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WO2007126117A1 - Compose 5-thioglucoside de phenyle - Google Patents

Compose 5-thioglucoside de phenyle Download PDF

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Publication number
WO2007126117A1
WO2007126117A1 PCT/JP2007/059394 JP2007059394W WO2007126117A1 WO 2007126117 A1 WO2007126117 A1 WO 2007126117A1 JP 2007059394 W JP2007059394 W JP 2007059394W WO 2007126117 A1 WO2007126117 A1 WO 2007126117A1
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WO
WIPO (PCT)
Prior art keywords
group
compound
mmol
methyl
phenol
Prior art date
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Ceased
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PCT/JP2007/059394
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English (en)
Japanese (ja)
Inventor
Hiroyuki Kakinuma
Hitomi Takahashi
Yuko Hashimoto
Yohei Kobashi
Takahiro Oi
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Taisho Pharmaceutical Co Ltd
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Taisho Pharmaceutical Co Ltd
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Publication of WO2007126117A1 publication Critical patent/WO2007126117A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a ferrule 5-thiodarcoside compound having an inhibitory activity on sodium-dependent glucose cotransporter 1 (SGLT1) involved in glucose reabsorption in the kidney.
  • SGLT1 sodium-dependent glucose cotransporter 1
  • the fasting blood glucose level is 126 mgZdL or more.
  • IGT impaired glucose tolerance
  • Non-Patent Document 2 administration of the a-darcosidase inhibitor acarbose, which inhibits sugar hydrolase and delays the absorption of sugar in the small intestine, suppresses the transition from IGT to type 2 diabetes. Furthermore, it has been reported that the onset of hypertension is also significantly suppressed (see Non-Patent Document 2).
  • SG LT1 Sodium-dependent glucose cotransporter 1
  • IGT Sodium-dependent glucose cotransporter 1
  • Non-Patent Documents sodium-dependent dalcose cotransporter 2 (SGLT2) is frequently expressed in the kidney, and glucose that has been glomerularly filtered is reabsorbed via SGLT2 (Non-Patent Documents). 3). SGLT2 inhibitors promote glucose excretion in the urine and reduce blood sugar. As a result, it has come to be considered as a target molecule for new antidiabetic drugs (see Non-Patent Document 4). against this background, SGLT2 inhibitors have been studied and aryl-5 thioglycoside derivatives have been provided (see Patent Document 7).
  • Patent Document 1 International Publication No. WO2002Z098893 Pamphlet
  • Patent Document 2 International Publication No. WO2004Z014932 Pamphlet
  • Patent Document 3 International Publication No. WO2004Z018491 Pamphlet
  • Patent Document 4 International Publication No. WO2004Z019958 Pamphlet
  • Patent Document 5 International Publication No. WO2005Z121161 Pamphlet
  • Patent Document 6 International Publication No. WO2004Z050122 Pamphlet
  • Patent Document 7 International Publication No. WO2004Z014931 Pamphlet
  • Non-Patent Document 1 Pan XR, et al. Diabets Care, 20th, 534, 1997
  • Non-Patent Document 2 J. Shias, et al. Lancent, 359, 2072, 2002
  • Non-Patent Document 3 E. M. Wright, Am. J. Physiol. Renal. Physiol., 280, F10, 2001
  • Non-Patent Document 4 G. Toggenburger, et al. Biochem. Biophys. Acta., 688, 557, 1 982
  • the present invention provides a novel phenol 5-thio-13D-darcopyranoside compound capable of controlling IGT by inhibiting SGLT1 activity and suppressing glucose absorption from the gastrointestinal tract.
  • the purpose is to do.
  • Aspect (1) of the present invention is a phenyl 5-thiodarcosidyl compound represented by the following formula (I), a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • R 1 and R 2 are the same or different and each represents a hydrogen atom, hydroxyl group, C alkyl group, C alkyl
  • 1-6 1-6 is a alkoxy group or a halogen atom
  • Z is —NHSO fuel, —NHSO NH, or —Y—Q,
  • Y is a single bond, a C alkylene group or a C alkylene group
  • 2 1-6 a 4- to 6-membered heterocycloalkyl group substituted with at least one of a kill group and an oxo group (the heterocycloalkyl group may be condensed with a phenyl group);
  • R A and R B are the same or different and each represents a hydrogen atom, a C alkyl group, C cycloalkyl.
  • R e is a C alkyl group substituted with 1 to 4 groups selected from the group consisting of a hydroxyl group, a carboxyl group, and —CONR ei R e2 force;
  • R ei and R e2 are the same or different, I together with a hydrogen atom or it may also be substituted with a hydroxyl group V, a force is C alkyl or by bonding R ei and R e2,, Ru nitrogen atom
  • a ring-constituting atom it may contain a heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom, and a 5- to 6-membered heterocycloalkyl group (the heterocycloalkyl group is substituted with a hydroxyl group).
  • C alkyl group or C alkoxy carbo May be substituted with a group ⁇ ).
  • R 1 is a hydrogen atom, a hydroxyl group, a C alkyl group or a C alkyl
  • the phenol of the above aspect (1) which is a alkoxy group and R 2 is a C alkyl group or a halogen atom.
  • Another embodiment of the present invention is a phenyl 5 of the above embodiment (3) wherein Y is a C alkylene group.
  • Z guard Y-NHCON (RA) R B (RA and Y are as defined in embodiment (1), R B is hydrogen atom) is a form (1) or (2) phenyl 5-thiodarcoside compound or a pharmaceutically acceptable salt thereof or a hydrate thereof.
  • Z guard Y-CONH (R E) ( R E are as defined in embodiment (1), Y is C alkylene group or a C Aruke - an alkylene group) Embodiment (1) or (
  • a phenyl 5-thiodarcoside compound of the embodiment (6) which is an alkyl group or a product thereof
  • a pharmaceutically acceptable salt or a hydrate thereof is provided.
  • R 1 and R 2 are the same or different and each is a hydrogen atom, a hydroxyl group, a C alkyl group, or a C alkoxy group,
  • R A and R B are the same or different and each represents a hydrogen atom, a C alkyl group, C cycloalkyl.
  • Y represents a C alkylene group or a C alkenylene group, and R c is substituted with —CONH.
  • the phenyl 5 thiodalcoside compound according to any one of aspects (1) to (8) or a pharmaceutically acceptable salt thereof or a hydrate thereof is used as an active ingredient.
  • SGLT1 sodium-dependent glucose cotransporter 1
  • the phenyl 5-thiodarcoside compound or a pharmaceutically acceptable salt or hydrate thereof according to any one of aspects (1) to (8) is effective. It is a preventive or therapeutic agent for diabetes included as a component.
  • the compound of the present invention has strong SGLT1 inhibitory activity, patients with borderline (pre-diabetes group) patients who have postprandial hyperglycemia even in the normal range of preprandial blood glucose obtained only by treatment of diabetic patients. It can also be treated to prevent the transition to diabetes.
  • borderline pre-diabetes group
  • C alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms
  • a methyl group, an ethyl group, an n propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert butyl group, a sec butyl group, an n pentyl group, and an n xyl group can be mentioned.
  • C cycloalkyl group refers to a cyclic alkyl group having 3 to 7 carbon atoms.
  • Examples include chloropropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, and cycloheptyl group. Of these, a cyclopentyl group and a cyclohexyl group are preferable.
  • C alkoxy group refers to a linear or branched alkoxy having 16 carbon atoms. Means a Si group, and a C alkoxy group is preferred. Examples of the C alkoxy group include meth
  • Examples thereof include a xy group, an ethoxy group, a propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, and a tert-butoxy group.
  • halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • ⁇ kill group '' refers to a heterocycloalkyl group having 4 to 6 ring atoms containing 1 to 2 heteroatoms with 0, S and N forces also selected, and Hydrogen atom is C
  • it is a 4- to 6-membered nitrogen-containing heteroalkyl group substituted with 1 or 2 oxo groups (the heterocycloalkyl group may be substituted with a C alkyl group).
  • imidazolidyl groups eg, 5,5-dimethyl-imidazolidine-1,2,4 dione and 3-yl groups
  • a kill group and an oxo group 1,3 dioxo-1,3 dihydro (1) 2H isoindole-2-yl group and the like.
  • Ethyl group 2-hydroxy 1,1-dimethylethyl group, 1,3 dihydroxy 2-methyl propane 2-yl group, strong rubamoylmethyl group, 2-strong rubamoylethyl group, benzyl group, phenethyl group, 3-pyridylmethyl group.
  • hydroxyl group, and carboxyl group is C alkyl group was substituted with CONR ei 1 to 4 radicals selected from the group consisting of R e2 'is a hydrogen atom on that group, hydroxyl group, carboxy
  • Group group consisting of a ru group and —CONR ei Re 2 represents a C alkyl group substituted by 1 to 4 (preferably 1 to 3) of at least one selected group. For example, hydroxymethyl
  • hydroxyethyl group 2-hydroxy 1,1-dimethylethyl group, 1,3 dihydroxy 2-methylpropane 2-yl group, 1,3-dihydroxy 2-hydroxymethyl pro Examples include pan 2-yl group, force ruberamoylmethyl group, 2-force rubermoylethyl group, 2-force rubermoyl 2-methylethyl group.
  • “It may be formed together with the nitrogen atom to which 1 and 2 are bonded, and may further include a hetero atom selected from an oxygen atom, a sulfur atom and a nitrogen atom as a ring-constituting atom.
  • a hetero atom selected from an oxygen atom, a sulfur atom and a nitrogen atom as a ring-constituting atom.
  • ⁇ 6-membered heterocycloalkyl group (the heterocycloalkyl group may be substituted with a C alkyl group which may be substituted with a hydroxyl group, or a C alkoxycarbonyl group) ”
  • 1-pyrrolidyl group 1-piveridyl group, 1-piperazyl group, 4 morpholino group, 4-thiomorpholino group, 4-methyl-1-piperazyl group, 4 (2 hydroxy shetyl) 1-piperazyl group, 4-methoxycarbolulu 1-piperazine group and the like can be mentioned.
  • C alkyl group optionally substituted with a hydroxyl group means at least one hydroxyl group
  • Examples thereof include a til group, a 2-hydroxy 1,1-dimethylethyl group, a 1,3-dihydroxy 2-methylpropane-2-yl group, and a 1,3-dihydroxy 2-hydroxymethylpropane 1-2-yl group.
  • the "C alkylene group” is a linear or branched divalent saturation composed of 1 to 6 carbon atoms.
  • hydrocarbon It is a hydrocarbon.
  • methylene, ethylene, trimethylene, tetramethylene, 2-methylpropylene, 2,2-dimethylpropylene and the like can be mentioned.
  • C alk-lene group means a straight chain or branched chain having 2 to 6 carbon atoms including a double bond.
  • ethylene, probelene, 2-butylene and the like can be mentioned. Of these, probelene is preferable.
  • “Pharmaceutically acceptable salt” refers to a salt with an alkali metal, an alkaline earth metal, an ammonium, an alkyl ammonium, a mineral acid or an organic acid.
  • Hydrate refers to a pharmaceutically acceptable hydrate of the compound of the present invention or a salt thereof.
  • the compound of the present invention or a salt thereof may be exposed to air or recrystallized to absorb moisture and form adsorbed water, or may become a hydrate.
  • the hydrate in the present invention includes such hydrates.
  • the compounds of the present invention may have a chiral center, they exist as various diastereomeric or enantiomeric forms. Some of the compounds of the present invention also exist as keto-enol tautomers, for example. In addition, some of the compounds of the present invention also exist as geometrically different bodies (E-form, Z-form). Accordingly, the compounds of the present invention include all the individual isomers above as well as mixtures thereof.
  • R 1 and R 2 are the same or different and are a hydrogen atom, a hydroxyl group, a C alkyl group, a C alkoxy group or a halogen atom, and more preferably a hydrogen atom.
  • Child hydroxyl group, methyl group, methoxy group or halogen atom.
  • R 2 is a cyano group or a halogen atom (especially a chlorine atom), and R 1 is a hydroxyl group, a methoxy group, or a methyl group. Furthermore, R 1 is a hydroxyl group. It is more preferable.
  • Y—CONH (R e ) is more preferred in that SGLT1 inhibitory activity is stronger.
  • Z is Y—NHCON (R A ) R B Y-NHCONH, Y-NHCONH-C alkyl (the alkyl is substituted with a hydroxyl group)
  • Y is a C alkylene group.
  • Y is a C alkylene group or C
  • R e examples include a C alkyl group substituted with a hydroxyl group and 1 to 4 (more preferably 1 to 3) groups selected from the group consisting of —CO—NR ei R e2. Yes , Rei and Re2
  • a hetero atom selected from an oxygen atom, a sulfur atom and a nitrogen atom as a ring atom together with the nitrogen atom to which Re and R e2 are bonded.
  • a 5- to 6-membered heterocycloalkyl group (the heterocycloalkyl group is substituted with a C alkyl group or a C alkoxycarbonyl group which may be substituted with a hydroxyl group).
  • the following compound groups are preferable in that they have strong SGLT1 inhibitory activity and strong SGLT2 inhibitory activity. These compounds can inhibit SGLT2 activity, which can not only be expected to have a therapeutic effect based on the SGLT1 inhibitory activity described below, thereby suppressing reabsorption of sugar and excreting excess sugar outside the body. Diabetes can be treated, hyperglycemia can be corrected without stressing pancreatic ⁇ cells, and insulin resistance can be improved.
  • a compound group having strong SGLT1 inhibitory activity and strong SGLT2 inhibitory activity is ⁇ - ⁇ -CONH (R C ), and Y is a C alkylene group or a C alkkelene group (more preferably propylene.
  • R C is selected from the group consisting of a hydroxyl group and —CO—NR C1 R C2 A C alkyl group substituted with 1 to 4 (more preferably 1 to 3) selected groups (the C
  • 1-6 1-6 alkyl group is a tertiary carbon atom bonded to —NH—, wherein 1 and 2 are the same or different and may be substituted with a hydrogen atom or a hydroxyl group Base
  • the ring member may further include a heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom. !, May form a 5- to 6-membered heterocycloalkyl group (the heterocycloalkyl group may be substituted with a hydroxyl group or a C alkyl group).
  • R 2 and preferred substitution position of Z are the same as above.
  • Z is —Y—CO—NH—C alkyl (including the above).
  • Alkyl is substituted with a hydroxyl group), -Y-CO-NH-C (CH) -CONH
  • NH) NH or NHCON (R A ) R B can be synthesized by the following method.
  • the phenol derivative (lla) can be synthesized according to International Publication WO2004Z050122.
  • the 5-thioglucose derivative (III) can be synthesized according to International Publication WO2004Z014931.
  • phosphines necessary as a reagent in this reaction include triphenylphosphine, tri-n-butylphosphine, tri-t-butylphosphine, tristolylphosphine and diphenyl-2-pyridylphosphine. Of these, triphenylphosphine and diphenyl-1-pyridylphosphine are preferred, and triphenylphosphine is more preferred.
  • azo reagents include jetyl dicarboxylate, diisopropyl azodicarboxyloxy tert-butinoreazodicanoloxylate, 1,1'-azobis (N, N-dimethylformamide) And 1, 1 (azodicarbol) dipiperidine can be used.
  • jetylazodicarboxylate (DEAD) and diisopropylazodicarboxylate are preferable.
  • the solvent used in this reaction is tetrahydrofuran, dioxane, toluene, dichloromethane, chloroform, acetonitrile, ethyl acetate, dimethyl sulfoxide, N, N-dimethylformamide or the like, preferably tetrahydrofuran or toluene.
  • the reaction temperature is preferably from 20 ° C to room temperature, more preferably from 5 ° C to + 5 ° C.
  • the compound (IVa) obtained above is converted into an amino group by catalytic hydrogenation in a hydrogen atmosphere using a catalyst such as palladium activated carbon, palladium hydroxide, or platinum-norradium activated carbon, and the compound ( IVb) is obtained.
  • a catalyst such as palladium activated carbon, palladium hydroxide, or platinum-norradium activated carbon
  • palladium activated carbon and palladium hydroxide are preferred as the catalyst.
  • the solvent used for this reaction include methanol, ethanol, isopropanol, ethyl acetate, and acetic acid.
  • the reaction temperature is preferably room temperature, reflux temperature, or room temperature.
  • Iron can also be used in the presence of tin chloride (11) monohydrate and salt ammonium.
  • solvent used in this reaction include methanol, ethanol, isopropanol and the like.
  • the reaction temperature is room temperature and reflux temperature.
  • the compound (I) of the present invention can be produced by the following method using the compound (IVb) as an intermediate.
  • R E represents a benzyloxycarbonyl group or a t-butoxycarbonyl group, and other symbols are as defined above.
  • phenylsulfur chloride or isocyanide Acid chlorosulfol can be used to derive compound (IVc) or (IVd).
  • Suitable bases include triethylamine, Nethyl N, N diisopropylamine, pyridine, DBU, potassium carbonate, calcium carbonate, cesium carbonate and the like.
  • the solvent to be used include black mouth form, dichloromethane, jetyl ether, tetrahydrofuran, N, N dimethylformamide, acetonitrile, ethyl acetate and the like, or a mixed solvent thereof.
  • the reaction temperature is 0 ° C force reflux temperature.
  • Compound (IVb) force can also be induced to compound (IVe) using guadinodination reagent (V).
  • the solvent used in this reaction include tetrahydrofuran, N, N dimethylformamide, methanol, ethanol, isopropanol, ethyl acetate, toluene and the like.
  • the reaction temperature is from room temperature to reflux temperature.
  • Suitable bases include triethylamine, Nethyl N, N diisopropylamine, pyridine, DBU, potassium carbonate, calcium carbonate, cesium carbonate and the like.
  • the solvent used include black mouth form, dichloromethane, jetyl ether, tetrahydrofuran, N, N dimethylformamide, acetonitrile, and ethyl acetate.
  • the reaction temperature is 0 ° C force and reflux temperature.
  • the protecting group for 5-thioglucose is removed using a suitable base to obtain the compound (I) of the present invention.
  • a suitable base sodium methoxide, sodium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, triethylamine and the like can be used.
  • Suitable solvents for the reaction are methanol, ethanol, water or a mixed solvent thereof.
  • 0 ° C force is also room temperature, and room temperature is preferred.
  • the protecting group R E of the guazino group is a benzyloxycarbon group, it can be removed by a catalytic hydrogenation catalyst described in Production Method 1.
  • a preferred catalyst at this time is palladium hydroxide.
  • the compound that is a Y-acetylene group can be produced by using, as a raw material, a compound having an amino group, which is a thioglucoside compound described in Patent Document 7, with reference to Step 5 of Production Method 1.
  • Y 1 represents a single bond or a C alkylene group, and other symbols are as defined above.
  • the phenol derivative (lib) force compound (IVg) can be synthesized by the Mitsunobu reaction shown in Step 1 of Production Method 1.
  • Step 7 (Heck reaction)
  • Compound (IVh) can be synthesized by subjecting compound (IVg) and olefin acetic acid (VI) to Heck reaction in the presence of a palladium catalyst, a phosphine ligand, and an appropriate base.
  • a palladium catalyst used at this time include palladium acetate, tetrakistriphenylphosphine palladium, dibenzylideneacetone palladium, bistriphenylphosphine paradium chloride, palladium activated carbon and the like.
  • the phosphine ligand include triphenylphosphine tris (2-methylphenol) phosphine.
  • triethylamine, N-ethyl-N, N-diisopropylamine, potassium carbonate, calcium carbonate, cesium carbonate, potassium t-butoxide and the like are used as the base.
  • the solvent used in the reaction include acetonitrile, toluene, tetrahydrofuran and the like.
  • the reaction temperature is from 0 ° C to the reflux temperature, but a microwave may be used.
  • N N-dicyclocarpoimide
  • N-ethyl-N N-ethyl-N
  • -3 Dimethylaminopropylcarbodiimide hydrochloride
  • CDI CDI
  • WSC 1-hydroxybenzotriazole monohydrate, etc.
  • the reaction temperature here is 0 ° C to 60 ° C.
  • Compound (IVk) can also be produced by subjecting the olefin moiety of compound (IVh) to the catalytic hydrogenation shown in Step 2 of Production Method 1 and then condensing with ammine (R e NH 3).
  • the compound in which Y is a single bond or a methylene group can be produced by using a compound having a carboxyl group described in Patent Document 7 as a raw material with reference to Step 8 of Production Method 2.
  • Y is a C alkylene group or a C alkylene group.
  • NHCON (R A ) R B or C alkyl group and oxo
  • a compound which is a 4- to 6-membered heterocycloalkyl group substituted with at least one group (the heterocycloalkyl group may be condensed with a phenyl group).
  • the heterocycloalkyl group may be condensed with a phenyl group
  • a compound for example, a (Vic) compound
  • a compound (IVm) that is a sum hydrocarbon ring (which may be condensed with a phenyl group) is converted to a compound (IVm) using the Heck reaction described in Step 7 of Production Method 2.
  • the compound (I) of the present invention which is an alkyl group can be synthesized by the following method.
  • RN and R NA represent a hydrogen atom or a C alkyl group, and other symbols are as defined above.
  • the compound (1) of the present invention which is a 4- to 6-membered heterocycloalkyl group substituted with at least one of an alkyl group and an oxo group, can be produced.
  • methanol or ethanol is preferable as the solvent preferred for sodium methoxide.
  • the compound of the present invention is a disease or condition that can be ameliorated by inhibiting the activity of SGLT1, eg, for example, it can be used as an active ingredient of a medicament for preventing or treating diabetes, diabetes-related diseases and diabetic complications.
  • the compound of the present invention is particularly excellent in that it inhibits SGLT1 activity, thereby suppressing absorption of sugar from the small intestine and improving IGT, thereby preventing the transition to diabetes. Yes.
  • diabetes includes type 1 diabetes, type 2 diabetes, and other types of diabetes due to specific causes.
  • diabetes-related disease means obesity, hyperinsulinemia, abnormal glucose metabolism, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, abnormal lipid metabolism, hypertension, congestive heart failure Edema, hyperuricemia, gout and the like.
  • diabetes complications are classified into acute complications and chronic complications.
  • Acute complications include hyperglycemia (eg ketoacidosis), infections (skin, soft tissue, biliary system, respiratory system, urinary tract infection, etc.).
  • hyperglycemia eg ketoacidosis
  • infections skin, soft tissue, biliary system, respiratory system, urinary tract infection, etc.
  • Chronic complications include microangiopathy (nephropathy, retinopathy), arteriosclerosis (atherosclerosis, myocardial infarction, cerebral infarction, lower limb arterial occlusion, etc.), neuropathy (sensory nerve, Motor nerves, autonomic nerves, etc.) and foot gangrene.
  • the major complications are diabetic retinopathy, diabetic nephropathy, diabetic neuropathy.
  • the compound of the present invention can be administered as a medicine systemically or locally, orally or parenterally.
  • the compound of the present invention is a therapeutic agent for diabetes having a different mechanism other than SGLT1 and SGLT2 activity inhibitors and diabetic complications for the purpose of enhancing the action of the compound or reducing the dose of the compound. It can be used in combination with drugs (hereinafter abbreviated as concomitant drugs) such as therapeutic agents, antihyperlipidemic agents, antihypertensive agents, antiobesity agents, diuretics and antithrombotic agents.
  • concomitant drugs drugs
  • the administration time of the compound of the present invention and the concomitant drug is not limited, and these may be administered simultaneously to the administration subject or may be administered with a time difference.
  • the compound of the present invention and the concomitant drug may be administered as two types of preparations containing each active ingredient, or may be administered as a single preparation containing both active ingredients.
  • the dose of the concomitant drug can be appropriately selected based on the clinically used dose.
  • the compounding ratio of the compound of the present invention and the concomitant drug is the subject of administration, administration route, target disease, symptoms, combination It can be appropriately selected depending on the combination.
  • the concomitant drug may be used in an amount of 0.01 to LOO parts by weight per 1 part by weight of the compound of the present invention.
  • diabetes therapeutic agents include insulin preparations (eg, animal insulin preparations extracted from sushi and swine spleen; human insulin preparations synthesized using E. coli or yeast and genetically engineered; Protamine insulin sub-insulin fragments or derivatives (eg, INS-1 etc.), oral insulin preparations), insulin resistance improvers (eg,
  • Pioglitazone or its salt preferably hydrochloride
  • rosiglitazone or its salt preferably maleate
  • riboglitazone CS—Oi l
  • Sipoglitazar TAK— 654
  • Metaglidasen M XB- 1 0 2
  • Naveglitazar LY—519818
  • MX—6054 Nolaglitazone
  • N—2344 Nolaglitazone
  • T—131 AMG131
  • PPAR y Ago-st PPAR y-antagost
  • a-Darcosidase inhibitor eg, voglibose, carbolose, miglitol, emidalitate
  • biguanide eg, phenformin, metformin, buformin or Their salts (eg, hydrochloride, fumarate, succinate)
  • insulin secretagogues sulfururea
  • Examples of the therapeutic agent for diabetic complications include aldose reductase inhibitors (eg, torles, epanolorestat, zenarestat, zoponolestat, minarerestat, fidarestat, CT-112) , Neurotrophic factor and its increasing drug (eg, NGF, NT-3, BDNF, neurotrophin production 'secretion promoter), nerve regeneration promoter (eg, Y-128), PKC inhibitor (eg, ruboxis) Taurine mesylate (LY- 333531)), AGE inhibitors (eg, ALT946, pimagedin, pyratoxatin, N-phenacyl thiazolium bromide (ALT766), ALT-711, EXO-226, pyridorin) , Pyridoxamine), active oxygen scavengers (eg, thiotate), cerebral vasodilators (eg, thiopride, mexiletine), somatostatin receptor agonist
  • Antihyperlipidemic agents include, for example, statin compounds (eg, pravastatin, sympastatin, oral pastatin, atonolepastatin, flupastatin, itapastatin, rosbastatin, pitapastatin or salts thereof (eg, Sodium salts, calcium salts)), squalene synthase inhibitors (eg, TAK-475), fibrate compounds (eg, bezafibrate, clofibrate, simfibrate, clinofibrate), ACAT inhibitors (eg, abashimibe ( Avasimibe), Eflucimibe), anion exchange scab (eg, cholestyramine), probuconole, nicotinic acid drugs (eg, nicomol), niceritro Niceritrol), icosapentate ethyl, plant sterols (eg, soysterol, gamma-oryzanol), CETP inhibitors (eg,
  • antihypertensive agents include angiotensin converting enzyme inhibitors (eg, captopril, enalapril, delapril), angiotensin II antagonists (eg, candesartan cilexetil, oral sultan, eprosartan, valsartan, telmisartan, Ilbesartan, tasosartan, azilzartan (TAK-536)), calcium antagonists (eg, iliapine, difedipine, amlodipine, efonidipine, dicanodipine), potassium channelnore openers (eg, lebucromacarim, L 27152, AL0671, NIP — 121), including clodin
  • Anti-obesity agents include, for example, central anti-obesity agents (eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, amphepramone, dexamphetamine, mazindol, phenol-propanolamine, clobenzolex).
  • central anti-obesity agents eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, amphepramone, dexamphetamine, mazindol, phenol-propanolamine, clobenzolex.
  • MCH receptor antagonist eg, compound described in W 006/035967, SB—568849; SNAP—7941, T 226296); neuropeptide antagonist (eg, CP—422935); cannapinoid receptor antagonist (Eg, Rimonabant (SR—141716), SR—147778); ghrelin antagonists; 1 1 ⁇ -hydroxysteroid dehydrogenase inhibitors (eg, BVT-3498, INCB1373 9)), spleen lipase inhibitors ( Eg, orlistat, ATL—962), DGAT—1 inhibitor, / 3 3 agonist (eg, AJ—9677, AZ40140), peptidic appetite suppressant (eg, leptin, CN TF (ciliary neurotrophic) factor)) , Cholecyst kyungagost (eg, Lynch tribute, FPL-15849), antifeedant (eg, P-57).
  • neuropeptide antagonist eg,
  • diuretics examples include xanthine derivatives (eg, sodium theoproyl salicylate, calcium theopromin salicylate), thiazide preparations (eg, ethiazide, cyclopenthiazide, trichloromethiazide, hydrothiazide, hydroflumethiazide, benzylhydride).
  • xanthine derivatives eg, sodium theoproyl salicylate, calcium theopromin salicylate
  • thiazide preparations eg, ethiazide, cyclopenthiazide, trichloromethiazide, hydrothiazide, hydroflumethiazide, benzylhydride.
  • Mouth-mouth mouth thiazide, penflutide, polythiazide, methiclothiazide), anti-aldosterone preparation eg, spironolatatone, triamterene
  • carbonic anhydrase inhibitor eg, acetazolamide
  • chlorobenzenesulfonamide preparation eg, chlorthalidone, mefluside, indapamide
  • Examples include fazosemide, isosorbide, ethacrynic acid, pyrethradide, bumetide, and furosemide.
  • Antithrombotic agents include, for example, heparin (eg, heparin sodium, heparin calcium, dalteparin sodium, AVE-5026), ⁇ rufarin (eg, ⁇ rufarin potassium, etc.), antithrombin Drugs (eg, argatroban, xymeragatran (Dimigatran), Dabigatran (Odiparcil, Lepirudin, bival irudin, Desirudin, ART—123, Idraparinux, SR—123781, AZD—0837, MCC—977, TGN— 255, TGN—167, RWJ—58436, LB—30870, MPC—09 20, Pegmusirudin ⁇ Org—426751, etc., thrombolytic drugs (eg, urokina se, tisokinase, anoleplase, alteplase) (natepla se), monteplase, pamiteplase,
  • a pharmaceutically acceptable carrier can be blended.
  • examples of such carriers include common excipients, bulking agents, binders, disintegrants, coating agents, dragees, pH adjusters, solubilizers or aqueous or non-aqueous solvents. Tablets, pills, capsules, granules, powders, powders, solutions, emulsions, suspensions, injections and the like can be prepared from the compound of the present invention and these carriers.
  • the solubility of the compound of the present invention can also be improved by inclusion in a, ⁇ or ⁇ -cyclodextrin, methylicyclodextrin, or the like.
  • the dose of the compound of the present invention varies depending on the disease, symptom, body weight, age, sex, route of administration, etc. S, for adults, 0.1 to 1 per person: LOOOmg / kg body weight Yes, 0.1 to 200 mg Zkg body weight is preferred 0.1 to 10 mg Zkg body weight is more preferred. This can be administered once to several times a day.
  • Methyl 3 Methyl 4— (4-Trobenzyl) 5— [(2, 3, 4, 6—Tetra-1-O-cetyl 5-thio-1—Dalcopyranosyl) oxy] phenyl carbonate instead of methyl 3
  • Reference Example 8 (2) The title compound was obtained in the same manner as (0. 242 g, 17%).
  • Compound 34 was synthesized in the same manner as in Example 15 using N-aryl N,-(2-hydroxy-1,1-dimethylethyl) urea.
  • Example 23 (4-Aminobenzil) -3 ethyl 5— [(2, 3, 4, 6—tetra-acetyl 5—thio 13 D-darcopyranosyl) oxy] phenol methyl carbonate synthesized in Reference Example 17 was used.
  • the title compound (0.076 g, 82%) was obtained in the same manner as in Example 3.
  • the structure, NMR data and MS data of the obtained compound are shown in Table 1.
  • the drug (the compound of the present invention) is mixed with lactose monohydrate, crystalline cellulose, carboxymethyl cellulose-calcium and hydroxypropylcellulose, and this mixture is pulverized with a pulverizer.
  • the pulverized mixture is mixed with a stirring granulator for 1 minute, and then granulated with water for 4-8 minutes.
  • the resulting granulate is dried at 70 ° C for 40 minutes.
  • the granulated dry powder after sieving and magnesium stearate are mixed at 30 rpm for 3 minutes using a V-type mixer.
  • the granules for tableting obtained using a mouth-tally tablet press are compression-molded and tableted.
  • a human SGLT1 sequence (NM-000343) was amplified from human small intestine-derived mRNA after reverse transcription and introduced into pCMV-tag5A (Stratagene).
  • a human SGLT2 sequence (NM-003 041) was prepared from human kidney-derived mRNA by the same method and introduced into pcDNA3.1 + hygro (Invitrogen). The sequence ability of each clone was confirmed to match the reported sequence.
  • Cells stably expressing human SGLT1 or human SGLT2 were used in a sodium-dependent glucose uptake activity inhibition test.
  • Pretreatment buffer 140 mM choline chloride, 2 mM KC1, ImM CaCl, ImM Mg
  • test compound ["C] methyl ⁇ -D-dalcopyranoside containing ⁇ -D-darcobilanoside (lmM), 145 mM NaCl, 2 mM KC1, ImM CaCl , ImM MgCl, lOmM HEPES / 5mM Tris, pH7.4
  • the drug group was orally administered with a drug (lmgZkg) suspended in a 0.5% carboxymethylcellulose (CMC) aqueous solution and only a 0.5% CMC aqueous solution in the control group.
  • CMC carboxymethylcellulose
  • glucose solution (2 gZkg) was orally administered, and blood was collected at a total of 5 points before drug administration (Otime) and 0.25, 0.5, 1, 2 hours after oral administration.
  • SGLT1 sodium-dependent glucose cotransporter expressed in the intestinal epithelium

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Abstract

La présente invention concerne un nouveau composé 5-thioglucoside de phényle pouvant contrôler l'IGT (tolérance abaissée au glucose) en inhibant l'activité SGLT1 et en inhibant l'absorption du glucose à travers le tube digestif. L'invention concerne un composé 5-thioglucoside de phényle représenté par la formule (I), un sel pharmaceutiquement acceptable de celui-ci ou un hydrate du composé ou du sel. (I) où R1 et R2 représentent indépendamment un atome d'hydrogène, un groupe hydroxyle, un groupe alkyle en C1-6 alkyl, un groupe alcoxy en C1-6 ou un atome d'halogène ; Z représente –NHSO2-phényle, -NHSO2NH2 ou –Y-Q ; Y représente une liaison simple, un groupe alkylène en C1-6 ou un groupe alcénylène ; et Q représente –NHC(=NH)NH2, -NHCON(RA)RB, -CONH(RC) ou un groupe hétérocycloalkyle ayant de 4 à 6 membres, substitué par au moins un élément sélectionné parmi un groupe alkyle en C1-6 et un groupe oxo (le groupe hétérocycloalkyle pouvant être fusionné avec un groupe phényle).
PCT/JP2007/059394 2006-05-02 2007-05-02 Compose 5-thioglucoside de phenyle Ceased WO2007126117A1 (fr)

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Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
WO2011070592A2 (fr) 2009-12-09 2011-06-16 Panacea Biotec Ltd. Nouveaux dérivés de sucres
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
US8080580B2 (en) 2008-08-28 2011-12-20 Pfizer Inc. Dioxa-bicyclo[3.2.1]octane-2,3,4-triol derivatives
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
JP2012518631A (ja) * 2009-02-23 2012-08-16 大正製薬株式会社 Ｓｇｌｔ１阻害剤としての４−イソプロピルフェニルグルシトール化合物
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
US8669380B2 (en) 2009-11-02 2014-03-11 Pfizer Inc. Dioxa-bicyclo[3.2.1]octane-2,3,4-triol derivatives
US9061060B2 (en) 2008-07-15 2015-06-23 Theracos Inc. Deuterated benzylbenzene derivatives and methods of use
US11084842B2 (en) 2018-01-23 2021-08-10 Sunshine Lake Pharma Co., Ltd. Glucopyranosyl derivative and use thereof
US11186602B2 (en) 2018-01-31 2021-11-30 Sunshine Lake Pharma Co., Ltd. Glucopyranosyl derivative and use thereof

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Publication number Priority date Publication date Assignee Title
WO2004014931A1 (fr) * 2002-08-09 2004-02-19 Taisho Pharmaceutical Co., Ltd. Derives aryle 5-thio-?-d-glucopyranoside et medicaments antidiabetiques contenant ces derives
JP2005247834A (ja) * 2004-02-04 2005-09-15 Taisho Pharmaceut Co Ltd ナトリウム依存性グルコース供輸送体２の活性阻害剤

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WO2004014931A1 (fr) * 2002-08-09 2004-02-19 Taisho Pharmaceutical Co., Ltd. Derives aryle 5-thio-?-d-glucopyranoside et medicaments antidiabetiques contenant ces derives
JP2005247834A (ja) * 2004-02-04 2005-09-15 Taisho Pharmaceut Co Ltd ナトリウム依存性グルコース供輸送体２の活性阻害剤

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
US9061060B2 (en) 2008-07-15 2015-06-23 Theracos Inc. Deuterated benzylbenzene derivatives and methods of use
US8080580B2 (en) 2008-08-28 2011-12-20 Pfizer Inc. Dioxa-bicyclo[3.2.1]octane-2,3,4-triol derivatives
JP2012518631A (ja) * 2009-02-23 2012-08-16 大正製薬株式会社 Ｓｇｌｔ１阻害剤としての４−イソプロピルフェニルグルシトール化合物
US8669380B2 (en) 2009-11-02 2014-03-11 Pfizer Inc. Dioxa-bicyclo[3.2.1]octane-2,3,4-triol derivatives
US9439902B2 (en) 2009-11-02 2016-09-13 Pfizer Inc. Dioxa-bicyclo[3.2.1]octane-2,3,4-triol derivatives
US9439901B2 (en) 2009-11-02 2016-09-13 Pfizer Inc. Dioxa-bicyclo[3.2.1]octane-2,3,4-triol derivatives
US9308204B2 (en) 2009-11-02 2016-04-12 Pfizer Inc. Dioxa-bicyclo[3.2.1]octane-2,3,4-triol derivatives
WO2011070592A2 (fr) 2009-12-09 2011-06-16 Panacea Biotec Ltd. Nouveaux dérivés de sucres
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
US11084842B2 (en) 2018-01-23 2021-08-10 Sunshine Lake Pharma Co., Ltd. Glucopyranosyl derivative and use thereof
US11186602B2 (en) 2018-01-31 2021-11-30 Sunshine Lake Pharma Co., Ltd. Glucopyranosyl derivative and use thereof

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