WO2010074219A1 - Composé de benzothiophène - Google Patents

Composé de benzothiophène Download PDF

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Publication number
WO2010074219A1
WO2010074219A1 PCT/JP2009/071569 JP2009071569W WO2010074219A1 WO 2010074219 A1 WO2010074219 A1 WO 2010074219A1 JP 2009071569 W JP2009071569 W JP 2009071569W WO 2010074219 A1 WO2010074219 A1 WO 2010074219A1
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Prior art keywords
compound
sglt
salt
benzothien
ylmethyl
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PCT/JP2009/071569
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English (en)
Japanese (ja)
Inventor
鈴木　貴之
雅一 今村
史良 岩▲崎▼
寿夫 黒崎
紋子 森友
博行 森口
真典 横野
冨山　泰
淳 野田
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アステラス製薬株式会社
壽製薬株式会社
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Publication of WO2010074219A1 publication Critical patent/WO2010074219A1/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
    • C07D409/10—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 aromatic rings
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • 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

Definitions

  • the present invention relates to a benzothiophene compound useful as an active ingredient of a pharmaceutical composition, particularly a pharmaceutical composition for treating diabetes.
  • Diabetes is due to a decrease in insulin secretion from pancreatic ⁇ -cells (insufficient amount of insulin) and a decrease in insulin sensitivity in peripheral tissues such as muscle and liver (insufficient qualities of insulin). It is one of the diseases with metabolic syndrome. Due to its pathophysiological characteristics, diabetes is basically divided into two categories, type 1 and type 2. Type 1 diabetes is mainly caused by a decrease in insulin secretion, and type 2 diabetes is considered to have both pathophysiologically important causes of both insulin secretion decrease and insulin sensitivity decrease.
  • chronic hyperglycemia is defined as a risk factor for complications including cardiovascular disease, nephropathy, neuropathy and retinopathy, and complications including cardiovascular disease, nephropathy, neuropathy and retinopathy (Annu. Rev. Med. 46, 257, 1995, Diabetes Care 18, 258, 1995, Ann. Intern. Med. 122, 561, 1995, Diabetes 44) , 968, 1995, Diabetes 47, 1703, 1995). Therefore, the treatment policy for diabetes is based on diet therapy and exercise therapy to control the increase in blood sugar.
  • Currently, several oral anti-diabetic drugs and insulin preparations have been developed (Joslin ’s Diabetes Mellitus. 13th ed., 508, 1994). Although each drug shows high effectiveness for a specific patient, it is difficult to control a good blood glucose state in many diabetic patients.
  • SGLT Na + -glucose cotransporter
  • Drugs Na + -glucose cotransporter inhibitors
  • SGLT has at least three types of isoforms, SGLT-1, SGLT-2 and SGLT-3. It is known that glucose in the small intestine is absorbed into the blood via SGLT-1, and the increase in blood glucose level can be suppressed by inhibiting SGLT-1 and inhibiting sugar absorption in the small intestine.
  • Na + -glucose cotransporter inhibitors are not only diabetics such as type 1 diabetes and type 2 diabetes, but also various insulin-related diseases including insulin resistance diseases and obesity, and non-alcoholic fats. It is expected as an excellent therapeutic agent and preventive agent for fatty liver diseases including non-alcoholic steatohepatis (NASH).
  • NASH non-alcoholic steatohepatis
  • glucose cotransporter inhibitors was known conventionally O- glycosides, in recent years, without using the oxygen of glucosidic linkages O- glycosides C- glycoside Na + - glucose cotransporter It has been developed as a transporter inhibitor.
  • a C-glycoside derivative represented by the following formula or a salt thereof is known to exhibit a hypoglycemic action as a Na + -glucose cotransporter inhibitor (see Patent Document 1, the symbols in the formula) See the publication.)
  • Patent Document 2 there is a document reporting that the compound described in Patent Document 1 can exist as a co-crystal with L-proline (Patent Document 2), but there is no specific disclosure or suggestion of the compound of the present invention.
  • 1-phenyl 1-thio-D-glucitol derivatives including the following compounds, inhibit both SGLT-1 and SGLT-2 activities, and have both glucose absorption suppression from the digestive tract and urinary glucose excretion promoting action. It has been reported that it can be an active ingredient of a therapeutic agent for diabetes (Patent Document 4). However, there is no specific disclosure or suggestion of the compound of the present invention in this document.
  • a compound useful as an active ingredient of a pharmaceutical composition particularly a pharmaceutical composition for treating diabetes.
  • the benzothiophene compound of the present invention has a double inhibitory action of SGLT-1 and SGLT-2. It has an excellent blood glucose lowering action not only for severe hyperglycemia but also for mild hyperglycemia, and has an excellent blood glucose lowering action regardless of the degree of hyperglycemia, and normal Knowing that it has an excellent urinary glucose excretion effect in a blood glucose state, the present invention has been completed. Further, the benzothiophene compound of the present invention has been found to have an extremely strong blood glucose lowering effect on mild hyperglycemia compared to a compound that selectively inhibits SGLT-2, and has completed the present invention.
  • the present invention relates to a compound of formula (I) or a salt thereof (hereinafter sometimes referred to as the compound of the present invention), and a pharmaceutical composition containing a compound of formula (I) or a salt thereof, and an excipient. .
  • R 1 is lower alkyl optionally substituted by —OH, lower alkyl optionally substituted by —O-, or cycloalkyl optionally substituted
  • R 2 is , -H, optionally substituted lower alkyl, -O-optionally substituted lower alkyl, or -OH, or R 1 and R 2 together form a lower alkylene.
  • the present invention also relates to a pharmaceutical composition for the treatment of diabetes, obesity or fatty liver disease comprising a compound of formula (I) or a salt thereof.
  • This pharmaceutical composition includes a therapeutic agent for diabetes, obesity or fatty liver disease containing the compound of formula (I) or a salt thereof.
  • the present invention also relates to the use of a compound of formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for the treatment of diabetes, obesity or fatty liver disease, and the effectiveness of a compound of formula (I) or a salt thereof. It relates to a method for treating diabetes, obesity or fatty liver disease comprising administering an amount to a patient.
  • the compound of formula (I) or a salt thereof is a double inhibitory action of SGLT-1 and SGLT-2, an excellent blood glucose lowering action regardless of the degree of hyperglycemia, and an excellent urinary glucose excretion action in normoglycemia And / or prevention and / or prevention of various diabetes-related diseases including type 1 diabetes, type 2 diabetes, insulin resistance disease and obesity, and nonalcoholic steatohepatitis (NASH) It can be used as an active ingredient of a therapeutic pharmaceutical composition.
  • NASH nonalcoholic steatohepatitis
  • the graph of a human small intestine glucuronic acid conjugation metabolism test result is shown.
  • the X axis is the elapsed time from the start of the reaction (reaction time)
  • the Y axis is the residual ratio of the test compound. Ex indicates an example number.
  • the present invention provides the following. [1] A compound of the formula (I) or a salt thereof.
  • R 1 is lower alkyl optionally substituted by —OH, lower alkyl optionally substituted by —O-, or cycloalkyl optionally substituted
  • R 2 is , -H, optionally substituted lower alkyl, -O-optionally substituted lower alkyl, or -OH, or R 1 and R 2 together form a lower alkylene.
  • [2] The compound of [1] or a salt thereof, wherein R 2 is —H, methyl, methoxy, or —OH.
  • R 3 The compound or a salt thereof according to [2], wherein R 2 is —H, methyl, or —OH.
  • [4] The compound of [3] or a salt thereof, wherein R 2 is —H.
  • R 1 is (a) lower alkyl optionally substituted with —OH, (b) —O-lower alkyl optionally substituted with 1 cyano or 1 to 3 fluoro, or (C) The compound or salt thereof according to any one of [1] to [4], which is cyclopropyl.
  • [6] The compound or a salt thereof according to [5], wherein R 1 is (a) lower alkyl optionally substituted with —OH, or (b) methoxy.
  • R 1 and R 2 are combined to form trimethylene or tetramethylene.
  • a pharmaceutical composition comprising the compound of [1] or a salt thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition for preventing or treating diabetes, obesity or fatty liver disease comprising the compound of [1] or a salt thereof.
  • [14] A method for preventing or treating diabetes, obesity or fatty liver disease, comprising administering an effective amount of the compound or salt thereof according to [1] to a patient.
  • [15] A compound of formula 1a or a salt thereof in the first production method described later.
  • this compound is a very important production intermediate for producing the compound of the formula (I) or a salt thereof.
  • this compound is a very important production intermediate for producing the compound of the formula (I) or a salt thereof.
  • [17] A process for producing the compound of [15] or a salt thereof, comprising a step of protecting the hydroxyl group of the compound of [16] or a salt thereof with P 1 .
  • this manufacturing method is a manufacturing method which should be employ
  • lower alkyl means linear or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, Pentyl, hexyl, etc .; in another embodiment, straight-chain or branched alkyl having 1 to 4 carbon atoms; and in another embodiment, straight-chain or branched carbon having 1 to 4 carbon atoms In still another embodiment, it is alkyl having 1 to 2 carbon atoms.
  • “Lower alkylene” means linear or branched alkylene having 3 to 5 carbon atoms, such as trimethylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, pentamethylene, 1-methyltetramethylene, 2-methyltetramethylene, 1-ethyltrimethylene, 2-ethyltrimethylene, 1,1-dimethyltrimethylene, 1,2-dimethyltrimethylene; in another embodiment, trimethylene or tetramethylene; Another embodiment is trimethylene.
  • Cycloalkyl is a saturated hydrocarbon ring group having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc .; another embodiment is cyclopropyl.
  • optionally substituted means unsubstituted or having 1 to 5 substituents.
  • those substituents may be the same, or may mutually differ.
  • R 1 An embodiment of “lower alkyl optionally substituted with —OH” in R 1 is lower alkyl; another embodiment is lower alkyl substituted with —OH.
  • lower alkyl optionally substituted with —O- in R 1, there is —O— (lower alkyl optionally substituted with cyano or halogen); -(Lower alkyl optionally substituted with cyano or fluoro); in yet another embodiment is -O-lower alkyl; in yet another embodiment, -O- (lower substituted with cyano Yet another embodiment is -O- (lower alkyl substituted with 1 to 3 fluoro).
  • R 1 One embodiment of “optionally substituted cycloalkyl” for R 1 is cycloalkyl.
  • One embodiment of “optionally substituted lower alkyl” for R 2 is lower alkyl.
  • lower alkyl optionally substituted with —O” in R 2 is —O-lower alkyl.
  • the compound wherein R 1 is methoxy, ethoxy, isopropoxy, cyanomethoxy, difluoromethoxy, 2-fluoroethoxy, or trifluoromethoxy.
  • the compound wherein R 2 is optionally substituted -O-lower alkyl. In another embodiment, the compound wherein R 2 is methoxy.
  • the compound wherein R 2 is —OH.
  • Examples of specific compounds included in the present invention include the following compounds.
  • tautomers and geometric isomers may exist depending on the type of substituent.
  • the compound of the formula (I) may be described in only one form of an isomer, but the present invention also includes other isomers, separated isomers, or those And mixtures thereof.
  • the compound of the formula (I) may have an asymmetric carbon atom or axial asymmetry, and optical isomers based on this may exist.
  • the present invention also includes separated optical isomers of the compound of formula (I) or a mixture thereof.
  • the present invention includes a pharmaceutically acceptable prodrug of the compound represented by the formula (I).
  • a pharmaceutically acceptable prodrug is a compound having a group that can be converted to an amino group, a hydroxyl group, a carboxyl group, or the like by solvolysis or under physiological conditions.
  • groups that form prodrugs include those described in Prog. Med., 5, 2157-2161 (1985), and “Development of Pharmaceuticals” (Yodogawa Shoten, 1990), Volume 7, Molecular Design 163-198. Is mentioned.
  • the salt of the compound of the formula (I) is a pharmaceutically acceptable salt of the compound of the formula (I), and may form an acid addition salt or a salt with a base depending on the type of substituent. is there.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid Acid addition with organic acids such as lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, ditoluoyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid Salts; inorganic bases such as sodium, potassium, magnesium, calcium and aluminum; salt
  • the present invention also includes various hydrates and solvates of the compound of formula (I) and salts thereof, and crystalline polymorphic substances.
  • the present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.
  • the compound of the formula (I) and a salt thereof can be produced by applying various known synthesis methods utilizing characteristics based on the basic structure or the type of substituent. At that time, depending on the type of functional group, it is effective in terms of production technology to replace the functional group with an appropriate protective group (a group that can be easily converted into the functional group) at the stage from the raw material to the intermediate. There is a case.
  • protecting groups include protecting groups described in “Greene's Protective Groups in Organic Synthesis (4th edition, 2006)” by PGM Wuts and TW Greene. These may be appropriately selected according to the reaction conditions. In such a method, after carrying out the reaction by introducing the protective group, the desired compound can be obtained by removing the protective group as necessary.
  • the prodrug of the compound of formula (I) introduces a specific group at the stage from the raw material to the intermediate as in the case of the protective group, or further reacts with the obtained compound of formula (I).
  • the reaction can be carried out by applying a method known to those skilled in the art, such as ordinary esterification, amidation, dehydration and the like.
  • the compound of the formula (I) can be produced by the method described in Patent Document 1 described above, a method analogous thereto, or a method obvious to those skilled in the art.
  • benzothiophene is added to halobenzaldehyde 1a substituted with an appropriate substituent to give 1c, the hydroxyl group is reduced to 1d, and glucose protected with a trimethylsilyl group is added, The trimethylsilyl group and the protecting group of the hydroxyl group that can be deprotected under the acidic condition shown by P 1 are removed to give 1f, the hydroxyl group is protected, methoxy or ethoxy at the anomeric position is reduced and removed, and the deprotection reaction is further performed. It is the method of manufacturing this invention compound by attaching
  • X is bromo
  • P 1 is methoxymethyl, ethoxyethyl, 1-methoxy-1-methylethyl, methoxyethoxymethyl, or tetrahydropyran-2-yl
  • R is methyl
  • Step 1-1 This step is a step of adding compound 1b to compound 1a.
  • the addition reaction is carried out by reacting compound 1b with a base in a solvent inert to the reaction at ⁇ 78 ° C. to room temperature, in one embodiment at ⁇ 78 ° C. to ⁇ 20 ° C., and then adding compound 1a. Stir for 5 hours.
  • the base used include n-butyllithium, sec-butyllithium, tert-butyllithium, lithium hexamethyldisilazide, potassium hexamethyldisilazide and the like.
  • solvent used here examples are not particularly limited, but ethers such as tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, dimethoxyethane and diglyme; saturated hydrocarbons such as hexane, pentane and heptane; Aromatic hydrocarbons such as benzene, toluene and xylene; and mixtures thereof.
  • ethers such as tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, dimethoxyethane and diglyme
  • saturated hydrocarbons such as hexane, pentane and heptane
  • Aromatic hydrocarbons such as benzene, toluene and xylene; and mixtures thereof.
  • Step 1-2 This step is a step of reducing compound 1c.
  • the reduction reaction is carried out by reacting compound 1c with a reducing agent in the presence of a Lewis acid in a solvent inert to the reaction at ⁇ 78 ° C. to room temperature, and in one embodiment at ⁇ 78 ° C. to ⁇ 40 ° C. Stir for hours.
  • a Lewis acid examples include triethylsilane
  • examples of the Lewis acid include boron trifluoride / diethyl ether complex and trimethylsilyl triflate.
  • solvent used here are not particularly limited, but halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and dichloroethane; ethers; saturated hydrocarbons; aromatic hydrocarbons Acetonitrile; and mixtures thereof.
  • halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and dichloroethane
  • ethers saturated hydrocarbons
  • aromatic hydrocarbons Acetonitrile and mixtures thereof.
  • Step 1-3 This process adds the Compound 1e to Compound 1d, a step of removing the hydroxyl-protecting group capable deprotection under acidic conditions represented by a trimethylsilyl group and P 1.
  • the addition reaction can be performed according to the first production method Step 1-1.
  • the reaction for removing the protecting group is carried out by allowing an acid to act on the product of the addition reaction in the previous step in methanol or ethanol under cooling to reflux, in one embodiment at 0 ° C. to room temperature, and usually stirring for 0.1 to 72 hours. Done.
  • the acid used include inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as trifluoroacetic acid, p-toluenesulfonic acid, camphorsulfonic acid, and methanesulfonic acid.
  • Step 1-4 In this step, in order to remove anomeric methoxy or ethoxy of compound 1f, the hydroxyl group is protected, the anomeric methoxy or ethoxy is reduced and removed, and the protecting group is further removed to obtain the compound of the present invention. It is.
  • the introduction of the protecting group is carried out by stirring in a solvent inert to the reaction under cooling to reflux, and in one embodiment, at 0 ° C. to room temperature, usually for 0.1 to 72 hours.
  • the protecting group may be any group that cannot be removed by the following reduction reaction, and specifically includes an acetyl group.
  • P. G. M. Wutsut and Green (T. W. Greene), ⁇ Greene's Protective Groups in Organic Synthesis (4th edition, 2006) ” can be used.
  • the reduction reaction can be carried out according to the first production method Step 1-2. However, it may be preferable for the reaction to proceed by adding water.
  • the reaction for removing the protecting group is carried out by stirring in a solvent inert to the reaction under cooling to reflux, and in one embodiment, at 0 ° C. to room temperature, usually for 0.1 to 72 hours.
  • a solvent inert to the reaction under cooling to reflux
  • removing acetyl, alcohols; water; or a mixed solvent thereof such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium methoxide, etc. It can also be carried out by allowing a base to act and stirring at 0 ° C. to room temperature for 0.1 to 72 hours.
  • the compound 1a or a salt thereof in this production method is a very useful production intermediate in the production of the compound of the formula (I) or a salt thereof. Can efficiently produce the compound of formula (I) or a salt thereof.
  • compound 1a or a salt thereof can be produced by introducing a protecting group P 1 into a compound in which P 1 in the structural formula of compound 1a is —H, and the method is obvious to those skilled in the art. Or a similar method can be employed.
  • P 1 is methoxymethyl
  • compound 1a or a salt thereof can be produced by reacting in an appropriate solvent using a methoxymethylating agent such as methoxymethyl chloride and performing an appropriate treatment. .
  • X is bromo and P 2 is benzyl or lower alkyl.
  • Step 2-1 This step is a step of adding compound 1b to compound 2a.
  • the addition reaction can be performed according to the first production method Step 1-1.
  • Step 2-2 This step is a step of reducing compound 2b.
  • the reduction reaction can be performed according to the first production method Step 1-2.
  • Step 2-3 This step is a step of adding compound 2d to compound 2c.
  • the addition reaction can be performed according to the first production method Step 1-1.
  • Step 2-4 This step is a step of obtaining the compound of the present invention by reducing and removing the anomeric hydroxyl group of compound 2e and further removing the benzyl group and the hydroxyl protecting group represented by P 2 .
  • the reduction reaction can be performed according to the first production method Step 1-2.
  • the reaction for removing the protecting group is carried out in a solvent inert to the reaction under cooling to reflux, and in one embodiment, at 0 ° C. to room temperature, usually for 0.1 to 72 hours with stirring.
  • the method can be selected from the methods described in “Greene's Protective Groups in Organic Synthesis (4th edition, 2006)” by PG M. Wuts and T. W. Greene.
  • P 2 is benzyl
  • a Lewis acid is allowed to act in a halogenated hydrocarbon solvent in the presence of pentamethylbenzene and stirred at -78 ° C to -20 ° C for 0.1 to 72 hours.
  • You can also Examples of the Lewis acid used here include boron trichloride, boron tribromide, boron trifluoride / dimethyl sulfide complex, and the like.
  • the raw material 1a of the first production method and the raw material 2a of the second production method are prepared by converting the hydroxyl group of 3b obtained by bromination of 3a using, for example, tetrabutylammonium tribromide or pyridinium bromide perbromide to P 1 or P 2 It can be produced by lithiation of 3c protected with ⁇ , reacting N, N-dimethylformamide to introduce a formyl group, and then brominating the resulting 3d with, for example, tetrabutylammonium tribromide.
  • the raw material 1a of the first manufacturing method and the raw material 2a of the second manufacturing method were obtained by hydroxymethylating 3e obtained by bromination of 3a using, for example, tetrabutylammonium tribromide or pyridinium bromide perbromide using formaldehyde Thereafter, the obtained 3f hydroxyl group can be protected by P 1 or P 2 according to a conventional method, and the obtained 3 g can be oxidized with a normal oxidizing agent.
  • the raw material 1a of the first production method and the raw material 2a of the second production method are prepared by converting the hydroxyl group of 4b obtained by bromination of 4a using, for example, tetrabutylammonium tribromide or pyridinium bromide perbromide into P 1 or P 2 It can manufacture by protecting with.
  • an intermediate of raw material synthesis 2 is produced, for example, by bromating 4c obtained by reacting 4a with a reducing agent such as sodium borohydride using tetrabutylammonium tribromide or pyridinium bromide perbromide. You can also.
  • a reducing agent such as sodium borohydride using tetrabutylammonium tribromide or pyridinium bromide perbromide. You can also.
  • the compound of formula (I) is isolated and purified as a free compound, its salt, hydrate, solvate, or crystalline polymorphic substance.
  • the salt of the compound of the formula (I) can also be produced by subjecting it to a conventional salt formation reaction.
  • Isolation and purification are performed by applying ordinary chemical operations such as extraction, fractional crystallization, and various fractional chromatography.
  • optical isomers can be produced by selecting an appropriate raw material compound, or can be separated by utilizing a difference in physicochemical properties between isomers.
  • optical isomers can be obtained by general optical resolution of racemates (for example, fractional crystallization leading to diastereomeric salts with optically active bases or acids, chromatography using chiral columns, etc.). Further, it can also be produced from a suitable optically active raw material compound.
  • Test Example 1 SGLT-1 and SGLT-2 Inhibitory Activity Measurement Test
  • the amplified fragment was cloned into pCR2.1-Topo vector using TopoTopTA Cloning kit (Invitrogen), introduced into competent cells of E. coli strain JM109, and ampicillin resistant clones were ampicillin (100 mg / Grown in LB medium containing L).
  • TopoTopTA Cloning kit Invitrogen
  • a plasmid was purified from the grown Escherichia coli by the method of Hanahan (see Maniatis et al., Molecular Cloning), and this plasmid was digested with HindIII and EcoRI.
  • a DNA fragment encoding human SGLT-2 was obtained by expression vector pcDNA3.1 ( Invitrogen) was ligated to the same site using T4 DNA ligase (Roche Diagonostics) and cloned. The ligated clone was introduced into a competent cell of E. coli JM109 strain in the same manner as described above, grown in LB medium containing ampicillin, and human SGLT-1 and SGLT-2 expression vectors were obtained by the method of Hanahan.
  • Human SGLT-1 or SGLT-2 expression vectors were introduced into CHO-K1 cells using Lipofectamine 2000 (Gibco). After gene transfer, cells contain penicillin (50 IU / mL Dainippon Pharmaceutical), streptomycin (50 ⁇ g / mL Dainippon Pharmaceutical), Geneticin (40 ⁇ g / mL Gibco) and 10% fetal bovine serum A geneticin-resistant clone was obtained by culturing in Ham's F12 medium (manufactured by Nissui Pharmaceutical) in the presence of 5% CO 2 at 37 ° C. for about 2 weeks. From these clones, cells stably expressing human SGLT-2 were selected using the specific activity of sugar uptake in the presence of sodium relative to the steady level as an index (see the following section for details of the method for measuring sugar uptake). .
  • Uptake buffer containing test compound (140 ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ mM sodium chloride, 2 mM potassium chloride, 1 mM calcium chloride, 1 mM magnesium chloride, 50 ⁇ M methyl- ⁇ -D-glucopyranoside, 2- [4- (2-hydroxyethyl) 1-piperazinyl] ethanesulfonic acid 10 mM, tris (hydroxymethyl) aminomethane 5 mM buffer pH 7.4) 1000 ⁇ L 11 ⁇ L methyl- ⁇ -D- (U-14C) glucopyranoside (Amersham Pharmacia Biotech) Product) and mixed to obtain a buffer for uptake.
  • An uptake buffer containing no test compound was prepared in the control group.
  • a basal uptake buffer solution containing 140 ⁇ M choline chloride instead of sodium chloride was prepared in the same manner for basal uptake measurement in the absence of the test compound and sodium.
  • the pretreatment buffer was removed, uptake buffer was added at 25 ⁇ L per well, and human SGLT-1 and SGLT-2 stably expressing cells were allowed to stand at 37 ° C. for 2 hours.
  • the uptake buffer was removed and the wash buffer (choline chloride 140 mM, potassium chloride 2 mM, calcium chloride 1 mM, magnesium chloride 1 mM, methyl- ⁇ -D-glucopyranoside 10 mM, 2- [4- (2 -Hydroxyethyl) -1-piperazinyl] ethanesulfonic acid 10 mM and tris (hydroxymethyl) aminomethane 5 mM in buffer pH 7.4) were added at 200 ⁇ L per well and immediately removed.
  • the wash buffer (choline chloride 140 mM, potassium chloride 2 mM, calcium chloride 1 mM, magnesium chloride 1 mM, methyl- ⁇ -D-glucopyranoside 10 mM, 2- [4- (2 -Hydroxy
  • This washing operation was performed once more, and 0.5% sodium lauryl sulfate was added at 25 ⁇ L per well to solubilize the cells.
  • 75 ⁇ L of micro scintillation 40 (manufactured by Packard) was added thereto, and radioactivity was measured with a micro scintillation countertop count (manufactured by Packard).
  • the value obtained by subtracting the basal uptake from the uptake of the control group was taken as 100%, and the concentration at which 50% of the uptake was inhibited (IC 50 value) was calculated from the concentration-inhibition curve by the least square method.
  • IC 50 values of some compounds of the present invention and reference compounds are shown in Table 1. Ex indicates an example number.
  • Reference compounds 1 and 2 are the compounds of Examples 159 and 127 described in WO 2004/080990, respectively, and are shown here as examples of compounds that selectively inhibit SGLT-2.
  • KK-Ay mice (Claire Japan, male) in satiety and fasting (fasted for 16 hours) were used as experimental animals.
  • KK-Ay mice Male
  • KK-Ay mice Male
  • a fasting blood glucose level about 150 to 200 mg / dL.
  • the test compound was suspended in a 0.5% aqueous methylcellulose solution to a concentration of 1 mg / lOmL.
  • the body weight of the mice was measured, the test compound suspension was forcibly administered orally at a dose of 10, 30 mg / kg (1, 3 mg / kg as the test compound), and the control group was administered only with a 0.5 wt% methylcellulose aqueous solution. .
  • the number of mice per group was 5 or 6, and fasting and water-fasting conditions were applied after test compound administration. Blood was collected from the tail vein immediately before drug administration and 1, 2, 4, and 8 hours after drug administration, and the blood glucose level was measured using Glucose CII Test Wako (Wako Pure Chemical Industries).
  • the strength of the hypoglycemic effect is calculated by calculating the blood glucose level-time curve area (AUC) using the trapezoidal method from the blood glucose level over time from 0 to 8 hours of each test compound administration group, and lowering the blood glucose level relative to that of the control group It was shown in rate (%).
  • AUC blood glucose level-time curve area
  • some of the compounds of the present invention show that the test animals are satiety and fasting, that is, a severe hyperglycemia state with a blood glucose level of about 400 to 500 mg / dL and a blood glucose level of 150 to 200 mg / dL.
  • a severe hyperglycemia state with a blood glucose level of about 400 to 500 mg / dL and a blood glucose level of 150 to 200 mg / dL.
  • the dose of 1 mg / kg has an excellent hypoglycemic effect.
  • Reference Compounds 1 and 2 which are compounds that selectively inhibit SGLT-2 showed an excellent blood glucose lowering effect at a dose of 1 mg / kg at the time of satiety, that is, in a severe hyperglycemic state.
  • Table 2 shows the blood glucose lowering rate of some compounds of the present invention and reference compounds. Ex indicates an example number. Reference compounds 1 and 2 represent the same compounds as those described in Test Example 1 above. NT also indicates that the test has not been performed on the compound.
  • Test Example 3 Hypoglycemic Action Confirmation Test in Mild Hyperglycemia State KK-Ay mice (Japan Claire, female) at the time of satiation were used as experimental animals.
  • the blood sugar level of KK-Ay mice (female) at the time of satiation is about 200 mg / dL, which is equivalent to the fasting blood sugar level of KK-Ay mice (male) in Test Example 2.
  • the test compound was suspended in a 0.5% aqueous methylcellulose solution to a concentration of 1 mg / lOmL.
  • the body weight of the mice was measured, and the test compound suspension was forcibly orally administered at a dose of 10 mL / kg (1 mg / kg as the test compound), and only 0.5% methylcellulose aqueous solution was administered to the control group.
  • the number of mice per group was 5 or 6, and fasting and water-fasting conditions were applied after test compound administration.
  • Blood was collected from the tail vein immediately before drug administration and 1, 2, 4, and 8 hours after drug administration, and the blood glucose level was measured using Glucose CII Test Wako (Wako Pure Chemical Industries).
  • the strength of hypoglycemic action is calculated by calculating the blood glucose level-time curve area (AUC) using the trapezoidal method from the blood glucose level over time from 0 to 8 hours of each test compound administration group It was shown in rate (%).
  • some of the compounds of the present invention have a blood glucose lowering action of 25% or more at a dose of 1 mg / kg when the test animal is satiety, that is, in a mild hyperglycemia state where the blood glucose level is about 200 mg / dL.
  • a blood glucose lowering action of 25% or more at a dose of 1 mg / kg when the test animal is satiety, that is, in a mild hyperglycemia state where the blood glucose level is about 200 mg / dL.
  • the fasting of the KK-Ay mouse (male) of Test Example 2 there was a compound having an excellent effect.
  • the compounds of the present invention showed almost the same inhibitory activity against both SGLT-1 and SGLT-2. It became clear that it has heavy inhibitory activity. In addition, some compounds of the present invention showed strong inhibitory activity of about 10 nM or less as IC 50 values for both SGLT-1 and SGLT-2.
  • Reference Compounds 1 and 2 that selectively inhibit SGLT-2 have an excellent hypoglycemic effect on severe hyperglycemic conditions. It has been clarified that it does not have a sufficient hypoglycemic effect for mild hyperglycemia.
  • some compounds of the present invention exert a powerful hypoglycemic action at a dose as low as 1 mg / kg not only for severe hyperglycemia but also for mild hyperglycemia. It became clear that the said effect
  • the compound of the present invention having a dual inhibitory action of SGLT-1 and SGLT-2 even for mild hyperglycemia where a compound that selectively inhibits SGLT-2 cannot achieve a sufficient effect, Because it exhibits an excellent blood glucose lowering effect and exhibits a blood glucose lowering effect regardless of the level of hyperglycemia, it can be applied to more patient groups regardless of the severity of the disease in diabetes and various diabetes-related diseases It is clear that it is useful as an active ingredient of a therapeutic agent for the disease.
  • Test Example 4 SGLT-1 and SGLT-2 Inhibitory Activity Measurement Test The following comparative compounds were tested in the same manner as Test Example 1.
  • Comparative Compounds 1 and 2 showed almost the same inhibitory activity against SGLT-1 and SGLT-2 as the compounds of the present invention.
  • Comparative Compounds 3 to 5 had almost the same inhibitory activity against SGLT-2 as that of the compound of the present invention, but the inhibitory activity against SGLT-1 was very weak compared with the compound of the present invention.
  • Table 3 shows the IC 50 values of Comparative Compounds 1 to 5.
  • Comparative compounds 1 to 5 are the compounds of Example 144, Table 37 (first row, third column), Examples 116, 142 and 143 described in International Publication No. 2004/080990, respectively. Is a compound in which R C in the following formula (II) is OH.
  • Test Example 5 Human Small Intestine Glucuronic Acid Conjugation Metabolism Test Reaction solution (50 mM Tris-HCl (pH 7.4), 50 ⁇ g / mg Alamethicin, 8 mM MgCl 2 , 0.1 mg / mL Human intestinal Microsome) containing 2 ⁇ M test compound Incubation was performed in a 37 ° C. water bath for 2 minutes, and 2 mM UDPGA was added to initiate the reaction. A part of the reaction solution was collected at 0, 10, 30, 60, 120 minutes after the start, and added to ice-cold acetonitrile to stop the reaction. The test compound in the solution where the reaction was stopped was analyzed by LC / MS / MS method, and the residual ratio of the test compound at each time point with respect to 0 minutes of reaction was calculated.
  • Comparative Compounds 1 and 2 showed almost the same inhibitory activity against SGLT-1 and SGLT-2 as some compounds of the present invention.
  • Compounds 3 to 5 have very weak inhibitory activity against SGLT-1 compared to some compounds of the present invention, and the IC 50 values of Comparative Compounds 3 to 5 with respect to SGLT-1 are shown in Table 1. Some compounds were found to be about 15-170 times the IC 50 values for SGLT-1 for some compounds.
  • glycemic control in diabetes is to prevent and prevent the development of macrovascular complications such as cardiovascular disease and correction of chronic hyperglycemia, and microvascular complications including nephropathy, neuropathy and retinopathy. is there.
  • HbA1c hemoglobin A1c
  • HbA1c primarily reflects fasting blood glucose or postprandial blood glucose, but strict management of both is important to improve HbA1c improvement in diabetics It is clear (Diabetes Care 26, 881, 2003) that correcting not only postprandial hyperglycemia but also fasting (pre-meal) and inter-meal hyperglycemia is a diabetic complication. It is thought to be important for prevention of onset and progress suppression. For example, in a patient who is severely hyperglycemic after meals, such as the KK-Ay mouse (male) used in Test Example 2, but who is mildly hyperglycemic on an empty stomach, It is very important to correct fasting hyperglycemia as well as hyperglycemia.
  • Comparative Compounds 1 and 2 are very susceptible to human small intestine glucuronidation metabolism.
  • some compounds of the present invention are not easily subjected to human small intestine glucuronidation metabolism. Since glucuronide conjugation metabolism is considered as one of the main metabolic pathways in vivo, some compounds of the present invention can exist stably and persistently as active substances in blood, It was suggested that it can be a long-lasting drug. It is well known that a long-lasting drug is useful as a medicine in that, for example, a single dose can be reduced or the number of administrations can be reduced.
  • Test Example 6 Confirmation of urinary glucose excretion in severe and mildly hyperglycemic conditions KK-Ay mice (CLEA Japan, male) in satiety and fasting (16-hour fast) were used as experimental animals.
  • the test compound was suspended in a 0.5% aqueous methylcellulose solution to a concentration of 1 mg / 10 mL. After measuring the body weight of the mice, the test compound suspension was forcibly administered orally at a dose of 10 mL / kg (1 mg / kg as the test compound), and only 0.5% methylcellulose aqueous solution was administered to the control group. Moved to. The number of animals per group was 5 or 6. Thereafter, spontaneous urine up to 24 hours was collected and urine volume was measured. The urine sample is centrifuged (3,000 rpm, 10 minutes), and the urinary glucose concentration in the supernatant is measured using Glucose CII Test Wako (Wako Pure Chemical Industries). The amount was calculated.
  • some of the compounds of the present invention have a dose of 1 mg / kg at a dose of 1 mg / kg or more (about 600-800 mg in the control group) in severe hyperglycemia, and 1 mg in mild hyperglycemia.
  • Test Example 7 Test for confirming urinary glucose excretion in normoglycemic state ICR mice (Japan SLC, male) at the time of satiation were used as experimental animals.
  • the test compound was suspended in a 0.5% aqueous methylcellulose solution to a concentration of 1 mg / 10 mL. After measuring the body weight of the mice, the test compound suspension was forcibly administered orally at a dose of 10 mL / kg (1 mg / kg as the test compound), and only 0.5% methylcellulose aqueous solution was administered to the control group. Moved. The number of animals per group was 5 or 6. Thereafter, spontaneous urine up to 24 hours was collected and urine volume was measured. The urine sample is centrifuged (3,000 rpm, 10 minutes), and the urinary glucose concentration in the supernatant is measured using Glucose CII Test Wako (Wako Pure Chemical Industries). The amount was calculated.
  • Test Example 8 Effect on non-alcoholic simple fatty liver model (KK-A y mouse) KK-A y mouse (female) was allowed to freely feed CMF (special breeding), and at 14 weeks of age, body weight and blood glucose Levels, plasma insulin levels, plasma triglyceride levels, and plasma alanine aminotransferase (ALT) are measured and grouped so that these items are uniform.
  • the test compound suspension is administered by oral gavage at a dose of 0.01 to 10 mg / kg once a day for 2 weeks. Only 0.5% methylcellulose solution is administered to the control group. The number of animals per group is 6-8. The day after the final administration, the liver is collected under ether anesthesia, frozen in liquid nitrogen and stored at -80 ° C.
  • the triglyceride content of the liver can be measured by the following procedure. 1. Part of the liver (50-150 mg) that has been stored frozen at -80 ° C is dispensed into an assist tube. 2. Add 2 mL of methanol and crush with POLYTRON (KINEMATICA). 3. Add 4 mL of chloroform and stir vigorously at room temperature for 10 minutes. 4). Add 1 mL of milliQ water and stir vigorously. 5). Centrifugation was performed with a low-speed centrifuge (2,500 rpm, 5 min, room temperature). 6). Transfer a portion of the lower layer (total volume 4.5 mL) to an Eppendorf tube, and remove the solvent using a centrifugal evaporator. 7).
  • Test Example 9 Effects on non-alcoholic steatohepatitis model (rats loaded with methionine / choline-deficient diet (MCD diet)) This study should be conducted with reference to the literature (J Hepatol., 2003, 39, 756-764) Can do. Wistar rats (male) are allowed to eat MCD diet (methionine / choline deficient diet) freely, and at 9 weeks of age, body weights are measured and divided into groups so as to be uniform (10 animals per group). ). The test compound suspension is administered by oral gavage at a dose of 0.01 to 10 mg / kg once a day for 16 weeks.
  • the liver is collected under ether anesthesia, and a part of the liver is fixed with 10% neutral buffered formalin.
  • Paraffin sections (3 ⁇ m) are prepared by a conventional method, and HE staining and van Gieson staining are performed. Inflamed lesions are assessed using HE-stained specimens, and fibrosis is assessed using Wangyson-stained specimens. The evaluation was based on the NASH activity score (NAS) for inflammatory lesions and the Brunt classification for fibrosis (edited by the Japan Liver Society, edited by NASH / NAFLD, 2006), 0, 1, 2, 3 respectively. 4 (see Table 5).
  • NAS NASH activity score
  • Test Example 10 Effect on non-alcoholic steatohepatitis model (choline-deficient amino acid substitution diet (CDAA diet) loaded rat) This study was based on literature (Biochem Biophys Res Commun., 2004, 315 (1), 187-195) A test can be performed. Wistar rats (male) are fed a CDAA diet (choline-deficient amino acid-substituted diet) freely, and at 9 weeks of age, body weights are measured and divided into groups so as to be uniform (10 animals in each group). ). The test compound suspension is administered by oral gavage at a dose of 0.01 to 10 mg / kg once a day for 5 weeks. Only 0.5% methylcellulose solution is administered to the control group. The liver is collected under ether anesthesia the day after the last dose.
  • CDAA diet choline-deficient amino acid substitution diet
  • a paraffin section (3 ⁇ m) is prepared by a conventional method, and then stained with van Gieson. Fibrosis can be evaluated based on the Brunt classification (edited by the Japan Liver Society, edited by NASH / NAFLD, 2006) on a scale of 0, 1, 2, 3, 4 (see Table 5). .
  • Test Example 11 Effect on Obesity Model Male ICR mice (5 weeks old) are bred with a high-fat diet from 8 weeks of age, and equally divided into groups based on body weight at the age of 10 weeks. The test compound suspension is administered by repeated oral gavage once a day for 3 weeks at a dose of 0.01 to 10 mg / kg. Only 0.5% methylcellulose solution is administered to the control group. The number of animals per group is 6-8. At 13 weeks of age, the body weight and the amount of body weight fluctuation from the start of administration are measured, and the data are shown as mean ⁇ standard error.
  • some compounds of the present invention can be administered at a dose of 1 mg / kg not only in severely hyperglycemic conditions but also in mildly hyperglycemic conditions. It was revealed that it exerts a sugar excretion action and exhibits an excellent action regardless of the degree of hyperglycemia.
  • the compound of the present invention is based on the excretion of urinary glucose in severe and mild hyperglycemic conditions and in normoglycemic conditions. And non-alcoholic steatohepatis (NASH), and is expected to have an excellent ameliorating effect on fatty liver diseases including non-alcoholic steatohepatis (NASH). These improvement effects can be confirmed in Test Examples 8 to 11.
  • the compound of the present invention has a double inhibitory action of SGLT-1 and SGLT-2, an excellent hypoglycemic action regardless of the degree of hyperglycemia, and an excellent urinary glucose excretion action in normoglycemia.
  • Prevention and / or treatment of various diabetes related diseases including type 1 diabetes, type 2 diabetes, insulin resistance disease, obesity, and fatty liver disease including non-alcoholic steatohepatis (NASH) It is clear that it is useful as an active ingredient of pharmaceutical compositions for medical use.
  • NASH non-alcoholic steatohepatis
  • a pharmaceutical composition containing one or more of the compounds of formula (I) or a salt thereof as an active ingredient is an excipient usually used in the art, that is, a pharmaceutical excipient or a pharmaceutical carrier. Can be prepared by a commonly used method.
  • Administration is orally by tablets, pills, capsules, granules, powders, solutions, etc., or injections such as intra-articular, intravenous, intramuscular, suppositories, eye drops, ophthalmic ointments, transdermal solutions, Any form of parenteral administration such as an ointment, a transdermal patch, a transmucosal liquid, a transmucosal patch, and an inhalant may be used.
  • Tablets, powders, granules, etc. are used as solid compositions for oral administration.
  • one or more active ingredients contain at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone. And / or mixed with magnesium aluminate metasilicate.
  • the composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, a stabilizer, or a solubilizing agent according to a conventional method. . If necessary, tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like, and commonly used inert diluents such as purified water. Or it contains ethanol.
  • the liquid composition may contain solubilizers, wetting agents, auxiliaries such as suspending agents, sweeteners, flavors, fragrances and preservatives in addition to the inert diluent.
  • the injection for parenteral administration contains a sterile aqueous or non-aqueous solution, suspension or emulsion.
  • aqueous solvent include distilled water for injection or physiological saline.
  • non-aqueous solvents include propylene glycol, polyethylene glycol or vegetable oil such as olive oil, alcohols such as ethanol, or polysorbate 80 (a pharmacopeia name).
  • Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.
  • the daily dose is about 0.001 to 100 mg / kg, preferably 0.05 to 30 mg / kg, more preferably 0.1 to 10 mg / kg per body weight. Or in 2 to 4 divided doses.
  • the appropriate daily dose is about 0.0001 to 10 mg / kg per body weight, and is administered once to several times a day.
  • a transmucosal agent about 0.001 to 100 mg / kg per body weight is administered once to several times a day. The dose is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like.
  • the compound of the formula (I) can be used in combination with various therapeutic agents or preventive agents for diseases for which the compound of the formula (I) is considered to be effective.
  • the combination may be administered simultaneously, separately separately, or at desired time intervals.
  • the simultaneous administration preparation may be a compounding agent or may be separately formulated.
  • the manufacturing method of the compound of Formula (I) is demonstrated in detail.
  • this invention is not limited to the compound as described in the following Example.
  • the manufacturing method of a raw material compound is shown in a manufacture example, respectively.
  • the production method of the compound of the formula (I) is not limited to the production methods of the specific examples shown below, and the compound of the formula (I) may be a combination of these production methods or a person skilled in the art. It can also be produced by methods that are self-evident.
  • reaction mixture was warmed to 0 ° C., saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate and washed with saturated brine.
  • the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (hexane-ethyl acetate), and 1-benzothien-2-yl [4- (benzyloxy) -5-bromo-2-ethylphenyl] methanol ( 4.26 g) was obtained as a light brown amorphous.
  • Tables 6 and 7 show the chemical structures of the compounds produced in the above production examples. Further, in the same manner as in the above production examples, the production example compounds shown in Tables 8 to 11 were produced using the corresponding raw materials. In addition, production methods and instrumental analysis data of these production example compounds are shown in Tables 12 to 23.
  • Example 3 Ice-cooled (1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -4-carboxy-2-hydroxyphenyl] -D-glucitol (72 mg) in a nitrogen stream Borane-tetrahydrofuran complex (1 M tetrahydrofuran solution) (1.0 mL) was added dropwise to a tetrahydrofuran (1 mL) solution, and the mixture was warmed to room temperature and stirred for 3 hours.
  • Borane-tetrahydrofuran complex (1 M tetrahydrofuran solution) (1.0 mL) was added dropwise to a tetrahydrofuran (1 mL) solution, and the mixture was warmed to room temperature and stirred for 3 hours.
  • Tetrahydrofuran (5 mL) and borane-tetrahydrofuran complex (1 M tetrahydrofuran solution) (0.67 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 3 days.
  • borane-tetrahydrofuran complex (1 M tetrahydrofuran solution) (1.67 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 days.
  • the reaction mixture was ice-cooled, water and 1 M hydrochloric acid (0.5 mL) were added, and the solvent was evaporated under reduced pressure.
  • the colorless amorphous solid obtained by purifying the residue by ODS column chromatography was pulverized with diethyl ether-hexane, and the powder was collected by filtration, dried by heating under reduced pressure, and (1S) -1,5 -Anhydro-1- [5- (1-benzothien-2-ylmethyl) -2-hydroxy-4- (hydroxymethyl) phenyl] -D-glucitol (28 mg) was obtained as a white solid.
  • Example 4 1,2 of (1S) -1,5-Anhydro-1- [5- (1-benzothien-2-ylmethyl) -2-hydroxy-3-methoxy-4-methylphenyl] -D-glucitol (187 mg) Boron trifluoride-dimethyl sulfide complex (383 mg) was added to a solution of -dichloroethane (4 mL), and the mixture was stirred at room temperature for 4 hours. Methanol was added to the reaction mixture, and the solvent was distilled off under reduced pressure.
  • the brown amorphous solid obtained by purifying the residue by silica gel column chromatography (chloroform-methanol) and ODS column chromatography (water-acetonitrile) was pulverized with hexane, dried by heating under reduced pressure, and (1S) -1 , 5-Anhydro-1- [5- (1-benzothien-2-ylmethyl) -2,3-dihydroxy-4-methylphenyl] -D-glucitol (22.6 mg) was obtained as a light brown solid.
  • the pale yellow amorphous solid obtained by purifying the residue by ODS column chromatography (water-acetonitrile) was pulverized with diethyl ether, dried by heating under reduced pressure, and (1S) -1,5-anhydro-1- [5 -(1-Benzothien-2-ylmethyl) -2-hydroxy-4- (1-hydroxy-1-methylethyl) phenyl] -D-glucitol (32 mg) was obtained as a pale orange solid.
  • Table 24 shows the chemical structures of the compounds produced in the above examples. Moreover, it carried out similarly to the method of the said Example, and manufactured the Example compound shown in Table 25 and Table 26, respectively using the corresponding raw material. In addition, Tables 27 to 30 show the production methods and instrumental analysis data of these Example compounds.
  • the compound of formula (I) or a salt thereof is a double inhibitory action of SGLT-1 and SGLT-2, an excellent blood glucose lowering action regardless of the degree of hyperglycemia, and an excellent urinary glucose excretion action in normoglycemia
  • Various diabetes related diseases including type 1 diabetes, type 2 diabetes, insulin resistance disease and obesity, and fatty liver disease including nonalcoholic steatohepatitis (NASH) and / or It can be used as an active ingredient of a therapeutic pharmaceutical composition.
  • NASH nonalcoholic steatohepatitis

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Abstract

Cette invention se rapporte à un composé utile en tant de substance active d'une composition pharmaceutique destinée à traiter le diabète. Des études approfondies ont été menées sur des composés qui présentent une double activité inhibitrice de la SGLT-1/SGLT-2 et on constate qu'un composé de benzothiophène de l'invention présente une double activité inhibitrice de la SGLT-1/SGLT-2, une excellente activité hypoglycémique sur un état d'hyperglycémie légère ainsi que sur un état d'hyperglycémie sérieuse et donc qu'il présente une excellente activité hypoglycémique indépendamment de la sévérité de l'état d'hyperglycémie, ainsi qu'une excellente activité d'excrétion urinaire de glucose sur un état qui présente un taux de glucose sanguin normal. On constate également que le composé de benzothiophène présente une activité hypoglycémique extrêmement élevée sur un état d'hyperglycémie légère en comparaison des composés qui peuvent inhiber de manière sélective la SGLT-2. Le composé présente une activité double inhibitrice de la SGLT-1/SGLT-2, une excellente activité hypoglycémique indépendamment de la sévérité de l'état d'hyperglycémie et une excellente activité d'excrétion urinaire de glucose sur un état qui présente un taux de glucose sanguin normal et il est donc possible de l'utiliser en tant que substance active d'une composition pharmaceutique destinée à empêcher et/ou à traiter des maladies liées au diabète parmi lesquelles il est possible de citer le diabète de type 1, le diabète de type 2, les maladies qui résistent à l'insuline, les maladies liées à l'obésité et à une stéatose hépatique, notamment la stéatohépatite non alcoolique (NASH).
PCT/JP2009/071569 2008-12-26 2009-12-25 Composé de benzothiophène WO2010074219A1 (fr)

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CN102757415A (zh) * 2011-04-25 2012-10-31 北京普禄德医药科技有限公司 一种钠依赖性葡萄糖转运蛋白抑制剂及其制备方法和用途
JP2013533291A (ja) * 2010-08-10 2013-08-22 シャンハイ ヘンルイ ファーマスーティカル カンパニー リミテッド Ｃ−アリールグルコシド誘導体、製造法およびその医薬用途
CN105085454A (zh) * 2014-05-13 2015-11-25 北京韩美药品有限公司 Sglt抑制剂及其药物组合物
JP2016516689A (ja) * 2013-03-11 2016-06-09 ヤンセン ファーマシューティカ エヌ．ベー． 二重ｓｇｌｔ１／ｓｇｌｔ２阻害剤
JP2016529298A (ja) * 2013-09-09 2016-09-23 ジエンス ハンセン ファーマセウティカル グループ カンパニー リミテッド Ｃ−アリールグルコシド誘導体、その製造方法およびその医薬適用
US20210238170A1 (en) * 2018-05-09 2021-08-05 Janssen Pharmaceutica Nv 5,5-Difluoro- and 5-Fluoro-5-Methyl-C-Glycoside Derivatives Useful As Dual SGLT1 / SGLT2 Modulators

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WO2004080990A1 (fr) * 2003-03-14 2004-09-23 Astellas Pharma Inc. Derives de c-glycoside et sels correspondants

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US9895389B2 (en) 2009-10-20 2018-02-20 Novartis Ag Glycoside derivatives and uses thereof
USRE49080E1 (en) 2009-10-20 2022-05-24 Novartis Ag Glycoside derivatives and uses thereof
US8466114B2 (en) 2009-10-20 2013-06-18 Novartis Ag Glycoside derivatives and uses thereof
US8163704B2 (en) 2009-10-20 2012-04-24 Novartis Ag Glycoside derivatives and uses thereof
US8828951B2 (en) 2009-10-20 2014-09-09 Novartis Ag Glycoside derivatives and uses thereof
JP2013533291A (ja) * 2010-08-10 2013-08-22 シャンハイ ヘンルイ ファーマスーティカル カンパニー リミテッド Ｃ−アリールグルコシド誘導体、製造法およびその医薬用途
CN102757415B (zh) * 2011-04-25 2015-07-29 北京普禄德医药科技有限公司 一种钠依赖性葡萄糖转运蛋白抑制剂及其制备方法和用途
CN102757415A (zh) * 2011-04-25 2012-10-31 北京普禄德医药科技有限公司 一种钠依赖性葡萄糖转运蛋白抑制剂及其制备方法和用途
JP2016516689A (ja) * 2013-03-11 2016-06-09 ヤンセン ファーマシューティカ エヌ．ベー． 二重ｓｇｌｔ１／ｓｇｌｔ２阻害剤
JP2016529298A (ja) * 2013-09-09 2016-09-23 ジエンス ハンセン ファーマセウティカル グループ カンパニー リミテッド Ｃ−アリールグルコシド誘導体、その製造方法およびその医薬適用
US10011627B2 (en) 2013-09-09 2018-07-03 Youngene Therapeutics Co., Ltd C-aryl glucoside derivative, preparation methods thereof, and medical applications thereof
CN105085454A (zh) * 2014-05-13 2015-11-25 北京韩美药品有限公司 Sglt抑制剂及其药物组合物
US20210238170A1 (en) * 2018-05-09 2021-08-05 Janssen Pharmaceutica Nv 5,5-Difluoro- and 5-Fluoro-5-Methyl-C-Glycoside Derivatives Useful As Dual SGLT1 / SGLT2 Modulators

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