04.8jhexa-
`deca-2(10),3,5,8-tetraene;
`.
`6-methyl-7-oxa-5, 14-diazatetracyclo[10.3.1.02.10,
`04 8Jnexadeca-2(10),3,5,8-tetraene;
`5-methyl-7-oxa-6,14-diazatetracyclof 10.3.1.02-10.
`04-8}nexadeca-2(10),3,5,8-tetraene;
`6-methyl-5-oxa-7, 14-diazatetracyclof 10.3. 1.02-10.
`048)nexadeca-2(10),3,6,8-tetraene;
`7-methy|-5-oxa-6, 14-diazatetracyclof10.3. 1.02-19,
`04.8]nexadeca-2(10),3,6,8-tetraene;
`4,5-diftuoro- 11 -azatricyclof{7.3.1,02-7}trideca-2(7),
`3,5-triene;
`4-chloro-5-fluoro-11-azatricyclo[7.3.1.0-7}trideca-
`2(7),3,5-triene;
`5-chloro-4-fluoro-11 -azatricyclof7.3. 1.02-7]trideca-
`2(7),3,5-triene;
`4-(1-ethynyl)-5-fluoro-11-azatricyclo[7. 3.1.02-7)}tri-
`deca-2(7).3,5-triene;
`5-(1-ethynyl)-4-fluoro-11 -azatricyclo[7.3.1.02-7}tri- .
`deca-2(7),3,5-triene;
`5,6-difluoro-11 -aza-tricyclo{7.3. 1.02-7}trideca-
`2,4,6-triene:
`6-trifluoromethy!-11-aza-tricyclo[7.3.1.02-7}trideca-
`2,4,6-triene:
`6-methoxy-11-aza-tricycto[7.3. 1.02-7}trideca-2(7),
`3,5-triene;
`11-aza-tricyclo[7.3.1.02-7}trideca-2(7),3,5-trien-
`6-al;
`6-fluoro-11-aza-tricyclo[7.3. 1.02.“trideca-2(7),
`3,5-triene;
`11-aza-tricyclo[7.3.1 (027}frideca-2(7),3,5-trien-
`5-ol;
`4-nitro-11-aza-tricyclo[7.3. 1.02-7]trideca-2(7),
`3,5-triene;
`5-nitro-11-aza-tricyclof[7.3. 1.02-"]trideca-2(7),
`3,5-triene;
`5-fluoro-11-aza-tricyclo[7.3.1.02-7}trideca-2(7),
`3,5-triene;
`6-hydroxy-5-methoxy-11 -aza-tricyclo[7.3. 1.02-7}tri-
`deca-2(7),3,5-triene and
`
`their pharmaceutically acceptable salts and their
`optical isomers.
`[0018] Apreferable nicotine receptor partial agonist is
`selected from
`
`9-bromo-1,2,3,4,5,6-hexahydro- 1,5-methano-pyri-
`do[1 ,2-a][1,5]diazocin-8 -one;
`9-chloro-1,2,3,4,5,6-hexahydro-1 ,5-methano-pyri-
`do[1,2-a][1,5]diazocin-8-one;
`9-fluoro-1,2,3,4,5,6-hexahydro-1 ,5-methano-pyri-
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`do[1,2-aj[1 ,5}Jdiazocin-B-one;
`9-acetyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyri-
`do[1,2a}[1, 5jdiazocin-8-one;
`9-iodo-1,2,3,4,5,6-hexahydro-1 ,5-methano-pyrido
`(1, 2a][1 ,5}diazocin-8-one:
`9-cyano-1,2,3,4,5,6-hexahydro-1,5-methano-pyri-
`do[1,2a][1,5]}diazocin-8-one;
`9-carbomethoxy-1,2,3,4,5,6-hexahydro-1,5-meth-
`ano-pyrido[1,2a][1,5]diazocin-8-one;
`9-carboxyaldehyde-1,2,3,4,5,6-hexahydro-
`1,5-methanopyrido[1 ,2a][1,5}diazocin-8-one;
`9-(2,6-difluorophenyl)-1,2,3,4,5,6-hexahydro-
`1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
`9-phenyl-1 ,2,3,4,5,6-hexahydro-1,5-methano-py-
`rido[1,2a][1, 5]Jdiazocin-8-one;
`9-(2-fluorophenyl)-1,2,3,4,5,6-shexahydro-
`1,5-methano-pyrido[1, 2a][1,5]diazocin-8-one;
`6-methy|-5-thia-5-dioxa-6, 13-diazatetracyclo
`[9.3.1.02-10 94-8)pentadeca-2(10),3,8-triene;
`4-fluoro-10-aza-tricyclo[6.3.1.0°-"}dodeca-2(7),
`3,5-triene;
`4-trifluoromethyl-10-aza-tricyclo[6.3.1.02:7]do-
`deca-2(7),3,5-triene;
`4-nitro-10-azatricyclo[6.3.1.02:7}dodeca-2(7), 4
`3,5-triene;
`“?
`6-methyl-5,7,13-triazatetracyclo[9.3.1.02-10 04.8) -
`pentadeca-2(10),3,5,8-tetraene;
`6,7-dimethyl-5,8, 14-triazatetracyclo[ 10.3. 1.02.11.
`04.9Ihexadeca-2(11),3,5,7,9-pentaene:
`5,8, 14-triazatetracyclo[10.3. 1.02-11_04.9]hexadeca-
`2(11),3,5,7,9-pentaene:
`5-0xa-7, 13-diazatetracyclo[9.3. 1.02.1004.elpenta-
`deca-2(10),3,6,8-tetraene;
`6-methy!-5-oxa-7, 13-diazatetracyclo[9.3. 1.02-19,
`04.8]pentadeca-2(10),3,6,8-tetraene;
`10-azatricyclo[6.3. 1.02-7|dodeca-2(7),3,5-trien-
`4-yl cyanide;
`1-(10-azatricyclo[6.3.1.0?-7|dodeca-2(7),3,5-trien-
`4-yl-1-ethanone;
`,
`11-azatricyclo[7.3. 1.02-7}trideca-2(7),3,5-triene-
`5-carbonitrile;
`1-{11-azatricyclo{7.3.1.02-’}trideca-2(7),3,5-trien-
`5-yl]-1-ethanone;
`1-{11-azatricyclof{7.3.1.02-7}trideca-2(7),3,5-trien-
`5-yl]-1-propanone;
`4-fluoro-11 -azatricyclo[7.3.1.02.-7}trideca-2(7),
`3,5-triene-5-carbonitrile;
`5-fluoro-1 -azatricyclo[7.3. 1.02.7]trideca-2(7),
`3,5-triene-4-carbonitrile;
`6-methy!-7-thia-5, 14-diazatetracyclo[10.3.1.02.19
`048jhexadeca-2(10),3,5,8-tetraene;
`6-methyI-5,7,14-triazatetracyclo[10.3.1.02:1004.8]
`hexadeca-2( 10),3,5,8-tetraene;
`6,7-dimethyl-5,7, 14-triazatetracyclo{10.3.1.02-10,
`04.8)nexadeca-2(10),3,5,8-tetraene;
`6-methyl-7-oxa-5, 14-diazatetracyclo[10.3. 1.02.19.
`0*8)Jnexacdeca-2(10),3,5,8-tetraene;
`6-methyl-5-oxa-7, 14-diazatetracyclo[10.3.1 02.10.
`
`1___1078637A2_1_>
`
`Apotex Exhibit 1007.461
`
`Apotex Exhibit 1007.461
`
`

`

`
`
`17
`
`EP 1 078 637 A2
`
`18
`
`04 8]nexadeca-2(10),3,6,8-tetraene;
`§,6-difluoro- 11 -aza-tricyclo[7.3. 1.02-7]trideca-
`2,4,6-triene;
`6-trifluoromethyl-11 -aza-tricyclo[7.3. 1.02-7}trideca-
`2,4,6-triene:
`6-methoxy-1-aza-tricyclo[7.3.1.02-7]trideca-2(7),
`3,5-triene;
`6-fluoro-11-aza-tricyclo[7.3. 1.02-7}trideca-2(7),
`3,5-triene;
`11-aza-tricyclo[7.3.1.02-7]trideca-2(7),3,5-trien-
`5-ol and
`
`their pharmaceutically acceptable salts and their
`optical isomers.
`[0019] The term "treating" as used herein, refers to
`reversing, alleviating, inhibiting or slowing the progress
`of, or preventing the disorder or condition to which such
`term applies, or one or more symptomsof such disorder
`or condition. The term "treatment", as used herein, re-
`fers to the act of treating, as “treating” is defined imme-
`diately above.
`[0020} Thechemist of ordinary skill will recognize that
`certain compoundsofthis invention will contain one or
`more atoms which maybein a particular stereochernical
`or geometric configuration. giving rise to stereoisomers
`and configurational isomers. All such isomers and mix-
`ture thereof are includedin this invention. Hydrates of
`the compounds of this invention are also included.
`[0021} The chemist of ordinary skill will recognize that
`certain combinations of heteroatom-containing substit-
`uent listed in this invention define compounds which will
`be less stable under physiological conditions (e.g.,
`those containing acetal or animal linkages). According,
`such compoundsare less preferred.
`
`Detailed Description of the Invention
`
`Incombination with the NAPA,the invention in-
`[0022]
`cludes an anti-depressant agent or a pharmaceutically
`acceptable salt of compounds suchasa tricyclic anti-
`depressant(e.g. amitryptyline, imipramine), a serotonin
`reuptakeinhibitor anti-depressant (SRI) (e.g. sertraline,
`paroxetine, or fluoxetine), an atypical antidepressant
`(bupropion, nefazodone) or a monoamine oxidase in-
`hibitor (e.g., phenelzine,
`tranyicypromine), and com-
`pounds in U.S. Patent No. 4,536,518 and may be used
`in this invention.
`
`In combination with the NRPA, the invention
`[0023]
`may include an anxiolytic agent or pharmaceutically ac-
`ceptable salt of compounds such as a benzodiazepine
`(e.g. diazepam, alprazolam, chlordiazepoxide) or non-
`benzodiazepine anxiolytic (e.g. buspirone, hydroxyzine,
`doxepin).
`[0024] The particular NRPA compoundslisted above,
`which can be employed in the method and pharm, com-
`positions of this invention, can be made by processes
`knownin the chemicalarts, for example by the methods
`described in WO 9818798 A1, WO 9935131-A1 and
`
`United States Provisional Patent Application No.
`60/083,556filed April 29, 1998. Some of the preparation
`methods useful for making the compoundsofthis inven-
`tion may require protection of remote functionality (i.e.
`primary amine, secondary amine, carboxy!). The need
`for such protection will vary depending on the nature of
`the remote functionality and the conditions of the prep-
`aration methods. The need for such protection is readily
`determinedby oneskilled in the art, and is described in
`examplescarefully described in the above cited appli-
`cations. The starting materials and reagents for the
`NRPA compounds employedin this invention are also
`readily available or can be easily synthesized by those
`skilled in the art using conventional methods of organic
`synthesis. Some of the compounds usedherein are re-
`lated to, or are derived from compoundsfoundin nature
`and accordingly many such compounds are commer-
`cially available or are reported in the literature or are
`easily prepared from other commonly available sub-
`stances by methods which are reportedin the literature.
`[0025]
`Some of the NRPA compounds employed in
`this invention are ionizable at physiological conditions.
`Thus, for example someof the compoundsofthis inven-
`tion are acidic and they form a salt with a pharmaceulti-
`cally acceptable cation. All such salts are within the
`scopeof this invention and they can be prepared by con-
`ventional methods. For example, they can be prepared
`simply by contacting the acidic and basic entities, usu-
`ally in a stoichiometric ratio, in either an aqueous, non-
`aqueous or partially aqueous medium, as appropriate.
`The salts are recovered either byfiltration, by precipita-
`tion with a non-solvent followedbyfiltration, by evapo-
`ration of the solvent,or, in the case of aqueoussolutions,
`by lyophilization, as appropriate.
`[0026]
`Inaddition, some of the NRPA compounds em-
`ployedin this invention are basic, and they form a salt
`with a pharmaceutically acceptable anion. All such salts
`are within the scope of this invention and they can be
`prepared by conventional methods. For example, they
`can be prepared simply by contacting the acidic and ba-
`sic entities, usually in a stoichiometric ratio, in either an
`aqueous, non-aqueousorpartially aqueous medium, as
`appropriate. The salts are recovered either byfiltration,
`by precipitation with a non-solvent followedbyfiltration,
`by evaporation of the solvent, or, in the case of aqueous
`solutions, by lyophilization, as appropriate.
`[0027]
`In addition, when the NRPA compounds em-
`ployed in this invention form hydrates or solvates they
`are also within the scope of the invention.
`[0028]
`Some of the compoundsof this invention are
`chiral, and as such are subject to preparation via chiral
`synthetic routes, or separable by conventional resolu-
`tion or chromatographic means. All optical forms of the
`compoundsof this invention are within the scope of the
`invention.
`
`The utility of the NRPA compounds employed
`[0029]
`‘in the present invention as medicinal agentsin the treat-
`mentof nicotine dependence (such as tobacco depend-
`
`1S
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`20
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`25
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`30
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`35
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`40
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`50
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`55
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`10
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`NSDOCID: <EP___1078637A2_I_>
`
`Apotex Exhibit 1007.462
`
`Apotex Exhibit 1007.462
`
`

`

`19
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`EP 1 078 637 A2
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`20
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`ence or addiction) in mammals (e.g. humans) is dem-
`onstrated bythe activity of the compoundsofthis inven-
`tion in conventional assays and, in particular the assays
`described below. These include neuronal nicotinic re-
`ceptor binding, dopamine turnover, and animal models
`of depression (mouse behavioral despair) and anxiety
`(Vogel anti-conflict). Such assays also provide a means
`wherebythe activities of the compoundsofthis invention
`can be compared between themselves and with the ac-
`tivities of other known compounds. The results of these
`comparisons are useful for determining dosage levels
`in mammals,
`including humans, for the treatment of
`such diseases.
`
`Biological Assays
`
`Procedures
`
`[0030] Receptor binding assay: The effectiveness of
`the active compounds in suppressing nicotine binding
`to specific receptor sites is determined by the following
`procedure whichis a modification of the methods of Lip-
`piello, P- M. and Femandes, K. G. (in The Binding of
`L-
`(SH]Nicotine To A Single Class of High-Affinity Sites in
`Rat Brain Membranes, Molecular Phanm., 29, 448-54,
`(1986)) and Anderson, D. J. and Americ, S. P. (in Nico-
`tinic_ Receptor Binding of 3H-Cystisine, SH-Nicotine
`and SH-Methyicarmbamylcholine In Rat Brain, Europe-
`an J. Pharm., 253, 261-67 (1994)). Male Sprague-Daw-
`ley rats (200-300 g) from Charles River were housedin
`groups in hanging stainless steel wire cages and were
`maintained on a 12 hour lightdark cycle (7 a.m.-7 p.m.
`light period). They received standard Purina Rat Chow
`and water ad libitum. The rats were killed by decapita-
`tion. Brains were removed immediately following decap-
`itation. Membranes were prepared from brain tissue ac-
`cording to- the methods of Lippiello and Femandez
`(Molec Pharmacol, 29, 448-454, (1986) with some mod-
`_ ifications. Whole brains were removed, rinsed with ice-
`cold buffer, and homogenized at O° in 10 volumes of
`buffer (w/v) using a Brinkmann Polytron™, setting 6,for
`30 seconds. The buffer consisted of 50 mM Tris HCI at
`a pH of 7.5 at room temperature. The homogenate was
`sedimented by centrifugation (10 minutes; 50,000 x g;
`O° to 4°C). The supernatant was poured off and the
`membranes were gently resuspendedwith the Polytron
`and centrifuged again (10 minutes; 50,000 x g; 0 to 4°C.
`Alter the second centrifugation, the membranes were
`resuspendedin assay buffer at a concentration of 1.0g/
`100mL. The composition of the standard assay buffer
`was 50 mM Tris HCI, 120 mM NaCl, 5 mM KCI, 2mM
`MgClz, 2 mM CaClo and has a pH of 7.4 at room tem-
`perature.
`[0031] Routine assays were performedin borosilicate
`glass test tubes. The assay mixture typically consisted
`of 0.9 mg of membrane protein in a final incubation vol-
`ume of 1.0 mL. Three sets of tubes were prepared
`wherein the tubes in each set contained SOuL of vehicle,
`
`blank, or test compoundsolution, respectively. To each
`tube was added 200yL of [SH]-nicotine in assay buffer
`followed by 750uL of the membrane suspension. The
`final concentration of nicotine in each tube was 0.9 nM.
`The final concentration of cytisine in the blank was 1M.
`The vehicle consisted of deionized water containing
`30pL of 1 N acetic acid per 50 mL of water. The test
`compounds and cytisine were dissolved in vehicle. As-
`says were initiated by vortexing after addition’ of the
`membrane suspension to the tube. The sampies were
`incubated at 0° to 4° C in an iced shaking water bath.
`Incubations were terminated by rapid fiitration under
`vacuum through Whatman GF/B™glassfiber filters us-
`ing a Brandel™ multi-manifold tissue harvester. Follow-
`ing the initialfiltration of the assay mixture, filters were
`washed two times with ice-cold assay buffer (5 meach).
`The filters were then placed in counting vials and mixed
`vigorously with 20 ml of Ready Safe™ (Beckman) be.
`fore quantification of radioactivity. Samples were count- ~
`ed ina LKB Wallach Rackbeta™liquid scintillation coun-
`ter at 40-50%efficiency. All determinations werein trip-
`licate.
`"
`
`[0032] Calculations: Specific binding (C) to the mem-
`brane is the difference betweentotal binding in thé’sam-
`ples containing vehicle only and membrane(A) andnon-
`specific binding in the samples containing the mem-
`brane and cytisine (B), i-e.,
`
`Specific binding = (C) = (A) - (B).
`
`Specific binding in the presence of the test
`[0033]
`compound (E) is the difference betweenthe total binding
`in the presence of the test compound (D) and non-spe-
`cific binding (B), Le., (E) = (D) - (B).
`
`%Inhibition = (1-((E)/(C)) times 100.
`
`{0034} Thecompoundsofthe invention that weretest-
`ed in the above assay exhibited ICc> valuesof less than
`-10uM.
`[0035] Dopamine Tumover: Rats wereinjected s.c. or
`p.o. (gavage) and then decapitated either 1 or 2 hours
`later. Nucleus accumbens was rapidly dissected (2 mm
`slices, 4°C, in 0.32 M sucrose), placed in 0.1 N perchio-
`ric acid, and then homogenized. After centrifugation
`10uL of the supernatant was assayed by HPLC-ECD.
`Tumover/ utilization of dopamine (DA) was calculated
`as the ratio of tissue concentrations of metabolites
`
`([DOPAC]+[HVA]) to DA and expressed as percent of
`control.
`,
`[0036] Mouse behavioral despair test: The ability of
`various agents to delay the onset of immobility was as-
`sayedin a behavioral despair test (Porsolt RD; Bertin A;
`Jalfre Mi; 1979; Arch Int Pharmacodyn Ther; 229 (2)
`p327-36). Male CD-1 mice from Charles River, weighing
`14-16 gon arrival and 25-35 g at the time of testing serve
`
`1S
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`30
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`35
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`1
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`eee oe =
`wet renee te
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`Goka
`
`ty
`whe
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`3NSDOCID: <EP__1078637A2_I_>
`
`Apotex Exhibit 1007.463
`
`Apotex Exhibit 1007.463
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`

`

`21
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`EP 1 078 637 A2
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`22
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`as subjects. Mice are housed 10/cage under standard
`laboratory conditions on a L:D/7a.m.:7p.m. lighting cy-
`cle of at least 7 days prior to experimentation. Food and
`water are available adlibitum until the time of testing.
`All compounds are administered in a volume of 10 mV
`kg. Agent vehicles will depend on compound solubiltiy,
`but testing will typically be done using saline ordistilled
`water as the injection vehicle.
`[0037]
`Subjects are administered test compound (sc,
`ip, Of po) at a predetermined pretreatment time. At the
`test time, groups of ten mice are placed individually in
`1000 ml beakersfilled with water to the 700 ml mark at
`22-23°C. A five minute test is started after the last sub-
`
`ject is placed in the beakers with ratings taken every thir-
`ty seconds. Ratings were either 1 for immobile swim or
`0 for mobile swim. The ten ratings were then totaled for
`each subject and the data was anaylzyed with Kruskail-
`Wallis and Mann-Whitney U tests.
`[0038] Vogel Anticonflict assay: The ability of various
`agents to increase punished responding was evaluated
`using a modification of the procedure described by Vo-
`gel, Beer and Clody (Psychopharmacologia 21(1);
`1971). The test chambers consisted of clear plexiglass
`boxes (25 em L x 22 cm W x 22 cm H) equipped with a
`stainless steel drinking tube and a floor of stainless steel
`bars, housed in sound-attenuating wooden cabinets.
`Training and testing were conducted between 900 and
`1600 h. After 48 hours of water deprivation,
`rats
`(N=8/group) were placed into the test chambers for a
`training period,
`in which they were allowed to explore
`the chamber and drink water freely for up to three min-
`utes. Animals that did not locate the drinking spout with-
`in 10 minutes were excluded from agent testing. Ani-
`mais were then administered vehicle or agent(i.p.) and
`were placed back into the chambers for conflict testing
`after a 15 min agent pretreatmentperiod. After every 20
`unpunished licks, subsequent licking resulted in the
`presentation of a 0.5 mA current (0.5 sec duration) ap-
`plied betweenthe drinking tube and the grid floor. The
`numberof shocks taken in a ten minute test period was
`recorded by computer and data were analyzed with
`ANOVAfollowed by Dunnett's t-tests for multiple com-
`parisons to a single control. Animals that did not begin
`to drink within five minutes after placementin the cham-
`ber were eliminated from the experiment and behavioral
`disruption due to agent treatment was assumed to have
`occurred.
`
`[0039] Administration of the compositions of this in-
`vention can be via any method which delivers a com-
`pound of
`this invention systemically and/or locally.
`These methods include oral routes and transdermal
`routes, etc. Generally, the compoundsof this invention
`are administered orally, but parenteral administration
`may be utilized (e.g., intravenous, intramuscular, sub-
`cutaneous or intramedullary). The two different com-
`pounds ofthis invention can be co-administered simul
`taneously or sequentially in any order, or a single phar-
`maceutical composition comprising a NRPA as de-
`
`10
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`12
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`scribed above and an anti-depressant or anxiolytic as
`described above ina pharmaceutically acceptable car-
`rier can be administered.
`
`[0040] The amount and timing of compounds admin-
`istered will, of course, be based on the judgementof the
`prescribing physician. Thus, becauseof patient to pa-
`tient variability, the dosages given below are a guideline
`and the physician maytitrate doses of the agent to
`achieve the activity that the physician considers appro-
`priate for the individual patient. In considering the de-
`gree of activity desired, the physician must balance a
`variety of factors such as cognitive function, age of the
`patient, presence of preexisting disease, as well as
`presence of other diseases (e.g., cardiovascular). The
`following paragraphs provide preferred dosage ranges
`for the various components of this invention (based on
`average human weightof 70 kg).
`[0041]
`In general, an effective dosage for the NRPA
`in the range of 0.01 to 200 mg/kg/day, preferably 0.05
`to 10.0 mg/kg/day.
`[0042]
`In particular, an effective dosage for sertraline,
`when usedin the combination compositions and meth-
`ods of this invention,
`is in the range of 0.01 to 1.0 mg/
`kg/day.
`In particular, an effective dosage for paroxet-
`[0043]
`ine, when used in the combmation compositions and
`methods of this invention, is in the range of 0.1 to 7.0
`mg/kg/day.
`[0044]
`In particular, an effective dosageforfluoxetine,
`when used in the combination compositions and meth-
`ods of this invention.is in the range of 0.1 to 1.1 mg/kg/
`day.
`In particular, an effective dosage for nefazo-
`[0045]
`done, when used in the combination compositions and
`methodsof this invention, is in the range of 1.4 to 8.6
`mg/kg/day.
`[0046]
`In particular, an effective dosagefor amitryptyl-
`ine, when used in the combination i compositions and
`methodsof this invention, is in the range of 0.1 to 3.0
`mg/kg/day.
`imi-
`[0047]
`in particular, an effective dosage for
`pramine, when used in the combination compositions
`and methodsof this invention, is in the range of 0.1 to
`1.5 mg/kg/day.
`[0048]
`In particular, an effective dosage for bupropi-
`on, when used in the combination compositions and
`methodsof this invention, is in the range of 0.1 to 10.0
`ma/kg/day.
`for
`dosage
`effective
`an
`particular,
`[0049]
`In
`phenelzine, when used in the combination compositions
`and methods of this invention, is in the range of 1.0 to
`4.3mg/kg/day
`[0050]
`In particular, an effective dosage for tranyicy-
`promine, when used in the combination compositions
`and methodsof this invention, is in the range of 0.1 to
`0.9 mg/kg/day
`[0051]
`In particular, an effective dosage for mo-
`clobemide, when used in the combination compositions
`
`SNSODOCID:. <EP__1078637A2_!_>
`
`Apotex Exhibit 1007.464
`
`Apotex Exhibit 1007.464
`
`

`

`23
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`EP 1 078 637 A2
`
`24
`
`and methods of this invention, is in the range of 1.0 to
`15 mg/kg/day
`,
`[0052]
`In particular, an effective dosagefor venlafax-
`ine, when used in the combination compositions and
`methods ol this invention, is in the range of 0.1 to 5.0
`mg/kg/day
`[0053]
`Inparticular, an effective dosage for diazepam,
`when usedin the combination compositions and meth-
`ods of this invention, is in the range of 0.02 to 2 mg/kg/
`day.
`In particular, an effective dosage for alpra-
`[0054]
`Zolam, when used in the combination compositions and
`methodsof this invention, is in the range of 0.003 to 0.2
`mg/kg/day.
`[00SS]
`in particular, an effective dosage for chlo-
`rdiazepoxide, when used in the combination composi-
`tions and methods of this invention, is in the range of
`0.07 to 1.4 mo/ka/day.
`[OOS6]
`In particular, an effective dosage for bupropi-
`on, when used in the combination compositions and
`methods of this invention, is in the range of 0.1 to 0.9
`mg/kg/day.
`[0057]
`In particular, an effective dosage for hydrox-
`yzine, when used in the combination compositions and
`methods of this invention, is in the range of 0.14 to 6
`mg/kg/day.
`[00S8