(19)
`
`(12)
`
`Europäisches Patentamt
`
`European Patent Office
`
`Office européen des brevets
`
`*EP001078637A2*
`EP 1 078 637 A2
`
`(11)
`
`EUROPEAN PATENT APPLICATION
`
`(43) Date of publication:
`28.02.2001 Bulletin 2001/09
`
`(21) Application number: 00307254.3
`
`(22) Date of filing: 23.08.2000
`
`(51) Int Cl.7: A61K 45/06
`
`(84) Designated Contracting States:
`AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU
`MC NL PT SE
`Designated Extension States:
`AL LT LV MK RO SI
`
`• Harrigan, Edmund Patrick
`Groton, Connecticut 06340 (US)
`• O’Neill, Brian Thomas
`Groton, Connecticut 06340 (US)
`• Sands, Steven Bradley
`Groton, Connecticut 06340 (US)
`
`(30) Priority: 27.08.1999 US 151089 P
`
`(71) Applicant: Pfizer Products Inc.
`Groton, Connecticut 06340 (US)
`
`(72) Inventors:
`• Coe, Jotham Wadsworth
`Groton, Connecticut 06340 (US)
`
`(74) Representative:
`Simpson, Alison Elizabeth Fraser et al
`Urquhart-Dykes & Lord,
`30 Welbeck Street
`London W1G 8ER (GB)
`
`(54)
`
`Composition for the treatment and prevention of nicotine addiction containing a nicotine
`receptor agonist and an anti-depressant or anti-anxiety drug
`
`(57)
`Pharmaceutical compositions are disclosed for
`the treatment of nicotine dependence or addiction, to-
`bacco dependence or addiction, reduction of nicotine
`withdrawal symptoms or aiding in the cessation or less-
`ening of tobacco use or substance abuse. The pharma-
`
`ceutical compositions are comprised of a therapeutically
`effective combination of a nicotine receptor partial ago-
`nist and an anti-depressant or anxiolytic agent and a
`pharmaceutically acceptable carrier. The method of us-
`ing these compounds is also disclosed.
`
`Printed by Jouve, 75001 PARIS (FR)
`
`EP1 078 637A2
`
`Pfizer Ex. 2003, p. 1
`
`

`

`1
`
`EP 1 078 637 A2
`
`2
`
`Description
`
`Background of the Invention
`
`[0001] The present invention relates to pharmaceuti-
`cal compositions for the treatment of nicotine depend-
`ence or addiction in a mammal (e.g. human) comprising
`a nicotine receptor partial agonist (NRPA) and an anti-
`depressant or anxiolytic agent. The term NRPA refers
`to all chemical compounds which bind at neuronal nic-
`otinic acetylcholine specific receptor sites in mammalian
`tissue and elicit a partial agonist response. A partial ag-
`onist response is defined here to mean a partial, or in-
`complete functional effect in a given functional assay.
`Additionally, a partial agonist will also exhibit some de-
`gree of antagonist activity by its ability to block the action
`of a full agonist (Feldman, R.S., Meyer, J.S. & Quenzer,
`L.F. Principles of Neuropsychopharmacology, 1997; Si-
`nauer Assoc. Inc.). The present invention may be used
`to treat mammals (e.g. humans) for tobacco depend-
`ence or addiction and nicotine dependence or addiction;
`to palliate the effects of nicotine withdrawal and to en-
`hance the outcomes of other smoking cessation thera-
`pies.
`[0002] The invention also relates to aryl fused aza-
`polycylic compounds that bind to neuronal nicotinic ace-
`tylcholine specific receptor sites and are useful in mod-
`ulating cholinergic function and are referred to in WO
`9818798-A1, WO 9935131-A1 and WO 9955680-A1.
`The foregoing applications are owned in common with
`the present application and are incorporated herein by
`reference in their entireties.
`[0003] The NRPA compounds that bind to neuronal
`nicotinic receptor sites can be used in combination with
`an anti-depressant such as for example, a tricyclic anti-
`depressant (e.g. amitryptyline, imipramine), a serotonin
`reuptake inhibitor anti-depressant (SRI) (e.g. sertraline,
`paroxetine, or fluoxetine), an atypical anti-depressant
`(bupropion, nefazodone), or a monoamine oxidase in-
`hibitor (e.g., phenelzine, tranylcypromine) in order to
`treat the depression associated with addiction such as
`to nicotine or tobacco, alcohol dependence, cocaine ad-
`diction or tobacco or nicotine dependence independent-
`ly of other psychiatric illness. The compounds that bind
`to neuronal nicotinic receptor sites can be used in com-
`bination with anxiolytic agents, such as for example, a
`benzodiazepine (e.g. diazepam, alprazolam, chlo-
`rdiazepoxide) or non-benzodiazepine anxiolytics (e.g.
`buspirone, hydroxyzine, doxepin) in order to treat the
`anxiety associated with addiction such as to nicotine or
`tobacco, alcohol dependence, cocaine addiction or to-
`bacco or nicotine dependence independently of other
`psychiatric illness.
`[0004] Tobacco dependence represents the most im-
`portant preventable cause of illness and death in our so-
`ciety, responsible for more than 400,000 deaths each
`year. Half of all smokers will die of diseases directly re-
`lated to tobacco use, and many smokers will suffer sig-
`
`nificant morbidity.
`[0005] People smoke because of the reinforcing ef-
`fects of nicotine. Nicotine is a powerful psychoactive
`agent that activates the same brain pathways as co-
`caine and other psychostimulants, producing agent-as-
`sociated tolerance and withdrawal effects.
`[0006] Nicotine replacement therapies (NRTs) have
`been used for smoking cessation. These are available
`in the form of gum, the transdermal patch, and nasal
`inhaler. The gum Nicorette® (nicotine polacrilex) deliv-
`ers nicotine through buccal absorption following chew-
`ing. There are also non-nicotine pharmacologic thera-
`pies for treating nicotine addiction.
`
`5
`
`10
`
`15
`
`Summary of Invention
`
`[0007] The invention provides a pharmaceutical com-
`position for treating nicotine dependence or addiction,
`tobacco dependence or addiction, reducing nicotine
`withdrawal symptoms or aiding in the cessation or less-
`ening of tobacco use or substance abuse. The thera-
`peutically effective pharmaceutical combination is com-
`prised of a nicotine receptor partial agonist and an anti-
`depressant or anxiolytic agent and a pharmaceutically
`acceptable carrier.
`[0008]
`In a more specific embodiment of the inven-
`tion, the anti-depressant is selected from a tricyclic anti-
`depressant, a serotonin reuptake inhibitor anti-depres-
`sant (SRI), an atypical anti-depressant or a monoamine
`oxidase inhibitor, their pharmaceutically active salts and
`their optical isomers. In another more specific embodi-
`ment of the invention, the anti-depressant is selected
`from amitryptyline, imipramine, sertraline, paroxetine,
`fluoxetine, bupropion, nefazodone, phenelzine, tranyl-
`cypromine, moclobemide, venlafaxine or a pharmaceu-
`tically acceptable salt or their optical isomers thereof. A
`preferred antidepressant is buproprion hydrochloride or
`one of its optical isomers.
`[0009]
`In another more specific embodiment of this in-
`vention, the 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-
`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-pyrido[1,2-a][1,5]diazocin-8-one;
`
`20
`
`25
`
`30
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`35
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`40
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`45
`
`50
`
`55
`
`2
`
`Pfizer Ex. 2003, p. 2
`
`

`

`3
`
`EP 1 078 637 A2
`
`4
`
`3-benzyl-9-bromo-1,2,3,4,5,6-hexahydro-
`1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
`3-benzyl-9-chloro-1,2,3,4,5,6-hexahydro-
`1,5-methano-pyrido[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-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][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-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-hexahydro-
`1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
`9-(3-fluorophenyl)-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-difluorophenyl)-1,2,3,4,5,6-hexahydro-
`1,5-methano-pyrido[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-diazatetracyclo[9.3.1.02,10.
`04,8]pentadeca-2(10),3,8-triene;
`5-oxo-6,13-diazatetracyclo[9.3.1.02,10.04,8]penta-
`deca-2(10),3,8-triene;
`6-oxo-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]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-10-aza-tricydo[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[6.3.1.02,7]dodeca-2(7),
`3,5-triene-4-carbonitrile;
`6-methyl-5-thia-5-dioxa-6,13-diazatetracydo
`[9.3.1.02,10.04,8]pentadeca-2(10),3,8-triene;
`10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
`4-fluoro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),
`3,5-triene;
`4-methyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),
`3,5-triene;
`4-trifluoromethyl-10-aza-tricyclo[6.3.1.02,7]do-
`
`5
`
`10
`
`15
`
`20
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`25
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`30
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`35
`
`40
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`45
`
`50
`
`55
`
`3
`
`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[9.3.1.02,10.04,8]
`pentadeca-2(10),3,5,8-tetraene;
`6-methyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]
`pentadeca-2(10),3,5,8-tetraene;
`6,7-dimethyl-5,7,13-triazatetracyclo[9.3.1.02,10.
`04,8]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-dimethyl-5,8,14-triazatetracyclo[10.3.1.02,11.
`04,9]hexadeca-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;
`14-methyl-5,8,14-triazatetracyclo[10.3.1.02,11.04,9]
`hexadeca-2(11),3,5,7,9-pentaene;
`5-oxa-7,13-diazatetracyclo[9.3.1.02,10.04,8]penta-
`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;
`4-chloro-10-azatricyclo[6.3.1.02,7]dodeca-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.
`04,8]pentadeca-2,4(8),6,9-tetraene;
`4,5-dichloro-10-azatricyclo[6.3.1.02,7]dodeca-2(7),
`3,5-triene;
`11-azatricyclo[7.3.1.02,7]trideca-2(7),3,5-triene-
`5-carbonitrile;
`1-[11-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[7.3.1.02,7]trideca-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-methyl-7-thia-5,14-diazatetracyclo[10.3.1.02,10.
`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-dimethyl-5,7,14-triazatetracyclo[10.3.1.02,10.
`04,8]hexadeca-2(10),3,5,8-tetraene;
`5,7,14-triazatetracyclo[10.3.1.02,10.04,8]hexadeca-
`2(10),3,5,8-tetraene;
`5,6-dimethyl-5,7,14-triazatetracyclo[10.3.1.02,10.
`04,8]hexadeca-2(10),3,6,8-tetraene;
`5-methyl-5,7,14-triazatetracyclo[10.3.1.02,10.04,8]
`hexadeca-2(10),3,6,8-tetraene;
`6-(trifluoromethyl)-7-thia-5,14-diazatetracyclo
`[10.3.1.02,10.04,8]hexadeca-2(10),3,5,8-tetraene;
`5,8,15-triazatetracyclo[11.3.1.02,11.04,9]heptade-
`
`Pfizer Ex. 2003, p. 3
`
`

`

`5
`
`EP 1 078 637 A2
`
`6
`
`ca-2(11),3,5,7,9-pentaene;
`7-methyl-5,8,15-triazatetracyclo[11.3.1.02,11.04,9]
`heptadeca-2(11),3,5,7,9-pentaene;
`6-methyl-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-diazatetracyclo[10.3.1.02,10.04,8]hexa-
`deca-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;
`5-methyl-7-oxa-6,14-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;
`7-methyl-5-oxa-6,14-diazatetracyclo[10.3.1.02,10.
`04,8]hexadeca-2(10),3,6,8-tetraene;
`4,5-difluoro-11-azatricyclo[7.3.1.02,7]trideca-2(7),
`3,5-triene;
`4-chloro-5-fluoro-11-azatricyclo[7.3.1.02,7]trideca-
`2(7),3,5-triene;
`5-chloro-4-fluoro-11-azatricyclo[7.3.1.02,7]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-trifluoromethyl-11-aza-tricyclo[7.3.1.02,7]trideca-
`2,4,6-triene;
`6-methoxy-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-
`6-ol;
`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;
`4-nitro-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),
`3,5-triene;
`5-nitro-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),
`3,5-triene;
`5-fluoro-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),
`3,5-triene; and
`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.
`[0010] Preferably, the 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-
`
`5
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`10
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`15
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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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`45
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`50
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`55
`
`4
`
`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-hexahydrol 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-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-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;
`6-methyl-5-thia-5-dioxa-6,13-diazatetracyclo
`[9.3.1.02,10.04,8]pentadeca-2(10),3,8-triene;
`4-fluoro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),
`3,5-triene;
`4-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),
`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.
`04,9]hexadeca-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-oxa-7,13-diazatetracyclo[9.3.1.02,10.04,8]penta-
`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[6.3.1.02,7]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[7.3.1.02,7]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[7.3,1.02,7]trideca-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-methyl-7-thia-5,14-diazatetracyclo[10.3.1.02,10.
`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-dimethyl-5,7,14-triazatetracyclo[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.
`
`Pfizer Ex. 2003, p. 4
`
`

`

`7
`
`EP 1 078 637 A2
`
`8
`
`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[7.3.1.02,7]trideca-
`2,4,6-triene;
`6-methoxy-11-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; and
`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.
`[0011] The invention also provides a method of treat-
`ing a mammal having a condition which presents with
`tobacco or nicotine addiction, nicotine withdrawal symp-
`toms, alcohol dependence or cocaine or other sub-
`stance addiction. The mammal is administered a nico-
`tine receptor partial agonist or a pharmaceutically ac-
`ceptable salt thereof, and an antidepressant or anxiolyt-
`ic agent or a pharmaceutically acceptable salt thereof.
`The nicotine receptor partial agonist and the anti-de-
`pressant or anxiolytic agent are present in amounts that
`render the composition effective in the treatment of to-
`bacco or nicotine addiction, nicotine withdrawal symp-
`toms, alcohol dependence or cocaine or other sub-
`stance addiction. In a more specific embodiment of the
`invention, the anti-depressant is selected from a tricyclic
`anti-depressant, a serotonin reuptake inhibitor anti-de-
`pressant, (SRI), an atypical anti-depressant, and a
`monoamine oxidase inhibitor. In another more specific
`embodiment of this invention anxiolytic agent is selected
`from a benzodiazepine or a non-benzodiazepine anxio-
`lytic. In another more specific embodiment of this inven-
`tion, the anxiolytic agent is a benzodiazepine or a non-
`benzodiazepine anxiolytic. In a more specific embodi-
`ment of the invention, the anxiolytic agent is selected
`from diazepam, alprazolam, chlordiazepoxide, bus-
`pirone, hydroxyzine and doxepin or a pharmaceutically
`acceptable salt thereof. A preferable anxiolytic is dox-
`epin or a pharmaceutically acceptable salt or optical iso-
`mers thereof.
`[0012]
`In another more specific embodiment of this in-
`vention the 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-
`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-
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`5
`
`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-pyrido[1,2-a][1,5]diazocin-8-one;
`3-benzyl-9-bromo-1,2,3,4,5,6-hexahydro-
`1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
`3-benzyl-9-chloro-1,2,3,4,5,6-hexahydro-
`1,5-methano-pyrido[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-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][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-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-hexahydro-
`1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
`9-(3-fluorophenyl)-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-difluorophenyl)-1,2,3,4,5,6-hexahydro-
`1,5-methano-pyrido[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-diazatetracyclo[9.3.1.02,10.
`04,8]pentadeca-2(10),3,8-triene;
`5-oxo-6,13-diazatetracyclo[9.3.1.02,10.04,8]penta-
`deca-2(10),3,8-triene;
`6-oxo-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]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-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[6.3.1.02,7]dodeca-2(7),
`3,5-triene-4-carbonitrile;
`6-methyl-5-thia-5-dioxa-6,13-diazatetracyclo
`[9.3.1.02,10.04,8]pentadeca-2(10),3,8-triene;
`10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
`
`Pfizer Ex. 2003, p. 5
`
`

`

`9
`
`EP 1 078 637 A2
`
`10
`
`4-fluoro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),
`3,5-triene;
`4-methyl-10-aza-tricyclo[6.3.1.02,7]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),
`3,5-triene;
`7-methyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]
`pentadeca-2(10),3,5,8-tetraene;
`6-methyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]
`pentadeca-2(10),3,5,8-tetraene;
`6,7-dimethyl-5,7,13-triazatetracyclo[9.3.1.02,10.
`04,8]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-dimethyl-5,8,14-triazatetracyclo[10.3,1.02,11.
`04,9]hexadeca-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;
`14-methyl-5,8,14-triazatetracyclo[10.3.1.02,11.04,9]
`hexadeca-2(11),3,5,7,9-pentaene;
`5-oxa-7,13-diazatetracyclo[9.3.1.02,10.04,8]penta-
`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;
`4-chloro-10-azatricyclo[6.3.1.02,7]dodeca-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.
`04,8]pentadeca-2,4(8),6,9-tetraene;
`4,5-dichloro-10-azatricyclo[6.3.1.02,7]dodeca-2(7),
`3,5-triene;
`11-azatricyclo[7.3.1.02,7]trideca-2(7),3,5-triene-
`5-carbonitrile;
`1-[11-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[7.3.1.02,7]trideca-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-methyl-7-thia-5,14-diazatetracyclo[10.3.1.02,10.
`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-dimethyl-5,7,14-triazatetracyclo[10.3.1.02,10.
`04,8]hexadeca-2(10),3,5,8-tetraene;
`5,7,14-triazatetracyclo[10.3.1.02,10.04,8]hexadeca-
`2(10),3,5,8-tetraene;
`5,6-dimethyl-5,7,14-triazatetracyclo[10.3.1.02,10.
`04,8]hexadeca-2(10),3,6,8-tetraene;
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`6
`
`5-methyl-5,7,14-triazatetracyclo[10.3.1.02,10.04,8]
`hexadeca-2(10),3,6,8-tetraene;
`6-(trifluoromethyl)-7-thia-5,14-diazatetracyclo
`[10.3.1.02,10.04,8]hexadeca-2(10),3,5,8-tetraene;
`5,8,15-triazatetracyclo[11.3.1.02,11.04,9]heptade-
`ca-2(11),3,5,7,9-pentaene;
`7-methyl-5,8,15-triazatetracyclo[11.3.1.02,11.04,9]
`heptadeca-2(11),3,5,7,9-pentaene;
`6-methyl-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-diazatetracyclo[10.3.1.02,10.04,8]hexa-
`deca-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;
`5-methyl-7-oxa-6,14-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;
`7-methyl-5-oxa-6,14-diazatetracyclo[10.3.1.02,10.
`04,8]hexadeca-2(10),3,6,8-tetraene;
`4,5-difluoro-11-azatricyclo[7.3.1.02,7]trideca-2(7),
`3,5-triene;
`4-chloro-5-fluoro-11-azatricyclo[7.3.1.02,7]trideca-
`2(7),3,5-triene;
`5-chloro-4-fluoro-11-azatricyclo[7.3.1.02,7]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-trifluoromethyl-11-aza-tricyclo[7.3.1.02,7]trideca-
`2,4,6-triene;
`6-methoxy-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-
`6-ol;
`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;
`4-nitro-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),
`3,5-triene;
`5-nitro-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),
`3,5-triene;
`5-fluoro-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),
`3,5-triene; and
`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.
`[0013] Preferably, the nicotine receptor partial agonist
`is selected from
`
`Pfizer Ex. 2003, p. 6
`
`

`

`11
`
`EP 1 078 637 A2
`
`12
`
`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-
`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-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-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;
`6-methyl-5-thia-5-dioxa-6,13-diazatetracyclo
`[9.3.1.02,10.04,8]pentadeca-2(10),3,8-triene;
`4-fluoro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),
`3,5-triene;
`4-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),
`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.
`04,9]hexadeca-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-oxa-7,13-diazatetracyclo[9.3.1.02,10.04,8]penta-
`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[6.3.1.02,7]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[7.3.1.02,7]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[7.3.1.02,7]trideca-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-methyl-7-thia-5,14-diazatetracyclo[10.3.1.02,10.
`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;
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`7
`
`6,7-dimethyl-5,7,14-triazatetracyclo[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-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-11-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; 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.
`
`[0014]
`In another more specific embodiment, the anti-
`depressant is selected from amitriptyline, imipramine,
`sertraline, paroxetine, fluoxetine, bupropion, nefazo-
`done, phenelzine, tranylcypromine, moclobemide, ven-
`lafaxine, and the pharmaceutically acceptable salts and
`optical isomers isomers. A preferred anti- depressant is
`buproprion hydrochloride or one of its optical isomers.
`[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
`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
`
`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-
`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-pyrido[1,2-a][1,5]diazocin-8-one;
`
`Pfizer Ex. 2003, p. 7
`
`

`

`13
`
`EP 1 078 637 A2
`
`14
`
`3-benzyl-9-bromo-1,2,3,4,5,6-hexahydro-
`1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
`3-benzyl-9-chloro-1,2,3,4,5,6-hexahydro-
`1,5-methano-pyrido[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-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][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-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-hexahydro-
`1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;
`9-(3-fluorophenyl)-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-difluorophenyl)-1,2,3,4,5,6-hexahydro-
`1,5-methano-pyrido[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-diazatetracyclo[9.3.1.02,10.
`04,8]pentadeca-2(10),3,8-triene;
`5-oxo-6,13-diazatetracyclo[9.3.1.02,10.04,8]penta-
`deca-2(10),3,8-triene;
`6-oxo-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]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-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[6.3.1.02,7]dodeca-2(7),
`3,5-triene-4-carbonitrile;
`6-methyl-5-thia-5-dioxa-6,13-diazatetracyclo
`[9.3.1.02,10.04,8]pentadeca-2(10),3,8-triene;
`10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
`4-fluoro-10-aza-tricyclo[6.3.1.02,7]