WO2014061764A1 - Dérivé de xanthène - Google Patents

Dérivé de xanthène Download PDF

Info

Publication number
WO2014061764A1
WO2014061764A1 PCT/JP2013/078258 JP2013078258W WO2014061764A1 WO 2014061764 A1 WO2014061764 A1 WO 2014061764A1 JP 2013078258 W JP2013078258 W JP 2013078258W WO 2014061764 A1 WO2014061764 A1 WO 2014061764A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
substituted
dimethyl
benzofuran
tert
Prior art date
Application number
PCT/JP2013/078258
Other languages
English (en)
Japanese (ja)
Inventor
克治 影近
剛 曽根田
目黒　正規
史尚 土居
朋子 荻山
亮 武藤
正博 小西
信二 古薗
祥子 吉田
晋一 井上
Original Assignee
第一三共株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 第一三共株式会社 filed Critical 第一三共株式会社
Publication of WO2014061764A1 publication Critical patent/WO2014061764A1/fr

Links

Classifications

    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a novel compound having an action such as lowering blood sugar and useful as a therapeutic and / or prophylactic agent for diabetes and the like and a pharmacologically acceptable salt thereof.
  • the present invention includes diabetes (type 1 diabetes, type 2 diabetes, gestational diabetes, etc.), postprandial hyperglycemia, impaired glucose tolerance, diabetic neuropathy, diabetes containing the above compound or a pharmacologically acceptable salt thereof as an active ingredient Therapeutic and / or prevention for diabetic nephropathy, diabetic retinopathy, hyperlipidemia, arteriosclerosis, thrombotic disease, obesity, hypertension, edema, insulin resistance, unstable diabetes, insulinoma, hyperinsulinemia, etc.
  • the present invention relates to a drug (preferably a therapeutic and / or preventive for diabetes).
  • the present invention provides a composition for the prevention or treatment of the above-mentioned diseases containing the above-mentioned compound as an active ingredient, the use of the above-mentioned compound for the manufacture of a medicament for the prevention or treatment of the above-mentioned diseases,
  • the present invention relates to a method for preventing or treating the above diseases, wherein a pharmacologically effective amount is administered to a mammal (preferably a human).
  • Diabetes is a disease whose main feature is chronic hyperglycemia, and develops due to an absolute or relative lack of insulin action. In clinical practice, it is roughly divided into insulin-dependent diabetes (type 1 diabetes) and non-insulin-dependent diabetes (type 2 diabetes).
  • diabetes treatment is basically diet therapy and exercise therapy.
  • a drug is administered. Therefore, there is a demand for safer and more effective drugs.
  • Patent Document 1 discloses a compound having a partial structure which is partly in common with the compound of the present invention and having an effect of treating and preventing infectious diseases caused by herpes simplex virus.
  • the present inventors have found that the compound represented by the following formula (I) has an excellent activity activity such as hypoglycemia based on its specific chemical structure, and further stability. It has also been found to be a safe and useful drug as a prophylactic / therapeutic agent for hyperglycemia, diabetes, and pathological conditions or diseases related to these diseases. Based on these findings, the present invention has been completed.
  • the present invention has a hypoglycemic action and the like, such as diabetes (type 1 diabetes, type 2 diabetes, gestational diabetes, etc.), postprandial hyperglycemia, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, diabetic retina
  • diabetes type 1 diabetes, type 2 diabetes, gestational diabetes, etc.
  • postprandial hyperglycemia impaired glucose tolerance
  • diabetic neuropathy diabetic nephropathy
  • diabetic retina As a prophylactic / therapeutic agent for diseases such as diabetes, hyperlipidemia, arteriosclerosis, thrombotic disease, obesity, hypertension, edema, insulin resistance, unstable diabetes, insulinoma, hyperinsulinemia, especially type 2 diabetes Useful.
  • C1-C3 alkoxy group which may be substituted 1 or 2 groups selected from substituent group ⁇ may be substituted with C2-C3 alkenyl group which may be substituted, 1 or 2 groups selected from substituent group ⁇ Selected from an optionally substituted C3-C6 cycloalkyl group, a C1-C3 alkoxycarbonyl group, an aminocarbonyl group optionally substituted by one or two groups selected from the substituent group ⁇ , nitrogen, oxygen and sulfur
  • R 2 is the same or different and represents a hydrogen atom, a C1-C3 alkyl group, a C3-C6 cycloalkyl group, a C1-C3 alkoxy group, a carboxyl group or a halogen atom
  • R 3 is a hydrogen atom, a C1-C3 alkyl group
  • R 10 is a hydrogen atom, a C1-C3 alkoxy group, a C1-C3 alkyl group optionally substituted with one or two groups selected from the substituent group ⁇ , a C6-C10 aryl group, nitrogen, oxygen and sulfur.
  • a group selected from 3 to 10-membered heterocyclic group containing 1 to 3 heteroatoms which are the same or different from each other, a C1-C3 alkoxycarbonyl group, and a group selected from substituent group ⁇ is substituted with 1 or 2 groups
  • X C (-R 8 )-
  • one of R 9 or R 10 is C1 -C3 alkoxycarbonyl group, a carboxyl group, a C1-C3 alkyl group substituted by one carboxyl group or a C2-C3 alkenyl group substituted by one carboxyl group
  • Z represents C (-R 10 )-.
  • Substituent group ⁇ A hydroxyl group, a C1-C3 alkyl group (the alkyl group is a carboxyl group, an aminocarbonyl group optionally substituted with a C1-C3 alkylsulfonyl group, a C3-C6 cycloalkyl group, or a hydroxyl group, Each may be substituted), a C3-C6 cycloalkyl group (the cycloalkyl group may be substituted with one or two hydroxyl groups), an aminocarbonyl group, a carboxyl group, C1-C3 alkylsulfonyl group, a 3-10 membered heterocyclic group containing 1-3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur (the heterocyclic group is substituted with one carboxyl group) 3-10 membered heterocyclic C1-C3 alkyl group containing the same or different 1-3 heteroatoms selected from nitrogen, oxygen and sulfur (the heterocyclic C1-C3 alky
  • R 1 is a hydrogen atom, a C1-C3 alkyl group which may be substituted with one or two groups selected from substituent group ⁇ , and one or two groups selected from substituent group ⁇ .
  • C1-C3 alkoxy group which may be substituted, 1 or 2 groups selected from substituent group ⁇ may be substituted with C2-C3 alkenyl group which may be substituted, 1 or 2 groups selected from substituent group ⁇ Selected from an optionally substituted C3-C6 cycloalkyl group, a C1-C3 alkoxycarbonyl group, an aminocarbonyl group optionally substituted by one or two groups selected from the substituent group ⁇ , nitrogen, oxygen and sulfur
  • R 2 is the same or different and represents a hydrogen atom, a C1-C3 alkyl group, a C3-C6 cycl
  • a group selected from 3 to 10-membered heterocyclic group containing 1 to 3 heteroatoms which are the same or different from each other, a C1-C3 alkoxycarbonyl group, and a group selected from substituent group ⁇ is substituted with 1 or 2 groups
  • a C2-C3 alkenyl group substituted by one aminocarbonyl group carboxyl group, or a carboxyl group, t represents 1 or 2.
  • Substituent group ⁇ A hydroxyl group, a C1-C3 alkyl group (the alkyl group is a carboxyl group, an aminocarbonyl group optionally substituted with a C1-C3 alkylsulfonyl group, a C3-C6 cycloalkyl group, or a hydroxyl group, Each may be substituted), a C3-C6 cycloalkyl group (the cycloalkyl group may be substituted with one or two hydroxyl groups), an aminocarbonyl group, a carboxyl group, C1-C3 alkylsulfonyl group, a 3-10 membered heterocyclic group containing 1-3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur (the heterocyclic group is substituted with one carboxyl group) 3-10 membered heterocyclic C1-C3 alkyl group containing the same or different 1-3 heteroatoms selected from nitrogen, oxygen and sulfur (the heterocyclic C1-C3 alky
  • R 1 is a hydrogen atom, a C1-C3 alkyl group which may be substituted with one or two groups selected from substituent group ⁇ , and one or two groups selected from substituent group ⁇ .
  • C1-C3 alkoxy group which may be substituted, 1 or 2 groups selected from substituent group ⁇ may be substituted with C2-C3 alkenyl group which may be substituted, 1 or 2 groups selected from substituent group ⁇ Selected from an optionally substituted C3-C6 cycloalkyl group, a C1-C3 alkoxycarbonyl group, an aminocarbonyl group optionally substituted by one or two groups selected from the substituent group ⁇ , nitrogen, oxygen and sulfur
  • R 2 is the same or different and represents a hydrogen atom, a C1-C3 alkyl group, a C3-C6 cycl
  • R 10 is a hydrogen atom, a C1-C3 alkoxy group, a C1-C3 alkyl group optionally substituted with one or two groups selected from the substituent group ⁇ , a C6-C10 aryl group, nitrogen, oxygen and sulfur.
  • a group selected from 3 to 10-membered heterocyclic group containing 1 to 3 heteroatoms which are the same or different from each other, a C1-C3 alkoxycarbonyl group, and a group selected from substituent group ⁇ is substituted with 1 or 2 groups
  • An optionally substituted aminocarbonyl group, a C2-C3 alkenyl group substituted with a carboxyl group or a carboxyl group Provided that any one of R 9 and R 10 is a C1-C3 alkoxycarbonyl group, a carboxyl group, a C1-C3 alkyl group substituted by one carboxyl group, or a C2-C3 alkenyl group substituted by one carboxyl group Indicates.
  • Substituent group ⁇ A hydroxyl group, a C1-C3 alkyl group (the alkyl group is a carboxyl group, an aminocarbonyl group optionally substituted with a C1-C3 alkylsulfonyl group, a C3-C6 cycloalkyl group, or a hydroxyl group, May be substituted), a C3-C6 cycloalkyl group (the cycloalkyl group may be substituted with one or two hydroxyl groups), an aminocarbonyl group, a carboxyl group, a C1-C3 alkylsulfonyl group, 3- to 10-membered heterocyclic group containing the same or different 1-3 heteroatoms selected from nitrogen, oxygen and sulfur (the heterocyclic group may be substituted with one carboxyl group), nitrogen A 3- to 10-membered heterocyclic C1-C3 alkyl group containing the same or different 1-3 heteroatoms selected from oxygen and sulfur (the heterocyclic C1-C
  • the “C1-C3 alkyl group” is a linear or branched alkyl group having 1 to 3 carbon atoms, for example, a methyl, ethyl, n-propyl or isopropyl group.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and the substituent group ⁇ are preferably methyl or ethyl groups.
  • the “C3-C6 cycloalkyl group” is a 3- to 6-membered saturated cyclic hydrocarbon group, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.
  • the substituents of R 1 , R 2 , R 3 , substituent group ⁇ and “C1-C3 alkyl group” of substituent group ⁇ are preferably cyclopropyl groups.
  • the “C1-C3 hydroxyalkyl group” is a group in which a hydroxyl group is substituted on the “C1-C3 alkyl group”, and examples thereof include hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 1-hydroxy n. -Propyl, 2-hydroxy n-propyl group, and the substituent group ⁇ “4-10 membered heterocyclic ring containing the same or different 1-3 heteroatoms selected from nitrogen, oxygen and sulfur
  • the substituent of “C1-C3 alkyl group” is preferably a hydroxymethyl group or a 1-hydroxyethyl group.
  • the “C1-C3 alkoxy group” is a group in which the “C1-C3 alkyl group” is bonded to an oxygen atom, and has, for example, a carbon number such as methoxy, ethoxy, n-propoxy, isopropoxy group. Mention may be made of 1 to 3 straight-chain or branched alkoxy groups.
  • the substituent of the “C1-C3 alkoxy group” of R 1 , R 2 , R 3 , R 3 and R 10 is preferably a methoxy or ethoxy group.
  • the “C2-C3 alkenyl group” is a linear or branched alkenyl group having 2 or 3 carbon atoms, and examples thereof include ethenyl, 1-propenyl, and 2-propenyl groups.
  • R 1 , R 9 and R 10 are preferably an alkenyl group having 2 carbon atoms, more preferably a 1-propenyl group.
  • the “C6-C10 aryl group” is an aromatic hydrocarbon group having 6 to 10 carbon atoms, and examples thereof include phenyl, indenyl, and naphthyl groups.
  • R 10 is preferably It is a phenyl group.
  • the “3- to 10-membered heterocyclic group containing the same or different 1-3 heteroatoms selected from nitrogen, oxygen and sulfur” includes 1 to 3 nitrogen, oxygen or sulfur.
  • To 10-membered heterocyclic group such as furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyl, Aromatic heterocyclic groups such as pyrimidinyl, pyrazinyl and this such as oxetanyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl,
  • the above “4- to 10-membered heterocyclic group” may be condensed with other cyclic groups, such as benzofuranyl, chromenyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolidinyl, isoquinolyl, quinolyl, Phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, isoindolinyl, 2,3-dihydro-1-benzofuranyl, 3,4-dihydro-1H-isochromenyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4 -A tetrahydroisoquinolinyl group can be mentioned.
  • other cyclic groups such as benzofuranyl, chromenyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl,
  • R 10 and substituent group ⁇ include pyridyl, oxetanyl, morpholinyl, piperidinyl and tetrahydrofuranyl groups, and a pyridyl group is more preferable.
  • the “4- to 10-membered heterocyclic group C1-C3 alkyl group containing 1-3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur” refers to the above-mentioned “C1-C3 alkyl group” Is a group substituted by the above “4- to 10-membered heterocyclic group containing the same or different 1-3 heteroatoms selected from nitrogen, oxygen and sulfur”, for example, pyridylmethyl, pyridylethyl, pyridylpropyl Oxetanylmethyl, oxetanylethyl, morpholinylmethyl, morpholinylethyl, piperidinylmethyl, piperidinylethyl, tetrahydrofuranylmethyl, tetrahydrofuranylethyl groups.
  • a pyridylmethyl or pyridylethyl group is preferable.
  • the “3- to 10-membered heterocyclic carbonyl group containing 1-3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur” is selected from the above “nitrogen, oxygen and sulfur” ⁇ 4-10 membered heterocyclic group containing 1-3 heteroatoms which are the same or different '' is a group bonded to a carbonyl group such as pyridylcarbonyl, oxetanylcarbonyl, morpholinylcarbonyl, piperidinylcarbonyl and tetrahydrofuranylcarbonyl The group can be mentioned.
  • R 1 is preferably a piperidinylcarbonyl group.
  • the “C1-C3 alkoxycarbonyl group” is a group in which the “C1-3 alkoxy group” is bonded to a carbonyl group, and examples thereof include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, and isopropoxycarbonyl. Examples thereof include straight-chain or branched alkoxycarbonyl groups having 1 to 3 carbon atoms, and R 1 , R 9 and R 10 are preferably methoxycarbonyl or ethoxycarbonyl groups.
  • the “C1-C3 alkylsulfonyl group” is a group to which the “C1-3 alkyl group” is bonded via a sulfonyl group, such as methanesulfonyl, ethanesulfonyl, n-propanesulfonyl, isopropane.
  • a sulfonyl group can be mentioned.
  • the substituents of the substituent group ⁇ and the C1-C3 alkyl group of the substituent group ⁇ are preferably methanesulfonyl groups.
  • the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and R 1 and R 2 are preferably a chlorine atom or a fluorine atom.
  • the “3-6 membered saturated carbocycle” is a cyclopropane, cyclobutane, cyclopentane or cyclohexane ring, and in the ring formed by combining R 4 and R 5 and R 6 and R 7 A cyclobutane ring is preferred.
  • the term “pharmacologically acceptable salt” refers to a case where a basic group such as an amino group is reacted with an acid, and a case where an acidic group such as a carboxyl group is present. By reacting with a base, it can be converted into a salt, so that salt is shown.
  • the salt based on the basic group is preferably a hydrohalide such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfuric acid.
  • Inorganic acid salts such as salts and phosphates; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate, aryl sulfones such as benzene sulfonate and p-toluene sulfonate Acid salt, acetate salt, malate salt, fumarate salt, succinate salt, citrate salt, ascorbate salt, tartrate salt, succinate salt, maleate salt, etc .; and glycine salt, lysine salt And amino acid salts such as arginine salt, ornithine salt, glutamate and aspartate.
  • it is a hydrohalide salt or an inorgan
  • the salt based on an acidic group is preferably an alkali metal salt such as a sodium salt, potassium salt or lithium salt, an alkaline earth metal salt such as a calcium salt or magnesium salt, an aluminum salt or an iron salt.
  • Metal salt; inorganic salt such as ammonium salt, 2-methylpropan-2-amine salt (also called tert-butylamine salt), tert-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester Salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl Phenethylamine salt, piperazine salt, tetramethylammonium salt Tris amine salt such
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof includes all isomers (keto-enol isomer, stereoisomer, etc.).
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has various isomers when an asymmetric carbon atom is present in the molecule.
  • these isomers and mixtures of these isomers are all represented by a single formula, that is, the general formula (I). Therefore, the present invention includes all of these isomers and a mixture of these isomers in an arbitrary ratio.
  • stereoisomers as described above can be obtained by isolating the synthesized compound according to the present invention, if desired, using a conventional optical resolution method or separation method.
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof may also contain an unnatural proportion of atomic isotopes at one or more of atoms constituting such a compound.
  • atomic isotopes include deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), carbon-14 ( 14 C), and the like.
  • the compound can also be radiolabeled with a radioisotope such as, for example, tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is left in the air or recrystallized to absorb moisture and adsorb water. It may become a hydrate, and such a hydrate is also included in the salt of the present invention.
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof may absorb a certain other solvent and become a solvate, and such a solvate is also present. Included in the salts of the invention.
  • the present invention relates to a compound that is metabolized in vivo and converted to a xanthene derivative having the general formula (I) or a salt thereof (for example, a derivative in which the carboxylic acid moiety of the general formula (I) is esterified) Is also included.
  • the general formula (I) of the present invention is preferably the following formula (IA) or (IB)
  • X is preferably ⁇ C (—R 8 ) — or —O—, and more preferably —O—.
  • Y is preferably ⁇ C (—R 9 ) —.
  • Z is preferably ⁇ C (—R 10 ) —.
  • N is preferably 0.
  • M is preferably 1.
  • T is preferably 1.
  • R 1 is preferably a C1-C3 alkyl group or a carboxyl group which may be substituted with one or two groups selected from the substituent group ⁇ , more preferably a carboxyl group. Or a C1-C3 alkyl group or a carboxyl group.
  • R 2 is preferably the same or different and is a hydrogen atom or a C1-C3 alkyl group, and more preferably a methyl group.
  • R 3 is preferably a hydrogen atom, a C1-C3 alkyl group (the alkyl group may be substituted with one carboxyl group) or a C1-C3 alkoxy group (the alkoxy group is a C1-C3 alkoxy group). And may be substituted by 1), more preferably a hydrogen atom, a methyl group or a methoxy group, and particularly preferably a hydrogen atom.
  • R 4 is preferably a C1-C3 alkyl group, and more preferably a methyl group.
  • R 5 is preferably a C1-C3 alkyl group, and more preferably a methyl group.
  • R 6 is preferably a C1-C3 alkyl group, and more preferably a methyl group.
  • R 7 is preferably a C1-C3 alkyl group, and more preferably a methyl group.
  • R 8 is preferably a hydrogen atom.
  • R 9 is preferably a hydrogen atom.
  • R 10 is preferably a C1-C3 alkyl group which may be substituted with one or two groups selected from the substituent group ⁇ , and more preferably a methyl group.
  • Substituent group ⁇ is When R 1 is a C1-C3 alkyl group optionally substituted by 1 or 2 groups selected from the substituent group ⁇ , it is preferably a carboxyl group.
  • R 1 is a C1-C3 alkoxy group which may be substituted with 1 or 2 groups selected from the substituent group ⁇ , it is preferably a hydroxyl group or a carboxyl group.
  • R 1 is a C2-C3 alkenyl group which may be substituted with one or two groups selected from the substituent group ⁇ , it is preferably a carboxyl group.
  • R 1 is a C3-C6 cycloalkyl group optionally substituted by 1 or 2 groups selected from the substituent group ⁇ , it is preferably a carboxyl group.
  • R 1 is an aminocarbonyl group optionally substituted by 1 or 2 groups selected from substituent group ⁇ , it is preferably a C1-C3 alkyl group (the alkyl group is a carboxyl group, C1- An aminocarbonyl group, a C3-C6 cycloalkyl group or a hydroxyl group which may be substituted by 1 or 2 with a C3 alkylsulfonyl group.
  • R 10 is a C1-C3 alkyl group optionally substituted by 1 or 2 groups selected from the substituent group ⁇ , preferably When R 10 is an aminocarbonyl group optionally substituted by 1 or 2 groups selected from the substituent group ⁇ , it is preferably a C1-C3 alkylsulfonyl group.
  • the compound having the general formula (I) of the present invention can be produced, for example, by the following method: Method A:
  • Method B Method for producing intermediate compound (1b).
  • R 1a represents R 1 (when R 1 has a hydroxyl group, an amino group or a carboxyl group, these groups may be protected by a protecting group), and R 1a 2a represents R 2 (in the case where R 2 has a carboxyl group, it may be protected by a protecting group); R 3a represents R 3 (in the case where R 3 has a carboxyl group, a protecting group) R 8a represents R 8 (in the case where R 8 has a carboxyl group, it may be protected by a protecting group), and R 9a represents R 9 (the R In the case where 9 has a carboxyl group, it may be protected by a protecting group, and R 10a may be protected by R 10 (when R 10 has a carboxyl group, it may be protected by a protecting group)
  • Y a C (-R 9a )-, -CH
  • P 1a represents a hydrogen atom or a C1-C3 alkyl group.
  • the protecting group used for protecting the hydroxyl group, amino group or carboxyl group is not particularly limited as long as it is a group used in the field of synthetic organic chemistry.
  • Green Watts The protecting groups described in the book, “Protective groups in organic synthesis 3rd edition” (Wiley-Interscience, USA) can be mentioned.
  • Method A Compound (I) of the present invention is produced by reacting intermediate (1) with 5,5-dimethylcyclohexane-1,3-dione in the presence of an acid to construct a three ring.
  • the step of producing the intermediate (1) can be produced by a method B, a method C, a production method described in the examples or the like according to a desired compound. If necessary, the protecting group can be removed by hydrolysis or the like.
  • the solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • water, halogenated hydrocarbons such as chloroform, ethers such as dioxane and tetrahydrofuran, methanol And alcohols such as ethanol are preferable, and ethanol, chloroform, dioxane or methanol is preferable.
  • Examples of the acid include dodecylbenzenesulfonic acid, pyrrolidine-paratoluenesulfonic acid monohydrate, pyrrolidine-2 N or 5 N hydrochloric acid, and preferably pyrrolidine-paratoluenesulfonic acid monohydrate, pyrrolidine-2 Normal or 5N hydrochloric acid.
  • the reaction temperature is 20 ° C to 120 ° C, preferably 60 ° C to 110 ° C.
  • the reaction time is 2 hours to 12 hours, preferably 3.5 hours to 4 hours.
  • Method B (Process B-1) This step is a step of introducing a propynyl group by reacting 3-bromo-1-propyne with a known compound or an intermediate compound (2) obtained by appropriately converting a substituent from a known compound in the presence of a base. It is.
  • the solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone
  • Sulfoxides such as dimethyl sulfoxide
  • ketones such as acetone and ethyl methyl ketone
  • ethers such as tetrahydrofuran, preferably N, N-dimethylformamide, N, N-dimethylacetamide or N -Methylpyrrolidone.
  • Examples of the base include metal carbonates such as potassium carbonate, metal hydroxides such as sodium hydroxide, metal alkoxides such as tert-butoxy potassium, and organic bases such as triethylamine.
  • metal carbonates such as potassium carbonate
  • metal hydroxides such as sodium hydroxide
  • metal alkoxides such as tert-butoxy potassium
  • organic bases such as triethylamine.
  • a metal carbonate such as potassium carbonate.
  • the reaction temperature is 0 ° C to 100 ° C, preferably 25 ° C.
  • the reaction time is 0.5 to 12 hours, preferably 5 hours.
  • This step is a step of cyclizing the intermediate compound (3) to construct a benzofuran ring.
  • the solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • anilines such as diethylaniline and dimethylaniline, ethers such as diphenyl ether, and aromatics such as xylene. Group hydrocarbons, and diethylaniline is preferred.
  • the reagent examples include alkali metal fluorides such as cesium fluoride, cesium chloride, aluminum chloride, and lanthanoid trifluoromethanesulfonates such as ytterbium trifluoromethanesulfonate, and preferably cesium fluoride.
  • alkali metal fluorides such as cesium fluoride, cesium chloride, aluminum chloride, and lanthanoid trifluoromethanesulfonates such as ytterbium trifluoromethanesulfonate, and preferably cesium fluoride.
  • the reaction temperature is 100 ° C to 300 ° C, preferably 200 ° C.
  • the reaction time is 4 to 24 hours, preferably 8 hours.
  • This step is a step for producing intermediate compound (5) by reducing intermediate compound (4).
  • the intermediate compound (5) can protect R 1Ab , R 2Ab , R3 Ab into a desired substituent by protecting the hydroxyl group as necessary.
  • the solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • halogenated hydrocarbons such as dichloromethane and chloroform
  • aromatic hydrocarbons such as benzene and toluene.
  • ethers such as tetrahydrofuran and diethyl ether, preferably dichloromethane.
  • the reducing agent examples include metal hydrides such as lithium aluminum hydride, lithium tetraborohydride, diisobutylaluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, and preferably diisobutylaluminum hydride. is there.
  • the reaction temperature is -78 ° C to room temperature, preferably 0 ° C.
  • the reaction time is 0.5 to 8 hours, preferably 4 hours.
  • This step is a step of producing intermediate compound (1b) by oxidizing intermediate compound (5).
  • the solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • halogenated hydrocarbons such as dichloromethane and chloroform
  • aromatic hydrocarbons such as benzene and toluene.
  • ethers such as 1,2-dimethoxyethane and 1,4-dioxane, preferably 1,2-dimethoxyethane or benzene.
  • Oxidizing agents include metal oxides such as manganese (IV) oxide and silver (II) oxide, perruthenic acids such as tetrapropylammonium perruthenate, and chromic acids such as pyridinium dichromate and pyridinium chlorochromate.
  • Activators such as dimethyl sulfoxide and oxalyl dichloride and sulfur trioxide, organic nitroxyl radicals such as 2,2,6,6-tetramethylpiperidine-1-oxyl radical and sodium hypochlorite Co-oxidants, quinones such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, 1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol Hypervalent iodine compounds such as -3 (1H) -one, preferably organic nitro such as manganese (IV) oxide, 2,2,6,6-tetramethylpiperidine-1-oxyl radical Xyl radicals and sodium hypochlorite It is a co-oxidant typified by lithium.
  • the reaction temperature is ⁇ 78 ° C. to 100 ° C., preferably 90 ° C.
  • the reaction time is 1 to 12 hours, preferably 6 hours.
  • the solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and examples thereof include dimethylformamide, N-methylformanilide and the like, and preferably N-methylformanilide. It is.
  • Examples of the reagent include phosphorus oxychloride and phosphorus oxybromide, and phosphorus oxychloride is preferable.
  • the reaction temperature is 0 ° C to 100 ° C, preferably 70 ° C to 90 ° C.
  • the reaction time is 1 to 9 hours, preferably 1 to 3 hours.
  • the target compound is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added, washed with water, and the target compound is then contained.
  • the organic layer is separated, dried over anhydrous magnesium sulfate, and the solvent is distilled off.
  • the obtained target product can be obtained by a conventional method such as recrystallization, reprecipitation, or a method usually used for separation and purification of organic compounds, such as adsorption column chromatography, distribution column chromatography, etc. Separation and purification by eluting with an appropriate eluent by combining a method using a synthetic adsorbent, a method using ion exchange chromatography, or a normal phase / reverse phase column chromatography method using silica gel or alkylated silica gel. can do.
  • the optically active substance can be separated and purified by a chiral column.
  • the xanthene derivative having the general formula (I) of the present invention and a pharmacologically acceptable salt thereof are administered in various forms.
  • the administration form is not particularly limited, and is determined according to various preparation forms, patient age, sex and other conditions, the degree of disease, and the like.
  • it is orally administered in the case of tablets, pills, powders, granules, syrups, solutions, suspensions, emulsions, granules and capsules.
  • a normal replacement fluid such as glucose or amino acid
  • it is administered intrarectally. Oral administration is preferred.
  • compositions are prepared by using known adjuvants that can be generally used in the field of known pharmaceutical preparations such as excipients, binders, disintegrants, lubricants, solubilizers, flavoring agents, and coating agents according to conventional methods. It can be formulated.
  • conventionally known carriers can be widely used as carriers, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and the like.
  • carriers such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and the like.
  • Form water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders, dry starch, sodium alginate, agar powder, laminaran powder Sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose and other disintegrants, sucrose, stearin, cacao butter, hydrogenated oil and other
  • the tablets can be made into tablets with ordinary coatings as necessary, for example, sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multilayer tablets.
  • those conventionally known in this field can be widely used as carriers, for example, glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc and other excipients, gum arabic powder, Examples thereof include binders such as tragacanth powder, gelatin and ethanol, and disintegrants such as lamina lankanten.
  • conventionally known carriers can be widely used as carriers, such as polyethylene glycol, cacao butter, higher alcohols, higher alcohol esters, gelatin, semi-synthetic glycerides and the like. it can.
  • the solutions and suspensions are preferably sterilized and isotonic with blood, and in the form of these solutions, emulsions and suspensions, this is used as a diluent.
  • Any of those commonly used in the field can be used, and examples thereof include water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters.
  • a sufficient amount of sodium chloride, glucose, or glycerin to prepare an isotonic solution may be contained in the pharmaceutical preparation.
  • Ordinary solubilizers, buffers, soothing agents, etc. may be added. It may be added.
  • colorants may be included.
  • preservatives may be included.
  • fragrances may be included.
  • flavors may be included.
  • sweeteners may be included.
  • the amount of the active ingredient compound contained in the pharmaceutical preparation is not particularly limited and is appropriately selected within a wide range, but is usually 1 to 70% by weight, preferably 1 to 30% by weight in the total composition. Is appropriate.
  • the dosage varies depending on symptoms, age, body weight, administration method, dosage form, etc., but is usually 0.001 mg / kg (preferably 0.01 mg / kg, more preferably 0.1 mg as a lower limit for adults per day) / mg), and 200 mg / kg (preferably 20 mg / kg, more preferably 10 mg / kg) as the upper limit can be administered once to several times.
  • the compound of the present invention can be used in combination with various therapeutic or prophylactic agents for the diseases for which the present invention is considered to be effective.
  • the combination may be administered simultaneously or separately in succession or at desired time intervals.
  • the simultaneous administration preparation may be a compounding agent or may be separately formulated.
  • the xanthene derivative and pharmacologically acceptable salt thereof, which are compounds of the present invention, have an excellent hypoglycemic action, such as diabetes (type 1 diabetes, type 2 diabetes, gestational diabetes, etc.), postprandial hyperglycemia, glucose tolerance Disorder, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, hyperlipidemia, arteriosclerosis, thrombotic disease, obesity, hypertension, edema, insulin resistance, unstable diabetes, insulinoma, hyperinsulinemia It is useful as a therapeutic or prophylactic agent for diseases such as diabetes (type 1 diabetes, type 2 diabetes, gestational diabetes, etc.), postprandial hyperglycemia, glucose tolerance Disorder, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, hyperlipidemia, arteriosclerosis, thrombotic disease, obesity, hypertension, edema, insulin resistance, unstable diabetes, insulinoma, hyperinsulinemia It is useful as a therapeutic or prophylactic agent for diseases such as
  • silica gel SK-85 230-400 mesh
  • silica gel SK-34 70-230 mesh
  • Fuji Silysia Chemical Chromatorex NH 200-350 mesh
  • Merck & Co., Inc. was used.
  • SP-1 Biotage's automated chromatography device
  • Yamazen's automated chromatography device Yamazen's automated chromatography device
  • Teledyne Isco's automated chromatography device CombiFlash Rf
  • 1 H NMR nuclear magnetic resonance
  • MS Mass spectrometry
  • Hexane represents n-hexane
  • THF represents tetrahydrofuran
  • DMF dimethylformamide
  • Example 2-1 Methyl 4-methyl-2- (prop-2-in-1-yloxy) benzoate To a solution of methyl 2-hydroxy-4-methylbenzoate (25.0 g, 150 mmol) in DMF (100 ml) was added potassium carbonate. (32.2 g, 233 mmol) was added and stirred vigorously at room temperature. Further, 3-bromo-1-propyne (16.3 ml, 217 mmol) was added at room temperature, and the mixture was vigorously stirred at room temperature for 6 hours. The reaction mixture was filtered, water was added, and the mixture was extracted twice with ethyl acetate.
  • Example 2-5 9- (2,4-Dimethyl-1-benzofuran-7-yl) -3,3,6,6-tetramethyl-3,4,5,6,7,9-hisahydro- 1, H-xanthene-1,8 (2H) -dione 2,4-dimethyl-1-benzofuran prepared according to Example 2-4 instead of 4-methoxy-2-methyl-1-benzofuran-7-carbaldehyde Reaction was carried out in the same manner as described in Example 1 using -7-carbaldehyde (174 mg, 1.00 mmol) to obtain the title compound (333 mg, yield: 80%).
  • Example 3-1 Methyl 5-bromo-4-methyl-2- (prop-2-in-1-yloxy) benzoate DMF of methyl 5-bromo-2-hydroxy-4-methylbenzoate (155 g, 625 mmol) To the solution (300 ml), potassium carbonate (135 g, 975 mmol) was added and stirred vigorously at room temperature. Further, 3-bromo-1-propyne (68.2 ml, 906 mmol) was added at room temperature, and the mixture was vigorously stirred at room temperature for 6 hours. The reaction solution was filtered, water was added, and the mixture was extracted twice with ethyl acetate.
  • Diisobutylaluminum hydride (1.02 M hexane solution, 147 ml, 150 mmol) was added dropwise to a dichloromethane solution (300 ml) of -dimethyl-1-benzofuran-7-carboxylate (17.0 g, 60.0 mmol). After the dropwise addition, the reaction solution was stirred at room temperature for 3 hours, and cooled again to -78 ° C. An aqueous potassium sodium tartrate solution was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was extracted twice with dichloromethane, and the obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • reaction solution was stirred at the same temperature for 1 hour, and then carbon dioxide was passed through for 10 minutes.
  • the reaction solution was further stirred for 1 hour, then warmed to room temperature, and acetic acid (5.84 ml, 102 mmol) was added.
  • the reaction mixture was concentrated, water was added, and the mixture was extracted 3 times with ethyl acetate.
  • the obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was pulverized in hexane and filtered to obtain the title compound (21.7 g, yield: 76%).
  • reaction solution was concentrated under reduced pressure, water was added to the residue, the mixture was stirred for 30 minutes, extracted three times with ethyl acetate, and the resulting organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.
  • Example 3-7 tert-butyl 7- (hydroxymethyl) -2,4-dimethyl-1-benzofuran-5-carboxylate With ice-cooled tetrabutylammonium fluoride (1.0 M THF solution 112 ml, 112 mmol) To a mixture with acetic acid (7.38 ml, 129 mmol) was added tert-butyl 7-( ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ methyl) hydroxymethyl) -2,4-dimethyl prepared according to Example 3-6.
  • Example 7-1 tert-butyl (2E) -3- [7-( ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ methyl) -2,4-dimethyl-1-benzofuran-5-yl] prop 2-Enoate [(5-Bromo-2,4-dimethyl-1-benzofuran-7-yl) methoxy] (tert-butyl) dimethylsilane (12.0 g, prepared according to Example 3-4 under nitrogen atmosphere) 32.4 mmol) in DMF (120 ml) at room temperature, t-butyl acrylate (47.4 ml, 324 mmol), triethylamine 45.4 ml, 325 mmol), palladium (II) acetate (1.46 g, 6.48 mmol), tri (o-tolyl) ) Phosphine (3.94 g, 13.0 mmol) was added, and the mixture was stirred with heating at 90 ° C.
  • Example 7-2 tert-butyl (2E) -3- [7- (hydroxymethyl) -2,4-dimethyl-1-benzofuran-5-yl] prop-2-enoate tert-butyl 7-( ⁇ [tert-Butyl (dimethyl) silyl] oxy ⁇ methyl) hydroxymethyl) -2,4-dimethyl-1-benzofuran-5-carboxylate instead of tert-butyl (2E)-prepared according to Example 7-1 Using 3- [7-( ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ methyl) -2,4-dimethyl-1-benzofuran-5-yl] prop-2-enoate (1.50 g, 3.60 mmol), The reaction was conducted in the same manner as described in Example 3-7 to obtain the title compound (980 mg, yield: 90%).
  • Example 8-1 tert-butyl 3- [7-( ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ methyl) -2,4-dimethyl-1-benzofuran-5-yl] propanoate Methanol ( 200 ml), magnesium (5.06 g, 208 mmol) was added, and while stirring vigorously, tert-butyl (2E) -3- [7-( ⁇ [tert-butyl ( A solution of dimethyl) silyl] oxy ⁇ methyl) -2,4-dimethyl-1-benzofuran-5-yl] prop-2-enoate (8.67 g, 20.8 mmol) in methanol (30 ml) was added dropwise.
  • Example 8-4 [2,4-Dimethyl-7- (3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8- Octahydro-1H-xanthen-9-yl) -1-benzofuran-5-yl] propanoic acid tert-butyl 7-formyl-2,4-dimethyl-1-benzofuran-5-carboxylate instead of Example 8-3 Reaction similar to that described in Example 3 using tert-butyl 3- (7-formyl-2,4-dimethyl-1-benzofuran-5-carboxylate instead of Example 8-3 Reaction similar to that described in Example 3 using tert-butyl 3- (7-formyl-2,4-dimethyl-1-benzofuran-5-carboxylate instead of Example 8-3 Reaction similar to that described in Example 3 using tert-butyl 3- (7-formyl-2,4-dimethyl-1-benzofuran-5-carboxylate instead of Example 8-3 Reaction similar to
  • Example 9 (2E) -3- [2,4-Dimethyl-7- (3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7, 8-Octahydro-1H-xanthen-9-yl) -1-benzofuran-5-yl] propanoic acid 2-methylpropan-2-amine 2,4-dimethyl-7- (3,3,6,6-tetramethyl -1,8-dioxo-2,3,4,5,6,7,8-octahydro-1H-xanthen-9-yl) -1-benzofuran-5-carboxylic acid instead of prepared according to Example 8 3- [2,4-dimethyl-7- (3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8-octahydro-1H-xanthene- 9-yl) -1-benzofuran-5-yl] propanoic acid (1.47 g, 3.00 mmol) was used in the
  • tert-butyl 3- (7-formyl-2,4-dimethyl-1) prepared according to Example 8-3 instead of tert-butyl 7-formyl-2,4-dimethyl-1-benzofuran-5-carboxylate -Benzofuran-5-yl] propanoate (637 mg, 2.00 mmol) was used in the same manner as in Example 6 to obtain the title compound (618 mg, yield: 60%).
  • Example 11-1 tert-butyl (2E) -3- [7-( ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ methyl) -2,4-dimethyl-1-benzofuran-5-yl]- 2-Methylprop-2-enoate [(5-Bromo-2,4-dimethyl-1-benzofuran-7-yl) methoxy] (tert-butyl) dimethylsilane (6.00 g, 16.2 mmol) prepared according to Example 3-4 at room temperature under nitrogen atmosphere ) In DMF solution (60 ml), t-butyl methacrylate (26.1 ml, 162 mmol), triethylamine 22.7 ml, 162 mmol), palladium (II) acetate (728 mg, 3.24 mmol), tri (o-tolyl) phosphine (1.97 g, 6.48 mmol) was added and the mixture was stirred with heating at 90 ° C.
  • Example 11-2 tert-butyl 3- [7-( ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ methyl) -2,4-dimethyl-1-benzofuran-5-yl] -2-methylprop Noate of tert-butyl (2E) -3- [7-( ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ methyl) -2,4-dimethyl-1-benzofuran-5-yl] prop-2-enoate Instead tert-butyl (2E) -3- [7-( ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ methyl) -2,4-dimethyl-1-benzofuran-5 prepared according to Example 11-1 -Il] -2-methylprop-2-enoate (3.71 g, 8.62 mmol) was used in the same manner as described in Example 8-1 to give the title compound (3.05 g, yield: 82%).
  • Example 12-1 tert-butyl 3- [7-( ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ methyl) -2,4-dimethyl-1-benzofuran-5-yl] -2,2- Dimethylpropanoate Under ice-cooling, n-butyllithium (2.69 M hexane solution, 1.89 ml, 5.09 mmol) was added dropwise to a THF solution (60 ml) of diisopropylamine (0.783 ml, 5.55 mmol) and kept at the same temperature for 10 minutes. Stir.
  • Example 13 3- [2,4-Dimethyl-7- (3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9- Octahydro-1H-xanthen-9-yl) -1-benzofuran-5-yl] -2,2-dimethylpropanoic acid 2-methylpropan-2-amine 2,4-dimethyl-7- (3,3,6, Example instead of 6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8-octahydro-1H-xanthen-9-yl) -1-benzofuran-5-carboxylic acid 3- [2,4-dimethyl-7- (3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9- Octahydro-1H-xanthen-9-yl) -1-benzofuran-5-yl] -2,2-dimethylpropanoic acid (1.46 g, 2.81 mmol) was used in the same
  • Example 14-1 tert-butyl (2E) -3- [7-( ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ methyl) -2,4-dimethyl-1-benzofuran-5-yl] butyl Tert-2-enoate
  • tert-butyl 2-but-2-enoate 25 ml, 156 mmol
  • tert-butyl methacrylate [(5-bromo-2,4- Dimethyl-1-benzofuran-7-yl) methoxy] (tert-butyl) dimethylsilane (12.5 g, 30.02 mmol) was reacted in the same manner as in Example 11-1 to obtain a crude product of the title compound.
  • Example 14-2 tert-butyl 3- [7-( ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ methyl) -2,4-dimethyl-1-benzofuran-5-yl] -3-methylprop Noate of tert-butyl (2E) -3- [7-( ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ methyl) -2,4-dimethyl-1-benzofuran-5-yl] prop-2-enoate Instead manufactured according to Example 14-1.
  • Example 14-4 tert-butyl 3- (7-formyl-2,4-dimethyl-1-benzofuran-5-yl) -3-methylpropanoate tert-butyl 7- (hydroxymethyl) -2, Tert-Butyl 3- [7- (hydroxymethyl) -2,4-dimethyl-1-benzofuran-5-yl prepared according to Example 14-3 instead of 4-dimethyl-1-benzofuran-5-carboxylate ] -3-Methylpropanoate (2.03 g, 6.07 mmol) was used in the same manner as in Example 3-8 to obtain the title compound (1.67 g, yield: 85%). .
  • Example 15-4 [2,4-Dimethyl-7- (3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9- Octahydro-1H-xanthen-9-yl) -1-benzofuran-5-yl] acetic acid tert-butyl 7-formyl-2,4-dimethyl-1-benzofuran-5-carboxylate instead of Example 15-3 Using the tert-butyl (7-formyl-2,4-dimethyl-1-benzofuran-5-carboxylate instead of Example 15-3 Using the tert-butyl (7-formyl-2,4-dimethyl-1-benzofuran-5-carboxylate instead of Example 15-3 Using the tert-butyl (7-formyl-2,4-dimethyl-1-benzofuran-5-carboxylate instead of Example 15-3 Using the tert-butyl (7-formyl-2,4-dimethyl-1-benzofuran
  • Example 17-1 tert-Butyl 2- [7- (hydroxymethyl) -2,4-dimethyl-1-benzofuran-5-yl] butanoate Prepared according to Example 15-1 with cooling at -78 ° C.
  • lithium bis (trimethylsilyl) amide (1.10 M hexane solution, 5.45 ml, 6.00 mmol
  • Example 18-1 Ethyl 3-bromo-2-methyl-6- (prop-2-en-1-yloxy) benzoate Ethyl 3-bromo-6-hydroxy-2-methyl-5- (prop-2- To a DMF solution (200 ml) of en-1-yl) benzoate (US 6127570A described compound, 36.8 g, 142 mmol) was added potassium carbonate (31.5 g, 227 mmol) at room temperature, and the mixture was vigorously stirred. Further, 3-bromo-1-propene (17.6 ml, 208 mmol) was added, and the mixture was vigorously stirred at room temperature for 6 hours. The reaction mixture was filtered, water was added, and the mixture was extracted twice with ethyl acetate.
  • Example 18-10 [2,6-dimethyl-7- (3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8- Octahydro-1H-xanthen-9-yl) -1-benzofuran-5-yl] propanoic acid tert-butyl 7-formyl-2,4-dimethyl-1-benzofuran-5-carboxylate instead of Example 18-9 Similar to the method described in Example 3 using tert-butyl 3- (7-formyl-2,6-dimethyl-1-benzofuran-5-yl) propanoate (1.18 g, 3.
  • Example 20-1 tert-butyl 2- [7-( ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ methyl) -2,6-dimethyl-1-benzofuran-5-yl] acetate [(5- Bromo-2,4-dimethyl-1-benzofuran-7-yl) methoxy] (tert-butyl) dimethylsilane prepared by Example 18-5 [(5-bromo-2,6-dimethyl-1 -Benzofuran-7-yl) methoxy] (tert-butyl) dimethylsilane (4.75 g, 12.8 mmol) was reacted in the same manner as described in Example 15-1 to give the title compound (4.77 g, yield).
  • Example 21-1 tert-butyl ⁇ [2,4-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-benzofuran-7 -Yl] methoxy ⁇ dimethylsilane [(5-bromo-2,4-dimethyl-1-benzofuran-7-yl) methoxy] (tert-butyl) dimethylsilane (22.6 g, 61.2) prepared according to Example 3-4 mmol) in dimethyl sulfoxide solution (200 ml) at room temperature with bis (pinacolato) diborane (17.1 g, 67.3 mmol), potassium acetate (18.1 g, 184 mmol), palladium (II) chloride bis (diphenylphosphino) ferrocene / dichloromethane complex (7.50 g, 9.18 mmol) was added, and the mixture was stirred with heating at 90 ° C.
  • Example 21-5 tert-butyl 2-[(7-formyl-2,4-dimethyl-1-benzofuran-5-yl) oxy] -2-methylpropanoate tert-butyl 7- (hydroxymethyl) Tert-Butyl 2- ⁇ [7- (hydroxymethyl) -2,4-dimethyl-1-benzofuran prepared according to Example 21-4 instead of -2,4-dimethyl-1-benzofuran-5-carboxylate -5-yl] oxy ⁇ -2-methylpropanoate (4.90 g, 14.6 mmol) was used in the same manner as described in Example 3-8
  • Example 25-1 Methyl 6-methoxy-5- (3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro- 1H-xanthen-9-yl) naphthalene-2-carboxylate methyl 5-formyl-6-methoxynaphthalene-2-carboxylate (4.8 g, 19.7 mmol) in ethanol (100 ml) at room temperature 1,3-Hexanedione (6.0 g, 42.9 mmol) and pyrrolidine (30 ⁇ l) were added, and the mixture was heated at 90 ° C. After returning to room temperature, the reaction solution was concentrated.
  • the obtained residue was dissolved in chloroform (100 ml), p-toluenesulfonic acid monohydrate (0.1 g, 0.5 mmol) was added, and the mixture was heated at 70 ° C. After returning to room temperature, p-toluenesulfonic acid monohydrate (1.0 g, 5.0 mmol) was added, and the mixture was heated at 80 ° C. After returning to room temperature, the reaction mixture was concentrated, and the resulting residue was crystallized using a mixed solvent of ethyl acetate and hexane to obtain crystals (9.0 g) containing impurities.
  • Example 26-1 Methyl 6-methoxy-1- ⁇ [(trifluoromethyl) sulfonyl] oxy ⁇ naphthalene-2-carboxylate Methyl 1-hydroxy-6-methoxynaphthalene carboxylate (3.48 g, 15.0 mmol) To the DMF solution (15 ml), potassium carbonate (6.22 g, 45.0 mmol) and N-phenylbis (trifluoromethanesulfonimide) (5.36 g, 15.0 mmol) were added at room temperature and heated at 70 ° C. for 2 hours. After returning the reaction solution to room temperature, water and ethyl acetate were added, and the mixture was separated.
  • Example 26-2 Methyl 6-methoxy-1-methylnaphthalene-2-carboxylate Methyl 6-methoxy-1- ⁇ [(trifluoromethyl) sulfonyl] prepared according to Example 26-1 under a nitrogen atmosphere
  • Oxy ⁇ naphthalene-2-carboxylate (1.82 g, 5.00 mmol) in dioxane (10 ml), potassium phosphate (3.29 g, 15.5 mmol), trimethylboroxine (3.5 MTHF solution, 0.86 ml, 3.0 mmol) at room temperature
  • 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex 81.7 mg, 0.1 mmol was added and heated at 110 ° C.
  • Example 26-3 Methyl 5-formyl-6-methoxy-1-methylnaphthalene-2-carboxylate
  • Methyl 6-methoxy-1-methylnaphthalene-2-carboxylate prepared according to Example 26-2 (15.4 g, 67.0 mmol) and N-methylformanilide (27.0 g, 199 mmol) were added with phosphorus oxychloride (42.7 g, 278 mmol) under ice-water cooling and heated at 85 ° C. for 6 hours. After returning the reaction solution to room temperature, water was added, extraction was performed with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate.
  • Example 26-4 Methyl 6-methoxy-1-methyl-5- (3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8, 9-octahydro-1H-xanthen-9-yl) naphthalene-2-carboxylate
  • Methyl 5-formyl-6-methoxy-1-methylnaphthalene-2-carboxylate prepared according to Example 26-3 (12.0 g, 47.0 mmol) in methanol (190 ml) at room temperature were added 5,5-dimethyl-1,3-hexanedione (15.0 g, 199 mmol) and pyrrolidine (3.67 g, 51.6 mmol) and heated at 70 ° C. for 90 minutes.
  • Example 26-5 6-methoxy-1-methyl-5- (3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9 -Octahydro-1H-xanthen-9-yl) naphthalene-2-carboxylic acid Methyl 6-methoxy-1-methyl-5- (3,3,6,6-tetramethyl-1 prepared by Example 26-4 , 8-Dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl) naphthalene-2-carboxylate (19.6 g, 39 mmol) in dichloromethane (40 ml), THF (60 ml), dissolved in methanol (120 ml), 2N aqueous sodium hydroxide solution (40 ml, 80 mmol) was added at room temperature, and the mixture was stirred at 40 ° C.
  • Example 27-1 Methyl 5-formyl-1,6-dimethoxynaphthalene-2-carboxylate Methyl 1,6-dimethoxynaphthalene, a known compound instead of 6-methoxy-1-methylnaphthalene-2-carboxylate The reaction was carried out in the same manner as described in Example 26-3 using -2-carboxylate (7.8 g, 31.7 mmol) to obtain the title compound (3.2 g, yield: 37%).
  • Example 27-2 Methyl 1,6-dimethoxy-5- (3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9- Octahydro-1H-xanthen-9-yl) naphthalene-2-carboxylate methyl 5-formyl-6-methoxy-1-methylnaphthalene-2-carboxylate instead of methyl 5-
  • the reaction was performed in the same manner as described in Example 26-4 using formyl-1,6-dimethoxynaphthalene-2-carboxylate (7.14 g, 26.1 mmol), and the title compound (8.68 g, yield: 64) was obtained. %).
  • Example 27-3 1,6-dimethoxy-5- (3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro -1H-xanthen-9-yl) naphthalene-2-carboxylic acid Methyl 1,6-dimethoxy-5- (3,3,6,6-tetramethyl-1,8-dioxo prepared by Example 27-2 -2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl) naphthalene-2-carboxylate (9.99g, 19.3mmol) in THF (100ml), methanol (200ml) 2N aqueous sodium hydroxide solution (100 ml, 200 mmol) was added at room temperature, and the mixture was stirred at 86 ° C.
  • Example 28-1 Methyl [6-methoxy-5- (3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro -1H-xanthen-9-yl) naphthalen-2-yl] acetate methyl 5-formyl-6-methoxy-1-methylnaphthalene-2-carboxylate instead of the known compound methyl (5-formyl-6- Methoxynaphthalen-2-yl) acetate (308.1 mg, 1.19 mmol) was used in the same manner as in Example 26-4 to obtain the title compound (376.1 mg, yield: 63%). .
  • Example 28-2 [6-Methoxy-5- (3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro- 1H-xanthen-9-yl) naphthalen-2-yl] acetic acid 1,6-dimethoxy-5- (3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6 , 7,8,9-Octahydro-1H-xanthen-9-yl) naphthalene-2-carboxylate instead of methyl [6-methoxy-5- (3,3,6 , 6-Tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl) naphthalen-2-yl] acetate (376.1 mg, 0.749 The title compound (301.2 mg, yield: 82%) was obtained in the same manner as in Example 27.
  • Example 29-1 Ethyl (2E) -3- (5-formyl-6-methoxynaphthalen-2-yl) prop-2-enoate Instead of methyl 1,6-dimethoxynaphthalene-2-carboxylate, known The reaction was carried out in the same manner as described in Example 27-1 using the compound methyl (6-methoxynaphthalen-2-yl) acetate (1.28 g, 5.00 mmol), and the title compound (301.2 mg, yield: 82%).
  • Example 29-2 Ethyl (2E) -3- [6-methoxy-5- (3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7 , 8,9-Octahydro-1H-xanthen-9-yl) naphthalen-2-yl] prop-2-enoate instead of methyl 5-formyl-6-methoxy-1-methylnaphthalene-2-carboxylate
  • Example 26-4 was described using ethyl (2E) -3- (5-formyl-6-methoxynaphthalen-2-yl) prop-2-enoate (487.3 mg, 1.72 mmol) prepared by 29-1.
  • Example 29-3 (2E) -3- [6-Methoxy-5- (3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7, 8,9-Octahydro-1H-xanthen-9-yl) naphthalen-2-yl] prop-2-enoic acid 1,6-dimethoxy-5- (3,3,6,6-tetramethyl-1,8- Instead of dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl) naphthalene-2-carboxylate, the ethyl (2E ) -3- [6-Methoxy-5- (3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthene -9-yl) naphthalen-2-yl] prop-2-enoate (237.3 mg, 0.449 mmol) was used in the same
  • Example 30-1 Ethyl 3- [6-methoxy-5- (3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9 -Octahydro-1H-xanthen-9-yl) naphthalen-2-yl] propanoate
  • Example 30-2 3- [6-Methoxy-5- (3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9- Octahydro-1H-xanthen-9-yl) naphthalen-2-yl] propanoic acid 1,6-dimethoxy-5- (3,3,6,6-tetramethyl-1,8-dioxo-2,3,4, Instead of 5,6,7,8,9-octahydro-1H-xanthen-9-yl) naphthalene-2-carboxylate, ethyl 3- [6-methoxy-5- ( 3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl) naphthalen-2-yl] propanoate (284.3 mg, 0.537 mmol) was used in the same manner as in Example 27 to obtain the title compound (259.9 mg, yield:
  • Example 31-1 Ethyl (4-formyl-5-methoxy-2,3-dihydro-1H-inden-1-yl) acetate and ethyl (6-formyl-5-methoxy-2,3-dihydro- 1H-Inden-1-yl) acetate ethyl 2- (5-methoxy-2,3-dihydro-1H-inden-1-yl) acetate (21.2 g, 90.4 mmol), dichloromethyl methyl ether (25 ml, 282.7 mmol) To a dichloromethane solution (400 ml) was added titanium tetrachloride (1.0 M dichloromethane solution, 400 ml, 400 mmol) under ice cooling.
  • Example 31-2 Ethyl [5-methoxy-4- (3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro -1H-xanthen-9-yl) -2,3-dihydro-1H-inden-1-yl] acetate
  • the crude product obtained in Example 31-1-1 and 2 was dissolved in ethanol (100 ml) at room temperature.
  • Example 31-3 [5-Methoxy-4- (3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro- 1H-xanthen-9-yl) -2,3-dihydro-1H-inden-1-yl] acetic acid ethyl [5-methoxy-4- (3,3,6,6- Tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl) -2,3-dihydro-1H-inden-1-yl] To a dioxane solution (50 ml) of acetate (4.40 g, 8.70 mmol) was added 2N hydrochloric acid (50 ml, 100 mmol) at room temperature, and the mixture was heated to reflux for 3 hours.
  • Example 32-1 Ethyl (4-formyl-5-methoxy-2,3-dihydro-1H-inden-1-yl) acetate and ethyl (6-formyl-5-methoxy-2,3-dihydro- 1H-Inden-1-yl) acetate ethyl 2- (5-methoxy-2,3-dihydro-1H-inden-1-yl) acetate (21.2 g, 90.4 mmol), dichloromethyl methyl ether (25 ml, 282.7 mmol) To a dichloromethane solution (400 ml), titanium tetrachloride (1.0 M dichloromethane solution, 400 ml, 400 mmol) was added under ice water cooling.
  • Example 32-2 Ethyl [5-methoxy-6- (3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthene-9- Yl) -2,3-dihydro-1H-inden-1-yl] acetate
  • the crude product obtained in Example 32-1 was dissolved in ethanol (100 ml) and pyrrolidine (0.5 ml, 6.12 mmol) and 5 at room temperature.
  • 5-dimethylcyclohexane-1,3-dione (26.6 g, 190 mmol) was added, and the mixture was heated to reflux for 2 hours.
  • the administration solution was prepared using a mixed solution (PG: Tween) / v%, Nacalai Tesque Co., Ltd./Tween 80 (20v / v%, Nacalai Tesque Co., Ltd.).
  • the administration solution was forcibly orally administered to 4 to 5 mice in each group at a dose of 10 mg / kg.
  • 0.5% methylcellulose solution or propylene glycol / Tween 80 mixed solution was orally administered in a volume of 10 ml / kg or 5 ml / kg, respectively.
  • the oral glucose load was performed 30 minutes after administration of the test compound by oral administration of a glucose solution (Otsuka sugar solution 50%: Otsuka Pharmaceutical Co., Ltd.) at a dose of 3 g / kg.
  • Blood was collected from the tail vein of the mouse immediately before administration of the test compound (T0), 25 minutes after administration of the test compound (T1), 30 minutes after oral glucose load (T2) and 90 minutes (T3). Blood glucose level was measured with Check Aviva: Roche Diagnostics Co., Ltd. The T1 blood glucose level was analyzed as the value immediately before glucose load 30 minutes after compound administration. From the following formula, the area under the blood glucose level curve was determined, and the blood glucose reduction rate (%) from the subject group was calculated and shown in Table 1.
  • the compound of the present invention has an excellent blood glucose lowering effect, postprandial blood glucose inhibitory effect, glucose tolerance deficiency improving effect and the like. Therefore, the compound of the present invention is considered to be useful as a prophylactic / therapeutic agent for hyperglycemia, diabetes, and pathological conditions or diseases associated with these diseases.
  • ⁇ Formulation example> (Formulation Example 1) Capsule 50 mg of the compound of Example 1 or 2 Lactose 128mg Corn starch 70mg Magnesium stearate 2mg ----------------- 250mg After mixing the powder of the above formulation and passing through a 60 mesh sieve, this powder is put into a 250 mg gelatin capsule to form a capsule.
  • (Formulation Example 2) Tablet Example 1 or 2 Compound 50 mg Lactose 126mg Corn starch 23mg Magnesium stearate 1mg -------------- 200mg
  • the powder of the above formulation is mixed, granulated and dried using corn starch paste, and then tableted by a tableting machine to make one tablet of 200 mg. This tablet can be sugar-coated if necessary.
  • novel xanthene derivative represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent hypoglycemic action and is useful as a medicine.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Child & Adolescent Psychology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé présentant un exceptionnel effet de réduction des sucres sanguins et représenté par la formule générale (I), et un sel pharmaceutiquement acceptable de celui-ci. Dans la formule, X représente =C(R8)-, -CH(R8)-, =N- ou -O- ; Y représente =C(R9)-, -CH(R9)- ou =N- ; Z représente =C(R10)-, -CH(R9)- ou =N- ; n et m valent 0-1 ; R8 représente H ou un groupe alkyle en C1-3 (substitué en 1 par un groupe carboxy) ; R9 représente H, un groupe alkyle en C1-3 (substitué en 1 par un groupe carboxy), un groupe alcoxycarbonyle en C1-3, un groupe carboxy ou un groupe alcényle en C2-3 substitué par un groupe carboxy ; R10 représente H, un groupe alcoxy en C1-3, un groupe alkyle en C1-3 (substitué), un groupe aryle en C6-10, un hétérocycle à 3-10 chaînons, un groupe alcoxycarbonyle en C1-3, un groupe aminocarbonyle (substitué), un groupe alcényle en C2-3 substitué en 1 par un groupe carboxy, ou un groupe carboxy ; R1 représente H, un groupe alkyle en C1-3 (substitué), un groupe alcoxy en C1-3 (substitué), un groupe alcényle en C2-3 (substitué), un groupe cycloalkyle en C3-6 (substitué), un groupe alcoxycarbonyle en C1-3, un groupe aminocarbonyle (substitué), un groupe carbonyle hétérocyclique à 3-10 chaînons, un groupe carboxy ou un atome d'halogène ; R2 représente H, un groupe alkyle en C1-3, un groupe cycloalkyle en C3-6, un groupe alcoxy en C1-3, un groupe carboxy ou un atome d'halogène ; t vaut 1-2 ; R3 représente H, un groupe alkyle en C1-3 (substitué en 1 par un groupe carboxy), un groupe cycloalkyle en C3-6, un groupe alcoxy en C1-3(substitué en 1 par un groupe carboxy), ou un groupe carboxy ; et R4, 5 et R6, 7 représentent des groupes alkyle en C1-3 ou sont liés ensemble pour former un cycle carboné saturé à 3-6 chaînons.
PCT/JP2013/078258 2012-10-19 2013-10-18 Dérivé de xanthène WO2014061764A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2012231583 2012-10-19
JP2012-231583 2012-10-19

Publications (1)

Publication Number Publication Date
WO2014061764A1 true WO2014061764A1 (fr) 2014-04-24

Family

ID=50488320

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2013/078258 WO2014061764A1 (fr) 2012-10-19 2013-10-18 Dérivé de xanthène

Country Status (2)

Country Link
TW (1) TW201422611A (fr)
WO (1) WO2014061764A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016204134A1 (fr) * 2015-06-15 2016-12-22 第一三共株式会社 Dérivé hétérocyclique à six chaînons
WO2016204135A1 (fr) * 2015-06-15 2016-12-22 第一三共株式会社 Dérivé hétérocyclique à cinq chaînons

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998047505A1 (fr) * 1997-04-23 1998-10-29 Banyu Pharmaceutical Co., Ltd. Antagoniste de recepteur de neuropeptide y
WO1999015516A1 (fr) * 1997-09-25 1999-04-01 Banyu Pharmaceutical Co., Ltd. Nouveaux antagonistes des recepteurs de neuropeptides y
WO2006065842A2 (fr) * 2004-12-13 2006-06-22 Synta Pharmaceuticals Corp. 5,6,7,8-tetrahydroquinoleines et composes associes et leurs utilisations

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998047505A1 (fr) * 1997-04-23 1998-10-29 Banyu Pharmaceutical Co., Ltd. Antagoniste de recepteur de neuropeptide y
WO1999015516A1 (fr) * 1997-09-25 1999-04-01 Banyu Pharmaceutical Co., Ltd. Nouveaux antagonistes des recepteurs de neuropeptides y
WO2006065842A2 (fr) * 2004-12-13 2006-06-22 Synta Pharmaceuticals Corp. 5,6,7,8-tetrahydroquinoleines et composes associes et leurs utilisations

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE CAS 25 September 2007 (2007-09-25), accession no. 47971-59-7 *
NAGARAJAN,K. ET AL.: "Synthesis and oral hypoglycemic properties of 3-(1-oxo-3-hydroxy- 2-cyclohexen-2-yl)-4-oxo-4,5,6,7- tetrahydroindoles", INDIAN JOURNAL OF CHEMISTRY, SECTION B: ORGANIC CHEMISTRY INCLUDING MEDICINAL CHEMISTRY, vol. 28B, no. 4, 1989, pages 326 - 332 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016204134A1 (fr) * 2015-06-15 2016-12-22 第一三共株式会社 Dérivé hétérocyclique à six chaînons
WO2016204135A1 (fr) * 2015-06-15 2016-12-22 第一三共株式会社 Dérivé hétérocyclique à cinq chaînons

Also Published As

Publication number Publication date
TW201422611A (zh) 2014-06-16

Similar Documents

Publication Publication Date Title
CA3029857C (fr) Compose d'acetylene aromatique ou d'ethylene aromatique, produit intermediaire, procede de preparation, composition pharmaceutique et leur utilisation
KR101021828B1 (ko) 2 이상의 치환기를 갖는 벤젠 화합물
KR102474640B1 (ko) 카르복실산 화합물, 이의 제조방법, 및 이의 용도
AU599029B2 (en) Ascorbic acid derivatives, production and use thereof
CN107793396B (zh) 环氧基取代的氧代吡啶类衍生物、其制备方法及其在医药上的应用
US8227511B2 (en) Substituted chromanol derivatives and their use
TW201718561A (zh) 苯並呋喃類衍生物、其製備方法及其在醫藥上的應用
WO2003070686A1 (fr) Derive de l'acide phenylalcanoyle substitue et son utilisation
CN114269755A (zh) 作为magl抑制剂的4,4a,5,7,8,8a-六吡啶并[4,3-b][1,4]噁嗪-3-酮化合物
CN110357789B (zh) 作为dhodh抑制剂的n-取代丙烯酰胺衍生物及其制备和用途
WO2019031618A1 (fr) Composé de pyridine substitué par un azole
CN103333134A (zh) 2-(3-氰基-4-烷氧基)苯基-4-取代噻唑-5-甲酸类化合物、组合物及其制备方法和用途
WO2014061764A1 (fr) Dérivé de xanthène
JP2013525267A (ja) ペルオキシソーム増殖剤活性化受容体リガンドのセレナゾール誘導体、その製造方法及びその化合物の用途
JP6219817B2 (ja) フェニルキサンテン誘導体
TW201236685A (en) New pyrazole amide derivatives
WO2022171088A1 (fr) Dérivé de pyrazolo[3,4-d]pyrimidin-3-one
CN110709393A (zh) Ldha活性抑制剂
CN114539229A (zh) 嘧啶二酮类衍生物、其制备方法及其在医药上的应用
EP4003955A1 (fr) Inhibiteurs de l'atgl humain
WO2022002100A1 (fr) Nouveau composé de benzimidazole
US5428059A (en) Benzopyran derivatives and an anti-allergic agent possessing the same as the active ingredient
CN106674245B (zh) 吡喃葡萄糖基衍生物的制备及医药上的应用
WO2010060277A1 (fr) Dérivés d'hydrazide de type acétyle substitué, leur synthèse et leurs applications
TW201710264A (zh) ５員雜環衍生物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 13847196

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 13847196

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP