WO2012176804A1 - Dérivé de glucopyranosyloxypyrazole - Google Patents

Dérivé de glucopyranosyloxypyrazole Download PDF

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WO2012176804A1
WO2012176804A1 PCT/JP2012/065744 JP2012065744W WO2012176804A1 WO 2012176804 A1 WO2012176804 A1 WO 2012176804A1 JP 2012065744 W JP2012065744 W JP 2012065744W WO 2012176804 A1 WO2012176804 A1 WO 2012176804A1
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group
alkyl group
compound
acceptable salt
hydrogen atom
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PCT/JP2012/065744
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Japanese (ja)
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藤倉　秀紀
稔 藤岡
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キッセイ薬品工業株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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 glucopyranosyloxypyrazole derivative or a prodrug thereof useful as a pharmaceutical, or a pharmacologically acceptable salt thereof, and a pharmaceutical use thereof.
  • the present invention relates to a glucopyranosyloxypyrazole derivative or a prodrug thereof having human SGLT2 inhibitory activity and useful as a preventive or therapeutic agent for diabetes, diabetes-related diseases or diabetic complications, or the like.
  • the present invention relates to a pharmacologically acceptable salt and its pharmaceutical use.
  • Diabetes is one of lifestyle-related diseases and is a disease that accompanies various complications as the disease progresses.
  • Diabetes treatment methods include diet therapy, exercise therapy, and drug therapy. All the treatment methods are performed mainly for improving blood glucose level.
  • the improvement of blood glucose level is used as a guideline for the treatment of diabetes in order to prevent the onset and exacerbation of various diabetic complications caused by hyperglycemia, particularly postprandial hyperglycemia, as well as improving the symptoms of diabetes.
  • diabetic complications such as diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, diabetic foot lesions, diabetic macroangiopathy, hypertension, and hyperlipidemia are known. .
  • diabetic patients often receive drug treatments in combination with therapeutic agents for these diseases and therapeutic agents for diabetes.
  • patient groups from males and females to a wide range of age groups from children to the elderly, and pregnant women. Therefore, as a therapeutic agent for diabetes, a drug having high safety and a characteristic that can be used in combination with multiple drugs is desirable.
  • sulfonylurea drugs which is the first choice drug, has a problem of so-called secondary ineffectiveness and hypoglycemia, in which blood sugar levels gradually increase in many patients after long-term use.
  • biguanide drugs have serious side effects such as lactose acidosis, ⁇ -glucosidase inhibitors have severe liver damage, and thiazolidine insulin sensitivity improving drugs have side effects such as edema in addition to liver dysfunction.
  • refer nonpatent literature 1 Therefore, it is desired to develop a new drug that eliminates the drawbacks of these existing drugs.
  • SGLT sodium-dependent glucose transporter
  • the subtypes include SGLT1, SGLT2, and the like.
  • SGLT2 is expressed specifically in the proximal tubule of the kidney and has been shown to play a major role in glucose reabsorption in raw urine (see, for example, Non-Patent Document 2).
  • SGLT1 is known to be expressed in other organs of the kidney.
  • SGLT2 inhibition as a drug that can reduce blood glucose level to normal blood glucose level by specifically suppressing the reabsorption of glucose in the body in the kidney and increasing the amount of glucose excreted in urine. Drugs are especially expected.
  • a decrease in blood glucose level and recovery of insulin secretion ability have been reported (for example, Non-Patent Document 2).
  • SGLT inhibitor a natural product-derived phlorizin, which is one of ⁇ -D-glucopyranoside derivatives, is the first report.
  • Various derivatives of phlorizin have been studied.
  • phlorizin derivatives were found to be hydrolyzed into aglycone and sugar by ⁇ -glucosidase present in the digestive tract when administered orally.
  • the SGLT inhibitory activity of the phlorizin derivative disappears after oral administration.
  • attempts have been made to produce prodrugs of phlorizin derivatives (see, for example, Non-Patent Document 3).
  • phloretin an aglycone of phlorizin, inhibits the facilitated diffusion sugar transporter (GLUT), thereby inhibiting glucose uptake at the blood-brain barrier (so-called BBB) and lowering the glucose concentration in the brain.
  • BBB blood-brain barrier
  • SGLT2 inhibitors having various structures have been developed.
  • ⁇ -D-glucopyranoside derivatives are disclosed.
  • a compound represented by the following formula is known (for example, see Patent Document 1).
  • R 1 when Q 1 is a methyl group, R 1 is a hydrogen atom or an isopropyl group, R 2 is an isopropyloxy group, and when Q 1 is a trifluoromethyl group, R 1 is hydrogen.
  • the atom, R 2 represents a methoxy group.
  • a biologic superior to the parent compound can be obtained by introducing a modifying group: R 2 OCOO— group into the 6-position of the sugar moiety as a prodrug as shown in the following formula. It is known that availability (BA) can be obtained (see, for example, Patent Document 2).
  • the ⁇ -D-glucopyranoside derivative SGLT2 inhibitor is orally or parenterally administered as the parent compound itself or a prodrug.
  • the ⁇ -D-glucopyranoside derivative has various pharmacological properties as well as pharmacological activity of each compound such as the parent compound, its prodrug and aglycone, such as various pharmacokinetic parameters, drug interaction, safety, It is necessary to control stability, physicochemical properties, etc.
  • An object of the present invention is to provide a glucopyranosyloxypyrazole derivative having human SGLT2 inhibitory activity or a prodrug thereof, or a pharmacologically acceptable salt thereof, and a pharmaceutical use thereof.
  • the present inventors have intensively studied to find a compound having human SGLT2 inhibitory activity. As a result, the present inventors have found that a glucopyranosyloxypyrazole derivative having a hydroxyl group at the 5-position alkyl group of pyrazole has a strong human SGLT2 inhibitory activity, thereby achieving the present invention.
  • R A represents the following a) to o): a) a hydrogen atom, b) a C 1-6 alkyl group, c) a C 2-6 alkenyl group, d) a C 2-6 alkynyl group, e) a halo C 1-6 alkyl group, f) hydroxy C 1-6 alkyl group, g) a C 1-6 alkoxy C 1-6 alkyl group, h) a cyano C 1-6 alkyl group, i) a C 3-6 cycloalkyl group, j) Substitutable phenyl group, k) a C 3-6 cycloalkyl C 1-6 alkyl group, l) Substitutable aralkyl group, m) a C 2-6 acyl group, n) a group selected from the group consisting of a substituted phenylcarbonyl group, and o) a C 1-6 alkoxycarbonyl group; R
  • R A is a hydrogen atom, a C 1-6 alkyl group, a C 2-6 alkenyl group, a halo C 1-6 alkyl group, a hydroxy C 2-6 alkyl group, a C 1-6 alkoxy C 1-6 alkyl A group, a substituted phenyl group, a substituted aralkyl group or a C 2-6 acyl group;
  • R B is a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group;
  • R A is a hydrogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy C 1-6 alkyl group or a C 2-6 acyl group
  • R B is a C 1-6 alkyl group or a C 1-6 alkoxy group
  • R C and R D are hydrogen atoms
  • R A is a hydrogen atom, a C 1-6 alkyl group or a C 2-6 acyl group; The compound or a pharmaceutically acceptable salt thereof according to [3], wherein R B is a C 1-6 alkoxy group.
  • the compound is 3- ( ⁇ -D-glucopyranosyloxy) -5-hydroxymethyl-4- (4-isopropoxybenzyl) -1H-pyrazole, or 3- ( ⁇ -D-glucopyranosyloxy) -5
  • the compound according to [5] or a drug thereof, wherein the compound is 3- ( ⁇ -D-glucopyranosyloxy) -5-hydroxymethyl-4- (4-isopropoxybenzyl) -1H-pyrazole Physically acceptable salt.
  • PG 1 , PG 2 and PG 3 are independently the following a) to d): a) a hydrogen atom, b) a C 2-6 acyl group, a group selected from the group consisting of c) a C 1-6 alkoxycarbonyl group, and d) a substituted aralkyloxycarbonyl group;
  • R A1 represents the following e) to t): e) a hydrogen atom, f) a C 1-6 alkyl group, g) a C 2-6 alkenyl group, h) a C 2-6 alkynyl group, i) a halo C 1-6 alkyl group, j) a hydroxy C 1-6 alkyl group, k) a C 1-6 alkoxy C 1-6 alkyl group, l) a cyano C 1-6 alkyl group, m) a C 3-6 cycloalkyl group, n) Substitutable phenyl group,
  • PG 1 is a C 2-6 acyl group or a C 1-6 alkoxycarbonyl group
  • PG 2 is a hydrogen atom, a C 2-6 acyl group or a C 1-6 alkoxycarbonyl group
  • R A1 is a hydrogen atom, a C 1-6 alkyl group or a C 2-6 acyl group
  • R B is a C 1-6 alkoxy group
  • R C and R D are hydrogen atoms
  • the SGLT2 inhibitor according to [14] which is administered in combination with a therapeutic agent for diabetes having a mechanism of action different from that of SGLT2 inhibition, a therapeutic agent for diabetes-related diseases, or a therapeutic agent for diabetic complications.
  • the SGLT2 inhibitor according to [15] which is administered as a combination drug.
  • a therapeutic agent for diabetes, a therapeutic agent for diabetes-related diseases or a therapeutic agent for diabetic complications having an action mechanism different from that of SGLT2 inhibition is (a) to (f): (A) an ⁇ -glucosidase inhibitor, (B) biguanide drugs, (C) a sulfonylurea drug, (D) a fast-acting insulin secretagogue, (e) a thiazolidine-based insulin sensitivity-improving drug, and (f) one or more drugs selected from the group consisting of DPPIV inhibitors, SGLT2 inhibition according to [15] medicine.
  • [18] Use of the compound of [1] or a prodrug thereof, or a pharmacologically acceptable salt thereof for the manufacture of a pharmaceutical composition for the prevention or treatment of diseases caused by hyperglycemia.
  • a pharmaceutical composition comprising the compound according to [1] to [13] or a prodrug thereof, or a pharmacologically acceptable salt thereof as an active ingredient.
  • the pharmaceutical composition according to [19] which is administered in combination with a therapeutic agent for diabetes, a therapeutic agent for diabetes-related diseases or a therapeutic agent for diabetic complications having an action mechanism different from that of SGLT2 inhibition.
  • the pharmaceutical composition according to [20] which is administered as a combination drug.
  • a therapeutic agent for diabetes, a therapeutic agent for diabetes-related diseases or a therapeutic agent for diabetic complications having an action mechanism different from that of SGLT2 inhibition is (a) to (f): (A) an ⁇ -glucosidase inhibitor, (B) biguanide drugs, (C) a sulfonylurea drug, (D) a fast-acting insulin secretagogue, (e) a thiazolidine insulin sensitizer, and (f) one or more drugs selected from the group consisting of DPPIV inhibitors Pharmaceutical composition.
  • the compound of the present invention showed a strong SGLT2 inhibitory activity in, for example, measurement of methyl- ⁇ -D-glucopyranoside (hereinafter sometimes referred to as ⁇ -MG) uptake inhibition. Therefore, the glucopyranosyloxypyrazole derivative and the prodrug thereof of the present invention can be used for the treatment or prevention of diabetes based on SGLT2 inhibitory activity.
  • ⁇ -MG methyl- ⁇ -D-glucopyranoside
  • Halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Preferably it is a fluorine atom or a chlorine atom. More preferably, it is a fluorine atom.
  • C 1-6 alkyl group means an optionally branched alkyl group having 1 to 6 carbon atoms.
  • examples include methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group and the like.
  • they are a methyl group, an ethyl group, a propyl group or an isopropyl group. More preferably, it is an isopropyl group.
  • the “C 2-6 alkenyl group” means a linear or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms having at least one double bond.
  • vinyl group, allyl group, 1-propenyl group, isopropenyl group, 2-methyl-1-propenyl and the like can be mentioned.
  • C 2-6 alkynyl group means a linear or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms having at least one triple bond. Examples include ethynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group and the like.
  • halo C 1-6 alkyl group means a C 1-6 alkyl group substituted with 1 to 3 same or different halogen atoms.
  • trifluoromethyl group 2-chloroethyl group, 2-fluoroethyl group, 2,2-difluoroethyl group, 1,1-difluoroethyl group, 1,2-difluoroethyl group, 2,2,2-trifluoro Ethyl group, 2,2,2-trichloroethyl, 3-fluoropropyl group, 2-fluoropropyl group, 2-fluoropropyl group, 3,3-difluoropropyl group, 2,2-difluoropropyl group, 1,1- A difluoropropyl group etc. are mentioned.
  • “Hydroxy C 1-6 alkyl group” means a C 1-6 alkyl group substituted with a hydroxyl group. Examples thereof include a hydroxymethyl group, 2-hydroxyethyl group, 1-hydroxyethyl group, 3-hydroxypropyl group, 2-hydroxypropyl group, 1-hydroxypropyl group, 4-hydroxybutyl group and the like. A 2-hydroxyethyl group, a 3-hydroxypropyl group, a 2-hydroxypropyl group, or a 4-hydroxybutyl group is preferable. More preferred is a 2-hydroxyethyl group or a 3-hydroxypropyl group.
  • “Hydroxy C 2-6 alkyl group” means an optionally branched alkyl group having 2 to 6 carbon atoms, which is substituted with a hydroxyl group. Examples thereof include 2-hydroxyethyl group, 1-hydroxyethyl group, 3-hydroxypropyl group, 2-hydroxypropyl group, 1-hydroxypropyl group, 4-hydroxybutyl group and the like. A 2-hydroxyethyl group, a 3-hydroxypropyl group, a 2-hydroxypropyl group, or a 4-hydroxybutyl group is preferable. More preferred is a 2-hydroxyethyl group or a 3-hydroxypropyl group.
  • the “C 1-6 alkoxy group” means an optionally branched alkoxy group having 1 to 6 carbon atoms. Examples include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, hexyloxy group and the like.
  • C 1-6 alkoxy C 1-6 alkyl group means a C 1-6 alkyl group substituted with a C 1-6 alkoxy group.
  • methoxymethyl group, ethoxymethyl group, propoxymethyl group, isopropoxymethyl group, butoxymethyl group, tert-butoxymethyl group, 2-methoxyethyl group, 2-ethoxyethyl group, 3-methoxypropyl group, 3-ethoxy A propyl group etc. are mentioned.
  • cyano C 1-6 alkyl group means a C 1-6 alkyl group substituted with a cyano group. Examples include cyanomethyl group, 2-cyanoethyl group, 1-cyanoethyl group, 3-cyanopropyl group, 2-cyanopropyl group, 1-cyanopropyl group, 1-cyano-1-methylethyl group and the like.
  • C 2-6 acyl group means an optionally branched acyl group having 2 to 6 carbon atoms.
  • acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, pivaloyl group and the like can be mentioned.
  • the “C 3-6 cycloalkyl group” means a monocyclic saturated alicyclic hydrocarbon group having 3 to 6 carbon atoms.
  • a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group can be exemplified.
  • substituted phenyl group means a phenyl group which is unsubstituted or substituted with 1 to 5 groups independently selected from the following substituent group ⁇ .
  • it is a phenyl group which is unsubstituted or substituted by 1 to 2 groups independently selected from the following substituent group ⁇ .
  • (C 1-6 alkyl) NH— means a mono-substituted amino group substituted with a C 1-6 alkyl group. Examples thereof include a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a butylamino group, an isobutylamino group, a sec-butylamino group, a pentylamino group, and a hexylamino group.
  • (C 1-6 alkyl) 2 N— means a disubstituted amino group substituted by two identical or different C 1-6 alkyl groups. Examples thereof include a dimethylamino group, a diethylamino group, a dipropylamino group, a di (isopropyl) amino group, a dibutylamino group, a diisobutylamino group, a di (sec-butyl) amino group, a dipentylamino group, and a dihexylamino group.
  • C 2-5 alicyclic amino group examples include the following:
  • C 3-6 cycloalkyl C 1-6 alkyl group means a C 1-6 alkyl group substituted with a C 3-6 cycloalkyl group. Examples thereof include a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, and a cyclohexylethyl group.
  • the “substitutable aralkyl group” is C substituted with an aromatic hydrocarbon having 6 to 10 carbon atoms which may be substituted with 1 to 5 groups independently selected from the above-mentioned substituent ⁇ group.
  • a substituted benzyl group is preferable.
  • “Substituteable benzyl group” means a benzyl group which may be substituted with 1 to 5 groups independently selected from the above-mentioned substituent ⁇ group. Preferably, it is a benzyl group which is unsubstituted or substituted with 1 to 2 groups independently selected from the substituent ⁇ group. More preferably, it is a benzyl group which is unsubstituted or substituted with one group independently selected from the above-mentioned substituent group ⁇ .
  • C 1-6 alkoxycarbonyl group means a carbonyl group substituted with a C 1-6 alkoxy group.
  • Substituted phenylcarbonyl group means a carbonyl group substituted with a substituted phenyl group. For example, a benzoyl group etc. are mentioned.
  • “Substituteable aralkyloxycarbonyl group” means an oxycarbonyl group substituted with a replaceable aralkyl group.
  • substituted benzyloxycarbonyl group, phenethyloxycarbonyl group, 1-phenylethyloxycarbonyl group, 3-phenylpropyloxycarbonyl group, 2-phenylpropyloxycarbonyl group, 1-phenylpropyloxycarbonyl group, 1-methyl- Examples include 2-phenylethyloxycarbonyl group.
  • a substituted benzyloxycarbonyl group is preferable.
  • trisubstituted silyl group examples include trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, dimethylisopropylsilyl group, dimethyltexylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, tribenzylsilyl group And di-tert-butylmethylsilyl group.
  • a “prodrug” is a compound in which the hydrogen atom on the oxygen atom or nitrogen atom of the parent compound is substituted with a pharmacologically acceptable modifying group, and the modifying group is cleaved by an enzyme or the like in vivo. Means a compound that is converted to the biologically active parent compound. Prodrugs are imparted with properties such as improved stability and improved gastrointestinal absorbability compared to the parent compound. When a prodrug is administered, it can be expected that desirable blood dynamics can be obtained as compared with the case where a parent compound is administered.
  • a compound represented by the general formula (1) can be used.
  • 3- ( ⁇ -D-glucopyranosyloxy) -5-hydroxymethyl-4- (4-isopropoxybenzyl) -1H-pyrazole 3- ( ⁇ -D-glucopyranosyloxy)- 5-hydroxymethyl-4- (4-isopropoxybenzyl) -1-isopropylpyrazole.
  • Examples of pharmacologically acceptable modifying groups that can be used for prodrugs include “Monthly Pharmacy Clinical Pharmacokinetics for Proper Use of Drugs”, March 2000 Special Issue, Vol. 42, No. 4, p. . 671-678 and “New Drug Delivery System”, issued by CMC Co., Ltd., January 31, 2000, p. And groups described in 123-135.
  • Examples of the pharmacologically acceptable modifying group for converting the glucopyranosyloxypyrazole derivative of the present invention into a prodrug include C 2-6 acyl group, C 1-6 alkoxycarbonyl group, C 3-6 cycloalkyl C A 1-6 alkyl group, a substituted aralkyloxycarbonyl group and the like can be mentioned.
  • a preferred embodiment of the present invention is a compound represented by the following general formula (1) (hereinafter sometimes abbreviated as compound (1) of the present invention) or a prodrug thereof, or a pharmaceutically acceptable salt thereof. It is.
  • R A represents the following a) to o): a) a hydrogen atom, b) a C 1-6 alkyl group, c) a C 2-6 alkenyl group, d) a C 2-6 alkynyl group, e) a halo C 1-6 alkyl group, f) hydroxy C 1-6 alkyl group, g) a C 1-6 alkoxy C 1-6 alkyl group, h) a cyano C 1-6 alkyl group, i) a C 3-6 cycloalkyl group, j) Substitutable phenyl group, k) a C 3-6 cycloalkyl C 1-6 alkyl group, l) Substitutable aralkyl group, m) a C 2-6 acyl group, n) a group selected from the group consisting of a substituted phenylcarbonyl group, and o) a C 1-6 alkoxycarbonyl group; R
  • R A is preferably a hydrogen atom or a C 1-6 alkyl group.
  • R B is preferably a fluorine atom, a methyl group, an ethyl group, a methoxy group, an ethoxy group or an isopropoxy group.
  • R C is preferably a hydrogen atom, a halogen atom, a methyl group or a methoxy group. More preferably, they are a hydrogen atom, a fluorine atom, a chlorine atom, or a methyl group. More preferably, they are a hydrogen atom or a fluorine atom.
  • R D is preferably a hydrogen atom, a halogen atom, a methyl group or a methoxy group. More preferably, they are a hydrogen atom, a fluorine atom, a chlorine atom, or a methyl group. More preferably, they are a hydrogen atom or a fluorine atom. More preferably, it is a hydrogen atom.
  • n is preferably an integer of 1 or 2. More preferably, 1.
  • a preferred embodiment of the compound (1) of the present invention or a pharmaceutically acceptable salt thereof is a compound comprising a combination of preferred substituents described in (1-1) to (1-5).
  • R A is a hydrogen atom or an isopropyl group
  • R B is more preferably a fluorine atom, a methyl group, an ethyl group, a methoxy group, an ethoxy group or an isopropoxy group
  • R C is a hydrogen atom or a fluorine atom
  • R D is a hydrogen atom or a fluorine atom
  • n is 1, a compound or a pharmacologically acceptable salt thereof.
  • a preferred embodiment of the present invention is a compound represented by the following general formula (2) (hereinafter sometimes abbreviated as prodrug (2) of the present invention) or a pharmacologically acceptable salt thereof.
  • PG 1 , PG 2 and PG 3 are independently the following a) to d): a) a hydrogen atom, b) a C 2-6 acyl group, a group selected from the group consisting of c) a C 1-6 alkoxycarbonyl group, and d) a substituted aralkyloxycarbonyl group;
  • R A1 represents the following e) to s): e) a C 1-6 alkyl group, f) a C 2-6 alkenyl group, g) a C 2-6 alkynyl group, h) a halo C 1-6 alkyl group, i) a hydroxy C 1-6 alkyl group, j) C 1-6 alkoxy C 1-6 alkyl group, k) a cyano C 1-6 alkyl group, l) a C 3-6 cycloalkyl group, m) Substitutable phenyl group, n) a C 3-6 cyclo
  • R A1 is preferably a C 1-6 alkyl group, a C 1-6 alkoxy C 1-6 alkyl group, a substituted aralkyl group, a C 2-6 acyl group, a C 1-6 alkoxycarbonyl group Or a substituted aralkyloxycarbonyl group.
  • R B is preferably a fluorine atom, a methyl group, an ethyl group, a methoxy group, an ethoxy group or an isopropoxy group.
  • R C is preferably a hydrogen atom, a halogen atom, a methyl group or a methoxy group. More preferably, they are a hydrogen atom, a fluorine atom, a chlorine atom, or a methyl group. More preferably, they are a hydrogen atom or a fluorine atom. More preferably, it is a hydrogen atom.
  • R D is preferably a hydrogen atom, a halogen atom, a methyl group or a methoxy group. More preferably, they are a hydrogen atom, a fluorine atom, a chlorine atom, or a methyl group. More preferably, they are a hydrogen atom or a fluorine atom.
  • n is preferably an integer of 1 or 2. More preferably, 1.
  • PG 1 is preferably a C 2-6 acyl group, a C 1-6 alkoxycarbonyl group or a substituted benzyloxycarbonyl group. More preferably, they are acetyl group, propionyl group, pivaloyl group, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group or benzyloxycarbonyl group.
  • PG 2 is preferably a hydrogen atom, a C 2-6 acyl group, a C 1-6 alkoxycarbonyl group or a substituted benzyloxycarbonyl group.
  • PG 3 is preferably a hydrogen atom, a C 2-6 acyl group, a C 1-6 alkoxycarbonyl group or a substituted benzyloxycarbonyl group. More preferably, they are a hydrogen atom, an acetyl group, a propionyl group, a pivaloyl group or an ethoxycarbonyl group. More preferably, it is a hydrogen atom.
  • a preferred embodiment of prodrug (2) or a pharmacologically acceptable salt thereof is a compound comprising a combination of preferred substituents described in (2-1) to (2-8).
  • R A1 is an isopropyl group
  • R B is a fluorine atom, a methyl group, an ethyl group, a methoxy group, an ethoxy group or an isopropoxy group
  • R C is a hydrogen atom or a fluorine atom
  • R D is a hydrogen atom or a fluorine atom
  • n is 1
  • PG 1 is a C 2-6 acyl group, a C 1-6 alkoxycarbonyl group or a benzyloxycarbonyl group
  • PG 2 is a hydrogen atom, a C 2-6 acyl group, a C 1-6 alkoxycarbonyl group or a benzyloxycarbonyl group
  • PG 3 is a hydrogen atom, a C 2-6 acyl group, a C 1-6 alkoxycarbonyl group or a benzyloxycarbonyl group, a prodrug or a pharmaceutically acceptable salt thereof
  • Embodiment 2-2 A more preferred embodiment of Embodiment 2-1 is: PG 1 is a C 1-6 alkoxycarbonyl group; PG 2 is a hydrogen atom or a C 1-6 alkoxycarbonyl group; PG 3 is a prodrug or a pharmacologically acceptable salt thereof, which is a hydrogen atom.
  • Embodiment 2-3 Another preferred embodiment of embodiment 2-1 is: PG 1 , PG 2 and PG 3 are a prodrug or a pharmacologically acceptable salt thereof, wherein C 2-6 acyl group or C 1-6 alkoxycarbonyl group.
  • “Pharmaceutically acceptable salt” means a pharmaceutically acceptable acid addition salt with a non-toxic acid or a salt with a non-toxic base.
  • Such acid addition salts include acid addition salts of mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, adipic acid, citric acid, fumaric acid, maleic acid. Acid, oleic acid, lactic acid, stearic acid, succinic acid, tartaric acid, propionic acid, butyric acid, oxalic acid, malonic acid, malic acid, carbonic acid, glutamic acid, aspartic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, adipic acid, citric acid, fumaric acid, maleic acid.
  • Acid addition salts with organic acids alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, etc. Can be mentioned.
  • salts with bases examples include 2-aminoethanol, piperidine, morpholine, pyrrolidine, N-methyl-D-glucamine, N, N′-dibenzylethylenediamine, tris (hydroxymethyl) aminomethane, arginine, and lysine.
  • a salt with an organic base, a salt with an inorganic salt such as a sodium salt, a potassium salt, a calcium salt, or a magnesium salt can be given.
  • the compound of the present invention or a prodrug thereof, or a pharmacologically acceptable salt thereof may exist as a hydrate or a solvate. Any hydrates and solvates formed by the compounds of the present invention or prodrugs thereof, or pharmaceutically acceptable salts thereof are all included in the scope of the present invention.
  • Solvents that can form solvates include methanol, ethanol, isopropanol, acetone, ethyl acetate, diisopropyl ether, and the like.
  • the compound of the present invention or a prodrug thereof, or a pharmacologically acceptable salt thereof includes stereoisomers such as optical isomers and geometric isomers.
  • an optical isomer of the prodrug or pharmacologically acceptable salt thereof may have any configuration of R configuration or S configuration at each asymmetric carbon atom.
  • any optical isomer is included in the present invention, and a mixture of these optical isomers is also included.
  • a racemate consisting of an equal amount of each optical isomer in a mixture of optically active substances is also included in the scope of the present invention.
  • the compound of the present invention or a prodrug thereof, or a pharmaceutically acceptable salt thereof is a racemic solid or crystal, a racemate, a racemic mixture and a racemic solid solution are also included in the scope of the present invention.
  • the present invention includes any of the geometric isomers.
  • the present invention encompasses any of the tautomers.
  • SGLT2 inhibition means inhibition of the glucose transport ability of sodium-dependent glucose cotransporter 2 (SGLT2) relating to glucose reabsorption.
  • SGLT2 inhibition suppresses sugar reabsorption from the kidney into the blood in the kidney. As a result, excess sugar in the blood is excreted out of the body as urine, so that hyperglycemia can be improved without imposing a load on the pancreatic ⁇ cells.
  • SGLT2 inhibitory activity can be evaluated by measuring inhibition of methyl- ⁇ -D-glucopyranoside uptake into human SGLT2 cells.
  • the inhibitory activity of the compound (1) of the present invention or a pharmacologically acceptable salt thereof can be confirmed, for example, by measuring according to the method described in Test Example 2 of International Publication No. 01/16147.
  • the inhibitory activity of the prodrug (2) of the present invention or a pharmacologically acceptable salt thereof can be confirmed, for example, by measuring according to the method described in Test Example 3 of WO 02/053573.
  • R A of compound (1) of the present invention is a hydrogen atom
  • compound (1) of the present invention can be produced as compound (H) by the method shown in Scheme 1.
  • R A represents a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a halo C 1-6 alkyl group, a hydroxy C 2-6 alkyl group, C 1 -6 alkoxy C 1-6 alkyl group, cyano C 1-6 alkyl group, C 3-6 cycloalkyl group, substituted phenyl group, C 3-6 cycloalkyl C 1-6 alkyl group, substituted aralkyl group, C
  • the compound (1) of the present invention can be produced as the compound (L) by the method shown in Scheme 2.
  • the prodrug (2) of the present invention can be prepared by the method shown in Schemes 1 and 2 with the protecting group in the compounds (G), (I), (J) and (K). Instead, it can be produced by substituting with a pharmacologically acceptable modifying group.
  • Each process in each scheme may be carried out by combining multistage reactions, and a plurality of processes that can be usually selected by those skilled in the art may be combined.
  • a protective group when required depending on the type of functional group, it can be carried out by appropriately combining introduction and removal operations according to a conventional method.
  • Examples of the type, introduction and removal of the protecting group include the methods described in “Gene's Protective Groups in Organic Synthesis”, fourth edition, Wiley-Interscience, edited by Greene & Wuts.
  • G 1 is an ⁇ -D-glucopyranosyl group having PG 1 as a hydroxyl protecting group
  • X 1 is a halogen atom, tosyl group or mesyl group
  • G 11 is PG 1 having a hydroxyl protecting group.
  • ⁇ -D-glucopyranosyl group, G—O— represents a ⁇ -D-glucopyranosyloxy group
  • R B , R C , R D , PG 1 and n are as defined above, provided that ⁇ -D-glucosyl group hydroxyl group and pyrazole 5-position hydroxyl group may be different.
  • Compound (C) can be produced by dehydration of compound (A) and the aldehyde represented by formula (B) in the presence or absence of an acid catalyst.
  • the acid catalyst include hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, trifluoroacetic acid and the like.
  • the solvent include tetrahydrofuran, methanol, ethanol, N, N-dimethylformamide, acetonitrile, water, a mixed solvent thereof and the like.
  • the reaction temperature is usually from 0 ° C. to reflux temperature, and the reaction time is usually from 1 to 16 hours, although it varies depending on the raw material used, solvent, reaction temperature and the like.
  • Compound (A) may be a commercially available product or a method described in Tetrahedron Letters, Vol. 32, p. 3063-3066 (1991) or Canadian Journal of Chemistry, 70, p. 147-1445 (1992). Or a method according to the method.
  • Process 2 Compound (D) can be produced by reducing compound (C).
  • Compound (D) can be produced by reducing compound (C) with triethylsilane or the like in an organic acid such as trifluoroacetic acid.
  • the reaction temperature is usually from 0 ° C. to reflux temperature, and the reaction time is usually from 0.5 to 24 hours, although it varies depending on the raw material used, solvent, catalyst, reaction temperature and the like.
  • Compound (D) can be produced by reducing compound (C) in the presence of a metal catalyst in a solvent under a hydrogen atmosphere.
  • a metal catalyst include palladium-carbon, palladium black, palladium hydroxide and the like.
  • the solvent include alcohol solvents such as methanol and ethanol, ester solvents such as ethyl acetate, ether solvents such as tetrahydrofuran, mixed solvents thereof and the like.
  • the pressure is usually normal pressure to 0.5 MPa
  • the reaction temperature is usually 0 ° C. to reflux temperature
  • the reaction time varies depending on the raw material, solvent, catalyst, reaction temperature, etc., but usually 0.5 to 24 hours.
  • Compound (D) can be produced by reducing compound (C) in a solvent using a borane hydride reducing agent.
  • the borane hydride reducing agent include sodium borohydride, sodium cyanoborohydride and the like.
  • the solvent include ether solvents such as tetrahydrofuran, water, and mixed solvents thereof.
  • the reaction temperature is usually from 0 ° C. to reflux temperature, and the reaction time is usually from 0.5 to 24 hours, although it varies depending on the raw material used, solvent, catalyst, reaction temperature and the like.
  • Compound (E) can be produced by condensing compound (D) with hydrazine or hydrazine monohydrate in a solvent.
  • the solvent include methanol, ethanol, toluene, tetrahydrofuran, N, N-dimethylformamide, acetonitrile, a mixed solvent thereof and the like.
  • the reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 1 hour to 24 hours, although it varies depending on the raw material used, solvent, reaction temperature and the like.
  • Compound (F) can be produced by protecting the hydroxyl group of compound (E) and the nitrogen atom of pyrazole by using conditions for introducing a protecting group that can be usually employed by those skilled in the art. For example, it can be carried out by the method described in “Green's Protective Groups in Organic Synthesis”, edited by Greene & Wuts, fourth edition, Wiley-Interscience, p.16-366, p.696-926.
  • the introduction of the protective group in this step can be performed simultaneously or stepwise by protecting the hydroxyl group and protecting the pyrazole on the nitrogen atom.
  • Process 5 Compound (G) can be produced by the following glycosylation reaction of compound (F).
  • Compound (G) can be produced by glycosylation of compound (F) using bromo- ⁇ -D-glucose having a protecting group in a solvent in the presence of a base such as potassium carbonate.
  • a base such as potassium carbonate.
  • the solvent include acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide and the like.
  • the reaction temperature is usually room temperature to reflux temperature.
  • the reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 1 hour to 1 day.
  • Compound (G) can be produced by glycosylating compound (F) using bromo- ⁇ -D-glucose having a protecting group in the presence of a base such as silver carbonate in a solvent.
  • a base such as silver carbonate
  • the solvent include tetrahydrofuran, toluene, ethyl acetate, acetonitrile, methylene chloride and the like.
  • the reaction temperature is usually room temperature to reflux temperature.
  • the reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 1 hour to 1 day.
  • Compound (G) is a glycosylated compound (F) using bromo- ⁇ -D-glucose having a protecting group in an organic solvent-water two-phase solvent using an inorganic base and a phase transfer catalyst.
  • inorganic base include sodium hydroxide, potassium hydroxide, potassium carbonate and the like.
  • phase transfer catalyst include benzyltri (n-butyl) ammonium bromide, tetra (n-butyl) ammonium hydrogensulfate, and the like.
  • the organic solvent include methylene chloride, toluene, benzotrifluoride and the like.
  • the reaction temperature is usually from 0 ° C. to reflux temperature, and the reaction time is usually from 1 to 24 hours, although it varies depending on the raw material used, solvent, reaction temperature and the like.
  • Step 6 Compound (H) can be produced by deprotecting the protecting group of compound (G).
  • the deprotection of the protective group on the hydroxyl group of compound (G) and the nitrogen atom of pyrazole can be carried out using conditions for removing the protective group that can be usually employed by those skilled in the art.
  • various protecting groups for example, the methods described in “Green's Protective Groups in Organic Synthesis”, fourth edition, Wiley-Interscience, p. 16-366, p. 696-926, edited by Greene & Wuts. be able to.
  • Method 1 When the protecting group of compound (G) is an acyl group, compound (H) can be produced by hydrolysis of compound (G).
  • the acyl group include an acetyl group, an isobutyryl group, a pivaloyl group, and a benzoyl group.
  • the base include sodium hydroxide and sodium ethoxide.
  • the solvent include methanol, ethanol, tetrahydrofuran, water, a mixed solvent thereof and the like.
  • the reaction temperature is usually from 0 ° C. to room temperature, and the reaction time is usually from 30 minutes to 6 hours, although it varies depending on the raw material used, solvent, reaction temperature and the like.
  • compound (H) can be produced by hydrogenolysis. It can be produced by stirring the compound (G) in a solvent at normal pressure or under pressure under a hydrogen atmosphere.
  • the solvent include alcohol solvents such as methanol or ethanol, ester solvents such as ethyl acetate, ether solvents such as tetrahydrofuran, acetic acid, and mixed solvents thereof.
  • the catalyst include palladium.
  • the pressure is usually under a pressure of 0.1 to 0.5 MPa
  • the reaction temperature is usually from 0 ° C. to the reflux temperature
  • the reaction time varies depending on the raw material used, solvent, catalyst, pressure, reaction temperature, etc. .5-24 hours.
  • the deprotection in this step can be performed simultaneously or stepwise by deprotection of the protective group of the hydroxyl group and deprotection of the protective group on the nitrogen atom of pyrazole.
  • Step 7 Compound (I) can be produced by glycosylating compound (E) according to method 2) and method 3) of step 5.
  • Process 8 Compound (H) can be produced by deprotecting the protecting group of compound (I) according to the method of Step 6.
  • G 2 —O— is a ⁇ -D-glucopyranosyloxy group having an acyl group such as isobutyryl group, pivaloyl group, benzoyl group, etc., and a protecting group such as benzyl group or trisubstituted silyl group at the 6-position.
  • R A1 is a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a halo C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, a C 1-6 alkoxy C 1- 6 alkyl group, cyano C 1-6 alkyl group, C 3-6 cycloalkyl group, substituted phenyl group, C 3-6 cycloalkyl C 1-6 alkyl group, substituted aralkyl group, C 2-6 acyl group, a substitutable phenyl group or a C 1-6 alkoxycarbonyl group, R B represents a hydrogen atom, a halogen atom, C 1-6 alkyl groups, C 2-6 alkenyl groups, C 2-6 alkynyl groups, C -6 alkoxy group, halo C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, C 1-6 alkoxy C 1-6 alkyl group,
  • Step 9 Compound (J) can be produced by protecting the hydroxyl group of compound (H) using conditions for introducing a protecting group that can be usually employed by those skilled in the art. For example, it can be performed by the method described in “Green's Protective Groups in Organic Synthesis”, edited by Greene & Wuts, fourth edition, Wiley-Interscience, p. 16-366.
  • the hydroxyl protecting group include acyl groups such as acetyl group, pivaloyl group and benzoyl group, carbonates such as benzyloxycarbonyl group, or trisubstituted silyl groups such as trimethylsilyl group, triisopropylsilyl group and tert-butyldimethylsilyl group.
  • a trisubstituted silyl group is preferable, and a trimethylsilyl group, a triisopropylsilyl group, and a tert-butyldimethylsilyl group are more preferable.
  • Step 10 Compound (K) was prepared by using an alkylating agent represented by the general formula (RE2), in the presence of a base, in a solvent, and optionally in the presence of a catalytic amount of sodium iodide.
  • a base organic bases such as triethylamine, N, N-diisopropylethylamine, potassium tert-butoxide, lithium diisopropylamide, inorganic bases such as potassium carbonate, cesium carbonate, sodium hydride, sodium hydroxide, and the like can be used.
  • the solvent examples include N, N-dimethylformamide, dimethoxyethane, dimethyl sulfoxide, tetrahydrofuran, ethanol, a mixed solvent thereof and the like.
  • the reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 30 minutes to 3 days, although it varies depending on the raw material used, solvent, reaction temperature and the like.
  • Step 11 Compound (L) can be produced by deprotecting compound (K) according to the method described in Step 6.
  • compound (L) can be produced by deprotection using a fluorine ion reagent of compound (K).
  • a fluorine ion reagent of compound (K) As the fluorine ion reagent, hydrogen fluoride, hydrogen fluoride pyridine, tetrabutylammonium fluoride, or the like can be used.
  • the solvent include tetrahydrofuran, acetonitrile, methanol, water, a mixed solvent thereof and the like.
  • the reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 30 minutes to 24 hours, although it varies depending on the raw material used, solvent, reaction temperature and the like.
  • the compound represented by the compounds (1) and (2) that can be produced by the method shown in the above scheme can be converted into a pharmacologically acceptable salt according to a conventional method as necessary.
  • salts include acid addition salts and salts with bases.
  • the scheme shown above is an example of a method for producing the compound of the present invention or a prodrug thereof, or a pharmacologically acceptable salt thereof, or a production intermediate thereof. These can be variously modified into schemes that can be easily understood by those skilled in the art.
  • the compound of the present invention or a prodrug thereof, or a pharmacologically acceptable salt thereof, and an intermediate used for producing the same are isolated and well known to those skilled in the art, if necessary. It can be isolated and purified by purification means such as solvent extraction, crystallization / recrystallization, chromatography, preparative high performance liquid chromatography and the like.
  • composition containing the compound of the present invention or a prodrug thereof, or a pharmacologically acceptable salt thereof
  • the pharmaceutical composition containing the compound of the present invention or a prodrug thereof, or a pharmacologically acceptable salt thereof as an active ingredient may be used in various dosage forms depending on the usage.
  • dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules, injections, solutions, ointments, suppositories, patches, sublinguals, etc. It is administered orally or parenterally.
  • compositions are prepared according to known methods depending on the dosage form, using appropriate excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives, wetting agents. It can be prepared by appropriately mixing or diluting / dissolving with pharmaceutical additives such as emulsifiers, dispersants, stabilizers, and solubilizing agents.
  • pharmaceutical additives such as emulsifiers, dispersants, stabilizers, and solubilizing agents.
  • the respective active ingredients are formulated in the same manner as described above. Can be manufactured.
  • the compound of the present invention or a prodrug thereof, or a pharmacologically acceptable salt thereof can be administered in appropriate combination with at least one drug other than the SGLT2 inhibitor.
  • the drug to be administered in combination is preferably a drug with a mechanism of action different from SGLT2 inhibition.
  • a drug having a mechanism of action different from SGLT2 inhibition means a drug for treating diabetes by an action mechanism other than SGLT2 inhibition.
  • examples of such drugs include anti-diabetic drugs, diabetic-related disease therapeutic drugs, diabetic complication therapeutic agents, and the like.
  • examples thereof include drugs having an action of suppressing absorption of glucose and the like from the gastrointestinal tract, an action of promoting insulin secretion, an action of inhibiting hepatic gluconeogenesis, an action of inhibiting sugar release, and an action of improving peripheral insulin sensitivity.
  • Examples of the drug having “inhibition of absorption of glucose and the like from the digestive tract” other than SGLT2 inhibition include SGLT1 inhibitor, ⁇ -glucosidase inhibitor, biguanide drug and the like.
  • Examples of the drug having “insulin secretion promoting action” include sulfonylurea (SU) drugs, fast-acting insulin secretagogues, DPPIV inhibitors and the like.
  • SU sulfonylurea
  • Examples of the drug having “liver gluconeogenesis inhibitory action” or “sugar release inhibitory action” include thiazolidine insulin sensitizers and sulfonylurea (SU) drugs.
  • Examples of the drug having “peripheral insulin sensitivity improving action” include biguanide drugs, thiazolidine insulin sensitivity improving drugs, sulfonylurea (SU) drugs, and the like.
  • the drug to be administered in combination is preferably a drug selected from the group consisting of an ⁇ -glucosidase inhibitor, a biguanide drug, a sulfonylurea drug, a fast-acting insulin secretagogue, a thiazolidine insulin sensitizer, and a DPPIV inhibitor. More preferably, it is a drug selected from the group consisting of DPPIV inhibitors, biguanides, and ⁇ -glucosidase inhibitors.
  • ⁇ -glucosidase inhibitor examples include acarbose, voglibose, miglitol and the like. Voglibose is preferable.
  • Biguanide drugs include metformin hydrochloride or buformin hydrochloride. Preferably, it is metformin hydrochloride.
  • sulfonylurea (SU) drug examples include tolbutamide, acetohexamide, chlorpropamide, glyclopyramide, glybsol, glibenclamide, gulpizide, gliclazide or glimepiride. Preferred is glibenclamide, glupizide, gliclazide or glimepiride.
  • the “rapid-acting insulin secretagogue” repaglinide, nateglinide, mitiglinide calcium hydrate and the like can be mentioned.
  • it is mitiglinide calcium hydrate.
  • DPPIV inhibitor examples include alogliptin, saxagliptin, sitagliptin, vildagliptin and the like.
  • thiazolidine insulin sensitizer examples include rosiglitazone and pioglitazone.
  • the drugs administered in combination are specifically exemplified as follows, but the contents of the present invention are not limited to these.
  • the present invention includes free forms and other pharmacologically acceptable salts in specific compounds.
  • SGLT1 inhibitor insulin sensitivity enhancer, sugar absorption inhibitor, biguanide drug, insulin secretagogue, insulin preparation, insulin receptor kinase stimulant, dipeptidyl peptidase IV (DPPIV) inhibitor, protein tyrosine phosphatase 1B inhibitor, Glycogen phosphorylase inhibitor, fructose-bisphosphatase inhibitor, hepatic gluconeogenesis inhibitor, glycogen synthase kinase-inhibitor, glucagon-like peptide-1 analog, glucagon-like peptide-1 agonist (GLP1 analog), amylin agonist (amylin analog) ), Aldose reductase inhibitor, protein kinase C inhibitor, ⁇ -aminobutyric acid (GABA) receptor antagonist, sodium channel antagonist, transcription factor NF- ⁇ B inhibitor, lipid peroxidase Inhibitors, insulin-like growth factor-I, epidermal growth factor (EGF), nerve growth factor, hydroxymethylgluta
  • the present invention includes the following 1) to 5): 1) Simultaneous administration with combination drug, 2) As separate formulations, co-administration by the same route of administration, 3) As separate formulations, co-administration by different routes of administration, Any method of administration, including 4) administration at different times by the same route of administration as separate formulations, and 5) administration at different times by different routes of administration as separate formulations is included.
  • the above-mentioned drug administered in combination with the compound of the present invention or a prodrug thereof, or a pharmaceutically acceptable salt thereof is not particularly limited.
  • the compound of the present invention or a prodrug thereof, or a pharmacologically acceptable salt thereof can be administered in combination with one or more kinds of the above drugs as appropriate, thereby providing an additive effect in preventing or treating the above diseases.
  • the above advantageous effects can be obtained.
  • reduce the amount used compared to when administered alone reduce the side effects of drugs other than SGLT2 inhibitors used together, or avoid side effects of drugs other than SGLT2 inhibitors used together Or it can be reduced.
  • the compound of the present invention or a prodrug thereof, or a pharmacologically acceptable salt thereof exhibits potent human SGLT2 inhibitory activity in measuring methyl- ⁇ -D-glucopyranoside uptake inhibitory activity. Therefore, the compound of the present invention can suppress or reduce an excessive increase in blood glucose level. Therefore, the pharmaceutical composition containing the compound of the present invention or a prodrug thereof, or a pharmacologically acceptable salt thereof as an active ingredient can be used as a therapeutic or prophylactic agent for diseases caused by hyperglycemia.
  • the compound of the present invention or a prodrug thereof, or a pharmacologically acceptable salt thereof is a postprandial hyperglycemia inhibitory or normalization, glucose intolerant (IGT), fasting blood glucose abnormal (IFG) or It is also useful for preventing the transition of patients with metabolic syndrome to diabetes. In particular, it is useful for postprandial hyperglycemia suppression or normalization, or for prevention of transition to diabetes in patients with impaired glucose tolerance (IGT) or metabolic syndrome patients with hyperglycemia.
  • Diseases caused by hyperglycemia include diabetes, diabetes-related diseases, diabetic complications, and the like.
  • Diabetes includes type 1 diabetes or type 2 diabetes, gestational diabetes, or borderline, insulin-independent, insulin-dependent diabetes, and the like.
  • the compounds of the invention or prodrugs thereof, or pharmaceutically acceptable salts thereof are preferably used for the treatment or prevention of type 2 diabetes, or borderline, insulin-independent or insulin-dependent conditions. More preferred is type 2 diabetes or borderline or non-insulin dependent diabetes.
  • Diabetes-related diseases include fatty liver, metabolic syndrome, hyperglycemia, insulin resistance, decreased glucose metabolism, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, vascular revascularization Examples include stenosis, ulcerative colitis, obesity, hyperinsulinemia, glucose metabolism disorder, hyperlipidemia, hypercholesterolemia, lipid metabolism disorder, hyperuricemia, gout, hypertension, congestive heart failure, edema, etc. It is done.
  • Diabetic complications includes both acute complications and chronic complications. Acute complications include diabetic coma and infections. Examples of chronic complications include diabetic microangiopathy and diabetic macroangiopathy. The compounds of the present invention or prodrugs thereof, or pharmacologically acceptable salts thereof are preferably used for the treatment or prevention of chronic complications. More preferred is diabetic microangiopathy or diabetic macroangiopathy. Examples of diabetic microangiopathy include diabetic retinopathy, diabetic nephropathy, diabetic neuropathy and the like. Examples of diabetic macroangiopathy include diabetic arteriosclerosis, diabetic foot lesions and periodontal disease.
  • Diabetic coma includes ketoacidosis coma, hyperosmotic hyperglycemia syndrome, and the like.
  • the compound of the present invention or a prodrug thereof, or a pharmacologically acceptable salt thereof is preferably used for the treatment or prevention of hyperosmotic hyperglycemia syndrome.
  • “Infectious diseases” as acute complications of diabetes include pulmonary tuberculosis, urinary tract infections, skin infections and the like.
  • Diabetic retinopathy includes vitiligo, capillary aneurysm, retinal edema, vitreous hemorrhage, retinal detachment, visual impairment, blindness, and the like.
  • Diabetic nephropathy means a pathological condition characterized by increased urinary excretion of albumin, increased blood pressure, and decreased renal function. According to its progress, it is classified into early nephropathy, overt nephropathy, and end stage renal failure.
  • the compound of the present invention or a prodrug thereof, or a pharmaceutically acceptable salt thereof is preferably used for the treatment or prevention of nephropathy at any stage.
  • Diabetic neuropathy includes multiple neuropathy (pervasive symmetry neuropathy) or single neuropathy.
  • Examples of polyneuropathy include sensory / motor nerves and autonomic nerve disorders.
  • Diabetic foot lesions include ringworm, wrinkles, foot ulcers, foot gangrene and the like.
  • Diabetic arteriosclerosis includes coronary arteriosclerosis, cerebrovascular disorder, lower limb obstructive arteriosclerosis and the like. Coronary arteriosclerosis, cerebrovascular disorder or lower limb obstructive arteriosclerosis is preferable.
  • the medicament of the present invention can be administered systemically or locally, orally or parenterally (nasal, pulmonary, intravenous, rectal, subcutaneous, intramuscular, transdermal, etc.).
  • the dose of the compound of the present invention or a prodrug thereof, or a pharmacologically acceptable salt thereof, which is the active ingredient depends on the age, sex, body weight of the patient. It is determined appropriately depending on the disease, the degree of treatment, and the like.
  • an adult (with a body weight of 60 kg) can be appropriately administered once or in several divided doses within a range of about 5 to 1000 mg / body per day.
  • the daily dose is preferably 5 to 100 mg / body.
  • parenteral administration it can be appropriately administered in one or several divided doses in the range of about 0.5 to 300 mg / body per day for adults.
  • the daily dose is preferably 0.5 to 10 mg / body.
  • the dose can be decreased according to the dose of a drug other than the SGLT2 inhibitor.
  • the compound of Example 1 was produced by the method described in Steps 1-1 to 1-5.
  • Step 1-1 3- [1- (4-Isopropyloxyphenyl) methylidene] furan-2,4-dione
  • a catalytic amount of concentrated hydrochloric acid was added to a mixture of tetronic acid (1.6 g) and 4-isopropoxybenzaldehyde (7.8 g), and the mixture was stirred at room temperature for 2 hours. Diethyl ether was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes, and a crystalline solid was collected by filtration. The crystals collected by filtration were washed with diethyl ether and dried under reduced pressure to obtain the title compound (1.6 g).
  • Step 1-5 5-Acetoxymethyl-1-acetyl-4- (4-isopropoxybenzyl) -3- (2,3,4,6-tetra-O-acetyl- ⁇ -D-glucopyranosyloxy) -1H-pyrazole
  • the compound of Example 2 was produced by the method described in Step 2-1.
  • Step 2-1 3- ( ⁇ -D-glucopyranosyloxy) -5-hydroxymethyl-4- (4-isopropoxybenzyl) -1H-pyrazole
  • the compound of Example 3 was produced by the method described in Steps 3-1 to 3-3.
  • Step 3-1 4- (4-Isopropoxybenzyl) -3- (6-O-triisopropylsilyl- ⁇ -D-glucopyranosyloxy) -5-triisopropylsilyloxymethyl-1H-pyrazole
  • Step 3-2 4- (4-Isopropoxybenzyl) -1-isopropyl-3- (6-O-triisopropylsilyl- ⁇ -D-glucopyranosyloxy) -5-triisopropylsilyloxymethylpyrazole
  • Step 3-3 4- (4-Isopropoxybenzyl) -1-isopropyl-3- ( ⁇ -D-glucopyranosyloxy) -5-hydroxymethylpyrazole
  • Example 4-1 3- (6-O-ethoxycarbonyl- ⁇ -D-glucopyranosyloxy) -5-ethoxycarbonyloxymethyl-4- (4-isopropoxybenzyl) -1-isopropylpyrazole
  • Example 4-2 3- (6-O-ethoxycarbonyl- ⁇ -D-glucopyranosyloxy) -5-hydroxymethyl-4- (4-isopropoxybenzyl) -1-isopropylpyrazole
  • the compounds of Examples 4-1 and 4-2 can be produced by the method described in Step 4-1.
  • Test example 1 Human SGLT inhibitory activity confirmation test
  • Human SGLT2 or human SGLT1 expression vectors were introduced into COS-7 cells by the lipofection method (Lipofectamine (registered trademark) 2000: manufactured by Invitrogen).
  • lipofection method Lipofectamine (registered trademark) 2000: manufactured by Invitrogen.
  • COS-7 cells were seeded in a 96-well plate at 5 ⁇ 10 4 cells / 100 ⁇ L / well and allowed to stand at 37 ° C. for 2 hours.
  • 0.3 ⁇ g of human SGLT2 or SGLT1 expression vector and 0.5 mL of Lipofectamine (registered trademark) 2000 were mixed per 50 mL of the medium to prepare a complex solution.
  • This complex solution was added to the COS-7 cells described above at 50 ⁇ L / well, gently stirred and cultured for 2 days.
  • cells stably expressing human SGLT2 or human SGLT1 were selected and subjected to measurement of methyl- ⁇ -D-glucopyranoside ( ⁇ -MG) uptake inhibitory activity.
  • Pretreatment buffer As pretreatment buffer, 140 mM choline chloride, 2 mM potassium chloride, 1 mM calcium chloride, 1 mM magnesium chloride, 10 mM 2- [4- (2-hydroxyethyl) -1-piperazinyl] ethanesulfonic acid, 5 mM Tris A buffer solution of pH 7.4 containing (hydroxymethyl) aminomethane was prepared.
  • Buffer for basal uptake The buffer for basal uptake was prepared by adding 1 mM ⁇ -MG (unlabeled (manufactured by Sigma), label (methyl- ⁇ -D- (U- 14C )) glucopyranoside (GE Health) to the pretreatment buffer. CARE BIO SCIENCE CO., LTD. (Hereinafter abbreviated as [ 14 C] - ⁇ -MG)).
  • the concentration of [ 14 C] - ⁇ -MG was 27.75 kBq / mL (for SGLT1). ) Or 123.3 kBq / mL (for SGLT2).
  • Double Concentration Uptake Buffer For the double concentration uptake buffer, a basic uptake buffer containing sodium chloride instead of choline chloride was prepared at a double concentration.
  • Buffer solution for test compound measurement A test compound is dissolved in dimethyl sulfoxide (DMSO) to prepare a 10 mmol / L solution, which is then appropriately diluted with distilled water to give a concentration of 2 nM, 6 nM, 20 nM, 60 nM, 200 nM, 600 nM, 2 ⁇ M, 6 ⁇ M. 20 ⁇ M, 60 ⁇ M, and 200 ⁇ M test compound solutions were prepared. A test compound solution at each concentration was added to an equal volume of a double concentration uptake buffer to prepare a test compound measurement buffer.
  • DMSO dimethyl sulfoxide
  • Buffer solution for control group As a buffer solution for the control group, a test compound-measuring buffer solution containing no test compound was prepared and used.
  • washing buffer As the washing buffer, a pretreatment buffer containing 10 mM ⁇ -MG (unlabeled) was prepared and used.
  • the compound of the present invention showed a stronger SGLT2 inhibitory activity than SGLT1.
  • Table 1 shows the inhibitory activity against SGLT2 and SGLT1 of representative compounds of the present invention as IC 50 values.
  • Test example 2 Urinary glucose excretion promoting action confirmation test (intravenous administration) The action of promoting urinary glucose excretion by intravenous administration of the compounds of Example 2 and Example 3 in SD rats can be confirmed according to the method described in International Publication No. 01/16147, Test Example 2, Method B).
  • Test example 3 Urinary glucose excretion promoting action confirmation test (subcutaneous administration) The action of promoting the excretion of urinary glucose by subcutaneous administration of the compounds of Example 2 and Example 3 in SD rats can be confirmed according to the method described in International Publication No. 01/16147, Test Example 2, Method A).
  • Test example 4 Urinary glucose excretion promoting test (oral administration) The action of promoting the urinary glucose excretion by oral administration of the compounds of Example 1, Example 4-1 and Example 4-2 in SD rats should be confirmed according to the method described in Test Example 3 of WO 02/053573. Can do.
  • Test Example 5 Bioavailability (BA) confirmation test
  • the BA in the oral administration of a prodrug can be confirmed according to the method described in Test Example 2 of WO 02/053573. That is, BA can be confirmed using the compound of Example 1, Example 4-1 or Example 4-2 as a prodrug and the compound of Example 2 or 3 as a parent compound.
  • the compound of the present invention or a prodrug thereof, or a pharmacologically acceptable salt thereof is provided as a human SGLT2 inhibitor.
  • the compounds of the present invention can also be used as preventive or therapeutic agents for diabetes, diabetes-related diseases or diabetic complications.

Abstract

La présente invention aborde le problème de fournir un composé ayant une activité inhibitrice de SGLT2 humain, un promédicament du composé, un sel pharmacologiquement acceptable du composé et une utilisation pharmaceutique du composé. La présente invention concerne un composé qui est représenté par la formule générale (1) (où RA représente un atome d'hydrogène, un groupe alkyle en C1-6 ou similaire ; RB représente un groupe alcoxy en C1-6 ou similaire ; chacun de RC et RD indépendamment représente un atome d'hydrogène, un atome d'halogène ou similaire ; et n représente un nombre de 1-3) et présente une activité inhibitrice de SGLT2 humain, un promédicament du composé ou un sel pharmacologiquement acceptable du composé. De plus, le composé de la présente invention peut être utilisé en tant qu'agent thérapeutique ou prophylactique pour des maladies associées à une hyperglycémie.
PCT/JP2012/065744 2011-06-20 2012-06-20 Dérivé de glucopyranosyloxypyrazole WO2012176804A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002098893A1 (fr) * 2001-05-30 2002-12-12 Kissei Pharmaceutical Co., Ltd. Derive de glucopyranosyloxypyrazole, composition medicinale contenant celui-ci, et utilisation medicinale et intermediaire de celui-ci
WO2004014932A1 (fr) * 2002-08-08 2004-02-19 Kissei Pharmaceutical Co., Ltd. Derive de pyrazole, composition medicinale contenant ce derive, utilisation therapeutique de ceux-ci et intermediaire pour la production de cette composition
WO2004019958A1 (fr) * 2002-08-27 2004-03-11 Kissei Pharmaceutical Co., Ltd. Derives de pyrazole, composition medicinale contenant ces derives et utilisation medicinale de celle-ci
JP2006510644A (ja) * 2002-12-12 2006-03-30 サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング 新しい複素環フルオログリコシド誘導体、該化合物を含有する医薬品、およびその使用
JP2009203230A (ja) * 2008-01-31 2009-09-10 Daiichi Sankyo Co Ltd ベンジルフェニルグルコピラノシド誘導体を含有する医薬組成物

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002098893A1 (fr) * 2001-05-30 2002-12-12 Kissei Pharmaceutical Co., Ltd. Derive de glucopyranosyloxypyrazole, composition medicinale contenant celui-ci, et utilisation medicinale et intermediaire de celui-ci
WO2004014932A1 (fr) * 2002-08-08 2004-02-19 Kissei Pharmaceutical Co., Ltd. Derive de pyrazole, composition medicinale contenant ce derive, utilisation therapeutique de ceux-ci et intermediaire pour la production de cette composition
WO2004019958A1 (fr) * 2002-08-27 2004-03-11 Kissei Pharmaceutical Co., Ltd. Derives de pyrazole, composition medicinale contenant ces derives et utilisation medicinale de celle-ci
JP2006510644A (ja) * 2002-12-12 2006-03-30 サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング 新しい複素環フルオログリコシド誘導体、該化合物を含有する医薬品、およびその使用
JP2009203230A (ja) * 2008-01-31 2009-09-10 Daiichi Sankyo Co Ltd ベンジルフェニルグルコピラノシド誘導体を含有する医薬組成物

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