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WO2010037886A1 - Dérivés de chromane et utilisations de ces derniers en tant qu'inhibiteurs de l'activité des protéines découplantes - Google Patents

Dérivés de chromane et utilisations de ces derniers en tant qu'inhibiteurs de l'activité des protéines découplantes Download PDF

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WO2010037886A1
WO2010037886A1 PCT/ES2009/070397 ES2009070397W WO2010037886A1 WO 2010037886 A1 WO2010037886 A1 WO 2010037886A1 ES 2009070397 W ES2009070397 W ES 2009070397W WO 2010037886 A1 WO2010037886 A1 WO 2010037886A1
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mmol
dimethylchroman
activity
bromo
isopropyl
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Inventor
Eduardo Rial Zueco
Alma Viso Beronda
Roberto FERNÁNDEZ DE LA PRADILLA SAINZ DE AJA
Esther CASTELLANOS SANTAMARÍA
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Consejo Superior de Investigaciones Cientificas CSIC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/74—Benzo[b]pyrans, hydrogenated in the carbocyclic ring

Definitions

  • the present invention relates to a series of compounds derived from chromane, as well as their different uses, more specifically in the identification of therapeutic compounds, as regulating compounds of decoupling proteins or their therapeutic use for the treatment of different diseases and conditions that are present with an increase in the activity of said proteins such as cancer, cachexia, non-insulin dependent diabetes, infections or fever.
  • ROS reactive oxygen species
  • Free radical precursor molecules such as H 2 O 2
  • ROS are another byproduct of oxidative metabolism, the action of NADPH oxidase, xanthine oxidase, cytochrome P450 and the electron transport chain of mitochondria being the most significant sources of ROS.
  • ROS participate in physiological processes, acting in many cases as intracellular signals [D'Autréaux B, Toledano MB (2007) ROS as signalling molecules: mechanisms that genérate specificity in ROS homeostasis. Nat. Rev. Mol. CeII Biol. 8: 813-24].
  • agents that cause an increase in the production of ROS is a strategy that has been successfully exploited in cancer therapy. This objective can be achieved through two approaches: (i) directly inducing the generation of ROS in the tumor cell or (ii) inhibiting defense systems.
  • chemical agents used for this strategy are procarbazine, vinblastine, doxorubicin, motexaphine, camptothecin, neocarzinostatin, and cisplatin [Renschler MF (2004) The emerging role of reactive oxygen species in cancer therapy. Eur. J. Cancer 40: 1934-1940; and Ozben T (2007) Oxidative stress and apoptosis: impact on cancer therapy. J. Pharm. Sci. 96: 2181-2196].
  • Cellular respiration is a mitochondrial process of oxidation of sugars and fats.
  • the transfer of electrons from the molecules that are oxidizing to oxygen takes place in the internal mitochondrial membrane and is coupled to a proton pumping from inside the mitochondrion, with which a proton gradient is formed.
  • the energy stored in this gradient is used for the synthesis of ATP through the oxidative phosphorylation of its precursor.
  • the ATP is the universal molecule that allows the energy to be stored and then distributed to the manufacture of cellular components, the transport of molecules, the transmission of signals, etc.
  • the two processes (respiration and synthesis of ATP) are coupled, so that the oxidation rate of substrates (respiration) adjusts to the cellular demand of ATP, thus avoiding wasting energy reserves.
  • the uncoupling proteins are transporters that belong to the superfamily formed by mitochondrial transporters of metabolites, evolutionarily related proteins and that have structural and functional similarities.
  • the function of the PCUs is to decrease the efficiency of oxidative phosphorylation, through a controlled dissipation of the proton gradient [Krauss S, Zhang CY & Lowell BB (2005) The mitochondrial uncoupling protein homologues. Nature Rev. Mol. CeII Biol. 6: 248-261].
  • Five mammals have been described in mammals, with a specific anatomical distribution for each of them.
  • the decoupling protein UCP1 exclusive of the brown adipose tissue of mammals, is the best known playing an important role for example in the maintenance of body temperature in newborns.
  • UCP1 When the UCP1 is activated by fatty acids, it causes the protons to return to the interior of the mitochondria without the synthesis of ATP. Therefore, breathing is accelerated, but the proton gradient energy dissipates in the form of heat [Nicholls DG, & Locke RM (1984) Thermogenic mechanisms in brown fat. Physiol Rev. 64: 1-64].
  • the transport activity is inhibited by the purine nucleotides that bind inside the protein, which they access from the face exposed to the intermembrane space.
  • Zinc-a2-glycoprotein secreted by cachectic tumors, promotes the oxidation of lipid stores and causes an increase in the levels of UCP2 in skeletal muscle, adipose tissue and liver as well as in UCP3 in muscle [Bing C et al. (2002) Expression of uncoupling proteins-1 -2 and -3 mRNA is induced by adenocarcinoma-derived lipid-mobilizing factor. Br. J.
  • the PCU could be playing a double role in this process: acting as energy dissipative pathways and as a mechanism of protection against oxidative stress that is caused by high lipid oxidation.
  • the PCU can therefore be pharmacological targets for the treatment of cancer and to mitigate the effects of tumor cachexia.
  • the development of inhibitors of its decoupling activity would serve to enhance the antitumor effect of all those agents that act by increasing oxidative stress and would also counteract the effect of the increase in UCP2 levels in cachectic tumors.
  • UCP2 as a secretion modulator of insulin
  • type 2 diabetes is well established [Zhang CY, et al. (2001) Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes. CeII 105: 745-755].
  • the cytotoxicity of genipin is low, it can cause oxidative stress and induce apoptosis [Kim BC, et al. (2005) Genipin-induced apoptosis in hepatoma cells is mediated by reactive oxygen species / c-Jun NH2-terminal kinase-dependent activation of mitochondrial pathway. Biochem Pharmacol. 70: 1398-407].
  • a series of compounds derived from chromane are described. These compounds have been characterized as inhibitors of the transport activity of the UCP1 after a first screening performed in yeasts and subsequently validated as inhibitors of the UCP2 using tumor cells. These compounds can be used for the treatment of diseases and ailments in which there is an increase in the levels and / or activity of the PCUs, for example, but not limited to, cancer, tumor cachexia, diabetes not dependent on insulin, infections or fever.
  • a first aspect of the present invention refers to compounds derived from chromane, which have the general formula (I), its enantiomers, and any of its pharmaceutically acceptable salts (from now on compounds of the invention):
  • R 1 and R 2 are the same or different from each other, and are represented by a hydrogen atom (H) or an alkyl group (Ci-Ce);
  • R 3 is represented by an H atom, a halogen, an aryl group or a -COOR 5 group; where R 5 is (C 1 -C 4 ) alkyl or a alkylaryl; and
  • R 4 is represented by a hydrogen atom (H), an alkylaryl group or a linear or branched (d-C ⁇ ) alkyl group.
  • a preferred embodiment of the compounds of the invention comprises 2,2-alkylchroman derivatives, wherein R 1 is an alkyl group (CrC 4 ), more preferably a methyl group, and R 2 is H.
  • Another preferred embodiment of the compounds of the invention comprises 4,4-alkylchroman derivatives, where R 1 is H and R 2 is a (C 1 -C 4 ) alkyl group, more preferably R 2 is a methyl group.
  • alkyl refers in the present invention to aliphatic, linear or branched chains, having 1 to 8 carbon atoms, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert- butyl, sec-butyl, n-pentyl, etc.
  • the alkyl group has between 1 and 4 carbon atoms.
  • aryl refers in the present invention to an aromatic carbocyclic chain, having from 6 to 12 carbon atoms, being able to be single or multiple ring, in the latter case with separate and / or condensed rings.
  • a non-limiting example of aryl is a phenyl group.
  • arylalkyl is understood in the present invention to an aryl group attached to the rest of the molecule by an alkyl group.
  • a non-limiting example of arylalkyl is a benzyl group.
  • halogen is meant in the present invention an atom of bromine, chlorine, iodine or fluorine.
  • Another preferred embodiment of the present invention comprises any of the compounds of the formula: 8-isopropyl-2,2-dimethylchroman; 6-Bromo-8-ethyl-2,2-dimethylchroman; 6-Bromo-2,2-dimethyl-8-propylchroman; 6-Bromo-8-isopropyl-2,2-dimethylchroman; 6-Bromo-8-tert-butyl-2,2-dimethylchroman; 6- bromo-8-isopropyl-4,4-dimethylchroman; 6-phenyl-8-isopropyl-2,2-dimethylchroman; Ethyl 8-isopropyl-2,2-dimethylchroman-6-carboxylate; or ethyl 4,4-dimethylchroman-8-isopropyl-6-carboxylate.
  • the compounds of the invention of general formula (I), in which R 1 is alkyl (d-Cs), R 2 is H, and R 3 is H or halogen are obtained by reacting an allylic alcohol with a phenol in presence of a catalytic amount of p-toluenesulfonic acid (Scheme 1).
  • the synthesis of the compounds of the invention, of general formula (I), in which R 1 is H, R 2 is alkyl (CrCs) and R 3 is H or halogen can be carried out in a sequence of three steps ( Scheme 2).
  • the first step is the reaction between an allyl bromide (a) and a phenol (b) in the presence of a base, which produces an aryl allyl ether (c).
  • the transformation of (c) into (d) is carried out by consecutive treatments with mercury acetate, sodium borohydride and finally NaOH.
  • (d) cycles in the presence of aluminum trichloride, giving rise to the chroman derivatives of general formula (I) in which R 2 is alkyl (CrCs) and R 3 is H or halogen.
  • the compounds of the invention may have the following applications or uses:
  • another aspect of the present invention relates to the use of any of the compounds of the invention for the preparation of a pharmaceutical composition.
  • the pharmaceutical composition is capable of inhibiting the decoupling activity of the decoupling proteins.
  • a further aspect of the present invention refers to the use of any of the compounds of the invention for the preparation of a pharmaceutical composition for the treatment of diseases and / or ailments in which there is an increase in the levels and / or activity of the UCP proteins, such as, for example, non-limiting, any of the group comprising cancer, tumor cachexia, non-insulin dependent diabetes, infections or fever.
  • Another aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of the invention in therapeutically effective amount, or mixtures thereof, a pharmaceutically acceptable salt, prodrug, solvate or stereoisomer thereof together with a pharmaceutically acceptable carrier, adjuvant or vehicle, for administration to a patient.
  • compositions are the adjuvants and vehicles known to those skilled in the art and commonly used in the elaboration of therapeutic compositions.
  • the expression “therapeutically effective amount” refers to the amount of the agent or compound capable of developing the therapeutic action determined by its pharmacological properties, calculated to produce the desired effect and, in general, will be determined, among other causes, due to the characteristics of the compounds, the age and condition of the patient, the severity of the alteration or disorder, and the route and frequency of administration.
  • Fig. 1A Decrease in the fluorescence of NADH over time due to its oxidation by mitochondria.
  • Fig. 1 B NADH consumption. Both figures show the results obtained at baseline (control) in the presence of the palmitate activator (circles), after the addition of the GDP inhibitor at a concentration of 100 ⁇ M (black triangles down) and after the addition of compound E379 to a 20 ⁇ M concentration (white triangles up).
  • Figure 2 Effects of different compounds derived from chroman at different concentrations (0, 2, 20 and 125 ⁇ M) on the respiration of mitochondria isolated from S. cerevisiae transformed with a vector with which no recombinant protein is expressed (black circle ) and transformed to express UCP1 (squares).
  • FIG. 3 Inhibitory activity of compounds derived from chroman.
  • the EC 50 is represented for the inhibition of the activity of the UCP1 determined from the rate of oxidation of NADH in isolated mitochondria of S. cerevisiae transformed to express UCP1 to which the effect of the same compounds observed in mitochondria was subtracted of S. cerevisiae not transformed.
  • the inhibitor concentrations used for the calculation of EC50 were 0, 2, 20, 125 and 250 ⁇ M.
  • the cut bars represent EC50 values greater than 200 ⁇ M.
  • Figure 4. Effect of compound E379 on the survival of the cells of the human colon adenocarcinoma cell line Caco-2, treated with arsenic trioxide.
  • Fig. 4A Immunodetection of the UCP2 decoupling protein in mitochondrial extracts obtained from cultures of the Caco-2 cell line. As a control, the signal obtained with mitochondria extracted from the spleen is shown.
  • Fig. 4B Effect of compound E379 on the viability of the cells of the Caco-2 line treated for 24 hours with different concentrations of arsenic trioxide in the absence (circles) or in the presence (squares) of the compound E379 at a concentration of 50 ⁇ M.
  • the general procedure is the dropwise addition of 3-methyl-2-buten-1-ol to a solution of a phenol and p-toluenesulfonic acid in 1,2-dichloroethane (3.5 mL / mmol) and subsequent heating to 80 0 C until the complete disappearance of the starting substrate. Subsequently the mixture is hydrolyzed with saturated NaHC03 (1, 5 mL / mmol) and H 2 O (2 mL / mmol) and the solution phases are separated.
  • EXAMPLE 2 Synthesis of 6-phenyl-8-isopropyl-2,2-dimethylchroman (E379).
  • E379) 6-phenyl-8-isopropyl-2,2-dimethylchroman (E379).
  • Pd (PPlIs) 4 4 mg, 0.034 mmol
  • BHT 2 crystals
  • the mixture was stirred and phenyltributyl ethannan (0.10 ml_, 0.26 mmol) was added dropwise. It was heated to toluene reflux (110 0 C) to observe the disappearance of the starting product.
  • the general procedure consisted of adding dropwise to a solution of 6-bromochroman in anhydrous THF (5 mL / mmol of 6- bromochroman) cooled to 78 0 C, a solution of ⁇ BuLi 1, 5 M in pentane (2.0 equiv) . The mixture was stirred at 78 0 C for 20 minutes, after which was added via cannula to a solution of ethyl chloroformate (1, 5 equiv) in anhydrous THF (3 mL / mmol of 6- bromochroman) also cooled to -78 0 C. The mixture was stirred at the same temperature for 30 minutes, until complete product formation.
  • the obtaining of mitochondria containing UCP1 was initiated by transformation of the W303 strain of Saccharomyces cerevisiae with the vector pYeDP-1 / 8-10, which inserts the sequence of UCP1 into the genome of the yeast under the control of the gal-cyc promoter [ Arechaga I, Raimbault S, et al. (1993) Cysteine residues are not essential for uncoupling protein function. Biochem J. 296: 693-700]. With this system, the expression of UCP1 is repressed in the presence of glucose and activated in the presence of galactose. The UCP1 expressed in these recombinant yeasts retains its characteristic properties: proton transport activated by fatty acids and inhibited by nucleotides.
  • the measurement of the activity of the UCP1 was performed by determining the fluorescence of the NADH, using 96-well plates and a plate reader, adjusted to an excitation wavelength of 340 nm and emission of 460 nm. In the wells of the plates containing the mitochondria the compound is added whose inhibitory activity of the PCU is to be determined.
  • Figure 1 shows the effect of the addition of 100 ⁇ M of GDP, inhibitor of the activity of UCP1, as well as of 20 ⁇ M of E379 (6-phenyl-8-isopropyl-2,2-dimethylchroman, synthesized as described in Example 2 of this report).
  • Panel A shows the effect of GDP and E379 determined by the decrease in fluorescence and in Panel B the speed of consumption of NADH once the fluorescence values have been transformed into NADH concentration by comparison with a standard curve thereof .
  • Both figures show the results obtained at baseline in the presence of the palmitate activator (circles), after the addition of the GDP inhibitor at a concentration of 100 ⁇ M (black triangles down) and after the addition of compound E379 at a concentration of 20 ⁇ M (white triangles up).
  • EXAMPLE 6 Inhibitory activity of compounds derived from Chroman on the activity of the UCP1 protein.
  • EXAMPLE 7 Effect of compound E379 on the viability of Caco-2 cells subjected to oxidative stress.
  • the Caco-2 cell line of human colorectal adenocarcinoma (ATCC HTB-37) was selected, in which the presence of UCP2 was previously confirmed by immunodetection in extracts mitochondrial
  • the cells were cultured in complete medium (MEM Alpha, Gibco, Invitrogen) supplemented with 20% fetal bovine serum, 100 U / ml penicillin and 100 ⁇ g / ml streptomycin) until they reached 70-80% confluence in culture bottles of 75 cm 2 (Falcon) at 37 ° C and 5% CO 2 .
  • the cells were washed with cold PBS buffer solution and collected with a scraper in 1 ml of 250 mM sucrose buffer, 10 mM Tris, 1 mM EDTA pH 7.4. They were washed at 4 0 C once in this medium and centrifuged at 2000 g 5 minutes. Cell pellets were resuspended in 1 ml of the same medium containing protease inhibitors (protease inhibitor cocktail Sigma P8340) and subjected to three cycles of freezing in liquid nitrogen for 5 minutes and thawing at 37 0 C for 10 minutes to disrupt the cells . Samples were centrifuged at 750 g, 10 minutes to remove unbroken cells and the supernatant was centrifuged again at 10,000 g, 20 minutes.
  • protease inhibitor cocktail Sigma P8340 protease inhibitors
  • the mitochondrial sediment was resuspended in 10-20 ⁇ l of medium containing protease inhibitors.
  • the mitochondrial extracts were subjected to gel electrophoresis under denaturing conditions (SDS-PAGE) and after electrophoresis the proteins were transferred to a nitrocellulose membrane.
  • the membrane was treated 2 hours with 0.1% PBS / Tween and 5% milk powder and then incubated overnight with polyclonal antibody against UCP2 (Santa Cruz Biotechnology, Inc, Santa Cruz, USA). Subsequently, it was washed 3 times with PBS / 0.1% Tween and incubated 2 hours with a peroxidase-conjugated IgG anti-goat antibody (Santa Cruz Biotechnology, Inc, Santa Cruz, USA).
  • FIG. 4 shows the presence of UCP2 in mitochondrial extracts of Caco-2 cells, showing as a control the signal obtained with mitochondria isolated from mouse spleen.
  • the viability was determined in vitro by the MTT assay (3- [4,5-dimethylliazol-2-yl] -2,5-diphenyl tetrazolium bromide), which is based on the mitochondrial dehydrogenases of viable cells breaking the tetrazolium ring of the MTT giving rise to formazan crystals that, after the solubilization of the cells, give a purple color.
  • MTT assay 3- [4,5-dimethylliazol-2-yl] -2,5-diphenyl tetrazolium bromide
  • the cells were treated with increasing concentrations of arsenic trioxide in the presence or absence of the E379 inhibitor (50 ⁇ M). After 24 hours, 0.5 mg / ml of MTT was added to each well and incubated for 40 minutes until the appearance of formazan crystals. A solution of acid isopropanol (0.1 N HCI) was added with 10% triton X-100, which allows dissolving said crystals, and absorbance of the extracts obtained at a wavelength of 595 nm was measured by spectrophotometry.
  • Figure 4 shows that, although treatment with arsenic trioxide causes death of the tumor cells, even at concentrations of 10 ⁇ M, the survival was greater than 70%. Under the same conditions, the addition of compound E379 at a concentration of 50 ⁇ M reduced the survival to approximately 50%. The same concentration of compound E379 when the concentration of arsenic trioxide is 0.5 ⁇ M reduces the survival to less than 70%, compared to a survival of approximately 95% in the absence of said compound.

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Abstract

La présente invention concerne des dérivés du chromane qui sont représentés par la formule générale (I) dans laquelle R1 et R2 sont identiques ou différents et représentent un atome d'hydrogène (H) ou un groupe alkyle (C1-C8); R3 représente un atome de H, un halogène, un groupe aryle ou un groupe -COOR5; où R5 représente alkyle (C1-C4) ou un alkylaryle; et R4 représente un atome d'hydrogène (H), un groupe alkylaryle ou un groupe alkyle (C1-C8), linéaire ou ramifié. L'invention porte également sur les différentes utilisations des dérivés selon l'invention, plus spécifiquement dans l'identification de composés thérapeutiques, en tant que composés régulateurs des protéines découplantes ou porte sur leur utilisation thérapeutique pour le traitement de différentes maladies et affections associées à une augmentation de l'activité desdites protéines.
PCT/ES2009/070397 2008-10-03 2009-09-23 Dérivés de chromane et utilisations de ces derniers en tant qu'inhibiteurs de l'activité des protéines découplantes Ceased WO2010037886A1 (fr)

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US6235771B1 (en) * 1998-12-21 2001-05-22 Takeda Chemical Industries, Ltd. Anilide derivative, production and use thereof
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YUS, M. ET AL.: "Reductive lithiation of cyclic benzofused ethers: a source of oxygen-functionalised organolithium compounds", TETRAHEDRON, vol. 58, 2002, pages 4907 - 4915 *

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ES2335849B1 (es) 2011-03-22

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