WO2007062568A1 - Composes utilises comme activateurs de la proteine kinase activee par l'amp (ampk) dans des cellules de mammifere - Google Patents

Composes utilises comme activateurs de la proteine kinase activee par l'amp (ampk) dans des cellules de mammifere Download PDF

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Publication number
WO2007062568A1
WO2007062568A1 PCT/CN2006/002685 CN2006002685W WO2007062568A1 WO 2007062568 A1 WO2007062568 A1 WO 2007062568A1 CN 2006002685 W CN2006002685 W CN 2006002685W WO 2007062568 A1 WO2007062568 A1 WO 2007062568A1
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compound
group
ampk
carboxylic acid
protein kinase
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PCT/CN2006/002685
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English (en)
Chinese (zh)
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Fajun Nan
Jia Li
Bing Liu
Tao Pang
Lifang Yu
Jingya Li
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Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences
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Publication of WO2007062568A1 publication Critical patent/WO2007062568A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • 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
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a small molecule organic compound useful as a human adenosine mononucleotide activating protein kinase (AMPK) activator. Such compounds are useful for preventing, delaying, or treating AMPK-mediated disorders, particularly type II diabetes, obesity, and tumors.
  • the invention also relates to a process for the preparation of this compound.
  • the present invention relates to the use of the compound for activating adenosine mononucleotide-activated protein kinase and for promoting intracellular glucose uptake and for the preparation of a medicament for treating a metabolic disease.
  • BACKGROUND OF THE INVENTION Diabetes has become one of the three major diseases that endanger human health.
  • Diabetes is a general term for a group of heterogeneous endocrine and metabolic diseases characterized by different causes and pathogenesis of insulin deficiency or insulin in the body, and clinically characterized by abnormal glucose metabolism.
  • Diabetes is a general term for a group of heterogeneous endocrine and metabolic diseases characterized by different causes and pathogenesis of insulin deficiency or insulin in the body, and clinically characterized by abnormal glucose metabolism.
  • AMPK adenosine mononucleotide-activated protein kinase
  • AMPK is a heterotrimer comprising an alpha catalytic subunit, two regulatory subunits, beta and gamma.
  • each subunit is encoded by 2-3 genes ( ⁇ 1, ⁇ 2; ⁇ 1, ⁇ 2; ⁇ 1, ⁇ 2, ⁇ 3), respectively.
  • the ⁇ -subunit contains a kinase catalytically active region at the terminus of the ⁇ -subunit, the C-terminal is an active regulatory region, and contains a self-inhibiting region and a binding region of a regulatory subunit; the ⁇ subunit acts as a scaffold for linking the ⁇ and ⁇ subunits.
  • AMPK in the body muscle tissue and other major Tissue enhances glucose uptake, enhances insulin sensitivity and plays a key role in glucose metabolism and lipid metabolism, making it an effective way to treat type 2 diabetes and obesity. Therefore, the use of human AMPK-al (aa 1-394) inactive fragments to screen AMPK's highly active, highly selective activators may provide an important basis for the study of AMPK molecular mechanisms and the development of new drugs for type II diabetes. . At present, there is no invention of AMPK activator, and currently used AICAR is only a non-specific AMPK activator.
  • the present invention contemplates and synthesizes a novel compound which can be used as a human AMPK activator and can effectively activate the activity of human AMPK-al (aa 1-394) to promote intracellular glucose uptake. Therefore, it can be used to prevent, delay or treat AMPK-mediated disorders, particularly type II diabetes, obesity and tumors.
  • the compounds of the present invention are relatively simple in structure and easy to prepare.
  • the novel compound of the present invention has a structure represented by the following formula 1: [Formula 1]
  • X is NH, O or S; is O or S;
  • Y 2 is NR 5 , O or S, wherein R 5 is H;
  • Ri is H, phenyl or a benzyl group, or a substituted or unsubstituted C1-C10 alkyl group or a cycloalkyl group; wherein R 9 and Ru) are each independently H; F; C1; trifluoromethyl; ethynyl, propynyl; a carboxyl group, a C1-C4 alkyl group of a carboxylate group, and the like.
  • R 3 each independently H, F, Cl, pyrrolyl, pyridyl, thiosalt,
  • R 7 > R 8 are each independently H, F, Cl, trifluoromethyl, trifluoromethoxy, nitro, amine, benzoylamide, C2-C6 alkanoamide, and C3 a cycloalkyl-substituted amide group of C6, a C1-C4 alkyl group or the like.
  • the unsubstituted C1-C10 alkyl or cycloalkyl group is cyclopropyl, cyclobutane, decyl, ethyl, n-propyl, n-butyl, n-pentyl, cyclopentanyl a substituent of a substituted C1-C10 alkyl or cycloalkyl group, including one or more alkoxy groups selected from the group consisting of F, Cl, C1-C10, a nitrile group, a carboxyl group, and a formic acid. a methyl ester group, a decanoic acid group or a substituent group of a hydroxyl group, and the like.
  • the novel human AMPK activator of the present invention is prepared by the following three steps: Step a: The carboxyl group in Compound 1 is reduced to an alcohol group according to the following chemical reaction formula 1.
  • compound 1 is reacted with lithium aluminum hydride to reduce the carboxyl group to an alcoholic hydroxyl group, and after quenching with water, extraction, drying, concentration, etc., to obtain compound 2;
  • the alcoholic hydroxyl group of the compound 2 is oxidized to the aldehyde group with active manganese dioxide at room temperature by using chloroform as a solvent, and after treatment with concentration and concentration, the compound 3 is obtained;
  • the compound 3, 4 is coupled with water acetic acid as a solvent and sodium acetate or with anhydrous ethanol as a solvent under the action of piperidine, and subjected to extraction, drying, concentration, silica gel column chromatography and the like, and obtained.
  • the final compound 5 .
  • X is ⁇ , 0 or S; ⁇ or S;
  • Y 2 is NR 5 , O or S; wherein R 5 is phenyl, Wait
  • ⁇ is phenyl or a benzyl group, or an alkyl or cycloalkyl group of a substituted or unsubstituted Cl-ClO;
  • R 9 and R 10 are each independently H; F; CI; trifluoromethyl; ethynyl, propynyl; CI-C4 alkyl having a carboxyl group or a carboxylate group.
  • R 2 , R 3 and R 4 are each independently H, F, Cl, pyrrolyl, pyridyl, thioenyl,
  • R 7 and R 8 are each independently H, F, Cl, trifluoromethyl, trifluoromethoxy, nitro, amine, benzamide, C2-C6 alkanoamide, and C3- a cycloalkyl-substituted amide group of C6, a C1-C4 alkyl group or the like.
  • the unsubstituted C1-C10 alkyl or cycloalkyl group is cyclopropyl, cyclobutane, decyl, ethyl, n-propyl, n-butyl, n-pentyl, cyclopentane a substituent, a n-hexane group, a cyclohexyl group or the like; a substituted C1-C10 alkyl or cycloalkyl substituent including one or more alkoxy groups selected from the group consisting of F, Cl, C1-C10, a nitrile group, a carboxyl group, and a formic acid a methyl ester group, a decanoic acid group or a substituent group of a hydroxyl group, and the like.
  • TLC Thin layer chromatography
  • the post-treatment methods generally employed after the completion of the reaction include cooling, concentration of the reaction solution to remove the solvent, extraction, column chromatography separation, and the like.
  • the final product was detected by NMR.
  • the novel compound of the present invention can be used as a human AMPK activator and can effectively activate the activity of human AMPK-al (aa 1-394), thereby preventing, delaying or treating AMPK-mediated disorders, especially II. Type 2 diabetes, obesity and cancer.
  • the present invention will be more specifically described by way of examples and comparative examples. However, the following examples are provided for the purpose of illustration only, and thus the invention is not limited to the embodiments.
  • DRAWINGS Fig. 1 shows the measurement of AMPK activity without adding the compound of the present invention and adding the compounds 5f, 5r, 5s, 5t, and 5u of the present invention, respectively.
  • (-) indicates that the compound was not treated with the compound, (+) indicates that the compound was treated with the compound;
  • pAMPK indicates the phosphorylation level of the AMPK catalytic subunit ⁇ -threonine (Thr) 172;
  • AMPK indicates the expression level of intracellular AMPK catalytic subunit ⁇ ;
  • pACC indicates the phosphorylation level of intracellular AMPK substrate ACC;
  • ACC indicates the expression level of intracellular ACC;
  • (-Actin) indicates intracellular actin To show the total amount of intracellular protein.
  • NMR was measured by a Mercury-Vx 300M instrument manufactured by Varian, NMR calibration: ⁇ H/C 7.26/77.0 ppm (CDC1 3 ); reagents were mainly supplied by Shanghai Chemical Reagent Co., Ltd. Column chromatography, silica gel (200-300 mesh), the silica gel model used for column chromatography is coarse air (ZLX-II), produced by Qingdao Ocean Chemical Plant.
  • Example 1 Preparation of Compound 5a
  • First step Add 28 mg of AlLi to a 25 ml round bottom flask, disperse it in 10 ml of freshly steamed THF, and add 101 mg of compound 3a (0.37 mmol) in 3 ml of freshly steamed THF solution at room temperature. (24-26 V) The reaction was stirred for 30 minutes, and the completion degree of the reaction was measured by TLC. After the reaction was completed, 0.5 ml of water was carefully added, stirring was continued for 10 minutes, diluted with water, extracted with ethyl acetate. The organic phase was dried over anhydrous Na 2 SO 4 and concentrated to remove solvent to afford 2b.
  • Step 2 Add 68 mg of compound 2a, 20 ml of chloroform to a 50 ml round bottom flask, add active Mn0 2 122 mg with stirring, stir the reaction at room temperature (24-26 ° C) for 5 hours, and use TLC to track the completion of the reaction. . After completion of the reaction, the insoluble matter was removed by filtration, and the solvent was concentrated to give 3a 38 mg.
  • Step 3 In a 5 ml round bottom flask, add 38 mg of compound 3a (0.16 mmol), 60 mg of compound 4a (0.16 mmol), 27 mg of piperidine, 3 ml of absolute ethanol, reflux with nitrogen (80"C to 120 °C) After 3 hours, the completion degree of the reaction was measured by TLC. After the completion of the reaction, the reaction mixture was cooled, and the reaction mixture was concentrated to remove the solvent and purified by column chromatography to give the product 5a 30 mg.
  • Compound 5a ! H NMR (CDC13, 300 MHz) ⁇ 6.78 (dd , 2H), 7.11 (m, 4H), 7.43 (m, 3H), 7.69 (t, lH).
  • Example 2 Preparation of compound 5b:
  • First step Compound 2b was prepared in the same manner as in the first step of Example 1, except that the starting material lb was used instead of the starting material in the first step of Example 1.
  • Second step Compound 3b was prepared in the same manner as in the second step of Example 1 except that the starting material 2b was used instead of the starting material 2a in the second step of Example 1.
  • Step 3 In a 5 ml round bottom flask, add 34 mg of compound 3b (0.28 mmol), 60 mg of compound 4b (0.28 mmol), 100 mg of AcONa, 2 ml of glacial acetic acid, and reflux with nitrogen (100 ° C to 120 ° C) 2 Hours, TLC tracks the response.
  • Example 7 Preparation of Compound 5g: Compound 5g was prepared in the same manner as in Example 1 except that a carboxylic acid or a carboxylic acid ester corresponding to compound 5g and a carbonyl compound were used. Structural formula of compound 5g:
  • Example 8 Preparation of Compound 5h: Compound 5h was obtained in the same manner as in Example 1 except that a carboxylic acid or a carboxylic acid ester corresponding to compound 5h and a carbonyl compound were used as a starting material.
  • Example 12 Preparation of Compound 51: Compound 51 was obtained in the same manner as in Example 1 except that a carboxylic acid or a carboxylic acid ester corresponding to Compound 51 and a carbonyl compound were used.
  • Example 14 Preparation of Compound 5 ⁇ : Compound 5n was produced in the same manner as in Example 1 except that a carboxylic acid or a carboxylic acid ester corresponding to Compound 5n and a base compound were used as a starting material. Structural formula of compound 5 ⁇ :
  • ruthenium catalytic subunit ⁇ inactive fragment cdd-394 amino acid A gene sequence encoding the human AMPK catalytic subunit ⁇ inactive fragment al (l-394 amino acid) was constructed in the pGEMEX- ⁇ vector.
  • the correctly identified pGEMEX-AMPK-1 (1 -394) recombinant plasmid was transformed into the expression type Escherichia coli BL21-Codon-Plus (DE3)-RIL strain, and the monoclonal colony was picked at 1 L containing 50 g/mL ampicillin and LB rich medium of 25 g/mL chloramphenicol, 180 to 37 per minute.
  • the above lysate containing the protein of interest was centrifuged at 12000 x g for 15 minutes at 4 ° C, centrifuged twice, and the precipitate was discarded, and the supernatant protein solution was passed through a Q column. It was carried out using a HiTrap-5ml QHP anion exchange column and an FPLC system.
  • the solution passing through the Q column was Buffer A (50 mM Tris-HCl, pH 7.5, 1 mM DTT) and Buffer B (50 mM Tris-HCl, pH 7.5, 1 mM DTT, 1 M NaCl).
  • the supernatant protein sample was injected, first equilibrated with Buffer A, and then eluted with a linear NaCl gradient consisting of Buffer A and 100% Buffei' B.
  • the protein composition and purity of the collected fractions were verified by SDS-PAGE - and the purer fractions were combined according to the results and protein concentrations.
  • the eluted target protein AMPK-ocl (l-394) was identified by 12% SDS-PAGE: the purity of the purified protein was about 95%.
  • mice AMPK-al (aa 1-392), which is identified by its size and enzymatic properties, corresponds to the amino acid sequence reported in the literature.
  • AMP-activated protein kinase kinase detection with recombinant AMPK al subunit (2002) Biochem. Biophys. Res. Commun. 293, 892-898; Crute et al, Functional domains of the al catalytic subunit of the AMP-activated protein kinase, (199S) J. Biol. Chem. 273, 35347-35354 ).
  • the inactive fragment al(l-394) of the catalytic subunit ⁇ of human ⁇ was purified, and the fragment contained its own self-inhibitory sequence for screening experiments.
  • the activated hydrazine can phosphorylate the substrate SAMS (MW: 1779), and the ⁇ -33 ⁇ on the [ ⁇ - 33P]-ATP in the solution is covalently bonded to the substrate SAMS to make its Ser residue.
  • Acidification, production of the isotope-labeled substrate 33P-SAMS, and finally the scintillation fluid was counted by liquid scintillation counter to quantify the enzyme activity. The activity of the compound was initially evaluated by observing the activation of its activity by different compounds.
  • HsAMPK-al (aa 1-394) was prephosphorylated by the upstream kinase CaM Kp for 4 hours, and then added to the substrate-containing assay reaction solution (20 mM Tris-HCl, pH 7.5, 1 mM) in a volume ratio of 1:4.
  • the substrate-containing assay reaction solution (20 mM Tris-HCl, pH 7.5, 1 mM) in a volume ratio of 1:4.
  • DTT 5 mM MgC12, 50 ⁇ [ ⁇ -33 ⁇ ]- ⁇ (0.4 ⁇ /assay), 50 ⁇ SAMS)
  • the total activity was 50 ⁇ at 30.
  • C was incubated for 10 min.
  • the protein reaction solution was adsorbed on P30 filter paper by Harvester, washed three times with 0.1% H3P04, dried, added with scintillation liquid, and sealed, and counted by a 96-well microplate scintillation counter.
  • the reaction rate obtained by the above measurement system is the reaction rate of the enzyme activity; DMSO (2 ⁇ l) in which the above compound is dissolved is substituted for DMSO (2 ⁇ 1) in the above system, and the reaction rate is determined as the reaction rate under the action of the compound.
  • Fig. 1 shows the measurement of AMPK activity without adding the compound of the present invention and adding the compounds 5f, 5r, 5s, 5t, and 5u of the present invention, respectively.
  • Figure 2 is a graph showing the catalytic activity of the compound 5r prepared in the examples of the present invention at various concentrations.
  • (-) indicates that the compound was not treated with the compound, (+) indicates that the compound was treated with the compound;
  • pAMPK indicates the phosphorylation level of the AMPK catalytic subunit ⁇ -threonine (Thr) 172;
  • AMPK indicates the expression level of intracellular AMPK catalytic subunit ⁇ ;
  • pACC indicates the phosphorylation level of intracellular AMPK substrate ACC;
  • ACC indicates the expression level of intracellular ACC;
  • (-Actin) indicates intracellular actin To show the total amount of intracellular protein.
  • the compound 5r prepared in Example 18 has a significant effect on enhancing the phosphorylation level of intracellular AMPK phosphorylation and its downstream target protein ACC at the L6 cell level and exhibits a concentration-dependent manner, indicating that the compound can be at the cellular level. Activate AMPK.

Abstract

La présente invention concerne des composés organiques à petites molécules utilisés comme activateurs de la protéine kinase activée par l'AMP (AMPK) dans des cellules de mammifère. Les composés de l'invention peuvent être utilisés pour prévenir, retarder ou traiter un trouble causé par AMPK, en particulier le diabète non insulino-dépendant, l'adiposité ou la tumeur. L'invention concerne également des méthodes de préparation desdits composés. Elle concerne les utilisations de ces composés pour activer la protéine kinase activée par l'AMP (AMPK) dans des cellules de mammifère, et pour faciliter l'absorption de glucose par les cellules. L'invention concerne en outre les utilisations de ces composés dans la préparation d'un médicament contre une maladie métabolique.
PCT/CN2006/002685 2005-12-02 2006-10-12 Composes utilises comme activateurs de la proteine kinase activee par l'amp (ampk) dans des cellules de mammifere WO2007062568A1 (fr)

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CN200510111115.9 2005-12-02
CN2005101111159A CN1978445B (zh) 2005-12-02 2005-12-02 一种可用作人源腺苷单核苷酸激活蛋白激酶激活剂的化合物及其制备方法和应用

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WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
EP2567959A1 (fr) 2011-09-12 2013-03-13 Sanofi Dérivés d'amide d'acide 6-(4-Hydroxy-phényl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
US20130090339A1 (en) * 2010-06-17 2013-04-11 The Uab Research Foundation Compounds useful as antiviral agents, compositions, and methods of use
US8889730B2 (en) 2012-04-10 2014-11-18 Pfizer Inc. Indole and indazole compounds that activate AMPK
US9394285B2 (en) 2013-03-15 2016-07-19 Pfizer Inc. Indole and indazole compounds that activate AMPK

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JP2013514385A (ja) * 2009-12-18 2013-04-25 ヤンセン ファーマシューティカ エヌ．ベー． エストロゲン関連受容体αモジュレーターとしての置換アミノチアゾロンインダゾール
CN104059060B (zh) * 2014-05-30 2017-08-01 西安交通大学 一种5‑(1h‑吲哚‑3‑亚甲基)‑1,3‑噻唑烷‑4‑酮类衍生物及其合成方法和应用

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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
US20130090339A1 (en) * 2010-06-17 2013-04-11 The Uab Research Foundation Compounds useful as antiviral agents, compositions, and methods of use
US8933075B2 (en) * 2010-06-17 2015-01-13 Fuzians Biomedicals, Inc. Compounds useful as antiviral agents, compositions, and methods of use
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
EP2567959A1 (fr) 2011-09-12 2013-03-13 Sanofi Dérivés d'amide d'acide 6-(4-Hydroxy-phényl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
US8889730B2 (en) 2012-04-10 2014-11-18 Pfizer Inc. Indole and indazole compounds that activate AMPK
US9394285B2 (en) 2013-03-15 2016-07-19 Pfizer Inc. Indole and indazole compounds that activate AMPK

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