WO2003030891A1 - Utilizacion del acido hidroxioleico y compuestos analogos del mismo en la fabricacion de medicamentos - Google Patents

Utilizacion del acido hidroxioleico y compuestos analogos del mismo en la fabricacion de medicamentos Download PDF

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Publication number
WO2003030891A1
WO2003030891A1 PCT/ES2002/000475 ES0200475W WO03030891A1 WO 2003030891 A1 WO2003030891 A1 WO 2003030891A1 ES 0200475 W ES0200475 W ES 0200475W WO 03030891 A1 WO03030891 A1 WO 03030891A1
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acid
general formula
hydroxyoleic
use according
compounds
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PCT/ES2002/000475
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English (en)
Spanish (es)
French (fr)
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Pablo Vicente Escriba Ruiz
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Universitat De Les Illes Balears
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Priority to BRPI0213165A priority Critical patent/BRPI0213165B8/pt
Priority to DE60210488T priority patent/DE60210488T2/de
Priority to EP02783094A priority patent/EP1435235B1/en
Priority to ES02783094T priority patent/ES2261752T3/es
Priority to MXPA04003255A priority patent/MXPA04003255A/es
Priority to JP2003533923A priority patent/JP4737931B2/ja
Priority to US10/488,726 priority patent/US20050014831A1/en
Priority to CA2463348A priority patent/CA2463348C/en
Publication of WO2003030891A1 publication Critical patent/WO2003030891A1/es
Priority to US12/082,938 priority patent/US7851507B2/en
Priority to US12/939,641 priority patent/US8778995B2/en

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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61P35/00—Antineoplastic agents
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to the application of hydroxyoleic acid (2-hydroxyoleic acid) and molecules of analogous structure as antitumor agents, as agents with hypotensive activity and as agents that allow inducing reductions in body weight.
  • the present invention also relates to the use of 2-hydroxyoleic acid and the like to regulate the membrane structure, regulate the activity and / or localization of G proteins and regulate the activity of receptors coupled to G proteins through the regulation of the membrane structure
  • the present invention also relates to the use of 2-hydroxyoleic acid and the like for the manufacture of medicaments intended for the treatment of cancer, medicaments intended for the treatment of cardiovascular diseases and medicaments intended for the treatment of body weight problems or obesity.
  • JP 10182338 refers to an oil-in-water emulsifying composition that shows low irritability and high salt compatibility, which contains: [A] non-ionic surfactants such as polyoxyethylene sorbitol monolaurate, monooleate from polyoxyethylene sorbitol and polyoxyethylene sorbitol monostearate, [B] 2-hydroxy C10-C22 fatty acids such as 2-hydroxystearic acid, [C] oils and [D] water, where the A / B ratio is between 1: 0 , 01 and 1: 2.
  • non-ionic surfactants such as polyoxyethylene sorbitol monolaurate, monooleate from polyoxyethylene sorbitol and polyoxyethylene sorbitol monostearate
  • 2-hydroxy C10-C22 fatty acids such as 2-hydroxystearic acid
  • [C] oils and [D] water where the A / B ratio is between 1: 0 , 01 and 1: 2.
  • JP 09110635 refers to compositions, useful as pharmaceuticals, cosmetics and food products containing: [A] polyglyceryl fatty acid esters, [B] C10-C22 2-hydroxy fatty acids, [C] oils and [D ] water, where the weight ratio of A / C and B / C is 2.0 and 0.5 respectively, and shows average particle sizes between 10 and 300 nm. These compositions show good stability even in acidic or low viscosity conditions or in the presence of high amounts of salts, thus being compatible with the skin.
  • this fatty acid has also been used as an inhibitor of oleamide hydrolase, an action that is associated with the effect of sleep induction of this substance (US Patents 6096784 and WO 9749667).
  • US patent 6096784 refers to the design and synthesis of oleamide hydrolase inhibitors, responsible for the hydrolysis of a lipid (cis-9-octadecenamide) inducer of sleep.
  • the most potent inhibitors have an electrophilic carbonyl group capable of reversibly forming a hemiacetal (thio) or a hemicetal (thio) to mimic the transition state of a reaction catalyzed by a cysteine or serine protease.
  • some of the inhibitors showed agonist activity which induces sleep in laboratory animals. Hexagonal membrane structures.
  • Membrane lipids are capable of ordering in a greater number of secondary structures than proteins and nucleic acids.
  • the tiplea lipid bilayer of biological membranes is only one of these secondary configurations. Much is unknown about the abundance and roles of other secondary structures in living cells. In a previous work of the inventors, a function of these structures is provided: to increase the binding affinity of G proteins to membranes (Write PV, Ozaita A, Ribas C, Miralles A, Fodor E, Farkas and Garcia-Sevilla JA; 1997 Proceedings of the National Academy of Sciences of the USA 94, 11375-11380).
  • the present invention aims to find new applications of 2-hydroxyoleic acid and analogous compounds thereof not related to those described in the state of the art.
  • a first objective of the present invention is to demonstrate that 2-hydroxyoleic acid and its analogs possess activity as antitumor agents.
  • a second objective of the present invention is to demonstrate that 2-hydroxyoleic acid and its analogs possess activity as hypotensive agents.
  • a third objective of the present invention is to demonstrate that 2-hydroxyoleic acid and its analogs possess activity as agents that induce body weight reduction.
  • a fourth objective of the present invention is to demonstrate that 2-hydroxyoleic acid and its analogs have application as regulating agents of the lamellar to hexagonal structure transition of cell membranes. Said regulation of the membrane structure influences the activity of G proteins, as well as the molecular entities of their transduction pathway, that is, their signal propagation path.
  • a high number of Drugs acts on G protein-coupled receptors through direct interaction with these types of molecules or with mechanisms related to cellular signals derived from their activity.
  • 2-Hydroxyoleic acid and its analogues act on the membrane structure.
  • 2-hydroxyoleic acid and its analogues have not been cited by anyone previously and their use may be beneficial for the treatment of certain pathologies.
  • 2-hydroxyoleic acid and its analogues have antitumor activity, hypotensive (or anti-hypertensive) activity and induce reductions in body weight.
  • the new applications of 2-hydroxyoleic acid and its analogs are justified using experimental models, in particular in vitro analysis systems, cell culture systems and living organisms.
  • 2-hydroxyoleic acid and its analogues are molecules that can be used to make drugs for the treatment of cancer, for the treatment of cardiovascular diseases and for the treatment of subjects with problems of body weight or obesity, as well as other diseases or deficiency states based on the regulation of signals associated with G proteins, mediated by the lamellar to hexagonal transition of the membrane structure.
  • 2-hydroxyoleic acid means ⁇ -hydroxyoleic acid, C18 octadecenoic acid: 1 cis ⁇ 9 or cis-2-Hydroxy-9-octadecenoic acid.
  • Its analogues mean those fatty acids that have the double bond displaced one or two positions of the central zone and / or which have the double bond displaced from one to five positions of the central zone and / or have one to six carbon atoms (CH Groups) more or less on each side of the double bond and / or having a residue (R) in position 2 different from OH, with a small atomic mass (Mw equal to or less than 200 Da).
  • Proteins G means guanine nucleotide binding proteins, formed by three subunits (one alpha, one beta and one gamma) that transmit signals from G-protein coupled receptors to effectors (adenylyl cyclase, guanilyl cyclase, phospholipase C, ion channels, etc.).
  • membrane structure is understood as the secondary structure or arrangement of lipids in natural or synthetic membranes (liposomes).
  • acute effect means the effect that occurs within a period of time between minutes and a few hours after a single administration of a drug.
  • chromenic effect means the effect that occurs within a period of time between a few days and several weeks of continuous administration of a drug.
  • pharmaceutically acceptable forms are understood as any of those routinely used in the sector, including, but not limited to: esters, especially ethyl ones, for their solubilizing properties of fatty acids, ethers, amides, salts, etc ...
  • An objective of the present invention is the application of 2-hydroxyoleic acid and its analogs in the regulation of the transition of lamellar to hexagonal structure of cell membranes.
  • the molecular basis of this phenomenon lies in the interaction of 2-hydroxyoleic acid and its analogs with membranes and in the modulation of the composition and / or membrane structure (Tables 1 and 2).
  • a T H indicates the transition temperature of lamellar to hexagonal structure.
  • Table 1 Indicates the transition temperature values of lamellar to hexagonal structures in Dielaidoyl phosphatidylethanolamine (DEPE) membranes.
  • the control value in the absence of 2-hydroxyoleic acid
  • the reduction (concentration dependent) induced by 2-hydroxyoleic acid (20HOA) indicates that this molecule stabilizes the presence of non-lamellar structures. This important alteration of the cell membrane has important consequences on molecular and cellular function. All tested 2-hydroxyoleic analogues that have therapeutic activity also induce effects on the membrane structure (Table 2).
  • Hydroxyoleic acid and the compounds analogous to it are capable of modulating protein activity
  • G protein-coupled receptors are ubiquitous, constituting 80% of membrane receptors that transmit signals initiated by neurotransmitters, hormones, neuromodulators, cytokines, growth factors, etc.
  • the molecules described in this invention can regulate said physiological processes.
  • the most effective and powerful technique for studying membrane structure is X-ray diffraction / scattering.
  • This technique we have determined that the membrane structure is altered by 2-hydroxyoleic acid and the like.
  • the reduction in the transition temperature of lamellar to hexagonal structure indicates an important effect on the rearrangement of lipid molecules in the membrane.
  • This regulation of rearrangement is the basis of the effect of 2-hydroxyoleic acid and the like.
  • All the analogues studied, which comply with the general formula, have activity of Modulate the membrane and regulate cell proliferation (effectiveness in cancer), blood pressure (effectiveness in cardiovascular processes) and body weight (effectiveness in obesity).
  • An objective of the present invention is to demonstrate that 2-hydroxyoleic acid and the like possess activity as antitumor agents.
  • the cell cycle is regulated by growth factors that bind to specific cell surface receptors.
  • the union of said growth factors with the receptors gives rise to a cascade of reactions destined to activate mitogenic kinases (cdk) that form dimeric complexes with the cell cycle associated proteins called cyclines.
  • cdk mitogenic kinases
  • the cdk / cyclin complexes regulate the phases of the cell cycle and its progression to produce mitosis and cell division.
  • G proteins are coupled to G proteins, so that when the interaction of the growth factor with the receptor occurs, the G protein is activated, triggering the aforementioned reaction cascade.
  • the mechanism associated with the antitumor effects of 2-hydroxyoleic acid and the like is based on the fact that they induce the modulation of the location and activity of G proteins and other peripheral proteins, such as protein kinase C or small G proteins (type Ras, Raf, etc.). This modulation is associated with the regulation of the structure of membrane lipids.
  • p53 protein which exerts a negative type control by slowing cell division at the Gl level (pre-mitosis stage). This protein is synthesized by the cell itself in response to the appearance or alterations of the DNA. If the replicated DNA can negatively influence the daughter cells, the p53 protein is activated resulting in apoptosis (programmed cell death). The activation of said p53 protein causes other genes to be expressed that code for regulatory proteins such as p21, p27, pl6, etc., that inhibit the activity / expression of cyclines and cdks (involved in the cell cycle process).
  • the p53 protein appears mutated and / or inactive, producing proliferation of transformed (cancerous) cells.
  • the presence of 2-hydroxyoleic acid and / or analogs in the cells induces the activation of the signal pathway associated with p53, which induces the onset of apoptosis or the cycle stop cell in different types of tumor cells.
  • in vitro and in vivo models have been used. In this sense, in this sense, 2-hydroxyoleic acid and all structural analogs that comply with the general formula I described above have been shown to have an important antitumor capacity.
  • the molecules analogous to 2-hydroxyoleic acid (2-hydroxy-cis-9-octadecenoic acid) tested have been: 2-methyl-oleic acid (2-methyl-cis-9-octadecenoic acid), 2-amino-oleic acid (2-amino -cis-9-octadecenoic acid, oleic acid (cis-9-octadecenoic acid), palmitoleic acid (cis-9-hexadecenoic acid), cis vaccenic acid (cis-11-octadecenoic acid) and nerve acid (cis-15-tetracosenoic acid) .
  • 2-hydroxyoleic acid and its analogues are molecules that can be used for the manufacture of drugs intended for the treatment of cancer; (b) that its spectrum of action is wide (it has been effective on different types of tumor cells in culture or in living organisms) and (c) that exceeds other molecules used for the treatment of cancer by its antitumor potency, by its absence of side effects and for being its administration orally, although it can also be performed intravenously or subcutaneously.
  • An objective of the present invention is to demonstrate that 2-hydroxyoleic acid and its analogs are agents with hypotensive activity.
  • G protein activity regulates blood pressure.
  • Blood pressure is controlled by several receptor systems coupled to G proteins, such as vasopressin receptors, adrenergic receptors, etc.
  • An objective of the present invention is to demonstrate that 2-hydroxyoleic acid and the like have activity as agents that induce body weight reductions (Figure 11).
  • Body weight is regulated, among others, by factors such as the individual's metabolic capacity and intake control.
  • the intake control is determined by the feeling of satiety, which in turn is regulated at the hormonal level. So for example, nutrient deficiency It stimulates the secretion of hormones that give rise to a feeling of appetite. After intake, once the nutrients are replenished, the secretion of hormones that give rise to a feeling of satiety is stimulated. It has been found that 2-hydroxyoleic acid and the like produce satiety effects, inducing reductions in food intake. This control is also mediated by cytokine receptors, leptins, adrenoreceptors, and other receptors coupled to G proteins, whose activity is modulated by these fatty acids.
  • Rats treated with these molecules decreased their body weight during chronic treatments (5 to 17 days).
  • rats treated with 2-hydroxyoleic acid or its analogs, in particular aminoleic acid had free access to food and water, similar to the group of control treated rats ( Figure 11).
  • the rats experienced a progressive decrease in body weight from the first day of treatment, up to 17 grams on the seventh day of treatment (5% of the normal body weight of a Sprague-Dowley rat of 2-3 months of age) .
  • the feed supplied to these animals was weighed and a lower consumption could be observed during the duration of the treatment, confirming that the treatments with the molecules related to this invention produce a satiety effect on the animal.
  • Similar experiments in adult mice, for periods of up to 28 days with 2-hydroxyoleic acid show reductions in body weight from 15% to 25%, compared to control mice (treated with vehicle).
  • Figure 1 Some of the many structures, in addition to the lamellar, that membranes can adopt.
  • Figure 2 shows the cellular localization of fluorescein-labeled G ⁇ i 2 protein in primary astrocytes of rat brain.
  • the marking indicates the presence of this protein in the whole cell, especially in the nucleus (arrow).
  • cells treated with 2-hydroxyoleic acid (20H0A) the marking appears in membrane and cytosol, but not in nucleus (arrow).
  • Figure 3 shows the effect of 2-hydroxyoleic acid on molecular markers of cell proliferation and death.
  • Panel A shows the effect of 2-hydroxyoleic acid (20H0A) on the cell cycle proteins cdk2, cyclin B and cyclin D3 in human lung cancer cells A549. The decrease of these proteins demonstrates that this fatty acid induces the cell cycle to stop, that is, the cell division to stop.
  • Panel B shows the effect of 2-hydroxyoleic acid (20H0A) on p21 protein in A549 cells after incubation for 24 and 48 hours. The p21 protein inhibits the cell cycle, making it an antiproliferative protein. The large increases induced by 2-hydroxyoleic acid on this protein justify the cycle stop and the proliferation of tumor cells.
  • Panel C shows the degradation of Poly-ADP Ribose polymerase (PARP) in human leukemia (Jurkat) cells (etoposide: 25 [El] and 250 ⁇ M [E2]; 2-hydroxyoleic acid: 10 [01], 100 [ 02] and 1000 ⁇ M [03]). Decreased levels of this enzyme, or evidence of its degradation, indicate the onset of apoptosis or programmed cell death. In these experiments the etoposide was used as a positive control, since it is a molecule known as inducer of apoptosis and antitumor.
  • PARP Poly-ADP Ribose polymerase
  • Figure 4 shows the effect of 2-hydroxyoleic acid and its analogs on the proliferation of human lung cancer cells A549 (A) and Jurkat cells of human leukemia (B).
  • 2-hydroxyoleic acid (20H0A) and its analogs which meet all the formula indicated above, induce the stopping of division and death of tumor cells (OA: oleic acid; VA: cis vaccenic acid; POA: palmitoleic acid; NA : nerve acid; 2MOA: 2-methyl oleic acid; 2NOA: 2-amino oleic acid.
  • Figure 5 shows the fixation of [ 35 S] GTP ⁇ S to membranes of NIH 3T3 cells transcribed with the rat ⁇ 2a / D adrenoceptor.
  • This parameter measures the activity of G proteins.
  • the presence of 2-hydroxyoleic induces a decrease in the function of G proteins even greater than anthracycline daunomycin (DNM).
  • DNS anthracycline daunomycin
  • Anthracyclines are potent antitumor drugs, so 2-hydroxyoleic acid is potentially more effective against tumors.
  • the 2-hydroxyoleic analogues produce an effect similar to that of 2-hydroxyoleic acid.
  • Figure 7 Levels of G proteins in erythrocyte membranes of normotensive (empty bars) and hypertensive (filled bars) subjects. Protein levels
  • G ⁇ i-L / 2 Gao (Go), Gas (Gs) and G G ⁇ (Gb) are significantly lower in hypertensive patients.
  • the values of the bars are means + standard error of the mean * P ⁇ 0.05, ** P ⁇ 0.01.
  • Figure 8 shows brain metastases (tumors), formed from a pulmonary adenocarcinoma.
  • the image on the left (8a) corresponds to the tumors before treatment and those on the right (8b, 8c and 8d) correspond to the tumors after treatment with 2-hydroxyoleic at different dates. As you can see, one of the tumors has disappeared more quickly and the other one more slowly.
  • Figure 9a shows the acute (2 hours, black bars) and chronic (3 daily injections for 7 days, white bars) effect of hydroxyoleic acid (30 mg / kg) on systolic blood pressure in Sprague-Dowley rats. Lower doses of this molecule (1-10 mg / kg) produced similar effects, although less marked. * P ⁇ 0.01.
  • Figure 9b shows the effect of 2-hydroxyoleic acid (30 mg / kg) on blood pressure in humans.
  • This graph represents systolic blood pressure according to the day of treatment. The days before treatment are indicated with negative values. * P ⁇ 0.05, ** P ⁇ 0.01.
  • Figure 10 shows the effect of acute treatments with 2-hydroxyoleic acid (20HOA) and its 2-methyl-oleic (2MOA), oleic (OA), palmitoleic (POA), vaccenic cis (VA) and nerve (NA) analogs . All treatments performed with 2-hydroxyoleic acid and the analogues that meet the general formula given above induced significant decreases (* P ⁇ 0.05, ** P ⁇ 0.001) of systolic blood pressure in Sprague-Dowley rats.
  • 2-hydroxyoleic acid (20HOA) and its 2-methyl-oleic (2MOA), oleic (OA), palmitoleic (POA), vaccenic cis (VA) and nerve (NA) analogs All treatments performed with 2-hydroxyoleic acid and the analogues that meet the general formula given above induced significant decreases (* P ⁇ 0.05, ** P ⁇ 0.001) of systolic blood pressure in Sprague-Dowley rats.
  • Figure 11 shows the effect of 2-hydroxyoleic acid (OHOA) and its analogues, oleic acid (OA) and palmitoleic acid (POA) on body weight (3 daily injections of 30 mg / kg).
  • the animals Sprague- rats Dowley) had free access to food and water at all times.

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PCT/ES2002/000475 2001-10-11 2002-10-09 Utilizacion del acido hidroxioleico y compuestos analogos del mismo en la fabricacion de medicamentos WO2003030891A1 (es)

Priority Applications (10)

Application Number Priority Date Filing Date Title
BRPI0213165A BRPI0213165B8 (pt) 2001-10-11 2002-10-09 uso de ácido hidroxioléico e compostos relacionados na manufatura de drogas
DE60210488T DE60210488T2 (de) 2001-10-11 2002-10-09 Verwendung von hydroxyölsäure und ähnlicher verbindungen bei der herstellung von medikamenten
EP02783094A EP1435235B1 (en) 2001-10-11 2002-10-09 Use of hydroxyoleic acid and similar compounds in the production of medicaments
ES02783094T ES2261752T3 (es) 2001-10-11 2002-10-09 Uso del acido hidroxioleico y compuestos similares en la produccion de medicamentos.
MXPA04003255A MXPA04003255A (es) 2001-10-11 2002-10-09 Utilizacion de acido hidrocioleico y compuestos analogos del mismo en la fabricacion de medicamentos.
JP2003533923A JP4737931B2 (ja) 2001-10-11 2002-10-09 医薬品の製造におけるヒドロキシオレイン酸及び類似化合物の使用
US10/488,726 US20050014831A1 (en) 2001-10-11 2002-10-09 Use of hydroxyoleic acid and similar compounds in the production of medicaments
CA2463348A CA2463348C (en) 2001-10-11 2002-10-09 Use of hydroxyoleic acid and related compounds in the manufacture of drugs
US12/082,938 US7851507B2 (en) 2001-10-11 2008-04-15 Use of hydroxyoleic acid and related compounds in the manufacture of drugs
US12/939,641 US8778995B2 (en) 2001-10-11 2010-11-04 Use of hydroxyoleic acid and related compounds in the manufacture of drugs

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ES200102269A ES2186576B1 (es) 2001-10-11 2001-10-11 Acido 2-hidroxioleico para utilizar como medicamento.
ESP200102269 2001-10-11

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US12/082,938 Division US7851507B2 (en) 2001-10-11 2008-04-15 Use of hydroxyoleic acid and related compounds in the manufacture of drugs

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ES2229935A1 (es) * 2003-10-10 2005-04-16 Universitat De Les Illes Balears Utilizacion del acido hidroxioleico y compuestos analagos del mismo como aditivos alimentarios funcionales.
WO2005041691A1 (en) * 2003-10-10 2005-05-12 Universitat De Les Illes Balears Use of hydroxyoleic acid and related compounds as functional food additives
EP2842556A2 (en) 2008-12-09 2015-03-04 Universitat de les Illes Balears Alpha-derivatives of cis-monounsaturated fatty acids for use as medicines
ES2342997A1 (es) * 2008-12-09 2010-07-20 Universitat De Les Illes Balears Derivados de acidos grasos cis-monoinsaturados para ser usados como medicamento.
RU2531353C2 (ru) * 2008-12-09 2014-10-20 Университат Де Лез Иль Балеар Альфа-производные цис-мононенасыщенных жирных кислот, предназначенные для применения в качестве лекарственного средства
WO2010066931A1 (es) 2008-12-09 2010-06-17 Universitat De Les Illes Balears Alfa-derivados de ácidos grasos cis-monoinsaturados para ser usados como medicamento
EP2842555A2 (en) 2008-12-09 2015-03-04 Universitat de les Illes Balears Alpha-derivatives of cis-monounsaturated fatty acids for use as medicines in the treatment of diabetes
US9000042B2 (en) 2008-12-09 2015-04-07 Universitat De Les Illes Balears α-Derivatives of cis-monounsaturated fatty acids intended for use as a drug
US9730906B2 (en) 2008-12-09 2017-08-15 Universitat De Les Illes Balears α-derivatives of cis-monounsaturated fatty acids for use as medicines
US10588883B2 (en) 2008-12-09 2020-03-17 Universitat De Les Illes Balears Alpha-derivatives of cis-monounsaturated fatty acids for use as medicines
CN101985420A (zh) * 2010-01-29 2011-03-16 苏州润新生物科技有限公司 油酸酯及其制备方法和在制备用于治疗高血压及其并发症的药物中的应用
US11411814B2 (en) 2015-01-26 2022-08-09 Rapid7, Inc. Network resource management devices methods and systems
US11418392B2 (en) 2015-01-26 2022-08-16 Rapid7, Inc. Network resource management devices methods and systems

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CN101259122B (zh) 2011-04-06
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ATE322261T1 (de) 2006-04-15
CA2463348A1 (en) 2003-04-17
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BRPI0213165B8 (pt) 2021-05-25
DE60210488D1 (de) 2006-05-18
US20050014831A1 (en) 2005-01-20
DE60210488T2 (de) 2006-12-14
CN101259121B (zh) 2011-04-06
JP4737931B2 (ja) 2011-08-03
EP1435235B1 (en) 2006-04-05
BR0213165A (pt) 2004-09-14
CA2463348C (en) 2011-04-05
US8778995B2 (en) 2014-07-15
CN100471492C (zh) 2009-03-25
BRPI0213165B1 (pt) 2018-01-23
RU2004114229A (ru) 2005-04-20
CN101259122A (zh) 2008-09-10
ES2186576A1 (es) 2003-05-01
ES2186576B1 (es) 2004-09-16
JP2005527479A (ja) 2005-09-15
US20090082446A1 (en) 2009-03-26
US7851507B2 (en) 2010-12-14

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