EP0858340A1 - Traitement combine du diabete et de l'obesite - Google Patents

Traitement combine du diabete et de l'obesite

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Publication number
EP0858340A1
EP0858340A1 EP96937097A EP96937097A EP0858340A1 EP 0858340 A1 EP0858340 A1 EP 0858340A1 EP 96937097 A EP96937097 A EP 96937097A EP 96937097 A EP96937097 A EP 96937097A EP 0858340 A1 EP0858340 A1 EP 0858340A1
Authority
EP
European Patent Office
Prior art keywords
compound
protein
agonist
pharmaceutically acceptable
selective
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP96937097A
Other languages
German (de)
English (en)
Other versions
EP0858340A4 (fr
Inventor
Roy G. Smith
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9603724.7A external-priority patent/GB9603724D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP0858340A1 publication Critical patent/EP0858340A1/fr
Publication of EP0858340A4 publication Critical patent/EP0858340A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/5759—Products of obesity genes, e.g. leptin, obese (OB), tub, fat
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/2264—Obesity-gene products, e.g. leptin
    • 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
    • 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
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention provides a combination useful in the treatment of obesity and diabetes, either as compounds, pharmaceutically acceptable salts or pharmaceutical composition ingredients. Methods of treating obesity and diabetes are also disclosed. More particularly, the combination of the present invention comprises a ⁇ 3 agonist and a compound which modifies feeding behavior (e.g., Ob protein, also known as leptin).
  • a ⁇ 3 agonist e.g., a compound which modifies feeding behavior (e.g., Ob protein, also known as leptin).
  • ⁇ -Adrenoceptors have been subclassif ⁇ ed as ⁇ i and ⁇ 2 since 1967. Increased heart rate is the primary consequence of ⁇ l -receptor stimulation, while bronchodilation and smooth muscle relaxation typically result from ⁇ 2 stimulation.
  • Adipocyte lipolysis was initially thought to be solely a ⁇ l -mediated process. However, more recent results indicate that the receptor-mediating lipolysis is atypical in nature. These atypical receptors, later called ⁇ 3-adrenoceptors, are found on the cell surface of both white and brown adipocytes where their stimulation promotes both lipolysis (breakdown of fat) and energy expenditure.
  • a major drawback in treatment of chronic diseases with ⁇ 3 agonists is the potential for stimulation of other ⁇ -receptors and subsequent side effects.
  • the most likely of these include muscle tremor ( ⁇ 2) and increased heart rate ( ⁇ l).
  • ⁇ 2 muscle tremor
  • ⁇ l increased heart rate
  • these phenylethanolamine derivatives do possess some ⁇ 3 selectivity, side effects of this type have been observed in human volunteers. It is reasonable to expect that these side effects resulted from partial ⁇ l and/or ⁇ 2 agonism. More recent developments in this area are disclosed in
  • Compound A [2-[[2-Hydroxy-2-(pyridin-3-yl)emyl]amino]ethyl]-phenyl]-4-[4-(3- cyclopentylpropyl)-5-tetrazolon-l -yl]benzenesulfonamide, hereinafter referred to as Compound A, has been identified.
  • OB gene product i.e., the OB protein (also known as leptin), a 167 amino acid polypeptide
  • IP intraperitoneal
  • the present invention provides a composition comprising a selective ⁇ 3 agonist and a compound which modifies feeding behavior (e.g., reduces food intake); and the pharmaceutically acceptable salts and esters thereof.
  • composition comprising a selective ⁇ 3 agonist and Ob protein or a derivative of the Ob protein; and the pharmaceutically acceptable salts and esters thereof.
  • the human Ob protein, or a derivative thereof is used in combination with a selective ⁇ 3 agonist.
  • the composition wherein the selective ⁇ 3 agonist is Compound A, i.e., (£0-N_-[4-[2-[[2-hydroxy-2- (pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[4-(3-cyclopentylpropyl)-5- tetrazolon-l-yl]benzenesulfonamide; and the pharmaceutically acceptable salts and esters thereof.
  • the selective ⁇ 3 agonist is the dihydrochloride salt of Compound A, i.e., (R N-[4-[2-[[2- hydroxy-2-(pyridin-3-yl)ethyl]amino]-ethyl]phenyl]-4-[4-(3- cyclopentylpropyl)-5-tetrazolon- 1 -yl]benzenesulfonamide dihydrochloride.
  • Illustrative of the invention is a method of treating obesity in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of any of the compositions described above.
  • Exemplifying the invention is a method of treating diabetes in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of any of the compositions described above.
  • An illustration of the invention is a pharmaceutical composition comprising a therapeutically effective amount of any of the compositions described above and a pharmaceutically acceptable carrier. Further illustrating the invention is the pharmaceutical composition made by combining a selective ⁇ 3 agonist, a compound which modifies feeding behavior and a pharmaceutically acceptable canier. Further exemplifying the invention is a process for making a pharmaceutical composition which comprises combining a selective ⁇ 3 agonist, a compound which modifies feeding behavior and a pharmaceutically acceptable carrier.
  • An example of the invention is the use of a selective ⁇ 3 agonist and Ob protein, or a derivative thereof, in the preparation of a medicament for the treatment of obesity.
  • Another example of the invention is the use of a selective ⁇ 3 agonist and Ob protein, or a derivative of the Ob protein, in the preparation of a medicament for the treatment of diabetes.
  • the effective ingredients of the said drug being a selective ⁇ 3 agonist and Ob protein, or a derivative of the Ob protein.
  • This invention is concerned with the combination of certain compounds, or pharmaceutically acceptable salts thereof, for the treatment of obesity and diabetes.
  • Obesity and diabetes mellitus are often treated by encouraging patients to lose weight by reducing their food intake and by increasing their metabolic rate.
  • the ob protein reduces food intake.
  • a ⁇ 3 selective agonist is targeted to fat and causes increases in metabolic rate.
  • combination treatment with Ob protein, or a compound that causes increased expression of ob protein, with a ⁇ 3 selective agonist is advantageous over treatment with either a ⁇ 3 selective agonist or Ob protein alone in the treatment of obesity and diabetes.
  • the ob protein has broad affects.
  • ob protein increases metabolic rate by unknown pathways and lowers glucose and insulin in diabetic mice.
  • ⁇ 3 selective agonists also increase metabolic rate by specifically targeting fat cells.
  • additional beneficial affects on metabolism occur in very obese people.
  • selective ⁇ 3 agonist and " ⁇ 3 selective agonists” are synonymous and refer to agonists which are selective for the ⁇ 3 adrenergic receptor subtype over the ⁇ l and ⁇ 2 adrenergic receptor subtypes in humans.
  • Examples of selective ⁇ 3 adrenergic agonists are Compound A and the compounds described in U.S. Patent No. 5,541,677.
  • subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
  • therapeutically effective amount means that amount of active compound(s) or pharmaceutical agent(s) that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated.
  • diabetes includes both insulin-dependent diabetes mellitus (i.e., IDDM, also known as type I diabetes) and non-insulin-dependent diabetes mellitus (i.e., NTDDM, also known as Type II diabetes).
  • IDDM insulin-dependent diabetes mellitus
  • NTDDM non-insulin-dependent diabetes mellitus
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • the combination comprises Compound A and Ob protein.
  • the combination comprises Compound A and human Ob protein.
  • the ⁇ 3 agonist, Compound A is synthesized as shown in Example 1, below, and as shown in Example 70 of U.S. Patent No. 5,561,142, issued October 1 , 1996, hereby incorporated by reference.
  • Compound A is (R)-N-[4-[2-[[2-Hydroxy-2-(pyridin-3- yl)e yl]amino]ethyl]-phenyl]-4-[4-(3-cyclopentylpropyl)-5- tetrazolon-l-yl]benzenesulfonamide, or a pharmaceutically acceptable salt thereof.
  • the dihydrochloride salt of Compound A is utilized in the combination.
  • Ob protein i.e., leptin
  • OB protein OB protein
  • ob protein all refer to the same protein and are also synonymous with the protein referred to as "leptin.”
  • the combination of the present invention comprises Compound A and the Ob protein, or pharmaceutically acceptable salts thereof.
  • the Ob protein is obtained by expression of the recently discovered Ob gene. Expression of mouse Ob gene product in Drosophila Schneider 2 (S2) cells is described in Example 13, below. Based on the published sequence of the human Ob cDN A [Y. Zhang et al.. Nature 372. 425-432 (1994); R.V. Considine et al., J. Clin. Invest. 95, 2986-2988 (1995)], one of ordinary skill in the art could isolate human cDNA and obtain human Ob protein by expression of the human Ob cDNA in Drosophila S2 cells according to the protocol of Example 13. Similarly, the Ob protein may also be expressed in a bacterial expression system such as E. coli or a yeast system and purified by one of ordinary skill in the art.
  • a bacterial expression system such as E. coli or a yeast system and purified by one of ordinary skill in the art.
  • glucocorticoids see P. De Vos, J. Biol. Chem. 270(27), 15958-15961 (1995)
  • derivatives of Ob protein in which the protein is truncated to produce a small peptide and/or one or more amino acids are deleted, added, substituted or modified but which derivatives maintain the biological effect on feeding behavior and food intake.
  • leptin derivatives e.g., truncated forms of leptin
  • the pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases.
  • acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tos
  • Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D- glucamine, and salts with amino acids such as arginine, lysine, and so forth.
  • the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyi sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • Other pharmaceutically acceptable salts include the sulfate salt ethanolate and sulfate salts.
  • the pharmaceutically acceptable salts of the composition of the instant invention include the composition wherein one of the individual components of the combination is in the form of a pharmaceutically acceptable salt, or the composition wherein all of the individual components are in the form of pharmaceutically acceptable salts (wherein the salts for each of the components can be the same or different), or a pharmaceutically acceptable salt of the combined components (i.e., a salt of the composition).
  • the hydrochloride salt of the composition is utilized.
  • esters in the present invention refer to non-toxic esters, preferably the alkyl esters such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl esters, of which the methyl ester is preferred.
  • other esters such as phenyl-Ci-5 alkyl may be employed if desired.
  • Esterification of alcohols, such as Compound A of the present invention is performed by a variety of conventional procedures, including reacting the alcohol group with the appropriate anhydride, carboxylic acid or acid chloride. These reactions, as well as other methods of esterification of alcohols, are readily apparent to the skilled artisan.
  • Reaction of the alcohol with the appropriate anhydride is carried out in the presence of an acylation catalyst, such as 4-DMAP (4- dimethylaminopyridine, also known as N,N-dimethylaminopyridine), pyridine, or l,8-bis[dimethylamino]napthalene.
  • an acylation catalyst such as 4-DMAP (4- dimethylaminopyridine, also known as N,N-dimethylaminopyridine), pyridine, or l,8-bis[dimethylamino]napthalene.
  • Reaction of the alcohol with the appropriate carboxylic acid is carried out in the presence of a dehydrating agent and, optionally, an acylation catalyst.
  • the dehydrating agent which serves to drive the reaction by the removal of water is selected from dicyclohexylcarbo- diimide (DCC), l-[3-dimethylaminopropyl]-3-ethylcarbodiimide (EDC) or other water soluble dehydrating agents.
  • reaction of the alcohol with appropriate carboxylic acid can also result in esterification, if performed instead in the presence of trifluoroacetic anhydride, and, optionally, pyridine.
  • a further variant is reacting the alcohol with appropriate carboxylic acid in the presence of N ,N-carbonyldiimidazole with pyridine.
  • Reaction of the alcohol with the acid chloride is carried out with an acylation catalyst, such as 4-DMAP or pyridine.
  • an acylation catalyst such as 4-DMAP or pyridine.
  • esters it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis. John Wiley & Sons, 1991.
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • the present invention provides a combination of compounds or a pharmaceutically acceptable ester thereof: or a pharmaceutically acceptable salt thereof for use in the treatment of obesity in human or non-human animals.
  • the present invention further provides a combination of compounds, or a pharmaceutically acceptable ester thereof; or pharmaceutically acceptable salt thereof, for use in the treatment of hyperglycemia (diabetes) in human or non-human animals.
  • the disease diabetes mellitus is characterized by metabolic defects in production and utilization of glucose which result in the failure to maintain appropriate blood sugar levels. The result of these defects is elevated blood glucose or hyperglycemia.
  • Research on the treatment of diabetes has centered on attempts to normalize fasting and postprandial blood glucose levels. Treatments have included parenteral administration of exogenous insulin, oral administration of drugs and dietary therapies. Two major forms of diabetes mellitus are now recognized.
  • Type I diabetes or insulin-dependent diabetes
  • Type II diabetes or insulin-independent diabetes (i.e., non- insulin-dependent diabetes mellitus)
  • non- insulin-dependent diabetes mellitus often occurs in the face of normal, or even elevated levels of insulin and appears to be the result of the inability of tissues to respond appropriately to insulin.
  • Most of the Type ⁇ diabetics are also obese.
  • the combination of the present invention is useful for treating both Type I and Type II diabetes.
  • the combination is especially effective for treating Type II diabetes.
  • the combination of compounds of the present invention is useful in the treatment of obesity and diabetes.
  • the combinations of the present invention may be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, or rectally, in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • a method of treating and a pharmaceutical composition for treating obesity and diabetes involves administering to a patient in need of such treatment a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of each compound in the combination of the present invention.
  • compositions may be in the form of orally-administrable suspensions or tablets; nasal sprays; sterile injectable preparations, for example, as sterile injectable aqueous or oleaginous suspensions or suppositories.
  • the individual components of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms.
  • treatment with Ob protein can commence prior to, subsequent to or concurrent with commencement of treatment with Compound A.
  • administering also encompasses the use of prodrugs of the ⁇ 3 agonist and/or Ob protein which convert in vivo to a selective ⁇ 3 agonist or Ob protein or derivative thereof.
  • the instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be inte ⁇ reted accordingly.
  • compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners/flavoring agents known in the art.
  • microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners/flavoring agents known in the art.
  • immediate release tablets these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.
  • compositions When administered by nasal aerosol or inhalation, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, abso ⁇ tion promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • the compounds utilized in the combination may also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous, topical with or without occlusion, or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts.
  • the injectable solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
  • compositions When rectally administered in the form of suppositories, these compositions may be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquidify and/or dissolve in the rectal cavity to release the drug.
  • a suitable non-irritating excipient such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquidify and/or dissolve in the rectal cavity to release the drug.
  • the active ingredients of the combination e.g., Compound
  • A) of the present invention may be administered as a pharmaceutical composition, for example, with an inert diluent, or with an assimilable edible carrier, or they may be enclosed in hard or soft shell capsules, or they may be compressed into tablets, or they may be inco ⁇ orated directly with the food of the diet.
  • these active compounds may be inco ⁇ orated with excipients and used in the form of tablets, pills, capsules, ampules, sachets, elixirs, suspensions, syrups, and the like.
  • Such compositions and preparations should contain at least 0.1 percent of the active ingredients.
  • the percentage of active ingredients in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit.
  • the amount of active ingredients in such therapeutically useful compositions is such that an effective dosage will be obtained.
  • the active compounds can also be administered intranasally as, for example, liquid drops or spray.
  • the effective dosage of each of the active ingredients employed in the combination may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated.
  • the dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound thereof employed.
  • a physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
  • Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug.
  • the compounds of this invention can be administered to humans in the dosage ranges specific for each compound.
  • Compound A or a pharmaceutically acceptable salt thereof, is administered at a daily dosage of from about 0.001 milligram to about 100 milligram per kilogram of animal body weight, preferably given in a single dose or in divided doses two to six times a day, or in sustained release form.
  • the total daily dose will generally be from about 0.07 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • the Ob protein is administered at a daily dosage of from about 0.05 mg/kg to about 20 mg/kg, preferably injected in a single dose or in divided doses 2 to 3 times per day, or in sustained release form.
  • the daily dosage of Ob protein is from about 0.05 mg/kg to about 5 mg/kg. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
  • Compound A When treating obesity, in conjunction with diabetes and/or hyperglycemia, or alone, generally satisfactory results are obtained when Compound A is administered at a daily dosage of from 0.01 milligram to about 100 milligrams per kilogram of animal body weight, preferably given in a single dose or in divided doses two to six times a day, or in sustained release form. In the case of an adult human, the total daily dose will generally be from about 0.7 milligrams to about 3500 milligrams.
  • the Ob protein is administered at a daily dosage of from about 0.05 mg/kg to about 20 mg/kg, preferably given in a single dose or in divided doses 2 to 3 times per day, or as a constant infusion.
  • the daily dosage of Ob protein is from about 0.05 mg/kg to about 5 mg/kg.
  • This dosage regimen may be adjusted to provide the optimal therapeutic response. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
  • the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as com starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
  • a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
  • Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
  • active compounds may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxy- propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • the diazonium salt mixture was stirred an additional 40 min at -20°C and then added in one portion to a solution of 32 mL of glacial acetic acid containing 690 mg of copper (I) chloride saturated with sulfur dioxide at 0°C.
  • the resultant reaction mixture instantly changed in color from a dark green with nitrogen evolution to a lime green slurry as time progressed.
  • the reaction mixture was allowed to warm from 0°C to room temperature over 50 min.
  • the mixture was then poured into ice-water and extracted with ethyl acetate.
  • the combined organic extracts were washed once with cold water, dried over magnesium sulfate, filtered, and concentrated in vacuo to remove acetic acid.
  • a 3.1-g sample of Boc derivative from Step F was dissolved in 50 mL of methanol and 10 mL of concentrated hydrochloric acid. The solution was heated at 50°C for 1 h. A precipitate of the hydrochloride salt was obtained. This was cooled and basified with excess sodium bicarbonate solution and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered, and concentrated in vacuo.
  • the final 501 bp fragment was sequenced using dye- primer chemistry on a Perkin-Elmer/Applied Biosystems 373A sequencer.
  • the deduced amino acid sequence encoded by this cDNA was identical to that previously described. [Y. Zhang et al., Nature 373, 425-432 (1994)].
  • the 501 bp fragment encoding the ob gene product was subcloned via EcoRI and BamHl sites into plasmid pRmHa3 [T.A. Bunch et al., Nucleic Acids Research 16, 1043-1061 (1988)].
  • Drosophila S2 cells were cotransfected with pUChsneo [H.
  • H.
  • Peak fractions were analyzed by HPLC electrospray mass spectrometry using a C4 column (1 x 100 mm) eluted in a linear gradient of acetonitrile (zero to sixty-seven percent in lOmM trifluoroacetic acid.
  • This reverse phase HPLC/mass spectrometry analysis demonstrated the immunoreactive protein to have a molecular mass of 16,004 Daltons, identidical to that predicted for the ob gene product after cleavage of the N terminal signal sequence between amino acids 21 and 22.
  • Antiserum 103-2 was isolated from a New Zealand white rabbit injected with a 4-branch multiple antigenic peptide corresponding to amino acids 22-41 of the mouse ob sequence, i.e., VPIQKVQDDTKTLIKTIVTR (SEQ. I.D. NO: 7). [Y. Zhang et al., Nature 372, 425-432 (1994)]. Western blot analysis was performed on nitrocellulose (BA85m 0.45 ⁇ M pore size, Schleicher and Schuell Inc.). Immunodetection of the ob gene product was performed in TBS-T (20 mM Tris-Cl pH 7.6, 137 mM NaCl, 0.1 % Tween 20) utilizing the ECL kit (Amersham).
  • the secondary antibody (anti- rabbit 1 g. horseradish peroxidase linked F(ab')2 fragment, Amersham) was used at 1 :3000 dilution. A single immunoreactive protein with an apparent molecular weight of 14.5 kDa was identified.
  • Human patients are given injections (i.e., subcutaneous, intramuscular or intravenous) of 0.05 to 20 mg/kg total ob protein (human) in vehicle (ob protein treated), administered one to three times per day, together with or followed by 0.001 to 100 mg/kg Compound A dihydrochloride, administered orally or by injection one to three times per day.
  • the first treatment is given on day 0, and the patients are treated daily for a six month period.
  • a set of control patients are untreated (e.g., placebo) for comparison.
  • Body weight data are collected each week. Statistical significance of body weight decreases is determined by performing a two-factor (group and day) analysis of variance (ANOVA) with repeated measures followed by a post hoc Least Squares Difference (LSD) test.
  • ANOVA analysis of variance
  • LSD post hoc Least Squares Difference
  • Plasma insulin and glucose levels Blood is collected into heparinized capillary tubes on the day before the first treatment and daily for the first week. Thereafter, patients should individually monitor their own blood glucose daily (using commercially available kits). Blood is collected for laboratory analysis weekly at the same time that body weight measurements are taken. Blood samples are analyzed (e.g., at a registered hospital or other GLP laboratory) for glucose and insulin levels.
  • NAME APPOLLINA, MARY A.
  • Val Pro lie Gin Lys Val Gin Asp Asp Thr Lys Thr Leu lie Lys Thr 1 5 10 15 lie Val Thr Arg 20

Abstract

L'invention porte sur la combinaison d'un composé A agoniste du récepteur adrénergique β3 et d'un composé modifiant le comportement alimentaire (par exemple la protéine OB) qui s'avèrent utiles contre l'obésité et le diabète. En utilisant soit la composition elle-même, soit ses sels pharmacocompatibles, soit des préparations pharmaceutiques dont ils sont les principes actifs. L'invention porte également sur les procédés de traitement associés.
EP96937097A 1995-11-01 1996-10-31 Traitement combine du diabete et de l'obesite Withdrawn EP0858340A4 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US713895P 1995-11-01 1995-11-01
US7138P 1995-11-01
GB9603724 1996-02-22
GBGB9603724.7A GB9603724D0 (en) 1996-02-22 1996-02-22 Combinatyion therapy for the treatment of diabebes and obesity
PCT/US1996/017444 WO1997016189A1 (fr) 1995-11-01 1996-10-31 Traitement combine du diabete et de l'obesite

Publications (2)

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EP0858340A1 true EP0858340A1 (fr) 1998-08-19
EP0858340A4 EP0858340A4 (fr) 1999-12-29

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EP (1) EP0858340A4 (fr)
JP (1) JPH11515027A (fr)
AU (1) AU7484596A (fr)
WO (1) WO1997016189A1 (fr)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6001968A (en) * 1994-08-17 1999-12-14 The Rockefeller University OB polypeptides, modified forms and compositions
JP2000504318A (ja) * 1996-01-19 2000-04-11 イーライ・リリー・アンド・カンパニー 肥満症タンパク質製剤
JP2001501177A (ja) * 1996-08-30 2001-01-30 アムジエン・インコーポレーテツド Ｏｂタンパク質受容体をアップレギュレートすることによりｏｂタンパク質に対する個体の感受性を増加させる方法
JP2002516605A (ja) * 1996-10-31 2002-06-04 メルク エンド カンパニー インコーポレーテッド 糖尿病および肥満の治療のための併用療法
EP0920864A1 (fr) * 1997-12-03 1999-06-09 Pfizer Products Inc. Thérapie de combinaison comprenant un beta-3 agoniste spécifique et un agent anorexigéne
US6515134B1 (en) * 1999-02-16 2003-02-04 Kaneka Corporation Substituted acetylpridine derivatives and process for the preparation of intermediates for optically active beta-3 agonist by the use of the same
JP2004331500A (ja) * 2001-02-16 2004-11-25 Dainippon Pharmaceut Co Ltd 血中濃度制御製剤
JPWO2003033468A1 (ja) * 2001-10-17 2005-02-03 株式会社カネカ （Ｓ）−α−ハロメチルピリジンメタノール誘導体の製造方法
NZ534757A (en) 2002-03-12 2006-07-28 Merck & Co Inc Substituted amides
GB0718415D0 (en) 2007-09-20 2007-10-31 Glaxo Group Ltd Compounds

Citations (3)

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EP0611003A1 (fr) * 1993-02-09 1994-08-17 Merck & Co. Inc. Phénylsulfonamides substitués comme B3-agonistes selectives pour le traitement du diabète et de l'obésité
WO1995029159A1 (fr) * 1994-04-26 1995-11-02 Merck & Co., Inc. SULFAMIDES SUBSTITUES UTILISES COMME AGONISTES SELECTIFS VIS-A-VIS DES RECEPTEURS β3-ADRENERGIQUES, POUR LE TRAITEMENT DU DIABETE ET DE L'OBESITE
EP0920864A1 (fr) * 1997-12-03 1999-06-09 Pfizer Products Inc. Thérapie de combinaison comprenant un beta-3 agoniste spécifique et un agent anorexigéne

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US5561142A (en) * 1994-04-26 1996-10-01 Merck & Co., Inc. Substituted sulfonamides as selective β3 agonists for the treatment of diabetes and obesity

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
EP0611003A1 (fr) * 1993-02-09 1994-08-17 Merck & Co. Inc. Phénylsulfonamides substitués comme B3-agonistes selectives pour le traitement du diabète et de l'obésité
WO1995029159A1 (fr) * 1994-04-26 1995-11-02 Merck & Co., Inc. SULFAMIDES SUBSTITUES UTILISES COMME AGONISTES SELECTIFS VIS-A-VIS DES RECEPTEURS β3-ADRENERGIQUES, POUR LE TRAITEMENT DU DIABETE ET DE L'OBESITE
EP0920864A1 (fr) * 1997-12-03 1999-06-09 Pfizer Products Inc. Thérapie de combinaison comprenant un beta-3 agoniste spécifique et un agent anorexigéne

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Title
See also references of WO9716189A1 *

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JPH11515027A (ja) 1999-12-21
AU7484596A (en) 1997-05-22
EP0858340A4 (fr) 1999-12-29

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