EP1549348A1 - Association between a ppar ligand and an antioxidant agent and use thereof for treating obesity - Google Patents

Association between a ppar ligand and an antioxidant agent and use thereof for treating obesity

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Publication number
EP1549348A1
EP1549348A1 EP03807889A EP03807889A EP1549348A1 EP 1549348 A1 EP1549348 A1 EP 1549348A1 EP 03807889 A EP03807889 A EP 03807889A EP 03807889 A EP03807889 A EP 03807889A EP 1549348 A1 EP1549348 A1 EP 1549348A1
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EP
European Patent Office
Prior art keywords
treatment
pharmaceutical compositions
prevention
obesity
ppar
Prior art date
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Withdrawn
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EP03807889A
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German (de)
French (fr)
Inventor
Louis Casteilla
Luc Penicaud
Catherine Dacquet
Pierre Renard
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Centre National de la Recherche Scientifique CNRS
Laboratoires Servier SAS
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Centre National de la Recherche Scientifique CNRS
Laboratoires Servier SAS
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Application filed by Centre National de la Recherche Scientifique CNRS, Laboratoires Servier SAS filed Critical Centre National de la Recherche Scientifique CNRS
Priority to EP07075195A priority Critical patent/EP1815858A3/en
Publication of EP1549348A1 publication Critical patent/EP1549348A1/en
Withdrawn legal-status Critical Current

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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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin

Definitions

  • the present invention relates to the association between one or more selective ligands of receptors activated by peroxisome proliferators (PPAR) and an antioxidant agent and its use in the treatment and / or prevention of obesity and overweight characterized by body weight index greater than 25.
  • PPAR peroxisome proliferators
  • Obesity is a major public health problem in all developed countries. Also growing steadily in developing countries, it is reaching an increasingly young population. Obesity is a chronic disorder of energy imbalance characterized by an excess of long-term energy intake compared to a limited energy expenditure resulting in the storage of this excess energy in the form of white adipose tissue.
  • Overloads of adipose tissue directly contribute to problems of fatigue, shortness of breath, sleep apnea and osteoarthritis.
  • Obesity is a well-established risk factor for the development of insulin resistance, dyslipidemia and ultimately non-insulin dependent diabetes. It is a factor favoring cardiovascular diseases and it is associated with a significant increase in the risks of strokes, gallbladder stones, respiratory dysfunction, osteoarthritis, several forms of cancer and premature death.
  • the pharmacological strategy for reducing obesity presents two alternatives: either reduce fat mass by modifying energy intake and / or by modifying the distribution of nutrients between fat and lean tissue, or oppose or reverse the metabolic consequences of l 'increased fat without necessarily having an impact on the degree of obesity by itself.
  • a human body In obese people, it has been shown that the generation of reactive oxygen species released by monocytes and leukocytes was greatly increased compared to non-obese subjects (J. Clin. Endocrinol. Metab., 2001, 86, 355-362 ).
  • the high plasma concentrations of tumor necrosis factor alpha (TNF ⁇ ) in the obese stimulate inflammatory processes (J. Clin. Endocrinol. Metab., 1998, 83, 2907-2910) and are responsible for the generation of reactive oxygen species by leukocytes (Oncogene, 1998, 17, 1639-1651).
  • TNF ⁇ tumor necrosis factor alpha
  • the pathological state of obesity is also associated with an increase in the oxidation of lipids and proteins which can be the source of significant plasma concentrations of 9- and 13-hydroxyoctadecadienoic acids (9-HODE and 13- HODE) (Totowa).
  • a strategy aimed at reducing the body's "oxidation load" while promoting lipid and carbohydrate metabolism should lead to an exacerbation of the effects and consequently to weight loss in obese or overweight subjects.
  • PPAR peroxisome proliferators
  • PPAR are a family of hormonal nuclear receptors comprising three distinct subtypes: ⁇ , ⁇ (also called ⁇ or NUCl) and ⁇ (which has three isoforms: ⁇ i, ⁇ 2 and
  • PPAR (s) proteins bind to promoters in the form of heterodimers with the 9 cis retinoic acid receptor: RXR.
  • the PPAR / RXR heterodimer can be activated by the binding of a specific ligand for one of the two receptors, but maximum activation takes place with the presence of two ligands.
  • PPAR are ligand-dependent transcription factors, which means that activation of transcription of target genes is strictly dependent on ligand binding.
  • Certain ligands such as mono or polyunsaturated fatty acids or saturated fatty acids bind to the three receptor subtypes.
  • Long chain polyunsaturated fatty acids such as linolenic acid or conjugated or oxidized fatty acids bind with high affinity on PPAR ⁇ .
  • PPAR PPAR
  • the PPAR ⁇ KO mouse develops obesity and hypertriglyceridemia even if the daily caloric intake does not increase. These effects are largely explained by the reduction in the capture of fatty acids by the liver and the inhibition of their oxidation (J. Biol. Chem., 1998, 273, 29577-29585).
  • the liver is an organ with oxidative capacity for fatty acids.
  • thermogenesis is activated and transforms the available energy into heat with a decrease in the respiratory quotient and an increase in the speed of basal metabolism.
  • the strategy consisting in inhibiting the enzymatic processes of the hepatic oxidation of fatty acids while ensuring a transcriptional stimulation of the genes activated by PPAR (s) and involved in the lipid and carbohydrate metabolic processes must lead to a reduction in the plasma free fatty acids. and moderate lipolysis of the adipocytes constituting the visceral adipose tissue, leading in the long term to a regression of visceral obesity and therefore a loss of body weight.
  • the present invention relates more particularly to the association between one or more ligand compounds of receptors activated by peroxisome proliferators and an antioxidant agent.
  • the PPAR ligands according to the invention are selective ligands of the ⁇ and / or ⁇ receptor subtypes.
  • the combination according to the invention contains a selective ligand PPAR ⁇ and a selective ligand PPAR ⁇ .
  • An advantageous variant concerns the association according to the invention in which the PPAR ligand is a mixed ligand of the receptor subtypes ⁇ and ⁇ .
  • the PPAR ⁇ and / or ⁇ ligands according to the invention are advantageously represented by gemfibrozyl, WY-14,643, pioglitazone and even more preferably by rosiglitazone.
  • the PPAR ligands according to the invention are also represented by the compounds described in applications WO 9736579, WO 9731907, WO9728115, WO9638415, WO9727857, WO9725042, WO9701420, WO9640128, WO2000064888 and WO2000064876.
  • antioxidant agents according to the invention are represented by different categories of compounds:
  • antioxidants capable of regenerating endogenous antioxidants such as glutathione, vitamin C or vitamin E.
  • the antioxidant agent of the combination according to the invention is more preferably represented by quinone derivatives such as ubiquinone or coenzyme Q 10 , which acts as a free radical scavenger but which is also capable of regenerating vitamin E .
  • hydrochloric hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methane acids. sulfonic, camphoric, etc.
  • the preferred combination according to the invention is rosiglitazone and coenzyme Q 10 .
  • the association according to the invention between one or more compound promoting lipid and carbohydrate metabolism and an antioxidant agent has quite surprising pharmacological properties: the Applicant has indeed demonstrated the existence of a synergy between these two classes of compounds make it possible to obtain a very significant reduction in body fat making it useful in the treatment and / or prevention of obesity and overweight characterized by a body weight index greater than 25.
  • Obesity in the United States affects 20% of men and 25% of women. Patients with body weight index (MC weight (kg) / height 2 (m 2 )) greater than or equal to 30 are considered obese (Int. J. Obes., 1998, 22, 39-47; Obesity Lancet , 1997, 350, 423-
  • Obesity CML> 30
  • overweight 25 ⁇ EV1C ⁇ 30
  • type II anti-diabetic treatment with sulphonylureas leads to weight gain in patients.
  • type I insulin-dependent
  • insulin therapy is also a source of body weight gain in patients (In
  • Obesity and overweight are well-established risk factors for cardiovascular disease: they are associated with a significant increase in the risk of stroke, non-msulino-dependent diabetes because they predispose to insulin resistance , dyslipidemia and the appearance of macrovascular diseases (nephropathies, retinopathies, angiopathies).
  • the combination according to the invention makes it possible to obtain weight loss which, even if moderate, significantly reduces all the risk factors associated with obesity (Int. J. Obes., 1997, 21, 55-9; Int. J. Obes., 1992, 21 ,, S5-9).
  • the combination according to the invention therefore finds its utility in the treatment and / or prevention of obesity and overweight characterized by a body weight index greater than 25 and less than 30.
  • the invention therefore relates to the use of a combination containing one or more PPAR ligands and an antioxidant agent for obtaining pharmaceutical compositions intended for the treatment and / or prevention of obesity as well as overweight characterized by body weight index greater than 25 and less than 30.
  • the combination according to the invention is useful in the treatment and / or prevention of obesity and overweight characterized by a body weight index greater than 25 and less than 30 induced by a therapeutic treatment, such as treatment of type I or II diabetes.
  • the invention therefore relates to the use of a combination containing one or more PPAR ligands and an antioxidant agent for obtaining pharmaceutical compositions intended for the treatment and / or prevention of obesity as well as overweight characterized by body weight index greater than 25 and less than 30 induced by therapeutic treatment, such as treatment of type I or IL diabetes
  • the invention also relates to pharmaceutical compositions containing the association between one or more derivatives promoting lipid and carbohydrate metabolism and more particularly one or more PPAR ligands and an antioxidant agent as defined above in combination with one or more pharmaceutically acceptable excipients.
  • compositions according to the invention mention may be made more particularly of those which are suitable for oral, parenteral, nasal administration, simple or coated tablets, sublingual tablets, capsules, tablets, suppositories, creams, ointments , dermal gels, etc.
  • the dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication or any associated treatments and ranges from 0.1 mg to 1 g of each component of the combination per 24 hours in one or more doses.
  • mice C57 Black 6 ob / ob from 8 to 12 weeks were used. These mice are diabetic (type II) and suffer from hyperglycemia, hypertriglyceridemia and hyperinsulinemia. After quarantining for one week, they were weighed and then randomized according to their weight, and 6 homogeneous groups (starting weight not significantly different) were formed. After being weighed, these mice are treated with rosiglitazone (antidiabetic) alone or in combination with coenzyme Q 10 . The molecules are injected intraperitoneally once a day for 14 days in a 5% DMSO / 15% Solutol / Qsp H 2 O solution heated to 65 ° C to ensure good dissolution. The solution is further preheated before injection.
  • mice are weighed daily and the weight obtained after 14 days of treatment is noted.
  • Treatment with rosiglitazone alone leads to an increase in weight of the mice greater than or equal to 5 grams corresponding approximately to 10% more than their initial weight.
  • the association rosiglitazone + coenzyme Q 10 reverses this weight gain by at least 50% and highlights the effectiveness of the association in reducing body weight.

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  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Diabetes (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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  • Obesity (AREA)
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  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Child & Adolescent Psychology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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  • Plural Heterocyclic Compounds (AREA)

Abstract

The invention concerns an association containing one or more ligands of the peroxisome proliferator activated receptors and an antioxidant agent. The invention is applicable to medicines.

Description

ASSOCIATION ENTRE UN LIGAND DES PPAR ET UN AGENT ANTIOXYDANT ET UTILISATIONASSOCIATION BETWEEN A LIGAND OF PPAR AND AN ANTIOXIDANT AGENT AND USE THEREOF
DANS LE TRAITEMENT DE L'OBESITEIN THE TREATMENT OF OBESITY
La présente invention concerne l'association entre un ou plusieurs ligands sélectifs des récepteurs activés par les proliférateurs de peroxisomes (PPAR) et un agent antioxydant et son utilisation dans le traitement et/ou la prévention de l'obésité et des surcharges pondérales caractérisées par un index de poids corporel supérieur à 25.The present invention relates to the association between one or more selective ligands of receptors activated by peroxisome proliferators (PPAR) and an antioxidant agent and its use in the treatment and / or prevention of obesity and overweight characterized by body weight index greater than 25.
L'obésité est un problème majeur de santé publique dans tous les pays développés. En progression constante également dans les pays en voie de développement, elle atteint une population de plus en plus jeune. L'obésité est un désordre chronique de déséquilibre énergétique caractérisé par un excès de prise énergétique à long terme comparé à une dépense énergétique limitée entraînant le stockage de cet excès d'énergie sous forme de tissu adipeux blanc.Obesity is a major public health problem in all developed countries. Also growing steadily in developing countries, it is reaching an increasingly young population. Obesity is a chronic disorder of energy imbalance characterized by an excess of long-term energy intake compared to a limited energy expenditure resulting in the storage of this excess energy in the form of white adipose tissue.
Les surcharges en tissus adipeux contribuent directement à des problèmes de fatigue, d'essoufflement, d'apnée du sommeil et dOstéoarthrite.Overloads of adipose tissue directly contribute to problems of fatigue, shortness of breath, sleep apnea and osteoarthritis.
L'obésité est un facteur de risque bien établi pour le développement de l'insulino- résistance, de la dyslipidémie et en dernier lieu du diabète non insulino-dépendant. C'est un facteur favorisant les maladies cardiovasculaires et elle est associée à une augmentation significative des risques d'accidents vasculaires cérébraux, de calculs vésiculaires, de dysfonctions respiratoires, dOstéoarthrite, de plusieurs formes de cancer et de mort prématurée.Obesity is a well-established risk factor for the development of insulin resistance, dyslipidemia and ultimately non-insulin dependent diabetes. It is a factor favoring cardiovascular diseases and it is associated with a significant increase in the risks of strokes, gallbladder stones, respiratory dysfunction, osteoarthritis, several forms of cancer and premature death.
La stratégie pharmacologique pour réduire l'obésité présente deux alternative : soit réduire la masse grasse en modifiant les entrées énergétiques et/ou en modifiant la répartition des nutriments entre la graisse et les tissus maigres, soit s'opposer ou réverser les conséquences métaboliques de l'augmentation de masse grasse sans nécessairement avoir un impact sur le degré d'obésité par lui-même. Chez les obèses, il a été démontré que la génération d'espèces oxygénées réactives libérées par les monocytes et les leucocytes était fortement augmentée par rapport à des sujets non obèses (J. Clin. Endocrinol. Metab., 2001, 86, 355-362). Les concentrations plasmatiques élevées de facteur de nécrose tumorale alpha (TNFα) chez les obèses stimulent les processus inflammatoires (J. Clin. Endocrinol. Metab., 1998, 83, 2907-2910) et sont responsables de la génération d'espèces oxygénées réactives par les leucocytes (Oncogene, 1998, 17, 1639-1651).The pharmacological strategy for reducing obesity presents two alternatives: either reduce fat mass by modifying energy intake and / or by modifying the distribution of nutrients between fat and lean tissue, or oppose or reverse the metabolic consequences of l 'increased fat without necessarily having an impact on the degree of obesity by itself. In obese people, it has been shown that the generation of reactive oxygen species released by monocytes and leukocytes was greatly increased compared to non-obese subjects (J. Clin. Endocrinol. Metab., 2001, 86, 355-362 ). The high plasma concentrations of tumor necrosis factor alpha (TNFα) in the obese stimulate inflammatory processes (J. Clin. Endocrinol. Metab., 1998, 83, 2907-2910) and are responsible for the generation of reactive oxygen species by leukocytes (Oncogene, 1998, 17, 1639-1651).
L'état pathologique de l'obésité est également associé à une augmentation de l'oxydation des lipides et des protéines qui peut être à l'origine de concentrations plasmatiques importantes d'acides 9- et 13-hydroxyoctadécadiénoïques (9-HODE et 13-HODE) (TotowaThe pathological state of obesity is also associated with an increase in the oxidation of lipids and proteins which can be the source of significant plasma concentrations of 9- and 13-hydroxyoctadecadienoic acids (9-HODE and 13- HODE) (Totowa
: Humano. Press., 1998, 147-155), index clés de la peroxydation lipidique (J. Clin. Endocrinol. Metab., 2001, 86, 355-362). Parallèlement, les capacités "antioxydantes" de l'organisme diminuent.: Humano. Press., 1998, 147-155), key indexes of lipid peroxidation (J. Clin. Endocrinol. Metab., 2001, 86, 355-362). At the same time, the body's "antioxidant" capacities decrease.
Chez les sujets obèses, il a été démontré que la prise alimentaire excessive génère des dommages lipidiques et protéiques importants. La surconsommation de calories chez les obèses peut entraîner la génération de radicaux libres et les exposer à des lésions oxydatives importantes contribuant à maintenir l'état d'obésité.In obese subjects, excessive food intake has been shown to cause significant lipid and protein damage. Overconsumption of calories in obese can lead to the generation of free radicals and expose them to significant oxidative damage helping to maintain obesity.
Les marqueurs spécifiques de l'oxydation sont significativement diminués lors d'une diète de 48 heures ou d'une restriction calorique qui s'accompagne de perte de poids (J. Clin. Endocrinol. Metab., 2001, 86, 355-362).Specific markers of oxidation are significantly reduced during a 48-hour diet or a calorie restriction which is accompanied by weight loss (J. Clin. Endocrinol. Metab., 2001, 86, 355-362) .
Une stratégie visant à réduire la "charge en oxydation" de l'organisme tout en favorisant les métabolismes lipidique et glucidique devrait conduire à une exacerbation des effets et par voie de conséquence à une perte de poids chez les sujets obèses ou présentant une surcharge pondérale.A strategy aimed at reducing the body's "oxidation load" while promoting lipid and carbohydrate metabolism should lead to an exacerbation of the effects and consequently to weight loss in obese or overweight subjects.
Parmi les composés capables de favoriser les métabolismes lipidique et glucidique, les ligands sélectifs des récepteurs activés par les proliférateurs de peroxisome ou PPAR sont des composés particulièrement intéressants. Les PPAR(s) sont une famille de récepteurs nucléaires hormonaux comprenant trois sous- types distincts : α, β (encore appelé δ ou NUCl) et γ (qui présente trois isoformes : γi, γ2 etAmong the compounds capable of promoting lipid and carbohydrate metabolism, the selective ligands for receptors activated by peroxisome proliferators or PPAR are particularly interesting compounds. PPAR (s) are a family of hormonal nuclear receptors comprising three distinct subtypes: α, β (also called δ or NUCl) and γ (which has three isoforms: γi, γ 2 and
Y3>-Y3> -
Ils ont été initialement clones comme des récepteurs nucléaires qui médient les effets de proliférateurs de peroxisomes sur la transcription génique, mais il est clair qu'un très grand nombre de composés naturels comme les eicosanoïdes et les acides gras peuvent également activer les PPAR(s).They were initially cloned as nuclear receptors which mediate the effects of peroxisome proliferators on gene transcription, but it is clear that a very large number of natural compounds such as eicosanoids and fatty acids can also activate PPAR (s) .
Comme un certain nombre d'autres récepteurs nucléaires aux hormones, les protéines PPAR(s) se lient sur des promoteurs sous la forme d'hétérodimères avec le récepteur à l'acide 9 cis rétinoïque : RXR. L'hétérodimère PPAR/RXR peut être activé par la liaison d'un ligand spécifique de l'un des deux récepteurs mais l'activation maximale s'effectue avec la présence de deux ligands.Like a number of other nuclear hormone receptors, PPAR (s) proteins bind to promoters in the form of heterodimers with the 9 cis retinoic acid receptor: RXR. The PPAR / RXR heterodimer can be activated by the binding of a specific ligand for one of the two receptors, but maximum activation takes place with the presence of two ligands.
Les PPAR(s) sont des facteurs de transcription, dépendants des ligands, ce qui signifie que l'activation de la transcription des gènes cibles dépend strictement de la liaison du ligand.PPAR (s) are ligand-dependent transcription factors, which means that activation of transcription of target genes is strictly dependent on ligand binding.
Certains ligands comme les acides gras mono ou polyinsaturés ou les acides gras saturés se lient sur les trois sous-types de récepteurs. Les acides gras polyinsaturés à longue chaîne comme l'acide linolénique ou des acides gras conjugués ou oxydés se lient avec une haute affinité sur PPARα.Certain ligands such as mono or polyunsaturated fatty acids or saturated fatty acids bind to the three receptor subtypes. Long chain polyunsaturated fatty acids such as linolenic acid or conjugated or oxidized fatty acids bind with high affinity on PPARα.
La plus importante fonction des PPAR(s) provient de leur expression tissu-dépendante et de l'identité de leurs gènes cibles très souvent impliqués exclusivement dans le transport et le métabolisme des lipides et des carbohydrates.The most important function of PPAR (s) comes from their tissue-dependent expression and the identity of their target genes very often involved exclusively in the transport and metabolism of lipids and carbohydrates.
La souris PPARα KO développe de l'obésité et de rhypertriglycéridémie même si la prise calorique quotidienne n'augmente pas. Ces effets sont expliqués en grande partie par la réduction de la capture des acides gras par le foie et l'inhibition de leur oxydation (J. Biol. Chem., 1998, 273, 29577-29585). Le foie est un organe à capacité oxydative pour les acides gras. Lorsque l'oxydation hépatique des acides gras est optimisée, la thermogénèse s'enclenche et transforme l'énergie disponible en chaleur avec diminution du quotient respiratoire et augmentation de la vitesse du métabolisme basai. Ces circonstances sont très favorables à la perte de tissu adipeux (Med. Hypothèses, 1999, 52(5), 407-416).The PPARα KO mouse develops obesity and hypertriglyceridemia even if the daily caloric intake does not increase. These effects are largely explained by the reduction in the capture of fatty acids by the liver and the inhibition of their oxidation (J. Biol. Chem., 1998, 273, 29577-29585). The liver is an organ with oxidative capacity for fatty acids. When the hepatic oxidation of fatty acids is optimized, thermogenesis is activated and transforms the available energy into heat with a decrease in the respiratory quotient and an increase in the speed of basal metabolism. These circumstances are very favorable for the loss of adipose tissue (Med. Hypotheses, 1999, 52 (5), 407-416).
La stratégie consistant à désinhiber les processus enzymatiques de l'oxydation hépatique des acides gras tout en assurant une stimulation transcriptionnelle des gènes activés par les PPAR(s) et impliqués dans les processus métaboliques lipidique et glucidique doit aboutir à une diminution des acides gras libres plasmatiques et une lipolyse modérée des adipocytes constituant le tissu adipeux viscéral entraînant à long terme une régression de l'obésité viscérale et donc une perte de poids corporel.The strategy consisting in inhibiting the enzymatic processes of the hepatic oxidation of fatty acids while ensuring a transcriptional stimulation of the genes activated by PPAR (s) and involved in the lipid and carbohydrate metabolic processes must lead to a reduction in the plasma free fatty acids. and moderate lipolysis of the adipocytes constituting the visceral adipose tissue, leading in the long term to a regression of visceral obesity and therefore a loss of body weight.
La présente invention concerne plus particulièrement l'association entre un ou plusieurs composés ligands des récepteurs activés par les proliférateurs de peroxisomes et un agent antioxydant.The present invention relates more particularly to the association between one or more ligand compounds of receptors activated by peroxisome proliferators and an antioxidant agent.
Cette association présente des propriétés pharmacologiques tout à fait remarquables dans le domaine de l'obésité.This association has quite remarkable pharmacological properties in the field of obesity.
Plus particulièrement, les ligands PPAR selon l'invention sont des ligands sélectifs des sous-types réceptoriels α et/ou γ.More particularly, the PPAR ligands according to the invention are selective ligands of the α and / or γ receptor subtypes.
Avantageusement, l'association selon l'invention contient un ligand sélectif PPARα et un ligand sélectif PPARγ.Advantageously, the combination according to the invention contains a selective ligand PPARα and a selective ligand PPARγ.
Une variante avantageuse concerne l'association selon l'invention dans laquelle le ligand PPAR est un ligand mixte des sous-types réceptoriels α et γ.An advantageous variant concerns the association according to the invention in which the PPAR ligand is a mixed ligand of the receptor subtypes α and γ.
Les ligands PPARα et/ou γ selon l'invention sont avantageusement représentés par le gemfibrozyl, le WY-14,643, la pioglitazone et encore plus préférentiellement par la rosiglitazone. Les ligands PPAR selon l'invention sont également représentés par les composés décrits dans les demandes WO 9736579, WO 9731907, WO9728115, WO9638415, WO9727857, WO9725042, WO9701420, WO9640128, WO2000064888 et WO2000064876.The PPARα and / or γ ligands according to the invention are advantageously represented by gemfibrozyl, WY-14,643, pioglitazone and even more preferably by rosiglitazone. The PPAR ligands according to the invention are also represented by the compounds described in applications WO 9736579, WO 9731907, WO9728115, WO9638415, WO9727857, WO9725042, WO9701420, WO9640128, WO2000064888 and WO2000064876.
Les agents antioxydants selon l'invention sont représentés par différentes catégories de composés :The antioxidant agents according to the invention are represented by different categories of compounds:
- des agents antiradicalaires ou piégeurs de radicaux libres,- anti-free radicals or free radical scavengers,
- des agents antilipoperoxydants,- antilipoperoxidants,
- des agents chélatants,- chelating agents,
- des agents capables de régénérer les antioxydants endogènes comme le glutathion, la vitamine C ou la vitamine E.- agents capable of regenerating endogenous antioxidants such as glutathione, vitamin C or vitamin E.
L'agent antioxydant de l'association selon l'invention est plus préférentiellement représenté par des dérivés de quinones comme l'ubiquinone ou coenzyme Q10, qui agit en tant que piégeur de radicaux libres mais qui est également capable de régénérer de la vitamine E.The antioxidant agent of the combination according to the invention is more preferably represented by quinone derivatives such as ubiquinone or coenzyme Q 10 , which acts as a free radical scavenger but which is also capable of regenerating vitamin E .
Les énantiomères, diastéréoisomères ainsi que les sels d'addition à un acide ou à une base pharmaceutiquement acceptable des composés ligands PPAR et antioxydants selon l'association font également partie intégrante de l'invention.The enantiomers, diastereoisomers as well as the addition salts with an acid or a pharmaceutically acceptable base of the PPAR ligand compounds and antioxidants according to the combination also form an integral part of the invention.
Parmi les acides pharmaceutiquement acceptables, on peut citer à titre non limitatif les acides chlorhydrique, bromhydrique, sulfurique, phosphonique, acétique, trifluoroacétique, lactique, pyruvique, malonique, succinique, glutarique, fumarique, tartrique, maléïque, citrique, ascorbique, oxalique, méthane sulfonique, camphorique, etc..Among the pharmaceutically acceptable acids, non-limiting mention may be made of hydrochloric, hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methane acids. sulfonic, camphoric, etc.
Parmi les bases pharmaceutiquement acceptables, on peut citer à titre non limitatif l'hydroxyde de sodium, l'hydroxyde de potassium, la triéthylamine, la tert-butylamine, etc..Among the pharmaceutically acceptable bases, non-limiting mention may be made of sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.
L'association préférée selon l'invention est la rosiglitazone et le coenzyme Q10. Par ailleurs, l'association selon l'invention entre un ou plusieurs composé favorisant les métabolismes lipidique et glucidique et un agent antioxydant possède des propriétés pharmacologiques tout à fait surprenantes : la demanderesse a en effet mis en évidence l'existence d'une synergie entre ces deux classes de composés permettant d'obtenir une réduction très significative de la masse grasse corporelle la rendant utile dans le traitement et/ou la prévention de l'obésité et des surcharges pondérales caractérisées par un index de poids corporel supérieur à 25.The preferred combination according to the invention is rosiglitazone and coenzyme Q 10 . Furthermore, the association according to the invention between one or more compound promoting lipid and carbohydrate metabolism and an antioxidant agent has quite surprising pharmacological properties: the Applicant has indeed demonstrated the existence of a synergy between these two classes of compounds make it possible to obtain a very significant reduction in body fat making it useful in the treatment and / or prevention of obesity and overweight characterized by a body weight index greater than 25.
L'obésité aux Etats-Unis atteint 20 % des hommes et 25 % des femmes. Sont considérés comme obèses les patients d'indice de poids corporel ( MC = poids (kg) / taille2 (m2)) supérieur ou égal à 30 (Int. J. Obes., 1998, 22, 39-47 ; Obesity Lancet, 1997, 350, 423-Obesity in the United States affects 20% of men and 25% of women. Patients with body weight index (MC = weight (kg) / height 2 (m 2 )) greater than or equal to 30 are considered obese (Int. J. Obes., 1998, 22, 39-47; Obesity Lancet , 1997, 350, 423-
426). L'obésité (LMC > 30) et les surcharges pondérales (25 < EV1C < 30) peuvent avoir plusieurs origines : elles peuvent survenir à la suite d'une dérégulation de la prise de nourriture, d'une dérégulation hormonale ou encore à la suite de l'administration d'un traitement : un traitement antidiabétique de type II avec les sulphonylurées entraîne une prise de poids chez les patients. De même dans le diabète de type I (insulino-dépendant), l'insulinothérapie est également une source de prise de poids corporel chez les malades (In426). Obesity (CML> 30) and overweight (25 <EV1C <30) can have several origins: they can occur following a deregulation of food intake, a hormonal deregulation or even following administration of treatment: type II anti-diabetic treatment with sulphonylureas leads to weight gain in patients. Similarly in type I (insulin-dependent) diabetes, insulin therapy is also a source of body weight gain in patients (In
Progress in Obesity Research, International Congress on Obesity, 1999, 739-746 ; Annals of Internai Medicine, 1998, 128, 165-175).Progress in Obesity Research, International Congress on Obesity, 1999, 739-746; Annals of Internai Medicine, 1998, 128, 165-175).
L'obésité et les surcharges pondérales sont des facteurs de risque bien établis pour les maladies cardiovasculaires : elles sont associées à une augmentation significative des risques d'accidents vasculaires cérébraux, de diabète non-msulino-dépendant car elles prédisposent à l'insulino-résistance, aux dyslipidémies et à l'apparition de maladies macrovasculaires (néphropathies, rétinopathies, angiopathies).Obesity and overweight are well-established risk factors for cardiovascular disease: they are associated with a significant increase in the risk of stroke, non-msulino-dependent diabetes because they predispose to insulin resistance , dyslipidemia and the appearance of macrovascular diseases (nephropathies, retinopathies, angiopathies).
D'autres pathologies sont la conséquence de l'obésité ou de surcharges pondérales : on peut citer en particulier les calculs vésiculaires, les dysfonctions respiratoires, rostéoarthrite, plusieurs formes de cancers et dans les cas d'obésité très sévère la mort prématurée (N.Other pathologies are the consequence of obesity or overweight: we can cite in particular gallbladder stones, respiratory dysfunction, osteoarthritis, several forms of cancer and in cases of very severe obesity premature death (N.
Engl. J. Med., 1995, 333, 677-385 ; JAMA, 1993, 270, 2207-2212).Engl. J. Med., 1995, 333, 677-385; JAMA, 1993, 270, 2207-2212).
L'association selon l'invention permet d'obtenir une perte de poids qui même modérée réduit significativement tous les facteurs de risque associés à l'obésité (Int. J. Obes., 1997, 21, 55-9 ; Int. J. Obes., 1992, 21,, S5-9). L'association selon l'invention trouve donc son utilité dans le traitement et/ou la prévention de l'obésité et des surcharges pondérales caractérisées par un index de poids corporel supérieur à 25 et inférieur à 30.The combination according to the invention makes it possible to obtain weight loss which, even if moderate, significantly reduces all the risk factors associated with obesity (Int. J. Obes., 1997, 21, 55-9; Int. J. Obes., 1992, 21 ,, S5-9). The combination according to the invention therefore finds its utility in the treatment and / or prevention of obesity and overweight characterized by a body weight index greater than 25 and less than 30.
L'invention concerne donc l'utilisation d'une association contenant un ou plusieurs ligands PPAR et un agent antioxydant pour l'obtention de compositions pharmaceutiques destinées au traitement et/ou à la prévention de l'obésité ainsi que des surcharges pondérales caractérisées par un index de poids corporel supérieur à 25 et inférieur à 30.The invention therefore relates to the use of a combination containing one or more PPAR ligands and an antioxidant agent for obtaining pharmaceutical compositions intended for the treatment and / or prevention of obesity as well as overweight characterized by body weight index greater than 25 and less than 30.
En particulier, l'association selon l'invention est utile dans le traitement et/ou la prévention de l'obésité et des surcharges pondérales caractérisées par un index de poids corporel supérieur à 25 et inférieur à 30 induites par un traitement thérapeutique, comme le traitement du diabète de type I ou II .In particular, the combination according to the invention is useful in the treatment and / or prevention of obesity and overweight characterized by a body weight index greater than 25 and less than 30 induced by a therapeutic treatment, such as treatment of type I or II diabetes.
L'invention concerne donc l'utilisation d'une association contenant un ou plusieurs ligands PPAR et un agent antioxydant pour l'obtention de compositions pharmaceutiques destinées au traitement et/ou à la prévention de l'obésité ainsi que des surcharges pondérales caractérisées par un index de poids corporel supérieur à 25 et inférieur à 30 induites par un traitement thérapeutique, comme le traitement du diabète de type I ou ILThe invention therefore relates to the use of a combination containing one or more PPAR ligands and an antioxidant agent for obtaining pharmaceutical compositions intended for the treatment and / or prevention of obesity as well as overweight characterized by body weight index greater than 25 and less than 30 induced by therapeutic treatment, such as treatment of type I or IL diabetes
L'invention concerne également les compositions pharmaceutiques contenant l'association entre un ou plusieurs dérivés favorisants les métabolismes lipidique et glucidique et plus particulièrement un ou plusieurs ligands PPAR et un agent antioxydant telle que définie précédemment en combinaison avec un ou plusieurs excipients pharmaceutiquement acceptable.The invention also relates to pharmaceutical compositions containing the association between one or more derivatives promoting lipid and carbohydrate metabolism and more particularly one or more PPAR ligands and an antioxidant agent as defined above in combination with one or more pharmaceutically acceptable excipients.
Parmi les compositions pharmaceutiques selon l'invention, on pourra citer plus particulièrement celles qui conviennent pour l'administration orale, parentérale, nasale, les comprimés simples ou dragéifiés, les comprimés sublinguaux, les gélules, les tablettes, les suppositoires, les crèmes, pommades, gels dermiques, etc..Among the pharmaceutical compositions according to the invention, mention may be made more particularly of those which are suitable for oral, parenteral, nasal administration, simple or coated tablets, sublingual tablets, capsules, tablets, suppositories, creams, ointments , dermal gels, etc.
La posologie varie selon le sexe, l'âge et le poids du patient, la voie d'administration, la nature de l'indication thérapeutique ou des traitements éventuellement associés et s'échelonne entre 0,1 mg et 1 g de chaque composant de l'association par 24 heures en une ou plusieurs prises.The dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication or any associated treatments and ranges from 0.1 mg to 1 g of each component of the combination per 24 hours in one or more doses.
Les exemples suivants illustrent l'invention mais ne la limitent en aucune façon.The following examples illustrate the invention but do not limit it in any way.
EXEMPLE A ; Variation dn poids corporelEXAMPLE A; Change in body weight
Des souris mâles C57 Black 6 ob/ob de 8 à 12 semaines ont été utilisées. Ces souris son diabétiques (type II) et souffrent d'hyperglycémie, d'hypertriglycéridémie et d'hyperinsulinémie. Après mise en quarantaine d'une semaine, elles ont été pesées puis randomisées en fonction de leur poids, et 6 groupes homogènes (poids de départ non significativement différent) ont été formés. Après avoir été pesées, ces souris sont traitées à la rosiglitazone (antidiabétique) seule ou en association avec le coenzyme Q10. Les molécules sont injectées par voie intrapéritonéale une fois par jour pendant 14 jours dans une solution DMSO 5 % / Solutol 15 % / Qsp H2O chauffée à 65°C pour assurer une bonne dissolution. La solution est de plus préchauffée avant injection. Les souris sont pesées tous les jours et le poids obtenu après 14 jours de traitement est relevé. Le traitement avec la rosiglitazone seule conduit à une augmentation de poids des souris supérieure ou égale à 5 grammes correspondant environ à 10% de plus que leur poids initial. L'association rosiglitazone+coenzyme Q10 permet de réverser cette prise de poids d'au moins 50% et met en évidence l'efficacité de l'association dans la réduction du poids corporel.Male mice C57 Black 6 ob / ob from 8 to 12 weeks were used. These mice are diabetic (type II) and suffer from hyperglycemia, hypertriglyceridemia and hyperinsulinemia. After quarantining for one week, they were weighed and then randomized according to their weight, and 6 homogeneous groups (starting weight not significantly different) were formed. After being weighed, these mice are treated with rosiglitazone (antidiabetic) alone or in combination with coenzyme Q 10 . The molecules are injected intraperitoneally once a day for 14 days in a 5% DMSO / 15% Solutol / Qsp H 2 O solution heated to 65 ° C to ensure good dissolution. The solution is further preheated before injection. The mice are weighed daily and the weight obtained after 14 days of treatment is noted. Treatment with rosiglitazone alone leads to an increase in weight of the mice greater than or equal to 5 grams corresponding approximately to 10% more than their initial weight. The association rosiglitazone + coenzyme Q 10 reverses this weight gain by at least 50% and highlights the effectiveness of the association in reducing body weight.
EXEMPLE B : Composition pharmaceutiqneEXAMPLE B Pharmaceutical composition
100 comprimés dosés à 30 mg de rosiglitazone et 10 mg de coenzyme Q10 100 tablets dosed with 30 mg rosiglitazone and 10 mg coenzyme Q 10
Rosiglitazone 3 gRosiglitazone 3 g
Coenzyme Q10 1 gCoenzyme Q 10 1 g
Amidon de blé 20 g Amidon de maïs 20 gWheat starch 20 g Corn starch 20 g
Lactose 30 g Stéarate de magnésium 2 gLactose 30 g Magnesium stearate 2 g
Silice 1 gSilica 1 g
Hydroxypropylcellulose 2 g Hydroxypropylcellulose 2 g

Claims

REVENDICATIQNS REVENDICATIQNS
1. Association contenant 1) un agent antioxydant et 2) un ligand PPAR mixte des sous- types réceptoriels α et γ, ou un ligand PPAR sélectif du sous-type réceptoriel α et un ligand PPAR sélectif du sous-type réceptoriel γ.1. Association containing 1) an antioxidant agent and 2) a mixed PPAR ligand of the receptor subtypes α and γ, or a selective PPAR ligand of the receptor subtype α and a selective PPAR ligand of the receptor subtype γ.
2. Association selon la revendication 1 dans laquelle le ligand PPAR est un ligand mixte des sous-types réceptoriels α et γ.2. Association according to claim 1 wherein the PPAR ligand is a mixed ligand of the receptor subtypes α and γ.
3. Association selon la revendication 1 contenant un ligand sélectif du sous-type réceptoriel α et un ligand sélectif du sous-type réceptoriel γ.3. Association according to claim 1 containing a selective ligand of the receptor subtype α and a selective ligand of the receptor subtype γ.
4. Association selon la revendication 1 dans laquelle le ligand PPAR sélectif du sous-type réceptoriel γ est la rosiglitazone ou un de ses sels d'addition à un acide ou à une base pharmaceutiquement acceptable.4. Association according to claim 1 in which the selective PPAR ligand of the receptor subtype γ is rosiglitazone or one of its addition salts with a pharmaceutically acceptable acid or base.
5. Association selon la revendication 1 dans laquelle l'agent antioxydant est l'ubiquinone ou coenzyme Qι0.5. Association according to claim 1 in which the antioxidant agent is ubiquinone or coenzyme Qι 0 .
6. Association qui est la rosiglitazone et le coenzyme Q10.6. Association which is rosiglitazone and coenzyme Q 10 .
7. Compositions pharmaceutiques contenant comme principe actif un ou plusieurs ligands7. Pharmaceutical compositions containing as active ingredient one or more ligands
PPAR en association avec un agent antioxydant selon l'une des revendications 1 à 6 seuls ou en combinaison avec un ou plusieurs excipients pharmaceutiquement acceptables.PPAR in combination with an antioxidant agent according to one of claims 1 to 6 alone or in combination with one or more pharmaceutically acceptable excipients.
8. Compositions pharmaceutiques selon la revendication 7 utiles pour la fabrication d'un médicament pour le traitement et/ou la prévention de l'obésité.8. Pharmaceutical compositions according to claim 7 useful for the manufacture of a medicament for the treatment and / or prevention of obesity.
9. Compositions pharmaceutiques selon la revendication 7 utiles pour la fabrication d'un médicament pour le traitement de l'obésité induite par un traitement thérapeutique. 9. Pharmaceutical compositions according to claim 7 useful for the manufacture of a medicament for the treatment of obesity induced by a therapeutic treatment.
10. Compositions pharmaceutiques selon la revendication 7 utiles pour la fabrication d'un médicament pour le traitement de l'obésité induite par un traitement du diabète de type I ou IL10. Pharmaceutical compositions according to claim 7 useful for the manufacture of a medicament for the treatment of obesity induced by a treatment of type I or IL diabetes
11. Compositions pharmaceutiques selon la revendication 7 utiles pour la fabrication d'un médicament pour le traitement et/ou la prévention des surcharges pondérales caractérisées par un index de poids corporel supérieur à 25 et inférieur à 30.11. Pharmaceutical compositions according to claim 7 useful for the manufacture of a medicament for the treatment and / or prevention of overweight characterized by a body weight index greater than 25 and less than 30.
12. Compositions pharmaceutiques selon la revendication 7 utiles pour la fabrication d'un médicament pour le traitement des surcharges pondérales caractérisées par un index de poids corporel supérieur à 25 et inférieur à 30 induites par un traitement thérapeutique.12. Pharmaceutical compositions according to claim 7 useful for the manufacture of a medicament for the treatment of overweight characterized by a body weight index greater than 25 and less than 30 induced by a therapeutic treatment.
13. Compositions pharmaceutiques selon la revendication 7 utiles pour la fabrication d'un médicament pour le traitement des surcharges pondérales caractérisées par un index de poids corporel supérieur à 25 et inférieur à 30 induites par un traitement du diabète de type I ou ïï.13. Pharmaceutical compositions according to claim 7 useful for the manufacture of a medicament for the treatment of overweight characterized by a body weight index greater than 25 and less than 30 induced by a treatment of type I or ïï diabetes.
14. Utilisation d'une association contenant un ou plusieurs ligands PPAR et un agent antioxydant pour l'obtention de compositions pharmaceutiques destinées au traitement et/ou à la prévention de l'obésité.14. Use of a combination containing one or more PPAR ligands and an antioxidant agent for obtaining pharmaceutical compositions intended for the treatment and / or prevention of obesity.
15. Utilisation d'une association selon l'une des revendications 1 à 6 pour l'obtention de compositions pharmaceutiques destinées au traitement et/ou à la prévention de l'obésité.15. Use of a combination according to one of claims 1 to 6 for obtaining pharmaceutical compositions intended for the treatment and / or prevention of obesity.
16. Utilisation d'une association contenant un ou plusieurs ligands PPAR et un agent antioxydant pour l'obtention de compositions pharmaceutiques destinées au traitement et/ou à la prévention de l'obésité induite par un traitement thérapeutique.16. Use of a combination containing one or more PPAR ligands and an antioxidant agent for obtaining pharmaceutical compositions intended for the treatment and / or prevention of obesity induced by a therapeutic treatment.
17. Utilisation d'une association selon l'une des revendications 1 à 6 pour l'obtention de compositions pharmaceutiques destinées au traitement et/ou à la prévention de l'obésité induite par un traitement thérapeutique. 17. Use of a combination according to one of claims 1 to 6 for obtaining pharmaceutical compositions intended for the treatment and / or prevention of obesity induced by a therapeutic treatment.
18. Utilisation d'une association contenant un ou plusieurs ligands PPAR et un agent antioxydant pour l'obtention de compositions pharmaceutiques destinées au traitement et/ou à la prévention de l'obésité induite par un traitement du diabète de type I ou IL18. Use of a combination containing one or more PPAR ligands and an antioxidant agent for obtaining pharmaceutical compositions intended for the treatment and / or prevention of obesity induced by a treatment of type I or IL diabetes
19. Utilisation d'une association selon l'une des revendications 1 à 6 pour l'obtention de compositions pharmaceutiques destinées au traitement et/ou à la prévention de l'obésité induite par un traitement du diabète de type I ou IL19. Use of a combination according to one of claims 1 to 6 for obtaining pharmaceutical compositions intended for the treatment and / or prevention of obesity induced by a treatment of type I or IL diabetes
20. Utilisation d'une association contenant un ou plusieurs ligands PPAR et un agent antioxydant pour l'obtention de compositions pharmaceutiques destinées au traitement et/ou à la prévention des surcharges pondérales caractérisées par un index de poids corporel supérieur à 25 et inférieur à 30.20. Use of a combination containing one or more PPAR ligands and an antioxidant agent for obtaining pharmaceutical compositions intended for the treatment and / or prevention of overweight characterized by a body weight index greater than 25 and less than 30 .
21. Utilisation d'une association selon l'une des revendications 1 à 6 pour l'obtention de compositions pharmaceutiques destinées au traitement et/ou à la prévention des surcharges pondérales caractérisées par un index de poids corporel supérieur à 25 et inférieur à 30.21. Use of a combination according to one of claims 1 to 6 for obtaining pharmaceutical compositions intended for the treatment and / or prevention of overweight characterized by a body weight index greater than 25 and less than 30.
22. Utilisation d'une association contenant un ou plusieurs ligands PPAR et un agent antioxydant pour l'obtention de compositions pharmaceutiques destinées au traitement et/ou à la prévention des surcharges pondérales caractérisées par un index de poids corporel supérieur à 25 et inférieur à 30 induites par un traitement thérapeutique.22. Use of a combination containing one or more PPAR ligands and an antioxidant agent for obtaining pharmaceutical compositions intended for the treatment and / or prevention of overweight characterized by a body weight index greater than 25 and less than 30 induced by therapeutic treatment.
23. Utilisation d'une association selon l'une des revendications 1 à 6 pour l'obtention de compositions pharmaceutiques destinées au traitement et/ou à la prévention des surcharges pondérales caractérisées par un index de poids corporel supérieur à 25 et inférieur à 30 induites par un traitement thérapeutique.23. Use of a combination according to one of claims 1 to 6 for obtaining pharmaceutical compositions intended for the treatment and / or prevention of overweight characterized by a body weight index greater than 25 and less than 30 induced by therapeutic treatment.
24. Utilisation d'une association contenant un ou plusieurs ligands PPAR et un agent antioxydant pour l'obtention de compositions pharmaceutiques destinées au traitement et/ou à la prévention des surcharges pondérales caractérisées par un index de poids corporel supérieur à 25 et inférieur à 30 induites par un traitement du diabète de type I ou24. Use of a combination containing one or more PPAR ligands and an antioxidant agent for obtaining pharmaceutical compositions intended for the treatment and / or prevention of overweight characterized by a body weight index greater than 25 and less than 30 induced by treatment of type I diabetes or
IL HE
25. Utilisation d'une association selon l'une des revendications 1 à 6 pour l'obtention de compositions pharmaceutiques destinées au traitement et/ou à la prévention des surcharges pondérales caractérisées par un index de poids corporel supérieur à 25 et inférieur à 30 induites par un traitement du diabète de type I ou IL 25. Use of a combination according to one of claims 1 to 6 for obtaining pharmaceutical compositions intended for the treatment and / or prevention of overweight characterized by a body weight index greater than 25 and less than 30 induced by treatment of type I or IL diabetes
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MY140562A (en) 2009-12-31
EA200500609A1 (en) 2005-10-27
BR0314539A (en) 2005-07-26
NZ566708A (en) 2009-11-27
AU2003299772C1 (en) 2009-08-27
EP1815858A2 (en) 2007-08-08
CA2501964A1 (en) 2004-04-22
CN100571776C (en) 2009-12-23
AR041579A1 (en) 2005-05-18
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US20060002911A1 (en) 2006-01-05
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MA27402A1 (en) 2005-06-01
WO2004032967A8 (en) 2005-05-06
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FR2845602A1 (en) 2004-04-16
AU2003299772B2 (en) 2009-03-12

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