EP2078031A2 - Monoester von östrogenen mit konjugierter linolsäure und anwendungen davon - Google Patents

Monoester von östrogenen mit konjugierter linolsäure und anwendungen davon

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Publication number
EP2078031A2
EP2078031A2 EP07846512A EP07846512A EP2078031A2 EP 2078031 A2 EP2078031 A2 EP 2078031A2 EP 07846512 A EP07846512 A EP 07846512A EP 07846512 A EP07846512 A EP 07846512A EP 2078031 A2 EP2078031 A2 EP 2078031A2
Authority
EP
European Patent Office
Prior art keywords
fatty acid
cis
acid
trans
estrogen
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Withdrawn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
EP07846512A
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English (en)
French (fr)
Inventor
Marià ALEMANY LAMANA
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.)
Oleoyl-Estrone Developments SL
Original Assignee
Oleoyl-Estrone Developments SL
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
Application filed by Oleoyl-Estrone Developments SL filed Critical Oleoyl-Estrone Developments SL
Publication of EP2078031A2 publication Critical patent/EP2078031A2/de
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0051—Estrane derivatives
    • C07J1/0059—Estrane derivatives substituted in position 17 by a keto group
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/566—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol having an oxo group in position 17, e.g. estrone
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom
    • C07C69/587—Monocarboxylic acid esters having at least two carbon-to-carbon double bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane

Definitions

  • the present invention relates to substantially pure monoesters of conjugated fatty acids and an estrogen. It also relates to pharmaceutical and/or cosmetic compositions which contain them, as well as to their uses.
  • Oleoyl estrone is a compound product of the condensation of the estrogen called estrone or 3-hydroxyestra-1 , 3,5(10)-trien-17-one, with the fatty acid called oleic acid or cis-9 octadecenoic acid.
  • EP0771817 discloses that oleoyl estrone (OE) is a compound with the capacity to treat obesity and/or weight problems in mammals.
  • EP1380300 also discloses the use of OE for the preparation of a drug for the treatment and/or prophylaxis of a metabolic disease selected from diabetes mellitus type 2, hyperlipidemia and metabolic syndrome or syndrome X.
  • diabetes mellitus type 2 also called non-insulin- dependent diabetes mellitus (NIDDM)
  • NIDDM non-insulin- dependent diabetes mellitus
  • diabetes mellitus type 2 entails less severe effects than diabetes mellitus type 1 or insulin-dependent, where there is a defect in the hormone production by the pancreatic cells responsible for it.
  • the hyperglycemia and hyperinsulinemia typical of diabetes mellitus type 2 are usually accompanied by other physiological dysfunctions such as arterial hypertension and/or hyperlipidemia, which contributes to making this pathology worse.
  • These symptoms of hyperglycemia and hyperinsulinemia with arterial hypertension and/or hyperlipidemia and obesity is also known with the name of metabolic syndrome.
  • conjugated linoleic acids CLA
  • Conjugated linoleic acid or CLA means any fatty acid of eighteen or more carbons with at least two double bonds arranged so that a double bond alternates with a single bond.
  • CLA relates more specifically to a family of eight geometric isomers of the linoleic acid (cis,cis-9,12-octadecadienoic acid), which is preferably found in meat and dairy products.
  • CLA has different isomers of C18:2, the most typical being cis9- trans11 acid or cis,trans-9,11-octadecadienoic acid and trans10-cis12 acid or trans,cis-10, 12-octadecadienoic acid.
  • linoleic acid conjugated
  • the linoleic acid is a specific and defined chemical species: an unsaturated omega-6 fatty acid, whose molecular formula is C 18 H 32 O 2 and with double bonds in cis in carbons 9 and 12, i.e. the linoleic acid is not a conjugated linoleic acid.
  • Conjugated linoleic acid and obesity control efficacy and mechanisms, lnt J Obesity 2004; 28: 941-955, Wang YM et al. Isomer specific anti-obese and hypolipidemic properties of conjugated linoleic acid in obese OLETF rats. Biosci Biotechnol Biochem 2006; 70: 355-362).
  • CLA is present in multiple functional foods, which are used to decrease body fat, but which entail undesired secondary effects and are not always successful.
  • Controlling the levels of insulin circulating in blood is of evident importance in the aforementioned diseases, for which purpose numerous efforts are being carried out to localize molecules which permit said control or which improve the effects of the already known drugs. Any substance which permits controlling or treating excess weight and obesity in mammals is also of interest.
  • the present invention has the object of a substantially pure fatty acid monoester of an estrogen, where the estrogen is estrone; and the fatty acid is a fatty acid of at least eighteen carbons with at least two double bonds arranged in a conjugated system.
  • Another object of the present invention is a substantially pure fatty acid monoester of an estrogen, where the estrogen is estrone and the fatty acid is a conjugated linoleic fatty acid, i.e. a fatty acid of at least eighteen carbons, with at least two double bonds separated by a single bond.
  • a conjugated fatty acid is defined as a molecule with a carboxyl group and an aliphatic chain which comprises two or more double bonds between carbons, said bonds being arranged according to a conjugated system, i.e. between carbon atoms covalently bonded together by a single and a multiple bond, double or triple, which are alternated.
  • the substantially pure fatty acid monoester of an estrogen according to the invention is characterized in that the estrogen is estrone and the conjugated fatty acid of at least eighteen carbons is a conjugated linoleic acid selected from the group consisting of: cis,cis-9,11-octadecadienoic acid; cis, trans-9,11- octadecadienoic acid; trans, cis-9,11-octadecadienoic acid; trans,trans-9,11- octadecadienoic acid; cis,cis-10,12-octadecadienoic acid; cis,trans-10,12- octadecadienoic acid; trans,cis-10,12- octadecadienoic acid; and trans.trans-10,12- octadecadienoic acid.
  • the fatty acid monoester of an estrogen is the monoester of estrone with the conjugated linoleic acid trans,cis-10,12-octadecadienoic, in accordance with formula I.
  • Another object of the invention is a pharmaceutical and/or cosmetic composition which comprises a therapeutically and/or cosmetically effective quantity of a fatty acid monoester of an estrogen, where the estrogen is estrone and the fatty acid is a fatty acid of at least eighteen carbons with at least two double bonds arranged in a conjugated system, and the appropriate quantities of excipients for the desired administration route.
  • the pharmaceutical and/or cosmetic composition object of the invention is characterized in that it comprises a therapeutically and/or cosmetically effective quantity of a fatty acid monoester of an estrogen, where the estrogen is estrone and the fatty acid is a conjugated linoleic acid.
  • the pharmaceutical and/or cosmetic composition comprises a substantially pure fatty acid monoester of an estrogen, where the estrogen is estrone and the conjugated linoleic fatty acid is a fatty acid selected from the group consisting of: cis, cis-9, 11 -octadecadienoic acid; cis, trans-9, 11 -octadecadienoic acid; trans, cis-9, 11 -octadecadienoic acid; trans,trans-9, 11 -octadecadienoic acid; cis,cis-10,12-octadecadienoic acid; cis.trans- 10,12-octadecadienoic acid; trans,cis-10,12-octadecadienoic acid; and trans.trans- 10,12-octadecadienoic acid.
  • the pharmaceutical and/or cosmetic composition comprises the monoester of estrone with the conjugated lino
  • composition according to the invention is characterized in that it is for oral administration a nd the f atty acid monoester o f an estrogen is in pure form or suspended in a lipophilic emulsion in the form of emulsion or solution.
  • the composition is in the form of gel, capsules or tablets.
  • a further object of the present invention is the use of a fatty acid monoester of an estrogen, where the estrogen is estrone and the fatty acid is a fatty acid of at least eighteen carbons with at least two double bonds arranged in a conjugated system, preferably a conjugated linoleic acid, for the preparation of a drug for the treatment and/or prophylaxis of obesity and/or excess weight in mammals.
  • the fatty acid monoester of an estrogen where the estrogen is estrone and the conjugated linoleic fatty acid is an acid selected from the group consisting of cis,cis-9,11-octadecadienoic acid; cis, trans-9,11-octadecadienoic acid; trans, cis-9,11-octadecadienoic acid; trans,trans-9, 11 -octadecadienoic acid; cis,cis-10,12-octadecadienoic acid; cis.trans-
  • 10,12-octadecadienoic acid is used for the preparation of a drug for the treatment and/or prophylaxis of obesity and/or excess weight in mammals.
  • the monoester of estrone with the conjugated linoleic acid trans,cis-10,12-octadecadienoic in accordance with formula I, is used for the preparation of a drug for the treatment and/or prophylaxis of obesity and/or excess weight in mammals.
  • a further object of the invention is the use of a fatty acid monoester of an estrogen, where the estrogen is estrone and the fatty acid is a fatty acid of at least eighteen carbons with at least two double bonds arranged in a conjugated system, preferably a conjugated linoleic acid, for the preparation of a drug for the treatment and/or prophylaxis of a mammal that suffers from a disease related to the metabolic syndrome, selected from diabetes mellitus type 2, hyperlipidemia, glucose intolerance, hyperinsulinemia or insulin resistance, or a combination thereof.
  • the monoester of estrone with the conjugated linoleic acid trans,cis-10,12-octadecadienoic in accordance with formula I, is used for the preparation of a drug for the treatment and/or prophylaxis of a mammal that suffers from a disease related to the metabolic syndrome, selected from diabetes mellitus type 2, hyperlipidemia, glucose intolerance, hyperinsulinemia or insulin resistance, or a combination thereof.
  • the metabolic disease is insulin resistance which constitutes the basis of diabetes mellitus type 2.
  • the metabolic disease is hyperlipidemia.
  • the fatty acid monoester of estrone is used for the preparation of a drug for the treatment and/or prophylaxis of hypertriglyceridemia, hypercholesterolemia and hyperlipoproteinemia.
  • the metabolic disease is the metabolic syndrome associated with glucose intolerance, hyperlipidemia, hyperinsulinemia, and/or insulin resistance.
  • the use of the fatty acid monoester of an estrogen according to the invention is characterized in that it is for a mammal and, specifically, a human being.
  • Fig. 1 corresponds to a graphic which compares the change in body weight in male Wistar rats treated with monoester of estrone and oleic acid (oleoyl estrone
  • Fig. 2 is a graphic which represents the food consumption per gram and day with respect to the days of treatment with CLE, OE or without treatment (Control: C);
  • Fig. 3 represents the balance of energy calculated for each group of the experiment.
  • Ei Supply or intake of energy
  • Is Energy storage
  • Ee Energy expenditure.
  • the columns represent the energy expenditure in watts (W) of six animals per each group. They also indicate the contribution or consumption of food and the reserves of internal energy; and
  • Fig. 4 corresponds to a bar diagram where the effects of OE and CLE have been compared on those physiological parameters which show significant differences with respect to the controls (C).
  • the data represent the effect of CLE on percentages of the effects of OE.
  • Example 1 Effect of CLE on body weight. Comparison with OE.
  • mice Male Wistar rats, 45 days old (Harlan-lnterfauna, Sant FeNu de Codines, Barcelona) were used to determine the effects of the monoester of estrone with conjugated linoleic acid (CLE), on body weight.
  • the rats were maintained in standard housing conditions in collective enclosures and they were fed "ad libitum" during five weeks with a modified cafeteria diet. At the end of this period, the animals had excess weight. The rats were then fed with maintenance fodder for rats (Panlab, Barcelona, Spain).
  • the rats were used when they were 90 days old and weighed 330 to 390 grams.
  • This protocol managed to achieve an accumulation of around 17% of the body weight in the form of fat, which represents approximately double the fat content of this type of rat and for this age.
  • This experimental model is comparable with a human with excess weight.
  • Group 1 Zero-time controls.
  • Group 2 Controls (C).
  • Group 3 Rats that received oleoyl estrone (OE) daily at a dose of 10 nmol per gram of weight of the rat.
  • OE oleoyl estrone
  • Group 4 Rats that received conjugated (trans 10-cis12) linoleoyl estrone (CLE) at the same dose as group 3.
  • the rats of group 1 were sacrificed and processed to obtain the proportions of the components at zero time.
  • the experiment lasted 10 days. At the end of it, the rats were sacrificed by decapitation and the blood was collected for it to coagulate. The serum was separated and stored at -8O 0 C. The rats were dissected, removing the content of the stomach and intestines.
  • the tract and the organs were heat treated in the autoclave and were homogenized.
  • the rat paste obtained was used to estimate the lipid and energy content (an adiabatic calorimeter of type C-7000 Ika, Heitersheim, Germany was used).
  • the percentages of the body composition of the control animals were used to determine the absolute content in lipids, proteins and energy of the rats at the start of the experiment, applying these values to their initial weight.
  • the measurement of the body weight and the composition of the rats at the end of the study was used to determine the changes in body size and in the composition, caused by the 10 days of treatment.
  • the energy supply was estimated from the food consumed, which contained metabolizable energy of 13.3 kJ/g; the reservation or storage of energy was the difference between the estimated energy on day 0 and the energy content at day 10. The average energy consumed was calculated as the difference between energy supply and energy store.
  • the serum was used to measure the following parameters: glucose, non- esterified fatty acids (NEFA), total triacylglycerols, total cholesterol, urea, insulin, leptin and adiponectin.
  • the details correspond to the mean ⁇ the standard error of the average of 6 different animals.
  • Fig. 2 represents the food consumption both in the animals that received CLE and those that received OE. From them, it was observed that each group followed a very different pattern, being the median of the controls of 18.610.1 grams per day during the 10-day period, those of group OE of 81 0.2 and those of group
  • Fig. 3 represents the calculated energy balance. From this, it is gathered that there are no differences in the energy expenditure value (Ee). This is due to the fact that the modifications in the energy supply are compensated by the body reserves.
  • Example 2 Effect of CLE on metabolites and circulating hormones. Comparison with the OE
  • the details correspond to the mean ⁇ the standard error of the mean of 11-12 different animals.
  • the other hormones, leptin and adiponectin, are found in lower proportion than in groups OE and CLE with respect to the controls, although they decrease in a similar proportion.
  • Oleoyl estrone reduces the insulin levels and, therefore, it is expected that the combination of an oleoyl estrone type activity and an additional effect of CLA cause a reduction in the efficacy of insulin in comparison with the oleoyl estrone administered alone. Nevertheless, the results of Examples 1 and 2 demonstrate the opposite, i.e. they lead to an improvement in the effects of the oleoyl estrone (OE). The effects of CLA in relation to insulin resistance are still not very clear and it is postulated that the oxidative stress induced by the fatty acids intervenes.
  • the "type OE" effects of the CLE result in a potent mobilization of fat from the adipose tissue and its subsequent oxidation in the muscle, which justifies its use against obesity and excess weight.
  • the levels of NEFA and lipids in the blood do not change despite their increased exchange.
  • the possible effects of CLE on the fatty acid dynamics on a cell level may be due to the fact that the CLA obtained once the CLE molecule has been hydrolyzed finds an environment which favours the inhibition of its actions or effects known to date.
  • the decrease in blood leptin and the increase in adiponectin caused by CLE are similar to those promoted by the OE molecule alone.
  • Fig. 4 compares the effects of OE and CLE on several parameters which have significant differences with respect to the controls.
  • CLE induces greater effects in the levels of insulin and leptin than OE.
  • the effects on cholesterol, glucose and adiponectin are similar for both compounds.
  • the decrease in food consumption, energy loss and triacylglycerols and circulating lipids in general, caused by the administration of CLE are somewhat less than the same effects caused by OE, although they maintain their efficacy. Nevertheless, this relatively lower capacity to mobilize lipids does not affect other parameters, such as their hypercholesterolemia effects or the modulation of the adiponectin levels, or the normalization of the glycemia.
  • the monoester of conjugated linoleic acid of estrone seems to produce a greater decrease in the leptin and insulin levels than the oleoyl estrone (OE). This fact can be explained by the CLA action and the "mimetic or type OE effect" in the target tissues. We can thus state that the monoester of estrone with conjugated linoleic acid (CLE) represents a considerable improvement with respect to the oleoyl estrone (OE) on its effects on insulin resistance, showing a greater efficacy in cytokine control.
  • the monoester of estrone with conjugated linoleic acid referred to corresponds to the monoester of estrone with the conjugated linoleic acid trans,cis-10,12-octadecadienoic or 10trans-12cis-linoleoyl- estrone according to formula I.
  • any of the stereoisomeric variants described above as conjugated linoleic fatty acid have similar effects. That it to say, the other conjugated linoleic acids selected from cis, cis-9,11-octadecadienoic acid; cis, trans-9,11- octadecadienoic acid; trans, cis-9,11-octadecadienoic acid; trans,trans-9,11- octadecadienoic acid; cis,cis-10,12-octadecadienoic acid; cis,trans-10,12- octadecadienoic acid; and trans,trans-10,12-octadecadienoic acid.
  • the monoester of estrone and conjugated linoleic acid is useful for the preparation of a drug for the treatment and/or prophylaxis of a human that suffers from a disease from among the following: diabetes mellitus type 2; hyperlipidemia; and Metabolic syndrome, associated to glucose intolerance, hyperinsulinemia or insulin resistance.
  • the so-called insulin resistance effect is produced, or in other words, the insulin hormone in the blood is incapable of promoting the uptake of glucose from the blood to the tissues.
  • the surprising effect of the monoester of estrone with conjugated linoleic acid (CLE), stated in Examples 1 and 2 of the present invention and according to which the CLE is capable of controlling the blood insulin levels with greater sensitivity and proportion are useful for the preparation of a drug for the treatment or prophylaxis of the aforementioned diseases.
  • compositions that contain monoester of estrone with conjugated linoleic acid (CLE) with the pharmaceutically acceptable excipients
  • preparations are produced with the suitable quantities of the active ingredient and the compounds useful for the correct formulation and preservation thereof.
  • excipients are used such as methylparaben or propylparaben, or carrier vehicles of the active ingredient such as sunflower or soy oil.
  • carrier vehicles of the active ingredient such as systems of liposomes, microcapsules or nanocapsules, etc.
  • compositions are formulated, preferably, so that they can be orally administered as drinkable preparations, such as gels or in tablets or capsules.
  • drinkable preparations such as gels or in tablets or capsules.
  • the monoester of estrone with conjugated linoleic acid is very advantageous in comparison with the majority of the drugs that are currently administered to persons who suffer from any of the aforementioned diseases.
  • the drugs administered can be substituted by injection (injectable) in the case of diabetes mellitus type 2.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Diabetes (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP07846512A 2006-10-30 2007-10-26 Monoester von östrogenen mit konjugierter linolsäure und anwendungen davon Withdrawn EP2078031A2 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ES200602751A ES2302449B1 (es) 2006-10-30 2006-10-30 Monoesteres de estrogenos con acido linoleico conjugado y usos de los mismos.
PCT/EP2007/009309 WO2008052709A2 (en) 2006-10-30 2007-10-26 Monoesters of estrogens with conjugated linoleic acid and uses thereof

Publications (1)

Publication Number Publication Date
EP2078031A2 true EP2078031A2 (de) 2009-07-15

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WO (1) WO2008052709A2 (de)

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Publication number Priority date Publication date Assignee Title
US8809560B2 (en) 2011-05-17 2014-08-19 Board Of Trustees Of The University Of Arkansas Trans-, trans-conjugated linoleic acid compositions and use thereof
EP2567959B1 (de) 2011-09-12 2014-04-16 Sanofi 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridin-4-carbonsäureamid-derivate als kinaseinhibitoren
US9062276B2 (en) 2012-12-03 2015-06-23 Board Of Trustees Of The University Of Arkansas Conjugated linoleic acid rich vegetable oil production from linoleic rich oils by heterogeneous catalysis

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Publication number Priority date Publication date Assignee Title
DE69626927T2 (de) * 1995-10-30 2003-11-20 Oleoyl-Estrone Developments, S.I. Oleat Monoester von Estrogenen zur Behandlung von Fettleibigkeit
WO2003018529A1 (en) * 2001-08-24 2003-03-06 Girouard Michael P Monounsaturated fatty acids of at least 20 carbon atoms and perhydrocyclopentanophenanthrene nucleus combination molecules and their use as weight-loss agents
AU2003294489A1 (en) * 2002-11-20 2004-06-15 Michael P. Girouard Combination of monounsaturated fatty acids and estrogen, and their use
US20060084636A1 (en) * 2004-10-18 2006-04-20 Maria Alemany Methods of using fatty-acid esters of estrogens and serotonin reuptake inhibiting compounds for reducing the body weight of a mammal and compositions containing the same
US20060084637A1 (en) * 2004-10-18 2006-04-20 Maria Alemany Methods of using fatty-acid esters of estrogens and thermogenic compounds for reducing the body weight of a mammal and compositions containing the same

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Title
See references of WO2008052709A2 *

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WO2008052709A2 (en) 2008-05-08
WO2008052709A3 (en) 2008-07-03
ES2302449B1 (es) 2009-06-12

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