WO2001026641A2

WO2001026641A2 - Morpholinol derivatives for the treatment of obesity

Info

Publication number: WO2001026641A2
Application number: PCT/US2000/027252
Authority: WO
Inventors: Jessica E. Matthews; David Lee Musso
Original assignee: Glaxo Group Limited
Priority date: 1999-10-13
Filing date: 2000-10-03
Publication date: 2001-04-19
Also published as: PE20010744A1; JP2003511410A; AU7750100A; EP1220673A2; WO2001026641A3; AR026022A1

Abstract

A method is disclosed for the treatment of obesity comprising administering to an animal in need thereof, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. Methods for the suppression of appetite, causing weight loss, preventing weight gain, preferentially affecting body fat composition, inhibiting food craving and maintaining weight loss are also disclosed.

Description

METHOD FOR THE TREATMENT OF OBESITY

FIELD OF THE INVENTION

The present invention relates generally to therapies for the treatment of obesity, and in particular to a compound for use in methods of treating obesity.

The prevalence of obesity in the United States has increased substantially during the past decade. One of three adults in the United States is now considered overweight. Nearly 20% of Western Europeans also suffer from this condition. Obesity contributes to many adverse health outcomes, including non-insulin-dependent diabetes meliitus and vascular diseases, as well as to an increase in both cardiovascular and all-cause mortality. Obesity- related conditions are estimated to contribute to 300,000 deaths yearly in the United States.

PRIOR ART BACKGROUND

The long-term outcome of non-surgical obesity treatment is frequently unsatisfactory. In spite of recent advances in the understanding of molecular mechanisms underlying obesity, the long-term reduction of body weight is largely ineffective, and 90 to 95 percent of persons who lose weight subsequently regain it. Serotonergic agents such as fenfluramine and dexfenfluramine (REDUX®) have shown efficacy in obesity, but have recently been withdrawn from the market as a result of the perception that serotonergic agents in general pose a risk to valvular function in humans. In addition, serotonergic agents typically present undesirable sexual dysfunction side effects.

Bupropion, a non-serotonergic agent, has been found to attenuate weight gain in smokers attempting to quit and to result in weight loss in patients treated for depression. K. Gadde, et al., Bupropion SR® in Obesity: A Randomized Double-Blind Placebo-Controlled Study, poster presentation at the American Psychiatric Association Meeting in Washington, D.C., 15-20 May 1999, reported that bupropion significantly increased weight loss in a group of obese patients maintained on a 1600 calorie diet after treatment with bupropion SR®400 mg.

Recently approved obesity drugs include orlistat (XENICAL®), a lipase inhibitor, and sibutramine (MERIDIA®) a Schedule IV, serotonin/noradrenaline reuptake inhibitor. In addition, a number of CNS stimulants including phentermine (Schedule IV), phendimetrazine (Schedule III), and methamphetamine (Schedule II) are marketed for obesity in the United States. However the use of these agents is for short-term (few weeks) therapy only. There remains a need for safe and effective treatments for obesity.

The compound (2S,3S,5fl)-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol and salts thereof are disclosed in U.S. Patent No. 5,104,870 to Kelley et al. The use of this compound for the treatment of depression states and other conditions, including attention deficit disorders, are also disclosed in U.S. Patent No. 5,104,870.

DISCLOSURE OF THE INVENTION

It has now been discovered that the compound (2S,3S,5R)-2-(3,5- difluorophenyl)-3,5-dimethyl-2-morpholinol and pharmaceutically acceptable salts or solvates thereof are useful for the treatment of obesity and for suppression of appetite.

It has also been discovered that the compound (2S,3S,5F?)-2-(3,5- difluorophenyl)-3,5-dimethyl-2-morpholinol and pharmaceutically acceptable salts or solvates thereof are useful for producing weight loss, preventing weight gain, maintaining weight loss, inhibiting food craving and preferentially affecting weight loss to induce loss of fat tissue or mass while preserving lean mass, bone mass and bone density. DETAILED DESCRIPTION OF THE INVENTION

According to a first aspect of the invention there is provided a method of treating obesity. More particularly, the present invention provides a method of treating obesity comprising administering to an animal in need thereof, a compound of formula (I):

that is (2S,3S,5f?)-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol, or a pharmaceutically acceptable salt or solvate thereof in an amount effective to treat obesity.

In a second aspect of the invention there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of obesity in an animal in need thereof.

In a third aspect of the invention there is provided a method for the suppression of appetite in an animal. The method comprises administering to the animal a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in an amount effective to suppress appetite.

In a fourth aspect of the invention there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the suppression of appetite in an animal.

In a fifth aspect of the invention there is provided a method for causing weight loss in an animal. The method comprises administering to the animal a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in an amount effective to cause weight loss in the animal. In a sixth aspect of the invention there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for causing weight loss in an animal.

In a seventh aspect of the invention there is provided a method for preventing weight gain in an animal. The method comprises administering to the animal a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in an amount effective to prevent weight gain in the animal.

In a eighth aspect of the invention there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for preventing weight gain in an animal.

In a ninth aspect of the invention there is provided a method for preferentially affecting body fat composition in an animal. The method comprises administering to the animal a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in an amount effective to preferentially affect body fat composition.

In a tenth aspect of the invention there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for preferentially affecting body fat composition in an animal.

In an eleventh aspect of the invention there is provided a method for inhibiting food craving in an animal. The method comprises administering to the animal a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in an amount effective to inhibit food craving. In a twelfth aspect of the invention there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for inhibiting food craving in an animal.

In a thirteenth aspect of the invention there is provided a method for maintaining weight loss in an animal. The method comprises administering to the animal a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in an amount effective to maintain weight loss.

In a fourteenth aspect of the invention there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for maintaining weight loss in an animal.

'Treatment of obesity" refers to both partial and complete alleviation of the condition. Thus, as well as alleviation of obesity, this will also include reducing the degree or severity of obesity. In some cases, the treatment of obesity may entail a weight loss of about 5 percent over a two-year treatment period.

"Suppression of appetite" refers to a decrease in the intensity and/or frequency of desire for food, or a decrease in food intake resulting from the foregoing.

"Prevent(ing) weight gain" refers to refers to both partial and complete prevention of weight gain. Thus, as well as avoiding weight gain, this will also include attenuating the amount of weight gain in an animal susceptible thereto.

"Preferentially affecting body fat composition" refers to causing weight loss attributable to a loss of fat tissue in the animal or an inhibition of an increase in fat tissue in the animal, with substantially no effect on lean mass, bone mass or bone density; in particular visceral fat mass loss is especially preferred.

"Food craving" refers to extreme desire, often for a particular type of food. "Inhibiting food craving" refers to decreasing in the intensity and/or frequency of food craving, as well as avoiding food craving.

"Maintaining weight loss" refers to preventing re-gain of weight lost as a result of treatment with the compound of formula (I) and preventing re-gain of weight lost as a result of diet or exercise in the absence of treatment with a compound of formula (I). Thus, the methods of the present invention are also useful for preventing weight re-gain in humans who have lost weight using conventional methods such as diet and/or exercise.

The methods of the present invention may be employed for suppressing appetite, inhibiting food craving, producing weight loss, maintaining weight loss, preventing weight gain, or preferentially affecting body fat composition even if the animal being treated is not obese or overweight according to clinical measures. The methods of preferentially affecting body fat composition may be employed to modify the body fat composition of healthy animal, even if weight loss or prevention of weight gain is not the primary concern. The methods of the present invention may employed pre-emptively to suppress appetite, inhibit food craving, prevent weight gain, prevent weight re-gain or prevent increases in body fat composition in those individuals at risk of the same. For example, the methods of the present invention may be useful in the treatment of individuals attempting to quit smoking, diabetics, and individuals being treated with certain drugs (including anti-diabetics and antidepressants, as well as steroids and contraceptives) which are known or suspected to promote weight gain. The methods of the present invention may also be useful in the treatment of individuals in the presence of other risk factors such as mild or controlled hypertension, type II diabetes, dyslipidemia, hypercholesteremia, impaired glucose tolerance, hyperinsulinemia, sleep apnoea, and truncal obesity. The methods of the present invention may also be useful in the treatment of obese patients with binge-eating disorder, in assisting weight loss in post-partum non-breast feeding obese women, or to control appetite in an individual following surgical obesity treatment.

The methods of the present invention may employ the compound of formula (I) in free base form, or pharmaceutically acceptable salts or solvates of the compound of formula (I). Suitable pharmaceutically acceptable salts according to the present invention will include acid addition salts prepared from the following acids: hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, salicylic, p-toluenesulfonic, tartaric, citric, methansulfonic, maleic, formic, malonic, succinic, isethionic, lactobionic, naphthalene-2-sulfonic, sulfamic, ethanesulfonic, benzenesulfonic, decanoic, saccharin, orotic, 1 - hydroxy-2-naphthoic, cholic, and pamoic. One preferred pharmaceutically acceptable salt form of the compound of formula (I) is the hydrochloride salt.

When used in medicine, the salts of a compound of formula (I) should be pharmaceutically acceptable, but pharmaceutically unacceptable salts may conveniently be used to prepare the corresponding free base or pharmaceutically acceptable salts thereof.

As used herein, the term "solvate" is a crystal form containing the compound of formula (I) or a pharmaceutically acceptable salt thereof and either a stoichiometric or a non-stoichiometric amount of a solvent. Solvents, by way of example, include water, methanol, ethanol, or acetic acid. Hereinafter, reference to a compound of formula (I) is to any physical form of that compound, unless a particular form or solvate thereof is specified.

The compound of formula (I) and pharmaceutically acceptable salts and solvates thereof, including (2S,3S,5f?)-2-(3,5-difluorophenyl)-3,5-dimethyl-2- morpholinol hydrochloride, may be prepared according to the methods described in U.S. Patent No. 5,104,870 to Kelley et al., the subject matter of which is incorporated herein by reference in its entirety. In a modified method of preparation, the starting material 3,5-difluoropropiophenone is reacted directly with bromine under conditions of controlled temperature (-35° C), the crude residual oil 2-bromo-3',5'-difluoropropiophenone is then diluted with acetonitrile, reacted with D-alaninol in situ (and without the presence of 2,6- lutidine) while maintaining a temperature of ~80°C for several hours, and then the reaction mixture is worked up by standard methods to produce the specified (2S,3S,5ft)-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol hydrobromide.

As used herein, the term "active ingredient" refers to the compound of formula (I) and pharmaceutically acceptable salts and solvates thereof, including solvates of pharmaceutically acceptable salts. In reference to amounts or weights of "active ingredient", the amount or weight is based upon the amount or weight of the compound of formula (I) in free base form, unless otherwise indicated.

According to the methods of the present invention, the active ingredient is employed in the treatment of obesity, the suppression of appetite, inhibition of food craving, weight loss, maintenance of weight loss, prevention of weight gain and preferential affect of body fat composition in a variety of animals, particularly mammals such as rats, cats, dogs, monkeys, and humans.

The methods of the present invention are particularly preferred for the treatment of obesity in humans and suppressing appetite in humans.

The methods of the present invention are also particularly preferred for inhibiting food craving in humans, causing weight loss in humans, maintaining weight loss in humans, preventing weight gain in humans, and preferentially affecting body fat composition in humans. The amount of the active ingredient required to achieve the desired therapeutic effect will, of course, depend on a number of factors, including but not limited to, the condition being treated (i.e., obesity, suppression of appetite, inhibition of food craving, weight loss, maintenance of weight loss, prevention of weight gain, and/or preferential affect on body fat composition) the route of administration and the particular recipient being treated, and will ultimately be at the discretion of the attendant physician. As will be appreciated by those skilled in the art, the precise dosage appropriate for any particular recipient will depend upon several clinical factors, including but not limited to the recipient's age and level of physical activity and the severity of the condition. Generally, the daily dose of active ingredient for the treatment of obesity, suppression of appetite, inhibition of food craving, weight loss, maintenance of weight loss, prevention of weight gain, and- preferential affect on body fat composition will be in the range of from about 2.5 to about 20 mg/day inclusive, preferably from about 5 to about 15 mg/day inclusive, and more preferably from about 10 to about 15 mg/day inclusive. In one preferred embodiment, the daily dose of active ingredient is about 10 mg/day. In one preferred embodiment, the daily dose of active ingredient is about 15 mg/day. Patients may be treated with two or more different daily doses accordingly to an optimized therapeutic regimen recommended by the supervising physician.

The methods of the present invention may be carried out using the active ingredient per se, but preferably the active ingredient is formulated with a pharmaceutically acceptable carrier in the form of a pharmaceutical formulation. The carrier must be acceptable in the sense of being compatible with the other ingredients of the pharmaceutical formulation and must not be deleterious to the recipient.

Preferably the pharmaceutical formulation is provided as a unit-dose formulation such as a tablet or a caplet, for administration to a human. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose or an appropriate fraction thereof, of the active ingredient. Each unit-dose typically contains from about 1.25 to about 10 mg of the active ingredient for administration. Multiple unit doses may be administered once daily or multiple times per day to achieve the daily dose required for the treatment of obesity or suppression of appetite in a particular recipient. A typical treatment regimen will generally involve dosing a unit dose of from about 1.25 mg to about 10.0 mg inclusive, of the active ingredient twice daily, preferably a unit dose of from about 2.5 mg to about 7.5 mg inclusive, more preferably a unit dose of from about 5.0 mg to about 7.5 mg inclusive, most preferably a unit dose of about 5.0 mg or about 7.5 mg. Where dosing can occur once-daily then these ranges and amounts would typically be doubled.

For the treatment of obesity, weight loss, maintenance of weight loss, prevention of weight gain or preferentially affecting body fat composition, such a dosing regimen would typically be continued for a period of from about 2 months up to about 10 years inclusive, preferably between about 6 months and about 10 years, and more preferably between about 5 and about 10 years. For appetite suppression, such a dosing regimen would typically be continued for a period of from about 1 month up to about 5 years inclusive, preferably between about 6 months and about 5 years, and more preferably about 2 years. The aforementioned treatment regimens essentially represent typical treatment. However, for some patients a more chronic treatment regimen may be appropriate in which the dosing regimen indicated above is typically continued for from about 10 up to about 20 years, or even for the lifetime of the patient.

According to a further aspect of the present invention, in the methods described above for treatment of obesity, suppression of appetite, inhibition of food craving, causing weight loss, maintaining weight loss, preventing weight gain, and preferentially affecting body fat composition, the compound of formula (I) or pharmaceutically acceptable salts and solvates thereof may also be administered in combination with other therapeutic agents used to treat obesity, for example the conventional agents referred to above, and/or in combination with a low calorie diet or other weight management programmes.

Pharmaceutical formulations containing the active ingredient, include those suitable for oral, rectal, topical, buccal (e.g., sub-lingual) and parenteral (e.g., subcutaneous, intramuscular, intradermal or intravenous) administration. Oral administration is currently the preferred route.

Pharmaceutical formulations containing the active ingredient also include those suitable for nasal administration or administration by inhalation.

Suitable pharmaceutical formulations for use in the methods of the present invention may conveniently be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

Formulations of the present invention suitable for oral administration may be presented as discrete dosage units such as capsules or tablets (including swallowable, dispersible and chewable tablets) each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. A tablet may be made by compression or moulding optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.

In one preferred embodiment of the present invention, the active ingredient is provided in a unit dose, pharmaceutical formulation suitable for oral administration, which contains the active ingredient together with an effective stabilizing amount of alginic acid as described in co-pending PCT Patent Application No. PCT/EP99/07117, filed 24 September 1999 in the name of Glaxo Group Limited, and published on 6 April 2000 under number WO00/18406, the subject matter of which is incorporated herein by reference in its entirety.

Formulations suitable for buccal (sublingual) administration include lozenges comprising the active ingredient in a flavoured base, usually sucrose and accacia or tragacanth, and pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia.

Formulations suitable for parenteral administration conveniently comprise sterile aqueous preparations of the active ingredient, preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although administration may also be effected by means of subcutaneous, intramuscular, or intradermal injection. ^' Such preparations may conveniently be prepared by admixing the active ingredient with water and rendering the resulting solution sterile and isotonic with the blood.

Formulations adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.

Formulations adapted for administration by inhalation include fine particle dusts or mists which may be generated by means of various types of metered dose pressurised aerosols, nebulizers or insufflators. Spray compositions may, for example, be formulated as aerosols delivered from pressurised packs, such as a metered dose inhaler, with the use of a suitable liquified propellant. Capsules and cartridges for use in an inhaler or insufflator, of for example gelatine, may be formulated containing a powder mix for inhalation of a compound of the invention and a suitable powder base such as lactose or starch. Each capsule or cartridge may generally contain between 1 μg- 10mg of the compound of formula (I) or a solvate thereof. Aerosol formulations are preferably arranged so that each metered dose or "puff" of aerosol contains 1μg-2000μg, preferably about 1 μg-500μg of a compound of formula (I) or a solvate thereof. Administration may be once daily or several times daily, for example 2, 3, 4 or 8 times, giving for example 1 , 2 or 3 doses each time. The overall daily dose with an aerosol will generally be within the range 10μg-10mg, preferably 100μg-2000μg. The overall daily dose and the metered dose delivered by capsules and cartridges in an inhaler or insufflator will generally be double those with aerosol formulations.

Formulations suitable for rectal administration are preferably presented as unit dose suppositories. These may be prepared by admixing the active ingredient with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.

Formulations suitable for topical application of the skin preferably take the form of an ointment, cream, lotion, past, gel, spray, transdermal patch, aerosol, or oil. Carriers which may be used include vaseline, lanolin, polyethylene glycols, alcohols, and combinations of two or more thereof. Further details regarding formulations of the compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof can be found in U.S. Patent No. 5,104,870 to Kelley et al., already incorporated by reference herein above.

It should be understood that in addition to the ingredients particularly mentioned above for the preparation of pharmaceutical formulations of the compounds of formula (I) and its pharmaceutically acceptable salts and solvates may include^' other agents conventional in the art of pharmacy, with regard to the particular type of formulation being prepared. For example, formulations suitable for oral administration may include flavoring agents or taste masking agents.

The compound of formula (I) and the pharmaceutically acceptable salts and solvates thereof possess a number of advantages over conventional therapeutic agents for the treatment of obesity and suppression of appetite.

The compound of formula (I) and pharmaceutically acceptable salts and solvates thereof are believed to possess superior efficacy as a result of their dual mode of action. It is currently believed that the compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof are inhibitors of the neuronal reuptake of dopamine (DA) and noradrenaline (NA), as shown by the experiment reported in Example 1. The use of a compound of formula

(I) or pharmaceutically acceptable salts or solvates thereof for the treatment of obesity or suppression of appetite is thought to be related to this neurotransmitter uptake inhibition profile.

In addition, the compound of formula (I) and its pharmaceutically acceptable salts and solvates, at the dosages contemplated by the instant invention, have no measurable effect on serotonin reuptake, therefore suggesting that the compound does not contribute to the perceived valvular risk and sexual dysfunction side effects associated with conventional serotonergic agents. The occurrence of dysphoria in patients treated with the compound of formula (I) and its pharmaceutically acceptable salts and solvates is also less prevalent than in patients treated with sibutramine. This is also believed to be as a result of the fact that the compound of formula (I) and its pharmaceutically acceptable salts and solvates have no measurable effect on serotonin reuptake. The compound of formula (I) and its pharmaceutically acceptable salts and solvates are also believed to possess a lower risk of seizure than bupropion.

In addition, it is believed that the compound of formula (I) and its pharmaceutically acceptable salts and solvates have a more predictable pharmacokinetic profile than conventional therapeutic agents for the treatment of obesity and suppression of appetite.

The following examples are provided for illustration only and are not intended to limit the scope of the invention in any way, the present invention being defined by the claims.

Example 1 : Evaluation of Noradrenaline, Dopamine, and Serotonin Uptake Inhibition Biogenic amine reuptake inhibition was studied using cell lines (pocine kidney NN12 cells) that were stably transfected with clones encoding the human cell- surface transporters for noradrenaline (NA), dopamine (DA) or serotonin (5HT) (obtained from Dr. Gary Rudnick, Yale University). Uptake was studied under initial velocity conditions (5-10 minutes) with either 3H- methylphenylpyridinium (for NA and DA transport) or 3H-serotonin at concentrations of -1 % of their Km values. Blank values were obtained by incubating the cells with 10 μM concentrations of either desmethylimipramine (for NA) mazindol (for DA) or fluoxetine (for serotonin). The uptake was terminated by diluting the medium with cold phosphate buffered saline and washing the cells. Radioactivity retained in the cell pellets was measured by liquid scintillation spectrometry. The results are reported in the following table: Table 1

Neuronal Reuptake

Compound DA NA 5HT

Formula (I) 60 90 >10,000

The foregoing results demonstrate that the compound of formula (I) is an inhibitor of neuronal reuptake of DA and NA, but not serotonin. The compound of formula (I) is believed to possess increased efficacy in the treatment of obesity and efficacy in the suppression of appetite at least in part because it is a potent and selective inhibitor of NA and DA.

Example 2: In vivo Studies in Rodents A. Effects in the AKR/J Mouse Diet-Induced Model of Obesity

AKR/J male mice (susceptible to obesity when fed a diet high in fat content) were housed 5 per plastic cage on Alpha-Dri bedding and maintained at 22 ± 2°C with a fixed 12 hour light - dark cycle (0.600-18.00). Animals were 4 weeks old when placed on a high fat (58 kcal%) diet. Food and tap water were available ad libitum. Dosing of compounds started when the animals were 9 weeks old (5 weeks on the high fat diet) and mice remained on the high fat diet throughout the duration of the study. The compound of formula (I) was dosed at 1 , 3, and 10 mg/kg (po). Sibutramine (3mg/kg, po) and vehicle controls were tested in parallel.

Each treatment group included 10-15 mice. Compounds were dissolved in vehicle and were dosed by oral gavage twice daily for 14 days. Body weights were measured daily. Food intake was not measured in this study due to the physical form of the food, which made it impossible to accurately measure. Male AKR mice became obese after being placed on a high fat diet for 5 weeks (diet induced obesity). The compound of formula (I) (10 mg/kg) and sibutramine (3 mg/kg) significantly reduced body weight in DIO-AKR mice relative to the vehicle treated mice. Results are expressed as the % change from the vehicle control animals at the end of the study and are reported in Table 2.

Table 2

GW320659A Dose Dependently Inhibits Body Weight Gain in Diet-Induced Obese AKR/J Mice

These results indicate that the compound of formula (I) dose dependently inhibited body weight gain in diet induced obese AKR/J mice. Analysis of percent change in blood chemistry parameters compared to vehicle treated mice showed that the compound of formula (I) at 3 and 10mg/kg, and Sibutramine (3 mg/kg) significantly lowered cholesterol, HDL-C, triglyceride, NEFA, and glycerol serum values relative to the vehicle treated mice while the compound of formula (I) (10 mg/kg) did not have a significant effect on serum glucose levels.

B. Effects in the OB/OB Mouse Model of Obesity

Experiments were performed on ob/ob mice (which produce a truncated, inactive leptin protein, a phenotype characterized by profound early-onset obesity, hyperphagia, extreme insulin resistance and mild to moderate hyperglycemia, which typically does not progress to frank diabetes), housed 3 per plastic cage on Alpha-Dri bedding and maintained at 22 ± 2°C with a fixed 12 hour light - dark cycle (0.600-18.00). Food and tap water were available ad libitum. Mice were 8-9 weeks old at the start of dosing and weighed at least 40 grams. The compound of formula (I) was dosed at 1 , 5, 10, and/or 25 mg/kg (po). Sibutramine (10mg/kg, po) was tested in parallel in most experiments. Bupropion (150 mg/kg, po) was tested in parallel in two experiments. Each experiment included a vehicle (water) treated group. Each treatment group included 9-12 mice (3-4 cages). Compounds were dissolved in vehicle and dosed by oral gavage twice daily for 14 days. Food intake and body weights were measured daily. The results are expressed as the % change from the vehicle control animals at the end of the study and are reported in Table 3:

Table 3

The Compound of Formula (I) Dose Dependently Inhibits Body Weight Gain and Reduces Cumulative Food Intake in ob/ob Mice

The results obtained demonstrate that the compound of formula (I) (5, 10, and 25 mg/kg) and Sibutramine (10 mg/kg) inhibited weight gain while Bupropion (150 mg/kg) had no effect on weight gain. These results indicate that the compound of formula (I) dose dependently inhibited body weight gain in ob/ob mice.

Percent reduction in food intake also demonstrated that the compound of formula (I) (5, 10, and 25 mg/kg), Sibutramine (10 mg/kg) and Bupropion (150 mg/kg) reduced cumulative food intake in ob/ob mice. These results demonstrate that the compound of formula (I) dose dependently reduced suppressed appetite in ob/ob mice relative to vehicle treated mice.

Analysis of percent change in blood chemistry parameters compared to vehicle treated mice showed that the compound of formula (I) lowered glucose, cholesterol, HDL-C, and triglcyeride levels relative to the vehicle treated mice, but had no effect on NEFA and glycerol levels. HDL-C, triglyceride, NEFA, and glycerol serum values were also slightly lowered by bupropion.

C. Effects in the Zucker (FA/FA) Rat Model of Obesity Zucker C&.ZUC rats (possessing a splice variant in the leptin receptor, which phenotype is characterized by profound early-onset obesity, hyperphagia, and extreme insulin resistance) were housed individually in stainless steel cages and maintained at 22 ± 2°C with a fixed 12 hour light - dark cycle (0.600- 18.00). Food and tap water were available ad libitum. Zuckers were 10 weeks old at the start of dosing and weighed 375 - 530 grams. Six rats per group were dosed with the compound of formula (I) at 1 , 3, and 10 mg/kg (po). A vehicle control (water) group (6 rats) was tested in parallel. Compounds were dissolved in vehicle and dosed twice daily for 28 days. Rats were pre-bled (tail vein under isoflurane anesthesia) and grouped according to their triglyceride levels. Rats were bled on days 14 and 28 of dosing. Whole body bone mineral and body composition measurements (DEXA scans) were made using the Hologic QDR-2000, before dosing (days -2 and -1 ) and on dosing days 23 and 24. Body weights were measured daily and food intake was measured Monday - Friday. The results are reported in Table 4:

Table 4

The Compound of Formula (I) Dose Dependently Inhibits Body Weight Gain and Reduces Cumulative Food Intake in Zucker Cr.ZUC Rats

The results obtained demonstrated that the compound of formula (I) (3 and 10 mg/kg) dose dependently inhibited weight gain relative to the vehicle treated Zucker Cr ZUC rats. The compound of formula (I) was also shown to reduce cumulative food intake in Zucker CrhZUC rats relative to the vehicle treated rats, thereby demonstrating that the compound of formula (I) suppressed appetite in Zucker CrhZUC rats relative to the vehicle treated rats.

The change in weight of Zucker (fa/fa) rats receiving either placebo or the compound of formula I (10 mg/kg bid) for 2 weeks and the proportion of weight gain as fat, lean and bone mass were also measured. The data are reported in Table 5:

Table 5 The Compound of Formula (I) Preferentially Inhibits Weight Gain in Fat with Substantially No Effect on Bone Mass and Density in Zucker Crl:ZUC Rats

The results obtained demonstrated that the compound of formula (I) preferentially inhibited weight gain attributable to an increase in fat. These results indicate that the compound of formula I produces metabolic effects which cause the preferential inhibition of fat while producing substantially no effect on lean mass, bone mass or bone density. Analysis of percent change in blood chemistry parameters compared to vehicle treated mice showed that triglyceride levels remained at the pre-dose level in the rats treated with the 10 mg/kg dose of the compound of formula (I), while triglyceride levels increased in the vehicle treated group and in the groups treated with 1 and 3 mg/kg of the compound of formula (I). No effect was noted on glucose, cholesterol, HDL-C, or NEFA levels. Comparison of the pre-dose to the end of study DEXA scans, showed that the compound of formula (I) decreased the amount of fat and lean grams gained during the 28 day dosing period.

Example 3: Observed Mean Effects on Weight in Humans One study was conducted using human ADHD patients aged 18-65. The population included 94 patients with a body mass index (BMI) >28 kg/m². Study participants were divided into five (5) groups, each group receiving placebo (0 mg of the compound of formula (I)), or 2.5, 5, 10, or 15 mg/day of the compound of formula (I). Study participants were not attempting to lose weight and were not requested to lose weight or attempt to lose weight. Study participants were not prescribed any modified diet and were not encouraged to increase or continue exercise routines during the study. Mean changes in weight from baseline were analyzed at week 6 and the results are reported in Table 6.

Table 6

The Compound of Formula (I) Dose Dependently Inhibits Body Weight Gain in Humans (Kg)

For participants having a BMI >28, mean weight loss was observed in participants receiving 10 or 15 mg of the compound of formula (I). The results from the study indicated a dose-dependent trend in weight loss after six weeks of treatment at doses of 0, 2.5, 5, 10 and 15 mg/day.

A second study was conducted using human chronic cigarette smokers averaging >15 cigarettes/day and having a body mass index (BMI) ≥28 kg/m². Study participants were divided into six (6) groups, each group receiving placebo (0 mg of the compound of formula (I)), or 2.5, 5, 10, or 15 mg/day of the compound of formula (I) or ZYBAN®. Typically, individuals gain weight when they stop smoking or decrease the daily number of cigarettes smoked. Study participants were not attempting to lose weight and were not requested to lose weight or attempt to lose weight. Study participants were not prescribed any modified diet and were not encouraged to increase or continue exercise routines during the study. The results are reported in Table 7.

Also in this study, 143 adult smokers were administered placebo, 142 received 1.25mg bid of the compound of formula (I), 142 received 2.5mg bid of the compound of formula (I), 143 received 5mg bid of the compound of formula (I), and 143 received 7.5mg bid of the compound of formula (I) for up to seven weeks. Adverse events coded as "feeding problems" were reported by 6 subjects (4%) in the placebo group, compared to 10 (7%), 15 (11%), 12 (8%), 20 (14%) in the 1.25, 2.5, 5, and 7.5 mg bid groups, respectively.

Investigator's verbatim text for the above adverse events was primarily

"anorexia" or "decreased appetite". Events of "decreased craving for chocolate", "decreased desire for coffee", "decreased craving for sweets" were also included in the "feeding problems" group, and were reported among only the treatment groups receiving the compound of formula (I). Table 7

The Compound of Formula (I) Dose Dependently Attenuates Weight Gain (Kg) in Smokers

^*Numbers are statistically significant compared to placebo.

For participants having a BMI >28, attenuation of mean^' weight gain was observed in participants receiving 2.5 or 10 mg/day of the compound of formula (I) and a mean weight loss was observed in participants receiving 15 mg/day of the compound of formula (I).

Example 4: Formulations

The following formulations were prepared using standard techniques:

A. Oral Tablet Formulations 1-4 Tablets (75 mg) were made containing 4 different amounts of the compound of formula (I) as the hydrochloride salt (active ingredient). The active ingredient was weighted so as to deliver 0.25 mg, 0.5 mg, 1.25 mg and 5 mg of the compound of formula (I) per tablet, respectively, based on conversion from the salt form to the base. Each tablet contains 5% by weight of alginic acid. The active ingredient is first sieved through a U.S. Standard 30 mesh hand screen to remove any large lumps. The sieved active ingredient is then milled with a centrifugal mill fitted with a 0.5 mm screen. The desired amount of milled active ingredient is then sieved with a vibratory screener fitted with a U.S. Standard 14-mesh stainless steel screen and then charged into a V- Blender.

The desired amounts of lactose monohydrate, modified spray dried, alginic acid and sodium starch glycolate, low pH are also sieved with the vibratory screener and added to the blender. The V-blender is then rotated for 20 minutes. The proper amount of glyceryl behenate is screened with the vibratory screener and added to the blender. The V-blender is rotated for an additional 5 minutes. The tablets are compressed on a rotary tablet press using conventional techniques. Oral tablets of each of the following formulations were obtained.

Table 8

B. Oral Tablet Formulations 5-8

Tablets (135 mg) are made containing 4 different amounts of the compound of formula (I) as the hydrochloride salt (active ingredient). The active ingredient is weighted so as to deliver 0.25 mg, 0.5 mg, 1.25 mg and 5 mg of compound of formula (I) per tablet, respectively, based on conversion from the salt form to the base. Each tablet contains 5% by weight of alginic acid. Procedures analogous to those described herein above can be employed to produce oral tablets of the following formulations:

Table 9

Claims

1. A method for treating obesity comprising administering to an animal in need thereof, a compound of formula (I):

or a pharmaceutically acceptable salt or solvate thereof in an amount effective to treat obesity.

2. A method for suppressing appetite in an animal, said method comprising administering to said animal, a compound of formula (I):

or a pharmaceutically acceptable salt or solvate thereof in an amount effective to suppress appetite.

3. A method for causing weight loss in an animal, said method comprising administering to said animal, a compound of formula (I):

or a pharmaceutically acceptable salt or solvate thereof in an amount effective to cause weight loss.

4. A method for preventing weight gain in an animal, said method comprising administering to said animal, a compound of formula (I):

or a pharmaceutically acceptable salt or solvate thereof in an amount effective to prevent weight gain.

5. A method for preferentially affecting body fat composition in an animal, said method comprising administering to said animal, a compound of formula

(I):

or a pharmaceutically acceptable salt or solvate thereof in an amount effective to preferentially affect body fat composition.

6. A method for inhibiting food craving in an animal, said method comprising administering to said animal, a compound of formula (I):

or a pharmaceutically acceptable salt or solvate thereof in an amount effective to inhibit food craving.

7. A method for maintaining weight loss in an animal, said method comprising administering to said animal, a compound of formula (I):

8. The use of a compound of formula (I):

or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of obesity in an animal.

9. The use of a compound of formula (I):

or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the suppression of appetite in an animal.

10. The use of a compound of formula (I):

or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for causing weight loss in an animal.

11. The use of a compound of formula (I):

or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for preventing weight gain in an animal.

12. The use of a compound of formula (I):

or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for preferentially affecting body fat composition in an animal.

13. The use of a compound of formula (I):

or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for inhibiting food craving in an animal.

14. The use of a compound of formula (I):

or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for maintaining weight loss in an animal.

15. A method as claimed in any one of claims 1 to 7, or the use as claimed in any one of claims 8 to 14, wherein the animal is a human.

16. The use of a compound of formula (I):

or a pharmaceutically acceptable salt or solvate thereof, in the treatment of obesity, for the suppression of appetite, to cause weight loss, to prevent weight gain, to preferentially affect body fat composition, to inhibit food craving, or to maintain weight loss.

17. A compound of formula (I)-

or a pharmaceutically acceptable salt or solvate thereof, intended for use in the treatment of obesity, for the suppression of appetite, to cause weight loss, to prevent weight gain, to preferentially affect body fat composition, to inhibit food craving, or to maintain weight loss.