WO2012169571A1 - Nouveau dérivé de n-(pyridin-2-yl)alcanamide et inhibiteur de ship2 contenant celui-ci en tant que substance active - Google Patents

Nouveau dérivé de n-(pyridin-2-yl)alcanamide et inhibiteur de ship2 contenant celui-ci en tant que substance active Download PDF

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WO2012169571A1
WO2012169571A1 PCT/JP2012/064638 JP2012064638W WO2012169571A1 WO 2012169571 A1 WO2012169571 A1 WO 2012169571A1 JP 2012064638 W JP2012064638 W JP 2012064638W WO 2012169571 A1 WO2012169571 A1 WO 2012169571A1
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pyridin
compound
nmr
mmol
mhz cdcl
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Japanese (ja)
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利安 笹岡
宏史 恒枝
和田　努
尚樹 豊岡
広野　修一
浩明 合田
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国立大学法人 富山大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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

Definitions

  • the present invention relates to the use of compounds that increase insulin sensitivity and pharmaceutically acceptable salts thereof. More specifically, the present invention relates to novel N- (pyridin-2-yl) alkanamide derivatives and SHIP2 inhibitors containing them as active ingredients.
  • insulin resistance improving drugs The mechanism of action of new drugs used for the treatment of diabetes under development in the world is roughly divided into insulin resistance improving drugs and insulin secretagogues.
  • insulin resistance improving agents represented by glitazones to insulin secretagogues related to inlectins.
  • SHIP2 inhibitors are of interest because they improve central and peripheral insulin resistance in diabetic conditions.
  • 3 kinase phosphatidylinositol 3 kinase
  • Non-patent Document 2 The basis for this is that SHIP2 is highly expressed in skeletal muscles and adipose tissue of db / db mice of type 2 diabetes model animals (Non-patent Document 2), and genetic polymorphisms of type 2 diabetes patients in which SHIP2 expression is enhanced (Non-patent Document 3), and further, it has been shown that insulin resistance and impaired glucose tolerance are induced in SHIP2 overexpressing mice (Non-patent Document 4). For this reason, the importance of developing SHIP2 inhibitors as next-generation diabetes therapeutic agents has been pointed out (Non-patent Document 5).
  • SHIP2 inhibitors are being developed all over the world as next-generation diabetes therapeutic agents, but only lead compounds that are not suitable for clinical use have been reported yet.
  • the compound having a pyrazole skeleton described in Non-Patent Document 6 selectively inhibits the reaction between SHIP2 and a substrate (BODIPY-PIP3) in a test tube, but its action in vivo is unknown.
  • a compound having a selective inhibitory effect on SHIP2 (AS1949490) described in Non-Patent Document 7 activates insulin signaling molecules, increases sugar uptake activity, and suppresses gluconeogenic activity in cultured skeletal muscle cells and cultured hepatocytes. And improve glucose tolerance in type 2 diabetic db / db mice.
  • the related compound exhibits an action of enhancing insulin signal and promoting glucose uptake by insulin in established rat skeletal muscle cells (L6 cells). However, their efficacy is not high enough and they are not used for the treatment of diabetes.
  • the present inventors Based on the structure of a plurality of existing SHIP2 inhibitors, the present inventors performed conformational analysis and molecular superposition calculation by the Ligand-based drug design method, and the pharmacophore (the tertiary of functional groups) that SHIP2 inhibitors should have. Based on the results of molecular superposition calculation, a new compound was designed. Furthermore, they were synthesized and their medicinal effects were examined using cultured neurons. As a result, it was confirmed that the synthesized novel N- (pyridin-2-yl) alkanamide derivative had an action to increase insulin sensitivity in vitro, and it was more potent than existing SHIP2 inhibitors. The present inventors have completed the present invention by finding a compound that increases insulin sensitivity. Hereinafter, the present invention will be described in detail.
  • a halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom
  • an alkyl group is a linear or branched group such as a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl group chain C 1 - 12 alkyl group; a lower alkyl group, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- butyl, straight-chain or branched pentyl and hexyl groups chain C 1 - 6 alkyl group; and the alkylene group include methylene, ethylene, propylene and straight-chain or branched C 1, such as isopropylene group - 6 alkylene group; and the alkyl group is
  • the present invention provides the following general formula [1]
  • R 1 represents a hydrogen atom or a halogen atom
  • R 2 represents a halogen atom or an alkyl group which may be substituted with a halogen atom, an optionally substituted phenyl group or a cyclohexyl group
  • m and n each represents an integer of 1 to 3
  • a novel N- (pyridin-2-yl) alkanamide derivative represented by the formula:
  • the present invention relates to an N- (pyridin-2-yl) phenylalkanamide derivative of the following general formula [1a] or a salt thereof and an N- (pyridin-2-yl) cyclohexylalkane of the general formula [1b]: An amide derivative or a salt thereof.
  • R 1 represents a hydrogen atom or a halogen atom
  • R 2a represents a halogen atom or an alkyl group optionally substituted with a halogen atom
  • A represents an alkylene group or a bond
  • Each represents an integer of ⁇ 3.
  • R 1 represents a hydrogen atom or a halogen atom
  • R 2b represents a halogen atom or an alkyl group optionally substituted with a halogen atom
  • A represents an alkylene group or a bond
  • Each represents an integer of ⁇ 3.
  • salts of N- (pyridin-2-yl) alkanamide derivatives of the general formulas [1], [1a] and [1b] include inorganic acids such as hydrochloride, perchlorate, sulfate and nitrate Salt; Organic acid salts such as acetate and methanesulfonate are included.
  • Preferred salts include pharmacologically acceptable salts.
  • N- (pyridin-2-yl) alkanamide derivatives of the general formulas [1], [1a] and [1b] or salts thereof isomers (for example, optical isomers, geometric isomers, tautomers, etc.)
  • the present invention includes all such isomers and also includes hydrates, solvates and all crystal forms.
  • a preferred compound in the present invention is an N- (pyridin-2-yl) phenylalkanamide derivative of the general formula [1a] or a salt thereof.
  • an N- (pyridin-2-yl) phenylalkanamide derivative or a salt thereof in which n is 1, and m is 1 or 2 is preferable, and a more preferable compound is that A is a methylene group or N- (pyridin-2-yl) phenylalkanamide derivative or a salt thereof which is a bond.
  • N- (pyridin-2-yl) alkanamide derivative of the general formula [1] can be produced, for example, by the following method. ⁇ Production method>
  • the compound of the general formula [1] can be produced by reacting the compound of the general formula [2] with the compound of the general formula [3] in the presence of a condensing agent, a base, a catalyst and the like.
  • a condensing agent such as methylene chloride and chloroform.
  • examples of the condensing agent used in this reaction include carbodiimides such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) and N, N-dicyclohexylcarbodiimide (DCC); halogens such as thionyl chloride.
  • a halogenating alkyl ester such as chloroformic acid ethyl ester; an activated amidating agent such as carbonyldiimidazole; and an azidating agent such as diphenylphosphoric acid azide.
  • the amount of the condensing agent used may be equimolar or more, preferably 1 to 5 times the molar amount of the compound of the general formula [2].
  • Examples of the base used in this reaction include triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), pyridine, tert-butoxypotassium, sodium carbonate, potassium carbonate and Examples thereof include organic bases and inorganic bases such as sodium hydride, and the amount of the base used may be equimolar or more, preferably 1 to 10-fold mol relative to the compound of the general formula [3].
  • Examples of the catalyst used as necessary in this reaction include N, N-dimethyl-4-aminopyridine (DMAP) and the like. The amount of the catalyst used is relative to the compound of the general formula [3]. 0.1 to 1 moles.
  • This reaction is usually carried out at ⁇ 50 to 200 ° C., preferably ⁇ 30 to 100 ° C., for 10 minutes to 20 hours.
  • the compound of General formula [2] can be manufactured by the method of a well-known method, For example, the method as described in Bioorganic & Medicinal Chemistry Letters, 19 (20), 5851-5856; 2009 etc. can be mentioned. .
  • the protecting group when using a compound in which an amino group is protected, the protecting group may be removed in advance.
  • the compound of the general formula [1] thus obtained can be isolated and purified by usual methods such as extraction, crystallization, distillation and column chromatography.
  • the compound of the present invention comprises an excipient, a binder, a disintegrant, a disintegration inhibitor, a caking / adhesion inhibitor, a lubricant, an absorption / adsorption carrier, a solvent, an extender, an isotonic agent, a solubilizing agent, and an emulsifier.
  • the administration method of the said formulation is not specifically limited, It determines suitably according to the form of a formulation, a patient's age, sex, other conditions, and the grade of a patient's symptom.
  • the dosage of the active ingredient of the preparation of the present invention is appropriately selected according to the usage, patient age, sex, disease form, other conditions, etc., but usually 0.1 to 500 mg per day for an adult. What is necessary is just to divide and administer from 1 time to several times.
  • Cerebellar granule cells were seeded at a density of 1.0 ⁇ 10 6 cells / mL in a 35 mm culture dish coated with a poly-D-lysine solution (0.05 mg / mL), at 37 ° C., 5% carbon dioxide gas and saturated water vapor. Cultured under.
  • HK-BME containing 10 ⁇ M cytosine arabinoside
  • phosphate buffered saline 2 mL
  • the cerebellar granule cells were cultured in a cell culture medium (basal modified Eagles medium: LK-BME) containing 5 mM potassium chloride, 2 mM glutamine, 100 U / mL penicillin, 100 ⁇ g / mL streptomycin at 37 ° C., 5%.
  • LK-BME basic modified Eagles medium
  • a Remli solution containing dithiothreitol was added to a cell lysate having a constant protein amount by Bradford method, and boiled for 5 minutes.
  • the protein was separated by molecular weight size using SDS-polyacrylamide gel electrophoresis and transferred to a polyvinylidene fluoride membrane.
  • the polyvinylidene fluoride membrane was blocked with 5% non-fat milk solution or 2.5% bovine serum albumin at 25 ° C. for 1.5 hours, and then anti-Ser473 phospho-Akt antibody and anti-Akt 1 at 4 ° C., 16-20 Incubated for hours.
  • AS1949490 did not show an increase in insulin action, but the compound of the present invention showed an increase in insulin action.
  • compound 17 is 1.47 times
  • compound 18 is 1.05 times
  • compound 20 is 1.02 times
  • compound 22 is 1.33 times
  • compound 23 is 1.27 times.
  • the compound 24 was increased 1.33 times, respectively.
  • Cerebral cortical cells are seeded at a density of 2.0 ⁇ 10 6 cells / mL in a 35 mm culture dish pre-coated with 0.05 mg / mL poly-D-lysine solution, at 37 ° C. under 10% carbon dioxide and saturated water vapor. In culture. The medium was replaced with serum-free DMEM on the 3rd and 5th days of culture.
  • the cells were treated with DMEM containing 10 ⁇ m of the solvent (0.1% DMSO), the compound of the present invention or 10 ⁇ m of the control compound (AS1949490) for 15 minutes, and then stimulated with 1 nM of insulin for 5 minutes.
  • DMEM containing 10 ⁇ m of the solvent (0.1% DMSO), the compound of the present invention or 10 ⁇ m of the control compound (AS1949490) for 15 minutes, and then stimulated with 1 nM of insulin for 5 minutes.
  • Test Example 3 ⁇ Phosphorylation of Thr308 residue of protein kinase B / Akt> 1.
  • Culture of 3T3-L1 adipocytes Mouse-derived 3T3-L1 preadipocytes contain 10% donor bovine serum (DBS) (Dulbecco's Modified Eagle Medium: (DMEM; 100 U / mL penicillin and 100 ⁇ g / mL streptomycin) , Life Technology Co., Ltd.), seeded on a 10 cm culture dish, and cultured under conditions of 37 ° C. and 10% carbon dioxide gas.
  • DBS donor bovine serum
  • DMEM Dulbecco's Modified Eagle Medium
  • the cells were seeded in a 6-well culture dish, grown to 100% confluent, and cultured in DMEM containing 10% DBS for 3 days. Further, for induction of differentiation into adipocytes, the cells were cultured for 3 days in DMEM containing 10% fetal bovine serum (FBS), 0.5 mM 3-isobutyl-1-methylxanthine, 1 ⁇ M dexamethasone, and 1 ⁇ M insulin. The medium was replaced with DMEM containing FBS and 0.8 ⁇ M insulin, and further cultured for 3 days to be differentiated into adipocytes.
  • FBS fetal bovine serum
  • 0.5 mM 3-isobutyl-1-methylxanthine 1 ⁇ M dexamethasone
  • 1 ⁇ M insulin 1 ⁇ M insulin
  • the cell culture medium was changed every 3 days with DMEM containing 10% -FBS until it was used in the experiment.
  • 3T3-L1 adipocytes were washed with phosphate buffered saline (PBS ( ⁇ )), replaced with serum-free medium, and 20 ⁇ g / mL tumor necrosis factor.
  • - ⁇ TNF- ⁇
  • stimulation was performed for 120 minutes with 17 nM of insulin.
  • the cell lysate was mixed with a Remli solution containing dithiothreitol, stirred with a vortex mixer, and boiled for 5 minutes. This sample was subjected to SDS-polyacrylamide gel electrophoresis to separate proteins according to molecular weight size and transferred to a polyvinylidene fluoride membrane. This polyvinylidene fluoride membrane was blocked with 5% non-fat milk solution at 25 ° C.
  • the compound of the present invention is, for example, 1.37 times for compound 11, 1.20 times for compound 14, 1.22 times for compound 15, 1.26 times for compound 16, and 1.27 times for compound 18.
  • Compound 20 increased 1.29 times
  • Compound 21 increased 1.21 times
  • Compound 28 increased 1.30 times.
  • mice Male 8-week-old C57BL / 6J or BKS.Cg- + Leprdb / + Leprdb / Jcl (db / db) mice were treated with AS1949490 or compound 11 (300 mg / kg) suspended in 0.5% methylcellulose 2 times a day. Orally administered twice. On the 10th day after administration, body weight and food intake were measured. On the 13th day (C57BL / 6J) or 10th day (db / db) after administration, a glucose tolerance test was performed under fasting for 6 hours.
  • the N- (pyridin-2-yl) alkanamide derivative of the present invention exhibits an action of increasing insulin signal (protein kinase B / Akt phosphorylation) in mouse cerebellar granule cells and rat cerebral cortical cells. This effect was more remarkable than AS1949490, which is a known compound that selectively inhibits SHIP2.
  • the N- (pyridin-2-yl) alkanamide derivative of the present invention exhibits an action of increasing insulin signal (protein kinase B / Akt phosphorylation) in 3T3-L1 adipocytes. This effect was more remarkable than AS1949490, which is a known compound that selectively inhibits SHIP2.
  • the N- (pyridin-2-yl) alkanamide derivative of the present invention does not exhibit a significant hypoglycemic effect in normal mice, but exhibits a significant hypoglycemic effect in diabetic model mice.
  • SHIP2 negatively regulates insulin signal by dephosphorylating PI (3,4,5) P3 to PI (3,4) P2 in the insulin target tissue.
  • FJ compounds enhance insulin signal by inhibiting SHIP2. It is a figure which shows the blood glucose level and AUC in the glucose tolerance test in a mouse
  • tert-butylamine 0.1 mL, 1.0 mmol
  • tosyl chloride 0.095 g, 0.5 mmol
  • saturated sodium bicarbonate water is added with stirring until the aqueous layer shows basicity.
  • the separated aqueous layer is extracted with methylene chloride (10 mL ⁇ 3), the combined methylene chloride is dried over potassium carbonate, and the solvent is distilled off.
  • lithium aluminum hydride (0.113 g, 3 mmol) was added to a solution of ethyl isonicotinate (0.274 mL, 2 mmol) in tetrahydrofuran (10 mL) at 0 ° C., and the mixture was heated to reflux for 7 hours. After cooling, a 10% aqueous sodium hydroxide solution was added to the reaction solution with stirring until the reaction solution was all white. Further, after extraction with ethyl acetate (10 mL ⁇ 3) while heating, the combined ethyl acetate is dried over potassium carbonate, and the solvent is distilled off.
  • metachloroperbenzoic acid 0.561 g, 2 mmol
  • 4- (4-Chloro-benzyloxymethyl) -pyridine 0.228 g, 0.98 mmol
  • methylene chloride 5 mL
  • a 10% aqueous sodium hydroxide solution was added with stirring until the aqueous layer showed basicity.
  • the separated aqueous layer is extracted with methylene chloride (10 mL ⁇ 3), the combined methylene chloride is dried over potassium carbonate, and the solvent is distilled off.
  • tert-butylamine (0.62 mL, 5.9 mmol) and tosyl chloride (0.450 g, 2.36 mmol) were sequentially added at 0 ° C. under an argon gas atmosphere for 10 minutes. Stir. Furthermore, tert-butylamine (0.12 mL, 1.18 mmol) and tosyl chloride (0.112 g, 0.59 mmol) were added and stirred for 10 minutes, and then tert-butylamine (0.12 mL, 1.18 mmol) and tosyl chloride ( 0.112 g, 0.59 mmol) was sequentially added and stirred for 10 minutes.
  • tert-Butyl- [4- (4-chlorobenzyloxy) pyridin-2-yl] amine (0.169 g, 0.58 mmol) in methylene chloride (10 mL) solution, trifluoroacetic acid (1.2 ml) And reflux with heating for 2 days. After completion of the reaction, a 10% aqueous sodium hydroxide solution is added with stirring until the aqueous layer shows basicity. The separated aqueous layer is extracted with methylene chloride (10 mL ⁇ 3), the combined methylene chloride is dried over potassium carbonate, and the solvent is distilled off.
  • the obtained crystals were made into a methylene chloride (5 mL) solution under an argon gas atmosphere, and 2- (trifluoromethyl) phenylacetic acid (0.092 g, 0.45 mmol), 1-ethyl-3- (3-dimethylaminopropyl) was obtained.
  • the compound of the present invention exhibited an insulin signal enhancing action in mouse cerebellar granule cells, mouse-derived adipocytes, rat cerebral cortex cells, etc., and further exhibited a blood glucose lowering action in diabetes model mice.
  • the compounds are useful as novel therapeutic agents for type 2 diabetes.
  • the effect of neurotrophic factor can be enhanced by inhibiting SHIP2 in the cranial nervous system, and the compound of the present invention is expected to be used as an agent for improving central degenerative diseases such as Alzheimer's dementia.

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Abstract

[Problème] Produire un nouveau dérivé de N-(pyridin-2-yl)alcanamide et un nouvel insulinosensibilisateur contenant ce dérivé en tant que substance active. [Solution] [Composé 1] La présente invention concerne un nouveau dérivé de N-(pyridin-2-yl)alcanamide ou un sel de celui-ci, R1 et R2a dans la formule générale [1a] ci-dessus représentent un atome d'hydrogène ou un atome d'halogène, et A représente un groupe alkylène ou une liaison, a un effet inhibiteur sur SHIP2, et est utile en tant qu'insulinosensibilisateur en causant une augmentation de l'insulinosensibilité.
PCT/JP2012/064638 2011-06-09 2012-06-07 Nouveau dérivé de n-(pyridin-2-yl)alcanamide et inhibiteur de ship2 contenant celui-ci en tant que substance active WO2012169571A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015016293A1 (fr) * 2013-08-02 2015-02-05 国立大学法人 富山大学 Dérivé (benzènesulfonylamino)benzamide et inhibiteur de ship2 contenant celui-ci en tant que principe actif

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JP2002322054A (ja) * 2001-04-26 2002-11-08 Dai Ichi Seiyaku Co Ltd 薬剤排出ポンプ阻害薬
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JP2002322054A (ja) * 2001-04-26 2002-11-08 Dai Ichi Seiyaku Co Ltd 薬剤排出ポンプ阻害薬
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KATSUNORI ICHIHARA ET AL.: "Shinki Kokkaku o Yusuru 5'-Lipid Phosphatase SHIP2 Sogaiyaku no Kaihatsu to Insulin Teikosei Kaizen Koka no Kento", THE JOURNAL OF THE JAPAN DIABETIC SOCIETY, vol. 55, no. 1, 25 April 2012 (2012-04-25), pages 276 *
TOSHIYASU SASAOKA ET AL.: "2-gata Tonyobyo Insulin Teikosei ni Kakawaru Inshi Tyrosine phosphatase and lipid phosphatase", JAPANESE JOURNAL OF CLINICAL MEDICINE, vol. 66, no. 935, 28 May 2008 (2008-05-28), pages 495 - 501 *
TOSHIYASU SASAOKA ET AL.: "Lipid Phosphatase ni yoru Insulin Signal no Seigyo", ENDOCRINOLOGY & DIABETOLOGY, vol. 24, no. 2, 28 February 2007 (2007-02-28), pages 109 - 117 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015016293A1 (fr) * 2013-08-02 2015-02-05 国立大学法人 富山大学 Dérivé (benzènesulfonylamino)benzamide et inhibiteur de ship2 contenant celui-ci en tant que principe actif
JPWO2015016293A1 (ja) * 2013-08-02 2017-03-02 国立大学法人富山大学 （ベンゼンスルホニルアミノ）ベンズアミド誘導体およびそれらを有効成分とするｓｈｉｐ２阻害剤

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