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Weight Loss Patent Abstract
Pharmaceutical compositions are disclosed for the treatment of obesity,
an overweight condition and compulsive overeating. The pharmaceutical
compositions are comprised of a therapeutically effective combination
of a nicotine receptor partial agonist and an anti-obesity agent
or weight loss facilitator or promoter and a pharmaceutically acceptable
carrier. The method of using these compounds is also disclosed.
Weight Loss Patent Claims
1. A pharmaceutical composition for the treatment of obesity, compulsive
overeating, or to promote or facilitate weight loss comprising:
(a) a nicotine receptor partial agonist or a pharmaceutically acceptable
salt thereof; (b) an anti-obesity agent or a weight loss promoter
or facilitator 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 obesity, compulsive
overeating or promoting or facilitating weight loss.
2. The pharmaceutical composition according to claim 1, wherein
said antiobesity agent or weight loss promoter or facilitator is
selected from Xenical.TM. (orlistat) and Meridia.TM. (sibutramine)
and their pharmaceutically active salts.
3. The pharmaceutically composition according to claim 1, wherein
said nicotine 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-on-
e; 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]diazoci-
n-8-one; 9-ethyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazo-
cin-8-one; 9-methyl-1,2,3,4,5,6-hexahydro- 1,5-methano-pyrido[1,2-a][1,5]d-
iazocin-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-pyr-
ido[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-he-
xahydro-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-on-
e; 9-iodo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-on-
e; 9-cyano-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-o-
ne; 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]d-
iazocin-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-pyri-
do[1,2a][1,5]diazocin-8-one; 9-carboxyaldehyde-1,2,3,4,5,6-hexahydro-1,5-m-
ethano-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-on-
e; 9-(2-fluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]d-
iazocin-8-one; 9-(4-fluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido-
[1,2a][1,5]diazocin-8one; 9-(3-fluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-met-
hano-pyrido[1,2a][1,5]diazocin-8-one; 9-(3,5-difluorophenyl)-1,2,3,4,5,6-h-
exahydro-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.sup.2,10.0.sup.4,8]pentadeca-2(10),3,8-triene; 5-oxo-6,13-diazatetracyc-
lo[9.3.1.0.sup.2,10.0.sup.4,8]pentadeca-2(10),3,8-triene; 6-oxo-5,7,13-triazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,8]pentadeca-2(10),-
3,8-triene; 4,5-difluoro-10-aza-tricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-t-
riene; 5-fluoro-10-aza-tricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-triene-4-c-
arbonitrile; 4-ethynyl-5-fluoro-10-aza-tricyclo[6.3.1.0.sup.2,7]dodeca-2(7-
),3,5-triene; 5-ethynyl-10-aza-tricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-tr-
iene-4-carbonitrile; 6-methyl-5-thia-5-dioxa-6,13-diazatetracyclo[9.3.1.0.-
sup.2,10.0.sup.4,8]pentadeca-2(10),3,8-triene; 10-aza-tricyclo[6.3.1.0.sup-
.2,7]dodeca-2(7),3,5-triene; 4-fluoro-10-aza-tricyclo[6.3.1.0.sup.2,7]dode-
ca-2(7),3,5-triene; 4-methyl-10-aza-tricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3-
,5-triene; 4-trifluoromethyl-10-aza-tricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3-
,5-triene; 4-nitro-10-azatricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-triene;
7-methyl-5,7,13-triazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,8]pentadeca-2(1-
0),3,5,8-tetraene; 6-methyl-5,7,13-triazatetracyclo[9.3.1.0.sup.2,10.0.sup-
.4,8]pentadeca-2(10),3,5,8-tetraene; 6,7-dimethyl-5,7,13-triazatetracyclo[-
9.3.1.0.sup.2,10.0.sup.4,8]pentadeca-2(10),3,5,8-tetraene; 6-methyl-7-phenyl-5,7,13-triazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,8]pent-
adeca-2(10),3,5,8-tetraene; 6,7-dimethyl-5,8,14-triazatetracyclo[10.3.1.0.-
sup.2,11.0.sup.4,9]hexadeca-2(11),3,5,7,9-pentaene; 5,8,14-triazatetracyclo[10.3.1.0.sup.2,11.0.sup.4,9]hexadeca-2(11),3,5,7,-
9-pentaene; 14-methyl-5,8,14-triazatetracyclo[10.3.1.0.sup.2,11.0.sup.4,9]-
hexadeca-2(11),3,5,7,9-pentaene; 5-oxa-7,13-diazatetracyclo[9.3.1.0.sup.2,-
10.0.sup.4,8]pentadeca-2(10),3,6,-8-tetraene; 6-methyl-5-oxa-7,13-diazatet-
racyclo[9.3.1.0.sup.2,10.0.sup.4,8]pentadeca-2(10),3,6,8-tetraene;
4-chloro-10-azatricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-triene;
10-azatricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-trien-4-yl cyanide;
1-(10-azatricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-trien-4-yl)-1-ethanone;
10-azatricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-trien-4-ol; 7-methyl-5-oxa-6,13-diazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,8]pentadeca--
2,4(8),6,9-tetraene; 4,5-dichloro-10-azatricyclo[6.3.1.0.sup.2,7]dodeca-2(-
7),3,5-triene; 11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene-5-ca-
rbonitrile; 1-[11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-trien-5-yl]-
-1-ethanone; 1-[11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-trien-5-yl-
]-1-propanone; 4-fluoro-11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-tr-
iene-5-carbonitrile; 5-fluoro-11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),-
3,5-triene-4-carbonitrile; 6-methyl-7-thia-5,14-diazatetracyclo[10.3.1.0.s-
up.2,10.0.sup.4,8]hexadeca-2(10),3,5,8-tetraene; 6-methyl-5,7,14-triazatet-
racyclo[10.3.1.0..sup.2,10.0.sup.4,8]hexadeca-2(10),3,5,8-tetraene;
6,7-dimethyl-5,7,14-triazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]hexadeca-
-2(10),3,5,8-tetraene; 5,7,14-triazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8-
]hexadeca-2(10),3,5,8-tetraene; 5,6-dimethyl-5,7,14-triazatetracyclo[10.3.-
1.0.sup.2,10.0.sup.4,8]hexadeca-2(10),3,6,8-tetraene; 5-methyl-5,7,14-triazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]hexadeca-2(1-
0),3,6,8-tetraene; 6-(trifluoromethyl)-7-thia-5,14-diazatetracyclo[10.3.1.-
0.sup.2,10.0.sup.4,8]hexadeca-2(10),3,5,8-tetraene; 5,8,15-triazatetracyclo[11.3.1.0.sup.2,11.0.sup.4,9]heptadeca-2(11),3,5,7-
,9-pentaene; 7-methyl-5,8,15-triazatetracyclo[11.3.1.0.sup.2,11.0.sup.4,9]-
heptadeca-2(11),3,5,7,9-pentaene; 6-methyl-5,8,15-triazatetracyclo[11.3.1.-
0.sup.2,11.0.sup.4,9]heptadeca-2(11),3,5,7,9-pentaene; 6,7-dimethyl-5,8,15-triazatetracyclo[11.3.1.0.sup.2,11.0.sup.4,9]heptadec-
a-2(11),3,5,7,9-pentaene; 7-oxa-5,14-diazatetracyclo[10.3.1.0.sup.2,10.0.s-
up.4,8]hexadeca-2(10),3,5,8-tetraene; 6-methyl-7-oxa-5,14-diazatetracyclo[-
10.3.1.0.sup.2,10.0.sup.4,8]hexadeca-2(10),3,5,8-tetraene; 5-methyl-7-oxa-6,14-diazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]hexadeca--
2(10),3,5,8-tetraene; 6-methyl-5-oxa-7,14-diazatetracyclo[10.3.1.0.sup.2,1-
0.0.sup.4,8]hexadeca-2(10),3,6,8-tetraene; 7-methyl-5-oxa-6,14-diazatetrac-
yclo[10.3.1.0.sup.2,10.0.sup.4,8]hexadeca-2(10),3,6,8-tetraene;
4,5-difluoro-11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene;
4-chloro-5-fluoro-11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene;
5-chloro-4-fluoro-11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene;
4-(1-ethynyl)-5-fluoro-11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-tr-
iene; 5-(1-ethynyl)-4-fluoro-11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3-
,5-triene; 5,6-difluoro-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2,4,6-trie-
ne; 6-trifluoromethyl-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2,4,6-triene-
; 6-methoxy-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene;
11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-trien-6-ol; 6-fluoro-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene;
11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-trien-5-ol; 4-nitro-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene;
5-nitro-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene;
5-fluoro-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene;
6-hydroxy-5-methoxy-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-trie-
ne; and their pharmaceutically acceptable salts and their optical
isomers.
4. The pharmaceutical composition according to claim 3 wherein
said nicotine 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-on-
e; 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]diazoci-
n-8-one; 9-acetyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazo-
cin-8-one; 9-iodo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazo-
cin-8-one; 9-cyano-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diaz-
ocin-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-py-
rido[1,2a][1,5]diazocin-8-one; 9-(2,6-difluorophenyl)-1,2,3,4,5,6-hexahydr-
o-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one; 9-phenyl-1,2,3,4,5,6-hexahy-
dro-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.sup.2,10.0.sup.4,8]p-
entadeca-2(10)3,8-triene; 4-fluoro-10-aza-tricyclo[6.3.1.0.sup.2,7]dodeca--
2(7),3,5-triene; 4-trifluoromethyl-10-aza-tricyclo[6.3.1.0.sup.2,7]dodeca--
2(7),3,5-triene; 4-nitro-10-azatricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-tr-
iene; 6-methyl-5,7,13-triazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,8]pentadec-
a-2(10),3,5,8-tetraene; 6,7-dimethyl-5,8,14-triazatetracyclo[10.3.1.0.sup.-
2,11.0.sup.4,9]hexadeca-2(11),3,5,7,9-pentaene; 5,8,14-triazatetracyclo[10-
.3.1.0.sup.2,11.0.sup.4,9]hexadeca-2(11),3,5,7,9-pentaene; 5-oxa-7,13-diazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,8]pentadeca-2(10),3,6-
,8-tetraene; 6-methyl-5-oxa-7,13-diazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,-
8]pentadeca-2(10),3,6,8-tetraene; 10-azatricyclo[6.3.1.0.sup.2,7]dodeca-2(-
7),3,5-trien-4-yl cyanide; 1-(10-azatricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3-
,5-trien-4-yl)-1-ethanone; 11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-
-triene-5-carbonitrile; 1-[11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-
-trien-5-yl]-1-ethanone; 1-[11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,-
5-trien-5-yl]-1-propanone; 4-fluoro-11-azatricyclo[7.3.1.0.sup.2,7]trideca-
-2(7),3,5-triene-5-carbonitrile; 5-fluoro-11-azatricyclo[7.3.1.0.sup.2,7]t-
rideca-2(7),3,5-triene-4-carbonitrile; 6-methyl-7-thia-5,14-diazatetracycl-
o[10.3.1.0.sup.2,10.0.sup.4,8]hexadeca-2(10),3,5,8-tetraene; 6-methyl-5,7,14-triazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]hexadeca-2(1-
0),3,5,8-tetraene; 6,7-dimethyl-5,7,14-triazatetracyclo[10.3.1.0.sup.2,10.-
0.sup.4,8]hexadeca-2(10),3,5,8-tetraene; 6-methyl-7-oxa-5,14-diazatetracyc-
lo[10.3.1.0.sup.2,10.0.sup.4,8]hexadeca-2(10),3,5,8-tetraene; 6-methyl-5-oxa-7,14-diazatetracyclo[10.3.1.0.sup.2,10.0.sup.4
8]hexadeca-2(10),3,6,8-tetraene; 5,6-difluoro-11-aza-tricyclo[7.3.1.0.sup-
.2,7]trideca-2,4,6-triene; 6-trifluoromethyl-11-aza-tricyclo[7.3.1.0.sup.2-
,7]trideca-2,4,6-triene; 6-methoxy-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-
-2(7),3,5-triene; 6-fluoro-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,-
5-triene; 11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-trien-5-ol,
and their pharmaceutically acceptable salts and their optical isomers
thereof.
5. A method of treating obesity, or promoting or facilitating weight
loss in a mammal comprising administering to said mammal: a. a nicotine
receptor partial agonist or a pharmaceutically acceptable salt thereof;
and b. an anti-obesity agent or weight loss promoter or facilitator,
or a pharmaceutically acceptable salt thereof, wherein the active
ingredients (a) and (b) are adminstered in amounts that render the
combination of the two active agent effective in the treatment of
obesity, or in promoting or facilitating weight loss.
6. The method of claim 5, wherein the anti-obesity agent or weight
loss facilitator is selected from, Xenical.TM. (orlistat) or Meridia.TM.
(sibutramine) and their pharmaceutically active salts.
7. The method according to claim 5, wherein the nicotine 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-pyr-
ido[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-methan-
o-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]dia-
zocin-8-one; 9-acetyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]d-
iazocin-8-one; 9-iodo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]d-
iazocin-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-hex-
ahydro-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-py-
rido[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-hexahy-
dro-1,5-methano-pyrido[1,2a][1,5]diazocin-8-one; 6-methyl-5-oxo-6,13-diaza-
tetracyclo[9.3.1.0.sup.2,10.0.sup.4,8]pentadeca-2(10),3,8-triene;
5-oxo-6,13-diazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,8]pentadeca-2(10),3,8-
-triene; 6-oxo-5,7,13-triazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,8]pentadec-
a-2(10),3,8-triene; 4,5-difluoro-10-aza-tricyclo[6.3.1.0.sup.2,7]dodeca-2(-
7),3,5-triene; 5-fluoro-10-aza-tricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-tr-
iene-4-carbonitrile; 4-ethynyl-5-fluoro-10-aza-tricyclo[6.3.1.0.sup.2,7]do-
deca-2(7),3,5-triene; 5-ethynyl-10-aza-tricyclo[6.3.1.0.sup.2,7]dodeca-2(7-
),3,5-triene-4-carbonitrile; 6-methyl-5-thia-5-dioxa-6,13-diazatetracyclo[-
9.3.1.0.sup.2,10.0.sup.4,8]pentadeca-2(10),3,8-triene; 10-aza-tricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-triene;
4-fluoro-10-aza-tricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-triene;
4-methyl-10-aza-tricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-triene;
4-trifluoromethyl-10-aza-tricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-triene;
4-nitro-10-azatricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-triene; 7-methyl-5,7,13-triazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,8]pentadeca-2(1-
0),3,5,8-tetraene; 6-methyl-5,7,13-triazatetracyclo[9.3.1.0.sup.2,10.0.sup-
.4,8]pentadeca-2(10),3,5,8-tetraene; 6,7-dimethyl-5,7,13-triazatetracyclo[-
9.3.1.0.sup.2,10.0.sup.4,8]pentadeca-2(10),3,5,8-tetraene; 6-methyl-7-phenyl-5,7,13-triazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,8]pent-
adeca-2(10),3,5,8-tetraene; 6,7-dimethyl-5,8,14-triazatetracyclo[10.3.1.0.-
sup.2,11.0.sup.4,9]hexadeca-2(11),3,5,7,9-pentaene; 5,8,14-triazatetracyclo[10.3.1.0.sup.2,11.0.sup.4,9]hexadeca-2(11),3,5,7,-
9-pentaene; 14-methyl-5,8,14-triazatetracyclo[10.3.1.0.sup.2,11.0.sup.4,9]-
hexadeca-2(11),3,5,7,9-pentaene; 5-oxa-7,13-diazatetracyclo[9.3.1.0.sup.2,-
10.0.sup.4,8]pentadeca-2(10),3,6,8-tetraene; 6-methyl-5-oxa-7,13-diazatetr-
acyclo[9.3.1.0.sup.2,10.0.sup.4,8]pentadeca-2(10),3,6,8-tetraene;
4-chloro-10-azatricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-triene;
10-azatricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-trien-4-yl cyanide;
1-(10-azatricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-trien-4-yl)-1-ethanone;
10-azatricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-trien-4-ol; 7-methyl-5-oxa-6,13-diazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,8]pentadeca--
2,4(8),6,9-tetraene; 4,5-dichloro-10-azatricyclo[6.3.1.0.sup.2,7]dodeca-2(-
7),3,5-triene; 11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene-5-ca-
rbonitrile; 1-[11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-trien-5-yl]-
-1-ethanone; 1-[11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-trien-5-yl-
]-1-propanone; 4-fluoro-11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-tr-
iene-5-carbonitrile; 5-fluoro-11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),-
3,5-triene-4-carbonitrile; 6-methyl-7-thia-5,14-diazatetracyclo[10.3.1.0.s-
up.2,10.0.sup.4,8]hexadeca-2(10),3,5,8-tetraene; 6-methyl-5,7,14-triazatet-
racyclo[10.3.1.0.sup.2,10.0.sup.4,8]hexadeca-2(10),3,5,8-tetraene;
6,7-dimethyl-5,7,14-triazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]hexadeca-
-2(10),3,5,8-tetraene; 5,7,14-triazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8-
]hexadeca-2(10),3,5,8-tetraene; 5,6-dimethyl-5,7,14-triazatetracyclo[10.3.-
1.0.sup.2,10.0.sup.4,8]hexadeca-2(10),3,6,8-tetraene; 5-methyl-5,7,14-triazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]hexadeca-2(1-
0),3,6,8-tetraene; 6-(trifluoromethyl)-7-thia-5,14-diazatetracyclo[10.3.1.-
0.sup.2,10.0.sup.4,8]hexadeca-2(10),3,5,8-tetraene; 5,8,15-triazatetracyclo[11.3.1.0.sup.2,11.0.sup.4,9]heptadeca-2(11),3,5,7-
,9-pentaene; 7-methyl-5,8,15-triazatetracyclo[11.3.1.0.sup.2,11.0.sup.4,9]-
heptadeca-2(11),3,5,7,9-pentaene; 6-methyl-5,8,15-triazatetracyclo[11.3.1.-
0.sup.2,11.0.sup.4,9]heptadeca-2(11),3,5,7,9-pentaene; 6,7-dimethyl-5,8,15-triazatetracyclo[11.3.1.0.sup.2,11.0.sup.4,9]heptadec-
a-2(11),3,5,7,9-pentaene; 7-oxa-5,14-diazatetracyclo[10.3.1.0.sup.2,10.0.s-
up.4,8]hexadeca-2(10),3,5,8-tetraene; 6-methyl-7-oxa-5,14-diazatetracyclo[-
10.3.1.0.sup.2,11.0.sup.4,8]hexadeca-2(10),3,5,8-tetraene; 5-methyl-7-oxa-6,14-diazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]hexadeca--
2(10),3,5,8-tetraene; 6-methyl-5-oxa-7,14-diazatetracyclo[10.3.1.0.sup.2,1-
0.0.sup.4,8]hexadeca-2(10),3,6,8-tetraene; 7-methyl-5-oxa-6,14-diazatetrac-
yclo[10.3.1.0.sup.2,10.0.sup.4,8]hexadeca-2(10),3,6,8-tetraene;
4,5-difluoro-11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene;
4-chloro-5-fluoro-11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene;
5-chloro-4-fluoro-11-azatricyclo [7.3.1.0.sup.2,7]trideca-2(7),3,5-triene-
; 4-(1-ethynyl)-5-fluoro-11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-t-
riene; 5-(1-ethynyl)-4-fluoro-11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),-
3,5-triene; 5,6-difluoro-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2,4,6-tri-
ene; 6-trifluoromethyl-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2,4,6-trien-
e; 6-methoxy-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene;
11-aza-tricyclo[7.3.1.0.sup.2,7]trien-6-ol; 6-fluoro-11-aza-tricyclo[7.3.-
1.0.sup.2,7]trideca-2(7),3,5-triene; 11-aza-tricyclo[7.3.1.0.sup.2,7]tride-
ca-2(7),3,5-trien-5-ol; 4-nitro-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(-
7),3,5-triene; 5-nitro-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-tr-
iene; 5-fluoro-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene;
6-hydroxy-5-methoxy-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-trie-
ne; and a pharmaceutically acceptable salt and an optical isomer
thereof.
8. The method according to claim 7, wherein the nicotine 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-pyrid-
o[1,2a][1,5]diazocin-8-one; 9-iodo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrid-
o[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-hexahyd-
ro-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-on-
e; 9-(2-fluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]d-
iazocin-8-one; 6-methyl-5-thia-5-dioxa-6,13-diazatetracyclo[9.3.1.0.sup.2,-
10.0.sup.4,8]pentadeca-2(10),3,8-triene; 4-fluoro-10-aza-tricyclo[6.3.1.0.-
sup.2,7]dodeca-2(7),3,5-triene; 4-trifluoromethyl-10-aza-tricyclo[6.3.1.0.-
sup.2,7]dodeca-2(7),3,5-triene; 4-nitro-10-azatricyclo[6.3.1.0.sup.2,7]dod-
eca-2(7),3,5-triene; 6-methyl-5,7,13-triazatetracyclo[9.3.1.0.sup.2,10.0.s-
up.4,8]pentadeca-2(10),3,5,8-tetraene; 6,7-dimethyl-5,8,14-triazatetracycl-
o[10.3.1.0.sup.2,11.0.sup.4,9]hexadeca-2(11),3,5,7,9-pentaene; 5,8,14-triazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,9]hexadeca-2(11),3,5,7,9-
-pentaene; 5-oxa-7,13-diazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,8]pentadeca-
-2(10),3,6,8-tetraene; 6-methyl-5-oxa-7,13-diazatetracyclo[9.3.1.0.sup.2,1-
0.0.sup.4,8]pentadeca-2(10),3,6,8-tetraene; 10-azatricyclo[6.3.1.0.sup.2,7-
]dodeca-2(7),3,5-trien-4-yl cyanide; 1-(10-azatricyclo[6.3.1.0.sup.2,7]dod-
eca-2(7),3,5-trien-4-yl)-1-ethanone; 11-azatricyclo[7.3.1.0.sup.2,7]tridec-
a-2(7),3,5-triene-5-carbonitrile; 1-[11-azatricyclo[7.3.1.0.sup.2,7]tridec-
a-2(7),3,5-trien-5-yl]-1-ethanone; 1-[11-azatricyclo[7.3.1.0.sup.2,7]tride-
ca-2(7),3,5-trien-5-yl]-1-propanone; 4-fluoro-11-azatricyclo[7.3.1.0.sup.2-
,7]trideca-2(7),3,5-triene-5-carbonitrile; 5-fluoro-11-azatricyclo[7.3.1.0-
.sup.2,7]trideca-2(7),3,5-triene-4-carbonitrile; 6-methyl-7-thia-5,14-diaz-
atetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]hexadeca-2(10),3,5,8-tetraene;
6-methyl-5,7,14-triazatetracyclo[10.3.1.0.sup.2,10]hexadeca-2(10),3,5,8-t-
etraene; 6,7-dimethyl-5,7,14-triazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]-
hexadeca-2(10),3,5,8-tetraene; 6-methyl-7-oxa-5,14-diazatetracyclo[10.3.1.-
0.sup.2,10.0.sup.4,8]hexadeca-2(10),3,5,8-tetraene; 6-methyl-5-oxa-7,14-diazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]hexadeca--
2(10),3,6,8-tetraene; 5,6-difluoro-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-
-2,4,6-triene; 6-trifluoromethyl-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2-
,4,6-triene; 6-methoxy-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-tr-
iene; 6-fluoro-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene;
11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-trien-5-ol; and
the pharmaceutically acceptable salts and optical isomers thereof.
9. The method according to claim 5, wherein the nicotine receptor
partial agonist and the anti-obesity agent or weight loss facilitator
are administered substantially simultaneously.
10. A pharmaceutical composition for treating a disorder or condition
selected from the group consisting of disorders and conditions in
which obesity or an overweight condition predominates, including
Type 2 diabetes mellitus, hypertension, dyslipidemia and increased
mortality in a mammal, the method comprising: (a) a nicotine receptor
partial agonist or a pharmaceutically acceptable salt thereof; (b)
an anti-obesity agent or a weight loss promoter or facilitator or
a 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 such disorder or condition.
11. A method of treating a disorder or condition selected from
the groups of disorders and conditions in which obesity or an overweight
condition predominates in a mammal including Type 2 diabetes mellitus,
hypertension, dyslipidemia and increased morality, the method comprising
administering to said mammal: (a) a nicotine receptor partial agonist
or a pharmaceutically acceptable salt thereof; and (b) an anti-obesity
agent or weight loss facilitation or a pharmaceutically acceptable
salt thereof; wherein the active agent "a" and "b"
above are present in amounts that render the composition effective
that render the composition effective in treating such disorder
or condition.
Weight Loss Patent Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates to pharmaceutical compositions
for the treatment of obesity, compulsive overeating; or to facilitate
or promote weight loss in a mammal (e.g. human) comprising a nicotine
receptor partial agonist (NRPA) and an anti-obesity or weight loss
promoting agent. The term NRPA refers to all chemical compounds
which 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. & Quenzer, L. F. Principles of Neuropsychopharmacology,
1997; Sinauer Assoc. Inc.). The present invention may be used to
treat mammals (e.g. humans) for obesity, an overweight condition
or compulsive overeating with a decrease in the severity of unwanted
side effects such as causing nausea and/or stomach upset.
[0002] Obesity is a major health risk that leads to increased mortality
and incidence of Type 2 diabetes mellitus, hypertension and dyslipidemia.
It is the second leading cause of preventable death in the United
States, and contributes to>300,000 deaths per year. The estimated
direct annual health cost associated with obesity is $70 billion,
while the total overall cost to the U.S. economy has been estimated
to be over $140 billion. In the U.S., more than 50% of the adult
population is overweight, and almost 1/4 of the population is considered
to be obese (BMI greater than or equal to 30). Furthermore, the
prevalence of obesity in the United States has increased by about
50% in the past 10 years. While the vast majority of obesity occurs
in the industrialized world, particularly in U.S. and Europe, the
prevalence of obesity is also increasing in Japan. The prevalence
of obesity in adults is 10%-25% in most countries of Western Europe.
The rise in the incidence of obesity has promoted the WHO to recognize
obesity as a significant disease. What is needed are orally active
agents that induce sustained weight loss of 10-15% of initial body
weight, due to selective loss of body fat in moderately obese patients.
These orally active agents should increase energy expenditure, decrease
food intake and partition energy away from adipose tissue. This
degree of sustained weight loss would then improve comorbidities
including hyperglycemia, hypertension and hyperlipidemia, all of
which are exacerbated by obesity.
[0003] However, even though weight loss agents have therapeutic
utility in the treatment of obesity, there are significant liabilities
to the use of weight loss compounds. Specifically, many of these
compounds that have been tested in humans can cause potentially
serious side effects such as gastrointestinal complications including
nausea, emesis, ulcers, constipation, flatulence, diarrhea, hypertension,
respiratory depression, and psychological and physical dependence.
SUMMARY OF INVENTION
[0004] The present invention relates to a pharmaceutical composition
for the treatment of obesity, compulsive overeating and/or to promote
or facilitate weight loss comprising
[0005] (a) a nicotine receptor partial agonist or a pharmaceutically
acceptable salt thereof;
[0006] (b) an anti-obesity agent or weight loss promoter or facilitator,
or a pharmaceutically acceptable salt thereof; and
[0007] (c) a pharmaceutically acceptable carrier;
[0008] wherein the active agents "a" and "b"
above are present in amounts that render the composition effective
in treating obesity, compulsive overeating and/or facilitating or
promoting weight loss.
[0009] In a more specific embodiment of the invention the anti-obesity
agent or weight loss promoter or facilitator is selected from Xenical.TM.
(orlistat) or Meridia.TM. (sibutramine) and their pharmaceutically
acceptable salts and optical isomers.
[0010] In another more specific embodiment of this invention, the
nicotine receptor partial agonist is selected from:
[0011] 9-bromo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazoci-
n-8-one;
[0012] 9-chloro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazoc-
in-8-one;
[0013] 9-fluoro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazoc-
in-8-one;
[0014] 9-ethyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazoci-
n-8-one;
[0015] 9-methyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazoc-
in-8-one;
[0016] 9-phenyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazoc-
in-8-one;
[0017] 9-vinyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazoci-
n-8-one;
[0018] 9-bromo-3-methyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,-
5]diazocin-8-one;
[0019] 3-benzyl-9-bromo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,-
5]diazocin-8-one;
[0020] 3-benzyl-9-chloro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1-
,5]diazocin-8-one;
[0021] 9-acetyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazoci-
n-8-one;
[0022] 9-iodo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin--
8-one;
[0023] 9-cyano-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-
-8-one;
[0024] 9-ethynyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazoc-
in-8-one;
[0025] 9-(2-propenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]d-
iazocin-8-one;
[0026] 9-(2-propyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]dia-
zocin-8-one;
[0027] 9-carbomethoxy-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]d-
iazocin-8-one;
[0028] 9-carboxyaldehyde-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,-
5]diazocin-8-one;
[0029] 9-(2,6-difluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-
a][1,5]diazocin-8-one;
[0030] 9-phenyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazoci-
n-8-one;
[0031] 9-(2-fluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1-
,5]diazocin-8-one;
[0032] 9-(4-fluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1-
,5]diazocin-8-one;
[0033] 9-(3-fluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1-
,5]diazocin-8-one;
[0034] 9-(3,5-difluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-
a][1,5]diazocin-8-one;
[0035] 9-(2,4-difluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-
a][1,5]diazocin-8-one;
[0036] 9-(2,5-difluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-
a][1,5]diazocin-8-one;
[0037] 6-methyl-5-oxo-6,13-diazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,8]pent-
adeca-2(10),3,8-triene;
[0038] 5-oxo-6,13-diazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,8]pentadeca-2(1-
0),3,8-triene;
[0039] 6-oxo-5,7,13-triazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,8]pentadeca--
2(10),3,8-triene;
[0040] 4,5-difluoro-10-aza-tricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-triene-
;
[0041] 5-fluoro-10-aza-tricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-triene-4-c-
arbonitrile;
[0042] 4-ethynyl-5-fluoro-10-aza-tricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5--
triene;
[0043] 5-ethynyl-10-aza-tricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-triene-4--
carbonitrile;
[0044] 6-methyl-5-thia-5-dioxa-6,13-diazatetracyclo[9.3.1.0.sup.2,10.0.sup-
.4,8]pentadeca-2(10),3,8-triene;
[0045] 10-aza-tricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-triene;
[0046] 4-fluoro-10-aza-tricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-triene;
[0047] 4-methyl-10-aza-tricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-triene;
[0048] 4-trifluoromethyl-10-aza-tricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-t-
riene;
[0049] 4-nitro-10-azatricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-triene;
[0050] 7-methyl-5,7,13-triazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,8]pentade-
ca-2(10),3,5,8-tetraene;
[0051] 6-methyl-5,7,13-triazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,8]pentade-
ca-2(10),3,5,8-tetraene;
[0052] 6,7-dimethyl-5,7,13-triazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,8]pen-
tadeca-2(10),3,5,8-tetraene;
[0053] 6-methyl-7-phenyl-5,7,13-triazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,-
8]pentadeca-2(10),3,5,8-tetraene;
[0054] -6,7-dimethyl-5,8,14-triazatetracyclo[10.3.1.0.sup.2,11.0.sup.4,9]h-
exadeca-2(11),3,5,7,9-pentaene;
[0055] 5,8,14-triazatetracyclo[10.3.1.0.sup.2,11.0.sup.4,9]hexadeca-2(11),-
3,5,7,9-pentaene;
[0056] 14-methyl-5,8,14-triazatetracyclo[10.3.1.0.sup.2,11.0.sup.4,9]hexad-
eca-2(11),3,5,7,9-pentaene;
[0057] 5-oxa-7,13-diazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,8]pentadeca-2(1-
0),3,6,8-tetraene;
[0058] 6-methyl-5-oxa-7,13-diazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,8]pent-
adeca-2(10),3,6,8-tetraene;
[0059] 4-chloro-10-azatricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-triene;
[0060] 10-azatricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-trien-4-yl
cyanide;
[0061] 1-(10-azatricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-trien-4-yl)-1-eth-
anone;
[0062] 10-azatricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-trien-4-ol;
[0063] 7-methyl-5-oxa-6,13-diazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,8]pent-
adeca-2,4(8),6,9-tetraene;
[0064] 4,5-dichloro-10-azatricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-triene;
[0065] 11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene-5-carbonitri-
le;
[0066] 1-[11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-trien-5-yl]-1-et-
hanone;
[0067] 1-[11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-trien-5-yl]-1-pr-
opanone;
[0068] 4-fluoro-11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-trien-5-ca-
rbonitrile;
[0069] 5-fluoro-11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene-4-c-
arbonitrile;
[0070] 6-methyl-7-thia-5,14-diazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]he-
xadeca-2(10),3,5,8-tetraene;
[0071] 6-methyl-5,7,14-triazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]hexade-
ca-2(10),3,5,8-tetraene;
[0072] 6,7-dimethyl-5,7,14-triazatetracyclo[10.3.1.0.sup.2,10.0.sup.4.8]he-
xadeca-2(10),3,5,8-tetraene;
[0073] 5,7,14-triazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]hexadeca-2(10),-
3,5,8-tetraene;
[0074] 5,6-dimethyl-5,7,14-triazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]he-
xadeca-2(10),3,6,8-tetraene;
[0075] 5-methyl-5,7,14-triazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]hexade-
ca-2(10),3,6,8-tetraene;
[0076] 6-(trifluoromethyl)-7-thia-5,14-diazatetracyclo[10.3.1.0.sup.2,10.0-
.sup.4,8]hexadeca-2(10),3,5,8-tetraene;
[0077] 5,8,15-triazatetracyclo[11.3.1.0.sup.2,11.0.sup.4,9]heptadeca-2(11)-
,3,5,7,9-pentaene;
[0078] 7-methyl-5,8,15-triazatetracyclo[11.3.1.0.sup.2,11.0.sup.4,9]heptad-
eca-2(11),3,5,7,9-pentaene;
[0079] 6-methyl-5,8,15-triazatetracyclo[11.3.1.0.sup.2,11.0.sup.4,9]heptad-
eca-2(11),3,5,7,9-pentaene;
[0080] 6,7-dimethyl-5,8,15-triazatetracyclo[11.3.1.0.sup.2,11.0.sup.4,9]he-
ptadeca-2(11),3,5,7,9-pentaene;
[0081] 7-oxa-5,14-diazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]hexadeca-2(1-
0),3,5,8-tetraene;
[0082] 6-methyl-7-oxa-5,14-diazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]hex-
adeca-2(10),3,5,8-tetraene;
[0083] 5-methyl-7-oxa-6,14-diazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]hex-
adeca-2(10),3,5,8-tetraene;
[0084] 6-methyl-5-oxa-7,14-diazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]hex-
adeca-2(10),3,6,8-tetraene;
[0085] 7-methyl-5-oxa-6,14-diazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]hex-
adeca-2(10),3,6,8-tetraene;
[0086] 4,5-difluoro-11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene-
;
[0087] 4-chloro-5-fluoro-11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-t-
riene;
[0088] 5-chloro-4-fluoro-11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-t-
riene;
[0089] 4-(1-ethynyl)-5-fluoro-11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),-
3,5-triene;
[0090] 5-(1-ethynyl)-4-fluoro-11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),-
3,5-triene;
[0091] 5,6-difluoro-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2,4,6-triene;
[0092] 6-trifluoromethyl-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2,4,6-tri-
ene;
[0093] 6-methoxy-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene;
[0094] 11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-trien-6-ol;
[0095] 6-fluoro-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene;
[0096] 11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-trien-5-ol;
[0097] 4-nitro-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene;
[0098] 5-nitro-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene;
[0099] 5-fluoro-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene;
and
[0100] 6-hydroxy-5-methoxy-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,-
5-triene and their pharmaceutically acceptable salts and their optical
isomers.
[0101] Preferably, the nicotine receptor partial agonist is selected
from
[0102] 9-bromo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazoci-
n-8-one;
[0103] 9-chloro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazoc-
in-8-one;
[0104] 9-fluoro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazoc-
in-8-one;
[0105] 9-acetyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazoci-
n-8-one;
[0106] 9-iodo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin--
8-one;
[0107] 9-cyano-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-
-8-one;
[0108] 9-carbomethoxy-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]d-
iazocin-8-one;
[0109] 9-carboxyaldehyde-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,-
5]diazocin-8-one;
[0110] 9-(2,6-difluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-
a][1,5]diazocin-8-one;
[0111] 9-phenyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazoci-
n-8-one;
[0112] 9-(2-fluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1-
,5]diazocin-8-one;
[0113] 6-methyl-5-thia-5-dioxa-6,13-diazatetracyclo[9.3.1.0.sup.2,10.0.sup-
.4,8]pentadeca-2(10),3,8-triene;
[0114] 4-fluoro-10-aza-tricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-triene;
[0115] 4-trifluoromethyl-10-aza-tricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-t-
riene;
[0116] 4-nitro-10-azatricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-triene;
[0117] 6-methyl-5,7,13-triazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,8]pentade-
ca-2(10),3,5,8-tetraene;
[0118] 6,7-dimethyl-5,8,14-triazatetracyclo[10.3.1.0.sup.2,11.0.sup.4,9]he-
xadeca-2(11),3,5,7,9-pentaene;
[0119] 5,8,14-triazatetracyclo[10.3.1.0.sup.2,11.0.sup.4,9]hexadeca-2(11),-
3,5,7,9-pentaene;
[0120] 5-oxa-7,13-diazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,8]pentadeca-2(1-
0),3,6,8-tetraene;
[0121] 6-methyl-5-oxa-7,13-diazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,8]pent-
adeca-2(10),3,6,8-tetraene;
[0122] 10-azatricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-trien-4-yl
cyanide;
[0123] 1-(10-azatricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-trien-4-yl)-1-eth-
anone;
[0124] 11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene-5-carbonitri-
le;
[0125] 1-[11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-trien-5-yl]-1-et-
hanone;
[0126] 1-[11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-trien-5-yl]-1-pr-
opanone;
[0127] 4-fluoro-11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene-5-c-
arbonitrile;
[0128] 5-fluoro-11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene-4-c-
arbonitrile;
[0129] 6-methyl-7-thia-5,14-diazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]he-
xadeca-2(10),3,5,8-tetraene;
[0130] 6-methyl-5,7,14-triazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]hexade-
ca-2(10),3,5,8-tetraene;
[0131] 6,7-dimethyl-5,7,14-triazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]he-
xadeca-2(10),3,5,8-tetraene;
[0132] 6-methyl-7-oxa-5,14-diazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]hex-
adeca-2(10),3,5,8-tetraene;
[0133] 6-methyl-5-oxa-7,14-diazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]hex-
adeca-2(10),3,6,8-tetraene;
[0134] 5,6-difluoro-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2,4,6-triene;
[0135] 6-trifluoromethyl-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2,4,6-tri-
ene;
[0136] 6-methoxy-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene;
[0137] 6-fluoro-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene;
and
[0138] 11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-trien-5-ol
and
[0139] their pharmaceutically acceptable salts and their optical
isomers.
[0140] The present invention also relates to a method of treating
obesity overeating, and/or facilitating or promoting weight loss
in a mammal comprising administering to said mammal respectively
an anti-obesity attenuating effective amount of a pharmaceutical
composition comprising
[0141] (a) a nicotine receptor partial agonist or a pharmaceutically
acceptable salt thereof; and
[0142] (b) an anti-obesity agent or a weight loss promoter or facilitator
or a pharmaceutically acceptable salt thereof;
[0143] wherein the active ingredients (a) and (b) are present in
amounts that render the composition effective in the treatment of
obesity, compulsive overeating or an overweight condition.
[0144] In another more specific embodiment of this invention the
nicotine receptor partial agonist is selected from:
[0145] 9-bromo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazoci-
n-8-one;
[0146] 9-chloro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazoc-
in-8-one;
[0147] 9-fluoro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazoc-
in-8-one;
[0148] 9-ethyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazoci-
n-8-one;
[0149] 9-methyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazoc-
in-8-one;
[0150] 9-phenyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazoc-
in-8-one;
[0151] 9-vinyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazoci-
n-8-one;
[0152] 9-bromo-3-methyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,-
5]diazocin-8-one;
[0153] 3-benzyl-9-bromo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,-
5]diazocin-8-one;
[0154] 3-benzyl-9-chloro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1-
,5]diazocin-8-one;
[0155] 9-acetyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazoci-
n-8-one;
[0156] 9-iodo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin--
8-one;
[0157] 9-cyano-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-
-8-one;
[0158] 9-ethynyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazoc-
in-8-one;
[0159] 9-(2-propenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]d-
iazocin-8-one;
[0160] 9-(2-propyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]dia-
zocin-8-one;
[0161] 9-carbomethoxy-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]d-
iazocin-8-one;
[0162] 9-carboxyaldehyde-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,-
5]diazocin-8-one;
[0163] 9-(2,6-difluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-
a][1,5]diazocin-8-one;
[0164] 9-phenyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazoci-
n-8-one;
[0165] 9-(2-fluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1-
,5]diazocin-8-one;
[0166] 9-(4-fluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1-
,5]diazocin-8-one;
[0167] 9-(3-fluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1-
,5]diazocin-8-one;
[0168] 9-(3,5-difluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-
a][1,5]diazocin-8-one;
[0169] 9-(2,4-difluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-
a][1,5]diazocin-8-one;
[0170] 9-(2,5-difluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-
a][1,5]diazocin-8-one;
[0171] 6-methyl-5-oxo-6,13-diazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,8]pent-
adeca-2(10),3,8-triene;
[0172] 5-oxo-6,13-diazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,8]pentadeca-2(1-
0),3,8-triene;
[0173] 6-oxo-5,7,13-triazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,8]pentadeca--
2(10),3,8-triene;
[0174] 4,5-difluoro-10-aza-tricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-triene-
;
[0175] 5-fluoro-10-aza-tricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-triene-4-c-
arbonitrile;
[0176] 4-ethynyl-5-fluoro-10-aza-tricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5--
triene;
[0177] 5-ethynyl-10-aza-tricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-triene-4--
carbonitrile;
[0178] 6-methyl-5-thia-5-dioxa-6,13-diazatetracyclo[9.3.1.0.sup.2,10.0.sup-
.4,8]pentadeca-2(10),3,8-triene;
[0179] 10-aza-tricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-triene;
[0180] 4-fluoro-10-aza-tricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-triene;
[0181] 4-methyl-10-aza-tricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-triene;
[0182] 4-trifluoromethyl-10-aza-tricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-t-
riene;
[0183] 4-nitro-10-azatricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-triene;
[0184] 7-methyl-5,7,13-triazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,8]pentade-
ca-2(10),3,5,8-tetraene;
[0185] 6-methyl-5,7,13-triazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,8]pentade-
ca-2(10),3,5,8-tetraene;
[0186] 6,7-dimethyl-5,7,13-triazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,8]pen-
tadeca-2(10),3,5,8-tetraene;
[0187] 6-methyl-7-phenyl-5,7,13-triazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,-
8]pentadeca-2(10),3,5,8-tetraene;
[0188] 6,7-dimethyl-5,8,14-triazatetracyclo[10.3.1.0.sup.2,11.0.sup.4,9]he-
xadeca-2(11),3,5,7,9-pentaene;
[0189] 5,8,14-triazatetracyclo[10.3.1.0.sup.2,11.0.sup.4,9]hexadeca-2(11),-
3,5,7,9-pentaene;
[0190] 14-triazatetracyclo[10.3.1.0.sup.2,11.0.sup.4,9]hexadeca-2(11),3,5,-
7,9-pentaene;
[0191] 5-oxa-7,13-diazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,8]pentadeca-2(1-
0),3,6,8-tetraene;
[0192] 6-methyl-5-oxa-7,13-diazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,8]pent-
adeca-2(10),3,6,8-tetraene;
[0193] 4-chloro-10-azatricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-triene;
[0194] 10-azatricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-trien-4-yl
cyanide;
[0195] 1-(10-azatricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-trien-4-yl)-1-eth-
anone;
[0196] 10-azatricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-trien-4-ol;
[0197] 7-methyl-5-oxa-6,13-diazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,8]pent-
adeca-2,4(8),6,9-tetraene;
[0198] 4,5-dichloro-10-azatricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-triene;
[0199] 11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene-5-carbonitri-
le;
[0200] 1-[11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-trien-5-yl]-1-et-
hanone;
[0201] 1-[11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-trien-5-yl]-1-pr-
opanone;
[0202] 4-fluoro-11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene-5-c-
arbonitrile;
[0203] 5-fluoro-11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene-4-c-
arbonitrile;
[0204] 6-methyl-7-thia-5,14-diazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]he-
xadeca-2(10),3,5,8-tetraene;
[0205] 6-methyl-5,7,14-triazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]hexade-
ca-2(10),3,5,8-tetraene;
[0206] 6,7-dimethyl-5,7,14-triazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]he-
xadeca-2(10),3,5,8-tetraene;
[0207] 5,7,14-triazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]hexadeca-2(10),-
3,5,8-tetraene;
[0208] 5,6-dimethyl-5,7,14-triazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]he-
xadeca-2(10),3,6,8-tetraene;
[0209] 5-methyl-5,7,14-triazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]hexade-
ca-2(10),3,6,8-tetraene;
[0210] 6-(trifluoromethyl)-7-thia-5,14-diazatetracyclo[10.3.1.0.sup.2,10.0-
.sup.4,8]hexadeca-2(10),3,5,8-tetraene;
[0211] 5,8,15-triazatetracyclo[11.3.1.0.sup.2,11.0.sup.4,9]heptadeca-2(11)-
,3,5,7,9-pentaene;
[0212] 7-methyl-5,8,15-triazatetracyclo[11.3.1.0.sup.2,11.0.sup.4,9]heptad-
eca-2(11),3,5,7,9-pentaene;
[0213] 6-methyl-5,8,15-triazatetracyclo[11.3.1.0.sup.2,11.0.sup.4,9]heptad-
eca-2(11),3,5,7,9-pentaene;
[0214] 6,7-dimethyl-5,8,15-triazatetracyclo[11.3.1.0.sup.2,11.0.sup.4,9]he-
ptadeca-2(11),3,5,7,9-pentaene;
[0215] 7-oxa-5,14-diazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]hexadeca-2(1-
0),3,5,8-tetraene;
[0216] 6-methyl-7-oxa-5,14-diazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]hex-
adeca-2(10),3,5,8-tetraene;
[0217] 5-methyl-7-oxa-6,14-diazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]hex-
adeca-2(10),3,5,8-tetraene;
[0218] 6-methyl-5-oxa-7,14-diazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]hex-
adeca-2(10),3,6,8-tetraene;
[0219] 7-methyl-5-oxa-6,14-diazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]hex-
adeca-2(10),3,6,8-tetraene;
[0220] 4,5-difluoro-11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene-
;
[0221] 4-chloro-5-fluoro-11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-t-
riene;
[0222] 5-chloro-4-fluoro-11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-t-
riene;
[0223] 4-(1-ethynyl)-5-fluoro-11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),-
3,5-triene;
[0224] 5-(1-ethynyl)-4-fluoro-11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),-
3,5-triene;
[0225] 5,6-difluoro-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2,4,6-triene;
[0226] 6-trifluoromethyl-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2,4,6-tri-
ene;
[0227] 6-methoxy-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene;
[0228] 11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-trien-6-ol;
[0229] 6-fluoro-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene;
[0230] 11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-trien-5-ol;
[0231] 4-nitro-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene;
[0232] 5-nitro-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene;
[0233] 5-fluoro-11-aza-tricyclo[7.3.1.0.sup.2 ]trideca-2(7),3,5-triene;
and
[0234] 6-hydroxy-5-methoxy-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,-
5-triene and
[0235] their pharmaceutically acceptable salts and their optical
isomers.
[0236] Preferably, the nicotine receptor partial agonist is selected
from:
[0237] 9-bromo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazoci-
n-8-one;
[0238] 9-chloro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazoc-
in-8-one;
[0239] 9-fluoro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazoc-
in-8-one;
[0240] 9-acetyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazoci-
n-8-one;
[0241] 9-iodo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin--
8-one;
[0242] 9-cyano-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazocin-
-8-one;
[0243] 9-carbomethoxy-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]d-
iazocin-8-one;
[0244] 9-carboxyaldehyde-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,-
5]diazocin-8-one;
[0245] 9-(2,6-difluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-
a][1,5]diazocin-8-one;
[0246] 9-phenyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1,5]diazoci-
n-8-one;
[0247] 9-(2-fluorophenyl)-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2a][1-
,5]diazocin-8-one;
[0248] 6-methyl-5-thia-5-dioxa-6,13-diazatetracyclo[9.3.1.0.sup.2,10.0.sup-
.4,8]pentadeca-2(10),3,8-triene;
[0249] 4-fluoro-10-aza-tricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-triene;
[0250] 4-trifluoromethyl-10-aza-tricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-t-
riene;
[0251] 4-nitro-10-azatricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-triene;
[0252] 6-methyl-5,7,13-triazatetracyclo[9.3.1.0.sup.2,10 .0.sup.4,8]pentadeca-2(10),3,5,8-tetraene;
[0253] 6,7-dimethyl-5,8,14-triazatetracyclo[10.3.1.0.sup.2,11.0.sup.4,9]he-
xadeca-2(11),3,5,7,9-pentaene;
[0254] 5,8,14-triazatetracyclo[10.3.1.0.sup.2,11.0.sup.4,9]hexadeca-2(11),-
3,5,7,9-pentaene;
[0255] 5-oxa-7,13-diazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,8]pentadeca-2(1-
0),3,6,8-tetraene;
[0256] 6-methyl-5-oxa-7,13-diazatetracyclo[9.3.1.0.sup.2,10.0.sup.4,8]pent-
adeca-2(10),3,6,8-tetraene;
[0257] 10-azatricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-trien-4-yl
cyanide;
[0258] 1-(10-azatricyclo[6.3.1.0.sup.2,7]dodeca-2(7),3,5-trien-4-yl)-1-eth-
anone;
[0259] 11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene-5-carbonitri-
le;
[0260] 1-[11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-trien-5-yl]-1-et-
hanone;
[0261] 1-[11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-trien-5-yl]-1-pr-
opanone;
[0262] 4-fluoro-11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene-5-c-
arbonitrile;
[0263] 5-fluoro-11-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene-4-c-
arbonitrile;
[0264] 6-methyl-7-thia-5,14-diazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]he-
xadeca-2(10),3,5,8-tetraene;
[0265] 6-methyl-5,7,14-triazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]hexade-
ca-2(10),3,5,8-tetraene;
[0266] 6,7-dimethyl-5,7,14-triazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]he-
xadeca-2(10),3,5,8-tetraene;
[0267] 6,7-dimethyl-5,7,14-triazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]he-
xadeca-2(10),3,5,8-tetraene;
[0268] 6-methyl-7-oxa-5,14-diazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]hex-
adeca-2(10),3,5,8-tetraene;
[0269] 6-methyl-5-oxa-7,14-diazatetracyclo[10.3.1.0.sup.2,10.0.sup.4,8]hex-
adeca-2(10),3,6,8-tetraene;
[0270] 5,6-difluoro-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2,4,6-triene;
[0271] 6-trifluoromethyl-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2,4,6-tri-
ene;
[0272] 6-methoxy-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene;
[0273] 6-fluoro-11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-triene;
and
[0274] 11-aza-tricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,5-trien-5-ol;
[0275] and the pharmaceutically acceptable salts stereoisomers
(including optical isomers), solvates and hydrates of the foregoing
compounds.
[0276] The above NRPA's and others are referred to, along with
methods for their synthesis in World Patent Applications WO 98/18798,
WO 99/35131 and WO 99/55680, which were published, respectively
on May 7, 1998, Jul. 15, 1999 and Nov. 4, 1999. The foregoing applications
are owned in common with the present application and are incorporated
herein by reference in their entireties. These compounds can be
used in combination with an anti-obesity agent or a weight loss
promoter in order to treat obesity or facilitate or promote weight
loss.
[0277] In another more specific embodiment, the anti-obesity agent
and/or weight loss promoter or facilitator is selected from Xenical.TM.
(orlistat) or Meridia.TM. (sibutramine) and their pharmaceutically
acceptable salts, stereo isomers (including optical isomers), hydrates
and solvates.
[0278] The invention also relates to pharmaceutical composition
for treating a disorder or condition selected from the group consisting
of disorders and conditions in which obesity or an overweight condition
predominates, including Type 2 diabetes mellitus, hypertension,
dyslipidemia and increased mortality in a mammal, including a human,
comprising;
[0279] (a) a nicotine receptor partial agonist or a pharmaceutically
acceptable salt thereof,
[0280] (b) an anti-obesity agent or weight-loss promoter or facilitator
or a pharmaceutically acceptable salt thereof;
[0281] (c) a pharmaceutically acceptable carrier;
[0282] wherein the active ingredients (a) and (b) above are present
in amounts that render the composition effective in treating obesity,
compulsive over-eating or an overweight condition.
[0283] The invention also relates to a method of treating a disorder
or condition selected from the group of disorders and condition
in which obesity or an overweight condition predominates, including
Type 2 diabetes mellitus, hypertension, dyslipidemia, and increased
mortality in a mammal, including a human, comprising administering
to said mammal;
[0284] (a) a nicotine receptor partial agonist or a pharmaceutically
acceptable salt thereof; and
[0285] (b) an anti-obesity agent or weight loss promoter or facilitator
or a pharmaceutically acceptable salt thereof;
[0286] wherein the active ingredients (a) and (b) above are present
in amounts that render the combination of the two active agents
effective in treating such disorder or condition.
[0287] The nicotine receptor partial agonist and the anti obesity
agent or weight loss promoter or facilitator can be administered
substantially simultaneously.
[0288] 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.
DETAILED DESCRIPTION OF THE INVENTION
[0289] In combination with the NRPA, the invention includes an
anti-obesity agent or a weight loss facilitator, or a pharmaceutically
acceptable salt of compounds such as Xenical.TM. (orlistat) or Meridia.TM.
(sibutramine).
[0290] A nicotine partial agonist combined with an anti-obesity
agent may facilitate weight loss while reducing the incidence of
undesirable side effects. Nicotine has long been appreciated to
have anorectic properties, but its use has been limited by a poor
spectrum of activity, side effects, and less efficacy than anti-obesity
agents. This may be due to lack of specificity of nicotine for neuromuscular,
ganglionic, and central nervous system receptors. The development
of nicotine partial agonists with specific receptor subtype affinities
is an approach to potentially reduce side effects and enhance efficacy.
[0291] Over the past several years it has become clear that obesity
has an important genetic component. Scientific investigation of
monogenic rodent models of obesity has revealed novel mechanisms
important in the regulation of body weight homeostasis including
leptin or a leptin receptor. Several of these genes are now the
targets of drug discovery efforts. Human obesity, however, is rarely
due to monogenic causes but rather is a result of complex multigenic
and environmental interactions. Despite the important role of genetics
in the predisposition to obesity in humans, the obese phenotype
results only after prolonged positive energy balance due to excess
energy consumption or insufficient energy expenditure. Conversely,
weight loss can only take place when energy expenditure exceeds
energy intake over an extended interval. Weight loss can be achieved
by stimulating energy expenditure, decreasing caloric intake, decreasing
energy absorption and/or favorable partitioning of energy to skeletal
muscle where it is converted to muscle mass as opposed to adipose
tissue where it is stored. The goal is to achieve sustained weight
loss of 5-15% or greater leading to an improvement of glycemic control
up to a 2% decrease in HbA1c in diabetics, reductions in diastolic
blood pressure to 90 mm Hg in hypertensives, and/or decreases in
LDL cholesterol by.gtoreq.15% in hyperlipidemic patients.
[0292] 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, WO 9935131-A1
and W09955680-A1. 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.
[0293] 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. The use of all such salts
are within the scope of the pharmaceutical compositions and methods
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.
[0294] In addition, some of the NRPA compounds employed in this
invention are basic, and they form a salt with a pharmaceutically
acceptable acid. 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 basic and acidic 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.
[0295] The utility of the NRPA compounds employed in the present
invention as medicinal agents in the treatment of obesity, compulsive
overeating, and an overweight condition 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.
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.
[0296] 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 which 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 single pharmaceutical composition
comprising a NRPA as described above and an analgesic agent as described
above in a pharmaceutically acceptable carrier can be administered.
PROCEDURES
[0297] 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-[.sup.3H]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.sup.3H-Cystisine,.sup.3H- -Nicotine and .sup.3H-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.degree. in 10 volumes of buffer (w/v) using a Brinkmann Polytron.TM.,
setting 6, for 30 seconds. The buffer consisted of 50 mM Tris HCI
at a pH of 7.5 at room temperature. The homogenate was sedimented
by centrifugation (10 minutes; 50,000.times.g; 0.degree. to 4.degree.
C.). The supernatant was poured off and the membranes were gently
resuspended with the Polytron and centrifuged again (10 minutes;
50,000.times.g; 0 to 4.degree. 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 HCI, 120 mM NaCl, 5 mM KCI, 2 mM MgCl.sub.2, 2 mM CaCl.sub.2
and has a pH of 7.4 at room temperature.
[0298] 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 .mu.L of
vehicle, blank, or test compound solution, respectively. To each
tube was added 200 .mu.L of [.sup.3H]-nicotine in assay buffer followed
by 750 .mu.L 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 .mu.M. The vehicle consisted of deionized
water containing 30 .mu.L 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.degree. to 4.degree.
C. in an iced shaking water bath. Incubations were terminated by
rapid filtration under vacuum through Whatman GF/B.TM. glass fiber
filters using a Brandel.TM. multi-manifold tissue harvester. Following
the initial filtration of the assay mixture, filters were washed
two times with ice-cold assay buffer (5 m 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.TM. liquid scintillation
counter at 40-50% efficiency. All determinations were in triplicate.
[0299] 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).
[0300] 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.
[0301] The compounds of the invention that were tested in the above
assay exhibited IC.sub.50 values of less than 10.mu.M.
[0302] 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).
[0303] 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.
[0304] In particular, an effective dosage for Xenical.TM. (orlistat)
when used in the combination compositions and methods of this invention,
is in the range of 1.0-5.0 mg/kg/day.
[0305] In particular, an effective dosage for Meridia.TM. (sibutramine)
when used in the combination compositions and methods of this invention,
is in the range of 0.01-0.2 mg/kg/day.
[0306] 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.
[0307] 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.
[0308] 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.
[0309] 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.
[0310] 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's Pharmaceutical Sciences, Mack Publishing
Company, Easter, Pa., 15th Edition (1975).
[0311] 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 obesity or compulsive overeating
of the subject being treated.
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