WO2008065796A1 - Inhibiteur de l'α -glucosidase - Google Patents

Inhibiteur de l'α -glucosidase Download PDF

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Publication number
WO2008065796A1
WO2008065796A1 PCT/JP2007/067919 JP2007067919W WO2008065796A1 WO 2008065796 A1 WO2008065796 A1 WO 2008065796A1 JP 2007067919 W JP2007067919 W JP 2007067919W WO 2008065796 A1 WO2008065796 A1 WO 2008065796A1
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Prior art keywords
darcosidase
inhibitory activity
fraction
patent document
column
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PCT/JP2007/067919
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English (en)
Japanese (ja)
Inventor
Sei Ozaki
Hiromi Oe
Shinichi Kitamura
Original Assignee
Fuji-Sangyo Co., Ltd.
Osaka Prefecture University
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Publication of WO2008065796A1 publication Critical patent/WO2008065796A1/fr

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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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D337/00—Heterocyclic compounds containing rings of more than six members having one sulfur atom as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention relates to a novel ⁇ -darcosidase inhibitor.
  • a Darcosidase is an exohydrolase that dissociates gnolecose from the non-reducing terminal side such as ⁇ -glucan and short-chain oligosaccharides.
  • This enzyme is involved in starch metabolism in plants, animal digestion and glycogen metabolism, and plays an important role in the carbohydrate metabolism system. Among them, many studies have been conducted on its inhibitors because it controls sugar absorption in the human small intestine, and it is used to prevent and treat diabetes, hyperlipidemia, obesity, etc. caused by hyperglycemic symptoms! It is effective.
  • ⁇ -darcosidase inhibitors in addition to inhibiting sugar absorption, are not only improved in insulin sensitivity and long-term administration to patients with impaired glucose tolerance (IGT) but also significantly suppressed the onset of type 2 diabetes. It has been shown that the occurrence of disease is significantly suppressed, and further, it has been revealed that it is also significantly suppressed in the development of hypertension (non-patent literature). 1, 2).
  • Non-Patent Document 4 Since a structure of nojirimycin, which was isolated as a metabolite of Streptomyces sp., Was clarified in 1966 (non-patent document 3), a large number of analogs have been isolated. Synthetic studies on compounds with these motifs have been made (Non-Patent Document 4). These compounds have a common feature in that they are a kind of pseudosaccharide belonging to aza sugar in which the oxygen atom in the monosaccharide bilanose is substituted with nitrogen. In addition to these compounds, compounds substituted with sulfur, phosphorus, carbon atoms, etc. are known as thio-, phospha-, and ruba-sugars, and carbol, voglibose, miglitol, etc., which are already pharmaceuticals, are also these compounds. Belonging to a group.
  • Nojirimycin was an excellent ⁇ - and / 3-darcosidase-inhibiting component, but because it is unstable, it was first reduced with a hydroxyl group at the C1-position.
  • Xinojirimycin was synthesized.
  • stability and inhibitory activity were further increased, there was a drawback that the activity decreased in vivo, and further derivatives were synthesized and studied, and miglitol was born.
  • voglibose which has the strongest inhibitory activity.
  • the structure-activity relationship research has been promoted by the discovery of acarbose, and chemical modification using powerful ruba sugar amines such as noridamine, norienamine, and variolamine as lead compounds. Has led to the synthesis.
  • Non-Patent Document 5 it is thought that dexinojirimycin and its isomer isofagogomine act as a selective inhibitory activity, and that they act by ion-pairing between the imino group and the enzyme active site! /.
  • Inhibitory components different from these pseudo-saccharides include attaridone alkaloids (Non-patent Document 6), coumarin glycosides (Non-patent Document 7), flavonoids (Non-patent Documents 8 and 9), tannins ( Non-patent literature 10, 11)
  • Non-patent literature 10, 11 Many known plant-derived components are known. These compounds have very low inhibition levels! /, So they are put to practical use! /, N! /.
  • Non-Patent Document 13 has also been clarified for their effects such as anti-obesity and liver protection.
  • Non-Patent Documents 14, 15, 16, 17, 18 have also been clarified for their effects such as anti-obesity and liver protection.
  • mutagenicity and acute toxicity tests have also been studied for safety.
  • Kotara Himubu is a plant that has both excellent efficacy and high safety. If there is, scientific support is obtained coming.
  • Non-Patent Document 1 Non-Patent Document 22
  • Nya Kota Ranole Non-Patent Document 23
  • Retikiyuranol Patent Document 2
  • it since it has a very strong inhibitory activity surpassing that of carbose, which is marketed as a pharmaceutical, isomer synthesis and the like have been actively conducted using this component as a lead compound (Non-patent Documents 24 and 25). .
  • Patent Document 1 Japanese Patent Application Laid-Open No. 11 29472
  • Patent Document 2 JP 2004-323420 A
  • Non-patent literature l Chiasson J. et al., JAMA, .290, p486-494, 2003,
  • Non-Patent Document 2 Yuichi Shinoda et al., Metabolism., 55, p935—939, 2006
  • Non-Patent Document 3 Inoue S et al., J. Antibiot., 19, p288—292, 1966
  • Non-Patent Document 4 Naoki Asano, Glycobiology., 13 (10), p 93-104, 2003
  • Non-Patent Document 5 Monique M.P. Hermans et al., J. Biol. Chem., 266 (21), pl3507—135
  • Non-Patent Document 6 Jean Duplex Wansi et al., Chem. Pharm. Bull., 54 (3), p292—296, 20 06
  • Non-Patent Document 7 Sung Ok Lee et al., Arch. Pharm. Res., 27 (12), pl207-1210, 2004
  • Non-Patent Document 8 Jun awabata et al., Biosci. Biotechnol. Biochem., 67 (2 ), P445-447, 2003.
  • Non-patent document 9 Kiran Iqbal et al., Chem. Pharm. Bull., 52 (7), p785-789, 2004
  • Non-patent document 10 Miou Toda et al., Biosci. Biotechnol. Biochem., 64 (2) , P294—298,
  • Non-patent literature ll Miou Toda et al., Biosci. Biotechnol. Biochem., 65 (3), p542-547, 2001
  • Non-Patent Document 12 Attygalle, Sinhalese Materia Medica., P43, 1917
  • Non-patent literature 13 E.H.Karunanayake et al., J Ethonopharmacol., 11, p223—231, 1984
  • Non-patent literature 14 Osami jimoto et al., Journal of Japan Nutrition's Food Society, 53 (5), pl99—205, 20
  • Non-patent literature 15 Masayuki Yoshikawa et al., J Nutr., 132, pl819-1824, 2002
  • Non-patent literature 16 Masayuki Yoshikawa et al., Biol. Pharm. Bull., 25, p72- 76, 2002
  • Non-patent literature 17 Masayuki Yoshikawa et al., Pharmaceutical Journal, 123 (10), p871—880, 2003
  • Non-Patent Literature 18 Hidehiko Beppu et al., Journal of Japan Food New Materials Research Society, 8 (2), pl05—117, 2005
  • Non-Patent Document 19 Hiroshi Shimoda et al., Edible Journal, 40 (3), pl98-205, 1999
  • Non-Patent Document 20 Hiroshi Shimoda et al., Edible Journal, 42 (2), pl44—147, 2001
  • Non-patent document 21 Hiroshi Shimoda et al., Medicine and pharmacy, 46 (4), p527-540, 2001
  • Non-patent document 22 Masayuki Yoshikawa et al., Tetrahedron Letters., 38 (48), p8367-8
  • Non-Patent Document 23 Masayuki Yoshikawa et al., Chem. Pharm. Bull ⁇ , 46 (8), pl339— 1340, 1998
  • Non-patent document 24 Ahmad Ghavami et al., J. Org. Chem., 66, p2312-2317, 2001
  • Non-patent document 25 Monica G. Szczepina et al., J. Am. Chem. Soc, 126 (39) , Pl2458—
  • Non-Patent Document 26 Masayuki Yoshikawa et al., Pharmaceutical Journal, 121 (5), p371-378, 2001 Disclosure of the Invention
  • the compound of the present invention has an unprecedented force, a novel chemical formula represented by It is a compound and has ⁇ -darcosidase inhibitory activity.
  • an ⁇ -darcosidase inhibitor having a stronger action than previously known ⁇ -darcosidase inhibitors which causes antihyperglycemia such as antidiabetic drugs and antihyperlipidemic drugs. It is expected to be applied to the specific health foods that have been clinically applied to each symptom.
  • FIG. 1 is an HPLC chart of a 70% acetonitrile nitrile eluate obtained by fractionating HP-20 fraction of Kotarahimbu water extract with an amino column.
  • FIG. 2 is a 1 H-NMR spectrum of the final fraction of Kotara Himbu extract.
  • FIG. 3 is a 13 C-NMR spectrum of a final fraction of Kotarahimbu extract.
  • FIG. 5 is an estimated plan structure diagram of the final fraction of Kotara Himbu extract.
  • FIG. 6 is a graph showing efficacy evaluation by a sugar tolerance test (sucrose).
  • FIG. 7 is a graph showing efficacy evaluation by a glucose tolerance test (maltose).
  • the novel compound according to the present invention has a structure represented by the following chemical formula (Chemical Formula 1), and is abundantly contained in the roots and aerial parts of the plant of the genus Sarchinae.
  • This compound has a very excellent ⁇ -darcosidase inhibitory activity.
  • This compound is mainly obtained from the solvent extract of the root and aerial parts of the genus Salacia plant, for example, Salacia reticulata, Salacia prinoides (Salacia reticulata). ), Sarachia oblonga and Sarachia chinensis.
  • the compound of the present invention may be extracted from other sites or plants other than the plant.
  • the purification method is not particularly limited, and can be obtained, for example, by combining various known methods. For example, it can be obtained by adding extraction solvent to the roots of the genus Sarakia or the cut parts of the above-ground parts, extracting the filtrate, collecting the filtrate, concentrating, and then purifying it by fractionation using a solvent or column. It is done.
  • the extraction solvent may be selected from water, alcohols, or a mixed solvent of water and a hydrophilic solvent such as alcohols or acetone, with water being particularly preferred.
  • a supercritical extraction method can also be used.
  • the extraction time is an appropriately determined force, and is preferably refluxed overnight or longer. Then remove the residue by centrifugation or filtration. The filtrate obtained is concentrated under reduced pressure and then lyophilized. By the above operation, Kotarahimbu extract powder as a starting material is obtained. Note that the solvent may be added again to the residue, and the same extraction operation may be repeated.
  • An aqueous solution is prepared using this Kotarahimbu extract powder, and an ethanol precipitation treatment is performed by adding an equivalent amount of ethanol.
  • methanol, isopropanol, acetonitrile, etc. may be used as the precipitation solvent.
  • the precipitate is removed by centrifugation or filtration.
  • column chromatography using the organic solvent removed by vacuum concentration It is possible to obtain the novel ⁇ -darcosidase inhibitor of the present invention by the separation force S.
  • the ⁇ -darcosidase inhibitor thus obtained can be used as a single component as it is. It can be used as an additive in various foods and beverages such as tea, suppresses the increase in blood sugar after meals, It is provided as a food for specified health use that can be used for the indications such as suppressing absorption.
  • it may be formulated in the form of tablets, capsules, soft capsules, powders, granules, and other internal preparations and injections together with appropriate excipients, preservatives, fragrances and the like. It can be used not only for pharmaceuticals but also for health foods similar to so-called pharmaceutical forms.
  • the pharmaceutical composition of the present invention comprises an ⁇ -darcosidase inhibitor (compound) represented by the chemical formula (Formula 1) and a pharmacologically acceptable carrier.
  • the pharmacologically acceptable carrier means an excipient, a binder, a disintegrant, a lubricant, a ⁇ adjuster, a solvent and the like that are necessary for formulation.
  • the excipients are lactose, sucrose, starch, bound cellulose, mannit, talc, etc.
  • the binders are syrup, gum arabic, dextrin, etc.
  • the disintegrants are polyethylene glycol, propylene glycol, D-mannitol, hydroxy Propyl cellulose, hydroxypropyl methylcellulose, etc.
  • lubricants include magnesium stearate, talc, etc.
  • pH adjusters include hydrochloric acid, citrate, phosphoric acid, sodium hydrogen phosphate, sodium hydroxide, etc. Examples thereof include water and ethanol.
  • the form of the pharmaceutical composition is not limited. Examples of the form of the pharmaceutical composition include internal preparations such as tablets, capsules, soft capsules, powders, granules, and injections as described above.
  • the pharmaceutical composition of the present invention includes a pharmaceutical composition containing other active ingredients than just a pharmaceutical composition containing only an ⁇ -darcosidase inhibitor (compound) represented by the chemical formula (Chemical Formula 1). Is included.
  • the food composition of the present invention comprises an ⁇ -darcosidase inhibitor (compound) represented by the chemical formula (Chemical Formula 1) and a nutritionally acceptable carrier.
  • the food composition refers to confectionery such as gum, candy, jelly, rice cakes such as udon and soba, dairy products such as yogurt and cheese, seasonings such as miso and soy sauce, sauces, soups, juices, For general foods such as coffee, tea, and nutritional drinks, and pharmaceuticals such as tablets and capsules It has a similar form! /, And refers to health foods (including foods for specified health use that are publicly approved to claim their effects).
  • Nutritionally acceptable carriers refer to raw materials for food preparation necessary for the preparation of these foods, including pigments such as food red, antioxidants such as vitamin E and vitamin C, vitamin A and vitamin B1, etc. These are used to include various additives such as vitamins, preservatives, and preservatives that are added as needed.
  • an extract derived from a natural product adjusted to contain an ⁇ -gnorecosidase inhibitor (compound) represented by the chemical formula (Chemical Formula 1) that is, a known Kotarahimbu extract Food compositions containing are excluded.
  • adding the ⁇ -darcosidase of the present invention to the food composition containing the extract to increase its effect is not excluded from the present invention.
  • the component of the present invention is at least 0.0001%, more preferably 0, based on the total weight. 005-0. About 1% is required. However, this amount can be appropriately set depending on the symptoms, age, intake form, etc. of the patient or animal to be administered.
  • a 500 ml aqueous solution was prepared again using this, and then treated with an HP-20 column (carrier used: 1 kg of a synthetic adsorbent HP-20 manufactured by Mitsubishi Chemical Corporation, column: 8 ⁇ 35 cm). Elution was carried out using water (5 U, 20 vol%, 40 vol%, 60 vol%, and 80 vol% methanol aqueous solution (2.5 U each, stepwise elution). W ”fraction; Yield 34. lg), 20 vol% methanol fraction (“: HP-20-20 ”fraction; Yield 5.89 g), 40 vol% methanol fraction (“: HP-20-20 40 Fraction; Yield 9.
  • Reagent 1 Rat small intestine acetone powder (manufactured by SIGMA), reagent 2: l OOmM potassium phosphate buffer (5 mM EDTA, pH 7.0), reagent 3: l OOmM potassium phosphate buffer (0.1% Triton , pH 7.0), Reagent 4: 10 mM potassium phosphate buffer (pH 7.0) is used.
  • reagent 1 crude enzyme solution
  • reagent 2 DMSO
  • reagent 3 l OOmM sucrose aqueous solution (25 mM maltose aqueous solution)
  • reagent 4 2MTris_HCl buffer (pH 7.0)
  • reagent 5 glucose CII test A coloring solution (manufactured by Wako Pure Chemical Industries) was prepared.
  • Inhibition rate (%) ⁇ (GlcO-Glcx) / GlcO ⁇ X 100 ⁇ ⁇ ⁇ ⁇ Equation 1
  • the fraction was made into a 200 mL aqueous solution, an equivalent amount of ethanol was added and stirred, and the insoluble portion was removed by centrifugation (7, 500 rpm / 30 min). The resulting supernatant was freed from ethanol by concentration under reduced pressure. This was made into a 40 mL aqueous solution and applied to an amino column (a carrier used: a column packed with 950 g of N H-DM 1020SG manufactured by Fuji Silicon Chemical Co., Ltd .: 8 ⁇ 49 cm).
  • HPLC fractionation was performed using this fraction.
  • the preparative conditions were as follows: column used: YMC pack polyamine-11 (20 250111111), mobile phase: 65% by volume acetonitrile, flow rate: 4.5 mL / min, column temperature: 30 ° C, detector: RI.
  • the sample for separation was dissolved in a mobile phase solvent. However, since a large amount of white precipitate was formed at this time, the supernatant portion obtained after centrifugation was used (the white precipitate was used, and when the inhibitory activity test was performed, the activity was not recognized. , Tsuta). From the HPLC eluates obtained at this time, Frl (7—15 min / yield 433.
  • Figure 1 shows the HPLC chart at this time. Furthermore, in order to recover the column adsorbed components, the column was washed with 20% by volume acetonitrile solution. Purification was performed (total recovery rate 88.2%). The obtained fraction was subjected to a ⁇ -darcosidase inhibitory activity test by the above method. The results are shown in Table 3.
  • Frl can also be separated by using 50 to 70% by volume aqueous acetonitrile as the mobile phase. In this case, the retention time varies, but it can be separated from other active ingredient fractions (Fr3-5) by collecting the peak within 10-25 min.
  • Preparative conditions are as follows: Column used: DAISOPAK SP-120-5-ODS_BP (20 X 250mm), mobile phase: water, flow rate: 5. OmL / min, column temperature: 30 ° C, detector: RI Carried out. From the obtained spectrum, ODSFrl (10—10 ⁇ 7min / yield 230 ⁇ 4mg), ODSFr2 (10 ⁇ 7—11 • 2min / 5.8mg), ODSFr3 (11.2-13min / 70.8mg) Three fractions were obtained. These fractions were then tested for inhibitory activity. The results are shown in Table 4.
  • the analysis temperature was 25 ° C.
  • FAB—MS analysis was performed with an analyzer: 7000QQ type (manufactured by JEOL Ltd.), ionization method: fast atom bombardment method (FAB), acceleration voltage: 6 kV, matrix: glycerin, measurement mass range: ⁇ m / zl000.
  • Fig. 2 shows the 1 H-NMR spectrum (inD O / 400MHz)
  • Fig. 3 shows the 13 C-NMR spectrum (inD O / 400MHz)
  • Wistar rats Male 5 weeks old were used for pre-feeding for 1 week before the test. During the preliminary breeding period, both feed and drinking water were freely consumed.
  • the groups were divided into 4 groups, 6 animals each, based on body weight and blood glucose level.
  • the administration groups were the control group (purified water) and the ⁇ -darcosidase inhibitor administration group (0.15, 0.30 and 0.4), respectively.
  • sucrose 2.5 g / kg was orally administered to each group, and before glucose tolerance (after 0 minutes),
  • the 0.15 mg / kg inhibitor administration group showed no difference in blood glucose level 60 minutes after glucose load compared to the control group.
  • Administration of 0.30 and 0.45 mg / kg The group showed significantly low values at a risk rate of 5% and 1%, confirming the sugar absorption inhibitory effect.
  • the test method was performed under the same conditions as in Example 2.
  • the administration groups were a control group (purified water) and an ⁇ -darcosidase administration group (0 ⁇ 30, 0.60 and 0.90 mg / kg), respectively.
  • the activity of the ⁇ -darcosidase inhibitor whose structure was determined was compared with previously reported components obtained from Kotarahimbu (cited from Non-Patent Document 26) and vodaribose, which is approved for sale as a pharmaceutical product.
  • the results are shown in Table 8.
  • the activity intensity is almost the same as that of voglibose on the market, and it is about 7;-103 times higher for maltase inhibition and about 10 times lower for sucrase inhibition compared to previously reported components obtained from the same plant
  • the inhibitory activity intensity was 19 to 34 times.
  • the ⁇ -darcosidase inhibitor according to the present invention is clearly a component exhibiting inhibitory activity far exceeding the previously reported components, and is considered to be the main active component in the Kotarahimbu extract.
  • the molar concentration in parentheses is calculated based on molecular weight.
  • the compound represented by the chemical formula (Formula 1) has excellent ⁇ -darcosidase inhibitory activity.
  • the ⁇ -darcosidase inhibitory activity of this compound is considerably higher than that of salacinol and kotalanol, which have been reported so far, in the kotarahimbu extract. The contribution ratio of such compounds is considered to be high.
  • ⁇ -Dalcosidase inhibitor of the present invention 0.07 g
  • Emulsifier 1 1. 8% by mass
  • alpha - Darukoshidaze inhibitor 0.2 wt 0/0
  • Soft capsules were produced in accordance with a conventional method using the contents according to the above formulation and a coating consisting mainly of gelatin.
  • the compound of the present invention has a novel and highly active ⁇ -darcosidase inhibitory action, whereby anti-diabetic drugs that are more effective for anti-diabetic patients and people in the pre-diabetes group are used for specific health care. Foods are provided.

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Abstract

L'invention a pour objectif de proposer un inhibiteur de l'α-glucosidase qui est nouveau et qui a une activité élevée. Par conséquent, après qu'une partie de racine et/ou aérienne de Salacia reticulata est extraite par de l'eau, des composants insolubles sont éliminés par addition d'éthanol. Ensuite, une séparation par fractionnement a été effectuée à l'aide d'une colonne d'absorbant synthétique HP-20 (fabriqué par Mitsubishi Chemical Corporation), une colonne amino ou une colonne ODS, ce par quoi un composé représenté par la formule chimique (Formule 1) est obtenu. Ce composé présente une excellente activité inhibitrice de l'α-glucosidase, et est proposé comme nouvel agent anti-diabétique, ou un aliment sain capable de présenter un effet inhibiteur de l'absorption de sucre.
PCT/JP2007/067919 2006-11-30 2007-09-14 Inhibiteur de l'α -glucosidase WO2008065796A1 (fr)

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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
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

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TWI529165B (zh) 2008-08-29 2016-04-11 Suntory Holdings Ltd Novel epigallocatechin gallate 3-mer, and the use of alpha-glucosidase inhibitors containing epigallocatechin gallate polymers
AU2010250330B2 (en) 2009-05-21 2014-03-06 Suntory Holdings Limited Anti-obesity agent comprising compound containing benzotropolone ring
US20120100248A1 (en) * 2010-08-17 2012-04-26 Abbott Laboratories Nutritional composition comprising cereal beta-glucan and salacia extract
JP2020184909A (ja) * 2019-05-13 2020-11-19 学校法人帝京大学 血糖降下剤、及び、該血糖降下剤を含有する飲食品

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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
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

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