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WO2013151033A1 - Dérivé de c-glycoside présentant un cycle spiro - Google Patents

Dérivé de c-glycoside présentant un cycle spiro Download PDF

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Publication number
WO2013151033A1
WO2013151033A1 PCT/JP2013/060052 JP2013060052W WO2013151033A1 WO 2013151033 A1 WO2013151033 A1 WO 2013151033A1 JP 2013060052 W JP2013060052 W JP 2013060052W WO 2013151033 A1 WO2013151033 A1 WO 2013151033A1
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Prior art keywords
mmol
benzofuran
compound
pyran
tetrahydro
Prior art date
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PCT/JP2013/060052
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English (en)
Japanese (ja)
Inventor
森　一樹
啓志 齋藤
幸子 関口
由美子 水野
真紀 餌取
正憲 泉
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Daiichi Sankyo Co Ltd
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Daiichi Sankyo Co Ltd
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Publication of WO2013151033A1 publication Critical patent/WO2013151033A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/01—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing oxygen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to a compound having an SGLT activity inhibitory action or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing these as active ingredients.
  • Non-Patent Document 1 Research and development of a drug with a new mechanism that increases glucose excretion in urine and lowers blood glucose level by inhibiting glucose reabsorption in the kidney (see Non-Patent Document 1, etc.).
  • This drug inhibits the reabsorption of sugar from raw urine by inhibiting sodium-dependent glucose transporter 2 (hereinafter referred to as SGLT2) present in the proximal tubule of the kidney It has been shown to reduce blood glucose levels by suppressing and increasing sugar excretion outside the body (see Non-Patent Document 2, etc.).
  • compounds that inhibit human SGLT2 are expected to normalize blood glucose levels by increasing urinary glucose excretion and are associated with various types of diabetes associated with type 1 and type 2 diabetes and hyperglycemia It becomes an effective drug for diseases.
  • an anti-obesity effect is expected by reducing excessive energy accumulation by increasing sugar excretion.
  • SGLT1 another subtype of SGLT (Sodium-dependent glucose cotransporter 1), is expressed in the small intestine and absorbs sugar (glucose, galactose, etc.) from food into the body.
  • sugar glucose
  • galactose galactose
  • Non-patent Document 4 Non-patent Document 4
  • drugs that inhibit SGLT1 are thought to exhibit postprandial hyperglycemia suppression and anti-obesity effects by inhibiting and delaying the absorption of sugar from the small intestine.
  • a transient influx of sugar after meal promotes insulin secretion, and it can be expected to correct hyperinsulinemia by correcting this.
  • a drug that suppresses human SGLT1 and / or SGLT2 activity has both an action of increasing urinary glucose excretion and an action of inhibiting sugar absorption from the small intestine, and such drugs include type 1 and type 2 diabetes, obesity, It is expected to be an effective drug for various related diseases accompanying hyperglycemia, hyperinsulinemia, fatty liver and the like.
  • examples of such drugs include compounds disclosed in Patent Documents 1 to 7, Non-Patent Document 5, and the like.
  • the present invention contains a compound or a pharmaceutically acceptable salt thereof having a novel structure, low side effects and excellent human SGLT1 and / or SGLT2 inhibitory activity, and an active ingredient thereof.
  • An object is to provide a pharmaceutical composition for treating and / or preventing gangrene, infection, ketosis and the like.
  • R 1 is a methyl or ethyl group
  • R 2 is a chlorine atom, a bromine atom, a C1-C3 alkyl group or a hydroxy C1-C3 alkyl group
  • Ring A may have one or two substituents selected from substituent group ⁇ , wherein:
  • a ring selected from the group consisting of Substituent group ⁇ is a halogen atom, C1-C3 alkyl group, C1-C3 alkoxy group, hydroxy C1-C3 alkyl group, hydroxy C1-C3 alkoxy group or mono (C1-C3 alkyl) amino group) Or a pharmaceutically acceptable salt thereof,
  • the monovalent group of ring A may have one or two substituents selected from substituent group ⁇ , the following:
  • the compound according to claim 1 or a pharmaceutically acceptable salt thereof which is one group selected from the group consisting of: (3)
  • the monovalent group of ring A may have one or two substituents selected from substituent group ⁇ .
  • a compound or a pharmaceutically acceptable salt thereof having low side effects and having excellent human SGLT1 and / or SGLT2 inhibitory activity and a pharmaceutical composition containing them as an active ingredient, Type 1 diabetes, Type 2 diabetes, gestational diabetes, hyperglycemia due to other factors, IGT, diabetes related diseases (obesity, hyperlipidemia, hypercholesterolemia, lipid metabolism disorder, hypertension, fatty liver, metabolic syndrome, Treatment of edema, heart failure, angina, myocardial infarction, arteriosclerosis, hyperuricemia, gout, etc.) or diabetic complications (retinopathy, nephropathy, neuropathy, cataract, foot gangrene, infection, ketosis, etc.) And / or can be prevented.
  • halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • C1-C3 alkyl group means a methyl group, an ethyl group, a propyl group, an isopropyl group, or a cyclopropyl group.
  • hydroxy C1-C3 alkyl group refers to a group in which one hydrogen atom of the “C1-C3 alkyl group” is substituted with a hydroxy group.
  • Specific examples include hydroxymethyl group, hydroxyethyl group, 2-hydroxyethyl group, hydroxypropyl group and the like.
  • C1-C3 alkoxy group means a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group or a cyclopropyloxy group.
  • hydroxy C1-C3 alkoxy group refers to a group in which one hydrogen atom of the “C1-C3 alkoxy group” is substituted with a hydroxy group.
  • Specific examples include hydroxymethoxy group, hydroxyethoxy group, hydroxypropoxy group, hydroxycyclopropyl group and the like.
  • “mono or di (C1-C3 alkyl) amino group” refers to a group in which one or two hydrogen atoms of an amino group are substituted with the above-mentioned “C1-C3 alkyl group”.
  • Examples of the mono (C1-C3 alkyl) amino group include a methylamino group, an ethylamino group, a propylamino group, and an isopropylamino group.
  • Examples of the di (C1-C3 alkyl) amino group include a dimethylamino group and a diethylamino group. N-ethyl-N-methylamino group, dipropylamino group and the like.
  • the “pharmaceutically acceptable salt” refers to a salt formed by reacting the compound of the present invention with an acid.
  • Salts include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide and hydroiodide; inorganic acid salts such as nitrate, perchlorate, sulfate and phosphate Methanesulfonate, trifluoromethanesulfonate, lower alkanesulfonates such as ethanesulfonate; arylsulfonates such as benzenesulfonate, p-toluenesulfonate; acetate, malate, fumarate And organic acid salts such as acid salts, succinates, citrates, ascorbates, tartrate, oxalates and maleates.
  • inorganic acid salts such as nitrate, perchlorate, sulfate and phosphate Methanesulfonate, trifluoromethanesulfonate, lower alkanesulfonates such as ethanesulfonate
  • the compound of the present invention may absorb water and become a hydrate when left in the air, for example, and such a hydrate is also included in the salt of the present invention.
  • stereoisomers and mixtures of stereoisomers are all represented by a single formula, that is, general formula (I). Accordingly, the present invention includes all of these stereoisomers and a mixture of these stereoisomers in an arbitrary ratio.
  • the definition of stereoisomers is as shown in "1996 IUPAC, Pure and Applied" Chemistry 68, 2193-2222.
  • the present invention can also include a compound in which one or more atoms of the compound represented by the general formula (I) are substituted with an isotope of the atom.
  • isotopes There are two types of isotopes: radioactive isotopes and stable isotopes. Examples of isotopes include hydrogen isotopes ( 2 H and 3 H), carbon isotopes ( 11 C, 13 C and 14 C ), Nitrogen isotopes ( 13 N and 15 N), oxygen isotopes ( 15 O, 17 O and 18 O), fluorine isotopes ( 18 F) and the like.
  • compositions containing isotope-labeled compounds are useful as therapeutic agents, prophylactic agents, research reagents, assay reagents, diagnostic agents, in vivo diagnostic imaging agents, and the like. All isotope-labeled compounds and mixtures of isotope-labeled compounds in any proportion are also encompassed by the invention.
  • An isotope-labeled compound can be produced by a method known in the art (for example, using an isotope-labeled raw material instead of the raw material in the method for producing the compound of the present invention described later).
  • the present invention can also include a prodrug of the compound represented by the general formula (I).
  • the prodrug is a derivative of the compound represented by the general formula (I) and refers to a compound that is converted in vivo to an enzyme or a chemical compound of the present invention.
  • Prodrugs include compounds in which the amino group in the molecule is acylated, alkylated or phosphorylated, compounds in which the hydroxy group in the molecule is acylated, alkylated or phosphorylated (for example, PovlP Krogsgaard- Larsen et al., “A Textbook of Drug Design and Development, 2nd edition, harwood academic publishers, 1996, pp. 351-385).
  • a prodrug can be produced from the compound represented by the general formula (I) by a method known in the art.
  • R 1 is preferably a methyl group.
  • R 2 is preferably a chlorine atom, a methyl group or a hydroxymethyl group.
  • the monovalent group of ring A may preferably have one or two substituents selected from substituent group ⁇ , the following:
  • One group selected from the group consisting of, and more preferably, may have one substituent selected from the substituent group ⁇ .
  • the substituent group ⁇ is preferably a hydroxypropyl group, a hydroxyethoxy group, an ethyl group or a monomethylamino group.
  • the compound (I) of the present invention can be produced, for example, according to Method A described later.
  • the target compound of each reaction can be collected from the reaction mixture by using a method known in the art after completion of each reaction. For example, after neutralizing the reaction mixture as appropriate, or if insoluble matter is present in the reaction mixture, the insoluble matter is removed from the reaction mixture by filtration, and then water and an organic matter that is not miscible with water, such as ethyl acetate. A solvent is added to the reaction mixture, an organic layer containing the target compound is separated, washed with water and the like, dried over anhydrous sodium sulfate and the like, and then the solvent is distilled off to obtain the target compound. If necessary, the obtained compound can be separated and purified by a method known in the art, for example, silica gel column chromatography.
  • the compound serving as a reaction substrate has a group that inhibits the target reaction such as an amino group, a hydroxyl group, or a carboxyl group
  • introduction and introduction of a protective group to those groups as necessary. Removal of the protecting group may be performed.
  • the protecting group is not particularly limited as long as it is a commonly used protecting group, and is described in THGreene, PGWuts, Protective Groups in Organic Synthesis, Third Edition, 1999, John Wiley & Sons, Inc. Groups.
  • Such protective group introduction reaction and removal reaction can be carried out according to the methods described in the above-mentioned literature.
  • R 1 , R 2 and ring A are as defined above, X 1 is a halogen atom or R 2 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 Are the same or different and each is a protecting group)
  • Step A1 is a step of producing compound (3) by adding (2) lithiated with alkyllithium (such as n-butyllithium) to (1) in an inert solvent.
  • alkyllithium such as n-butyllithium
  • the inert solvent examples include aromatic hydrocarbons, ethers, etc., preferably tetrahydrofuran (hereinafter sometimes referred to as “THF”) or a mixed solvent of toluene and THF in any ratio.
  • THF tetrahydrofuran
  • the reaction temperature is -78 ° C to 0 ° C, although it varies depending on the raw material compound and inert solvent.
  • reaction time varies depending on the starting compound, inert solvent, reaction temperature, etc., but the lithiation step is 15 minutes to 2 hours, the subsequent addition reaction is 1 hour to 3 hours, more preferably 20 minutes to 40 minutes, 1 Hours to 1 and a half hours.
  • Step A2 is a step for producing compound (4) by removing R 15 and R 16 in compound (3) in a mixed solvent of an inert solvent and an alcohol in the presence of an acid and cyclization.
  • the inert solvent examples include hydrocarbons and ethers, preferably THF.
  • the alcohol is preferably methanol.
  • Examples of the acid include hydrochloric acid, sulfuric acid, and sulfonic acids, and p-toluenesulfonic acid monohydrate is preferable.
  • the reaction temperature varies depending on the raw material compound, reaction solvent and the like, but is 40 ° C. to reflux temperature, preferably about 60 ° C.
  • the reaction time varies depending on the raw material compound, reaction solvent, reaction temperature, etc., but is 30 minutes to 6 hours, preferably 2 hours to 3 hours.
  • Step A3 is a step for producing compound (5) by introducing a protecting group into compound (4) in an inert solvent.
  • the protecting group is not particularly limited as long as it is a commonly used protecting group, and is preferably a methoxymethyl group.
  • protecting groups varies depending on the type, but is described in methods known in the art, for example, THGreene, PGWuts, Protective Groups in Organic Synthesis, Third Edition, 1999, ⁇ John Wiley & Sons, Inc. Can be done according to the method.
  • Step A4 is a step for producing compound (6) by condensing compound (5) and alkylboric acid (such as methylboric anhydride) in an inert solvent in the presence of a transition metal catalyst and a base.
  • alkylboric acid such as methylboric anhydride
  • inert solvent examples include aromatic hydrocarbons, ethers, hydrous alcohols, and the like, preferably 1,4-dioxane.
  • transition metal catalyst examples include a palladium complex, and tetrakis (triphenisphosphine) palladium (0) or palladium (II) acetate is preferable.
  • Examples of the base include inorganic bases, and although it varies depending on the raw material compound, potassium carbonate or sodium carbonate is preferred.
  • the reaction temperature varies depending on the raw material compound, reaction solvent, etc., but is 80 ° C. to reflux temperature, preferably 100 ° C. to 110 ° C.
  • the reaction time varies depending on the raw material compound, the reaction solvent, the reaction temperature, etc., but is 1 hour to 9 hours, more preferably 2 hours to 4 hours.
  • Step A5 is a step for producing compound (7) by removing R 17 in compound (6) in an inert solvent.
  • inert solvent examples include alcohols and ethers, and a mixed solvent of methanol and 1,4-dioxane is preferable.
  • R 17 when R 17 is a methoxymethyl group, it can be carried out by reacting a hydrogen chloride solution at room temperature in a mixed solvent of methanol and 1,4-dioxane.
  • Step A6 is a step of producing compound (8) by bromine substitution of the hydroxyl group of compound (7) in an inert solvent.
  • brominating agent examples include carbon tetrabromide in the presence of triphenylphosphine, N-bromosuccinimide, etc., preferably carbon tetrabromide in the presence of triphenylphosphine.
  • inert solvent examples include halogenated hydrocarbons, preferably methylene chloride.
  • Step A7 comprises condensing compound (9) by condensing compound (7) and arylboric acids (such as 1,4-benzodioxan-6-boric acid) in the presence of a transition metal catalyst and a base in an inert solvent. It is a manufacturing process.
  • arylboric acids such as 1,4-benzodioxan-6-boric acid
  • inert solvent examples include aromatic hydrocarbons, ethers, hydrous alcohols, and the like, and preferably a toluene-ethanol-water mixed solvent.
  • transition metal catalyst examples include a palladium complex, and tetrakis (triphenisphosphine) palladium (0) is preferable.
  • Examples of the base include inorganic bases, and sodium carbonate is preferable.
  • the reaction temperature varies depending on the raw material compound, reaction solvent, etc., but is 80 ° C. to reflux temperature, preferably about 100 ° C.
  • the reaction time varies depending on the raw material compound, reaction solvent, reaction temperature, etc., but is 30 minutes to 9 hours, preferably 1 hour to 2 hours.
  • Step A8 is a step for producing compound (I) by removing R 11 , R 12 , R 13 and R 14 in compound (9) in an inert solvent.
  • the removal of the protecting group can be performed, for example, according to the method described in the literature shown in the step A3.
  • R 11 , R 12 , R 13 and R 14 are benzyl groups
  • the protecting group is removed from compound (9) by the action of hydrogen in the presence of a palladium carbon catalyst in a mixed solvent of methanol and THF. can do.
  • an additive such as 1,2-dichlorobenzene
  • the reaction can be accelerated and side reactions can be suppressed.
  • Compound (1) as a raw material of Method A can be produced, for example, by the following Method B, and Compound (2) can be produced, for example, by the following Method C, or can be produced according to the method described in WO2008 / 016132 and the like.
  • R 1 , R 11 , R 12 , R 13 and R 14 are as defined above, and R 18 is a protecting group.
  • Step B1 is a step for producing compound (11) by introducing R 18 into compound (10).
  • Protecting group may be introduced in the same manner as in step A3.
  • Step B2 is a step for producing compound (12) by reacting compound (10) with trichloroacetonitrile in the presence of a base in an inert solvent.
  • inert solvent examples include halogenated hydrocarbons and ethers, preferably halogenated hydrocarbons, more preferably methylene chloride.
  • Examples of the base include organic amines, and preferably 1,8-diazabicyclo [5.4.0] -7-undecene.
  • the reaction temperature varies depending on the raw material compound, base, inert solvent and the like, but is -20 ° C to reflux temperature, preferably 0 ° C to room temperature.
  • the reaction time varies depending on the raw material compound, base, inert solvent, reaction temperature, etc., but is 15 minutes to 48 hours, preferably 30 minutes to 5 hours.
  • Step B3 is a step of producing compound (11) by reacting compound (12) with an alcohol in the presence of a Lewis acid in an inert solvent.
  • inert solvent examples include halogenated hydrocarbons, aromatic hydrocarbons, ethers, nitriles, etc., preferably halogenated hydrocarbons, more preferably methylene chloride.
  • Lewis acids examples include boron trifluoride-diethyl ether complex and trimethylsilyl trifluoromethanesulfonate, and boron trifluoride-diethyl ether complex is preferred.
  • the reaction temperature varies depending on the raw material compound, Lewis acid, inert solvent and the like, but is -30 ° C to reflux temperature, preferably 0 ° C to room temperature.
  • the reaction time varies depending on the raw material compound, Lewis acid, inert solvent, reaction temperature, etc., but is 5 minutes to 24 hours, preferably 10 minutes to 12 hours.
  • Step B4 is a step of producing compound (13) by removing the benzoyl group of compound (11).
  • Removal of the benzoyl group can be carried out according to a method known in the art, for example, the method described in THGreene, WPGWuts, Protective Groups in Organic Synthesis, Third Edition, 1999, John Wiley & Sons, Inc. .
  • Step B5 is a step for producing compound (14) by introducing R 11 , R 12 , R 13 and R 14 into compound (13).
  • Protecting group may be introduced in the same manner as in step A3.
  • R 11 , R 12 , R 13 and R 14 are benzyl groups
  • compound (13) is reacted with benzyl bromide, benzyl chloride, etc. in the presence of a base in an inert solvent to give compound (13)
  • a protecting group can be introduced into the.
  • inert solvent examples include amides and ethers, preferably amides, more preferably N, N-dimethylformamide.
  • Examples of the base include sodium hydride and alkali hydroxides, preferably sodium hydride.
  • reaction can also be accelerated
  • the reaction temperature varies depending on the raw material compound, inert solvent, base and the like, but is ⁇ 30 ° C. to reflux temperature, preferably 0 ° C. to room temperature.
  • the reaction time varies depending on the raw material compound, inert solvent, base, reaction temperature, etc., but is 15 minutes to 48 hours, preferably 30 minutes to 12 hours.
  • Step B6 is a step for producing compound (15) by removing R 18 in compound (14).
  • the removal of the protecting group can be performed according to the method described above.
  • R 18 when R 18 is an allyl group, the allyl group is isomerized in the presence of a base in an inert solvent, and then an oxidizing agent such as N-iodosuccinimide in the presence of water in an inert solvent. R 18 can be removed from compound (14) by reacting the compound with compound (14).
  • Step B7 is a step of producing compound (1) by reacting compound (12) with an oxidizing agent in an inert solvent.
  • inert solvent examples include halogenated hydrocarbons, preferably methylene chloride.
  • oxidizing agent examples include dimethyl sulfoxide, chromic acid, Dess-Martin Periodinane (hereinafter sometimes referred to as “DMP”), and preferably DMP.
  • DMP Dess-Martin Periodinane
  • the reaction temperature varies depending on the raw material compound, oxidizing agent, inert solvent, etc., but is -30 ° C to reflux temperature, preferably 0 ° C to room temperature.
  • the reaction time varies depending on the raw material compound, oxidizing agent, inert solvent, reaction temperature, etc., but is 5 minutes to 24 hours, preferably 10 minutes to 12 hours.
  • Step C1 is a step of producing compound (17) by reacting compound (16) with a reducing agent in an inert solvent.
  • inert solvent examples include ethers and alcohols, preferably ethers, more preferably THF.
  • the reducing agent examples include alkali metal borohydrides such as lithium borohydride, aluminum hydride compounds such as lithium aluminum hydride and lithium triethoxide aluminum, and hydride reagents such as sodium tellurium hydride.
  • alkali metal borohydrides such as lithium borohydride
  • aluminum hydride compounds such as lithium aluminum hydride and lithium triethoxide aluminum
  • hydride reagents such as sodium tellurium hydride.
  • R 19 and R 20 are methyl groups, lithium borohydride is preferred.
  • the reaction temperature varies depending on the raw material compound, reducing agent, inert solvent, etc., but is -30 ° C to reflux temperature, preferably 0 ° C to room temperature.
  • the reaction time varies depending on the raw material compound, reducing agent, inert solvent, reaction temperature, etc., but is 10 minutes to 48 hours, preferably 30 minutes to 24 hours.
  • Step C2 is a step for producing compound (2) by introducing R 15 and R 16 into compound (17).
  • Protecting group may be introduced in the same manner as in step A3.
  • the compound of the present invention can also be produced from a known compound with reference to Examples described later or methods well known in the art.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof has an excellent hypoglycemic action, type 1 diabetes, type 2 diabetes, gestational diabetes, hyperglycemia due to other factors, IGT, obesity, diabetes-related diseases (Hyperlipidemia, hypercholesterolemia, dyslipidemia, hypertension, fatty liver, metabolic syndrome, edema, heart failure, angina, myocardial infarction, arteriosclerosis, hyperuricemia, gout, etc.) or diabetes It can be used as an active ingredient of a pharmaceutical composition that can be used for the treatment and / or prevention of diseases (retinopathy, nephropathy, neuropathy, cataract, foot gangrene, infection, ketosis, etc.).
  • diseases retinopathy, nephropathy, neuropathy, cataract, foot gangrene, infection, ketosis, etc.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof can also be used in combination with other therapeutic agents for diabetes, therapeutic agents for diabetic complications, therapeutic agents for hyperlipidemia, therapeutic agents for hypertension and the like.
  • a pharmaceutical composition containing a compound of the present invention or a pharmaceutically acceptable salt thereof is systemically or locally when administered to a mammal (human, horse, cow, pig, etc., preferably human). And can be administered orally or parenterally.
  • the pharmaceutical composition of the present invention can be prepared by selecting an appropriate form according to the administration method and preparing various preparations usually used.
  • an oral pharmaceutical composition examples include tablets, pills, powders, granules, capsules, liquids, suspensions, emulsions, syrups, elixirs and the like.
  • the pharmaceutical composition in such a form comprises excipients, binders, disintegrants, lubricants, swelling agents, swelling aids, coating agents, plasticizers, stabilizers, preservatives, antioxidants that are usually used as additives.
  • Coloring agents, solubilizers, suspending agents, emulsifiers, sweeteners, preservatives, buffers, diluents, wetting agents, and the like may be appropriately selected as necessary and produced according to conventional methods.
  • compositions for parenteral use include injections, ointments, gels, creams, poultices, patches, sprays, inhalants, sprays, eye drops, nasal drops, suppositories, etc.
  • the pharmaceutical composition in such a form comprises a stabilizer, preservative, solubilizer, moisturizer, preservative, antioxidant, flavoring agent, gelling agent, neutralizing agent, buffer, Isotonic agents, surfactants, colorants, buffering agents, thickeners, wetting agents, fillers, absorption enhancers, suspending agents, binders, etc. are selected as necessary and manufactured according to conventional methods. Can be done.
  • the dose of the compound of the present invention or a pharmaceutically acceptable salt thereof varies depending on symptoms, age, body weight, etc. In the case of oral administration, it is 1 to several times a day, once per adult, as a compound. The amount is 1 to 2000 mg, preferably 1 to 400 mg, and in the case of parenteral administration, it is 0.01 to 500 mg, preferably 0.1 to 300 mg in terms of compound per adult once or several times a day. .
  • the reaction mixture was allowed to stand at room temperature overnight, neutralized with a saturated aqueous ammonium chloride solution (200 mL), and diluted with ethyl acetate (250 mL). This was washed successively with 10% w / v saline (200 mL, twice) and saturated brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 99: 1 ⁇ 80: 20 (concentration gradient) V / V) to obtain the title compound (27.2 g).
  • the obtained residue was dissolved in THF (120 mL) and water (30 mL), and N-iodosuccinimide (11.3 g, 50.2 mmol) was gradually added thereto at room temperature.
  • the reaction mixture was stirred at room temperature for 15 minutes, ethyl acetate (100 mL) was added thereto, and the mixture was washed successively with 10% w / v aqueous sodium thiosulfate solution (50 mL, twice) and saturated brine (50 mL). .
  • the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • This diol was dissolved in methylene chloride (100 mL), and diisopropylethylamine (52.0 mL, 0.31 mol) and chloromethyl methyl ether (15.5 mL, 0.20 mol) were added to the solution under ice cooling.
  • the reaction solution was stirred for 5 hours while gradually warming to room temperature, allowed to stand overnight, then saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to the reaction solution, and the solvent was distilled off to about half amount under reduced pressure.
  • the concentrate was diluted with ethyl acetate (50 mL), and washed successively with water (30 mL), saturated aqueous ammonium chloride solution (50 mL, twice) and saturated brine (50 mL).
  • the obtained residue was dissolved in methylene chloride (100 mL), and diisopropylethylamine (77.0 mL, 0.45 mol) and chloromethyl methyl ether (23.0 mL, 0.30 mol) were added thereto under ice cooling.
  • the reaction mixture was stirred for 3 hours while gradually warming to room temperature, and then allowed to stand overnight.
  • the reaction mixture was diluted with ethyl acetate (150 mL) and washed successively with saturated aqueous ammonium chloride solution (50 mL, 3 times) and saturated brine (50 mL).
  • the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • This diol was dissolved in methylene chloride (150 mL), and diisopropylethylamine (121 mL, 0.71 mol) and chloromethyl methyl ether (36.0 mL, 0.48 mol) were added to the solution under ice cooling.
  • the reaction solution was stirred for 5 hours while gradually warming to room temperature, water (100 mL) was added to the reaction solution, and the solvent was distilled off to about half amount under reduced pressure.
  • the obtained crude product (33.3 g) was dissolved in a mixed solvent of methanol (80 mL) and THF (80 mL), and p-toluenesulfonic acid monohydrate (21.3 g, 112 mmol) was reacted at room temperature. Added to. The reaction mixture was stirred at 60 ° C. for 3 hours under a nitrogen atmosphere, cooled to room temperature, and saturated aqueous sodium hydrogen carbonate solution (80 mL) was added. The reaction solution was concentrated to about half amount under reduced pressure. The concentrate was diluted with ethyl acetate (100 mL) and washed successively with saturated aqueous sodium carbonate solution (50 mL) and saturated brine (50 mL, 2 times).
  • reaction solution was stirred at -78 ° C for 1 hour and a half, then heated to 0 ° C and stirred for 5 minutes.
  • a saturated aqueous ammonium chloride solution 50 mL was added to the reaction solution, diluted with ethyl acetate (100 mL), and washed with saturated brine (50 mL, 2 times).
  • the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained crude product was dissolved in a mixed solvent of methanol (150 mL) and THF (150 mL), and p-toluenesulfonic acid monohydrate (27.0 g, 142 mmol) was added at room temperature.
  • the reaction solution was stirred at 60 ° C. for 2.5 hours under a nitrogen atmosphere, and then allowed to stand at room temperature overnight.
  • saturated aqueous sodium hydrogen carbonate solution 80 mL was added, and the mixture was concentrated under reduced pressure to about half. This was diluted with ethyl acetate (100 mL), and washed successively with saturated aqueous sodium carbonate solution (50 mL) and saturated brine (50 mL, 2 times).
  • the obtained residue was diluted with ethyl acetate (60 mL), and washed successively with saturated aqueous ammonium chloride solution (50 mL) and saturated brine (50 mL).
  • the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 100: 0 ⁇ 80: 20 (concentration gradient) V / V). Purification gave the title compound (4.63 g).
  • reaction mixture was ice-cooled, water (10 mL) was added thereto, and the mixture was diluted with ethyl acetate (60 mL).
  • the reaction mixture was washed with saturated brine (50 mL), the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 100 0 ⁇ 75: 25 (concentration gradient) V / V) to obtain the title compound (3.56 g).
  • Methyl 2,3,4-tri-O-benzyl- ⁇ -D-glucopyranoside (Heterocycles, 2007, vol. 73, 165-168) (9.0 g, 19 mmol) with ethyl acetate (45 mL) and water (17 mL) ), And sodium hydrogen carbonate (3.3 g, 39 mmol) and tetra n-butylammonium bromide (0.25 g, 0.78 mmol) were added at room temperature.
  • reaction mixture was ice-cooled, 2,2,6,6-tetramethylpiperidine 1-oxyl (60 mg, 0.38 mmol) was added, and a hypochlorous acid aqueous solution (37.5 mL) was added in small portions over 3 hours and a half. Added.
  • the reaction solution was stirred for 2 hours while warming to room temperature.
  • 1M hydrochloric acid 100 mL was added to acidify the reaction solution, followed by extraction with ethyl acetate (50 mL, 2 times). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure.
  • the crude product of the title compound was used for the next step without purification.
  • Example 6b Using the compound obtained in Reference Example 13h (0.50 g, 0.70 mmol), carbon tetrabromide (0.60 g, 1.8 mmol), triphenylphosphine (0.48 g, 36 mmol) and methylene chloride (7 mL), In the same manner as in Example 6b, a crude product of the title compound was obtained. The obtained crude product was purified by silica gel flash column chromatography (hexane: ethyl acetate, 98: 2 ⁇ 80: 20 (concentration gradient) V / V) to obtain the title compound (0.21 g).
  • Example 14f Using the compound obtained in Reference Example 14f (0.37 g, 0.51 mmol), carbon tetrabromide (0.34 g, 1.0 mmol), triphenylphosphine (0.26 g, 0.99 mmol) and methylene chloride (5 mL), In the same manner as in Example 6b, a crude product of the title compound was obtained. The resulting crude product was purified by silica gel flash column chromatography (hexane: ethyl acetate, 97: 3 ⁇ 70: 30 (concentration gradient) V / V) to obtain the title compound (0.18 g).
  • 6-Bromo-5-fluoro-2,3-dihydro-1,4-benzodioxin (1.0 g, 4.3 mmol), bis (pinacolato) diboron (1.2 g, 4.7 mmol) obtained according to the method described in WO2008 / 128942 , Potassium acetate (1.3 g, 13 mmol), 1,1'-bis (diphenylphosphino) ferrocene (72 mg, 0.13 mmol), [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride
  • the title compound (0.49 g) was obtained in the same manner as in Reference Example 15e using dichloromethane adduct (0.11 g, 0.13 mmol) and 1,4-dioxane (25 mL).
  • reaction solution was diluted with ethyl acetate (10 mL), washed with water (10 mL), saturated aqueous sodium bicarbonate (20 mL), and saturated brine (20 mL) successively, and the organic layer was dried over anhydrous sulfuric acid. Dry with sodium. The solvent of the organic layer was distilled off under reduced pressure, and the resulting residue (462 mg) was used in the next step without purification.
  • Example 1a (1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (benzyloxy) Ethyl] -5-chloro-6- (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran- 1,2'-Pyran]
  • Example 1b (1S, 3′R, 4 ′S, 5 ′S, 6′R) -5-chloro-6- (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) -6 ′-[ (1R) -1-hydroxyethyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol
  • Example 1a The compound (0.19 g, 0.23 mmol) obtained in Example 1a was dissolved in a mixed solvent of THF (8.0 mL) and methanol (4.0 mL), and 1,2-dichlorobenzene (0.13 mL, 1.2 mmol) was dissolved in the mixture. And 10% w / w palladium carbon (0.19 g) was added, and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. After filtering this reaction liquid, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol, 98: 2 ⁇ 80: 20 (concentration gradient) V / V) to obtain the title compound (83 mg).
  • Example 2a (1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (benzyloxy) Ethyl] -6- (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) -5-methyl-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran- 1,2'-Pyran]
  • Example 2b (1S, 3′R, 4 ′S, 5 ′S, 6′R) -6- (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) -6 ′-[(1R)- 1-hydroxyethyl] -5-methyl-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol
  • Example 2a The compound obtained in Example 2a (202 mg, 0.25 mmol) was dissolved in a mixed solvent of THF (6 mL) and methanol (3 mL), and 1,2-dichlorobenzene (0.14 mL, 1.25 mmol) was dissolved therein. 10% w / w palladium / carbon (200 mg) was added, and this was stirred at room temperature for 1 hour in a hydrogen atmosphere. After filtering the reaction solution, the solvent of the filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (methylene chloride: methanol, 97: 3-85: 15 (concentration gradient) V / V) to give the title object compound (97 mg, yield 87%). Obtained.
  • Example 3a (1S, 3′R, 4 ′S, 5 ′S, 6′R) -6- (1-benzofuran-5-ylmethyl) -3 ′, 4 ′, 5′-tris (benzyloxy) -6 ′ -[(1R) -1- (benzyloxy) ethyl] -5-chloro-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran]
  • Example 3a The compound obtained in Example 3a (0.18 g, 0.22 mmol) and 1,2-dichlorobenzene (0.12 mL, 1.1 mmol) were dissolved in a mixed solvent of THF (5 mL) -methanol (2.5 mL), 10 % W / w palladium carbon (0.18 g) was added, and the mixture was stirred at room temperature for 1 hour 30 minutes in a hydrogen atmosphere. After filtering the reaction solution, the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (methylene chloride: methanol, 100: 0 ⁇ 85: 15 (concentration gradient) V / V) to obtain the title object compound as a mixture (92 mg) with a by-product. It was.
  • Example 3c (1S, 3′R, 4 ′S, 5′R, 6′R) -6 ′-[(1R) -1- (acetyloxy) ethyl] -6- (1-benzofuran-5-ylmethyl ) -5-Chloro-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triyl triacetate
  • Example 3b The compound obtained in Example 3b (92 mg, 0.21 mmol) was dissolved in ethyl acetate (2 mL), pyridine (0.20 mL, 2.5 mmol), acetic anhydride (0.24 mL, 2.5 mmol), and 4-dimethylamino. Pyridine (3 mg, 0.021 mmol) was added and stirred at room temperature for 17 hours. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL).
  • Example 3c The compound (90 mg, 0.15 mmol) obtained in Example 3c was dissolved in a mixed solvent of 2-propanol (3 mL) -THF (1 mL) -water (1 mL), and 5 M aqueous sodium hydroxide solution (0.18 mL, 0.88 mmol) was added, and the mixture was stirred at room temperature for 2 hours and 15 minutes.
  • the reaction mixture was neutralized with 1 M hydrochloric acid (0.88 mL, 0.88 mmol) under ice-cooling, saturated brine (5 mL) was added, and the mixture was extracted with methylene chloride (30 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 4a The compound obtained in Example 4a (400 mg, 0.49 mmol), 4-ethylphenylboronic acid (74 mg, 0.49 mmol), tetrakistriphenylphosphine palladium (0) (57 mg, 0.049 mmol), and sodium carbonate ( 104 mg, 0.98 mmol) was dissolved in a mixed solvent of toluene (2 mL) -ethanol (1.5 mL) -water (0.49 mL), and the mixture was stirred at 80 ° C. for 5 hours under a nitrogen atmosphere. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL, twice).
  • Example 4b The compound (326 mg, 0.39 mmol) obtained in Example 4b was dissolved in a mixed solvent of N, N-dimethylformamide (2 mL) and methanol (2 mL), and this was dissolved in 1,3-bis (diphenylphosphino). ) Propane (32 mg, 0.078 mmol), N, N-diisopropylethylamine (0.27 mL, 1.55 mmol), and palladium acetate (17 mg, 0.078 mmol) were added, and the mixture was stirred at 80 ° C. for 16 hours in a carbon monoxide atmosphere. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with saturated brine (20 mL).
  • Example 4c The compound obtained in Example 4c (132 mg, 0.16 mmol) was dissolved in a mixed solvent of THF (6 mL) and methanol (3 mL), and to this, 1,2-dichlorobenzene (90 ⁇ L, 0.81 mmol), and 10% w / w palladium / carbon (130 mg) was added, and the mixture was stirred at room temperature for 1 hr in a hydrogen atmosphere. After filtering the reaction solution, the solvent was distilled off from the filtrate under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (methylene chloride: methanol, 97: 3-90: 10 (concentration gradient) V / V) to give the title object compound (66 mg, 89% yield). Obtained.
  • Example 4d The compound (66 mg, 0.14 mmol) obtained in Example 4d was dissolved in THF (3.5 mL), and 1 M lithium aluminum hydride THF solution (0.86 mL, 0.86 mmol) was added to this at 0 ° C. under a nitrogen atmosphere. The mixture was further stirred at room temperature for 1 hour. Under ice-cooling, 1 M hydrochloric acid (20 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride: methanol (10: 1, V / V, 20 mL, twice). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 4a Using the compound (0.33 g, 0.40 mmol) obtained in Example 4a and (4-ethoxyphenyl) boronic acid (66 mg, 0.40 mmol) as raw materials, the title compound (65 mg) was prepared in the same manner as in Example 4. Obtained.
  • Example 4a Using the compound (0.40 g, 0.49 mmol) obtained in Example 4a and (1,4-benzodioxan-6-yl) boronic acid (97 mg, 0.54 mmol) as raw materials, the title was obtained in the same manner as in Example 4. Compound (75 mg) was obtained.
  • Example 7b 7-( ⁇ (1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (Benzyloxy) ethyl] -5-chloro-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -6-yl ⁇ methyl) -2, 3-Dihydro-4H-chromen-4-one
  • Example 7c 7-( ⁇ (1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (Benzyloxy) ethyl] -5-chloro-3 ′, 4 ′, 5 ′, 6′-tetrahydro-3H-spiro [2-benzofuran-1,2′-pyran] -6-yl ⁇ methyl) -3, 4-Dihydro-2H-chromen-4-ol
  • Example 7b The compound obtained in Example 7b (0.25 mg, 0.30 mmol) was dissolved in a mixed solvent of methanol (3 mL) -THF (1 mL), and sodium borohydride (18 mg, 0.45 mmol) under ice cooling. ) was added and stirred for 30 minutes. To this reaction solution was added a saturated aqueous ammonium chloride solution (5 mL) under ice-cooling, followed by extraction with ethyl acetate (40 mL). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title target compound as a crude product (0.25 g).
  • Example 7d 7-( ⁇ (1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (Benzyloxy) ethyl] -5-chloro-3 ′, 4 ′, 5 ′, 6′-tetrahydro-3H-spiro [2-benzofuran-1,2′-pyran] -6-yl ⁇ methyl) -3, 4-Dihydro-2H-chromen-4-yl acetate
  • Example 7c The compound obtained in Example 7c (0.25 g, 0.30 mmol) was dissolved in ethyl acetate (3 mL), and pyridine (73 ⁇ L, 0.90 mmol), acetic anhydride (66 ⁇ L, 0.69 mmol), and 4- Dimethylaminopyridine (4 mg, 0.030 mmol) was added and stirred at room temperature for 19 hours. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL).
  • Example 7d The compound obtained in Example 7d (0.18 g, 0.21 mmol) was dissolved in methylene chloride (4 mL) and cooled to -78 ° C. Triethylsilane (0.34 mL, 2.1 mL) and boron trifluoride ethyl ether complex (0.12 mL, 0.95 mmol) were added thereto and stirred for 2 hours. A saturated aqueous ammonium chloride solution (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • Example 7f (1S, 3'R, 4'S, 5'S, 6'R) -5-chloro-6- (3,4-dihydro-2H-chromen-7-ylmethyl) -6 '-[(1R) -1-hydroxyethyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol
  • Example 7e The compound obtained in Example 7e (0.18 g, 0.34 mmol) and 1,2-dichlorobenzene (0.19 mL, 1.7 mmol) were dissolved in a mixed solvent of THF (4 mL) -methanol (2 mL). 10% palladium carbon (0.18 g) was added thereto, and the mixture was stirred at room temperature for 1 hour 30 minutes in a hydrogen atmosphere. After filtering the reaction solution, the solvent was distilled off under reduced pressure. The obtained residue was purified using silica gel flash column chromatography (methylene chloride: methanol, 100: 0 ⁇ 85: 15 (concentration gradient) V / V) to give the title object compound (0.10 g, yield 63%). Obtained.
  • Example 8 (1S, 3′R, 4 ′S, 5 ′S, 6′R) -5-bromo-6- (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) -6 ′-[ (1R) -1-hydroxyethyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol
  • Example 8a (1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (benzyloxy) Ethyl] -5-bromo-6- (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran- 1,2'-Pyran]
  • Example 4a Compound obtained in Example 4a (0.40 g, 0.49 mmol), (1,4-benzodioxan-6-yl) boronic acid (0.11 g, 0.61 mmol), sodium carbonate (0.10 g, 0.94 mmol), tetrakistri Using a mixed solvent of phenylphosphine palladium (0) (57 mg, 0.049 mmol) and toluene (4 mL) -ethanol (3 mL) -water (1 mL) in the same manner as in Example 1a, the title compound (0.21 )
  • Example 8b (1S, 3′R, 4 ′S, 5 ′S, 6′R) -5-bromo-6- (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) -6 ′-[ (1R) -1-hydroxyethyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol
  • Example 8a The compound obtained in Example 8a (100 mg, 0.11 mmol) and pentamethylbenzene (179 mg, 1.21 mmol) were dissolved in methylene chloride (5 mL). A solution of boron fluoride in methylene chloride (1.0 M, 1.10 mL, 1.10 mmol) was added. The reaction mixture was stirred at -78 ° C for 40 minutes, and methanol (1 mL) was added. The reaction mixture was warmed to room temperature, the solvent was distilled off under reduced pressure, water (3 mL) and saturated brine (3 mL) were added to the resulting residue, and methylene chloride and 2-propanol (3: 1) were added. ) Was extracted twice with a mixed solvent.
  • Example 9b 3- [4-( ⁇ (1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (benzyloxy) ethyl] -5-chloro-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -6-yl ⁇ methyl) Phenyl] propan-1-ol
  • Example 9a The compound (0.17 g, 0.20 mmol) obtained in Example 9a was dissolved in THF (2.0 mL) under a nitrogen atmosphere. This was cooled to 0 ° C., lithium aluminum hydride (12 mg, 0.32 mmol) was added, and the mixture was stirred at 0 ° C. for 1 hour. To this reaction solution were added waterpox (15 ⁇ L), 5 ⁇ M aqueous sodium hydroxide solution (15 ⁇ L) and waterpox (45 ⁇ L). After filtering the reaction solution, the solvent was distilled off under reduced pressure. The obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate, 10: 90 ⁇ 0: 100 (concentration gradient V / V)) to obtain the title compound (0.15 g).
  • Example 9c (1S, 3′R, 4 ′S, 5 ′S, 6′R) -5-chloro-6 ′-[(1R) -1-hydroxyethyl] -6- [4- (3-hydroxypropyl) Benzyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol
  • Example 9b The compound (0.15 g, 0.18 mmol) obtained in Example 9b was dissolved in a mixed solvent of THF (6.7 mL) and methanol (3.3 mL), and 1,2-dichlorobenzene (0.11 mL, 0.98 mmol) was dissolved in the mixture. 10% w / w palladium carbon (0.15 g) was added, and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. After filtering the reaction solution, the solvent of the filtrate was distilled off under reduced pressure.
  • Example 11a (1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (benzyloxy) Ethyl] -6- ⁇ 4- [2- (methoxymethoxy) ethoxy] benzyl ⁇ -5-methyl-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2' -Piran]
  • Example 11b 2- [4-( ⁇ (1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (benzyloxy) ethyl] -5-methyl-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -6-yl ⁇ methyl) Phenoxy] ethanol
  • Example 11a The compound obtained in Example 11a (0.28 g, 0.38 mmol) was dissolved in methanol (2.0 mL), 4 M dioxane solution (2.0 mL, 8.0 mmol) was added thereto, and the mixture was stirred at room temperature for ⁇ 40 minutes. Saturated aqueous sodium hydrogen carbonate solution (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL, 2 ⁇ 2). The organic layer was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate, 90: 10 ⁇ 0: 100 (concentration gradient) V / V) to obtain the title compound (0.22 g).
  • Example 11c (1S, 3′R, 4 ′S, 5 ′S, 6′R) -6- [4- (2-hydroxyethoxy) benzyl] -6 ′-[(1R) -1-hydroxyethyl] -5 -Methyl-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol
  • Example 11b The compound obtained in Example 11b (0.22 g, 0.17 mmol) was dissolved in a mixed solvent of THF (10 mL) and methanol (5.0 mL), and 1,2-dichlorobenzene (0.16 mL, 1.4 mmol) was dissolved therein. 10% w / w palladium carbon (0.22 g) was added, and the mixture was stirred at room temperature for 1 hour in a hydrogen atmosphere. After filtering the reaction solution, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol, 98: 2 ⁇ 80: 20 (concentration gradient) V / V) to obtain the title compound (0.11 g).
  • Example 12b (1S, 3′R, 4 ′S, 5 ′S, 6′R) -5-chloro-6 ′-[(1R) -1-hydroxyethyl] -6- [4- (methylamino) benzyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol
  • Example 12a The compound obtained in Example 12a (123 mg, 0.14 mmol) was dissolved in a mixed solvent of THF (5 mL) and methanol (2.5 mL), to which 1,2-dichlorobenzene (77 ⁇ L, 0.69 mmol), and 10% w / w palladium / carbon (120 mg) was added, and this was stirred at room temperature for 1 hour in a hydrogen atmosphere. After filtering the reaction solution, the solvent of the filtrate was distilled off under reduced pressure.
  • Example 13b (1S, 3′R, 4 ′S, 5 ′S, 6′R) -6 ′-[(1R) -1-hydroxyethyl] -5-methyl-6- [4- (methylamino) benzyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol
  • Example 13a The compound obtained in Example 13a (212 mg, 0.24 mmol) was dissolved in a mixed solvent of THF (5 mL) and methanol (2.5 mL), and to this, 1,2-dichlorobenzene (136 ⁇ L, 1.21 mmol), and 10% w / w palladium / carbon (200 mg) was added, and this was stirred at room temperature for 1 hour in a hydrogen atmosphere. After filtering the reaction solution, the solvent of the filtrate was distilled off under reduced pressure.
  • Example 17a The compound (183 mg, 0.21 mmol) obtained in Example 17a was dissolved in N, N-dimethylformamide (5 mL), and sodium hydride (oil, 63% w / w, 24 mg) was cooled with ice. Then, the mixture was stirred for 30 minutes while warming to room temperature. Methyl iodide (78 ⁇ L, 1.3 ⁇ mmol) was added to the reaction solution under ice cooling, and the mixture was stirred for 1 hour and a half while warming to room temperature. After completion of the reaction, saturated aqueous ammonium chloride solution (1 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL, twice).
  • Example 17b The compound obtained in Example 17b (158 mg, 0.18 mmol) was dissolved in methylene chloride (2 mL), and trifluoroacetic acid (0.7 mL) was gradually added thereto under ice cooling. The reaction solution was stirred for 1 hour while warming to room temperature, and then the solvent was distilled off under reduced pressure. The obtained residue was diluted with ethyl acetate (10 mL), and this was washed successively with saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 17d (1S, 3′R, 4 ′S, 5 ′S, 6′R) -5-chloro-6 ′-[(1R) -1-hydroxyethyl] -6- [3- (methylamino) benzyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol
  • Example 17c The compound obtained in Example 17c (130 mg, 0.16 mmol) was dissolved in a mixed solvent of THF (2 mL) and methanol (2 mL), and to this, 1,2-dichlorobenzene (130 ⁇ L, 1.16 mmol), and 10% w / w palladium / carbon (195 mg) was added, and this was stirred at room temperature for 1 hour under a hydrogen atmosphere. After filtering the reaction solution, the solvent of the filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (methylene chloride: methanol, 95: 5-80: 20 (concentration gradient) V / V) to give the title object compound (49 mg, yield 70%). Obtained.
  • Example 19a The compound obtained in Example 19a (0.18 g, 0.22 mmol) was dissolved in acetic acid (1.1 mL). This was cooled to 10 ° C, sodium cyanoborohydride (44 mg, 0.70 mmol) was added thereto, and the mixture was stirred at 10 ° C for 30 minutes. To this reaction solution was added chickenpox (20 mL), neutralized with potassium carbonate, and extracted with ethyl acetate (30 mL, 2 times). The organic layer was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate, 95: 5 ⁇ 50: 50 (concentration gradient) V / V) to obtain the title compound (0.14 g).
  • Example 19b Compound obtained in Example 19b (0.14 g, 0.18 mmol), 1,2-dichlorobenzene (0.10 mL, 0.89 mmol), 10% w / w palladium on carbon (0.14 g), and THF (6.0 mL) and methanol
  • the title compound (54 mg) was obtained in the same manner as in Example 1b using a mixed solvent of (3.0 mL).
  • Example 21a 5-Methoxy-2-( ⁇ (1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-tris (benzyloxy) -6 ′-[(1R ) -1- (Benzyloxy) ethyl] -5-chloro-3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -6-yl ⁇ methyl Pyridine
  • this reaction solution was prepared in advance with tri (2-furyl) phosphine (28 mg, 0.12 mmol), tris (dibenzylideneacetone) dipalladium (0) (14 mg, 0.015 mmol), and THF (2 mL). To the mixture. Further, a THF (0.5 mL) solution of 2-bromo-5-methoxypyridine (0.12 g, ⁇ ⁇ 0.64 mmol) was added to the reaction solution, and the mixture was stirred at 80 C for 2 hours under nitrogen atmosphere. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL, 2 times).
  • Example 21b (1S, 3′R, 4 ′S, 5 ′S, 6′R) -5-chloro-6 ′-[(1R) -1-hydroxyethyl] -6-[(5-methoxypyridine-2- Yl) methyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol
  • Example 21a Compound obtained in Example 21a (0.13 g, 0.16 mmol), 1,2-dichlorobenzene (92 ⁇ L, 0.82 mmol), 10% w / w palladium on carbon (65 mg), THF (4.0 mL), methanol ( 2.0 mL) and in the same manner as in Example 1b, the title compound (58 mg) was obtained.
  • reaction solution was prepared in advance with tri (2-furyl) phosphine (28 mg, 0.12 mmol), tris (dibenzylideneacetone) dipalladium (0) (14 mg, 0.015 mmol), and THF (2 mL).
  • 2-bromo-6-methoxypyridine (0.12 g, 0.64 mmol) in THF (0.5 mL) was added to the reaction solution, and the mixture was stirred at 80 ° C. for 3 hours under a nitrogen atmosphere.
  • Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL, 2 times).
  • Example 22b (1S, 3′R, 4 ′S, 5 ′S, 6′R) -5-chloro-6 ′-[(1R) -1-hydroxyethyl] -6-[(6-methoxypyridine-2- Yl) methyl] -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3', 4 ', 5'-triol
  • Example 22a Compound obtained in Example 22a (0.26 g, 0.33 mmol), 1,2-dichlorobenzene (0.19 mL, 1.7 mmol), 10% w / w palladium on carbon (0.26 g), and THF (6.0 mL) and methanol
  • the title compound (30 mg) was obtained in the same manner as in Example 00 using a mixed solvent of (3.0 mL).
  • Example 23b The compound obtained in Example 23b (510 mg, 0.61 mmol) was dissolved in THF (12 mL), and a solution of lithium aluminum hydride in THF (1.0 M, 2.14 mL, 2.14 mL) at -78 ° C under a nitrogen atmosphere. mmol) was added dropwise. The reaction mixture was stirred for 2 hours while gradually warming to room temperature, further stirred for 1 hour at 50 ° C., and then allowed to stand overnight. The reaction mixture was ice-cooled, and water (1 mL), 10% w / v Rochelle salt aqueous solution (2 mL), 1 M sodium hydroxide (2 mL), and diethyl ether (30 mL) were added. Stir for hours.
  • the reaction mixture was washed with saturated brine (10 mL), the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 90: 10 ⁇ 60: 40 (concentration gradient) V / V) to obtain the title compound (250 mg).
  • Example 23c The compound obtained in Example 23c (130 mg, 0.16 mmol), 10% w / w palladium on carbon (130 mg), 1,2-dichlorobenzene (0.09 mL, 0.8 mmol), and THF (4.0 mL) and methanol
  • the title compound (70 mg) was obtained in the same manner as in Example 1b using a mixed solvent of (2.0 mL).
  • Example 24a (1S, 3′R, 4 ′S, 5 ′S, 6′R) -3 ′, 4 ′, 5′-Tris (benzyloxy) -6 ′-[(1R) -1- (benzyloxy) Ethyl] -5-chloro-6- (4-ethylbenzyl) -3 ', 4', 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran]
  • Example 24b (1S, 3′R, 4 ′S, 5 ′S, 6′R) -5-chloro-6- (4-ethylbenzyl) -6 ′-[(1R) -1-hydroxyethyl] -3 ′ , 4 ', 5', 6'-Tetrahydro-3H-spiro [2-benzofuran-1,2'-pyran] -3 ', 4', 5'-triol
  • Example 24a Compound obtained in Example 24a (0.25 g, 0.32 mmol), 1,2-dichlorobenzene (0.18 mL, 1.6 mmol), 10% w / w palladium on carbon (0.25 g), and THF (12 mL) and methanol
  • the title compound (0.13 g) was obtained in the same manner as in Example 1b using a mixed solvent of (6.0 mL).
  • Example 25 to 63 The compounds of Examples 25 to 63 were obtained with reference to the above Reference Examples and Examples.
  • the target DNA fragment is recovered from a single band corresponding to 2013 bases, cleaved with restriction enzymes HindIII and XhoI, and then placed on the HindIII / XhoI site of the vector pCMV-Script (Stratagene).
  • the SGLT1 expression plasmid pCMV-SGLT1 was introduced.
  • a HindIII / XhoI fragment was excised from pCMV-SGLT1 and introduced into the BamHI / XhoI site of pENTR1A (Gateway, Invitrogen) to create pENTR-SGLT1.
  • SGLT1-expressing retroviral vector pLPCX-SGLT1 was prepared using the retroviral vector pLPCX (Clontech) into which Gateway Vector Conversion System Cassette A (Invitrogen) was introduced as the destination plasmid.
  • the retrovirus pLPCX-SGLT1 obtained in 1) was transfected into integrin ⁇ v ⁇ 3-expressing HEK-293 cells, followed by antibiotic G418 (trade name: Geneticin, manufactured by Invitrogen), puromycin ( The cells were treated with Clontech), and stable expression cells HEK-SGLT1 of the target vector having resistance were obtained.
  • Culture and maintenance of stably expressing cells was performed using DMEM medium containing 250 ⁇ g / ml G418, 1 ⁇ g / ml puromycin, 3 ⁇ M KGT-1075, and 10% FBS.
  • HEK-SGLT1 cells were suspended in DMEM medium containing 250 ⁇ g / ml G418, 1 ⁇ g / ml puromycin and 10% FBS at a density of 10 6 cells / ml, and a 96-well culture plate coated with type I collagen ( 100 ⁇ l was seeded in each well of Corning).
  • liquid scintillation cocktail (trade name: Supermix, manufactured by Perkin Elmer) to each well of a 96-well plate, stir for 10 minutes, and then radiate with micro ⁇ (produced by PerkinElmer), a type of liquid scintillation counter. Activity was measured. The value obtained by subtracting from each measured value with the radioactivity in the presence of an excessive amount of SGLT1 inhibitor as the background is the sugar uptake activity, and the control sugar uptake activity obtained without using the test compound and the test compound at a certain concentration are used. The inhibition rate (%) was determined from the sugar uptake activity at the time of the test, and the concentration of the test compound that inhibits the sugar uptake activity by 50% was examined. The results are shown in Table 11.
  • the target DNA fragment is recovered from a single band corresponding to 2037 bases, cleaved with restriction enzymes HindIII and XhoI, and then placed on the HindIII / XhoI site of the vector pCMV-Script (Stratagene). Introduced. This was designated as SGLT2 expression plasmid pCMV-SGLT2.
  • a HindIII / XhoI fragment was excised from pCMV-SGLT2 and introduced into the BamHI / XhoI site of pENTR1A (Gateway, Invitrogen) to create pENTR-SGLT2.
  • SGLT2-expressing retrovirus vector pLPCX-SGLT2 was prepared using the retrovirus vector pLPCX (Clontech) into which Gateway Vector Conversion System Cassette A (Invitrogen) was introduced as a destination plasmid.
  • the retrovirus pLPCX-SGLT2 obtained in 1) was transfected into integrin ⁇ v ⁇ 3-expressing HEK-293 cells, followed by antibiotic G418 (trade name: Geneticin, manufactured by Invitrogen), puromycin ( The cells were treated with Clontech), and stable expression cells HEK-SGLT2 of the target vector having resistance were obtained.
  • Culture and maintenance of stably expressing cells was performed using DMEM medium containing 250 ⁇ g / ml G418, 1 ⁇ g / ml puromycin, 3 ⁇ M KGT-1075, and 10% FBS.
  • HEK-SGLT2 cells were suspended in DMEM medium containing 250 ⁇ g / ml G418, 1 ⁇ g / ml puromycin and 10% FBS at a density of 10 6 cells / ml, and a 96-well culture plate coated with type I collagen ( 100 ⁇ l was seeded in each well of Corning).
  • liquid scintillation cocktail (trade name: Supermix, manufactured by Perkin Elmer) to each well of a 96-well plate, stir for 10 minutes, and then radiate with micro ⁇ (produced by PerkinElmer), a type of liquid scintillation counter. Activity was measured. The value obtained by subtracting from each measured value with the radioactivity in the presence of an excessive amount of SGLT2 inhibitory compound as the background is the sugar uptake activity, and the control sugar uptake activity obtained without using the test compound and the test compound at a certain concentration are used. The inhibition rate (%) was determined from the sugar uptake activity at the time of the test, and the concentration of the test compound that inhibits the sugar uptake activity by 50% was examined. The results are shown in Table 11.
  • Urinary glucose excretion test SGLT2 inhibitory activity in vivo is examined using as an index the excretion of urinary glucose, which occurs mainly as a result of inhibiting SGLT2.
  • Each test compound is suspended or dissolved in a solvent (such as 0.5% methylcellulose solution or a solution of propylene glycol and Tween 80 mixed at a ratio of 4: 1) to a dosage of 1 to 10 mL / kg, and multiple doses (preferably 0.03-10mg / kg) is orally administered to various animals (mouse, rat, dog, monkey, etc.). The same amount of solvent is orally administered to the control group.
  • a solvent such as 0.5% methylcellulose solution or a solution of propylene glycol and Tween 80 mixed at a ratio of 4: 1
  • multiple doses preferably 0.03-10mg / kg
  • the same amount of solvent is orally administered to the control group.
  • Test Example 4 Antihyperglycemic test after glucose load or postprandial Evaluate the inhibitory effect of each test compound on hyperglycemia after glucose load or postprandial, and detect the total increase in blood glucose suppression based on SGLT1 and SGLT2 inhibition can do. Furthermore, SGLT1-specific inhibitory activity can be evaluated by examining the blood glucose elevation-inhibiting effect of the test compound in the presence of a selective SGLT2 inhibitor (such as dapagliflozin). Mice, rats, dogs and monkeys are preferred as animals used in the test.
  • a selective SGLT2 inhibitor such as dapagliflozin
  • dapagliflozin was suspended in a solvent (0.5% methylcellulose solution) to a dose of 1-10 mL / kg and orally administered to C57BL / 6NCrlCrlj mice (7-10 weeks old, male) fasted overnight.
  • a solvent such as a 0.5% methylcellulose solution or a solution prepared by mixing propylene glycol and Tween 80 at a ratio of 4: 1 to a dose of 1 to 10 mL / kg, and multiple doses ( Preferably, it is orally administered (within a range of 0.03 to 10 mg / kg).
  • the same amount of solvent is orally administered to the control group.
  • a certain amount of glucose eg 2 g / 10 mL / kg
  • the blood glucose level is measured at a certain time (for example, after 30 minutes).
  • the compound of the present invention exhibits excellent human SGLT1 and / or SGLT2 inhibitory activity, type 1 diabetes, type 2 diabetes, gestational diabetes, hyperglycemia due to other factors, IGT, diabetes related diseases (obesity, hyperlipidemia) , Hypercholesterolemia, dyslipidemia, hypertension, fatty liver, metabolic syndrome, edema, heart failure, angina, myocardial infarction, arteriosclerosis, hyperuricemia, gout), or diabetic complications (retina) , Nephropathy, neuropathy, cataract, foot gangrene, infection, ketosis, etc.) are useful as an active ingredient of a pharmaceutical composition for treating or preventing.
  • SEQ ID NO: 1 PCR sense primer for human SGLT1
  • SEQ ID NO: 2 PCR antisense primer for human SGLT1
  • SEQ ID NO: 3 PCR sense primer for human SGLT2
  • SEQ ID NO: 4 PCR antisense primer for human SGLT2

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Abstract

L'invention concerne un composé ou un sel pharmaceutiquement acceptable de celui-ci représenté par une formule générale (I) permettant d'obtenir un composé ou un sel pharmaceutiquement acceptable de celui-ci présentant une nouvelle structure, des effets secondaires faibles et une excellente activité d'inhibition de SGLT1 et/ou de SGLT2 humains, et une composition pharmaceutique destinée au traitement et/ou à la prévention du diabète et analogues contenant ceux-ci comme principe actif.
PCT/JP2013/060052 2012-04-03 2013-04-02 Dérivé de c-glycoside présentant un cycle spiro Ceased WO2013151033A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017112719A1 (fr) 2015-12-23 2017-06-29 Merck Sharp & Dohme Corp. Modulateurs allostériques 6,7-dihydro-5h-pyrrolo[3,4-b] pyridine-5-one du récepteur de l'acétylcholine muscarinique m4

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006080421A1 (fr) * 2005-01-28 2006-08-03 Chugai Seiyaku Kabushiki Kaisha Dérivé de spirocétal et emploi dudit dérivé au titre de médicament contre le diabète
WO2007140191A2 (fr) * 2006-05-23 2007-12-06 Theracos, Inc. Inhibiteurs de transport de glucose et procédés d'utilisation
WO2008013280A1 (fr) * 2006-07-27 2008-01-31 Chugai Seiyaku Kabushiki Kaisha Dérivé de spirocétal substitué et utilisation de celui-ci comme médicament dans le traitement du diabète
WO2008016132A1 (fr) * 2006-08-04 2008-02-07 Daiichi Sankyo Company, Limited Dérivé du benzyl phényl glucopyranoside

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006080421A1 (fr) * 2005-01-28 2006-08-03 Chugai Seiyaku Kabushiki Kaisha Dérivé de spirocétal et emploi dudit dérivé au titre de médicament contre le diabète
WO2007140191A2 (fr) * 2006-05-23 2007-12-06 Theracos, Inc. Inhibiteurs de transport de glucose et procédés d'utilisation
WO2008013280A1 (fr) * 2006-07-27 2008-01-31 Chugai Seiyaku Kabushiki Kaisha Dérivé de spirocétal substitué et utilisation de celui-ci comme médicament dans le traitement du diabète
WO2008016132A1 (fr) * 2006-08-04 2008-02-07 Daiichi Sankyo Company, Limited Dérivé du benzyl phényl glucopyranoside

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017112719A1 (fr) 2015-12-23 2017-06-29 Merck Sharp & Dohme Corp. Modulateurs allostériques 6,7-dihydro-5h-pyrrolo[3,4-b] pyridine-5-one du récepteur de l'acétylcholine muscarinique m4

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