‘1
`
`EP1078637A2 '
`
`12
`
`9-bromo-1,2,3,4,5,6-hexahydro—1 ,5-methano-pyri-
`do[1 2-,a][1 Sldiazocin-8-one;
`9-chloro-1,2,3,4,5,6-,hexahydro-1 5-methano- pyri-
`do[1 2~.a][1 5]diazocim8—one:
`9-fluoro---1,2,3,4.5,6 hexahydro-1,S-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,S-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 .2,3,4,5,64"Iexahydro—
`1,5-methano-pyrido[1.2a][1,5[diazocin-8-one;
`9—(2,6-difluorophenyl)—1,2,3,4,5.6-hexahydro-
`1,5-methano-pyrido[1,Za][1,5]diazocin43-one;
`9-phenyl-1 ,2,3,4,5,6-hexahydro-1,5-methano-pyri-
`do[1,23][1,5]diazocin-8-one;
`9-(2-fluorophenyl)-1,2,3,4,5,6-hexahydro-
`1,5-methano-pyrido[1,2a][1 ,5]diazocin—8-one;
`6—methyl~5-thia-S-dioxave,13-diazatetracyclo
`[9.3.1 .02-‘°.04-3]pentadeca-2(10),3,8—triene;
`4—fluoro-10—aza—tricycio[6.3.1 .02-7jdodeca-2(7),
`3,5-triene;
`4-trifluoromethyl-10-aza-tricyclo[6.3. 1 .02.7]do-
`deca-2(7).3,5-triene;
`4-nitro-1 O-azatricyclo[6. 3.1 .02-7ldodeca-2(7),
`3,5-triene;
`6-methyl—5.7.13-triazatetracyclo[9.3.102-10043]
`pentadeca-2(10),3.5,8-tetraene;
`6,7dimethyl-5,8,14—triazatetracyclo[10.3.1 .02-11.
`04-9lhexadeca-2(11),3,5,7,9—pentaene;
`5,8,14-triazatetracyclo[10.3.1.02-‘1.O4-9]hexadeca-
`2(11),3,5,7,9~pentaene;
`5-oxa-7,1 3-diazatetracyclo[9. 3.1 .02-1 0.04-31penta-
`deca-2(10).3,6,8—tetraene;
`6~methy|-5-oxa-7,13-diazatetracyclo[9.3.1 .02-10.
`O4~3]pentadeca-2(10),3,6,8-tetraene;
`10-azatricyclo[6. 3.1 .02~7]dodeca-2(7),3,5-trien-
`4-yl cyanide;
`1-(1O-azatricyclo[6.3.1.02~7]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[7.3.1.02-71trideca-2(7),3,5-trien-
`5-yI|-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 ,02~7]tn‘deca-2(7).
`3,5-triene-5-carbonitrile;
`5-fluoro-11 -azatricyclo[7.3.1.02-7]trideca-2(7),
`3,5-triene-4-carbonitrile;
`6--methy|-7--~thia5,14-diazatetracyclo[10.3.1.02-10.
`04-5]hexadeca-2(1 0), 3,5 8-tetraene;
`6methyl--5 7 14-triazatetracyclo[10.3.1.0219-043]
`hexadeca---2(10),3.5,8tetraene;
`
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`20
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`6,7-dimethyl-5,7,14-triazatetracyclo[10.3.1 .02-10.
`04«3]hexadeca—2(1O),3,5,8-tetraene;
`6-methyl-7—oxa-5,14-diazatetracyclol103.1,02-‘0.
`04»3]hexadeca-2(10),3,5,8—tetraene:
`6-methyl-5-oxa-7,14-diazatetracyclol103.1.02-10.
`04-8]hexadeca—2(10),3,6,8-tetraene;
`' 5,6-difluoro-11 -aza-tricyclo[7. 3.1 .02-7]trideca-
`2 4 6-triene;
`6-trifluoromethyl-11-aza—tricyclo[7 3 1.027]trideca-
`2. 4, 6-triene;
`6-methoxy-1-1-aza-tricyclo[7. 3 1O27]trideca-2(7),
`3, 5-triene;
`6-fluoro-11-aza-tricyclo[7.3.1.02'7ltrideca-2(7),
`3,5-triene; and
`11 -aza-tricyclo[7,3, 1 .02-7]trideca-2(7),3,5—trien-
`5-ol and the pharmaceutically acceptable salts and
`optical isomers of the foregoing compounds.
`
`In another more specific embodiment, the anti-
`[0014]
`depressant is selected from amitriptyline, irnipramine,
`sertraline, paroxetine, fluoxetine, bupropion, nefazo-
`done, phenelzine. tranylcypromine, moclobemide, ven-
`lafaxine. and the pharmaceUtically acceptable salts and ‘
`optical isomers isomers. A preferred anti- depressafii‘is
`buproprion hydrochloride or one of its optical isom'iers.
`[0015] The anxiolytic agent can be a benzodiazepine
`or a non-benzodiazepine and are selected trom di-
`azepam, alprazolam, chlordiazepoxide, buspirone, hy-
`droxyzine or doxepin or a pharmaceutically acceptable '
`salt 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 to a
`mammal a 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
`dependence or cocaine or other substance addiction.
`The nicotine partial receptor agonist is selected from
`
`Q-bromo-t .2,3,4,5,6-hexahydro—1,S-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-tluoro-1,2.3.4.5,6-he‘xahydro-1,5-methano-pyri-
`, do[1,2-a][1.5]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-8—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-pyridol1.2-a][1 .5]diazocin-8-one;
`
`ENSDOCID: <EP_
`
`1078B7A2_|_>
`
`Apotex Exhibit 1007.459
`
`Apotex Exhibit 1007.459
`
`

`

`13
`
`EP 1 078 637 A2
`
`14
`
`3-benzyI-9—bromo-1,2,3,4,5,6-hexahydro—
`1.5-methano-pyrido[1,2-a][1.5]diazocan-8-one;
`3~ben2yl-9-chloro-1.2.3,4.5.6—hexahydro-
`1.5-methano-pyrido[1 .2—a][1.5]diazocin-8-one:
`9-acetyI-1.2.3.4.5.6-hexahydro-1 .S-methano-pyri-
`do[1,23][1,5]diazocin-8Aone;
`9-iodo-1,2,3,4,5.6-hexahydro-1,S-methano-pyrido
`[1 ,2a][1 ,5]diazocin—8-one:
`9—cyano-1,2,3,4.5,6-hexahydro-1 ,S-methano-pyri-
`do[1,2a][1,5]diazocin~8-one;
`9-ethynyl-1,2.3,4,5.5-hexahydro~1.5-methano-py-
`rido[1 ,2a][1,5]diazocin-8—one;
`9-(2-propenyI)-1,2.3,4,5,6-hexahydro—1,5-meth-
`ano-pyrido[1,2a][1,5]diazocin-8—one;
`9-(2vpropyI)-1,2,3,4,5,6-hexahydro«1,S—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-melhano-pyrido{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,S-methano-pyri-
`do[1 ,2a][1,5]diazocin-8-one;
`9-(2—fluorophenyl)-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-h§xahydro-
`1,5-methano—pyrido[1 ,Za][1 ,5]diazocin-8—one;
`9-(3~fluorophenyI)-1,2,3,4,5,6-hexahydro-
`1,5-methano-pyrido[1 ,2a][1 ,5]diazocin-8-one;
`9-(3.5—difluorophenyI)-1,2.3,4,5.6-hexahydro—
`1,5-methano-pyrido[1,2a][1,5]diazocin—8-one;
`9-(2.4-difluorophenyl)~12.3.4.5.6-hexahydro-
`1 ,5-methanopyrido[1,2a][1 ,5]diazocin~8-one;
`9-(2,5—difluorophenyI)-1,2,3,4,5.6-hexahydro—
`1.5-methano-pyrido[1,2a][1 ,5]diazocin-8-ona;
`6-methyl-5-oxo-6,13-diazatetrapyclo{9.3.1 .0230.
`0445]pentadeca-2(10).3,8-triene;
`5-oxo-6.13-diazatetracyclo[9.3.1.02-‘°.04~3]penta-
`deca—2(10),3,8-triene;
`(from-5,7,133-triazatetracycl<:.[9.3.1.0a1 0.04-5]pen-
`tadeca-2(10).3.8-triene;
`4,5—difluoro-10—aza-tricyclo[6.3.1 .02-7]dodeca-2(7),
`3,5-triene;
`5-fluoro-1 O-aza-tricyclo[6. 3.1 .02-7]dodeca-2(7),
`3,5-Iriene4-carbonitrile;
`4-ethynyI-5-fluoro-1 0-aza-tricyclo{6.3.1 .02~7]do-
`deca-2(7),3,5-triene;
`SvethynyI-10~aza-tricyclo[6.3. 1 .02.7]dodeca-2(7),
`3,5-1riene-4-carbonitrile;
`6-methyl—5-thia-5—dioxa-6, 1 3-diazatetracyclo
`[9.3.1 .02-‘°.0‘-8]pentadeca-2(10),3,8-triene;
`1 O-aza-1ricyclo{6.3.1 .02-7]dodeca-2(7),3.5.triene;
`4-fluoro-1 0-aza-lricyclo[6.3.1 .02-7]dodeca-2(7),
`3,5-triene;
`4-methyl-10-aza-1ricyclo[6.3.1.02~7]dodeca-2(7).
`3.5-1riene;
`4-1 rifluoromethyI-1 O-aza-tricyc|o[6.3.1.02-7]do-
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`deca-2(7), 3,5-triene;
`4-ni1ro-10-azatricyclo{6.3 1.02-7]dodeca-2(7),
`3.5-triene;
`7-methyI-5,7.13-triazatetracyclo[9.3.102-19043)
`pentadeca-2(10),3.5.8-tetraene:
`6-melhyl-5,7,13-1riazatetracyclo[9,3.10210.043]
`pentadeca-2(10).3.5,8—tetraene;
`6,7odimethyl—5,7,13-triazatetracyclo[9.3.1.02-10.
`04-3]pentadeca-2(10),3,5,8—tetraene;
`6-methy1-7-phenyl-5,7,13-triazatelracyclo
`[9.3.1 .02A‘°.04-3]pentadeca-2(10),3,5,8-letraene;
`6,7-dime1hyI-5,8,14-triazatetracyclo[10.3.102-“.
`04-9]hexadeca-2(11 ),3.5,7,9-pentaene;
`5,8,14-triazaletracyclo[10.3.1 .02-11 .04-9]hexadeca-
`2( 11 ),3,5,7,9-pentaene;
`14-methyI-5.8,14-triazatetracyclo[10.3.1.02-'[0419]
`hexadeca-2(11),3.5,7,9-pemaene;
`5—oxa-7,13-diazatetracyclo[9.3.1.02-‘°.O‘~5]penta-
`deca-2(10),3.6,8-tetraene;
`6-melhyI-5-oxa-7,13-diazaletracyclo[9.3.1 .02-10.
`04-3]pentadeca-2(1O).3,6.8-tetraene;
`4-chloro-1O-azatricyclo[6.3.1.02-7]dodeca-2(7),
`3,5—triene;
`1O-azatricyclo[6.3.1.02~7]dodeca-2(7),3,5-trien-
`4-yI cyanide;
`1—(1O-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-diazatelracyclo[9.3.1 .0210.
`04-3]pentadeca-2,4(8),6.9-letraene;
`4,5—dichloro-10-azatricyclol6.3.1 .02-7]dodeca—2(7),
`3,5—triene:
`11 -azatricyc|o[7.3.1.02-7]trideca-2(7),3.5‘triene-
`5—carbonitrile;
`1-[11-azatricyclof7.3.1.02-7]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—1 1 —azatricyclo[7.3.1 .02-7]trideca-2(7),
`3,5-triene-5-carbonitrile;
`5-quoro-11 -azatricyclo[7. 3.1 .02-7]trideca-2(7).
`3,5-triene-4-carbonitn'le;
`6-methyI-7-thia-5,14-diazatetracyclo{10.3.1.02.10.
`04-31hexadeca-2(10).3,5,8-tetraene;
`6—methyl-5,7. 1 4—triazatetracyclo[10.3.102-19043]
`hexadeca-2(10),3,5,8-tetraene;
`6.7-dimelhyl-5,7,14-lriazatetracyclo[10.3.1 .02-10.
`04'3]hexadeca-2(10),3,5,8-1etraane;
`5.7.14-triazatetracyclo[10.3.1 .02.‘°.04-3]hexadeca-
`2(10),3,5,8—letraene;
`5,6—dimethy|~5,7.14-triazaletracydo{10_3.1.02-10.
`0443]h exadeca-2 (1 O), 3,6,8-tetraene;
`5-methyl-5,7.14-tr1'azatetracyclof103.10210.043]
`hexadeca-2(10),3,6.8-tetraene;
`6-(1rifluoromethyI)-7-thia-5,14—diazatetracyc10
`[10.3.1 .02~‘°.04.3]hexadem-2(1O).3.5.8-tetraene;
`5.8, 1 5-1riazaletracyclo[11 .31 .02-1‘ .O4~9]heptade-
`
`aNsoocm. <EP~1078637A2_I_>
`
`Apotex Exhibit 1007.460
`
`Apotex Exhibit 1007.460
`
`

`

`15
`
`EP 1 078 637 A2
`
`.16
`
`ca-2(11),3,5,7,9~pentaene;
`do[1,2-a][1,5]diazocin-8-one;
`7-methyI-5,8,15-triazatetracyclo[11.3.1.02-“04-9]
`9-acetyl-1.2,3,4,5.6-hexahydro-1,5-methano-pyri-
`heptadeca-2(11),3.5.7,9-pentaene;
`do[1,2a][1,5]diazocin-8—one;
`9-iodo-1.2,3,4,5,6-hexahydro-1,5-methano-pyrido
`6-methyI-5.8,15-triazétetracyclo[11.3.1 02-11049]
`[1,2a][1.5]diazocIn-8-one:
`heptadeca-2(11),3,5,7,9-pentaene;
`9cyano-1,2.3,4,5,6-hexahydro-1,5-methano-pyri-
`6.7-dimethyI-5,8,15-triazatetracyclol11 ,3.1 .02-11.
`do[1,2a][1,Sldiazocin-B-one;
`04-9111eptadeca12(11 ),3,5,7,9-pentaene;
`9-carbomethoxy-1.2.3,4.5,6-hexahydro-1,5—meth-
`7-oxa-5,141diazatetracydo[10,3,1,0211°.O4-3]hexa-
`ano-pyrido[1,2a][1,5]diazocin—8-one;
`‘
`deca-2(10),3,5,8—tetraene;
`..
`9-carboxyaldehyde-1 .2.3,4.5.6-hexahydro-
`6-methyI—7-oxa—5,14-diazatetracyclo[10.3.1 .0210.
`1,5-methanopyrido[1 ,2a][1,5]diazocin-8-one;
`04-3]hexadeca-2(1O).3,5.8-tetraene;
`9—(2,6-difluorophenyI)-1 ,2,3,4,5,6-hexahydro—
`5-methyl17-oxa-6,14diazatetracyclo{10.3.1.02-10.
`1,5-methano-pyrido[1,2a][1,5]diazocin-8—one;
`0415]hexadeca-2(10).3,5,8—tetraene;
`9—phenyI-1 ,2,3,4,5,6-hexahydro-1 ,5-methano-py-
`6-methyl-5-oxa-7,14-diazatetracyclo[10.3.1 .02110.
`rido[1,2a][1,5]diazocin-8-one;
`.
`04-3lhexadeca-2(10),3,6,8—tetraene;
`9-(2—tluorophenyI)-1,2,3,4,5,6-hexahydro-
`7-methyI-5-oxa-6, 1 4-diazatetracyclo{1 O. 3.1 .02-10.
`1,5-methano-pyrido[1,23][1,5]diazocin—8-one;
`04-3]hexadeca-2(10),3,6,8—tetraene;
`6-methyI-5-thia-S-dioxa-B,1S-diazatetracyclo
`4,5—diquoro-11 -azatricyclo[7.3. 1 ,021711rideca-2(7),
`[9.3.1 .02 ‘° .04a]pentadeca-2-(10), 3, 8—triene;
`3,5-triene;
`4~quoro-10--azalricyclo[6.3.1.027]dodeca-2(7),
`4-chloro-5-fluoro-11-azatricyclo[7.3.1.02-7}trideca-
`3, 5--triene;
`2(7),3,5-triene;
`4-triquoromethyI-1O-aza-tricycIo[6.3.1.02~7]do— '
`5-chloro-4-fluoro-11-azatricyclol7.3.1 .02-7]trideca-
`deca—2(7),3,5-triene;
`2(7), 3, 5-triene;
`I???»
`4-nitro- 10azatricyclO[6.3.1.0217]dodeca-2(7),
`4-(-1 ethyny|)---5IIuoro-11-azatricyclo[7.3. 1 .0217]tri-
`v
`3,5triene;
`deca--2(7) 3, 5—triene;
`6-methyI-5,7,13-triazatetracycIo[9.3.102-19043]
`5-(1-ethynyI)-4-f-Iuoro-11-azatricyc|o[7.3.1.0217]tri- ,
`peniadeca-QUO), 3, 5, 8--tetraene;
`deca-2(7),3.5-triene;
`6,7-dimethyI-5,8,14-triazatetracycto(10,3.1 .0231.
`5,6—difluoro-11-aza—tricyclo[7.3.1 .02-7]trideca-
`04~91hexadeca-2(11),3,5,7,9-pentaene;
`2,4,6-1riene;
`5,8,14-triazatetracycio[10.3.1 .02-1‘.O4-9]hexadeca-
`6-trifluoromethyI-11-aza-tricycIo[7.3.1.02~7]trideca-
`2(11).3.5,7,9-pentaene;
`~
`2.4,6—triene;
`5-oxa-7.13-diazatetracycIo{9.3. 1 .02-‘°.O4-3]penta-
`6-methoxy-11-aza-tricycIo[7.3.1.0217ltrideca-2(7).
`deca-2(10),3,6,8-tetraene;
`3.5-triene;
`6-methyI-5-oxa-7,13—diazatetracyclol9.3.1.02~‘°.
`11 -aza-tricyc|o[7. 3.1 .02-7]trideca-2(7),3,5—1rien-
`04-8]pentadeca-2(1O).3.6.8—tetraene;
`35
`6-01;
`6-fluoro--11-aza-tricyclo[7. 3. 1 02-7]trideca-2(7),1O-azatricyc|o(6.3.1.02-7]dodeca-2(7),3,5-trien-
`3, 5-triene;
`4-yI cyanide;
`11 -aza-tricyc|o[7.3.1.02-7ltrideca-2(7),3.5-Irien-
`1 -(10-azatricycIo[6.3.1 .02-7]dodeca-2(7),3.5-trien-
`5-oI;
`4-yI 1 -;ethanone
`'
`4-nitro-11-aza-tricyclo[7.3.1.0217]trideca-2(7),
`11-azatricyc|o[7.3.1.027]trideca--2(7), 3, 5-triene-
`3,5-triene;
`5-carbonitrile;
`5-nitro-11-aza-tricyclo[7.3.1.02~7]trideca-2(7),
`1-[111azatricyclo[7 3.1 027]trideca--2(7), 3, 5-trien-
`3,5-triene;
`5--y|]-1-;ethanone
`5-quoro-11-aza-tricyclo[7.3.1.02-7]trideca-2(7),
`1-[11-azatricyclo[7.3.1.0217]trideca-2(7)3,5-trien—
`3,5-Iriene;
`5--yI-]--1-;propanone
`6-hydroxy-5-methoxy-11-aza-tricyclo[7.3.1 .027an-
`4-quoro-11 -aza_tricyclo[7.3. 1 .0217]trideca-2(7).
`3 5-1riene-5carbonitrile;
`deca-2(7),3,5-triene and
`5-fluoro— 1--azatricycIo[7. 3. 1 .027]trideca-2(7),
`3, 5-triene-4-carbonitrile;
`6methyI-7-thia-5,14-diazateiracyclol10. 3 1 02-10
`O43]hexadeca-2(10),3,5,8-tetraene;
`61methyI-5,7,14-triazatetracyclo[10.3.102-19043]
`hexadeca-2(10),3,5,8~tetraene;
`6.7-dimethyI-5.7,14-triazatetracyclo[10.3.1.0110.
`0413]hexadeca-2(1O),3,5,8-tetraene;
`6-methyI-7-oxa-5,14-diazatetracyclo[10.3.1.0210.
`04-3]hexadeca-2(10),3,5.8-tetraene;
`>6-methyI-5-oxa-7,14-diazatetracyclo[10.3.1.0310.
`
`their pharmaceutically acceptable salts and their
`optical isomers.
`[0018] A preferable nicotine receptor partial agonist is
`selected from
`
`9-bromo-1.2.3,4,5.6-hexahydro—1.S-methano-pyri-
`do[1,2-a][1,5]diazocin—8-one;
`9-chIoro-1,2,3,4.5.6-hexahydro-1 .S-methano-pyri-
`do[1,2-a][1,5]diazocin-8-one;
`9-fluoro—1 ,2,3,4,5,6-hexahydro-1,S-methano-pyri-
`
`5
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`10
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`15
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`2‘0
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`25
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`50
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`55
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`BNSDCXIID: <EP_
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`1 o7eaa7A2_I_>
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`9
`
`Apotex Exhibit 1007.461
`
`Apotex Exhibit 1007.461
`
`

`

`
`
`17
`
`EP1 078637 A2
`
`18
`
`O4~3]hexadeca-2(10),3,6,8-tetraene;
`5,6-difluoro-11-aza-tricyclo[7.3.1.02-7]trideca-
`2,4,6-triene;
`6-trifluoromethyI-11«a2a—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-t 1-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 pharrnaceutically 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 symptoms of such disorder
`or condition. The term 'treatment', as used herein, re-
`lers to the act of treating, as 'treating' is defined imme~
`diately above.
`[0020] The chemist of ordinary skill will recognize that
`certain compounds of this invention will contain one or
`more atoms which may be in a particular stereochemical
`or geometric configuration, giving rise to stereoisomers
`and configurational isomers. All such isomers and mix:
`ture thereof are included in 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 compounds are less preferred.
`
`Detailed Description of the Invention
`
`In combination with the NFiPA, the invention in-
`[0022]
`cludes an anti-depressant agent or a pharmaceutically
`acceptable salt of compounds such as a tricyclic anti-
`depressant (e.g. amitryptyline, imipramine), a serotonin
`reuptake inhibitor anti-depressant (SRI) (e.g. sertraline,
`paroxetine, or fluoxetine), an atypical antidepressant
`(bupropion, nefazodone) or a monoamine oxidase in-
`hibitor (e.g., phenelzine,
`tranylcypromine). and com-
`pounds in US. Patent No. 4,536,518 and may be used
`in this invention.
`
`In combination with the NFlPA, 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 compounds listed above,
`which can be employed in the method and pharm, com-
`positions of this invention, can be made by processes
`known in the chemical arts, for example by the methods
`described in WC 9818798 A1, WO 9935131 -A1 and
`
`United States Provisional Patent Application No.
`60/083,556 filed April 29, 1998, Some of the preparation
`methods useful for making the compounds of this inven-
`tion may require protection of remote functionality (i.e..
`primary amine, secondary amine, carboxyl). The need
`for such protection will vary depending on the nature 01
`the remote functionality and the conditions of the prep-
`aration methods. The need for such protection is readily
`determined by one skilled in the art, and is described in
`examples carefully described in the above cited appli-
`cations. The starting materials and reagents for the
`NRPA compounds employed in 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 used herein are re-
`lated to, or are derived from compounds found in 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 reported in the literature.
`[0025]
`Some of the NFlPA compounds employed in
`this invention are ionizable at physiological conditions.
`Thus, for example some of the compounds of this inven-
`tion are acidic and they form a salt with a pharmaceuti-
`cally acceptable cation. All such salts are within the
`scope of 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 by filtration, by precipita-
`tion with a non—solvent followed by filtration, by evapo-
`ration of the solvent, or, in the case of aqueous solutions,
`by lyophilization, as appropriate.
`[0026]
`In addition, some of the NRPA compounds em-
`ployed in 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-aqueous or partially aqueous medium, as
`appropriate. The salts are recovered either by filtration,
`by precipitation with a non-solvent followed by filtration,
`by evaporation of the solvent, or, in the case of aqueous
`solutions, by lyophilization, as appropriate.
`[0027]
`In additionfwhen the NFtPA compounds em-
`ployed in this invention form hydrates or solvates they
`are also within the scope of the invention.
`[0028]
`Some of the compounds of 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
`compounds of this invention are within the scope of the
`invention.
`
`[0029] The utility of the NRPA compounds employed
`' in the present invention as medicinal agents in the treat-
`ment of nicotine dependence (such as tobacco depend-
`
`1O
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`15
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`25
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`35
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`10
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`NSDmtD: <EP__1078657A2_I_)
`
`Apotex Exhibit 1007.462
`
`Apotex Exhibit 1007.462
`
`

`

`19
`
`EP 1 078 637 A2
`
`20
`
`ence or addiction) in mammals (e.g. humans) is dem-
`onstrated by the activity of the compounds of this 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
`whereby the activities of the compounds of this 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.
`
`Biolmical 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 which is a modification of the methods of Lip-
`piello, P. M. and Femandes, K. G. (in The Binding of
`-
`[3H Nicotine To A Single Class of High-Affinity Sites in
`Rat Brain Membranes, Molecular Pharrn.l _2__9. 448-54.
`(1986)) and Anderson, D. J. and Americ, S. P. (in M92
`tinic Receptor Binding of 3H-Cystisine, 3H-Nicotine
`and 3H-Methylcannbamylcholine In Rat Brain, Europe-
`an J. Pharm., g5_3, 261-67 (1994)). Male Sprague—Daw—
`ley rats (200-300 g) from Charles River were housed in
`groups in hanging stainless steel wire cages and were
`maintained on a 12 hour light/dark cycle (7 a.m.-7 pm.
`light period). They received standard Purina Rat Chow
`and water ad Iibitum. 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 Fernandez
`(Molec Pharmacol, 29, 448-454, (1986) with some mod-
`‘ ifications. Whole brains were removed, rinsed with ice-
`cold buffer. and homogenized at 0" in 10 volumes of
`buffer (w/v) using a Brinkmann PolytronW'= setting 6. for
`30 seconds. The bufferconsisted 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 9;
`0° to 4°C). The supernatant was poured off and the
`membranes were gently resuspended with the Polytron
`and centrifuged again (10 minutes; 50,000 x g; 0 to 4°C.
`After the second centrifugation, the membranes were
`resuspended in assay buffer at a concentration of 1.09/
`100mL. The composition of the standard assay buffer
`was 50 mM Tris HCl, 120 mM NaCl, 5 mM KCI, 2 mM
`MgCl2, 2 mM CaClz and has a pH of 7.4 at room tem-
`perature.
`[0031] Routine assays were performed in 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 50p.L of vehicle,
`
`blank, or test compound solution, respectively. To each
`tube was added 200pL of [3H]-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 biank was tuM.
`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 samples were
`incubated at 0° to 4° C in an iced shaking water bath.
`Incubations were terminated by rapid filtration under
`vacuum through Whatman GF/BTWI glass fiber filters us-
`ing a BranclelTM muIti-manitold tissue harvester, Follow-
`ing the initial filtration of the assay mixture, filters were
`washed two times with ice-cold assay butter (5 mweach)
`The filters were then placed in counting Vials and mixed
`vigorously with 20 ml of Ready SafeTM (Beckman) bet.
`fore quantification of radioactivity. Samples were count-
`ed in a LKB Wallach RackbetaTM liquid scintillation coun-
`ter at 40-50% efficiency. All determinations were in trip—
`licate.
`"
`
`[0032] Calculations: Specific binding (C) to the mem-
`brane is the difference between total binding in‘th‘é“'s‘am-
`ples containing vehicle only and membrane (A) 571d non-
`specific binding in the samples containing the mem-
`brane and cytisine (3). Le,
`
`Specific binding = (o) = (A) . (B).
`
`Specific binding in the presence of the test
`[0033]
`compound (E) is the difference between the total binding
`in the presence of the test compound (D) and non-spe—
`cific binding (B), E, (E) : (D) - (B).
`
`% Inhibition = (1-((E)/(C)) times 100.
`
`[0034] The compounds of the invention that were test-
`ed in the above assay exhibited ICSO values of less than
`> 10pM.
`[0035] Dopamine Turnover: Rats were injected 5.0. 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 perchlo-
`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.
`7
`[0036] Mouse behavioral despair test: The ability of
`various agents to delay the onset of immobility was as-
`sayed in a behavioral despair test (Porsolt RD; Benin A;
`.Jalfre MI; 1979; Arch lnt Pharmacodyn Ther; 229 (2)
`p327-36). Male CD-1 mice from Charles River. weighing
`14-16 g on arrival and 25-35 g at the time of testing serve
`
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`‘iitil1:,iii'L
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`“a;
`L.m
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`3Nsoocmn <EP_io7e&a7A2_i_>
`
`Apotex Exhibit 1007.463
`
`Apotex Exhibit 1007.463
`
`

`

`21
`
`EP 1 078 637 A2
`
`22
`
`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 ad libitum 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 or distilled
`water as the injection vehicle.
`[0037]
`Subjects are administered test compound (sc,
`ip. or po) at a predetermined pretreatment time. At the
`test time, groups of ten mice are placed individually in
`1000 ml beakers filled 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 everythir-
`ty seconds. Ratings were either 1 for immobile swim or
`O for mobile swim. The ten ratings were then totaled for
`each subject and the data was anaylzyed with Kruskall-
`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 cm 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=8lgroup) 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-
`mals were then administered vehicle or agent (ip.) and
`were placed back into the chambers for conflict testing
`after a 15 min agent pretreatment period. After every 20
`unpunished licks, subsequent licking resulted in the
`presentation of a 0.5 mA current (0.5 sec duration) ap-
`plied between the drinking tube and the grid floor. The
`number of shocks taken in a ten minute test period was
`recorded by computer and data were analyzed with
`ANOVA followed by Dunnett's t-tests for multiple com-
`parisons to a single control. Animals that did not begin
`to drink with in five minutes after placement in 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 compounds of this invention
`are administered orally, but parenteral administration
`may be utilized (9.9.. intravenous, intramuscular, sub-
`cutaneous or intramedullary). The two different corn-
`pounds of this invention can be co-administered simul-
`taneously or sequentially in any order, or a single phar-
`maceutical composition comprising a NRPA as de-
`
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`scribed above and an anti-depressant or anxiolytic as
`described above in a pharmaceutically acceptable car-
`rier can be administered.
`
`[0040] The amount and timing of compounds admin-
`istered will, of course, be based on the judgement ol the
`prescribing physician. Thus, because of patient to pa-
`tient variability, the dosages given below are a guideline
`and the physician may titrate 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 (99., cardiovascular). The
`following paragraphs provide preferred dosage ranges
`for the various components of this invention (based on
`average human weight of 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 senraline,
`when used in 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 combination compositions and
`methods of this invention, is in the range of 0.1 to 7.0
`mg/kg/day.
`[0044]
`In particular, an effective dosage for fluoxetine,
`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
`methods of this invention, is in the range of 1.4 to 8.6
`mg/kg/day.
`[0046]
`In particular. an effective dosage for amitryptyl-
`ine, when used in the combination i compositions and
`methods of 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 methods of this invention, is in the range of 0.1 to
`1.5 mglkg/day.
`[0048]
`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 10.0
`mg/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 tranylcy-
`promine, when used in the combination compositions
`and methods of this invention, is in the range of 0.1 to
`0.9 mg/kg/day
`[0051]
`In particular, an effective dosage for me-
`clobemide, when used in the combination compositions
`
`ausooctcz <EP_1O7B$7A2AL>
`
`Apotex Exhibit 1007.464
`
`Apotex Exhibit 1007.464
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`

`

`23
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`EP 1 078 637 A2
`
`24
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`and methods of this invention, is in the range of 1.0 to
`15 mg/kg/day
`‘
`[0052]
`In particular, an effective dosage for venlafax-
`ine, when used in the combination compositions and
`methods oi this invention, is in the range of 0.1 to 5.0
`mg/kg/day
`[0053]
`In particular, an effective dosage for diazepam,
`when used in 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]
`zoiam, when used in the combination compositions and
`methods ofthis invention, is in the range of 0.003 to 0.2
`mg/kg/day.
`[0055]
`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 mg/kg/day.
`[0056]
`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