MXPA01005550A - A pharmaceutical composition for the treatment of obesity or to facilitate or promote weight loss, comprising a nicotine receptor partial agonist and an anti-obesity agent - Google Patents
A pharmaceutical composition for the treatment of obesity or to facilitate or promote weight loss, comprising a nicotine receptor partial agonist and an anti-obesity agentInfo
- Publication number
- MXPA01005550A MXPA01005550A MXPA/A/2001/005550A MXPA01005550A MXPA01005550A MX PA01005550 A MXPA01005550 A MX PA01005550A MX PA01005550 A MXPA01005550 A MX PA01005550A MX PA01005550 A MXPA01005550 A MX PA01005550A
- Authority
- MX
- Mexico
- Prior art keywords
- triene
- hexahydro
- diazocin
- methano
- pyrido
- Prior art date
Links
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- 229930015196 nicotine Natural products 0.000 title claims abstract description 28
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- 239000000883 anti-obesity agent Substances 0.000 title claims abstract description 22
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 20
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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.
Description
A PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF OBESITY OR TO FACILITATE OR PROMOTE THE WEIGHT LOSS
BACKGROUND OF THE INVENTION
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., a human), comprising a partial nicotine receptor agonist (NRPA) and an anti-obesity agent or weight loss promoter. The term "NRPA" refers to all chemical compounds that bind to sites of specific neuronal nicotinic acetylcholine receptors in the tissue of mammals and that elicit a partial agonist response. A partial agonist response is defined herein as a partial, or incomplete, functional effect in a given functional assay. Additionally, a partial agonist will also show some degree of antagonistic activity by its ability to block the action of a full agonist (Feldman, R.S., Meyer, J.S. and Quenzer, L.F. Principles of Neuropsychopharmacology, 1997, Sinauer Assoc. Inc.). The present invention can be used to treat mammals (e.g., humans) against obesity, a state of overweight or compulsive overfeeding, with a decrease in the severity of unwanted side effects, such as nausea provocation and / or Stomach indispositions
Obesity is a major health risk that leads to higher mortality and incidence of type 2 diabetes mellitus, hypertension and dyslipidemia. It is the second cause that leads to predictable death in the United States of America, and contributes to > 300,000 deaths per year. The estimated direct annual health cost, associated with obesity, is $ 70 billion, while the total global cost in the US economy has been estimated to be around $ 140 billion. In the United States, more than 50% of the adult population is overweight, and it is considered that almost% of the population is obese (BMI greater or equal to 30). In addition, the prevalence of obesity in the United States has increased by around 50% in the last 10 years. While the vast majority of obesity appears in the industrialized world, particularly in the US, and Europe, the prevalence of obesity is also growing in Japan. The prevalence of obesity in adults is 10% -25% in most Eastern European countries. The increase in the incidence of obesity has caused 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 the selective loss of body fat in moderately obese patients. These orally active agents should increase energy expenditure, decrease food intake and separate energy from adipose tissue. This degree of sustained weight loss would then improve the associated morbid states, including hyperglycemia, hypertension and hyperlipidemia, all of which are exacerbated by obesity. However, although weight loss agents have therapeutic utility in the treatment of obesity, there are significant impediments 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, vomiting, ulcers, constipation, flatulence, diarrhea, hypertension, dyspnea, and psychological and physical dependence.
BRIEF DESCRIPTION OF THE INVENTION
The present invention relates to a pharmaceutical composition for the treatment of obesity, compulsive overeating and / or to facilitate or promote weight loss comprising: (a) a partial nicotine receptor 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 above "a" and "b" agents are present in amounts that make the composition effective in treating obesity, compulsive overeating and / or facilitating or promoting weight loss. In a more specific embodiment of the invention, the anti-obesity agent or promoter or facilitator of weight loss is selected from Xenical ™ (orlistat) or Meridia ™ (sibutramine) and its pharmaceutically acceptable salts and optical isomers. In another more specific embodiment of this invention, the partial agonist or nicotine receptor 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 [, 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-pyrid [1,2-a] [1,5] diazocin-8-one; 9-iodo-1, 2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazocin-8-one; 9-cyano-1, 2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazocin-8-one; 9-ethynyl-1, 2,3,4, 5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazocin-8-one; 9- (2-propenyl) -1, 2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazocin-8-one; 9- (2-propyl) -1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazocin-8-one; 9-carbomethoxy-1, 2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazocin-8-one; 9-carboxyaldehyde-1, 2,3,4, 5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazocin-8-one;
9- (2,6-Di- fluo-phenyl) -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 [1,2-a] [1,5] diazocin-8-one; 9- (2-fluorophenyl) -1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazocin-8-one; 9- (4-fluorophenyl) -1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazocin-8-one; 9- (3-fluorophenyl) -1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazocin-8-one; 9- (3,5-Dilufuorophenyl) -1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1, 2a] [1,5] diazocin-8-one; 9- (2,4-Di- ufuorophenyl) -1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1, 2a] [1,5] diazocin-8-one; 9- (2,5-Di- fluo-phenyl) -1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-] [1,5] diazocin-8-one; 6-methyl-5-oxo-6,13-d-azatetracycline [9.3.1.02,10.04,8] pentadeca-2 (10), 3,8-triene; 5-oxo-6,13-diazatetracyclo [9.3.1.02,10.04'8] pentadeca-2 (10), 3,8-triene; 6-0X0-5,7,13-triazatetraciclo [9.3.1.02'10.04'8] pentadeca-2 (10), 3,8-triene; 4,5-difluoro-10-aza-tricyclo [6.3.1.02] dodeca-2 (7), 3,5-triene;
-fluoro-10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene-4-carbonitrile; 4-ethynyl-5-fluoro-10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene; 5-ethynyl-10-aza-tricyclo [6.3.1.02,7] dodeca-2 (7), 3,5-triene-4-carbonitrile; 6-methyl-5-thia-5-dioxa-6,13-diazatetracyclo [9.3.1.O ^ .O ^ pentadeca l 0), 3,8-triene; 10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene; 4-fluoro-10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene; 4-methyl-10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene; 4-trifluoromethyl-10-aza-tricyclo [6.3.1.02,7] dodeca-2 (7), 3,5-triene,
4-ntr-10-azatri-cyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene; 7-methyl-5,7,13-triazatetracyclo [9.3.1.02, 10.04'8] pentadeca-2 (10), 3,5,8-tetraene; 6-methyl-5,7,13-triazatetracyclo [9.3.1.02 '10 .04'8] pentadeca-2 (10), 3,5,8-tetraene; 6,7-dimethyl-5,7,13-triazatetracyclo [9.3.1.02 'l0.04'8] pentadeca-2 (10), 3,5,8-tetraene; 6-methyl-7-phenyl-5,7,13-triazatetracyclo [9.3.1.02'10.0 '8] pentadeca-2 (10), 3,5,8-tetraene; 6,7-dimethyl-5,8,14-triazethac [10.3.1.02'11.0, 9] hexadeca-2 (11), 3,5,7,9-pentaene;
,8,14-triazatetracyclo [10.3.1.02,11.04,9] hexadeca-2 (11), 3,5,7,9-pentaeno; 14-methyl-5,8,14-triazatetracyclo [10.3.1.02'11.049] hexadeca-2 (11), 3,5,7,9-pentaeno; 5-oxa-7,13-diazatetracyclo [9.3.1.02'10.04'8] pentadeca-2 (10), 3,6,8-tetraene; 6-methyl-5-oxa-7,13-diazatetracyclo [9.3.1.02'10.04,8] pentadeca-2 (10), 3,6,8-tetraene, 4-chloro-10-azatricyclo [6.3.1.02'7 ] dodeca-2 (7), 3,5-triene; 10-azatricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-trien-4-yl cyanide; 1- (10-azatricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-trien-4-yl) -1-ethanone; 10-azatricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-trien-4-ol; 7-methyl-5-oxa-6,13-diazatetracyclo [9.3.1.02,10.04'8] pentadeca-2,4 (8), 6,9-tetraene; 4,5-dichloro-10-azatricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene, 11-azatricyclo [7.3.1.02'7] trideca-2 (7), 3,5- triene-5-carbonitrile; 1- [11-azatricyclo [7.3.1.02'7] trideca-2 (7), 3,5-trien-5-yl] -1-ethanone; 1- [11-azatricyclo [7.3.1.02'7] trideca-2 (7), 3,5-trien-5-yl] -1-propanone; 4-fluoro-11-azatricyclo [7.3.1.02'7] trideca-2 (7), 3,5-triene-5-carbonitrile; 5-fluoro-11-azatricyclo [7.3.1.02'7] trideca-2 (7), 3,5-triene-4-carbonitrile;
6-methyl-7-thia-5,14-diazatetracyclo [10.3.1.02'10.04'8] hexadeca-2 (10), 3,5,8-tetraene; 6-methyl-5,7,14-triazatetracyclo [10.3.1.02,10.04'8] hexadeca-2 (10), 3,5,8-tetraene; 6,7-dimethyl-5,7,14-triazatetracyclo [10.3.1.02'10.04'8] hexadeca-2 (10), 3,5,8-tetraene; 5,7, 14-triazatetracyclo [10.3.1.02'10.04'8] hexadeca-2 (10), 3,5,8-tetraene; 5,6-dimethyl-5,7I14-triazatetracyclo [10.3.1.02'10.04'8] hexadeca-2 (10), 3,6,8-tetraene; 5-methyl-5,7,14-triazatetracyclo [10.3.1.02'10.04'8] hexadeca-2 (10), 3,6,8-tetraene; 6- (trifluoromethyl) -7-thia-5,14-diazatetracyclo [10.3.1.02'10.04 8] hexadeca-2 (10), 3,5,8-tetraene; 5,8,15-triazatetracyclo [11.3.1.02,11,049] heptadeca- 2 (11), 3,5,7,9, pentaeno; 7-methyl-5,8,15-triazatetracyclo [11.3.1.02, 1.04'9] heptadeca-2 (11), 3,5,7,9-pentaeno, 6-methyl-5,8,15-triazatetracyclo [11.3 .1.02 '1.04'9] heptadeca-2 (11), 3,5,7,9-pentaeno; 6,7-dimethyl-5,8,15-triazatetracyclo [11.3.1.02'11.04,9] heptadeca-2 (11), 3,5,7,9-pentaene;
7-oxa-5,14-diazatetracyclo [10.3.1.02'10.04'8] hexadeca-2 (10), 3,5,8-tetraene, 6-methyl-7-oxa-5,14-diazatetracyclo [10.3 .1.02-10.04'8] hexadeca-2 (10), 3,5,8-tetraene; 5-methyl-7-oxa-6,14-diazatetracyclo [10.3.1.02 | 10.04'8] hexadeca- 2 (10), 3,5,8-tetraene; 6-methyl-5-oxa-7,14-diazatetracyclo [10.3.1.02'10.04'8] hexadeca-2 (10), 3,6,8-tetraene, 7-methyl-5-oxa-6,14-diazatetracyclo [10.3.1.02'10.04'8] hexadeca-2 (10), 3,6,8-tetraene, 4,5-difluoro-11-azatricyclo [7.3.1.02'7] trideca-2 (7), 3,5 -triene, 4-chloro-5-fluoro-11-azatricyclo [7.3.102.7] trideca-2 (7), 3,5-triene, 5-chloro-4-fluoro-11-azatricyclo [7.3.1.02, 7] trideca-2 (7), 3,5-triene; 4- (1-ethynyl) -5-fluoro-11-azatrichlor [7.3.1.02'7] trideca-2 (7), 3,5-triene; 5- (1-ethynyl) -4-fluoro-11-azatricyclo [7.3.1.02'7] trideca-2 (7), 3,5-triene; 5,6-difluoro-11-aza-tricyclo [7.3.1.02'7] trideca-2,4,6-triene; 6-trifluoromethyl-11-aza-tricyclo [7.3.1.02'7] trideca-2,4,6-triene; 6-methoxy-11-aza-tricyclo [7.3.1.02,7] trideca-2 (7), 3,5-triene, 11-aza-tricyclo [7.3.1.02'7] trideca-2 (7), 3, 5-trien-6-ol; 6-fluoro-11-aza-tricyclo [7.3.1.02'7] trideca-2 (7), 3,5-triene; 11-aza-tricyclo [7.3.1.02'73trideca-2 (7), 3,5-trien-5-oI; 4-nitro-11-aza-tricyclo [7.3.1.02'7] tr-deca-2 (7), 3,5-triene, 5-nitro-11-aza-tricyclo [7.3.1.02'7] trideca-2 (7), 3,5-triene, 5-fluoro-11-aza-tricyclo [7.3.1.02'7] trideca-2 (7), 3,5-triene, and 6-hydroxy-5-methoxy-11- aza-tricyclo [7.3.1.02,7] trideca-2 (7), 3,5-triene and its pharmaceutically acceptable salts and its optical isomers. Preferably, the partial nicotine receptor 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] d-azocin-8-one; 6-methyl-5-thia-5-dioxa-6,13-diazatetracyclo [9.3.1.02 '0.04'8] pendadeca-2 (10), 3,8-trinone; 4-fluoro-10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene) 4-trifluoromethyl-10-aza-tricyclo [6.3.1.02l7] dodeca-2 ( 7), 3,5-triene,
4-nitro-10-azatricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene, 6-methyl-5,7,13-triazatetracyclo [9.3.1.02'10.048] pentadeca-2 (10 ), 3,5,8-tetraene; 6,7-dimethyl-5,8, 14-triazatetracyclo [10.3.102'11.04,9] hexadeca-2 (11), 3,5,7,9-pentaeno, 5,18,14-triazatetracyclo [10.3.1.02] '11 .04 > 9lhexadeca-2 (11), 3f5,7,9-pentaeno; 5-oxa-7,13-diazatetracyclo [9.3.1.02'10.0 '8] pentadeca-2 (10), 3,6,8-tetraene; 6-methyl-5-oxa-7,13-diazatetracyclo [9.3.1.02,10.04'8] pentadeca-2 (10), 3,6,8-tetraene; 10-azatricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-trien-4-yl cyanide; 1- (10-azatricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-trien-4-yl) -1-ethanone;
11-azatricyclo [7.3.1.02,7] trideca-2 (7), 3,5-triene-5-carbonitrile; 1- [11-azatry] [7.3.1.02'7] trideca-2 (7), 3,5-trien-5-yl] -1-ethanone; 1 - [11 -azatricyclo [7.3.1.02,7] trideca-2 (7), 3,5-trien-5-yl] -1-propanone; 4-fluoro-11-azatricyclo [7.3.1.02'7] trideca-2 (7), 3,5-trien-5-carbonitrile; 5-fluoro-11-azatricyclo [7.3.1.02'7] trideca-2 (7), 3,5-triene-4-carbonitrile; 6-methyl-7-thia-5,14-diazatetracyclo [10.3.1.02'10.04'8] hexadeca-2 (10), 3,5,8-tetraene; 6-methyl-5,7,14-triazatetracyclo [10.3.1.02 10.0 exadeca- 2 (10), 3,5,8-tetraene; 6,7-dimethyl-5,7,14-triazatetracyclo [10.3.1.02'10.04'8] hexadeca-2 (10), 3,5,8-tetreaeno; 6-methyl-7-oxa-5,14-diazatetracyclo [10.3.1.02 l0.04'8] hexadeca-2 (10), 3,5,8-tetraene; 6-methyl-5-oxa-7,14-diazatetracyclo [10.3.1.02'10.04'8] hexadeca-2 (10), 3,6,8-tetraene; 5,6-difluoro-11-aza-tricyclo [7.3.1.02] trideca-2,4,6-triene; 6-Trifluoromethyl-11-aza-tricyclo [7.3.1.02'7] trdeca-2,4,6-trine, 6-methoxy-11-aza-tricyclo [7.3.1.02'7] trideca 2 (7), 3,5-triene; 6-fluoro-11-aza-tricyl [7.3.1.02'7] trideca-2 (7), 3,5-triene, and 11-aza-tricyclo [7.3.1.02'7] trideca-2 (7), 3 , 5-trien-5-ol and its pharmaceutically acceptable salts and its optical isomers.
The present invention also relates to a method for treating overfeeding with obesity, 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: a) a partial nicotine receptor agonist or a pharmaceutically acceptable salt thereof; and (b) an anti-obesity agent or a weight loss promoter or facilitator, or a pharmaceutically acceptable salt thereof; wherein the ingredients (a) and (b) are present in amounts that make the composition effective for the treatment of obesity, compulsive overeating or a state of overweight. In another more specific embodiment of this invention, the partial nicotine receptor agonist is selected from: 9-bromo-1, 2,3,4, 5,6-hexahydro-1,5-methane-pyrid [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 [9.3.1.02,10.04,8] pentadeca-2 (10), 3,8-triene; 5-0X0-6,13-diazatetracycle [9.3.1.02'10.04'8] pentadeca-2 (10), 3,8-triene; 6-0X0-5,7,13-triazatetracyclo [9.3.1 tri-ene; 4,5-difluoro-10-aza-tricyclo [6.3.1.0 2A, 7 '-], dodeca-2 (7), 3,5-triene; 5-fluoro-10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene-4-carbonitrile; 4-ethynyl-5-fluoro-10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene; 5-ethynyl-10-aza-tricyclo [6.3.1.02,7] dodeca-2 (7), 3,5-triene-4-carbonitrile; 6-methyl-5-thia-5-dioxa-6,13-diazatetracyclo [9.3.1.02'10.04,8] pentadeca-2 (10), 3,8-triene; 10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene; 4-fluoro-10-aza-tricyclo [6.3.1.02,7] dodeca-2 (7), 3,5-triene; 4-methyl-10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene; 4-trifluoromethyl-10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene; 4-nitro-10-aza-tricyclo [6.3.1.02,7] dodeca-2 (7), 3,5-triene; 7-methyl-5,7,13-triazatetracyclo [9.3.1.02,10.04,8] pentadeca-2 (10), 3,5,8-tetraene; 6-methyl-5,7,13-triazatetracyclo [9.3.1.02,10.04,8] pentadeca-2 (10), 3,5,8-tetraene;
6,7-dimethyl-5,7,13-triazatetracyclo [9.3.1.02 ', 0.04'8] pentadeca-2 (10), 3,5,8-tetraene; 6-methy1-7-phenyl-5,7,13-triazatetracyclo [9.3.1.02'10.04'8] pentadeca-2 (10), 3) 5,8-tetraene; 6,7-dimethyl-5,8,14-triazatetracyclo [10.3.1.02 | 11.0 '9] hexaadeca-2 (11), 3,5,7,9-pentaene; 5,8,14-triazatetracyclo [10.3.1.02 11.04'9] hexadeca-2 (11), 3,5,7,9-pentaeno; 14-methyl-5,8,14-triazatetracyclo [10.3.1.02 11.04,9] hexadeca-2 (11), 3,5,7,9-pentaeno; 5-oxa-7,13-d-azatetraciclo [9.3.1.02'10.048] pentadeca-2 (10), 3,6,8-tetraene; 6-methyl-5-oxa-7,13-d-azatetracyclo [9.3.1.02'10.04,8] pentadeca-2 (10), 3,6,8-tetraene; 4-chloro-10-azatricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene; 10-azatricyclo [6.3.1.02,7] dodeca-2 (7), 3,5-trien-4-yl cyanide; 1- (10-azatricyclo [6.3.1.02,7] dodeca-2 (7), 3,5-trien-4-yl) -1-ethanone; 10-azatricyclo [6.3.1.02,7] dodeca-2 (7), 3,5-trien-4-ol; 7-methyl-5-oxa-6,13-diazatetracyclo [9.3.1.02 10.04 8] pentadeca-2,4 (8), 6,9-tetraene; 4,5-dichloro-10-azatricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene; 11-azatricyclo [7.3.1.02,7] trdeca-2 (7), 3,5-triene-5-carbonitrile; 1- [11-azatricyclo [7.3.1.02'7] trideca-2 (7), 3,5-trien-5-yl) -1-ethanone;
1- [11-azatricyclo [7.3.1.02,7] trideca-2 (7), 3,5-trien-5-yl) -1-propanone; 4-fluoro-11-azatricyclo [7.3.1.02'7] trideca-2 (7), 3,5-triene-5-carbonitrile; 5-fluoro-11-azatricyclo [7.3.1.02,7] trideca-2 (7), 3,5-trien-4-carbonitrile; 6-methyl-7-thia-5,14-diazatetracyclo [10.3.1.02'10.04'8] hexadeca-2 (10), 3,5,8-tetraene; 6-methyl-5,7,14-triazatetracyclo [10.3.1.02'10.04,8] hexadeca-2 (10), 3,5,8-tetraene; 6,7-dimethyl-5,7,14-triazatetracyclo [10.3.1.02'10.0 '8] hexadeca-2 (10), 3,5,8-tetraene; 5,7,14-triazatetracyclo [10.3.1.02'10.04'8] hexadeca-2 (10), 3,5,8-tetraene; 5,6-dimethyl-5,7,14-triazatetracyclo [10.3.1.02'10.04'8] hexadeca-2 (10), 3,6,8-tetraene; 5-methyl-5,7,14-triazatetracyclo [10.3.1.02'10.04'8] hexadeca-2 (10), 3,6,8-tetraene; 6- (trifluoromethyl) -7-thia-5,14-diazatetracyclo [10.3.1.02'10.04'8] hexadeca-2 (10), 3,5,8-tetraene; 5,8,15-triazatetracyclo [11.3.1.02 11.04'9] heptadeca-2 (11), 3,5,7,9-pentaeno; 7-methyl-5,8,15-triazatetracyclo [11.3.1.02'11.04,9] heptadeca-2 (11), 3,5,7,9-pentaene;
6-methyl-5,8,15-triazatetracyclo [11.3.1.O ^ .O ^ heptadeca-2 (11), 3,5,7,9-pentaene; 6,7-dimethyl-5,8,15-triazatetracyclo [11.3.1.02'11.04 > 9] hetadeca-2 (11), 3,5,7,9-pentane; 7-oxa-5,14-diazatetracyclo [10.3.1.02'10.04'8] hexadeca-2 (10), 3,5,8-tetraene; 6-methyl-7-oxa-5,14-diazatetracyclo [10.3.1.02,10.0 '8] hexadeca-2 (10), 3,5,8-tetraene; 5-methy1-7-oxa-6,14-dlazatetracyclo [10.3.1.02'10.04,8lhexadeca-2 (10), 3,5,8-tetraene; 6-methyl-5-oxa-7,14-diazatetracyclo [10.3.1.02'10.0 '8] hexadeca-2 (10), 3,6,8-tetraene; 7-methyl-5-oxa, 6,14-diazatetracyclo [10.3.1.02'10.04'8] hexadeca-2 (10), 3,6,8-tetraene; 4,5-difluoro-11-azatricyclo [7.3.1.02'7] trideca-2 (7), 3,5, triene; 4-chloro-5-fluoro-11-azatricyclo [7.3.1.02'7] trideca-2 (7), 3,5-trine; 5-chloro-4-fluoro-11-azatricyclo [7.3.1.02,7] trideca-2 (7), 3,5-triene; 4- (1-ethynyl) -5-fluoro-11-azatricyclo [7.3.1.02'7] trideca-2 (7), 3,5-triene; 5- (1-ethynyl) -4-fluoro-11-azatricyclo [7.3.1.02,7] trideca-2 (7), 3,5-triene; 5,6-difluoro-11-aza-tricyclo [7.3.1.02'7] trideca-2,4,6-triene; 6-Trifluoromethyl-11-aza-tricyclo [7.3.1.02'7] trideca-2,4,6-trine; 6-methoxy-11-aza-tricyclo [7.3.1.02'7] trideca-2 (7), 3,5-triene; 11-aza-tricyclo [7.3.1.02,7] trideca-2 (7), 3,5-trien-6-ol;
6-fluoro-11-aza-tricyclo [7.3.1.02'7] trideca-2 (7), 3,5-triene; 11-aza-tricyclo [7.3.1.02'7] trideca-2 (7), 3,5-trien-5-ol; 4-nitro-11-aza-tricyclo [7.3.1.02'7] trideca-2 (7) > 3 > 5-trine; 5-nitro-11-aza-tricyclo [7.3.1.02'7] tr-deca-2 (7), 3,5-triene; 5-fluoro-11-aza-tricyclo [7.3.1.02'7] trideca-2 (7), 3,5-triene; and 6-hydroxy-5-methoxy-11-aza-tricyclo [7.3.1.02'7] trideca-2 (7), 3,5-triene and their pharmaceutically acceptable salts and their optical isomers. Preferably, the partial nicotine receptor agonist is selected from: 9-bromo-1, 2,3,4,5,6-hexahydro-l, 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-carboxymethoxy-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 [9.3.1.02'10.0 -8] pentadeca-2 (10), 3,8-triene; 4-fluoro-10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene; 4-trifluoromethyl-10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene; 4-nitro-10-azatricyclo [6.3.1.027] dodeca-2 (7), 3,5-triene; 6-methyl-5,7,13-triazatetracyclo [9.3.1.02'10.048] pentadeca-2 (10), 3,5,8-tetraene; 6,7-dimethyl-5,8,14-triazatetracyclo [10.3.1.02,11.04'9] hexadeca-2 (11), 3,5,7,9-pentaeno; 5,8,14-triazatetracyclo [10.3.1.02,11.04'9] hexadeca-2 (11), 3,5,7,9-pentaeno; 5-oxa-7,13-diazatetracyclo [9.3.1.02'10.048] pentadeca-2 (10), 3,6,8-tetraene; 6-methy1-5-oxa-7,13-d-azatetracyclo [9.3.1.02 'l0.04'80] pentadeca-2 (10), 3,6,8-tetraene;
-azatricyclo [6.3.1.02,7] dodeca-2 (7), 3,5-trien-4-yl cyanide; 1- (10-azatricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-trien-4-yl) -1-ethanone; 11-azatricyclo [7.3.1.02'7] trideca-2 (7), 3,5-triene-5-carbonitrile; 1- [11-azatricyclo [7.3.1.02'7] trideca-2 (7), 3,5-trien-5-yl] -1-ethanone; 1- [11-azatricyclo [7.3.1.02,7] trideca-2 (7), 3,5-trien-5-yl] -1-propanone; 4-fluoro-11-azatricyclo [7.3.1.02'7] trideca-2 (7), 3,5-triene-5-carbonitrile; 5-fluoro-11-azatricyclo [7.3.1.02,7] trideca-2 (7), 3,5-triene-4-carbonitrile; 6-methyl-7-thia-5,14-diazatetracyclo [10.3.1.02 | 10.0 -8] hexadeca- 2 (10), 3,5,8-tetraene; 6-methyl-5,7,14-triazatetracyclo [10.3.1.02 'l0.04'8] hexadeca-2 (10), 3,5,8-tetraene; 6,7-dimethyl-5,7,14-triazatetracyclo [10.3.1.02'10.04'8] hexadeca-2 (10), 3,5,8-tetraene; 6-methyl-7-oxa-5,14-diazatetracyclo [10.3.1.02'10.04-8] hexadeca-2 (10), 3,5,8-tetraene; 6-methyl-5-oxa-7,14-diazatetracyclo [10.3.1.02'10.04'8] hexadeca-2 (10), 3,6,8-tetraene; 5,6-difluoro-11-aza-tricyclo [7.3.1.02'7.04'8] trideca-2,4,6-triene; 6-trifluoromethyl-11-aza-tricyclo [7.3.1.02,7] trideca-2,4,6-trine; 6-methoxy-11-aza-tricyclo [7.3.1.02,7] trideca-2 (7), 3,5-triene; 6-fluoro-11-aza-tricyclo [7.3.1.02'7] trideca-2 (7), 3,5-triene; and 11-aza-tricyclo [7.3.1.02'7] tr-deca-2 (7), 3,5-trien-5-ol; and pharmaceutically acceptable salts, stereoisomers (including optical isomers), solvates and hydrates of the above compounds. The above NRPAs and others are cited, together with methods for their synthesis, in the worldwide patent applications WO 98/18798, WO 99/35131 and WO 99/55680, which were published, respectively on May 7, 1998, 15 July 1999 and November 4, 1999. The above applications are from the same owner as the present application and are hereby incorporated by reference in their entirety. These compounds can be used in combination with an anti-obesity agent, or a weight loss promoter, to treat obesity or facilitate or promote weight loss. In another more specific embodiment, the anti-obesity agent and / or weight loss promoter or facilitator is selected from Xenical ™ (orlistat) or Meridia ™ (sibutramine) and its pharmaceutically acceptable salts, stereoisomers (including optical isomers), hydrates and solvates acceptable The invention also relates to a pharmaceutical composition for treating a disorder or condition selected from the group consisting of disorders and conditions in which obesity predominates or a state of overweight, including diabetes mellitus type 2, hypertension, dyslipidemia and increased mortality in a mammal, including a human being, comprising: (a) a partial nicotine receptor agonist or a pharmaceutically acceptable salt thereof, (b) an anti-obesity agent or a weight loss promoter or facilitator, or one of its pharmaceutically acceptable salts; (c) a pharmaceutically acceptable vehicle; wherein the active ingredients (a) and (b) above are present in amounts that make the composition effective for treating obesity, compulsive overeating or a state of overweight. The invention also relates to a method for treating a disorder or condition selected from the group of disorders and conditions in which obesity or a state of overweight predominates, including type 2 diabetes mellitus, hypertension, dyslipidemia and increased mortality in a mammal including a human being, comprising administering to said mammal: (a) a partial agonist of the nicotine receptor or a pharmaceutically acceptable salt thereof; and (b) an anti-obesity agent or a weight loss promoter or facilitator, or a pharmaceutically acceptable salt thereof; wherein the active ingredients (a) and (b) above are present in amounts which make the combination of the two active agents effective to treat such disorder or condition.
The partial agonist of the nicotine receptor and the anti-obesity agent or the promoter or facilitator of the weight loss can be administered substantially simultaneously. The term "treat" as used herein, refers to intervening, 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 treating, as "treating" is defined immediately above.
DETAILED DESCRIPTION OF THE INVENTION
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 ™ (orlistat) or Meridia ™ (sibutramine). A partial nicotine agonist combined with an anti-obesity agent can facilitate weight loss while reducing the incidence of undesirable side effects. Nicotine has been much appreciated for having anorexic 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 the lack of specificity of nicotine by neuromuscular, ganglionic, and central nervous system receptors. The development of partial nicotine agonists with affinities for specific receptor subtype is an approach to potentially reduce side effects and increase efficacy. Over the past few years it has become clear that obesity has an important generic component. The scientific investigation of obesity models of monogenic rodents has revealed new important mechanisms in the regulation of body weight homeostasis including leptin or a leptin receptor. Several of these agents are now the targets of drug discovery efforts. However, human obesity is rarely due to monogenic causes but rather is the result of complex multigenic and environmental interactions. Despite the important role of genetics in the predisposition to obesity in humans, the obese phenotype only results from a prolonged positive energy balance due to excessive energy consumption or insufficient energy expenditure. Conversely, weight loss can only have a place when the energy expenditure exceeds the energy input during a prolonged interval. Weight loss can be achieved by stimulating the expenditure of energy, decreasing caloric intake, decreasing the absorption of energy and / or the favorable distribution of energy to the skeletal muscle in which it becomes muscle mass, opposite to adipose tissue in which it is stored. The goal is to achieve a sustained weight loss of 5-15% or greater, leading to an improvement in glycemic control of up to 2% decrease in HbA1 c in diabetics, reductions in diastolic blood pressure to 90 mm Hg in hypertensive patients, and / or decreases in LDL cholesterol in > 15% in hyperlipidemic patients. The particular NRPA compounds listed above, which may be employed in the methods and pharmaceutical compositions of this invention, may be obtained by methods known in the chemical art, for example by the methods described in WO 9818798 A1, WO 9935131-A1 and WO9955680-A1. Some of the preparation methods, useful for obtaining the compounds of this invention, may require the protection of a remote functionality (ie, 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 easily determined by the person skilled in the art, and is described in the examples described carefully in the applications cited above. 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 or obtained from compounds found in nature and, consequently, many such compounds are commercially available or are described in the literature or are readily prepared from other substances, usually available, by methods that are given in the bibliography.
Some of the NRPA compounds employed in this invention are ionizable in physiological states. Thus, for example, some of the compounds of this invention are acidic and form a salt with a pharmaceutically acceptable cation. The use of all those salts is within the scope of the pharmaceutical compositions and methods of this invention and can be prepared by conventional methods. For example, they can be prepared by simply contacting the acidic and basic entities, usually in a stoichiometric ratio, either in an aqueous, non-aqueous or partially aqueous medium, as appropriate. The salts are recovered 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. In addition, some of the NRPA compounds employed in this invention are basic, and form a salt with a pharmaceutically acceptable acid. All those salts are within the scope of this invention and can be prepared by conventional methods. For example, they can be prepared by simply contacting the acidic and basic entities, usually in a stoichiometric ratio, either in an aqueous, non-aqueous or partially aqueous medium, as appropriate. The salts are recovered 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.
The utility of the NRPA compounds employed in the present invention as medicinal agents in the treatment of obesity, compulsive overeating, and a state of overweight in mammals (e.g., humans), is demonstrated by the activity of the compounds of this invention in conventional tests and, in particular, the tests described below. Such assays also provide a means by which the activities of the compounds of this invention can be compared with each other 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. The administration of the compositions of this invention can be via any method that provides a compound of this invention systemically and / or locally. These methods include oral and transdermal routes, etc. Generally, the compounds of this invention are administered orally, but parenteral administration (e.g., intravenous, intramuscular, subcutaneous or intramedullary) can be used. The two different compounds of this invention can be co-administered simultaneously or sequentially in any order, or a single pharmaceutical composition comprising an NRPA as described above and an analgesic agent as described above can be administered in a pharmaceutically acceptable carrier.
Procedures
Assay of receptor binding The effectiveness of the active compounds for suppressing nicotine binding to specific receptor sites is determined by the following procedure which is a modification of the methods of Lippiello, PM and Fernandes, KG (in The Binding of L- [3H] Nicotine To A Single Class of High-Affinitv Sites in Rat Brain Membranes, Molecular Pharm .. 29 448-54, (1986)) and Anderson, DJ and Arneric, SP (in Nicotinic Receptor Binding of 3H-Cystisine. -Nicotine and 3H-methylcarbamylcholine 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 cages of stainless steel wire and maintained in a 12-hour day / night cycle (light period 7 a.m.-7 p.m.). They received standard Purina Rat Chow and water at will. The rats were sacrificed by decapitation. The brains were removed immediately after decapitation. Membranes were prepared from brain tissue according to the methods of Lippiello and Fernandes (Molec Pharmacol., 448-454, (1986) with some modifications. Whole brains were removed, rinsed with ice-cold buffer, and homogenized at 0 ° C in 10 volumes of buffer (w / v) using a Brinkmann Polytron ™, setting number 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 x g; 0 ° to 4 ° C). The supernatant was separated by pouring and the membranes were gently resuspended with the Polytron and centrifuged again (10 minutes, 50,000 x g, 0 ° to 4 ° C). After the second centrifugation, the membranes were resuspended in assay buffer at a concentration of 1.0 g / 100 ml. The composition of the standard assay buffer was 50 mM Tris HCl, 120 mM NaCl, 5 mM KCl, 22 mM MgCl, 2 mM CaCl 2 and has a pH of 7.4 at room temperature. Routine tests were performed on 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 in which the tubes in each set contained 50 μl of vehicle, blank or test compound solution, respectively. 200 μl of [3 H] -nicotine was added to each tube 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 the vehicle. The swirl tests were started after the addition of the membrane suspension to the tube. The samples were incubated at 0 to 4 ° C in a water bath with shaken ice. Incubations were terminated by rapid vacuum filtration through Whatman GF / B ™ glass fiber filters using a Brandel ™ multi-aperture tissue harvester. After the initial filtration of the test mixture, the filters were washed twice with ice-cold assay buffer (5 ml each). The filters were then placed in vials for counting 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 made in triplicate.
Calculations The specific binding (C) to the membrane is the difference between the total binding in the samples that contain only vehicle and membrane (A) and the non-specific binding in the samples that contain the membrane and cytisine (B), that is, Specific union = (C) = (A) - (B). The 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 the non-specific binding (B), ie. (E) = (D) - (B). % inhibition = (1 - ((E) / (C)) x 100. The compounds of the invention that were analyzed in the previous test showed IC 50 values of less than 10 μM. Of course, the amount and duration of the compounds administered will be based on the judgment of the prescribing physician.Thus, due to the variability between patients, the doses given below are a guide, and the doctor can adjust the agent dose to achieve the activity that he considers appropriate for the patient. individual patient.When considering the degree of activity desired, the physician must balance a variety of factors such as cognitive function, age of the patient, presence of pre-existing disease, as well as presence of other diseases (eg, cardiovascular) .The following paragraphs provide Preferred dose ranges for the various components of this invention (based on the average human weight of 70 kg) In general, an effective dose for the NRPA is in the interest value from 0.01 to 200 mg / kg / day, preferably 0.05 to 10.0 mg / kg / day. In particular, an effective dose of Xenical ™ (orlistat), when used in the compositions and methods of the combination of this invention, is in the range of 1.0-5.0 mg / kg / day. In particular, an effective dose of Meridia ™ (sibutramine), when used in the compositions and methods of the combination of this invention, is in the range of 0.01-0.2 mg / kg / day. 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 carrier or diluent. In this way, the compounds of this invention can be administered individually or together in any oral, parenteral or transdermal dosage form. For oral administration, the pharmaceutical composition can take the form of solutions, suspensions, tablets, pills, capsules, powders and the like. Tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate are used together with various disintegrating agents such as starch, and preferably potato starch or tapioca, and certain complex silicates, together with binding agents such as polyvinylpyrrolidone. , sucrose, gelatin and gum arabic. Additionally, lubricating agents, such as magnesium stearate, sodium lauryl sulfate and talc, are often very useful in order to form tablets. Solid compositions of a similar type are also employed as fillers in hard and soft filled gelatin capsulesGLY
; Preferred materials in this regard also include lactose or milk sugar as well as high molecular weight polyethylene ols. 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 diluents such as water, ethanol. , propylene ol, erin and various similar combinations thereof. For the purposes of parenteral administration, solutions in sesame or peanut oil, or in aqueous propylene ol, as well as sterile aqueous solutions of the corresponding water-soluble salts can be employed. Such aqueous solutions can be suitably buffered, if necessary, and the liquid diluent first made isotonic with sufficient saline or glucose. These aqueous solutions are especially suitable for the purposes of intravenous, intramuscular, subcutaneous and intraperitoneal injection. In this regard, the sterile aqueous media used is all easily obtained by standard techniques well known to the person skilled in the art. For the purposes of transdermal administration (eg, topical), dilute, sterile, aqueous or partially aqueous solutions are prepared (usually in about 0.1% to 5% concentration), similar to the previous parenteral solutions. Methods for preparing various pharmaceutical compositions with a certain amount of active ingredient are known, or will be apparent in the light of this disclosure, by those skilled in the art. For example, see Remington's Pharmaceutical Sciences. Mack
Publishing Company, Easter, Pa., 15th edition (1975). The pharmaceutical compositions according to the invention may contain 0.1% -95% of the compound (s) of this invention, preferably 1% -70%. In any case, the composition or formulation to be administered will contain an amount of a compound (s) according to the invention in an amount effective to treat obesity or compulsive overfeeding of the treated individual.
Claims (11)
1. A pharmaceutical composition for the treatment of obesity, compulsive overfeeding, or to promote or facilitate weight loss, comprising: (a) a partial agonist of the nicotine receptor 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 make the composition effective in treating obesity, compulsive overfeeding, or promoting or facilitating weight loss.
2. The pharmaceutical composition according to claim 1, wherein said anti-obesity agent or promoter or facilitator of weight loss is selected from Xenical ™ (orlistat) and Meridia ™ (sibutramine) and their pharmaceutically active salts.
3. The pharmaceutical composition according to claim 1, wherein said partial nicotine receptor agonist is selected from: 9-bromo-1, 2,3,4,5,6-hexahydro-1,5-methane-pyro [1, 2a] [1,5] diazocin-8-one; 9-chloro-1, 2,3,4,5,6-hexahydro-1,5-methano-pyrido [1, 2a] [1,5] diazocin-8-one; 9-fluoro-1, 2,3,4,5,6-hexahydro-1,5-methano-pyrido [1, 2a] [1,5] diazocin-8-one; 9-ethyl-1, 2,3,4,5,6-hexahydro-1,5-methano-pyrido [1, 2a] [1,5] diazocin-8-one; 9-methyl-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-vinyl-1, 2,3,4, 5,6-hexahydro-1,5-methano-pyrido [1, 2a] [1,5] diazocin-8-one; 9-bromo-3-methyl-1, 2,3,4,5,6-hexahydro-1,5-methano-pyrido [1, 2a] [1,5] diazocin-8-one; 3-benzyl-9-bromo-1, 2,3,4,5,6-hexahydro-pyrido [1, 2a] [1,5] diazocin-8-one; 3-benzyl-9-chloro-1, 2,3,4,5,6-hexahydro-l, 5-methano-pyrido [1, 2a] [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-l, 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-methy1-5-oxo-6,13-diazatetracyclic [9.3.1.02'10.0 '8] pentadeca-2 (10), 3,8-triene; 5-oxo-6,13-diazatetracyclo [9.3.1.02 '0.04'8] pentadeca-2 (10), 3,8-triene; 6-oxo-5,7,13-triazatetracyclo [9.3.1.02'10.04,8] pentadeca-2 (10), 3,8-triene; 4,5-difluoro-10-aza-tricyclo [6.3.1.02,7] dodeca-2 (7), 3 > 5-triene; 5-fluoro-10-aza-tricyclo [6.3.1.02,7] dodeca-2 (7), 3,5-triene-4-carbonitrile; 4-ethynyl-5-fluoro-10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene; 5-ethynyl-10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene-4-carbonitrile; 6-methyl-5-thia-5-dioxa-6,13-diazatetracyclo [9.3.1.02,10.04'8] pentadeca-2 (10), 3,8-triene; 10-aza-tricyclo [6.3.02'7] dodeca-2 (7), 3,5-triene; 4-fluoro-10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene; 4-methyl-10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene; 4-trifluoromethyl-10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene; 4-nitro-10-azatricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene; 7-methyl-5,7,13-triazatetracyclo [9.3.1.02'10.0, 8] pentadeca-2 (10), 3,5,8-tetraene; 6-methyl-5,7,13-triazatetracyclo [9.3.1.02 '0.04'8] pentadeca-2 (10), 3,5,8-tetraene; 6,7-dimethyl-5,7,13-triazatetracyclo [9.3.1.02'10.04'8] pentadeca-2 (10), 3,5,8-tetraene; 6-methyl-7-phenyl-5,7,13-triazatetracyclo [9.3.1.02 'l0.04'8] pentadeca-2 (10), 3,5,8-tetraene; 6,7-dimethyl-5,8,14-triazatetracyclo [10.3.1.02'11.04,9] hexadeca-2 (11), 3,5,7,8,9-pentaeno; 5,8,14-triazethac [10.3.1.02'11.0 '9] hexadeca-2 (11), 3,5,7,9-pentaeno; 14-methyl-5,8,14-triazatetracyclo [10.3.1.02'11.04,9] hexadeca- 2 (11), 3,5,7,9-pentaeno; 5-oxa-7,13-diazatetracyclo [9.3.1.02 'l0.04'8] pentadeca-2 (10), 3,6,8-tetraene; 6-methyl-5-oxa-7,13-diazatetracyclo [9.3.1.02'10.04'8] pentadeca-2 (10), 3,6J8-tetraene; 4-chloro-10-azatricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene; 10-azatricyl cyanide [6.3.1.02'7] dodeca-2 (7), 3,5-trien-4-yl; 1- (10-azatricyclo [6.3.1.02'7] dodeca-2 (7) > 3,5-trien-4-yl) -1-ethanone; 10-azatricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-trien-4-ol; 7-methyl-5-oxa-6,13-diazatetracyclo [9.3.1.02,10.04 8] pentadeca-2,4 (8), 6,9-tetraene; 4,5-dichloro-10-azatricyclo [6.3.1.02,7] dodeca-2 (7) r3,5-triene; 11-azatricyclo [7.3.1.02'7] trideca-2 (7), 3,5-triene-5-carbonitrile; 1- [11-azatricyclo [7.3.1.02'7] trideca-2 (7), 3,5-trien-5-yl] -1-ethanone; 1 - [11 -azatricyclo [7.3.1.02'7] trideca-2 (7), 3,5-trien-5-yl] -1-propanone; 4-fluoro-11-azatricyclo [7.3.1.02,7] trideca-2 (7), 3,5-triene-5-carbonitrile; 4-fluoro-11-azatricyclo [7.3.1.02,7] trideca-2 (7), 3,5-trien-4-carbonitrile; 6-methyl-7-thia-5,14-diaza tetracyclo [10.3.1.02,10.04'8] hexadeca-2 (10), 3,5,8-tetraene; 6-methyl-5,7,14-triazethacryclo [10.3.1.02'10.04'8] hexadeca-2 (10), 3,5,8-tetraene; 6,7-dimethyl-5,7,14-triazatetracyclo [10.3.1.02'10.04'8] hexadeca-2 (10), 3,5,8-tetraene; 5,7,14-triazatetracyclo [10.3.1.02'10.04'8] hexadeca-2 (10), 3,5,8-tetraene; 5,6-domethyl-5,7,14-triazatetracyclo [10.3.1.02'10.04'8] hexadeca-2 (10), 3,6,8-tetraene; 5-methyl-5,7,14-triazatetracyclo [10.3.1.02 10.04'8] hexadeca-2 (10), 3,6,8-tetraene; 6- (trifluoromethyl) -7-tia-5,14-diazatetracyclo [10.3.1.02,10.04'8] hexadeca-2 (10), 3,5,8-tetraene; 5,8,15-triazatetracyclo [11.3.1.02'11.04,9] heptadeca-2 (11), 3,5,7,9-pentaeno; 7-methyl-5,8,15-triazatetracyclo [11.3.1.02,11.0, 9] heptadeca-2 (11), 3,5,7,9-pantane; 6-methyl-5,8,15-triazatetracyclo [11.3.1.02'11.0 '9] heptadeca-2 (11), 3,5,7,9-pantane; 6,7-dimethyl-5,8,15-triazatetracyclo [11.3.1.02'11.04'9] heptadeca-2 (11), 3,5,7,9-pantane; 7-oxa-5,14-diazatetracyclo [10.3.1.02'10.04'8] hexadeca-2 (10), 3,5,8-tetraene; 6-methyl-7-oxa-5,14-diazatetracyclo [10.3.1.02-10.0 '8] hexadeca-2 (10), 3,5,8-tetraene; 5-methyl-7-oxa-6,14-diazatetracyclo [10.3.1.02'10.04,8] hexadeca-2 (10), 3,5,8-tetraene; 6-methyl-5-oxa-7,14-diazatetracyclo [10.3.1.02'10.0 '8] hexadeca-2 (10), 3,6,8-tetraene; 7-methyl-5-oxa-6,14-diazatetracyclo [10.3.1.02'10.04 8] hexadeca-2 (10), 3,6,8-tetraene; 4,5-difluoro-11-azatricyclo [7.3.1.02'7] trideca-2 (7), 3,5-triene; 4-chloro-5-fluoro-11-azatricyclo [7.3.1.02'7] tr-deca-2 (7), 3,5-triene; 5-chloro-4-fluoro-11-azatricyclo [7.3.1.02'7] trideca-2 (7), 3! 5-triene; 4- (1-ethynyl) -5-fluoro-11-azatricyclo [7.3.1.02'7] trideca-2 (7), 3,5-triene; 5- (1-ethynyl) -4-fluoro-11-azatricyclo [7.3.1.02'7] tr-deca-2 (7), 3,5-triene; 5,6-difluoro-11-azatricyclo [7.3.1.02,7] trideca-2,4,6-triene; 6-trifluoromethyl-11-aza-tricyclo [7.3.1.02,7] trideca-2,4,6-triene; 6-methoxyl-11-aza-tricyclo [7.3.1.02'7] tr-deca-2 (7), 3,5-trine; 11-aza-tricyclo [7.3.1.02'7] trideca- 2 (7), 3,5-trien-6-ol; 6-fluoro-11-aza-tricyclo [7.3.1.02'7] trideca-2 (7), 3,5-triene; 11-aza-tricyclo [7.3.1.02'7] trideca-2 (7), 3,5-trien-5-ol; 4-nitro-11-aza-tricyclo [7.3.1.02'7] trideca-2 (7), 3,5-triene; 5-nitro-11-aza-tricyclo [7.3.1.02'7] trideca-2 (7), 3,5-triene; 5-fluoro-11-aza-tricyclo [7.3.1.02'7] trideca-2 (7), 3,5-triene; 6-hydroxy-methoxy-11-azatricyclo [7.3.1.02,7] trideca-2 (7), 3I5-trine; and its pharmaceutically acceptable salts and optical isomers.
4. The pharmaceutical composition according to claim 3 wherein said partial nicotine receptor 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 [1,2-a] [1,5] diazocin-8-one; 9-iodo-1, 2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazocin-8-one; 9-cyano-1, 2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazocin-8-one; 9-carbomethoxy-1, 2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazocin-8-one; 9-carboxyaldehyde-1, 2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazocin-8-one; 9- (2,6-difluorophenyl) -1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] d-azocin-8-one; 9-phenyl-1, 2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazocin-8-one; 9- (2-fluorophenyl) -1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazocin-8-one; 6-methyl-5-thia-5-dioxa-6,13-diazatetracyclo [9.3.1.02,804'8] pentadeca-2 (10), 3,8-triene; 4-fluoro-10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene; 4-trifluoromethyl-10-aza-tricyclo [6.3.1.02'7] dodeca-2 (7), 3,5-triene; 4-nitro-10-aza-tricyclo [6.3.1.02,7] dodeca-2 (7), 3,5-trine; 6-methyl-5,7,13-triazatetracyclo [9.3.1.02,10.04'8] pentadeca-2 (10), 3,5,8-tretraene; 6,7-dimethyl-5,8,14-triazatetracyclo [10.3.1.02'10.04'8] hexadeca-2 (11), 3,5,7,9-pentaeno; 5,8,14-triazatetracyclo [10.3.1.02'11.04,9] hexadeca-2 (11), 3,5,7,9-pentaeno; 5-oxa-7,12-diazatetracyclo [9.3.1.02,10.04'8] pentadeca-2 (10), 3,6,8-tetraene; 6-methyl-5-oxa-7,13-diazatetracyclo [9.3.1.02'10.04'8] pentadeca-2 (10), 3,6,8-tetraene; 10-azatricyclo [6.3.1.02] dodeca-2 (7), 3,5-trien-4-yl cyanide; 1- (10-azatricyclo [6.3.1.02,7] dodeca-2 (7), 3,5-trin-4-yl) -1-ethanone; 11-azatricyclo [7.3.1.02,7] trideca-2 (7)! 3,5-triene-5-carbonitrile; 1- [11-azatricyclo [7.3.1.02,7] trideca-2 (7), 3,5-trien-5-yl] -1-ethanone; 1- [11-azatricyclo [7.3.1.02,7] trideca-2 (7), 3, 5-trien-5-yl] -1-propanone; 4-fluoro-11-azatricyclo [7.3.1.02'7] trideca-2 (7), 3,5-triene-5-carbonitrile; 5-fluoro-11-azatricyclo [7.3.1.02'7] trideca-2 (7), 3,5-triene-4-carbonitrile; 6-methyl-7-thia-5,14-diazatetracyclo [10.3.1.02'10.04'8] hexadeca-2 (10), 3,5,8-tretraene; 6-methyl-5,7,14-triazatetracyclo [10.3.1.02'10.0 8] hexadeca-2 (10), 3,5,8-tretraene; 6,7-dimethyl-5,7,14-triazatetracyclo [10.3.1.02'10.0 '8] hexadeca-2 (10), 3,5,8-tretraene; 6-methyl-7-oxa-5,14-diazatetracyclo [10.3.1.02'10.04'8] hexadeca-2 (10), 3,5,8-tretraene; 6-methyl-5-oxa-7,14-diazatetracyclo [10.3.1.02'10.04'8] hexadeca-2 (10), 3,6,8-tretraene; 5,6-difluoro-11-aza-tricyclo [7.3.1.02,7] trideca-2,4,6-triene; 6-trifluoromethyl-11-aza-tricyclo [7.3.1.02'7] trideca-2,4,6-triene; 6-methoxy-11-aza-tricyclo [7.3.1.02'7] trideca-2,4,6-triene; 6-fluoro-11-aza-tricyclo [7.3.1.02,7] trideca-2 (7), 3,5-triene; 11-aza-tricyclo [7.3.1.02'7] trideca-2 (7), 3,5-trien-5-ol, and their pharmaceutically acceptable salts and their optical isomers.
5. A method for treating obesity, or promoting or facilitating weight loss in a mammal, which comprises administering said mammal; a.- a partial agonist of the nicotine receptor or one of its pharmaceutically acceptable salts, and b.- an anti-obesity agent or promoter or facilitator of weight loss, or a pharmaceutically acceptable salt thereof, in which the active ingredients ( a) and (b) are administered in amounts that make the combination of the two active agents effective in the treatment of obesity, or to promote or facilitate weight loss.
6. The method of claim 5, wherein the anti-obesity agent or weight loss facilitator is selected from Xenical ™ (orlistat) and Meridia ™ (sibutramine) and their pharmaceutically active salts.
7. The method according to claim 5, wherein the partial nicotine 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 [1,2-a] [1,5] diazocin-8-one; 9-iodo-1, 2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazocin-8-one; 9-cyano-1, 2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazocin-8-one; 9-ethynyl-1, 2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazocin-8-one; 9- (2-propenyl) -1, 2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazocin-8-one; 9- (2-propyl) -1, 2,3,4, 5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazocin-8-one; 9-carbomethoxy-1, 2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazocin-8-one; 9-carboxyaldehyde-1, 2,3,4, 5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazocin-8-one; 9- (2,6-difluorophenyl) -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- (2-fluorophenyl) -1,2,3,4,5,6-hexahydro-1,5-methano-pyridium [1, 2a] [1,5] diazocin-8-one; 9- (4-fluorophenyl) -1,2,3,4,5,6-hexahydro-1,5-methano-pyridium [1, 2a] [1,5] diazocin-8-one; 9- (3-fluorophenyl) -1,2,3,4,5,6-hexahydro-1,5-methano-pyridium [1, 2a] [1,5] diazocin-8-one; 9- (3,5-difluorophenyl) -1,2,3,4,5,6-hexahydro-1,5-methane-pyridyl [1, 2a] [1,5] diazocin-8-one; 9- (2,4-difluorophenyl) -1,2,3,4,5,6-hexahydro-1,5-methano-pyridium [1, 2a] [1,5] diazocin-8-one; 9- (2,5-difluorophenyl) -1,2,3,4,5,6-hexahydro-1,5-methane-pyridyl [1, 2a] [1,5] diazocin-8-one; 6-methyl-5-oxo-6,13-diazatetracyclo [9.3.1.02'10.048] pentadeca-2 (10), 3,8-triene; 5-oxo-6,13-diazatetracyclo [9.3.1.02 l0.0 -8] pentadeca-2 (10), 3,8-triene; 6-oxo-5,6,13-triazatetracyclo [9.3.1.02 10,048] pentadeca-2 (10), 3,8-triene; 4,5-difluoro-10-aza-tricyclo [6.3.1.02 7] dodeca-2 (7), 3,5-triene; 5-fluoro-10-aza-tricyclo [6.3.1.027] dodeca-2 (7), 3,5-triene-4-carbonitrile; 4-ethynyl-5-fluoro-10-aza-tricyclo [6.3.1.02 7] dodeca-2 (7), 3,5-triene; 5-ethynyl-10-aza-tricyclo [6.3.1.027] dodeca-2 (7), 3,5-triene-4-carbonitrile; 6-methyl-5-thia-5-dioxa-6,13-diazatetracyclo [9.3.1.02 10.04 8] pentadeca-2 (10), 3,8-triene; 10-aza-tricyclo [6.3.1.02 7] dodeca-2 (7), 3,5-triene; 4-fluoro-IO-aza-tricyclo [6.3.1.02-7] dodeca-2 (7), 3,5-triene; 4-methyl-10-aza-tricyclo [6.3.1.02 7] dodeca-2 (7), 3,5-triene; 4-trifluoromethyl-10-aza-tricyclo [6.3.1.02 7] dodeca-2 (7), 3,5-triene; 4-nitro-10-azatricyclo [6.3.1.O2 7] dodeca-2 (7), 3,5-triene; 7-methyl-5,7,13-triazatetracyclo [9.3.1.02 10,048] pentadeca-2 (10), 3,5,8-tetraene; 6-methyl-5,7,13-triazatetracyclo [9.3.1.02 10.04-8] pentadeca-2 (10), 3! 5,8-tetraene; 6,7-dimethyl-5,7,13-triazatetracyclo [9.3.1.02-10.04-8] pentadeca-2 (10), 3,5,8-tetraene; 6-methyl-7-phenyl-5,7,13-triazatetracyclo [9.3.1.02-10.04-8] pentadeca-2 (10), 3,5,8-tetraene; 6,7-dimethyl-5,8,14-triazatetracyclo [10.3.1.02 11,049] hexadeca-2 (11), 3,5,7,9-pentaeno; 5,8, 14-triazatetracyclo [10.3.1.02 11,049] hexadeca-2 (11), 3,5,7,9-pentaeno; 14-methyl-5,8,14-triazatetracyclo [10.3.1.02-11.049] hexadeca- 2 (11), 3,5,7,9-pentaeno; 5-oxa-7,13-diazatetracyclo [9.3.1.02-10.048] pentadeca-2 (10), 3,6,8-tetraene; 6-methyl-5-oxa-7,13-diazatetracyclo [9.3.1.02 10.04-8] pentadeca-2 (10), 3,6,8-tetraene; 4-chloro-10-azatricyclo [6.3.1.02 7] dodeca-2 (7), 3,5-triene; 10-azatricyclo [6.3.1.027] dodeca-2 (7), 3,5-trien-4-yl cyanide; 1- (10-azatricyclo [6.3.1.02-7] dodeca-2 (7), 3,5-trien-4-yl) -1-ethanone; 10-azatricyclo [6.3.1.02-7] dodeca-2 (7), 3,5-trien-4-ol; 7-methyl-5-oxa-6,13-diazatetracyclo [9.3.1.02-10.04-8] pentadeca-2,4 (8), 6,9-tetraene; 4,5-dichloro-10-azatricyclo [6.3.1.02J] dodeca-2 (7), 3,5-triene; 11-azatricyclo [7.3.1.027] trdeca-2 (7), 3,5-triene-5-carbonitrile; 1- [11-azatricyclo [7.3.1.02 7] trideca-2 (7), 3,5-trien-5-yl] -1-ethanone; 1- [11-azatricyclo [7.3.1.02 7] trideca-2 (7), 3,5-trien-5-yl] -1-propanone; 4-fluoro-11-azatricyclo [7.3.1.02 7] trideca-2 (7), 3,5-triene-5-carbonitrile; 5-fluoro-11-azatricyclo [7.3.1.02 7] trideca-2 (7), 3,5-triene-4-carbonitrile; 6-methyl-7-thia-5,14-diazatetracyclo [10.3.1.02 10,048] hexadeca-2 (10), 3,5,8-tetraene; 6-methyl-5,7,14-triazatetracyclo [10.3.1.02 10,048] hexadeca-2 (10), 3,5,8-tetraene; 6,7-dimethyl-5,7,14-triazatetracyclo [10.3.1.02 10.04-8] hexadeca-2 (10), 3,5,8-tetraene; 5,7,14-triazatetracyclo [10.3.1.02 10,048] hexadeca-2 (10), 3,5,8-tetraene; 5,6-dimethyl-5,7,14-triazatetracyclo [10.3.1.02 10.04-8] hexadeca-2- (10), 3,6,8-tetraene; 5-methyl-5,7,14-triazatetracyclo [10.3.1.02 10.04-8] hexadeca-2 (10), 3,6,8-tetrane; 6- (trifluoromethyl) -7-thia-5,14-diazatetracyclo [10.3.1.02 10.04 8] hexadeca-2 (10), 3,5,8-tetraene; 5,8, 15-triazatetracyclo [11.3.1.02-11.049] heptadeca-2 (11), 3,5,7,9-pentaeno; 7-methyl-5,8,15-triazatetracyclo [11.3.1.02 11,049] heptadeca- 2 (11), 3,5,7,9-pentaene; 6-methyl-5,8,15-triazatetraciclop i .S.I.O ^^. O ^ Jheptadeca ^ íHÍ.S.SJ.T-pentano; 6,7-dimethyl-5,8,15-triazatetracyclo [11.3.1.02 11.04-9] heptadeca-2 (11), 3,5,7,9-pentaene; 7-oxa-5,14-diazatetracyclo [10.3.1.02 'l0.04-8] hexadeca-2 (10), 3,5,8-tetraene; 6-methyl-7-oxa-5,14-diazatetracyclo [10.3.1.02-10.04-8] hexadeca-2 (10), 3,5,8-tetraene; 5-methyl-7-oxa-6,14-diazatetracyclo [10.3.1.02 l0.04 8] hexadeca-2 (10), 3,5,8-tetraene; 6-methyl-5-oxa-7,14-diazatetracyclo [10.3.1.02 10,048] hexadeca-2 (10), 3,6,8-tetraene; 7-methyl-5-oxa-6,14-diazatetracyclo [10.3.1.02-10.04-8] hexadeca-2 (10), 3,6,8-tetraene; 4,5-difluoro-11-azatricyclo [7.3.1.02'7] trideca-2 (7), 3,5-triene; 4-chloro-5-fluoro-11-azatricyclo [7.3.1.02-7] trideca-2 (7), 3,5-triene; 5-chloro-4-fluoro-11-azatricyclo [7.3.1.02 7] trideca-2 (7), 3,5-triene; 4- (1-ethynyl) -5-fluoro-11-azatricyclo [7.3.1.02 7] trideca-2 (7), 3,5-triene; 5- (1 -eti n i I) -4-f I u o ro- 11 -zatri cycle [7.3.1.02 7] trideca-2 (7), 3,5-triene; 5,6-D-fluoro-11-aza-tricyclo [7.3.1- »27 '?] Trideca-2,4,6-triene; 6-trifluoromethyl-11-aza-tricyclo [7.3.1.02 7] trideca-2,4,6-triene; 6-methoxy-11-aza-tricyclo [7.3.1.02J] trideca-2 (7), 3,5-triene; 11-aza-tricyclo [7.3.1.02J] trideca-2 (7), 3,5-trien-6-ol; 6-fluoro-11-aza-tricyclo [7.3.1.02 7] trideca-2 (7)! 3,5-triene; 11-aza-tricyclo [7.3.1.02 7] trideca-2 (7), 3,5-trien-5-ol; 4-nitro-11-aza-tricyclo [7.3.1.02 7] trideca-2- (7), 3,5-triene; 5-nitro-11-aza-tricyclo [7.3.1.02 7] trideca-2 (7), 3,5-triene; 5-fluoro-11-aza-tricyclo [7.3.1.02 7] trideca-2 (7), 3,5-triene; 6-hydroxy-5-methoxy-11-aza-tricyclo [7.3.1.02 7] trideca-2 (7), 3,5-triene and one of its pharmaceutically acceptable salts and one of its optical isomers.
8. The method according to claim 7, wherein the partial nicotine 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, 2a] [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 [1,2-a] [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-pyrid [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-d-oxa-6,13-d-azatetracyclo [9.3.1.02-10.04 8] pentadeca-2 (10), 3,8-triene; 4-fluoro-10-aza-trichloride [6.3.1.027] dodeca-2 (7), 3,5-triene, 4-trifluoromethyl-10-aza-tricyclo [6.3.1.02-7] dodeca-2 (7), 3,5-triene; 4-nitro-10-azatricyclo [6.3.1.02 7] dodeca-2 (7), 3,5-triene; 6-methyl-5,7,13-triazatetracyclo [9.3.1.02 10,048] pentadeca-2 (10), 3,5,8-tetraene; 6,7-dimethyl-5,8,14-triazatetracyclo [10.3.1.02 11,049] hexadeca-2 (11), 3,5,7,9-pentaene; 5,8,14-triazatetracyclo [10.3.1.02 11.0 -9] hexadeca-2 (11), 3,5,7,9-pentaeno; 5-oxa-7,13-diazatetraciclo [9.3.1.02 10.04 8] pentadeca-2 (10), 3I6,8-tetraene; 6-methyl-5-oxa-7,13-diazatetracyclo [9.3.1.02 10,048] pentadeca-2 (10), 3,6,8-tetraene; 10-azatricyclo [6.3.1.02-7] dodeca-2 (7), 3,5-trien-4-yl cyanide; 1- (10-azatricyclo [6.3.1.02 7] dodeca-2 (7), 3,5-trien-4-yl) -1-ethanone; 11-azatricyclo [7.3.1.02J] trideca-2 (7), 315-triene-5-carbonitrile; 1- [11-azatricyclo [7.3.1.02 7] trideca-2 (7), 3,5-trien-5-yl] -1-ethanone; 1- [11-azatricyclo [7.3.1.02-7] trideca-2 (7), 3,5-trien-5-yl] -1-propanone; 4-fluoro-11-azatricyclo [7.3.1.02-7] trideca-2 (7), 3) 5-triene-5-carbonitrile; 5-fluoro-11-azatricyclo [7.3.1.02'7] trideca-2 (7), 3,5-triene-4-carbonitrile; 6-methyl-7-thia-5,14-diazatetracyclo [10.3.1.02 10.04 8] hexadeca-2 (10), 3,5,8-tetraene; 6-methy-5,7,14-triazatetracyclo [10.3.1.02 10,048] hexadeca-2 (10), 3,5,8-tetraene; 6,7-dimethyl-5,7,14-triazatetracyclo [90.3.1.02 10,048] hexadeca-2 (10), 3,5,8-tetraene; 6-methyl-7-oxa-5,14-diazatetracyclo [10.3.1.02 0.04-8] hexadeca-2 (10), 3,5,8-tetraene; 6- methyl-5-oxa-7,14-diazatetracyclo [10.3.1.02 10,048] hexadeca-2 (10), 3,6,8-tetraene; 5,6-difluoro-11-aza-tricyclo [7.3.1.02 7] trideca-2,4,6-triene; 6-trifluoromethyl-11-aza-tricyclo [7.3.1.O2 7] trideca-2,4,6-triene; 6-methoxy-11-aza-tricyclo [7.3.1.02 7] trideca-2 (7), 3,5-triene; 6-fluoro-11-aza-tricyclo [7.3.1.02 7] trideca-2 (7), 3,5-triene; 11 -aza-tricyclo [7.3.1.02 7] trideca- 2 (7), 3,5-trien-5-ol; and its pharmaceutically acceptable salts and optical isomers.
9. The method according to claim 5, wherein the partial nicotine receptor 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 states in which obesity predominates or a state of overweight, including diabetes mellitus type 2, hypertension, dyslipidemia and increased mortality in a mammal, the method comprising: (a) a partial agonist of the recipient of nicotine 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 make the composition effective to treat disorder or condition.
11. A method for treating a disorder or condition selected from the groups of disorders and states in which obesity predominates or a state of overweight in a mammal, including diabetes mellitus type 2, hypertension, dyslipidemia and increasing mortality, the method comprising administering to said mammal: (a) a partial agonist of the nicotine receptor or a pharmaceutically acceptable salt thereof; (b) an anti-obesity agent or a weight loss facilitator, or a pharmaceutically acceptable salt thereof; wherein the active agents "a" and "b" above are present in amounts which make the composition effective to treat disorder or condition.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60/208,856 | 2000-06-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA01005550A true MXPA01005550A (en) | 2002-06-05 |
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