WO1990013294A1 - Procede servant a reduire le poids et l'absorption de nourriture au moyen d'un agoniste recepteur de dopamine d2 - Google Patents

Procede servant a reduire le poids et l'absorption de nourriture au moyen d'un agoniste recepteur de dopamine d2 Download PDF

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Publication number
WO1990013294A1
WO1990013294A1 PCT/US1990/002135 US9002135W WO9013294A1 WO 1990013294 A1 WO1990013294 A1 WO 1990013294A1 US 9002135 W US9002135 W US 9002135W WO 9013294 A1 WO9013294 A1 WO 9013294A1
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group
thienyl
hydrocarbyl radicals
isomer
carbon atoms
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PCT/US1990/002135
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English (en)
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James D. Belluzzi
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Whitby Research, Inc.
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Publication of WO1990013294A1 publication Critical patent/WO1990013294A1/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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof

Definitions

  • This invention relates to compositions comprising a dopaminergic agent and to a method for administering said compositions in an amount effective to induce anorexia and weight loss in the body of a human or animal.
  • Dopamine systems in the central nervous system have long been implicated in the anorexic effects of stimulant drugs such as amphetamine. Direct tests of dopaminergic involvement have become possible with the discovery of more specific dopamine agonists.
  • Anorexia was produced in rats given dopamine agonists such as lisuride, lergotrile and bromocriptine (Carruba, M.O., Ricciardi, S., Muller, E. E. and Mantegassa, P., "Anorectic effect of lisuride and other ergot derivatives in the rat," Eur. J. Pharmacol.
  • the ability of compounds known to produce temporary loss of appetite in an animal to which it is administered does not necessarily predict that sustained weight loss can be achieved in animals or humans to which the same drug is administered over a period of weeks.
  • the temporary anorexia induced in an animal during a 30-minute feeding test does not predict whether the animal will experience a rebound effect as soon as the drug wears off such that food consumption over a 24-hour period is the same with or without administration of the drug despite a brief period of drug-induced reduced food intake.
  • Figure 1 of the drawing is a graph showing the effects of dopamine agonists on body weight.
  • Figure 2 of the drawing is a graph showing the effect of continuous 24-hour infusion of N-0923 on body weight in free-feeding rats.
  • Figure 3 of the drawing is a graph showing the influence of starting body weight on the anorexic effects of N-0923.
  • Figure 4 is a graph comparing affects of 1 week and 4 weeks of continuous infusions of N-0923.
  • This invention provides a method for inducing anorexia and weight loss in mammals, e.g., humans, which comprises administering to a mammal suffering from obesity an effective amount of a compound selected from the group of optically active compounds represented by the general formula: wherein x is selected from the group consisting of methyl, substituted or unsubstituted phenyls, pyridyl, hydroxyphenyl,
  • X is oxygen or sulfur
  • Y is selected from the group consisting of hydroxy, nitro, cyano, azido, amino, acylamino, carboxyamido, trifluoromethyl, sulfate, suifonamido, halogen, hydrocarbyl and hetero atom-substituted hydrocarbyl radicals, wherein said heteroatoms are selected from the group consist ⁇ ing of halogen, nitrogen, oxygen, sulfur and phosphorus and said hydrocarbyl radicals comprise from 1 to 12 carbon atoms, and a is an integer of from zero to 3,
  • R 2 , R 3 and 4 are each selected from the group consisting of H and OA, A is H or is selected from the group consisting of hydrocarbyl radicals, -C-R 5 , and -CNHR 5 ,
  • R 5 is selected from the group consisting of hydrocarbyl radicals; n is an integer between 1 and 3; and R 6 is an alkyl chain having between 1 and 3 carbon atoms with the provision that at least one of R 2 , R 3 and R A is H, that at least one of R 2 , R 3 and R 4 is not H, and that R 2 and R « are not both OA, except that when R x is meta-hydroxyphenyl, phenyl, or 2- thienyl, the compound is optically active and pharmaceutically acceptable salts thereof.
  • R 2 is oxygen.
  • the compound selected for use in the method of the present invention be an optically active compound or mixture thereof capable of selectively activating either the postsynaptic or the presynaptic D2 dopamine receptor, e.g., in a human.
  • the (+) and (-) enantiomers of 5-hydroxy-2-(N-n-propyl-N-2-[2- thienyl]ethylamino)tetralin are especially preferred for use in the methods of inducing anorexia and weight loss of the present invention.
  • R x is selected from the group consisting of organic radicals methyl, substituted or unsubstituted phenyls, pyridyl, hydroxyphenyl,
  • X is oxygen or sulfur
  • Y is selected from the group consisting of hydroxy, nitro, cyano, azido, amino, acylamino, carboxyamido, trifluoromethyl, sulfate, suifonamido, halogen, hydrocarbyl and hetero atom-substituted hydrocarbyl radicals, wherein said heteroatoms are selected from the group consisting of halogen, nitrogen, oxygen, sulfur and phosphorus and said hydrocarbyl radicals comprise from 1 to 12 carbon atoms, and a is an integer of from 0 to 3,
  • R 2 , R 3 and R 4 are each selected from the group consisting of H and OA, A is H or is selected from the group consisting of hydrocarbyl radicals, -C-R s , and -CNHR 5 ,
  • R 5 is selected from the group consisting of hydrocarbyl radicals; n is an integer between 1 and 3; and R 6 is an alkyl chain having between 1 and 3 carbon atoms with the provision that at least one of R 2 , R 3 and R 4 is H, that at least one of R 2 , R 3 and R_, is not H, and that R 2 and R 4 are not both OA, except that when R x is meta-hydroxyphenyl, phenyl, or 2- thienyl, the compound is optically active and pharmaceutically acceptable salts thereof.
  • R 2 is oxygen.
  • A is preferably H or is selected from the group consisting of phenyl and alkyl radicals having from 1 to 12 carbon atoms, and more preferably R 5 is an alkyl or aryl radical that would serve to extend the activity of the compound in the body, for example phenyl, methyl t-butyl, d-methylphenyl, o-, m- or p- methoxyphenyl, or nonyl.
  • the more preferred groups represented by ⁇ are thienyl, phenyl, hydroxyphenyl, furanyl and naphthalenyl, e.g., 2- thienyl, 3-thienyl, 3-hydroxyphenyl, 4-hydroxyphenyl, etc.
  • n 2 and R 2 is OA; and most preferably A is H and R 6 is propyl.
  • the compound selected for use in the method of inducing anorexia and weight loss is an optically active compound or mixture thereof capable of substantially activating the postsynaptic dopamine D2 receptor, e.g., in a human. It has been found that the negative isomers of the claimed compounds possess the ability to predominately stimulate postsynaptic D2 dopamine receptors. As is shown in the Examples hereafter, the (-) isomers are unexpectedly more potent than the positive isomers for inducing anorexia and long term weight loss. A loss of as much as 12 percent of body weight has been achieved by administering a (-) isomer. However, at high dosages, for example, 3 mg/kg, the (-) isomers have been found to induce undesirable side effects of the central nervous system, such as stereotypy in rats.
  • the (-) isomer of 5- hydroxy-2-(N-n-propyl-N-2-[2-thienylJethylamino)tetralin is especially preferred for use in the method of the present invention because the (-) isomer is a strong agonist at post ⁇ synaptic receptors and possesses unexpectedly high potency for inducing anorexia and weight loss.
  • the positive (+) isomers of the compounds disclosed herein are preferred in the method of inducing anorexia and weight loss because at therapeutic doses the (+) isomers produce fewer side effects showing undesirable central nervous system involvement, such as stereotypy in rats. This freedom from side effects persists at dosages ten times as high as the effective dose for the (-) isomer.
  • the (+) isomers of the compounds of the invention are known to be more efficacious at presynaptic than at postsynaptic D2 dopamine receptors and while not wishing to be bound by theory, it is believed that the (+) isomers produce no side effects at the dosages preferred herein because they act preferentially at presynaptic D2 dopamine receptor sites or at a different subset of postsynaptic receptors than do the (-) isomers. It should be remembered, however, that the (+) isomers require a dosage much higher than that required to achieve comparable weight loss using the (-) isomer, i.e, more than ten times as much (+) isomer is required as is needed for comparable result if the (-) isomer is employed.
  • the embodiment of the invention employing the (+) isomer should be practiced when it is practical to administer a higher effective dosage of dopaminergic compound to achieve the advantage of avoiding the risk of side effects to the central nervous system. It is preferred that the (+) isomer of5-hydroxy-2-(N-n-propyl-N-2-[2-thienyl]ethylamino)tetralin be employed to achieve anorexia and weight loss without danger of producing side effects at high dosage.
  • designation of the (-) isomer shall mean that the (-) isomer is present in excess of the (+) isomer.
  • the mixture is greater than 90 mole percent of the (-) isomer.
  • the (-) isomer is substantially pure, i.e., greater than 99 mole percent.
  • Designation of the (+) isomer is defined by inverse analogy, i.e., most preferably the (+) isomer is substantially pure., i.e, greater than 99 mole percent.
  • R x is selected from the group consisting of radicals represented by the general formula:
  • x is selected from the group of radicals represented by the general formulae:
  • Y and a are as defined above. More preferably, Y comprises no more than 5 carbon atoms and a is 0 or l. Specific preferred compounds of this group include:
  • R 1 is phenyl and/or substituted phenyl and is selected from the group of radicals represented by the general formula:
  • This invention provides a method of treatment of the symptoms of obesity by inducing anorexia and weight loss, which method comprises administering a therapeutically effective amount of one of the foregoing compounds to a patient suffering such symptoms. Even more preferably, the method of the present invention comprises administering the (-) isomer of 5-hydroxy-2-(N-n-propyl-N-2-[2-thienyl] ethyl-amino)tetralin to a human or other mammal to reduce the symptoms of obesity.
  • the pharmaceutically effective dose will generally be selected within the above range so as to avoid undesirable side effects to the central nervous system while achieving significant antiobesity effects.
  • a pharmacologically-effective daily dose can be from 0.01 g./kg. to 100 g./kg. per day, bearing in mind, of course, that in selecting the appropriate dosage, in any specific case, consideration must be given to the patient's weight, general health, metabolism, age and other factors which influence response to the drug.
  • a preferred dosage is 0.3 to 3 mg./I kg. of body weight.
  • a particularly preferred dose is 0.3 mg./kg. per day.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preserving agents in order to provide a pharmaceutically elegant and palatable preparation.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for manufacture of tablets.
  • excipients can be, for example, inert diluents, for example calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents, for example maize starch, or alginic acid; binding agents, for example starch, gelatine, or acacia; and lubricating agents, for example magnesium stearate, stearic acids, or talc.
  • the tablets can be uncoated or they can be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • Formulations for oral use may also be presented as hard gelatine capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate, or kaolin, or as soft gelatine capsules wherein the active ingredient is mixed with an oil medium, for example archis oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active compound in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl- pyrrolidone, gum tragacanth, and gum acacia; dispersing or wetting agents may be naturally-occurring phosphatides, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecethyleneoxy-cetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol, for example, polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate.
  • dispersing or wetting agents may be naturally-occurring phosphatides, for example lecithin
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, n-propyl, or p-hydroxy benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, saccharin, or sodium or calcium cyclamate.
  • preservatives for example ethyl, n-propyl, or p-hydroxy benzoate
  • coloring agents for example ethyl, n-propyl, or p-hydroxy benzoate
  • flavoring agents such as sucrose, saccharin, or sodium or calcium cyclamate.
  • sweetening agents such as sucrose, saccharin, or sodium or calcium cyclamate.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., talc, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol,
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, preservative, flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example as sterile injectable aqueous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example, as a solution in 1,3-butane diol.
  • compositions may be tableted or otherwise formulated so that for every 100 parts by weight of the composition there are present between 5 and 95 parts by weight of the active ingredient.
  • the dosage unit form will generally contain between about 1 mg. and about 100 mg. of the active ingredient of the formula stated above.
  • compositions of this invention can be administered orally or parenterally.
  • parenteral as used herein includes subcutaneous injection, intravenous, intramuscular, or intrasternal injection or infusion techniques, as illustrated in the following examples.
  • the compositions can also be administered transdermally by topical administration to skin and mucosal membranes.
  • Example 1 Racemic 2-(N-n-propylamino)-5-methoxytetralin was resolved into its (-) and (+) isomers according to the method of Ten Hoeve and Wynberg (J. Org. Chem. 1985, 5J), 4508) , using the (+) isomer of 4-(2-chlorophenyl)-5,5-dimethyl-2-hydroxy- 1,3,2-dioxaphosphorinane 2-oxide.
  • the animals received intraperitoneal injections of one of the following drugs prepared daily: as shown in Figure 1 N-0923 (0.3 « ), 1 or 3 ( ⁇ ) mg/kg), N-0924 (3 mg/kg (Q)), d- amphetamine ( ⁇ .) (3 mg/kg) , apomorphine (3 mg/kg) or distilled water vehicle ( ) (1 ml/kg).
  • An individual timer was used for each animal to insure that feeding commenced 30 minutes after the injections and that food was available for two hours.
  • Each animal received 5 consecutive daily injections of one drug at a constant dose. Weight loss for each drug is shown in the difference in weights of the animals administered vehicle control and those of the animals administered the selected drug.
  • N-0923 0.3 mg/kg
  • the animals receiving a comparable dose of amphetamine also exhibited side effects to the central nervous system including heightened excitability and some symptoms of stereotypy. No stereotypic behavior or other signs of increased nervousness or irritability were noticed in any animals receiving the (+) isomer.
  • Table 1 The effects of dopamine agonists on body weight and food intake
  • the (-) isomer was slightly more potent than d- amphetamine in producing weight loss, although both produced significant weight loss (Table 1) . While considerably less potent than the (-) isomer, N-0924, the (+) isomer, showed a slight trend to produce weight loss. Stereoselectivity of the antiobesity effect of N-0437 is, thus, illustrated bythe substantial increase in potency of the (-) isomer over the (+) isomer.
  • Experiment 3 Continuous 4-week drug infusion on free-feeding schedule
  • Thirty-six animals were treated as in Experiment 2 above except that they received minipumps (2ML4) that delivered drugs at 2.5 ⁇ l/hr continuously for 4 weeks.
  • the pumps were loaded with N-0923 (50 ⁇ g/2.5 ⁇ l/hr), amphetamine 7.15 ⁇ g/2.5 ⁇ l/hr) or vehicle (5% dextrose in water) .
  • Body weight and food intake measurements were taken for a total of 3 months comprising 1 week prior to pump implantation, 1 month during drug infusion, and 7 weeks after pump removal.

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Abstract

Un procédé de traitement des symptomes d'obésité comportant l'administration à un être humain ou à un autre mammifère souffrant des symptomes de l'obésité d'une quantité efficace d'un composé sélectionné dans le groupe formé des composés à activité optique et notamment des stéréo-isomères négatifs (-) représentés par la formule (I), dans laquelle R1 est sélectionné dans le groupe constitué de méthyle, de phényles substitués ou non susbtitués, de pyridyle, d'hydroxyphényle, (a), (b), (c), (d) (e), (f), (g), X est de l'oxygène ou du soufre, Y est selectionné dans le groupe d'hydroxy, cyano, nitro, azido, amino, acylamino, carboxyamido, trifluorométhyle, sulfate, sulfonamido, halogène, hydrocarbyle, et de radicaux hydrocarbyle substitués par des hétéroatomes, dans lequel les hétéroatomes sont sélectionnés dans le groupe constitué d'halogène, azote, oxygène, soufre et phosphore et lesdits radicaux d'hydrocarbyle comportent entre 1 et 12 atomes de carbone, et a est un nombre entier entre zéro et 3, R2, R3 et R4 sont chacun sélectionnés dans le groupe constitué de H et OA, A est H ou est selectionné dans le groupe constitué de radicaux d'hydrocarbyle, (h), et (i), R5 est sélectionné dans le groupe constitué de radicaux d'hydrocarbyle; n est un nombre entier entre 1 et 3; et R6 est une chaîne alcoyle ayant entre 1 et 3 atomes de carbone, pourvu qu'au moins un élément parmi R2, R3 et R4 soit H, qu'au moins un élément parmi R2, R3 et R4 ne soit pas H, et que R2 et R4 ne soient pas tous les deux OA. On décrit également des sels de ces composés acceptables en pharmacologie. De préférence, R2 est de l'oxygène. Idéalement, R2 est OA et A est H, et le composé est l'isomère (-).
PCT/US1990/002135 1989-05-09 1990-04-19 Procede servant a reduire le poids et l'absorption de nourriture au moyen d'un agoniste recepteur de dopamine d2 WO1990013294A1 (fr)

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WO2002015903A2 (fr) * 2000-08-24 2002-02-28 Schwarz Pharma Ag Nouvelle composition pharmaceutique permettant l'administration de n-0923
WO2003028710A2 (fr) * 2001-09-28 2003-04-10 Boehringer Ingelheim Pharma Gmbh & Co. Kg Composes pour reduire la prise de nourriture excedentaire
US7375111B2 (en) 2003-04-29 2008-05-20 Orexigen Therapeutics, Inc. Compositions for affecting weight loss
US7425571B2 (en) 2002-05-17 2008-09-16 Orexigen Therapeutics, Inc. Method for treating obesity
US7429580B2 (en) 2004-01-13 2008-09-30 Orexigen Therapeutics, Inc. Compositions of an anticonvulsant and an antipsychotic drug and methods of using the same for affecting weight loss
WO2010043571A1 (fr) * 2008-10-13 2010-04-22 Interquim, S.A. Procédé pour la préparation de composés (s)-(-)-2-(n-propylamino)-5-méthoxytétraline et (s)-(-)-2-(n-propylamino)-5-hydroxytétraline optiquement actifs
US8916195B2 (en) 2006-06-05 2014-12-23 Orexigen Therapeutics, Inc. Sustained release formulation of naltrexone
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US9248123B2 (en) 2010-01-11 2016-02-02 Orexigen Therapeutics, Inc. Methods of providing weight loss therapy in patients with major depression
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US9633575B2 (en) 2012-06-06 2017-04-25 Orexigen Therapeutics, Inc. Methods of treating overweight and obesity
US11324741B2 (en) 2008-05-30 2022-05-10 Nalpropion Pharmaceuticals Llc Methods for treating visceral fat conditions

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Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002015903A2 (fr) * 2000-08-24 2002-02-28 Schwarz Pharma Ag Nouvelle composition pharmaceutique permettant l'administration de n-0923
WO2002015903A3 (fr) * 2000-08-24 2002-05-23 Sanol Arznei Schwarz Gmbh Nouvelle composition pharmaceutique permettant l'administration de n-0923
US8604076B2 (en) 2000-08-24 2013-12-10 Ucb Pharma Gmbh Method for producing a pharmaceutical composition comprising rotigotine
WO2003028710A2 (fr) * 2001-09-28 2003-04-10 Boehringer Ingelheim Pharma Gmbh & Co. Kg Composes pour reduire la prise de nourriture excedentaire
WO2003028710A3 (fr) * 2001-09-28 2003-09-12 Boehringer Ingelheim Pharma Composes pour reduire la prise de nourriture excedentaire
US7425571B2 (en) 2002-05-17 2008-09-16 Orexigen Therapeutics, Inc. Method for treating obesity
US7754748B2 (en) 2002-05-17 2010-07-13 Duke University Method for treating obesity
US10238647B2 (en) 2003-04-29 2019-03-26 Nalpropion Pharmaceuticals, Inc. Compositions for affecting weight loss
US7375111B2 (en) 2003-04-29 2008-05-20 Orexigen Therapeutics, Inc. Compositions for affecting weight loss
US7429580B2 (en) 2004-01-13 2008-09-30 Orexigen Therapeutics, Inc. Compositions of an anticonvulsant and an antipsychotic drug and methods of using the same for affecting weight loss
US9457005B2 (en) 2005-11-22 2016-10-04 Orexigen Therapeutics, Inc. Compositions and methods for increasing insulin sensitivity
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