WO2007079317A2 - Utilisation d’hypno-sedatifs pour traiter l’obesite ou maintenir la perte de poids - Google Patents

Utilisation d’hypno-sedatifs pour traiter l’obesite ou maintenir la perte de poids Download PDF

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Publication number
WO2007079317A2
WO2007079317A2 PCT/US2006/061679 US2006061679W WO2007079317A2 WO 2007079317 A2 WO2007079317 A2 WO 2007079317A2 US 2006061679 W US2006061679 W US 2006061679W WO 2007079317 A2 WO2007079317 A2 WO 2007079317A2
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sedative hypnotic
receptor
obesity
compound
phenyl
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PCT/US2006/061679
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English (en)
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WO2007079317A3 (fr
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Phillip B. Chappell
David C. Gruben
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Neurocrine Biosciences, Inc.
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Publication of WO2007079317A2 publication Critical patent/WO2007079317A2/fr
Publication of WO2007079317A3 publication Critical patent/WO2007079317A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents

Definitions

  • the present invention relates to a method and combination therapies for treating obesity or a related eating disorder by administering a GABA-A receptor-active compound, such as a sedative hypnotic, alone or in combination with another sedative hypnotic or an anti-obesity agent.
  • a GABA-A receptor-active compound such as a sedative hypnotic, alone or in combination with another sedative hypnotic or an anti-obesity agent.
  • this invention relates to a method for treating obesity or a related eating disorder by administering indiplon.
  • Obesity is a major public health concern because of its increasing prevalence and associated health risks.
  • the increase in obesity is of concern because of the excessive health risks associated with obesity, including coronary heart disease, stroke, hypertension, type 2 diabetes mellitus, dyslipidemia, sleep apnea, osteoarthritis, gall bladder disease, depression, and certain forms of cancer (e.g., endometrial, breast, prostate, and colon).
  • the negative health consequences of obesity make it the second leading cause of preventable death in the United States and impart a significant economic and psychosocial effect on society. See, McGinnis M, Foege WH., "Actual Causes of Death in the United States," JAMA, 270, 2207-12 (1993).
  • Obesity is now recognized as a chronic disease that requires treatment to reduce its associated health risks.
  • weight loss is an important treatment outcome
  • one of the main goals of obesity management is to improve cardiovascular and metabolic values to reduce obesity-related morbidity and mortality. It has been shown that a 5-10% loss of body weight can substantially improve metabolic values, such as blood glucose, blood pressure, and lipid concentrations. Hence, it is believed that a 5- 10% intentional reduction in body weight may reduce morbidity and mortality.
  • the present invention provides a method for treating obesity or a related eating disorder, which includes reducing food consumption, promoting weight loss, preventing or inhibiting weight gain, maintaining weight loss, or inducing weight loss in an overweight patient, comprising administering a therapeutically effective amount of a sedative hypnotic compound to a patient in need of such treatment.
  • Another aspect of the present invention provides a method for treating obesity or a related eating disorder comprising administering a therapeutically effective amount of a combination of a) indiplon and another sedative hypnotic; b) a sedative hypnotic and an anti-obesity agent; or c) a sedative hypnotic and a weight reduction program or weight-loss related intervention, to a patient in need of such treatment.
  • the present invention provides a method for treating obesity or a related eating disorder, which includes reducing food consumption, promoting weight loss, preventing or inhibiting weight gain, maintaining weight loss, or inducing weight loss in an overweight patient, comprising administering a therapeutically effective amount of a sedative hypnotic compound to a patient in need of such treatment.
  • the sedative hypnotic compound used in the present inventions is a GABA-A receptor-active compound.
  • GABA-A receptor-active compounds that may be used in the present invention include benzodiazepine sedative hypnotic compounds and nonbenzodiazepine sedative hypnotic compounds.
  • the GABA receptor-active compound used in the present invention is indiplon.
  • treating embrace both preventative, i.e., prophylactic, and palliative treatment.
  • patient refers to humans (male or female, adults, adolescents and/or children), companion animals (e.g., dogs, cats and horses), food-source animals, zoo animals, marine animals, birds and other similar animal species.
  • companion animals e.g., dogs, cats and horses
  • food-source animals e.g., zoo animals, marine animals, birds and other similar animal species.
  • Preferred patients include humans, companion animals, and food- source animals, and more preferably, humans.
  • the term "food” refers to food or drink for consumption by the patient.
  • a "disease, condition or disorder” subject to treatment by the present invention includes obesity or a related eating disorder, reducing food consumption, promoting weight loss, preventing or inhibiting weight gain, maintaining weight loss, or inducing weight loss in an overweight patient.
  • BMI body mass index
  • eating disorders refers to illnesses in which the patient suffers disturbances in their eating behaviors and related thoughts and emotions.
  • Representative examples of obesity-related eating disorders include overeating, bulimia, binge-eating disorder, nocturnal sleep-related eating disorder, and night-eating syndrome.
  • Bulimia also referred to as Bulimia Nervosa
  • Bulimia Nervosa is characterized by self-perpetuating and self- defeating cycles of binge-eating and purging. A person binges by rapidly consuming a large amount of food (or what s/he perceives to be a large amount) in a discrete period of time and in an automatic and helpless manner.
  • BED binge eating disorder
  • Symptoms of night-eating syndrome include: little or no appetite for breakfast; eating more food after dinner than during the meal; eating more than half of daily food intake after the dinner hour; the pattern persists for at least two months; feeling tense, anxious, upset, or guilty while eating; difficulty falling asleep or staying asleep; unlike bingeing (which is done in relatively short episodes), continual eating throughout evening hours; and eating produces guilt and shame, not enjoyment .
  • a person suffering from nocturnal sleep-related eating disorder eats during periods in which they appear to be asleep.
  • NS-RED nocturnal sleep-related eating disorder
  • the person may appear to be sleep-walking and, in essence, sleep-eating.
  • Food consumed during episodes of NS- RED episodes typically is high-fat, high sugar food.
  • awake the person may have little or no memory of the NS-RED episodes.
  • a "GABA-A receptor-active compound” is a compound, such as a sedative hypnotic, which induces sleep by acting at various moieties of the gamma-aminobutyric acid A [GABA A ]-benzodiazepine receptor complex.
  • the receptor complex is part of a group of ligand-gated ion channel complexes comprised of several glycoprotein subunits, each of which appears in multiple isoforms.
  • GABA-A receptor-active compounds include compounds which are direct agonists, partial agonists, or allosteric modulators of the [GABA A ]-benzodiazepine receptor complex.
  • GABA-A receptor- active compounds also include compounds which increase brain GABA activity or affect activity at the GABA-A receptor through extra-synaptic mechanisms of action, such as gaboxadol.
  • the pharmacologic effects of the GABA-A receptor-active compounds result from their saturable, stereospecific binding to a specific recognition site.
  • sedative hypnotic compound includes benzodiazepine sedative hypnotic compounds and nonbenzodiazepine sedative hypnotic compounds.
  • Benzodiazepine sedative hypnotic compounds include, but are not limited to, quazepam (Doral ® ), flurazepam (Dalmane ® ), triazolam (Halcion ® ), estazolam (ProSom ® ), temazepam (Restoril ® ), loprazolam (Dormonoct ® ), flunitrazepam (Rohypnol ® ), lormetazepam (Loramet ® ), nitrazepam (Alodorm ® ).
  • Quazepam can be prepared as described in U.S. Pat. No. 3,845,039; flurazepam can be prepared as described in U.S. Pat. No. 3,299,053; triazolam and estazolam can be prepared as described in U.S. Pat. No. 3,701 ,782; temazepam can be prepared as described in U.S. Pat. Nos. 3,197,467, 3,340,253, and 3,374,225; loprazolam can be prepared as described in U.S. Pat. No. 4,044,142; flunitrazepam can be prepared as described in U.S. Pat. No. 4,044,142; lormetazepam can be prepared as described in Belgian Pat No. 621 ,819; and nitrazepam can be prepared as described in U.S. Pat. Nos. 3,109,843, 3,1 16,203 and 3,123,529.
  • Nonbenzodiazepine sedative hypnotic compounds include, but are not limited to, Zolpidem tartrate (Ambien ® ), zaleplon (Sonata ® ), zopliclone (Imovane ® ), eszopliclone (Lunesta ® ) and indiplon.
  • Zolpidem tartrate is based on the imidazopyridine backbone (see U.S. Patent Nos. 4,382,938 and 4,460,592).
  • Zaleplon is a pyrazolopyrimidine-based compound (see U.S. Patent No. 4,626,538).
  • Other nonbenzodiazepine, sedative hypnotics include zopliclone and eszopliclone which are based on the cyclopyrrolone backbone (see, e.g., 6,319,926, 6,444,673, and 6,854,257).
  • Indiplon N-methyl-N-(3- ⁇ 3-[2-thienylcarbonyl]-pyrazol-[1 ,5- ⁇ ]- pyrimidin-7-yl ⁇ phenyl)acetamide
  • IR Immediate Release
  • MR Modified Release
  • U.S. Patent Nos. 6,472,528 and 6,485,746 are directed to the synthesis of indiplon and to a controlled release pharmaceutical composition containing indiplon, respectively.
  • U.S. Patent Nos. 6,384,221 and 6,544,999 are directed to certain polymorphic forms of indiplon (i.e., Forms I and II), while U.S. Patent No. 6,903,106 is directed to an additional polymorphic form (i.e., Form MI) Of indiplon.
  • melatonin is a hormone endogenously produced in the pineal gland, retina, and intestinal tract.
  • melatonin-1 melatonin-1
  • MT2 melatonin-2
  • MT3 melatonin-3
  • Melatonin receptor agonists of the present invention include selective agonists for the melatonin-1 receptor, such as, but not limited to TAK-375 (ramelteon), agomelatine, BMS-214778 and LY-156735.
  • TAK-375 ramelteon
  • agomelatine BMS-214778
  • LY-156735 a selective melatonin agonist with an estimated 15-fold greater affinity for mt1 receptors than melatonin itself.
  • Agomelatine is a serotonergic/melatonergic antidepressant.
  • Ramelteon can be prepared as described in U.S. Pat. No. 6,034,239, EP Pat No. 0 885 210 B1 and PCT Publication No. WO/ 97/32871 ; agomelatine can be prepared as described in EP447285 and US Pat Nos. 5,194,614 and 5,225,442; BMS-214778 can be prepared as described in PCT Publication No. WO1998025606; LY-156735 can be prepared as described in U.S. Pat. No. 4,997,845 and EP Pat Nos. 0 656 209 B1 and 0 281 242 B1.
  • nonhypnotics includes compounds which are sometimes used to aid sleep, such as clonazepam (Klonopin ® ), diazepam (Valium ® ), and chlordiazepoxide (Librium ® ).
  • Suitable anti-obesity agents include, but are not limited to cannabinoid-1 (CB-1 ) antagonists (such as rimonabant), 1 1 ⁇ -hydroxy steroid dehydrogenase-1 (1 1 ⁇ -HSD type 1 ) inhibitors, MCR-4 agonists, cholecystokinin-A (CCK-A) agonists, monoamine reuptake inhibitors (such as sibutramine), sympathomimetic agents, ⁇ 3 adrenergic receptor agonists, dopamine receptor agonists (such as bromocriptine), melanocyte-stimulating hormone receptor analogs, 5HT2c receptor agonists, melanin concentrating hormone antagonists, leptin (the OB protein), leptin analogs, leptin receptor agonists, galanin antagonists, lipase inhibitors (such as tetrahydrolipstatin, i.e.
  • CBD-1 cannabinoid-1
  • anorectic agents such as a bombesin agonist
  • neuropeptide-Y receptor antagonists e.g., NPY Y5 receptor antagonists
  • thyromimetic agents dehydroepiandrosterone or an analog thereof
  • glucocorticoid receptor agonists or antagonists orexin receptor antagonists
  • glucagon-like peptide-1 receptor agonists ciliary neurotrophic factors (such as AxokineTM available from Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Procter & Gamble Company, Cincinnati, OH)
  • human agouti-related protein (AGRP) inhibitors ghrelin receptor antagonists, histamine 3 receptor antagonists or inverse agonists
  • neuromedin U receptor agonists e.g., MTP/ApoB inhibitors (e.g., gut-selective MTP inhibitors, such as dirlotapide) and the like.
  • MTP/ApoB inhibitors e.g.
  • Anti-obesity agents for use in the combination aspects of the present invention include CB-1 receptor antagonists, gut-selective MTP inhibitors, CCKa agonists, 5HT2c receptor agonists, PYY 3 . 36 and analogs thereof (e.g., peglated PYY 3 . 36 ), NPY Y5 receptor antagonists, bromocriptine, orlistat, and sibutramine.
  • Compounds of the present invention and combination therapies may be administered in conjunction with exercise and a sensible diet.
  • Sibutramine can be prepared as described in U.S. Pat. No. 4,929,629; bromocriptine can be prepared as described in U.S. Pat. Nos.
  • 3,752,814 and 3,752,888; orlistat can be prepared as described in U.S. Pat. Nos. 5,274,143; 5,420,305; 5,540,917; and 5,643,874; and PYY 3 . 36 (including analogs) can be prepared as described in US Publication No. 2002/0141985 and WO 03/027637; and 5HT2c receptor agonists can be prepared as described in US Patent No. 6,825,198.
  • CB-1 receptor antagonists include: rimonabant (SR141716A also known under the tradename AcompliaTM) is available from Sanofi-Synthelabo or can be prepared as described in U.S. Patent No. 5,624,941 ; ⁇ / ⁇ piperidin-i-yO-i ⁇ -dichlorophenyO-S ⁇ -iodophenylH-methyl-I H-pyrazole-S- carboxamide (AM251 ) is available from TocrisTM, Ellisville, MO; [5-(4-bromophenyl)-1-(2,4-dichloro- phenyl)-4-ethyl- ⁇ /-(1-piperidinyl)-1/-/-pyrazole-3-carboxamide] (SR147778) which can be prepared as described in U.S.
  • rimonabant SR141716A also known under the tradename AcompliaTM
  • AcompliaTM is available from Sanofi-Sy
  • WO 03/075660 the hydrochloride, mesylate and besylate salt of 1-[9-(4-chloro-phenyl)-8-(2-chloro- phenyl)-9H-purin-6-yl]-4-ethylamino-piperidine-4-carboxylic acid amide which can be prepared as described in U.S. Publication No.
  • Intestinal-acting MTP inhibitors include dirlotapide ((S)- ⁇ /- ⁇ 2-[benzyl(methyl)amino]-2-oxo-1- phenylethyl ⁇ -1-methyl-5-[4'-(trifluoromethyl)[1 ,1'-biphenyl]-2-carboxamido]-1/-/-indole-2-carboxamide) and i-methyl-S- ⁇ '-trifluoromethyl-biphenyl ⁇ -carbony ⁇ -aminol-I H-indole ⁇ -carboxylic acid (carbamoyl- phenyl-methyl)-amide which can both be prepared using methods described in U.S. Patent No.
  • the anti-obesity agent used in combination with a sedative hypnotic compound according to the present invention is selected from the group of dirlotapide, mitratapide, (S)-2- [(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-6-carboxylic acid (pentylcarbamoyl-phenyl- methyl)-amide, (S ⁇ - ⁇ '-tert-butyl-biphenyl ⁇ -carbony ⁇ -aminol-quinoline- ⁇ -carboxylic acid ⁇ [(4-fluoro- benzyl)-methyl-carbamoyl]-phenyl-methyl ⁇ -amide, or (S)-2-[(4'-tert-butyl-biphenyl-2-carbonyl)-amino]- quinoline-6-carboxylic acid [(4-fluoro-benzylcarbamoyl)-phenyl-methyl]
  • a particular CCKa agonist that may be used in the present invention is N-benzyl-2-[4-(1 H-indol-3- ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-acetamide which can be prepared as described in US Patent Application Serial No. 1 1/134790.
  • NPY Y5 receptor antagonists that may be used in the present invention include: 2-oxo-N-(5- phenylpyrazinyl)-spiro[isobenzofuran-1(3H),4'-piperidine]-1'-carboxamide which can be prepared as described in U.S. Publication No.
  • terapéuticaally effective amount is an amount of a compound or compounds used in the methods or combinations of the present invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
  • phrases "pharmaceutically acceptable” indicates that the substance or composition is compatible chemically and/or toxicologically, with the other ingredients comprising a formulation and/or the patient being treated.
  • the compounds utilized in the combinations of the present invention may be administered separately or together. If administered separately, the compounds may be administered simultaneously or sequentially and in any order. Typically, the combination therapy is administered in conjunction with exercise and a sensible diet.
  • the combination therapies may be administered as (a) a single pharmaceutical composition comprising two compounds to be utilized in a combination of the present invention and a pharmaceutically acceptable excipient, diluent or carrier; or (b) two separate pharmaceutical compositions comprising (i) a first composition comprising a compound to be utilized in a combination of the present invention and a pharmaceutically acceptable excipient, diluent or carrier; and (ii) a second composition comprising a compound to be utilized in a combination of the present invention and a pharmaceutically acceptable excipient, diluent or carrier.
  • the pharmaceutical compositions may be administered simultaneously or sequentially and in any order.
  • the compounds of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the routes previously indicated, and such administration may be carried out in single or multiple doses.
  • the therapeutic agents of this invention can be administered in a wide variety of different dosage forms, Le., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, suppositories, jellies, gels, pastes, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like.
  • Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc.
  • oral pharmaceutical compositions can be suitably sweetened and/or flavored.
  • tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes.
  • compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
  • solutions of a compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed.
  • the aqueous solutions should be suitably buffered (preferably pH greater than 8) if necessary and the liquid diluent first rendered isotonic.
  • These aqueous solutions are suitable for intravenous injection purposes.
  • the oily solutions are suitable for intraarticular, intra-muscular and subcutaneous injection purposes.
  • the preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
  • the compounds to be utilized in the methods or combinations of the present invention can be administered to a patient by any method which delivers the compounds preferentially to the desired tissue (e.g., brain, renal, or intestinal tissues).
  • these methods include oral (solid or liquid form), parenteral (such as subcutaneous, intravenous, intramuscular, and infusion techniques), rectal, transdermal, buccal or intranasal routes using means well-known to those of skill in the art.
  • these compounds are most desirably administered in doses ranging from about 0.1 mg to about 600 mg per day, in single or multiple doses (Le 1 , from 1 to 4 doses per day).
  • the amount and timing of the compounds administered will, of course, be dependent on the subject being treated, the weight and physical condition of the patient being treated and the patient's individual response to the medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out.
  • the physician must balance a variety of factors such as age of the patient, presence of preexisting disease, lifestyle, as well as the presence of other diseases (e.g., cardiovascular disease).
  • a daily dosage level that is in the range of about 1 mg to about 100 mg per day is most commonly employed.
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effects.
  • Studies IR 103 and MR 204 were originally designed to be six-month studies, but were amended to be three months in duration. A number of patients had gone past three months at the time of the amendments; therefore, data past three months were available on a limited number of patients from these studies. Analyses of the data from studies IR 103 and MR 204 were conducted initially on all patients enrolled into the studies regardless of their duration of treatment (constituting the "3-6 Months" group).
  • days of study termination were calculated relative to the start of study medication and divided into ranges that reflected the chronological offset from Day 1 (for example, Month 6 was defined as more than 165 days from Day 1 ).
  • a complete list is provided in Table 2 below.
  • BMI Body Mass Index
  • the weight loss data was analyzed descriptively by determining the mean change from baseline in body weight (kg) and the count or frequency of the number of patients who achieved at least a 5% decrease in body weight. Both endpoints were calculated by treatment duration (2 weeks, 4 weeks, 3-6 months), dose, and baseline obesity status.
  • “Week 2” includes some patients who withdrew before Week 2 or whose weight was measured closer to 3 weeks rather than 2.
  • Week 4" also includes patients whose weight value was measured closer to 5 weeks from baseline.

Abstract

L’invention concerne un procédé et des thérapies associées pour traiter l’obésité ou un trouble de l’alimentation associé en administrant un composé actif du récepteur GABA-A, tel qu’un hypno-sédatif, seul ou en combinaison avec un autre hypno-sédatif ou un agent anti-obésité. Spécifiquement, l’invention concerne un procédé pour traité l’obésité ou un trouble de l’alimentation associé en administrant de l’indiplon.
PCT/US2006/061679 2005-12-06 2006-12-06 Utilisation d’hypno-sedatifs pour traiter l’obesite ou maintenir la perte de poids WO2007079317A2 (fr)

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