Abstract:
Pharmaceutical compositions are disclosed for the treatment of alcohol or cocaine dependence or addiction, alcohol dependence or addiction, reduction of alcohol withdrawal symptoms or aiding in the cessation or lessening of tobacco use or substance abuse or other behavioral dependencies. The pharmaceutical compositions are comprised of a therapeutically effective combination of a nicotinic receptor partial agonist and an alpha2delta ligand and a pharmaceutically acceptable carrier. The method of using these compounds is also disclosed.

Description:
BACKGROUND OF THE INVENTION  
       [0001]     The present invention relates to pharmaceutical compositions for the treatment of alcohol, cocaine or tobacco dependence or addiction in a mammal (e.g. human) comprising a nicotinic receptor partial agonist (NRPA) and an alpha2delta ligand. The term NRPA refers to all chemical compounds that bind at neuronal nicotinic acetylcholine specific receptor sites in mammalian tissue and elicit a partial agonist response. A partial agonist response is defined here to mean a partial, or incomplete functional effect in a given functional assay. Additionally, a partial agonist will also exhibit some degree of antagonist activity by its ability to block the action of a full agonist (Feldman, R. S., Meyer, J. S. &amp; Quenzer, L. F.  Principles of Neuropsychopharmacology,  1997; Sinauer Assoc. Inc.). The present invention may be used to treat mammals (e.g. humans) for alcohol or cocaine dependence or addiction and nicotine dependence or addiction; to palliate the effects of alcohol withdrawal, to enhance the outcomes of other alcohol cessation therapies and to treat substance abuse and behavioral dependencies, including gambling.  
         [0002]     The invention also relates to aryl fused azapolycylic compounds that bind to neuronal nicotinic acetylcholine specific receptor sites and are useful in modulating cholinergic function and are referred to in WO 9818798 A1 (U.S. Pat. No. 6,235,734), WO 9935131-A1 (U.S. Pat. No. 6,410,550) and WO9955680-A1 (U.S. Pat. No. 6,462,035). The foregoing applications are owned in common with the present application and are incorporated herein by reference in their entireties.  
         [0003]     Several alpha2delta ligands are known. Gabapentin, a cyclic alpha2delta ligand, is now commercially available (Neurontin®, Warner-Lambert Company) and extensively used clinically for treatment of epilepsy and neuropathic pain. Such cyclic alpha2delta ligands are described in U.S. Pat. No. 4,024,175, which issued on May 17, 1977, and U.S. Pat. No. 4,087,544, which issued on May 2, 1978 and are incorporated by reference in their entireties.  
         [0004]     The NRPA compounds that bind to neuronal nicotinic receptor sites can be used in combination with an alpha2delta ligand to treat addiction such as to alcohol or tobacco, alcohol dependence, cocaine addiction or alcohol or nicotine dependence independently of other psychiatric illness or other behavioral dependencies, eg. gambling.  
         [0005]     Approximately 13.5 million individuals in the US suffer from alcohol abuse and dependence (AAD). Untreated alcoholics are among the highest users of US health care, consuming 15% of each health care dollar. In addition, the indirect costs associated with productivity loss, property damage, and premature death are estimated at $100 billion per year. Only 20% receive any treatment and less than 10% receive any drug treatment related to AAD. AAD is increasingly viewed as a disease amenable to a combination of psychosocial and drug intervention. Yet it is increasingly viewed as a disease amenable to drug interventions.  
       SUMMARY OF INVENTION  
       [0006]     The present invention relates to a pharmaceutical composition for treating alcohol or cocaine dependence or addiction, tobacco dependence or addiction, reducing alcohol withdrawal symptoms or aiding in the cessation or lessening of alcohol use or substance abuse or behavioral dependencies including gambling, comprising: 
        (a) a nicotinic receptor partial agonist or a pharmaceutically acceptable salt thereof;     (b) an alpha2delta ligand or pharmaceutically acceptable salt thereof; and     (c) a pharmaceutically acceptable carrier;     wherein the active agents “a” and “b” above are present in amounts that render the composition effective in treating alcohol or cocaine dependence or addiction, tobacco dependence or addiction, reducing alcohol withdrawal symptoms or aiding in the cessation or lessening of alcohol use or substance abuse or behavioral dependencies. The therapeutically effective pharmaceutical combination is comprised of a nicotinic receptor partial agonist, an alpha2delta ligand and a pharmaceutically acceptable carrier.        
 
         [0011]     In a more specific embodiment the alpha2delta ligands are selected from: 
        3-Amino-5-methyl-octanoic acid;     3-Amino-5-methyl-nonanoic acid;     (3S,5R)-3-Amino-5-methyl-heptanoic acid;     (3S,5R)-3-Amino-5-methyl-octanoic acid;     (3S,5R)-3-Amino-5-methyl-nonanoic acid;     3-Amino-7-cyclopentyl-5-methyl-heptanoic acid;     3-Amino-7-cyclohexyl-5-methyl-heptanoic acid;     (3S,5R)-3-Amino-7-cyclopentyl-5-methyl-heptanoic acid;     (3S,5R)-3-Amino-7-cyclohexyl-5-methyl-heptanoic acid;     3-Amino-5-methyl-7-phenyl-heptanoic acid;     3-Amino-5-methyl-7-(2,4-difluoro-phenyl)-heptanoic acid;     3-Amino-8-(2,3-difluoro-phenyl)-5-methyl-octanoic acid;     3-Amino-8-(2,4-difluoro-phenyl)-5-methyl-octanoic acid;     2-Aminomethyl-4-methyl-heptanoic acid;     (2R, 4R)-2-Aminomethyl-4-methyl-heptanoic acid;     (2R, 4S)-2-Aminomethyl-4-methyl-heptanoic acid;     2-Aminomethyl-3-[1-4-methyl-pentyl)-cyclopropyl]-propionic acid;     2-Aminomethyl-4-ethyl-8-methyl-nonanoic acid;     2-Aminomethyl-3-(1-methyl-cyclopropy)-propionic acid;     2-Aminomethyl-4,4-dimethyl-8-methyl-nonanoic acid;     2-Aminomethyl-4-cyclohexyl-3-methyl-butyric acid;     2-Aminomethyl-4,6-dimethyl-heptanoic acid;     1-(aminomethyl)-cyclohexane acetic acid;     (1-aminomethyl-3-methylcyclohexyl) acetic acid;     (1-aminomethyl-3-methylcyclopentyl) acetic acid;     (1-aminomethyl-3,4-dimethylcyclopentyl) acetic acid;     (S)-3-(aminomethyl)-5-methylhexanoic acid;     3-(1-aminoethyl)-5-methylheptanoic acid or 3-(1-aminoethyl)-5-methylhexanoic acid;     C-[1-(1H-Tetrazol-5-ylmethyl)-cycloheptyl]-methylamine;     (3S,4S)-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid;     (3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid;     3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one;     3-(1-aminomethyl-cycloheptylmethyl)-4H-[1,2,4]oxadiazol-5-one; and     3-(1-aminomethyl-cycloheptylmethyl)-4H-[1,2,4]oxadiazol-5-one hydrochloride.     tert-Butyl ({2-[(4-bromophenyl)sulfanyl]ethyl}amino)acetate;     tert-Butyl ({2-[(4-chlorophenyl)sulfanyl]ethyl}amino)acetate;     tert-Butyl {[2-(2,4-dichlorophenoxy)ethyl]amino}acetate;     tert-Butyl ({2-[(4-chlorobenzyl)sulfanyl]ethyl}amino)acetate;     tert-Butyl {[2-(7-isoquinolinylsulfanyl)ethyl]amino}acetate;     ({2-[(4-Chlorophenyl)sulfanyl]ethyl}amino)acetic acid;     ({2-[(4-Bromophenyl)sulfanyl]ethyl}amino)acetic acid;     [(2-{[4-(Aminomethyl)phenyl]sulfanyl}ethyl)amino]acetic acid;     {[2-(2,4-Dichlorophenoxy)ethyl]amino}acetic acid;     ({2-[(4-Chlorobenzyl)sulfanyl]ethyl}amino)acetic acid;     {[2-(7-Isoquinolinylsulfanyl)ethyl]amino}acetic acid;     Ethyl ({2-[(4-chlorophenyl)sulfanyl]ethyl}amino)acetate;     [2-(4-chloro-phenoxy)-propylamino]-acetic acid tert-butyl ester;     [2-(4-chloro-phenoxy)-propylamino]-acetic acid hydrochloride salt;     [2-(4-Methylsufanyl-phenylsufanyl)-ethylamino]-acetic acid tert-butyl ester;     [2-(4-Methylsufanyl-phenylsufanyl)-ethylamino]-acetic acid hydrochloride salt;     (4-Phenyl-butylamino)-acetic acid methyl ester;     4-Phenylbutylamino acetic acid hydrochloride salt;     [2-(3-Chloro-phenoxy)-butylamino]-acetic acid; dihydrochloride;     2-aminomethyl-5-chloro-benzoic acid;     2-aminomethyl-4,5-dichloro-benzoic acid;     2-aminomethyl-3-bromo-benzoic acid;     2-aminomethyl-6-chloro-benzoic acid;     2-(1-aminoethyl)-benzoic acid;     2,3-dihydro-1H-isoindole-4-carboxylic acid;     3-(2-aminomethyl-5-chloro-phenyl)-4H-[1,2,4]oxadiazol-5-one     tert-Butyl ({2-[(4-bromophenyl)sulfanyl]ethyl}amino)acetate;     tert-Butyl ({2-[(4-chlorophenyl)sulfanyl]ethyl}amino)acetate;     tert-Butyl {[2-(2,4-dichlorophenoxy)ethyl]amino}acetate;     tert-Butyl ({2-[(4-chlorobenzyl)sulfanyl]ethyl}amino)acetate;     tert-Butyl {[2-(7-isoquinolinylsulfanyl)ethyl]amino}acetate;     ({2-[(4-Chlorophenyl)sulfanyl]ethyl}amino)acetic acid;     ({2-[(4-Bromophenyl)sulfanyl]ethyl}amino)acetic acid;     [(2-{[4-(Aminomethyl)phenyl]sulfanyl}ethyl)amino]acetic acid;     {[2-(2,4-Dichlorophenoxy)ethyl]amino}acetic acid;     ({2-[(4-Chlorobenzyl)sulfanyl]ethyl}amino)acetic acid;     {[2-(7-Isoquinolinylsulfanyl)ethyl]amino}acetic acid;     Ethyl ({2-[(4-chlorophenyl)sulfanyl]ethyl}amino)acetate;     [2-(4-chloro-phenoxy)-propylamino]-acetic acid tert-butyl ester;     [2-(4-chloro-phenoxy)-propylamino]-acetic acid hydrochloride salt;     [2-(4-Methylsufanyl-phenylsufanyl)-ethylamino]-acetic acid tert-butyl ester;     [2-(4-Methylsufanyl-phenylsufanyl)-ethylamino]-acetic acid hydrochloride salt;     (4-Phenyl-butylamino)-acetic acid methyl ester;     4-Phenylbutylamino acetic acid hydrochloride salt;     [2-(3-Chloro-phenoxy)-butylamino]-acetic acid; dihydrochloride;     2-aminomethyl-5-chloro-benzoic acid;     2-aminomethyl-4,5-dichloro-benzoic acid;     2-aminomethyl-3-bromo-benzoic acid;     2-aminomethyl-6-chloro-benzoic acid;     2-(1-aminoethyl)-benzoic acid;     2,3-dihydro-1H-isoindole-4-carboxylic acid;     3-(2-aminomethyl-5-chloro-phenyl)-4H-[1,2,4]oxadiazol-5-one;     (1R,5R,6S)-[6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid; and     (1α,3α,5α)-[3-(aminomethyl)bicyclo[3.2.0]hept-3-yl]acetic acid.        
 
         [0100]     In another more specific embodiment of this invention, the nicotinic receptor partial agonist is selected from: 
        9-bromo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;     9-chloro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;     9-fluoro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[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-pyrido[1,2-a][1,5]diazocin-8-one;     9-phenyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[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-pyrido[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-pyrido[1,2a][1,5]diazocin-8-one;     9-ethynyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;     9-(2-propenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-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-methano-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-pyrido[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[9.3.1.0 2,10 .0 4,8 ]pentadeca-2(10),3,8-triene;     5-oxo-6,13-diazatetracyclo[9.3.1.0 2,10 .0 4,8 ]pentadeca-2(10),3,8-triene;     6-oxo-5,7,13-triazatetracyclo[9.3.1.0 2,10 .0 4,8 ]pentadeca-2(10),3,8-triene;     4,5-difluoro-10-aza-tricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-triene;     5-fluoro-10-aza-tricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-triene-4-carbonitrile;     4-ethynyl-5-fluoro-10-aza-tricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-triene;     5-ethynyl-10-aza-tricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-triene-4-carbonitrile;     6-methyl-5-thia-5-dioxa-6,13-diazatetracyclo[9.3.1.0 2,10 .0 4,8 ]pentadeca-2(10),3,8-triene;     10-aza-tricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-triene;     4-fluoro-10-aza-tricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-triene;     4-methyl-10-aza-tricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-triene;     4-trifluoromethyl-10-aza-tricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-triene;     4-nitro-10-azatricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-triene;     7-methyl-5,7,13-triazatetracyclo[9.3.1.0 2,10 .0 4,8 ]pentadeca-2(10),3,5,8-tetraene;     6-methyl-5,7,13-triazatetracyclo[9.3.1.0 2,10 .0 4,8 ]pentadeca-2(10),3,5,8-tetraene;     6,7-dimethyl-5,7,13-triazatetracyclo[9.3.1.0 2,10 .0 4,8 ]pentadeca-2(10),3,5,8-tetraene;     6-methyl-7-phenyl-5,7,13-triazatetracyclo[9.3.1.0 2,10 .0 4,8 ]pentadeca-2(10),3,5,8-tetraene;     6,7-dimethyl-5,8,14-triazatetracyclo[10.3.1.0 2,11 .0 4,9 ]hexadeca-2(11),3,5,7,9-pentaene;     5,8,14-triazatetracyclo[10.3.1.0 2,11 .0 4,9 ]hexadeca-2(11),3,5,7,9-pentaene;     14-methyl-5,8,14-triazatetracyclo[10.3.1.0 2,11 .0 4,9 ]hexadeca-2(11),3,5,7,9-pentaene;     5-oxa-7,13-diazatetracyclo[9.3.1.0 2,10 .0 4,8 ]pentadeca-2(10),3,6,8-tetraene;     6-methyl-5-oxa-7,13-diazatetracyclo[9.3.1.0 2,10 .0 4,8 ]pentadeca-2(10),3,6,8-tetraene;     4-chloro-10-azatricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-triene;     10-azatricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-trien-4-yl cyanide;     1-(10-azatricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-trien-4-yl)-1-ethanone;     10-azatricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-trien-4-ol;     7-methyl-5-oxa-6,13-diazatetracyclo[9.3.1.0 2,10 .0 4,8 ]pentadeca-2,4(8),6,9-tetraene;     4,5-dichloro-10-azatricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-triene;     11-azatricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-triene-5-carbonitrile;     1-[11-azatricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-trien-5-yl]-1-ethanone;     1-[11-azatricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-trien-5-yl]-1-propanone;     4-fluoro-11-azatricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-triene-5-carbonitrile;     5-fluoro-11-azatricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-triene-4-carbonitrile;     6-methyl-7-thia-5,14-diazatetracyclo[10.3.1.0 2,10 .0 4,8 ]hexadeca-2(10),3,5,8-tetraene;     6-methyl-5,7,14-triazatetracyclo[10.3.1.0 2,10 .0 4,8 ]hexadeca-2(10),3,5,8-tetraene;     6,7-dimethyl-5,7,14-triazatetracyclo[10.3.1.0 2,10 .0 4,8 ]hexadeca-2(10),3,5,8-tetraene;     5,7,14-triazatetracyclo[10.3.1.0 2,10 .0 4,8 ]hexadeca-2(10),3,5,8-tetraene;     5,6-dimethyl-5,7,14-triazatetracyclo[10.3.1.0 2,10 .0 4,8 ]hexadeca-2(10),3,6,8-tetraene;     5-methyl-5,7,14-triazatetracyclo[10.3.1.0 2,10 .0 4,8 ]hexadeca-2(10),3,6,8-tetraene;     6-(trifluoromethyl)-7-thia-5,14-diazatetracyclo[10.3.1.0 2,10 .0 4,8 ]hexadeca-2(10),3,5,8-tetraene;     5,8,15-triazatetracyclo[11.3.1.0 2,11 .0 4,9 ]heptadeca-2(11),3,5,7,9-pentaene;     7-methyl-5,8,15-triazatetracyclo[11.3.1.0 2,11 .0 4,9 ]heptadeca-2(11),3,5,7,9-pentaene;     6-methyl-5,8,15-triazatetracyclo[11.3.1.0 2,11 .0 4,9 ]heptadeca-2(11),3,5,7,9-pentaene;     6,7-dimethyl-5,8,15-triazatetracyclo[11.3.1.0 2,11 .0 4,9 ]heptadeca-2(11),3,5,7,9-pentaene;     7-oxa-5,14-diazatetracyclo[10.3.1.0 2,10 .0 4,8 ]hexadeca-2(10),3,5,8-tetraene;     6-methyl-7-oxa-5,14-diazatetracyclo[10.3.1.0 2,10 .0 4,8 ]hexadeca-2(10),3,5,8-tetraene;     5-methyl-7-oxa-6,14-diazatetracyclo[10.3.1.0 2,10 .0 4,8 ]hexadeca-2(10),3,5,8-tetraene;     6-methyl-5-oxa-7,14-diazatetracyclo[10.3.1.0 2,10 .0 4,8 ]hexadeca-2(10),3,6,8-tetraene;     7-methyl-5-oxa-6,14-diazatetracyclo[10.3.1.0 2,10 .0 4,8 ]hexadeca-2(10),3,6,8-tetraene;     4,5-difluoro-11-azatricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-triene;     4-chloro-5-fluoro-11-azatricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-triene;     5-chloro-4-fluoro-11-azatricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-triene;     4-(1-ethynyl)-5-fluoro-11-azatricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-triene;     5-(1-ethynyl)-4-fluoro-11-azatricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-triene;     5,6-difluoro-11-aza-tricyclo[7.3.1.0 2,7 ]trideca-2,4,6-triene;     6-trifluoromethyl-11-aza-tricyclo[7.3.1.0 2,7 ]trideca-2,4,6-triene;     6-methoxy-11-aza-tricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-triene;     11-aza-tricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-trien-6-ol;     6-fluoro-11-aza-tricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-triene;     11-aza-tricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-trien-5-ol;     4-nitro-11-aza-tricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-triene;     5-nitro-11-aza-tricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-triene;     5-fluoro-11-aza-tricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-triene; and     6-hydroxy-5-methoxy-11-aza-tricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-triene and their pharmaceutically acceptable salts and their optical isomers.        
 
         [0191]     Preferably, the nicotinic receptor partial agonist is selected from 
        9-bromo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;     9-chloro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;     9-fluoro-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-pyrido[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-pyrido[1,2a][1,5]diazocin-8-one;     9-carbomethoxy-1,2,3,4,5,6-hexahydro-1,5-methano-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-pyrido[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[9.3.1.0 2,10 .0 4,8 ]pentadeca-2(10),3,8-triene;     4-fluoro-10-aza-tricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-triene;     4-trifluoromethyl-10-aza-tricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-triene;     4-nitro-10-azatricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-triene;     6-methyl-5,7,13-triazatetracyclo[9.3.1.0 2,10 .0 4,8 ]pentadeca-2(10),3,5,8-tetraene;     6,7-dimethyl-5,8,14-triazatetracyclo[10.3.1.0 2,11 .0 4,9 ]hexadeca-2(11),3,5,7,9-pentaene;     5,8,14-triazatetracyclo[10.3.1.0 2,11 .0 4,9 ]hexadeca-2(11),3,5,7,9-pentaene;     5-oxa-7,13-diazatetracyclo[9.3.1.0 2,10 .0 4,8 ]pentadeca-2(10),3,6,8-tetraene;     6-methyl-5-oxa-7,13-diazatetracyclo[9.3.1.0 2,10 .0 4,8 ]pentadeca-2(10),3,6,8-tetraene;     10-azatricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-trien-4-yl cyanide;     1-(10-azatricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-trien-4-yl)-1-ethanone;     11-azatricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-triene-5-carbonitrile;     1-[11-azatricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-trien-5-yl]-1-ethanone;     1-[11-azatricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-trien-5-yl]-1-propanone;     4-fluoro-11-azatricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-triene-5-carbonitrile;     5-fluoro-11-azatricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-triene-4-carbonitrile;     6-methyl-7-thia-5,14-diazatetracyclo[10.3.1.0 2,10 .0 4,8 ]hexadeca-2(10),3,5,8-tetraene;     6-methyl-5,7,14-triazatetracyclo[10.3.1.0 2,10 .0 4,8 ]hexadeca-2(10),3,5,8-tetraene;     6,7-dimethyl-5,7,14-triazatetracyclo[10.3.1.0 2,10 .0 4,8 ]hexadeca-2(10),3,5,8-tetraene;     6-methyl-7-oxa-5,14-diazatetracyclo[10.3.1.0 2,10 .0 4,8 ]hexadeca-2(10),3,5,8-tetraene;     6-methyl-5-oxa-7,14-diazatetracyclo[10.3.1.0 2,10 .0 4,8 ]hexadeca-2(10),3,6,8-tetraene;     5,6-difluoro-11-aza-tricyclo[7.3.1.0 2,7 ]trideca-2,4,6-triene;     6-trifluoromethyl-11-aza-tricyclo[7.3.1.0 2,7 ]trideca-2,4,6-triene;     6-methoxy-11-aza-tricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-triene;     6-fluoro-11-aza-tricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-triene; and     11-aza-tricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-trien-5-ol and their pharmaceutically acceptable salts and their optical isomers.        
 
         [0229]     The present invention also relates to a method of treating alcohol or cocaine dependence or addiction, tobacco dependence or addiction, reducing alcohol withdrawal symptoms or aiding in the cessation or lessening of alcohol use or substance abuse or behavioral dependencies, including gambling, comprising: 
        (a) a nicotinic receptor partial agonist or a pharmaceutically acceptable salt thereof;     (b) an alpha2delta ligand or pharmaceutically acceptable salt thereof; and     (c) a pharmaceutically acceptable carrier;     wherein the active agents (a) and (b) above are present in amounts that render the composition effective in treating alcohol dependence or addiction, tobacco dependence or addiction, reducing alcohol withdrawal symptoms or aiding in the cessation or lessening of alcohol use or substance abuse or behavioral dependencies.        
 
         [0234]     The nicotinic receptor partial agonist and the alpha2delta ligand are present in amounts that render the composition effective in the treatment of alcohol or nicotine addiction, alcohol withdrawal symptoms, substance abuse or other behavioral dependencies. In a more specific embodiment of the invention, the alpha2delta ligand is selected from: 
        3-Amino-5-methyl-octanoic acid;     3-Amino-5-methyl-nonanoic acid;     (3S,5R)-3-Amino-5-methyl-heptanoic acid;     (3S,5R)-3-Amino-5-methyl-octanoic acid;     (3S,5R)-3-Amino-5-methyl-nonanoic acid;     3-Amino-7-cyclopentyl-5-methyl-heptanoic acid;     3-Amino-7-cyclohexyl-5-methyl-heptanoic acid;     (3S,5R)-3-Amino-7-cyclopentyl-5-methyl-heptanoic acid;     (3S,5R)-3-Amino-7-cyclohexyl-5-methyl-heptanoic acid;     3-Amino-5-methyl-7-phenyl-heptanoic acid;     3-Amino-5-methyl-7-(2,4-difluoro-phenyl)-heptanoic acid;     3-Amino-8-(2,3-difluoro-phenyl)-5-methyl-octanoic acid;     3-Amino-8-(2,4-difluoro-phenyl)-5-methyl-octanoic acid;     2-Aminomethyl-4-methyl-heptanoic acid;     (2R, 4R)-2-Aminomethyl-4-methyl-heptanoic acid;     (2R, 4S)-2-Aminomethyl-4-methyl-heptanoic acid;     2-Aminomethyl-3-[1-4-methyl-pentyl)-cyclopropyl]-propionic acid;     2-Aminomethyl-4-ethyl-8-methyl-nonanoic acid;     2-Aminomethyl-3-(1-methyl-cyclopropy)-propionic acid;     2-Aminomethyl-4,4-dimethyl-8-methyl-nonanoic acid;     2-Aminomethyl-4-cyclohexyl-3-methyl-butyric acid;     2-Aminomethyl-4,6-dimethyl-heptanoic acid;     1-(aminomethyl)-cyclohexane acetic acid;     (1-aminomethyl-3-methylcyclohexyl) acetic acid;     (1-aminomethyl-3-methylcyclopentyl) acetic acid;     (1-aminomethyl-3,4-dimethylcyclopentyl) acetic acid.     (S)-3-(aminomethyl)-5-methylhexanoic acid;     3-(1-aminoethyl)-5-methylheptanoic acid or 3-(1-aminoethyl)-5-methylhexanoic acid;     C-[1-(1H-Tetrazol-5-ylmethyl )-cycloheptyl]-methylamine;     (3S,4S)-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid;     (3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid;     3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one;     3-(1-aminomethyl-cycloheptylmethyl)-4H-[1,2,4]oxadiazol-5-one; and     3-(1-aminomethyl-cycloheptylmethyl)-4H-[1,2,4]oxadiazol-5-one hydrochloride.     tert-Butyl ({2-[(4-bromophenyl)sulfanyl]ethyl}amino)acetate;     tert-Butyl ({2-[(4-chlorophenyl)sulfanyl]ethyl}amino)acetate;     tert-Butyl {[2-(2,4-dichlorophenoxy)ethyl]amino}acetate;     tert-Butyl ({2-[(4-chlorobenzyl)sulfanyl]ethyl}amino)acetate;     tert-Butyl {[2-(7-isoquinolinylsulfanyl)ethyl]amino}acetate;     ({2-[(4-Chlorophenyl)sulfanyl]ethyl}amino)acetic acid;     ({2-[(4-Bromophenyl)sulfanyl]ethyl}amino)acetic acid;     [(2-{[4-(Aminomethyl)phenyl]sulfanyl}ethyl)amino]acetic acid;     {[2-(2,4-Dichlorophenoxy)ethyl]amino}acetic acid;     ({2-[(4-Chlorobenzyl)sulfanyl]ethyl}amino)acetic acid;     {[2-(7-Isoquinolinylsulfanyl)ethyl]amino}acetic acid;     Ethyl ({2-[(4-chlorophenyl)sulfanyl]ethyl}amino)acetate;     [2-(4-chloro-phenoxy)-propylamino]-acetic acid tert-butyl ester;     [2-(4-chloro-phenoxy)-propylamino]-acetic acid hydrochloride salt;     [2-(4-Methylsufanyl-phenylsufanyl)-ethylamino]-acetic acid tert-butyl ester;     [2-(4-Methylsufanyl-phenylsufanyl)-ethylamino]-acetic acid hydrochloride salt;     (4-Phenyl-butylamino)-acetic acid methyl ester;     4-Phenylbutylamino acetic acid hydrochloride salt;     [2-(3-Chloro-phenoxy)-butylamino]-acetic acid; dihydrochloride;     2-aminomethyl-5-chloro-benzoic acid;     2-aminomethyl-4,5-dichloro-benzoic acid;     2-aminomethyl-3-bromo-benzoic acid;     2-aminomethyl-6-chloro-benzoic acid;     2-(1-aminoethyl)-benzoic acid;     2,3-dihydro-1H-isoindole-4-carboxylic acid;     3-(2-aminomethyl-5-chloro-phenyl)-4H-[1,2,4]oxadiazol-5-one     tert-Butyl ({2-[(4-bromophenyl)sulfanyl]ethyl}amino)acetate;     tert-Butyl ({2-[(4-chlorophenyl)sulfanyl]ethyl}amino)acetate;     tert-Butyl {[2-(2,4-dichlorophenoxy)ethyl]amino}acetate;     tert-Butyl ({2-[(4-chlorobenzyl)sulfanyl]ethyl}amino)acetate;     tert-Butyl {[2-(7-isoquinolinylsulfanyl)ethyl]amino}acetate;     ({2-[(4-Chlorophenyl)sulfanyl]ethyl}amino)acetic acid;     ({2-[(4-Bromophenyl)sulfanyl]ethyl}amino)acetic acid;     [(2-{[4-(Aminomethyl)phenyl]sulfanyl}ethyl)amino]acetic acid;     {[2-(2,4-Dichlorophenoxy)ethyl]amino}acetic acid;     ({2-[(4-Chlorobenzyl)sulfanyl]ethyl}amino)acetic acid;     {[2-(7-Isoquinolinylsulfanyl)ethyl]amino}acetic acid;     Ethyl ({2-[(4-chlorophenyl)sulfanyl]ethyl}amino)acetate;     [2-(4-chloro-phenoxy)-propylamino]-acetic acid tert-butyl ester;     [2-(4-chloro-phenoxy)-propylamino]-acetic acid hydrochloride salt;     [2-(4-Methylsufanyl-phenylsufanyl)-ethylamino]-acetic acid tert-butyl ester;     [2-(4-Methylsufanyl-phenylsufanyl)-ethylamino]-acetic acid hydrochloride salt;     (4-Phenyl-butylamino)-acetic acid methyl ester;     4-Phenylbutylamino acetic acid hydrochloride salt;     [2-(3-Chloro-phenoxy)-butylamino]-acetic acid; dihydrochloride.     2-aminomethyl-5-chloro-benzoic acid;     2-aminomethyl-4,5-dichloro-benzoic acid;     2-aminomethyl-3-bromo-benzoic acid;     2-aminomethyl-6-chloro-benzoic acid;     2-(1-aminoethyl)-benzoic acid;     2,3-dihydro-1H-isoindole-4-carboxylic acid;     3-(2-aminomethyl-5-chloro-phenyl)-4H-[1,2,4]oxadiazol-5-one;     (1R,5R,6S)-[6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid; and     (1α,3α,5α)-[3-(aminomethyl)bicyclo[3.2.0]hept-3-yl]acetic acid.        
 
         [0323]     In another more specific embodiment of this invention the nicotinic receptor partial agonist is selected from: 
        9-bromo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;     9-chloro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;     9-fluoro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[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-pyrido[1,2-a][1,5]diazocin-8-one;     9-phenyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[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-pyrido[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-pyrido[1,2a][1,5]diazocin-8-one;     9-ethynyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one;     9-(2-propenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-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-methano-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-pyrido[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[9.3.1.0 2,10 .0 4,8 ]pentadeca-2(10),3,8-triene;     5-oxo-6,13-diazatetracyclo[9.3.1.0 2,10 .0 4,8 ]pentadeca-2(10),3,8-triene;     6-oxo-5,7,13-triazatetracyclo[9.3.1.0 2,10 .0 4,8 ]pentadeca-2(10),3,8-triene;     4,5-difluoro-10-aza-tricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-triene;     5-fluoro-10-aza-tricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-triene-4-carbonitrile;     4-ethynyl-5-fluoro-10-aza-tricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-triene;     5-ethynyl-10-aza-tricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-triene-4-carbonitrile;     6-methyl-5-thia-5-dioxa-6,13-diazatetracyclo[9.3.1.0 2,10 .0 4,8 ]pentadeca-2(10),3,8-triene;     10-aza-tricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-triene;     4-fluoro-10-aza-tricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-triene;     4-methyl-10-aza-tricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-triene;     4-trifluoromethyl-10-aza-tricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-triene;     4-nitro-10-azatricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-triene;     7-methyl-5,7,13-triazatetracyclo[9.3.1.0 2,10 .0 4,8 ]pentadeca-2(10),3,5,8-tetraene;     6-methyl-5,7,13-triazatetracyclo[9.3.1.0 2,10 .0 4,8 ]pentadeca-2(10),3,5,8-tetraene;     6,7-dimethyl-5,7,13-triazatetracyclo[9.3.1.0 2,10 .0 4,8 ]pentadeca-2(10),3,5,8-tetraene;     6-methyl-7-phenyl-5,7,13-triazatetracyclo[9.3.1.0 2,10 .0 4,8 ]pentadeca-2(10),3,5,8-tetraene;     6,7-dimethyl-5,8,14-triazatetracyclo[10.3.1.0 2,11 .0 4,9 ]hexadeca-2(11),3,5,7,9-pentaene;     5,8,14-triazatetracyclo[10.3.1.0 2,11 .0 4,9 ]hexadeca-2(11),3,5,7,9-pentaene;     14-methyl-5,8,14-triazatetracyclo[10.3.1.0 2,11 .0 4,9 ]hexadeca-2(11),3,5,7,9-pentaene;     5-oxa-7,13-diazatetracyclo[9.3.1.0 2,10 .0 4,8 ]pentadeca-2(10),3,6,8-tetraene;     6-methyl-5-oxa-7,13-diazatetracyclo[9.3.1.0 2,10 .0 4,8 ]pentadeca-2(10),3,6,8tetraene;     4-chloro-10-azatricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-triene;     10-azatricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-trien-4-yl cyanide;     1-(10-azatricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-trien-4-yl)-1-ethanone;     10-azatricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-trien-4-ol;     7-methyl-5-oxa-6,13-diazatetracyclo[9.3.1.0 2,10 .0 4,8 ]pentadeca-2,4(8),6,9-tetraene;     4,5-dichloro-10-azatricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-triene;     11-azatricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-triene-5-carbonitrile;     1-[11-azatricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-trien-5-yl]-1-ethanone;     1-[11-azatricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-trien-5-yl]-1-propanone;     4-fluoro-11-azatricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-triene-5-carbonitrile;     5-fluoro-11-azatricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-triene-4-carbonitrile;     6-methyl-7-thia-5,14-diazatetracyclo[10.3.1.0 2,10 .0 4,8 ]hexadeca-2(10),3,5,8-tetraene;     6-methyl-5,7,14-triazatetracyclo[10.3.1.0 2,10 .0 4,8 ]hexadeca-2(10),3,5,8-tetraene;     6,7-dimethyl-5,7,14-triazatetracyclo[10.3.1.0 2,10 .0 4,8 ]hexadeca-2(10),3,5,8-tetraene;     5,7,14-triazatetracyclo[10.3.1.0 2,10 .0 4,8 ]hexadeca-2(10),3,5,8-tetraene;     5,6-dimethyl-5,7,14-triazatetracyclo[10.3.1.0 2,10 .0 4,8 ]hexadeca-2(10),3,6,8-tetraene;     5-methyl-5,7,14-triazatetracyclo[10.3.1.0 2,10 .0 4,8 ]hexadeca-2(10),3,6,8-tetraene;     6-(trifluoromethyl)-7-thia-5,14-diazatetracyclo[10.3.1.0 2,10 .0 4,8 ]hexadeca-2(10),3,5,8-tetraene;     5,8,15-triazatetracyclo[11.3.1.0 2,11 .0 4,9 ]heptadeca-2(11),3,5,7,9-pentaene;     7-methyl-5,8,15-triazatetracyclo[11.3.1.0 2,11 .0 4,9 ]heptadeca-2(11),3,5,7,9-pentaene;     6-methyl-5,8,15-triazatetracyclo[11.3.1.0 2,11 .0 4,9 ]heptadeca-2(11),3,5,7,9-pentaene;     6,7-dimethyl-5,8,15-triazatetracyclo[11.3.1.0 2,11 .0 4,9 ]heptadeca-2(11),3,5,7,9-pentaene;     7-oxa-5,14-diazatetracyclo[10.3.1.0 2,10 .0 4,8 ]hexadeca-2(10),3,5,8-tetraene;     6-methyl-7-oxa-5,14-diazatetracyclo[10.3.1.0 2,10 .0 4,8 ]hexadeca-2(10),3,5,8-tetraene;     5-methyl-7-oxa-6,14-diazatetracyclo[10.3.1.0 2,10 .0 4,8 ]hexadeca-2(10),3,6,8-tetraene;     6-methyl-5-oxa-7,14-diazatetracyclo[10.3.1.0 2,10 .0 4,8 ]hexadeca-2(10),3,6,8tetraene;     7-methyl-5-oxa-6,14-diazatetracyclo[10.3.1.0 2,10 .0 4,8 ]hexadeca-2(10),3,6,8tetraene;     4,5-difluoro-11-azatricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-triene;     4-chloro-5-fluoro-11-azatricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-triene;     5-chloro-4-fluoro-11-azatricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-triene;     4-(1-ethynyl)-5-fluoro-11-azatricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-triene;     5-(1-ethynyl)-4-fluoro-11-azatricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-triene;     5,6-difluoro-11-aza-tricyclo[7.3.1.0 2,7 ]trideca-2,4,6-triene;     6-trifluoromethyl-11-aza-tricyclo[7.3.1.0 2,7 ]trideca-2,4,6-triene;     6-methoxy-11-aza-tricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-triene;     11-aza-tricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-trien-6-ol;     6fluoro-11-aza-tricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-triene;     11-aza-tricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-trien-5-ol;     4-nitro-11-aza-tricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-triene;     5-nitro-11-aza-tricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-triene;     5-fluoro-11-aza-tricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-triene; and     6-hydroxy-5-methoxy-11-aza-tricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-triene and their pharmaceutically acceptable salts and their optical isomers.        
 
         [0414]     Preferably, the nicotinic receptor partial agonist is selected from: 
        9-bromo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;     9-chloro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;     9-fluoro-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-pyrido[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-pyrido[1,2a][1,5]diazocin-8-one;     9-carbomethoxy-1,2,3,4,5,6-hexahydro-1,5-methano-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-pyrido[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[9.3.1.0 2,10 .0 4,8 ]pentadeca-2(10),3,8-triene;     4-fluoro-10-aza-tricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-triene;     4-trifluoromethyl-10-aza-tricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-triene;     4-nitro-10-azatricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-triene;     6-methyl-5,7,13-triazatetracyclo[9.3.1.0 2,10 .0 4,8 ]pentadeca-2(10),3,5,8-tetraene;     6,7-dimethyl-5,8,14-triazatetracyclo[10.3.1.0 2,11 .0 4,9 ]hexadeca-2(11),3,5,7,9-pentaene;     5,8,14-triazatetracyclo[10.3.1.0 2,11 .0 4,9 ]hexadeca-2(11),3,5,7,9-pentaene;     5-oxa-7,13-diazatetracyclo[9.3.1.0 2,10 .0 4,8 ]pentadeca-2(10),3,6,8-tetraene;     6-methyl-5-oxa-7,13-diazatetracyclo[9.3.1.0 2,10 .0 4,8 ]pentadeca-2(10),3,6,8-tetraene;     10-azatricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-trien-4-yl cyanide;     1-(10-azatricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-trien-4-yl)-1-ethanone;     11-azatricyclo[7.3.1.0 2,.7 ]trideca-2(7),3,5-triene-5-carbonitrile;     1-[11-azatricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-trien-5-yl]-1-ethanone;     1-[11-azatricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-trien-5-yl]-1-propanone;     4-fluoro-11-azatricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-triene-5-carbonitrile;     5-fluoro-11-azatricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-triene-4-carbonitrile;     6-methyl-7-thia-5,14-diazatetracyclo[10.3.1.0 2,10 .0 4,8 ]hexadeca-2(10),3,5,8-tetraene;     6-methyl-5,7,14-triazatetracyclo[10.3.1.0 2,10 .0 4,8 ]hexadeca-2(10),3,5,8-tetraene;     6,7-dimethyl-5,7,14-triazatetracyclo[10.3.1.0 2,10 .0 4,8 ]hexadeca-2(10),3,5,8-tetraene;     6-methyl-7-oxa-5,14-diazatetracyclo[10.3.1.0 2,10 .0 4,8 ]hexadeca-2(10),3,5,8-tetraene;     6-methyl-5-oxa-7,14-diazatetracyclo[10.3.1.0 2,10 .0 4,8 ]hexadeca-2(10),3,6,8-tetraene;     5,6-difluoro-11-aza-tricyclo[7.3.1.0 2,7 ]trideca-2,4,6-triene;     6-trifluoromethyl-11-aza-tricyclo[7.3.1.0 2,7 ]trideca-2,4,6-triene;     6-methoxy-11-aza-tricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-triene;     6-fluoro-11-aza-tricyclo[7.3.1.0 2,7 ]trideca-2(7),3,5-triene; and     11-aza-tricyclo[7.3.1.0 2.7 ]trideca-2(7),3,5-trien-5-ol and the pharmaceutically acceptable salts and optical isomers of the foregoing compounds.        
 
         [0452]     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, refers to the act of treating, as “treating” is defined immediately above.  
         [0453]     The term “substance abuse”, as used herein, for example in “drug addiction” and “nicotine addiction”, unless otherwise indicated, refers to a maladaptive use of a substance, which may be either with physiological dependence or without. The term “substance abuse” thus includes both substance abuse (e.g. nicotine, amphetamine, cocaine or an opioid, for example morphine, opium, or heroine, abuse) and substance dependence (e.g. alcohol, amphetamine, cocaine or an opioid, for example morphine, opium, or heroine dependence). The maladaptive pattern of substance use may manifest itself in recurrent and significant adverse consequences related to the repeated use of the substance. The recurrent substance use may result in a failure to fulfill major role obligations at work, school, or home. The maladaptive use of a substance may involve continued use of the substance despite persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of the substance (e.g., arguments with spouse, physical fights). The maladaptive pattern of substance use may involve clinically significant impairment or distress, for example manifested by tolerance for the substance, withdrawal symptoms, unsuccessful efforts to cut down or control the substance use, and/or taking larger amounts of the substance and/or taking amounts of the substance over a longer period than was intended. Substances to which an addiction may be formed include, but are not limited to, the drugs recited above (including alcohol), as well as others, for example benzodiazepines such as Valium®.  
         [0454]     Behavioral dependencies as used here means enduring or persistent patterns of behavior which deviates markedly from the expectations of an individual&#39;s culture, is pervasive and inflexible, is stable over time, and leads to distress or impairment, and can include either Axis I or Axis II diagnoses (1994; DSM-IV, American Psychiatric Association). Such diagnoses may include, but are not limited to, substance abuse (nicotine, alcohol, narcotics, inhalants), gambling, eating disorders, and impulse control disorders.  
         [0455]     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 mixture thereof are included in this invention. Hydrates of the compounds of this invention are also included.  
         [0456]     The chemist of ordinary skill will recognize that certain combinations of heteroatom-containing substituent 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  
       [0457]     In combination with the NRPA, the invention includes an alpha2delta ligand and a pharmaceutically acceptable salt thereof.  
         [0458]     Other series of alpha2delta ligands are described in U.S. Pat. No. 5,563,175, which issued on Oct. 8, 1996, U.S. Pat. No. 6,316,638, which issued on Nov. 13, 2001, U.S. Provisional Patent Application 60/353,632, which was filed on Jan. 31, 2002, U.S. Provisional Patent Application 60/248,630, which was filed on Nov. 2, 2002, U.S. Provisional Patent Application 60/421,868, which was filed on Oct. 28, 2002, U.S. Provisional Patent Application 60/421,867, which was filed on Oct. 28, 2002, U.S. Provisional Patent Application 60/413,856, which was filed on Sep. 25, 2002, U.S. Provisional Patent Application 60/411,493, which was filed on Sep. 16, 2002, U.S. Provisional Patent Application 60/421,866, which was filed on Oct. 28, 2002, U.S. Provisional Patent Application 60/441,825, which was filed on Jan. 22, 2003, U.S. Provisional Patent Application 60/452,871, which was filed on Mar. 7, 2003, European Patent Application EP 1112253, which was published on Jul. 4, 2001, PCT Patent Application WO 99/08671, which was published on Feb. 25, 1999, and PCT Patent Application WO 99/61424, which was published on Dec. 2, 1999. These patents and applications are incorporated herein by reference in their entireties.  
         [0459]     The particular NRPA compounds listed above, which can be employed in the methods and pharmaceutical compositions of this invention, can be made by processes known in the chemical arts, for example by the methods described in WO 9818798 A1 (U.S. Pat. No. 6,235,734), WO 9935131-A1 (U.S. Pat. No. 6,410,550) and WO9955680-A1 (U.S. Pat. No. 6,462,035). Some of the preparation methods useful for making the compounds of this invention may require protection of remote functionality (i.e., primary amine, secondary amine, carboxyl). The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation 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 applications. 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 related to, or are derived from compounds found in nature and accordingly many such compounds are commercially available or are reported in the literature or are easily prepared from other commonly available substances by methods which are reported in the literature.  
         [0460]     Some of the NRPA compounds employed in this invention are ionizable at physiological conditions. Thus, for example some of the compounds of this invention are acidic and they form a salt with a pharmaceutically acceptable cation. 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 basic 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.  
         [0461]     In addition, some of the NRPA compounds employed 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 basic 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.  
         [0462]     In addition, when the NRPA compounds employed in this invention form hydrates or solvates they are also within the scope of the invention.  
         [0463]     Some of the compounds of this invention are chiral, and as such are subject to preparation via chiral synthetic routes, or separable by conventional resolution or chromatographic means. All optical forms of the compounds of this invention are within the scope of the invention.  
         [0464]     The utility of the NRPA compounds employed in the present invention as medicinal agents in the treatment of alcohol dependence and tobacco dependence or addiction in mammals (e.g. humans) is demonstrated by the activity of the compounds of this invention in conventional assays and, in particular the assays described below. These include neuronal nicotinic receptor binding, dopamine turnover. Such assays also provide a means whereby the activities of the compounds of this invention can be compared between themselves and with the activities 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  
       [0465]     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 Lippiello, P. M. and Fernandes, K. G. (in  The Binding of L -[ 3   H]Nicotine To A Single Class of High - Affinity Sites in Rat Brain Membranes, Molecular Pharm.,  29, 448-54, (1986)) and Anderson, D. J. and Arneric, S. P. (in  Nicotinic Receptor Binding of    3   H - Cystisine,    3   H - Nicotine and    3   H - Methylcarmbamylcholine In Rat Brain, European J. Pharm.,  253, 261-67 (1994)). Male Sprague-Dawley 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 p.m. light period). They received standard Purina Rat Chow and water ad libitum. The rats were killed by decapitation. Brains were removed immediately following decapitation. Membranes were prepared from brain tissue according to the methods of Lippiello and Fernandez ( Molec Pharmacol,  29, 448-454, (1986) with some modifications. Whole brains were removed, rinsed with ice-cold buffer, and homogenized at 0° in 10 volumies of buffer (w/v) using a Brinkmann Polytron™, setting 6, for 30 seconds. The buffer consisted of 50 mM Tris HCl at a pH of 7.5 at room temperature. The homogenate was sedimented by centrifugation (10 minutes; 50,000×g; 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×g; 0 to 4° C. After the second centrifugation, the membranes were resuspended in assay buffer at a concentration of 1.0 g/100 mL. The composition of the standard assay buffer was 50 mM Tris HCl, 120 mM NaCl, 5 mM KCl, 2 mM MgCl 2 , 2 mM CaCl 2  and has a pH of 7.4 at room temperature.  
         [0466]     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 volume of 1.0 mL. Three sets of tubes were prepared wherein the tubes in each set contained 50 μL of vehicle, blank, or test compound solution, respectively. To each tube was added 200 μL of [ 3 H]-nicotine in assay buffer followed by 750 μL 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 1 μM. The vehicle consisted of deionized water containing 30 μL of 1 N acetic acid per 50 mL of water. The test compounds and cytisine were dissolved in vehicle. Assays 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/B™ glass fiber filters using a Brandel™ multi-manifold tissue harvester. Following the initial filtration of the assay mixture, filters were washed two times with ice-cold assay buffer (5 mL each). The filters were then placed in counting vials and mixed vigorously with 20 ml of Ready Safe™ (Beckman) before quantification of radioactivity. Samples were counted in a LKB Wallach Rackbeta™ liquid scintillation counter at 40-50% efficiency. All determinations were in triplicate.  
         [0467]     Calculations: Specific binding (C) to the membrane is the difference between total binding in the samples containing vehicle only and membrane (A) and non-specific binding in the samples containing the membrane and cytisine (B), i.e.,
 
Specific binding=(C)=(A)−(B).
 
         [0468]     Specific binding in the presence of the test compound (E) is the difference between the total binding in the presence of the test compound (D) and non-specific binding (B), i.e., (E)=(D)−(B).
 
% Inhibition=(1−((E)/(C)) times 100.
 
         [0469]     The compounds of the invention that were tested in the above assay exhibited IC 50  values of less than 10 μM.  
         [0470]     Dopamine Turnover: Rats were injected 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 perchloric acid, and then homogenized. After centrifugation 10 uL of the supernatant was assayed by HPLC-ECD. Turnover/utilization of dopamine (DA) was calculated as the ratio of tissue concentrations of metabolites ([DOPAC]+[HVA]) to DA and expressed as percent of control.  
         [0471]     Biological Data  
         [0472]     The biological activity of the alpha2delta ligands of the invention may be measured in a radioligand binding assay using [ 3 H]gabapentin and the α 2 δ subunit derived from porcine brain tissue (Gee N. S., Brown J. P., Dissanayake V. U. K., Offord J., Thurlow R., Woodruff G. N.,  Biol. Chem.,  1996;271:5776-5879). Result may be expressed in terms of μM or nM α2δ binding affinity.  
         [0473]     Compounds of the invention were tested in the radioligand binding assay described within and were found to have binding affinities as follows:  
                                                       Example   α2δ                       1   100 nM           5   270 nM           2   435 nM           4   383 nM           7    8 μM                       Example   Activity (nM)                       9   1665           8   987           12   5406           6   198           10   507           11   71           20   59                      
 
         [0474]     Administration of the compositions of this invention can be via any method which delivers a compound 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 (e.g., intravenous, intramuscular, subcutaneous or intramedullary). The two different compounds of this invention can be co-administered simultaneously or sequentially in any order, or a single pharmaceutical composition comprising a NRPA as described above and an alpha2delta ligand as described above in a pharmaceutically acceptable carrier can be administered.  
         [0475]     The amount and timing of compounds administered will, of course, be based on the judgement of the prescribing physician. Thus, because of patient to patient 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 appropriate for the individual patient. In considering the degree 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 weight of 70 kg).  
         [0476]     In general, an effective dosage for the NRPA in the range of 0.1 to 200 mg/kg/day, preferably 0.005 to 10.0 mg/kg/day.  
         [0477]     In general, an effective dosage for the alpha2delta ligand when used in the combination compositions and methods of this invention, is in the range of 0.01 to 300 mg/kg/day, preferably 0.01 to 100 mg/kg/day.  
         [0478]     The compositions of the present invention are generally administered in the form of a pharmaceutical composition comprising at least one of the compounds of this invention together with a pharmaceutically acceptable vehicle or diluent. Thus, the compounds of this invention can be administered individually or together in any conventional oral, parenteral or transdermal dosage form.  
         [0479]     For oral administration a pharmaceutical composition can take the form of solutions, suspensions, tablets, pills, capsules, powders, and the like. Tablets containing various excipient such as sodium citrate, calcium carbonate and calcium phosphate are employed along with various disintegrants such as starch and preferably potato or tapioca starch and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the compounds of this invention can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents and/or suspending agents, as well as such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.  
         [0480]     For purposes of parenteral administration, solutions in sesame or peanut oil or in aqueous propylene glycol can be employed, as well as sterile aqueous solutions of the corresponding water-soluble salts. Such aqueous solutions may be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose. These aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection purposes. In this connection, the sterile aqueous media employed are all readily obtainable by standard techniques well-known to those skilled in the art.  
         [0481]     For purposes of transdermal (e.g.,topical) administration, dilute sterile, aqueous or partially aqueous solutions (usually in about 0.1% to 5% concentration), otherwise similar to the above parenteral solutions, are prepared.  
         [0482]     Methods of preparing various pharmaceutical compositions with a certain amount of active ingredient are known, or will be apparent in light of this disclosure, to those skilled in this art. For examples, see  Remington&#39;s Pharmaceutical Sciences,  Mack Publishing Company, Easter, Pa., 15th Edition (1975).  
         [0483]     Pharmaceutical compositions according to the invention may contain 0.1%-95% of the compound(s) of this invention, preferably 1%-70%. In any event, the composition or formulation to be administered will contain a quantity of a compound(s) according to the invention in an amount effective to treat the dependence of the subject being treated.