WO2014061764A1 - Xanthene derivative - Google Patents

Xanthene derivative Download PDF

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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
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Prior art keywords
group
substituted
dimethyl
benzofuran
tert
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PCT/JP2013/078258
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French (fr)
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
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第一三共株式会社
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Publication of WO2014061764A1 publication Critical patent/WO2014061764A1/en

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    • 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.

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Abstract

A compound having an exceptional blood-sugar-reducing effect and represented by general formula (I), and a pharmaceutically acceptable salt thereof. In the formula, X is =C(R8)-, -CH(R8)-, =N-, or -O-; Y is =C(R9)-, -CH(R9)-, or =N-; Z is =C(R10)-, -CH(R9)-, or =N-; n and m are 0-1; R8 is H or a (carboxy-1-substituted)C1-3 alkyl; R9 is H, a (carboxy-1-substituted) C1-3 alkyl, a C1-3 alkoxycarbonyl, a carboxy, or a carboxy-substituted C2-3 alkenyl; R10 is H, a C1-3 alkoxy, a (substituted) C1-3 alkyl, a C6-10 aryl, a 3-10 membered heterocycle, a C1-3 alkoxycarbonyl, a (substituted) aminocarbonyl, a carboxy-1-substituted C2-3 alkenyl, or a carboxy); R1 is H, a (substituted) C1-3 alkyl, a (substituted) C1-3 alkoxy, a (substituted) C2-3 alkenyl, a (substituted) C3-6 cycloalkyl, a C1-3 alkoxycarbonyl, a (substituted) aminocarbonyl, a 3-10-member heterocyclic carbonyl, a carboxy, or a halogen; R2 is H, a C1-3 alkyl, a C3-6 cycloalkyl, a C1-3 alkoxy, a carboxy, or a halogen; t is 1-2; R3 is H, a (carboxy-1-substituted) C1-3 alkyl, a C3-6 cycloalkyl, a (carboxy-1-substituted) C1-3 alkoxy, or carboxy; and R4, 5 and R6, 7 are C1-3 alkyls, or bond together to form a 3-6-member saturated carbon ring.

Description

キサンテン誘導体Xanthene derivatives
　本発明は、血糖低下等の作用を有し、糖尿病等の治療薬及び／又は予防薬として有用な新規な化合物及びその薬理上許容される塩に関する。 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.
　本発明は、上記化合物又はその薬理上許容される塩を有効成分として含有する糖尿病（1型糖尿病、2型糖尿病、妊娠糖尿病等）、食後過血糖症、耐糖能障害、糖尿病性神経障害、糖尿病性腎症、糖尿病性網膜症、高脂血症、動脈硬化症、血栓性疾患、肥満、高血圧、浮腫、インスリン抵抗性、不安定糖尿病、インスリノーマ、高インスリン血症等の治療薬及び／又は予防薬（好適には糖尿病の治療薬及び／又は予防薬である）に関する。 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).
　更に、本発明は、上記化合物を有効成分として含有する上記疾病の予防若しくは治療のための組成物、上記疾病の予防若しくは治療のための医薬を製造するための上記化合物の使用、又は上記化合物の薬理的な有効量を哺乳動物（好適には人間である）に投与する上記疾病の予防若しくは治療方法に関する。 Furthermore, 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).
　糖尿病は、慢性的な高血糖を主徴とする疾患であり、インスリン作用の絶対的または相対的な不足により発症する。臨床においてはその特徴からインスリン依存性糖尿病（1型糖尿病）とインスリン非依存性糖尿病（2型糖尿病）に大別される。 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).
　現在、糖尿病の治療は基本的に食事療法と運動療法である。しかし、これらだけで血糖値をコントロールできなくなった場合、薬物が投与される。そこで、より安全で効果の高い薬剤が求められている。 Currently, diabetes treatment is basically diet therapy and exercise therapy. However, if the blood sugar level cannot be controlled by these alone, a drug is administered. Therefore, there is a demand for safer and more effective drugs.
　特許文献１には、本発明の化合物と一部共通する部分構造を有し、単純疱疹ウイルスによって惹起される感染症の治療及び予防効果を有する化合物が開示されている。 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.
国際公開第2010/011318号パンフレット（対応する米国特許番号：US6162918及びUS5969139）International Publication No. 2010/011318 (corresponding US Patent Numbers: US6162918 and US5969139)
　本発明者らは、鋭意研究を重ねた結果、後記式(I)で表わされる化合物がその特異的な化学構造に基づいて、非常に優れた血糖低下等の作用活性を有し、更に安定性等の医薬品としての物性においても優れた性質を有しており、高血糖症、糖尿病及びそれら疾病に関連する病態または疾患の予防・治療薬として安全でかつ有用な医薬となることを見出し、これらの知見に基づいて本発明を完成した。 As a result of intensive research, 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.
　即ち、本発明は、血糖降下作用等を有し糖尿病（1型糖尿病、2型糖尿病、妊娠糖尿病等）、食後過血糖症、耐糖能障害、糖尿病性神経障害、糖尿病性腎症、糖尿病性網膜症、高脂血症、動脈硬化症、血栓性疾患、肥満、高血圧、浮腫、インスリン抵抗性、不安定糖尿病、インスリノーマ、高インスリン血症などの疾患、特に、2型糖尿病に対する予防・治療剤として有用である。 That is, 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 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.
　本発明は、
（１）　下記一般式（I） The present invention
(1) The following general formula (I)
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
［式中、 [Where:
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
は二重結合又は単結合を示し、
Xは、=C(-R8)-、-CH(-R8)-、 =N- 又は -O- を示し、
Yは、=C(-R9)- 、 -CH(-R9)-又は =N- を示し、
Zは、=C(-R10)- 、 -CH(-R9)-又は =N- を示し、
R1は、水素原子、置換基群αから選ばれる1若しくは2個の基に置換されていてもよいC1-C3アルキル基、置換基群αから選ばれる1若しくは2個の基に置換されていてもよいC1-C3アルコキシ基、置換基群αから選ばれる1若しくは2個の基に置換されていてもよいC2-C3アルケニル基、置換基群αから選ばれる1若しくは2個の基に置換されていてもよいC3-C6シクロアルキル基、C1-C3アルコキシカルボニル基、置換基群αから選ばれる1又は2個の基に置換されていてもよいアミノカルボニル基、窒素、酸素及び硫黄から選択される同一若しくは異なった1-3個のヘテロ原子を含む3-10員複素環カルボニル基、カルボキシル基又はハロゲン原子を示し、
R2は、同一又は異なって、水素原子、C1-C3アルキル基、C3-C6シクロアルキル基、C1-C3アルコキシ基、カルボキシル基若しくはハロゲン原子を示し、
R3は、水素原子、C1-C3アルキル基（該アルキル基は、カルボキシル基で1個置換されていても良い）、C3-C6シクロアルキル基、C1-C3アルコキシ基（該アルコキシ基は、C1-C3アルコキシ基で1個置換されていても良い）、カルボキシル基、を示し、
R4及びR5は、それぞれ同一若しくは異なって、C1-C3アルキル基を示すか又は、R4及びR5が結合して3-6員飽和炭素環を形成していてもよく、
R6及びR7は、それぞれ同一若しくは異なって、C1-C3アルキル基を示すか又は、R6及びR7が結合して3-6員飽和炭素環を形成していてもよく、
R8は、水素原子、C1-C3アルキル基（該アルキル基は、カルボキシル基で1個置換されていても良い）を示し、
R9は、水素原子、C1-C3アルキル基（該アルキル基は、カルボキシル基で1個置換されていても良い）、C1-C3アルコキシカルボニル基、カルボキシル基、カルボキシル基で1個置換されたC2-C3アルケニル基を示し、
R10は、水素原子、C1-C3アルコキシ基、置換基群αから選ばれる1又は2個の基に置換されていてもよいC1-C3アルキル基、C6-C10アリール基、窒素、酸素及び硫黄から選択される同一若しくは異なった1-3個のヘテロ原子を含む3-10員複素環基、C1-C3アルコキシカルボニル基、置換基群αから選ばれる基に1又は2個の基に置換されていてもよいアミノカルボニル基、カルボキシル基で1個置換されたC2-C3アルケニル基、若しくはカルボキシル基を示し、
nは、0又は1を示し、
mは、0又は1を示し、
tは、1又は2を示し、
ただし、Xが=C(-R8)-、Yが=C(-R9)- 及びZが=C(-R10)- を示す場合、R9又はR10のいずれか一つが、C1-C3アルコキシカルボニル基、カルボキシル基、カルボキシル基で1個置換されたC1-C3アルキル基若しくはカルボキシル基で1個置換されたC2-C3アルケニル基を示し、
Xが-O- を示す場合、Zは=C(-R10)-を示す。 Represents a double bond or a single bond,
X represents = C (-R 8 )-, -CH (-R 8 )-, = N- or -O-
Y represents = C (-R 9 )-, -CH (-R 9 )-or = N-
Z represents = C (-R 10 )-, -CH (-R 9 )-or = N-
R 1 is a hydrogen atom, a C1-C3 alkyl group which may be substituted with one or two groups selected from substituent group α, and one or two groups selected from substituent group α. C1-C3 alkoxy group which may be substituted, 1 or 2 groups selected from substituent group α may be substituted with C2-C3 alkenyl group which may be substituted, 1 or 2 groups selected from substituent group α 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 α, nitrogen, oxygen and sulfur A 3- to 10-membered heterocyclic carbonyl group containing the same or different 1-3 heteroatoms, a carboxyl group or a halogen atom,
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 (the alkyl group may be substituted with one carboxyl group), a C3-C6 cycloalkyl group, a C1-C3 alkoxy group (the alkoxy group is C1 -Optionally substituted with a -C3 alkoxy group), a carboxyl group,
R 4 and R 5 are the same or different and each represents a C1-C3 alkyl group, or R 4 and R 5 may be bonded to form a 3-6 membered saturated carbocycle,
R 6 and R 7 are the same or different and each represents a C1-C3 alkyl group, or R 6 and R 7 may be bonded to form a 3-6 membered saturated carbocycle,
R 8 represents a hydrogen atom or a C1-C3 alkyl group (the alkyl group may be substituted with one carboxyl group),
R 9 is a hydrogen atom, a C1-C3 alkyl group (the alkyl group may be substituted with one carboxyl group), a C1-C3 alkoxycarbonyl group, a carboxyl group, or a C2 substituted with one carboxyl group. -C3 represents an alkenyl 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 α, 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 α is substituted with 1 or 2 groups An aminocarbonyl group, a C2-C3 alkenyl group substituted with one carboxyl group, or a carboxyl group,
n represents 0 or 1,
m represents 0 or 1,
t represents 1 or 2,
However, when X is = C (-R 8 )-, Y is = C (-R 9 )-and Z is = C (-R 10 )-, 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,
When X represents -O-, Z represents = C (-R 10 )-.
　（置換基群α）
水酸基、C1-C3アルキル基（該アルキル基は、カルボキシル基、C1-C3アルキルスルホニル基で1若しくは2個置換されていてもよいアミノカルボニル基、C3-C6シクロアルキル基又は水酸基で、1若しくは2個置換されていても良い）、C3-C6シクロアルキル基（該シクロアルキル基は、水酸基で1又は2個置換されていても良い）、アミノカルボニル基、カルボキシル基、
C1-C3アルキルスルホニル基、窒素、酸素及び硫黄から選択される同一若しくは異なった1-3個のヘテロ原子を含む3-10員複素環基（該複素環基は、カルボキシル基で1個置換されていても良い）、窒素、酸素及び硫黄から選択される同一若しくは異なった1-3個のヘテロ原子を含む3-10員複素環C1-C3アルキル基（該複素環C1-C3アルキル基は、C1-C3ヒドロキシアルキル基又はカルボキシル基で1若しくは2個置換されていても良い）］で表される化合物又はその薬理上許容される塩、
（２）　Xが=C(-R8)- 又は -O- である、上記（１）に記載の化合物又はその薬理上許容される塩、
（３）　Zが=C(-R10)- である、上記（１）又は（２）に記載の化合物又はその薬理上許容される塩、
（４）　下記一般式（IA） (Substituent group α)
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 alkyl group is Or a pharmacologically acceptable salt thereof, which may be substituted with one or two C1-C3 hydroxyalkyl groups or carboxyl groups)],
(2) The compound or pharmacologically acceptable salt thereof according to (1) above, wherein X is = C (-R 8 )-or -O-,
(3) The compound or pharmacologically acceptable salt thereof according to the above (1) or (2), wherein Z is = C (-R 10 )-
(4) The following general formula (IA)
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
［式中、
R1は、水素原子、置換基群αから選ばれる1若しくは2個の基に置換されていてもよいC1-C3アルキル基、置換基群αから選ばれる1若しくは2個の基に置換されていてもよいC1-C3アルコキシ基、置換基群αから選ばれる1若しくは2個の基に置換されていてもよいC2-C3アルケニル基、置換基群αから選ばれる1若しくは2個の基に置換されていてもよいC3-C6シクロアルキル基、C1-C3アルコキシカルボニル基、置換基群αから選ばれる1又は2個の基に置換されていてもよいアミノカルボニル基、窒素、酸素及び硫黄から選択される同一若しくは異なった1-3個のヘテロ原子を含む3-10員複素環カルボニル基、カルボキシル基又はハロゲン原子を示し、
R2は、同一又は異なって、水素原子、C1-C3アルキル基、C3-C6シクロアルキル基、C1-C3アルコキシ基、カルボキシル基若しくはハロゲン原子を示し、
R4及びR5は、それぞれ同一若しくは異なって、C1-C3アルキル基を示すか又は、R4及びR5が結合して3-6員飽和炭素環を形成していてもよく、
R6及びR7は、それぞれ同一若しくは異なって、C1-C3アルキル基を示すか又は、R6及びR7が結合して3-6員飽和炭素環を形成していてもよく、
R10は、水素原子、C1-C3アルコキシ基、置換基群αから選ばれる1又は2個の基に置換されていてもよいC1-C3アルキル基、C6-C10アリール基、窒素、酸素及び硫黄から選択される同一若しくは異なった1-3個のヘテロ原子を含む3-10員複素環基、C1-C3アルコキシカルボニル基、置換基群αから選ばれる基に1又は2個の基に置換されていてもよいアミノカルボニル基カルボキシル基で1個置換されたC2-C3アルケニル基、若しくはカルボキシル基を示し、
tは、1又は2を示す。 [Where:
R 1 is a hydrogen atom, a C1-C3 alkyl group which may be substituted with one or two groups selected from substituent group α, and one or two groups selected from substituent group α. C1-C3 alkoxy group which may be substituted, 1 or 2 groups selected from substituent group α may be substituted with C2-C3 alkenyl group which may be substituted, 1 or 2 groups selected from substituent group α 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 α, nitrogen, oxygen and sulfur A 3- to 10-membered heterocyclic carbonyl group containing the same or different 1-3 heteroatoms, a carboxyl group or a halogen atom,
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 4 and R 5 are the same or different and each represents a C1-C3 alkyl group, or R 4 and R 5 may be bonded to form a 3-6 membered saturated carbocycle,
R 6 and R 7 are the same or different and each represents a C1-C3 alkyl group, or R 6 and R 7 may be bonded to form a 3-6 membered saturated carbocycle,
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 α, 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 α 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.
　（置換基群α）
水酸基、C1-C3アルキル基（該アルキル基は、カルボキシル基、C1-C3アルキルスルホニル基で1若しくは2個置換されていてもよいアミノカルボニル基、C3-C6シクロアルキル基又は水酸基で、1若しくは2個置換されていても良い）、C3-C6シクロアルキル基（該シクロアルキル基は、水酸基で1又は2個置換されていても良い）、アミノカルボニル基、カルボキシル基、
C1-C3アルキルスルホニル基、窒素、酸素及び硫黄から選択される同一若しくは異なった1-3個のヘテロ原子を含む3-10員複素環基（該複素環基は、カルボキシル基で1個置換されていても良い）、窒素、酸素及び硫黄から選択される同一若しくは異なった1-3個のヘテロ原子を含む3-10員複素環C1-C3アルキル基（該複素環C1-C3アルキル基は、C1-C3ヒドロキシアルキル基又はカルボキシル基で1若しくは2個置換されていても良い）］で表される化合物又はその薬理上許容される塩、
（５）　R1が置換基群αから選ばれる1若しくは2個の基に置換されていてもよいC1-C3アルキル基又はカルボキシル基である、上記（４）に記載の化合物又はその薬理上許容される塩、
（５－１）　R1が、カルボキシル基に置換されていてもよいC1-C3アルキル基又はカルボキシル基である、上記（４）に記載の化合物又はその薬理上許容される塩、
（６）　R2が、同一又は異なって、水素原子若しくはC1-C3アルキル基である、上記（４）又は（５）に記載の化合物若しくはその薬理上許容される塩、
（６－１）　R2が、メチル基である、上記（４）又は（５）に記載の化合物若しくはその薬理上許容される塩、
（７）　R10が置換基群αから選ばれる1又は2個の基に置換されていてもよいC1-C3アルキル基である、上記（１）乃至（６）から選択されるいずれか１つに記載の化合物若しくはその薬理上許容される塩、
（７－１）　R10がメチル基である、上記（１）乃至（６）から選択されるいずれか１項に記載の化合物若しくはその薬理上許容される塩、
（８）　R4、R5、R6及びR7がC1-C3アルキル基である上記（１）乃至（７）から選択されるいずれか１つに記載の化合物又はその薬理上許容される塩、
（８－１）　R4、R5、R6及びR7がメチル基である上記（１）乃至（７）から選択されるいずれか１項に記載の化合物又はその薬理上許容される塩、
（９）　下記式 (Substituent group α)
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 alkyl group is Or a pharmacologically acceptable salt thereof, which may be substituted with one or two C1-C3 hydroxyalkyl groups or carboxyl groups)],
(5) The compound according to (4) above or a pharmacologically acceptable salt thereof, wherein R 1 is a C1-C3 alkyl group or a carboxyl group optionally substituted with one or two groups selected from substituent group α. Salt,
(5-1) The compound according to (4) or a pharmacologically acceptable salt thereof, wherein R 1 is a C1-C3 alkyl group or a carboxyl group optionally substituted with a carboxyl group,
(6) The compound or pharmacologically acceptable salt thereof according to (4) or (5), wherein R 2 is the same or different and is a hydrogen atom or a C1-C3 alkyl group,
(6-1) The compound according to (4) or (5) above, wherein R 2 is a methyl group, or a pharmacologically acceptable salt thereof,
(7) Any one selected from (1) to (6) above, wherein R 10 is a C1-C3 alkyl group optionally substituted by one or two groups selected from substituent group α. Or a pharmacologically acceptable salt thereof,
(7-1) The compound according to any one of (1) to (6), wherein R 10 is a methyl group, or a pharmaceutically acceptable salt thereof,
(8) The compound according to any one of (1) to (7) or a pharmacologically acceptable salt thereof, wherein R 4 , R 5 , R 6 and R 7 are C1-C3 alkyl groups. ,
(8-1) The compound according to any one of (1) to (7), wherein R 4 , R 5 , R 6 and R 7 are methyl groups, or a pharmacologically acceptable salt thereof,
(9) The following formula
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
で表される、2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-カルボン酸、
（１０）　下記式 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-carboxylic acid,
(10) The following formula
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
で表される、7-(1’,8’-ジオキソ-1’,4’,5’,7’,8’,9’-ヘキサヒドロ-2’H-ジスピロ[シクロブタン-1,3’-キサンテン-6’,1”-シクロブタン]-9’-イル)-2,4-ジメチル-1-ベンゾフラン-5-カルボン酸、
（１１）　下記式 7- (1 ′, 8′-dioxo-1 ′, 4 ′, 5 ′, 7 ′, 8 ′, 9′-hexahydro-2′H-dispiro [cyclobutane-1,3′-xanthene -6 ', 1 "-cyclobutane] -9'-yl) -2,4-dimethyl-1-benzofuran-5-carboxylic acid,
(11) The following formula
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
で表される、3-[2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-イル]-2-メチルプロパン酸、
（１２）　下記式 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-methylpropanoic acid,
(12) The following formula
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
で表される、2-[2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-イル]ブタン酸、
（１３）　下記式 2- [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] butanoic acid,
(13) The following formula
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
で表される、6-メトキシ-1-メチル-5-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)ナフタレン-2-カルボン酸、
（１４）　下記式 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,
(14) The following formula
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
で表される、1,6-ジメトキシ-5-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)ナフタレン-2-カルボン酸、
（１５）　上記（９）乃至（１４）から選択されるいずれか１つに記載の化合物若しくはその薬理上許容される塩、
（１６）　上記（９）乃至（１４）から選択されるいずれか１つに記載の化合物の2-メチルプロパン-2-アミン塩、
（１７）　上記（９）乃至（１４）から選択されるいずれか１つに記載の化合物のナトリウム塩、
（１８）　上記（１）乃至（１７）から選択されるいずれか１つに記載の化合物又はその薬理上許容される塩を有効成分として含有する血糖降下剤、
（１９）　上記（１）乃至（１７）から選択されるいずれか１つに記載の化合物又はその薬理上許容される塩を有効成分として含有する医薬、
（２０）　糖尿病、食後過血糖症、耐糖能障害、糖尿病性神経障害、糖尿病性腎症、糖尿病性網膜症、高脂血症、動脈硬化症、血栓性疾患、肥満、高血圧、浮腫、インスリン抵抗性、不安定糖尿病、インスリノーマ又は高インスリン血症の治療若しくは予防のための、上記（１９）に記載の医薬、
（２１）　糖尿病、食後過血糖症、耐糖能障害又はインスリン抵抗性の治療若しくは予防のための、上記（１９）に記載の医薬、
（２２）　2型糖尿病の治療のための、上記（１９）に記載の医薬、
（２３）　医薬組成物を製造するための、上記（１）乃至（１７）から選択されるいずれか一つに記載された化合物又はその薬理上許容される塩の使用、
（２４）　上記（１）乃至（１７）から選択されるいずれか一つに記載された化合物又はその薬理上許容される塩の薬理的な有効量を温血動物に投与することを含む、2型糖尿病の治療又は予防方法、
（２５）　下記一般式（IB） 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,
(15) The compound according to any one of (9) to (14) or a pharmacologically acceptable salt thereof,
(16) a 2-methylpropan-2-amine salt of the compound according to any one of (9) to (14),
(17) A sodium salt of the compound according to any one of (9) to (14),
(18) A hypoglycemic agent comprising as an active ingredient the compound according to any one of (1) to (17) or a pharmacologically acceptable salt thereof,
(19) A medicament comprising as an active ingredient the compound according to any one of (1) to (17) or a pharmacologically acceptable salt thereof,
(20) Diabetes, postprandial hyperglycemia, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, hyperlipidemia, arteriosclerosis, thrombotic disease, obesity, hypertension, edema, insulin resistance The medicament according to (19) above for the treatment or prevention of sex, unstable diabetes, insulinoma or hyperinsulinemia,
(21) The medicament according to (19) above for the treatment or prevention of diabetes, postprandial hyperglycemia, impaired glucose tolerance or insulin resistance,
(22) The medicament according to (19) above for the treatment of type 2 diabetes,
(23) Use of the compound described in any one of (1) to (17) or a pharmacologically acceptable salt thereof for producing a pharmaceutical composition,
(24) comprising administering to a warm-blooded animal a pharmacologically effective amount of the compound described in any one of (1) to (17) above or a pharmacologically acceptable salt thereof, Treatment or prevention of type 2 diabetes,
(25) The following general formula (IB)
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
［式中、
R1は、水素原子、置換基群αから選ばれる1若しくは2個の基に置換されていてもよいC1-C3アルキル基、置換基群αから選ばれる1若しくは2個の基に置換されていてもよいC1-C3アルコキシ基、置換基群αから選ばれる1若しくは2個の基に置換されていてもよいC2-C3アルケニル基、置換基群αから選ばれる1若しくは2個の基に置換されていてもよいC3-C6シクロアルキル基、C1-C3アルコキシカルボニル基、置換基群αから選ばれる1又は2個の基に置換されていてもよいアミノカルボニル基、窒素、酸素及び硫黄から選択される同一若しくは異なった1-3個のヘテロ原子を含む3-10員複素環カルボニル基、カルボキシル基又はハロゲン原子を示し、
R2は、同一又は異なって、水素原子、C1-C3アルキル基、C3-C6シクロアルキル基、C1-C3アルコキシ基、カルボキシル基若しくはハロゲン原子を示し、
R3は、水素原子、C1-C3アルキル基（該アルキル基は、カルボキシル基で1個置換されていても良い）、C3-C6シクロアルキル基、C1-C3アルコキシ基（該アルコキシ基は、C1-C3アルコキシ基で1個置換されていても良い）、カルボキシル基を示し、
R4及びR5は、それぞれ同一若しくは異なって、C1-C3アルキル基を示すか又は、R4及びR5が結合して3-6員飽和炭素環を形成していてもよく、
R6及びR7は、それぞれ同一若しくは異なって、C1-C3アルキル基を示すか又は、R6及びR7が結合して3-6員飽和炭素環を形成していてもよく、
R8は、水素原子、C1-C3アルキル基（該アルキル基は、カルボキシル基で1個置換されていても良い）を示し、
R9は、水素原子、C1-C3アルキル基（該アルキル基は、カルボキシル基で1個置換されていても良い）、C1-C3アルコキシカルボニル基、カルボキシル基、カルボキシル基で1個置換されたC2-C3アルケニル基を示し、
R10は、水素原子、C1-C3アルコキシ基、置換基群αから選ばれる1又は2個の基に置換されていてもよいC1-C3アルキル基、C6-C10アリール基、窒素、酸素及び硫黄から選択される同一若しくは異なった1-3個のヘテロ原子を含む3-10員複素環基、C1-C3アルコキシカルボニル基、置換基群αから選ばれる基に1又は2個の基に置換されていてもよいアミノカルボニル基、カルボキシル基で1個置換されたC2-C3アルケニル基若しくはカルボキシル基を示し、
ただし、R9又はR10のいずれか一つが、C1-C3アルコキシカルボニル基、カルボキシル基、カルボキシル基で1個置換されたC1-C3アルキル基若しくはカルボキシル基で1個置換されたC2-C3アルケニル基を示す。 [Where:
R 1 is a hydrogen atom, a C1-C3 alkyl group which may be substituted with one or two groups selected from substituent group α, and one or two groups selected from substituent group α. C1-C3 alkoxy group which may be substituted, 1 or 2 groups selected from substituent group α may be substituted with C2-C3 alkenyl group which may be substituted, 1 or 2 groups selected from substituent group α 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 α, nitrogen, oxygen and sulfur A 3- to 10-membered heterocyclic carbonyl group containing the same or different 1-3 heteroatoms, a carboxyl group or a halogen atom,
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 (the alkyl group may be substituted with one carboxyl group), a C3-C6 cycloalkyl group, a C1-C3 alkoxy group (the alkoxy group is C1 -Optionally substituted with a -C3 alkoxy group), indicating a carboxyl group,
R 4 and R 5 are the same or different and each represents a C1-C3 alkyl group, or R 4 and R 5 may be bonded to form a 3-6 membered saturated carbocycle,
R 6 and R 7 are the same or different and each represents a C1-C3 alkyl group, or R 6 and R 7 may be bonded to form a 3-6 membered saturated carbocycle,
R 8 represents a hydrogen atom or a C1-C3 alkyl group (the alkyl group may be substituted with one carboxyl group),
R 9 is a hydrogen atom, a C1-C3 alkyl group (the alkyl group may be substituted with one carboxyl group), a C1-C3 alkoxycarbonyl group, a carboxyl group, or a C2 substituted with one carboxyl group. -C3 represents an alkenyl 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 α, 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 α 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.
　（置換基群α）
水酸基、C1-C3アルキル基（該アルキル基は、カルボキシル基、C1-C3アルキルスルホニル基で1若しくは2個置換されていてもよいアミノカルボニル基、C3-C6シクロアルキル基又は水酸基で、1若しくは2個置換されていても良い）、C3-C6シクロアルキル基（該シクロアルキル基は、水酸基で1又は2個置換されていても良い）、アミノカルボニル基、カルボキシル基、C1-C3アルキルスルホニル基、窒素、酸素及び硫黄から選択される同一若しくは異なった1-3個のヘテロ原子を含む3-10員複素環基（該複素環基は、カルボキシル基で1個置換されていても良い）、窒素、酸素及び硫黄から選択される同一若しくは異なった1-3個のヘテロ原子を含む3-10員複素環C1-C3アルキル基（該複素環C1-C3アルキル基は、C1-C3ヒドロキシアルキル基又はカルボキシル基で1若しくは2個置換されていても良い）］で表される化合物又はその薬理上許容される塩、
（２６）　R1が水素原子である、上記（２５）に記載の化合物又はその薬理上許容される塩、
（２７）　R2が、C1-C3アルコキシ基である、上記（２５）又は（２６）に記載の化合物又はその薬理上許容される塩、
（２８）　R3が、C1-C3アルキル基（該アルキル基は、カルボキシル基で1個置換されていても良い）又はC1-C3アルコキシ基である、上記（２５）乃至（２７）のいずれか１つに記載の化合物又はその薬理上許容される塩、
（２９）　R8が水素原子である、上記（２５）乃至（２８）のいずれか１つに記載の化合物又はその薬理上許容される塩、
（３０）　R9が水素原子である、上記（２５）乃至（２９）のいずれか１つに記載の化合物又はその薬理上許容される塩、
（３１）　R10が置換基群αから選ばれる1又は2個の基に置換されていてもよいC1-C3アルキル基若しくはカルボキシル基である、上記（２５）乃至（３０）のいずれか１つに記載の化合物又はその薬理上許容される塩、
（３２）　上記（２５）乃至（３１）のいずれか１つに記載の化合物の2-メチルプロパン-2-アミン塩、
（３３）　上記（２５）乃至（３２）のいずれか１つに記載の化合物又はその薬理上許容される塩を有効成分として含有する医薬である。 (Substituent group α)
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-C3 alkyl group is a C1-C3 hydroxyalkyl group or 1 young with carboxyl group Two optionally substituted) compound or a pharmacologically acceptable salt thereof represented by,
(26) The compound according to (25) or a pharmacologically acceptable salt thereof, wherein R 1 is a hydrogen atom.
(27) The compound or pharmacologically acceptable salt thereof according to (25) or (26) above, wherein R 2 is a C1-C3 alkoxy group,
(28) Any of the above (25) to (27), wherein R 3 is a C1-C3 alkyl group (the alkyl group may be substituted with one carboxyl group) or a C1-C3 alkoxy group. The compound according to one or a pharmacologically acceptable salt thereof,
(29) The compound according to any one of (25) to (28) above, wherein R 8 is a hydrogen atom, or a pharmacologically acceptable salt thereof,
(30) The compound according to any one of (25) to (29) above, wherein R 9 is a hydrogen atom, or a pharmacologically acceptable salt thereof,
(31) Any one of the above (25) to (30), wherein R 10 is a C1-C3 alkyl group or a carboxyl group optionally substituted by one or two groups selected from substituent group α Or a pharmacologically acceptable salt thereof,
(32) 2-methylpropan-2-amine salt of the compound according to any one of (25) to (31) above,
(33) A medicament comprising the compound according to any one of (25) to (32) above or a pharmacologically acceptable salt thereof as an active ingredient.
 
　本発明において、「C1-C3アルキル基」とは、炭素原子を1個乃至3個有する直鎖状又は分枝鎖状のアルキル基であり、例えば、メチル、エチル、n-プロピル若しくはイソプロピル基を挙げることができる。R1、R2、R3、R4、R5、R6、R7、R8、R9、R10及び置換基群αにおいては、好適にはメチル又はエチル基である。
In the present invention, 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. Can be mentioned. R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and the substituent group α are preferably methyl or ethyl groups.
　本発明において、「C3-C6シクロアルキル基」とは、3乃至6員飽和環状炭化水素基であり、例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル基を挙げることができる。R1、R 2、R3、置換基群α及び置換基群αの「C1-C3アルキル基」の置換基においては、好適にはシクロプロピル基である。 In the present invention, 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 α and “C1-C3 alkyl group” of substituent group α are preferably cyclopropyl groups.
　本発明において、「C1-C3ヒドロキシアルキル基」とは前記「C1-C3アルキル基」に水酸基が置換した基であり、例えば、ヒドロキシメチル、2-ヒドロキシエチル、1-ヒドロキシエチル、1-ヒドロキシ n-プロピル、2-ヒドロキシ n-プロピル基を挙げることができ、置換基群αの「窒素、酸素及び硫黄から選択される同一若しくは異なった1-3個のヘテロ原子を含む4-10員複素環C1-C3アルキル基」の置換基においては、好適にはヒドロキシメチル基又は1-ヒドロキシエチル基である。 In the present invention, 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 α “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.
　本発明において、「C1-C3アルコキシ基」とは、前記「C1-C3アルキル基」が酸素原子に結合した基であり、例えば、メトキシ、エトキシ、n-プロポキシ、イソプロポキシ基のような炭素数1乃至3個の直鎖又は分枝鎖アルコキシ基を挙げることができる。R1、R 2、R3、R3及びR10の「C1-C3アルコキシ基」の置換基においては、好適にはメトキシ又はエトキシ基である。 In the present invention, 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.
　本発明において、「C2-C3アルケニル基」とは、炭素数2又は3個の直鎖又は分枝鎖アルケニル基であり、例えば、エテニル、1-プロペニル、2-プロペニル基を挙げることができる。R1、R9及びR10においては、好適には、炭素数2個のアルケニル基であり、更に好適には1-プロペニル基である。 In the present invention, 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.
　本発明において、「C6-C10アリール基」とは、炭素数6乃至10個の芳香族炭化水素基であり、例えば、フェニル、インデニル、ナフチル基を挙げることができ、R10においては好適にはフェニル基である。 In the present invention, 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.
　本発明において、「窒素、酸素及び硫黄から選択される同一若しくは異なった1-3個のヘテロ原子を含む3-10員複素環基」とは、窒素、酸素又は硫黄を1乃至3個含む3乃至10員複素環基であり、例えばフリル、チエニル、ピロリル、アゼピニル、ピラゾリル、イミダゾリル、オキサゾリル、イソキサゾリル、チアゾリル、イソチアゾリル、1,2,3-オキサジアゾリル、トリアゾリル、テトラゾリル、チアジアゾリル、ピラニル、 ピリジル、ピリダジニル、ピリミジニル、ピラジニルのような芳香族複素環基及びオキセタニル、モルホリニル、チオモルホリニル、ピロリジニル、ピロリニル、イミダゾリジニル、イミダゾリニル、ピラゾリジニル、ピラゾリニル、ピペリジニル、ピペラジニル、テトラヒドロフラニル、テトラヒドロピラニルのようなこれらの基に対応する、部分若しくは完全還元型の基を挙げることができる。尚、上記「4乃至10員複素環基」は、他の環式基と縮環していてもよく、例えば、ベンゾフラニル、クロメニル、インドリジニル、イソインドリル、インドリル、インダゾリル、プリニル、キノリジニル、イソキノリル、キノリル、フタラジニル、ナフチリジニル、キノキサリニル、キナゾリニル、イソインドリニル、2,3-ジヒドロ-1-ベンゾフラニル、3,4-ジヒドロ-1H-イソクロメニル、1,2,3,4-テトラヒドロキノリニル、1,2,3,4-テトラヒドロイソキノリニル基を挙げることができる。R10及び置換基群αにおいては、好適には、ピリジル、オキセタニル、モルホリニル、ピペリジニル、テトラヒドロフラニル基を挙げることができ、さらに好適には、ピリジル基である。 In the present invention, 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, pyrazolinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl Mention may be made of partially or fully reduced groups corresponding to these groups. 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. Preferable examples of R 10 and substituent group α include pyridyl, oxetanyl, morpholinyl, piperidinyl and tetrahydrofuranyl groups, and a pyridyl group is more preferable.
　本発明において、「窒素、酸素及び硫黄から選択される同一若しくは異なった1-3個のヘテロ原子を含む4-10員複素環基C1-C3アルキル基」とは、前記「C1-C3アルキル基」に上記「窒素、酸素及び硫黄から選択される同一若しくは異なった1-3個のヘテロ原子を含む4-10員複素環基」が置換した基であり、例えばピリジルメチル、ピリジルエチル、ピリジルプロピル、オキセタニルメチル、オキセタニルエチル、モルホリニルメチル、モルホリニルエチル、ピペリジニルメチル、ピペリジニルエチル、テトラヒドロフラニルメチル、テトラヒドロフラニルエチル基を挙げることができる。置換基群αにおいては、好適には、ピリジルメチル又はピリジルエチル基である。 In the present invention, 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. In the substituent group α, a pyridylmethyl or pyridylethyl group is preferable.
　本発明において、「窒素、酸素及び硫黄から選択される同一若しくは異なった1-3個のヘテロ原子を含む3-10員複素環カルボニル基」とは、前記「窒素、酸素及び硫黄から選択される同一若しくは異なった1-3個のヘテロ原子を含む4-10員複素環基」がカルボニル基に結合した基であり例えばピリジルカルボニル、オキセタニルカルボニル、モルホリニルカルボニル、ピペリジニルカルボニル及びテトラヒドロフラニルカルボニル基を挙げることができる。R1においては、好適には、ピペリジニルカルボニル基である。 In the present invention, 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.
　本発明において、「C1-C3アルコキシカルボニル基」とは、前記「C1-3アルコキシ基」がカルボニル基に結合した基であり、例えば、メトキシカルボニル、エトキシカルボニル、n-プロポキシカルボニル、イソプロポキシカルボニルのような炭素数1乃至3個の直鎖又は分枝鎖アルコキシカルボニル基を挙げることができ、R1、R9及びR10においては、好適にはメトキシカルボニル又はエトキシカルボニル基である。 In the present invention, 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.
　本発明において、「C1-C3アルキルスルホニル基」とは、前記「C1-3アルキル基」がスルホニル基を介して結合する基であり、例えば、メタンスルホニル、エタンスルホニル、n-プロパンスルホニル、イソプロパンスルホニル基を挙げることができる。置換基群α及び置換基群αのC1-C3アルキル基の置換基においては、好適にはメタンスルホニル基である。 In the present invention, 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 α and the C1-C3 alkyl group of the substituent group α are preferably methanesulfonyl groups.
　本発明において、「ハロゲン原子」とは、弗素原子、塩素原子、臭素原子又は沃素原子であり、R1及びR2においては、好適には、塩素原子又は弗素原子である。 In the present invention, 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.
　本発明において、「3-6員飽和炭素環」とは、シクロプロパン、シクロブタン、シクロペンタン又はシクロヘキサン環であり、R4及びR5並びに、R6及びR7が結合して形成する環においては、シクロブタン環が好適である。 In the present invention, 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.
　本発明において、「薬理上許容される塩」とは、アミノ基のような塩基性の基を有する場合には酸と反応させることにより、又、カルボキシル基のような酸性基を有する場合には塩基と反応させることにより、塩にすることができるので、その塩を示す。 In the present invention, 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.
　塩基性基に基づく塩としては、好適には、弗化水素酸塩、塩酸塩、臭化水素酸塩、沃化水素酸塩のようなハロゲン化水素酸塩、硝酸塩、過塩素酸塩、硫酸塩、燐酸塩等の無機酸塩；メタンスルホン酸塩、トリフルオロメタンスルホン酸塩、エタンスルホン酸塩のような低級アルカンスルホン酸塩、ベンゼンスルホン酸塩、p-トルエンスルホン酸塩のようなアリールスルホン酸塩、酢酸塩、りんご酸塩、フマ－ル酸塩、コハク酸塩、クエン酸塩、アスコルビン酸塩、酒石酸塩、蓚酸塩、マレイン酸塩等の有機酸塩；及び、グリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩、アスパラギン酸塩のようなアミノ酸塩を挙げることができる。好適には、ハロゲン化水素酸塩又は無機酸塩である。 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. Preferably, it is a hydrohalide salt or an inorganic acid salt.
　一方、酸性基に基づく塩としては、好適には、ナトリウム塩、カリウム塩、リチウム塩のようなアルカリ金属塩、カルシウム塩、マグネシウム塩のようなアルカリ土類金属塩、アルミニウム塩、鉄塩等の金属塩；アンモニウム塩のような無機塩、2-メチルプロパン-2-アミン塩（tert-ブチルアミン塩ともいう）、tert-オクチルアミン塩、ジベンジルアミン塩、モルホリン塩、グルコサミン塩、フェニルグリシンアルキルエステル塩、エチレンジアミン塩、N-メチルグルカミン塩、グアニジン塩、ジエチルアミン塩、トリエチルアミン塩、ジシクロヘキシルアミン塩、N,N’-ジベンジルエチレンジアミン塩、クロロプロカイン塩、プロカイン塩、ジエタノ－ルアミン塩、N-ベンジルフェネチルアミン塩、ピペラジン塩、テトラメチルアンモニウム塩、トリス（ヒドロキシメチル）アミノメタン塩のような有機塩等のアミン塩；及び、グリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩、アスパラギン酸塩のようなアミノ酸塩を挙げることができる。 On the other hand, 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 as organic salt such as (hydroxymethyl) aminomethane salts; and include glycine salts, lysine salts, arginine salts, ornithine salts, glutamic acid salts, amino acid salts such as aspartate.
　本発明の一般式(I)で表される化合物又はその薬理上許容される塩は、全ての異性体（ケト－エノール異性体、立体異性体等）を包含する。 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.).
　本発明の一般式(I)で表される化合物又はその薬理上許容される塩は、その分子内に不斉炭素原子が存在する場合、種々の異性体を有する。本発明の化合物においては、これらの異性体およびこれらの異性体の混合物がすべて単一の式、即ち一般式(I)で示されている。従って、本発明はこれらの異性体およびこれらの異性体の任意の割合の混合物をもすべて含むものである。 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. In the compounds of the present invention, 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.
　上記のような立体異性体は、合成した本発明に係る化合物を所望により通常の光学分割法又は分離法を用いて単離することにより得ることができる。 The 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.
　本発明の一般式(I)で表される化合物又はその薬理上許容される塩は、このような化合物を構成する原子の1以上に、原子同位体の非天然割合も含有し得る。原子同位体としては、例えば、重水素(2H)、トリチウム(3H)、ヨウ素－125(125I)又は炭素－14(14C)などが挙げられる。また、前記化合物は、例えば、トリチウム(3H)、ヨウ素－125(125I)又は炭素－14(14C)などの放射性同位体で放射性標識され得る。放射性標識された化合物は、治療又は予防剤、研究試薬、例えば、アッセイ試薬、及び診断剤、例えば、インビボ画像診断剤として有用である。本発明の化合物の全ての同位体変異種は、放射性であると否とを問わず、本発明の範囲に包含されるものとする。 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. Examples of 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.
　本発明の一般式(I)で表される化合物又はその薬理上許容される塩は、大気中に放置したり、又は、再結晶をすることにより、水分を吸収し、吸着水が付いたり、水和物となる場合があり、そのような水和物も本発明の塩に包含される。 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.
　本発明の一般式(I)で表される化合物又はその薬理上許容される塩は、他のある種の溶媒を吸収し、溶媒和物となる場合があり、そのような溶媒和物も本発明の塩に包含される。 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.
　更に本発明は、生体内において代謝されて前記一般式(I)を有するキサンテン誘導体又はその塩に変換される化合物（例えば、前記一般式(I)のカルボン酸部分がエステル化された誘導体等）もすべて含むものである。 Furthermore, 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.
　本発明の一般式(I)は好適には、以下の式（IA）又は(IB) The general formula (I) of the present invention is preferably the following formula (IA) or (IB)
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
[式中の記号は前記と同義を示す]であり、さらに好適には、上記式（IA）である。 [The symbols in the formula are as defined above], and more preferably, the formula (IA).
 
　Xは好適には、=C(-R8)-又は -O- であり、更に好適には、-O- である。
X is preferably ═C (—R 8 ) — or —O—, and more preferably —O—.
　Yは好適には、=C(-R9)- である。 Y is preferably ═C (—R 9 ) —.
　Zは好適には、=C(-R10)- である。 Z is preferably ═C (—R 10 ) —.
　nは好適には、0である。 N is preferably 0.
　mは好適には、1である。 M is preferably 1.
　tは好適には、1である。 T is preferably 1.
　R1は好適には、置換基群αから選ばれる1若しくは2個の基に置換されていてもよいC1-C3アルキル基又はカルボキシル基であり、更に好適には、カルボキシル基に置換されていてもよいC1-C3アルキル基又はカルボキシル基である。 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 α, more preferably a carboxyl group. Or a C1-C3 alkyl group or a carboxyl group.
　R2は好適には、同一又は異なって水素原子若しくはC1-C3アルキル基であり、更に好適には、メチル基である。 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.
　R3は好適には、水素原子、C1-C3アルキル基（該アルキル基は、カルボキシル基で1個置換されていても良い）又はC1-C3アルコキシ基（該アルコキシ基は、C1-C3アルコキシ基で1個置換されていても良い）であり、さらに好適には、水素原子、メチル基又はメトキシ基であり、特に好適には、水素原子である。 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.
　R4は好適には、C1-C3アルキル基であり、さらに好適には、メチル基である。 R 4 is preferably a C1-C3 alkyl group, and more preferably a methyl group.
　R5は好適には、C1-C3アルキル基であり、さらに好適には、メチル基である。 R 5 is preferably a C1-C3 alkyl group, and more preferably a methyl group.
　R6は好適には、C1-C3アルキル基であり、さらに好適には、メチル基である。 R 6 is preferably a C1-C3 alkyl group, and more preferably a methyl group.
　R7は好適には、C1-C3アルキル基であり、さらに好適には、メチル基である。 R 7 is preferably a C1-C3 alkyl group, and more preferably a methyl group.
　R8は好適には、水素原子である。 R 8 is preferably a hydrogen atom.
　R9は好適には、水素原子である。 R 9 is preferably a hydrogen atom.
　R10は好適には、置換基群αから選ばれる1又は2個の基に置換されていてもよいC1-C3アルキル基であり、更に好適には、メチル基である。 R 10 is preferably a C1-C3 alkyl group which may be substituted with one or two groups selected from the substituent group α, and more preferably a methyl group.
　置換基群αは、
　　R1が置換基群αから選ばれる1若しくは2個の基に置換されていてもよいC1-C3アルキル基である場合、好適には、カルボキシル基である。 Substituent group α is
When R 1 is a C1-C3 alkyl group optionally substituted by 1 or 2 groups selected from the substituent group α, it is preferably a carboxyl group.
　　R1が置換基群αから選ばれる1若しくは2個の基に置換されていてもよいC1-C3アルコキシ基である場合、好適には、水酸基又はカルボキシル基である。 When R 1 is a C1-C3 alkoxy group which may be substituted with 1 or 2 groups selected from the substituent group α, it is preferably a hydroxyl group or a carboxyl group.
　　R1が置換基群αから選ばれる1若しくは2個の基に置換されていてもよいC2-C3アルケニル基である場合、好適には、カルボキシル基である。 When R 1 is a C2-C3 alkenyl group which may be substituted with one or two groups selected from the substituent group α, it is preferably a carboxyl group.
　　R1が置換基群αから選ばれる1若しくは2個の基に置換されていてもよいC3-C6シクロアルキル基である場合、好適には、カルボキシル基である。 When R 1 is a C3-C6 cycloalkyl group optionally substituted by 1 or 2 groups selected from the substituent group α, it is preferably a carboxyl group.
　　R1が置換基群αから選ばれる1若しくは2個の基に置換されていてもよいアミノカルボニル基である場合、好適には、C1-C3アルキル基（該アルキル基は、カルボキシル基、C1-C3アルキルスルホニル基で1若しくは2個置換されていてもよいアミノカルボニル基、C3-C6シクロアルキル基又は水酸基で、1若しくは2個置換されていても良い）である。 When R 1 is an aminocarbonyl group optionally substituted by 1 or 2 groups selected from substituent group α, 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.
　　R10が置換基群αから選ばれる1若しくは2個の基に置換されていてもよいC1-C3アルキル基である場合、好適には、
　　R10が置換基群αから選ばれる1若しくは2個の基に置換されていてもよいアミノカルボニル基である場合、好適には、C1-C3アルキルスルホニル基である。 When R 10 is a C1-C3 alkyl group optionally substituted by 1 or 2 groups selected from the substituent group α, preferably
When R 10 is an aminocarbonyl group optionally substituted by 1 or 2 groups selected from the substituent group α, it is preferably a C1-C3 alkylsulfonyl group.
 
　本発明の一般式(I)を有する化合物は、例えば、以下の方法により製造することができる
　Ａ法： 
The compound having the general formula (I) of the present invention can be produced, for example, by the following method: Method A:
Figure JPOXMLDOC01-appb-C000021
 
Figure JPOXMLDOC01-appb-C000021
 
　Ｂ法：中間体化合物(1b)の製造方法。 Method B: Method for producing intermediate compound (1b).
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
　Ｃ法：中間体化合物(1c)の製造方法。 Method C: Method for producing intermediate compound (1c).
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023
　上記式中及び以下の記載においてX、Y、Z、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、n、m及びtは、前述したものと同意義を示す。 In the above formula and the following description, X, Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , n, m and t are Shows the same significance as described above.
　上記式中及び以下の記載において、R1aはR1（該R1が水酸基、アミノ基又はカルボキシル基を有する場合には、それらの基が保護基により保護されていてもよい）を示し、R2aはR2（該R2がカルボキシル基を有する場合には、保護基により保護されていてもよい）を示し、R3aはR3（該R3がカルボキシル基を有する場合には、保護基により保護されていてもよい）を示し、R8aはR8（該R8がカルボキシル基を有する場合には、保護基により保護されていてもよい）を示し、R9aはR9（該R9がカルボキシル基を有する場合には、保護基により保護されていてもよい）を示し、R10aはR10（該R10がカルボキシル基を有する場合には、保護基により保護されていてもよい）を示し、Xaは=C(-R10a)- 、 -CH(-R9a)-又は =N- を示し、Yaは=C(-R9a)- 、 -CH(-R9a)-又は =N- を示し、Z aは、=C(-R10a)- 、 -CH(-R9a)-又は =N- を示す。 In the above formula and the following description, 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) X a represents = C (-R 10a )-, -CH (-R 9a )-or = N-, Y a = C (-R 9a )-, -CH (-R 9a ) -or = Indicates N-, Z a is, = C (-R 10a) - , -CH (-R 9a) - or = indicates the N-.
　上記式中及び以下の記載において、P1aは水素原子又はC1-C3アルキル基を示す。 In the above formula and the following description, P 1a represents a hydrogen atom or a C1-C3 alkyl group.
　上記工程中及び以下の記載において、水酸基、アミノ基又はカルボキシル基の保護に用いられる保護基とは、有機合成化学の分野で使用される基であれば特に限定はされないが、例えば、グリーン・ワッツ著、「プロテクティブ　グループス　イン　オーガニック　シンセシス第3版(Protective groups in organic synthesis )」（米国、Wiley-Interscience社）に記載の保護基を挙げることができる。 In the above process and the following description, 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. For example, Green Watts The protecting groups described in the book, "Protective groups in organic synthesis 3rd edition" (Wiley-Interscience, USA) can be mentioned.
　以下、各工程につき、説明する。
(A法)
　(第A-1工程)
　本発明の化合物(I)は、酸存在下、中間体(1)に5,5-ジメチルシクロヘキサン-1,3-ジオンを反応させ、3環を構築することにより製造される。中間体(1)を製造する工程は、所望する化合物に応じてB法、C法、実施例記載の製法などにより製造できる。また、必要に応じて、加水分解等で保護基の除去を行うこともできる。 Hereinafter, each step will be described.
(Method A)
(Process A-1)
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.
　溶媒としては、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、水、クロロホルムのようなハロゲン化炭化水素類、ジオキサン、テトラヒドロフランのようなエーテル類、メタノール、エタノールのようなアルコール類が挙げられ、好適には、エタノール、クロロホルム、ジオキサン又はメタノールである。 The solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, 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.
　酸としては、ドデシルベンゼンスルホン酸、ピロリジン-パラトルエンスルホン酸一水和物、ピロリジン-2規定または5規定塩酸が挙げられ、好適には、ピロリジン-パラトルエンスルホン酸一水和物、ピロリジン-2規定または5規定塩酸である。 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.
　反応温度は、20℃乃至120℃であり、好適には60℃乃至110℃である。 The reaction temperature is 20 ° C to 120 ° C, preferably 60 ° C to 110 ° C.
　反応時間は、2時間乃至12時間であり、好適には3.5時間乃至4時間である。 The reaction time is 2 hours to 12 hours, preferably 3.5 hours to 4 hours.
 
(B法)
　(第B-1工程)
　本工程は、公知化合物又は公知化合物から適宜置換基を変換して得られる中間体化合物(2)に、塩基存在下、3-ブロモ-1-プロピンを反応させることにより、プロピニル基を導入する工程である。
(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.
　溶媒としては、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、N-メチルピロリドンのようなアミド類、ジメチルスルホキシドのようなスルホキシド類、アセトン、エチルメチルケトンのようなケトン類、テトラヒドロフランのようなエーテル類が挙げられ、好適には、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド又はN-メチルピロリドンである。 The solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, 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.
　塩基としては、例えば、炭酸カリウムのような金属炭酸塩、水酸化ナトリウムのような金属水酸化物、tert-ブトキシカリウムのような金属アルコキシド、トリエチルアミンのような有機塩基が挙げられ、好適には、炭酸カリウムのような金属炭酸塩である。 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. A metal carbonate such as potassium carbonate.
　反応温度は、0℃乃至100℃であり、好適には25℃である。 The reaction temperature is 0 ° C to 100 ° C, preferably 25 ° C.
　反応時間は、0.5時間乃至12時間であり、好適には5時間である。 The reaction time is 0.5 to 12 hours, preferably 5 hours.
　(第B-2工程)
　本工程は、中間体化合物(3)を環化し、ベンゾフラン環を構築する工程である。 (Process B-2)
This step is a step of cyclizing the intermediate compound (3) to construct a benzofuran ring.
　溶媒としては、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ジエチルアニリン、ジメチルアニリンようなアニリン類、ジフェニルエーテルのようなエーテル類、キシレンのような芳香族炭化水素類が挙げられ、好適には、ジエチルアニリンである。 The solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, anilines such as diethylaniline and dimethylaniline, ethers such as diphenyl ether, and aromatics such as xylene. Group hydrocarbons, and diethylaniline is preferred.
　試薬としては、ふっ化セシウムのようなアルカリ金属ふっ化物、塩化セシウム、塩化アルミニウム、トリフルオロメタンスルホン酸イッテルビウムのようなランタノイドトリフルオロメタンスルホン酸塩が挙げられ、好適には、ふっ化セシウムである。 Examples of the reagent include alkali metal fluorides such as cesium fluoride, cesium chloride, aluminum chloride, and lanthanoid trifluoromethanesulfonates such as ytterbium trifluoromethanesulfonate, and preferably cesium fluoride.
　反応温度は、100℃乃至300℃であり、好適には200℃である。 The reaction temperature is 100 ° C to 300 ° C, preferably 200 ° C.
　反応時間は、4時間乃至24時間であり、好適には8時間である。 The reaction time is 4 to 24 hours, preferably 8 hours.
　(第B-3工程)
　本工程は、中間体化合物(4)を還元し、中間体化合物(5)を製造する工程である。中間体化合物(5)は、必要に応じて、水酸基の保護を行い、R1Ab, R2Ab, R3Abを望む置換基に変換をおこなうことができる。 (Process B-3)
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.
　溶媒としては、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ジクロロメタン、クロロホルムのようなハロゲン化炭化水素類、ベンゼン、トルエンのような芳香族炭化水素類、テトラヒドルフラン、ジエチルエーテルのようなエーテル類が挙げられ、好適には、ジクロロメタンである。 The solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, halogenated hydrocarbons such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene and toluene. And ethers such as tetrahydrofuran and diethyl ether, preferably dichloromethane.
　還元剤としては、水素化リチウムアルミニウム、テトラヒドリドほう酸リチウム、水素化ジイソブチルアルミニウム、水素化ビス（２－メトキシエトキシ）アルミニウムナトリウムのような金属水素化物が挙げられ、好適には、水素化ジイソブチルアルミニウムである。 Examples of the reducing agent include metal hydrides such as lithium aluminum hydride, lithium tetraborohydride, diisobutylaluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, and preferably diisobutylaluminum hydride. is there.
　反応温度は、-78℃乃至室温であり、好適には0℃である。 The reaction temperature is -78 ° C to room temperature, preferably 0 ° C.
　反応時間は、0.5時間乃至8時間であり、好適には4時間である。 The reaction time is 0.5 to 8 hours, preferably 4 hours.
　(第B-4工程)
　本工程は、中間体化合物(5)を酸化し、中間体化合物(1b)を製造する工程である。 (Process B-4)
This step is a step of producing intermediate compound (1b) by oxidizing intermediate compound (5).
　溶媒としては、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ジクロロメタン、クロロホルムのようなハロゲン化炭化水素類、ベンゼン、トルエンのような芳香族炭化水素類、1,2-ジメトキシエタン、1,4-ジオキサンのようなエーテル類が挙げられ、好適には、1,2-ジメトキシエタン又はベンゼンである。 The solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, halogenated hydrocarbons such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene and toluene. And ethers such as 1,2-dimethoxyethane and 1,4-dioxane, preferably 1,2-dimethoxyethane or benzene.
　酸化剤としては、酸化マンガン(IV)並びに酸化銀(II) のような金属酸化物，過ルテニウム酸テトラプロピルアンモニウムのような過ルテニウム酸類、二クロム酸ピリジニウムやクロロクロム酸ピリジニウムのようなクロム酸類、ジメチルスルホキシドと二塩化オキサリルや三酸化硫黄のような活性化剤、2,2,6,6-テトラメチルピペリジン-1-オキシルラジカルなどの有機ニトロキシルラジカル類と次亜塩素酸ナトリウムのような共酸化剤、2,3-ジクロロ-5,6-ジシアノ-1,4-ベンゾキノンのようなキノン類、1,1,1-トリアセトキシ-1,1-ジヒドロ-1,2-ベンゾヨードキソル-3(1H)-オンのような超原子価ヨウ素化合物類が挙げられ、好適には、酸化マンガン(IV)、2,2,6,6-テトラメチルピペリジン-1-オキシルラジカルなどの有機ニトロキシルラジカル類と次亜塩素酸ナトリウムなどを代表とする共酸化剤である。 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.
　反応温度は、-78℃乃至100℃であり、好適には90℃である。 The reaction temperature is −78 ° C. to 100 ° C., preferably 90 ° C.
　反応時間は、1時間乃至12時間であり、好適には6時間である。 The reaction time is 1 to 12 hours, preferably 6 hours.
 
(C法)
　(第C1工程)
　公知化合物より、適宜置換基を変換して得られる中間体化合物(6)に、アルデヒド基を導入する工程である。
(Method C)
(Process C1)
In this step, an aldehyde group is introduced into an intermediate compound (6) obtained by appropriately converting a substituent from a known compound.
　溶媒としては、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定はないが、例えば、ジメチルホルムアミド、N-メチルホルムアニリドなどが挙げられ、好適には、N-メチルホルムアニリドである。 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.
　試薬としては、オキシ塩化リン、オキシ臭化リンなどが挙げられ、好適には、オキシ塩化リンである。 Examples of the reagent include phosphorus oxychloride and phosphorus oxybromide, and phosphorus oxychloride is preferable.
　反応温度は、0℃乃至100℃であり、好適には70℃乃至90℃である。 The reaction temperature is 0 ° C to 100 ° C, preferably 70 ° C to 90 ° C.
　反応時間は、1時間乃至9時間であり、好適には1時間乃至3時間である。 The reaction time is 1 to 9 hours, preferably 1 to 3 hours.
 
　上記各工程の反応終了後、目的化合物は常法に従って、反応混合物から採取される。例えば、反応混合物を適宜中和し、又、不溶物が存在する場合には濾過により除去した後、水と酢酸エチルのような混和しない有機溶媒を加え、水等で洗浄後、目的化合物を含む有機層を分離し、無水硫酸マグネシウム等で乾燥後、溶剤を留去することによって得られる。
After completion of the reaction in each of the above steps, the target compound is collected from the reaction mixture according to a conventional method. For example, 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.
　得られた目的物は必要ならば常法、例えば再結晶、再沈殿、又は、通常、有機化合物の分離精製に慣用されている方法、例えば、吸着カラムクロマトグラフィー法、分配カラムクロマトグラフィー法等の合成吸着剤を使用する方法、イオン交換クロマトグラフィーを使用する方法、又は、シリカゲル若しくはアルキル化シリカゲルによる順相・逆相カラムクロマトグラフィー法を適宜組み合わせ、適切な溶離剤で溶出することによって分離、精製することができる。 If necessary, 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.
　さらに、必要に応じて、キラルカラムにより光学活性体の分離、精製を行なうこともできる。 Furthermore, if necessary, the optically active substance can be separated and purified by a chiral column.
 
　本発明の前記一般式(I)を有するキサンテン誘導体、その薬理上許容される塩は、種々の形態で投与される。その投与形態としては特に限定はなく、各種製剤形態、患者の年齢、性別その他の条件、疾患の程度等に応じて決定される。例えば錠剤、丸剤、散剤、顆粒剤、シロップ剤、液剤、懸濁剤、乳剤、顆粒剤およびカプセル剤の場合には経口投与される。また注射剤の場合には単独であるいはぶどう糖、アミノ酸等の通常の補液と混合して静脈内投与され、更には必要に応じて単独で筋肉内、皮内、皮下もしくは腹腔内投与される。坐剤の場合には直腸内投与される。好適には経口投与である。
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. For example, it is orally administered in the case of tablets, pills, powders, granules, syrups, solutions, suspensions, emulsions, granules and capsules. In the case of an injection, it is administered intravenously alone or mixed with a normal replacement fluid such as glucose or amino acid, and further administered alone intramuscularly, intradermally, subcutaneously or intraperitoneally as necessary. In the case of a suppository, it is administered intrarectally. Oral administration is preferred.
　これらの各種製剤は、常法に従って主薬に賦形剤、結合剤、崩壊剤、潤沢剤、溶解剤、矯味矯臭、コーティング剤等既知の医薬製剤分野において通常使用しうる既知の補助剤を用いて製剤化することができる。 These various preparations 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.
　錠剤の形態に成形するに際しては、担体としてこの分野で従来公知のものを広く使用でき、例えば乳糖、白糖、塩化ナトリウム、ぶどう糖、尿素、澱粉、炭酸カルシウム、カオリン、結晶セルロース、ケイ酸等の賦形剤、水、エタノール、プロパノール、単シロップ、ぶどう糖液、澱粉液、ゼラチン溶液、カルボキシメチルセルロース、セラック、メチルセルロース、リン酸カリウム、ポリビニルピロリドン等の結合剤、乾燥澱粉、アルギン酸ナトリウム、カンテン末、ラミナラン末、炭酸水素ナトリウム、炭酸カルシウム、ポリオキシエチレンソルビタン脂肪酸エステル類、ラウリル硫酸ナトリウム、ステアリン酸モノグリセリド、澱粉、乳糖等の崩壊剤、白糖、ステアリン、カカオバター、水素添加油等の崩壊抑制剤、第４級アンモニウム塩基、ラウリル硫酸ナトリウム等の吸収促進剤、グリセリン、澱粉等の保湿剤、澱粉、乳糖、カオリン、ベントナイト、コロイド状ケイ酸等の吸着剤、精製タルク、ステアリン酸塩、硼酸末、ポリエチレングリコール等の滑沢剤等が例示できる。更に錠剤は必要に応じ通常の剤皮を施した錠剤、例えば糖衣錠、ゼラチン被包錠、腸溶被錠、フィルムコーティング錠あるいは二重錠、多層錠とすることができる。 In molding into tablets, 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. 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 disintegration inhibitors, Class Ammoni Absorption accelerators such as mud base, sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid, purified talc, stearate, boric acid powder, polyethylene glycol, etc. Examples of these lubricants can be given. Further, 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.
　丸剤の形態に成形するに際しては、担体としてこの分野で従来公知のものを広く使用でき、例えばぶどう糖、乳糖、澱粉、カカオ脂、硬化植物油、カオリン、タルク等の賦形剤、アラビアゴム末、トラガント末、ゼラチン、エタノール等の結合剤、ラミナランカンテン等の崩壊剤等が例示できる。 In molding into the form of pills, 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.
　坐剤の形態に成形するに際しては、担体としてこの分野で従来公知のものを広く使用でき、例えばポリエチレングリコール、カカオ脂、高級アルコール、高級アルコールのエステル類、ゼラチン、半合成グリセライド等を挙げることができる。 In molding into the form of suppository, 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.
　注射剤として調製される場合には、液剤および懸濁剤は殺菌され、且つ血液と等張であるのが好ましく、これら液剤、乳剤および懸濁剤の形態に成形するに際しては、希釈剤としてこの分野において慣用されているものを全て使用でき、例えば水、エチルアルコール、プロピレングリコール、エトキシ化イソステアリルアルコール、ポリオキシ化イソステアリルアルコール、ポリオキシエチレンソルビタン脂肪酸エステル類等を挙げることができる。なお、この場合、等張性の溶液を調製するに十分な量の食塩、ぶどう糖、あるいはグリセリンを医薬製剤中に含有せしめてもよく、また通常の溶解補助剤、緩衝剤、無痛化剤等を添加してもよい。 When prepared as injections, 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. In this case, 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.
　更に必要に応じて着色剤、保存剤、香料、風味剤、甘味剤等や他の医薬品を含有せしめてもよい。 Furthermore, if necessary, colorants, preservatives, fragrances, flavors, sweeteners, and other pharmaceuticals may be included.
　上記医薬製剤中に含まれる有効成分化合物の量は、特に限定されず広範囲に適宜選択されるが、通常全組成物中1～70重量％、好ましくは1～30重量％含まれる量とするのが適当である。 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.
　その投与量は、症状、年令、体重、投与方法および剤型等によって異なるが、通常は成人に対して１日、下限として0.001mg/kg（好ましくは0.01mg/kg、更に好ましくは0.1mg/kg）であり、上限として200mg/kg（好ましくは20mg/kg、更に好ましくは10mg/kg）を1回ないし数回投与することができる。 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.
　本発明の化合物は、前述の本発明が有効と考えられる疾患の種々の治療又は予防剤と併用することができる。当該併用は、同時投与或いは別個に連続して若しくは所望の時間間隔をおいて投与してもよい。同時投与製剤は、配合剤であっても別個に製剤化されていてもよい。 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.
　本発明の化合物である、キサンテン誘導体及びその薬理上許容される塩は、優れた血糖降下作用を有し、糖尿病（1型糖尿病、2型糖尿病、妊娠糖尿病等）、食後過血糖症、耐糖能障害、糖尿病性神経障害、糖尿病性腎症、糖尿病性網膜症、高脂血症、動脈硬化症、血栓性疾患、肥満、高血圧、浮腫、インスリン抵抗性、不安定糖尿病、インスリノーマ、高インスリン血症などの疾患等の治療薬または予防薬として有用である。 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
　また、毒性が低く、安全性に優れることから、医薬として極めて有用であるといえる。 Also, since it is low in toxicity and excellent in safety, it can be said that it is extremely useful as a medicine.
　次に実施例等をあげて本発明を更に詳細に説明するが、本発明はこれらに限定されるものではない。 Next, the present invention will be described in more detail with reference to examples and the like, but the present invention is not limited thereto.
　実施例のカラム用シリカゲルはメルク社製のシリカゲルSK-85(230～400メッシュ)、シリカゲルSK-34(70～230メッシュ)もしくは富士シリシア化学　Chromatorex NH (200-350メッシュ)を用いた。通常のカラムクロマトグラフィーの他に、Biotage社の自動クロマトグラフィー装置（SP-1)、山善社の自動クロマトグラフィー装置（Parallel Frac FR-260）、テレダインイスコ社の自動クロマトグラフィー装置（CombiFlash Rf）を適宜使用した。尚、実施例で用いる略号は、次のような意義を有する。
mg：ミリグラム，g：グラム，ml：ミリリットル，MHz：メガヘルツ。 As the silica gel for the column of Examples, silica gel SK-85 (230-400 mesh), silica gel SK-34 (70-230 mesh) or Fuji Silysia Chemical Chromatorex NH (200-350 mesh) manufactured by Merck & Co., Inc. was used. In addition to conventional column chromatography, Biotage's automated chromatography device (SP-1), Yamazen's automated chromatography device (Parallel Frac FR-260), Teledyne Isco's automated chromatography device (CombiFlash Rf) Were used as appropriate. The abbreviations used in the examples have the following significance.
mg: milligram, g: gram, ml: milliliter, MHz: megahertz.
　以下の実施例において、核磁気共鳴（以下、1H NMR)スペクトルは、テトラメチルシランを標準物質として、ケミカルシフト値をδ値(ppm)にて記載した。***パターンは一重線をs、二重線をd、三重線をt、四重線をq、多重線をmで示した。 In the following examples, nuclear magnetic resonance (hereinafter, 1 H NMR) spectra are described with chemical shift values expressed as δ values (ppm) using tetramethylsilane as a standard substance. The splitting pattern is indicated by s for single lines, d for double lines, t for triple lines, q for quadruple lines, and m for multiple lines.
　質量分析（以下、MS)は、FAB(Fast Atom Bombardment) 法、EI(Electron Ionization)法、もしくはESI（Electron Spray Ionization)法で行った。 Mass spectrometry (hereinafter referred to as MS) was performed by FAB (Fast Atom Bombardment) method, EI (Electron Ionization) method, or ESI (Electron Spray Ionization) method.
　ヘキサンは、n-ヘキサンを示し、THFはテトラヒドロフランを示し、DMFはジメチルホルムアミドを示す。 Hexane represents n-hexane, THF represents tetrahydrofuran, and DMF represents dimethylformamide.
 
（実施例１）　9-(4-メトキシ-2-メチル-1-ベンゾフラン-7-イル)-3,3,6,6-テトラメチル-3,4,5,6,7,9-ヘキサヒドロ-1H-キサンテン-1,8(2H)-ジオン
Example 1 9- (4-Methoxy-2-methyl-1-benzofuran-7-yl) -3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro- 1H-xanthene-1,8 (2H) -dione
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024
　室温で4-メトキシ-2-メチル-1-ベンゾフラン-7-カルバルデヒド(190mg, 1.00mmol)、5, 5-ジメチル-1,3-ヘキサンジオン(280mg, 2.00mmol)、ドデシルベンゼンスルホン酸（3滴）を混合し、水(15ml)、エタノール(3ml)の混合溶媒中にて一昼夜加熱還流した。生じた固体をろ取し、シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル=1:0-3:1, v/v）で精製して、標記化合物（295mg, 収率:68%）を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
6.87(1H, d, J = 2.5Hz), 6.73(1H, d, J = 2.5Hz), 6.19(1H, d, J = 1.0Hz), 4.98(1H, s), 3.79(3H, s), 2.49(2H, dd, J = 1.0, 17.5Hz), 2.42(2H, d, J = 17.5Hz), 2.38(3H, d, J = 1.0Hz), 2.21(2H, d, J = 16.5Hz), 2.12(2H, dd, J = 1.0, 16.5Hz), 1.09(6H, s), 0.86(6H, s)
MS (FAB) m/z: 434[M+]。 4-Methoxy-2-methyl-1-benzofuran-7-carbaldehyde (190 mg, 1.00 mmol), 5,5-dimethyl-1,3-hexanedione (280 mg, 2.00 mmol), dodecylbenzenesulfonic acid (3 The mixture was mixed with water (15 ml) and ethanol (3 ml) and heated under reflux overnight. The resulting solid was collected by filtration and purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0-3: 1, v / v) to obtain the title compound (295 mg, yield: 68%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
6.87 (1H, d, J = 2.5Hz), 6.73 (1H, d, J = 2.5Hz), 6.19 (1H, d, J = 1.0Hz), 4.98 (1H, s), 3.79 (3H, s), 2.49 (2H, dd, J = 1.0, 17.5Hz), 2.42 (2H, d, J = 17.5Hz), 2.38 (3H, d, J = 1.0Hz), 2.21 (2H, d, J = 16.5Hz), 2.12 (2H, dd, J = 1.0, 16.5Hz), 1.09 (6H, s), 0.86 (6H, s)
MS (FAB) m / z: 434 [M + ].
 
（実施例２）　9-(2,4-ジメチル-1-ベンゾフラン-7-イル)-3,3,6,6-テトラメチル-3,4,5,6,7,9-ヒキサヒドロ-1H-キサンテン-1,8(2H)-ジオン
Example 2 9- (2,4-Dimethyl-1-benzofuran-7-yl) -3,3,6,6-tetramethyl-3,4,5,6,7,9-hisahydro-1H- Xanthene-1,8 (2H) -dione
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025
(実施例２-１)　メチル 4-メチル-2-(プロプ-2-イン-1-イルオキシ)ベンゾエート
　メチル 2-ヒドロキシ-4-メチルベンゾエート (25.0g, 150mmol)のDMF溶液(100ml)に炭酸カリウム(32.2g, 233mmol)を加え、室温で激しく攪拌した。更に室温で3-ブロモ-1-プロピン(16.3ml, 217mmol)を加え、室温で6時間激しく攪拌した。反応液をろ過した後、水を加え、酢酸エチルで2回抽出し、得られた有機層を水、飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、減圧下にて溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル=1:0-3:1, v/v）にて精製し、標記化合物（26.2g, 収率:86%）を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
7.74(1H, d, J = 7.0Hz), 6.93(1H, s), 6.80(1H, m), 4.78(2H, d, J = 2.5Hz), 3.87(3H, s), 2.53(1H, t, J = 2.5Hz), 2.40(3H, s)
（実施例２－２）　メチル 2,4-ジメチル-1-ベンゾフラン-7-カルボキシレート
　実施例２－１により製造されるメチル 4-メチル-2-(プロプ-2-イン-1-イルオキシ)ベンゾエート(5.03g, 24.6mmol)のジエチルアニリン溶液(50ml)に、室温でフッ化セシウム(5.70g, 37.5mmol)を加え、窒素雰囲気下200℃にて8時間攪拌した。室温まで冷却した後、酢酸エチルで3回抽出し、得られた有機層を5規定塩酸、水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥、減圧下にて、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル=1:0-5:1, v/v）で精製して、標記化合物(3.42g, 収率:68%）を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
7.77(1H, d, J = 7.8Hz), 7.03(1H, dd, J = 7.8, 1.0Hz), 6.44(1H, m), 3.98(3H, s), 2.54(3H, d, J = 1.0Hz), 2.51(3H, s)
（実施例２－３）　(2,4-ジメチル-1-ベンゾフラン-7-イル)メタノール
　氷冷下、水素化リチウムアルミニウム(186mg, 4.90mmol)のTHF懸濁液(40ml)に、実施例２－２により製造されるメチル 2,4-ジメチル-1-ベンゾフラン-7-カルボキシレート (1.00g, 4.90mmol)のTHF溶液(10ml)を滴下した。滴下後、反応液を5℃で2時間攪拌した後に酢酸エチルを加え希釈した。酒石酸カリウムナトリウム水溶液を加え、室温で30分攪拌した後に反応液を酢酸エチルで2回抽出し、得られた有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、減圧下にて溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル=1:0-3:1, v/v）で精製して、標記化合物(823mg, 収率:96%）を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
7.09(1H, d, J = 7.3Hz), 6.96(1H, d, J = 7.3Hz), 6.40(1H, m), 4.94(2H, d, J = 6.3Hz), 2.48(3H, d, J = 1.0Hz), 2.46(3H, s), 1.89(1H, t, J = 6.3Hz)
（実施例２－４）　2,4-ジメチル-1-ベンゾフラン-7-カルバルデヒド
　実施例２－３により製造される(2,4-ジメチル-1-ベンゾフラン-7-イル)メタノール(823mg, 4.67mmol)を酸化マンガン(IV)(4.06g, 46.7mmol)と共にベンゼン(20ml)中で加熱還流した。反応終了後、冷却しセライトろ過し、ろ液を濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル=1:0-5:1, v/v）で精製して、標記化合物(595mg, 収率:73%）を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
10.4(1H, s), 7.61(1H, d, J = 7.3Hz), 7.11(1H, d, J = 7.3Hz), 6.47(1H, d, J = 1.0Hz), 2.55(3H, d, J = 1.0Hz), 2.54(3H, s)
（実施例２－５）　9-(2,4-ジメチル-1-ベンゾフラン-7-イル)-3,3,6,6-テトラメチル-3,4,5,6,7,9-ヒキサヒドロ-1H-キサンテン-1,8(2H)-ジオン
　4-メトキシ-2-メチル-1-ベンゾフラン-7-カルバルデヒドの代わりに、実施例２－４により製造される2,4-ジメチル-1-ベンゾフラン-7-カルバルデヒド(174mg, 1.00mmol)を用い、実施例1に記載された方法と同様に反応を行い、標記化合物(333mg, 収率:80%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
7.20(1H, d, J = 7.5Hz), 6.87(1H, d, J = 7.5Hz), 6.27(1H, d, J = 1.0Hz), 4.98(1H, s), 2.49(2H, dd, J = 1.5, 18.0Hz), 2.39-2.43(5H, m), 2.35(3H, s), 2.21(2H, d, J = 16.5Hz), 2.10(2H, dd, J = 1.5, 16.5Hz), 1.08(6H, s), 0.83(6H, s)
MS (FAB) m/z: 418[M+]。 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. The obtained organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0-3: 1, v / v) to obtain the title compound (26.2 g, yield: 86%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.74 (1H, d, J = 7.0Hz), 6.93 (1H, s), 6.80 (1H, m), 4.78 (2H, d, J = 2.5Hz), 3.87 (3H, s), 2.53 (1H, t , J = 2.5Hz), 2.40 (3H, s)
Example 2-2 Methyl 2,4-dimethyl-1-benzofuran-7-carboxylate Methyl 4-methyl-2- (prop-2-yn-1-yloxy) benzoate prepared according to Example 2-1 To a diethylaniline solution (50 ml) of (5.03 g, 24.6 mmol), cesium fluoride (5.70 g, 37.5 mmol) was added at room temperature, and the mixture was stirred at 200 ° C. for 8 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was extracted 3 times with ethyl acetate. The obtained organic layer was washed with 5N hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0-5: 1, v / v) to obtain the title compound (3.42 g, yield: 68%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.77 (1H, d, J = 7.8Hz), 7.03 (1H, dd, J = 7.8, 1.0Hz), 6.44 (1H, m), 3.98 (3H, s), 2.54 (3H, d, J = 1.0Hz ), 2.51 (3H, s)
Example 2-3 (2,4-Dimethyl-1-benzofuran-7-yl) methanol Example 2 was added to a THF suspension (40 ml) of lithium aluminum hydride (186 mg, 4.90 mmol) under ice-cooling. A THF solution (10 ml) of methyl 2,4-dimethyl-1-benzofuran-7-carboxylate (1.00 g, 4.90 mmol) prepared according to -2 was added dropwise. After the dropwise addition, the reaction solution was stirred at 5 ° C. for 2 hours, and diluted with ethyl acetate. After adding potassium sodium tartrate aqueous solution and stirring at room temperature for 30 minutes, the reaction solution was extracted twice with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Left. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0-3: 1, v / v) to obtain the title compound (823 mg, yield: 96%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.09 (1H, d, J = 7.3Hz), 6.96 (1H, d, J = 7.3Hz), 6.40 (1H, m), 4.94 (2H, d, J = 6.3Hz), 2.48 (3H, d, J = 1.0Hz), 2.46 (3H, s), 1.89 (1H, t, J = 6.3Hz)
Example 2-4 2,4-Dimethyl-1-benzofuran-7-carbaldehyde (2,4-Dimethyl-1-benzofuran-7-yl) methanol (823 mg, 4.67) prepared according to Example 2-3 mmol) was heated to reflux in benzene (20 ml) with manganese (IV) oxide (4.06 g, 46.7 mmol). After completion of the reaction, the mixture was cooled and filtered through Celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0-5: 1, v / v) to give the title compound (595 mg, Yield: 73%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
10.4 (1H, s), 7.61 (1H, d, J = 7.3Hz), 7.11 (1H, d, J = 7.3Hz), 6.47 (1H, d, J = 1.0Hz), 2.55 (3H, d, J = 1.0Hz), 2.54 (3H, s)
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%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.20 (1H, d, J = 7.5Hz), 6.87 (1H, d, J = 7.5Hz), 6.27 (1H, d, J = 1.0Hz), 4.98 (1H, s), 2.49 (2H, dd, J = 1.5, 18.0Hz), 2.39-2.43 (5H, m), 2.35 (3H, s), 2.21 (2H, d, J = 16.5Hz), 2.10 (2H, dd, J = 1.5, 16.5Hz), 1.08 (6H, s), 0.83 (6H, s)
MS (FAB) m / z: 418 [M + ].
 
（実施例３）　2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-カルボン酸
Example 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-carboxylic acid
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
（実施例３－１）　メチル 5-ブロモ-4-メチル-2-(プロプ-2-イン-1-イルオキシ)ベンゾエート
　メチル 5-ブロモ-2-ヒドロキシ-4-メチルベンゾエート(155g, 625mmol)のDMF溶液(300ml)に炭酸カリウム(135g, 975mmol)を加え、室温で激しく攪拌した。更に室温で3-ブロモ-1-プロピン(68.2ml, 906mmol)を加え、室温で6時間激しく攪拌した。反応液をろ過した後、水を加え、酢酸エチルで2回抽出し、得られた有機層を水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥、減圧下にて、溶媒を留去した。得られた残渣を酢酸エチルにて再結晶することにより、標記化合物(166g, 収率:94%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
7.99(1H, s), 7.01(1H, s), 4.77 (2H, d, J = 2.5Hz), 3.88(3H, s), 2.54(1H, t, J = 2.5Hz), 2.43(3H, s) 
（実施例３－２）　メチル 5-ブロモ-2,4-ジメチル-1-ベンゾフラン-7-カルボキシレート
　実施例３－１により製造されるメチル 5-ブロモ-4-メチル-2-(プロプ-2-イン-1-イルオキシ)ベンゾエート(166g, 586mmol)のジエチルアニリン溶液(400ml)に、室温でフッ化セシウム(115g, 762mmol)を加え、窒素雰囲気下200℃にて12時間攪拌した。室温まで冷却した後、酢酸エチルで3回抽出し、得られた有機層を5規定塩酸、水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥、減圧下にて、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン：酢酸エチル=1:0-5:1, v/v)で精製して、標記化合物(56.6g, 収率:35%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
8.19(1H, s), 6.44(1H, d, J = 1.0Hz), 3.98(3H, s), 2.54(3H, s), 2.53(3H, d, J = 1.0Hz), 
（実施例３－３）　(5-ブロモ-2,4-ジメチル-1-ベンゾフラン-7-イル)メタノール
　-78℃冷却下、実施例３－２により製造されるメチル 5-ブロモ-2,4-ジメチル-1-ベンゾフラン-7-カルボキシレート(17.0g, 60.0mmol)のジクロロメタン溶液(300ml)に、水素化ジイソブチルアルミニウム(1.02Mヘキサン溶液, 147ml, 150mmol)を滴下した。滴下後、反応液を室温で3時間攪拌し、再び-78℃に冷却した。酒石酸カリウムナトリウム水溶液を加え、室温で30分攪拌した。反応液をジクロロメタンで2回抽出し、得られた有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、減圧下にて溶媒を留去した。得られた残渣をヘキサン中で粉砕し、ろ取することにより標記化合物(15.1g, 収率:99%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
7.39(1H, s), 6.40(1H, s), 4.91(2H, d, J = 6.0Hz), 2.49(3H, s), 2.47(3H, s), 1.86(1H, t, J = 6.0Hz)
（実施例３－４）　[(5-ブロモ-2,4-ジメチル-1-ベンゾフラン-7-イル)メトキシ](tert-ブチル)ジメチルシラン
　氷冷下、実施例３－３により製造される(5-ブロモ-2,4-ジメチル-1-ベンゾフラン-7-イル)メタノール(20.0g, 78.4mmol)、イミダゾール(6.94g,102mmol)をジクロロメタン(250ml)に溶解し、tert-ブチルジメチルクロロシラン(14.2g, 94.1mmol)を徐々に加え、その後、室温で30分攪拌した。反応液に10%クエン酸水溶液(20ml)を加え、ジクロロメタンで2回抽出し、得られた有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、減圧下にて、溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン：酢酸エチル=1:0-10:1, v/v)で精製して、標記化合物(29.4g, 収率:100%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
7.43(1H, s), 6.37(1H, s), 4.96(2H, s), 2.47(3H, s), 2.45(3H, s), 0.96(9H, s), 0.13(6H, s)
（実施例３－５）　7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-カルボン酸
　-78℃冷却下、実施例３－４により製造される[(5-ブロモ-2,4-ジメチル-1-ベンゾフラン-7-イル)メトキシ](tert-ブチル)ジメチルシラン(31.5g, 85.3mmol)のTHF溶液(600ml)にn-ブチルリチウム　ヘキサン溶液(2.69M, 37.9ml, 102mmol)を30分かけて滴下した。同温下、反応液を1時間攪拌した後に、二酸化炭素を10分間通じた。反応液をさらに1時間攪拌した後、室温まで昇温し、酢酸(5.84ml, 102mmol)を加えた。反応液を濃縮後、水を加え、酢酸エチルで3回抽出し、得られた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧下にて、溶媒を留去した。得られた残渣をヘキサン中にて粉砕、ろ別することにより、標記化合物(21.7g, 収率:76%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
8.06(1H, s), 6.51(1H, s), 5.00(2H, s), 2.77(3H, s), 2.48(3H, s), 0.97(9H, s), 0.14(6H, s)
（実施例３－６）　tert-ブチル7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレート
　氷冷下、実施例３－５により製造される7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-カルボン酸(21.7g, 64.9mmol)のジクロロメタン溶液(200ml)に、tert-ブチル N, N’-ジプロパン-2-イルカルバアミデート（3.5M tert -ブタノール溶液, 92.7ml, 324mmol）を滴下し、室温で12時間攪拌を行った。反応液を減圧下濃縮し、残渣に水を加えて30分攪拌し、酢酸エチルで3回抽出、得られた有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥した。減圧下にて溶媒を留去し得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン：酢酸エチル=1:0-10:1, v/v)で精製して、標記化合物(21.9g, 収率:87%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
7.86(1H, s), 6.46(1H, s), 5.00(2H, s), 2.68(3H, s), 2.46(3H, s), 1.60(9H, s), 0.97(9H, s), 0.14(6H, s)
（実施例３－７）　tert-ブチル 7-(ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレート
　氷冷下、フッ化テトラブチルアンモニウム (1.0M THF溶液112ml, 112mmol)と酢酸(7.38ml,129mmol)との混合物に、実施例３－６により製造されるtert-ブチル 7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレート(21.9g, 56.0mmol)のTHF(30.0mmol)を滴下し、室温で12時間攪拌した。反応液に水を加え、酢酸エチルで3回抽出し、得られた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下にて溶媒を留去し得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン：酢酸エチル=1:0-4:1, v/v)で精製して、標記化合物(15.7g, 収率:100%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
7.74(1H, s), 6.48(1H, s), 4.94(2H, d, J = 6.5Hz), 2.67(3H, s), 2.48(3H, s), 1.64(1H, t, J = 6.5Hz), 1.61(9H, s)
（実施例３－８）　tert-ブチル 7-ホルミル-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレート
　実施例３－７により製造されるtert-ブチル 7-(ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレート(15.6g, 56.4mmol)を酸化マンガン(IV)(24.5g, 282mmol)と共に1,2-ジメトキシエタン(250ml)中で加熱還流した。反応終了後、室温に戻した後、セライトろ過し、ろ液を濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン：酢酸エチル=1:0-5:1, v/v)で精製して、標記化合物(11.2g, 収率:73%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
10.3(1H, s), 8.22(1H, s), 6.55(1H, s), 2.77(3H, s), 2.56(3H, s), 2.44(3H, s), 1.63(3H, s)
（実施例３－９）　2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-カルボン酸
　実施例３－８により製造されるtert-ブチル 7-ホルミル-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレート(548mg, 2.00mmol)、5, 5-ジメチル-1,3-ヘキサンジオン(561mg, 4.00mmol)を室温で水(40ml)、1,4-ジオキサン(5ml)に混合し、ドデシルベンゼンスルホン酸(5滴)を加え、一昼夜加熱還流した。生じた固体をろ取し、シリカゲルカラムクロマトグラフィー（酢酸エチル）で精製して、標記化合物(694mg, 収率:75%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
7.89(1H, s), 6.39(1H, s), 5.07(1H, s), 2.63(3H, s), 2.49(2H, d, J = 17.5Hz), 2.44(3H, s), 2.43(2H, d, J = 17.5Hz), 2.21(2H, d, J = 17.0Hz), 2.10(2H, d, J = 17.0Hz), 1.07(6H, s), 0.87(6H, s)
MS (ESI) m/z: 462[M+H]+。 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. The obtained organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. . The obtained residue was recrystallized from ethyl acetate to obtain the title compound (166 g, yield: 94%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.99 (1H, s), 7.01 (1H, s), 4.77 (2H, d, J = 2.5Hz), 3.88 (3H, s), 2.54 (1H, t, J = 2.5Hz), 2.43 (3H, s )
Example 3-2 Methyl 5-bromo-2,4-dimethyl-1-benzofuran-7-carboxylate Methyl 5-bromo-4-methyl-2- (prop-2) prepared according to Example 3-1. To a diethylaniline solution (400 ml) of -in-1-yloxy) benzoate (166 g, 586 mmol), cesium fluoride (115 g, 762 mmol) was added at room temperature, and the mixture was stirred at 200 ° C. for 12 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was extracted 3 times with ethyl acetate. The obtained organic layer was washed with 5N hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0-5: 1, v / v) to obtain the title compound (56.6 g, yield: 35%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
8.19 (1H, s), 6.44 (1H, d, J = 1.0Hz), 3.98 (3H, s), 2.54 (3H, s), 2.53 (3H, d, J = 1.0Hz),
Example 3-3 (5-Bromo-2,4-dimethyl-1-benzofuran-7-yl) methanol Methyl 5-bromo-2,4 prepared according to Example 3-2 under cooling at -78 ° C. 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. The obtained residue was pulverized in hexane and collected by filtration to obtain the title compound (15.1 g, yield: 99%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.39 (1H, s), 6.40 (1H, s), 4.91 (2H, d, J = 6.0Hz), 2.49 (3H, s), 2.47 (3H, s), 1.86 (1H, t, J = 6.0Hz )
Example 3-4 [(5-Bromo-2,4-dimethyl-1-benzofuran-7-yl) methoxy] (tert-butyl) dimethylsilane Prepared according to Example 3-3 under ice cooling ( 5-Bromo-2,4-dimethyl-1-benzofuran-7-yl) methanol (20.0 g, 78.4 mmol), imidazole (6.94 g, 102 mmol) was dissolved in dichloromethane (250 ml) and tert-butyldimethylchlorosilane (14.2 g) was dissolved. g, 94.1 mmol) was gradually added, and then the mixture was stirred at room temperature for 30 minutes. A 10% aqueous citric acid solution (20 ml) was added to the reaction mixture, and the mixture was extracted twice with dichloromethane. 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 purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0-10: 1, v / v) to obtain the title compound (29.4 g, yield: 100%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.43 (1H, s), 6.37 (1H, s), 4.96 (2H, s), 2.47 (3H, s), 2.45 (3H, s), 0.96 (9H, s), 0.13 (6H, s)
Example 3-5 7-({[tert-butyl (dimethyl) silyl] oxy} methyl) hydroxymethyl) -2,4-dimethyl-1-benzofuran-5-carboxylic acid To a THF solution (600 ml) of [(5-bromo-2,4-dimethyl-1-benzofuran-7-yl) methoxy] (tert-butyl) dimethylsilane (31.5 g, 85.3 mmol) prepared by 3-4 n-Butyllithium hexane solution (2.69M, 37.9ml, 102mmol) was added dropwise over 30 minutes. The 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%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
8.06 (1H, s), 6.51 (1H, s), 5.00 (2H, s), 2.77 (3H, s), 2.48 (3H, s), 0.97 (9H, s), 0.14 (6H, s)
Example 3-6 tert-butyl 7-({[tert-butyl (dimethyl) silyl] oxy} methyl) hydroxymethyl) -2,4-dimethyl-1-benzofuran-5-carboxylate 7-({[tert-Butyl (dimethyl) silyl] oxy} methyl) hydroxymethyl) -2,4-dimethyl-1-benzofuran-5-carboxylic acid (21.7 g, 64.9 mmol) prepared according to Example 3-5 To a dichloromethane solution (200 ml) was added dropwise tert-butyl N, N′-dipropan-2-ylcarbamidate (3.5 M tert-butanol solution, 92.7 ml, 324 mmol), and the mixture was stirred at room temperature for 12 hours. The 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. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0-10: 1, v / v) to give the title compound (21.9 g, yield: 87%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.86 (1H, s), 6.46 (1H, s), 5.00 (2H, s), 2.68 (3H, s), 2.46 (3H, s), 1.60 (9H, s), 0.97 (9H, s), 0.14 (6H, s)
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. 1-benzofuran-5-carboxylate (21.9 g, 56.0 mmol) in THF (30.0 mmol) was added dropwise, and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0-4: 1, v / v) to give the title compound (15.7 g, yield: 100%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.74 (1H, s), 6.48 (1H, s), 4.94 (2H, d, J = 6.5Hz), 2.67 (3H, s), 2.48 (3H, s), 1.64 (1H, t, J = 6.5Hz ), 1.61 (9H, s)
Example 3-8 tert-Butyl 7-formyl-2,4-dimethyl-1-benzofuran-5-carboxylate tert-Butyl 7- (hydroxymethyl) -2,4 prepared according to Example 3-7 -Dimethyl-1-benzofuran-5-carboxylate (15.6 g, 56.4 mmol) was heated to reflux in 1,2-dimethoxyethane (250 ml) with manganese (IV) oxide (24.5 g, 282 mmol). After completion of the reaction, the reaction mixture is cooled to room temperature, filtered through Celite, and the filtrate is concentrated. The residue is purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0-5: 1, v / v). The title compound (11.2 g, yield: 73%) was obtained.
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
10.3 (1H, s), 8.22 (1H, s), 6.55 (1H, s), 2.77 (3H, s), 2.56 (3H, s), 2.44 (3H, s), 1.63 (3H, s)
Example 3-9 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 tert-butyl 7-formyl-2,4-dimethyl-1-benzofuran-5-carboxylate prepared according to Example 3-8 (548 mg, 2.00 mmol), 5,5-dimethyl-1,3-hexanedione (561 mg, 4.00 mmol) is mixed with water (40 ml) and 1,4-dioxane (5 ml) at room temperature, and dodecylbenzenesulfonic acid (5 drops) is added. In addition, the mixture was heated to reflux for a whole day and night. The resulting solid was collected by filtration and purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (694 mg, yield: 75%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.89 (1H, s), 6.39 (1H, s), 5.07 (1H, s), 2.63 (3H, s), 2.49 (2H, d, J = 17.5Hz), 2.44 (3H, s), 2.43 (2H , d, J = 17.5Hz), 2.21 (2H, d, J = 17.0Hz), 2.10 (2H, d, J = 17.0Hz), 1.07 (6H, s), 0.87 (6H, s)
MS (ESI) m / z: 462 [M + H] < +>.
 
（実施例４）　2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-カルボン酸　ナトリウム
　実施例３により製造される2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-カルボン酸(2.16g, 4.17mmol)をTHF(300ml)、メタノール(20ml)に溶かし、氷冷下、ナトリウムメトキシド(1.01Mメタノール溶液、4.60ml, 4.17mmol)を加えた。溶媒を減圧留去、乾燥させた後に標記化合物(2.17g, 収率:97%)を得た。
1H-NMRスペクトル(500MHz, CD3OD）δppm：
7.31(1H, s), 6.41(1H, d, J = 1.0Hz), 4.98(1H, s), 2.58(2H, d, J = 17.5Hz), 2.53(2H, d, J = 17.5Hz), 2.48(3H, s), 2.44(3H, s),  2.25(2H, d, J = 16.0Hz), 2.07(2H, dd, J = 1.0, 16.0Hz), 1.08(6H, s), 0.85(6H, s)
Anal. Calcd for C28H29NaO6: C, 69.41; H, 6.03. Found: C, 68.11; H, 6.22.
 
（実施例５）　2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-カルボン酸  2-メチルプロパン-2-アミン
　実施例３により製造される2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-カルボン酸(54.0g, 117mmol)をエタノール(1500ml)に懸濁させ、室温で2-メチルプロパン-2-アミン(24.6ml, 234mmol)をゆっくり加えた。生じた沈殿をろ別し、冷エタノールで洗浄後、乾燥し、標記化合物(53.2g, 収率:85%)を得た。
1H-NMRスペクトル(500MHz, CD3OD）δppm：
7.33(1H, s), 6.42(1H, d, J = 1.0Hz), 4.97(1H, s), 2.59(2H, d, J = 17.5Hz), 2.53(2H, d, J = 17.5Hz), 2.49(3H, s), 2.44(3H, s),  2.26(2H, d, J = 16.5Hz), 2.07(2H, d, J = 16.5Hz), 1.32(9H, s), 1.08(6H, s), 0.85(6H, s)
Anal. Calcd for C32H41NO6: C, 71.75 ; H, 7.71 ; N,2.61, Found: C, 71.61 ; H, 7.92 ; N, 2.55
 
（実施例６）　7-(1’,8’-ジオキソ-1’,4’,5’,7’,8’,9’-ヘキサヒドロ-2’H-ジスピロ[シクロブタン-1,3’-キサンテン-6’,1”-シクロブタン]-9’-イル)-2,4-ジメチル-1-ベンゾフラン-5-カルボン酸
Example 4 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-carboxylic acid sodium 2,4-dimethyl-7- (3,3,6,6-tetramethyl-1,8-dioxo-2, prepared according to Example 3 3,4,5,6,7,8-octahydro-1H-xanthen-9-yl) -1-benzofuran-5-carboxylic acid (2.16 g, 4.17 mmol) was dissolved in THF (300 ml) and methanol (20 ml). Sodium methoxide (1.01 M methanol solution, 4.60 ml, 4.17 mmol) was added under ice cooling. After the solvent was distilled off under reduced pressure and dried, the title compound (2.17 g, yield: 97%) was obtained.
1 H-NMR spectrum (500 MHz, CD 3 OD) δ ppm:
7.31 (1H, s), 6.41 (1H, d, J = 1.0Hz), 4.98 (1H, s), 2.58 (2H, d, J = 17.5Hz), 2.53 (2H, d, J = 17.5Hz), 2.48 (3H, s), 2.44 (3H, s), 2.25 (2H, d, J = 16.0Hz), 2.07 (2H, dd, J = 1.0, 16.0Hz), 1.08 (6H, s), 0.85 (6H , s)
Anal. Calcd for C28H29NaO6: C, 69.41; H, 6.03. Found: C, 68.11; H, 6.22.

Example 5 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-carboxylic acid 2-methylpropan-2-amine 2,4-dimethyl-7- (3,3,6,6-tetramethyl-1 prepared according to Example 3 , 8-Dioxo-2,3,4,5,6,7,8-octahydro-1H-xanthen-9-yl) -1-benzofuran-5-carboxylic acid (54.0 g, 117 mmol) in ethanol (1500 ml) Suspended and 2-methylpropan-2-amine (24.6 ml, 234 mmol) was added slowly at room temperature. The resulting precipitate was filtered off, washed with cold ethanol and dried to give the title compound (53.2 g, yield: 85%).
1 H-NMR spectrum (500 MHz, CD 3 OD) δ ppm:
7.33 (1H, s), 6.42 (1H, d, J = 1.0Hz), 4.97 (1H, s), 2.59 (2H, d, J = 17.5Hz), 2.53 (2H, d, J = 17.5Hz), 2.49 (3H, s), 2.44 (3H, s), 2.26 (2H, d, J = 16.5Hz), 2.07 (2H, d, J = 16.5Hz), 1.32 (9H, s), 1.08 (6H, s ), 0.85 (6H, s)
Anal. Calcd for C 32 H 41 NO 6 : C, 71.75; H, 7.71; N, 2.61, Found: C, 71.61; H, 7.92; N, 2.55

Example 6 7- (1 ′, 8′-Dioxo-1 ′, 4 ′, 5 ′, 7 ′, 8 ′, 9′-Hexahydro-2′H-dispiro [cyclobutane-1,3′-xanthene -6 ', 1 "-cyclobutane] -9'-yl) -2,4-dimethyl-1-benzofuran-5-carboxylic acid
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027
　5, 5-ジメチル-1,3-ヘキサンジオンの代わりにスピロ[3.5]ノナン-6,8-ジオン(304mg, 2.00mmol)を用い、実施例３－８により製造されるtert-ブチル 7-ホルミル-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレート(274mg, 1.00mmol)と実施例３に記載された方法と同様に反応を行い、標記化合物(340mg, 収率:70％)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
7.81(1H, s), 6.38(1H, s), 5.06(1H, s), 2.75(2H, d, J = 17.0Hz), 2.63(3H, s), 2.64(2H, d, J = 17.0Hz), 2.48(3H, s), 2.40(2H, d, J = 16.5Hz), 2.35(2H, d, J = 17.0Hz), 1.80-1.90(6H, m), 1.71-1.76(2H, m), 1.53-1.58(4H, m)
MS (ESI) m/z: 487[M+H]+。 Tert-Butyl 7-formyl prepared by Example 3-8 using spiro [3.5] nonane-6,8-dione (304 mg, 2.00 mmol) instead of 5,5-dimethyl-1,3-hexanedione Reaction was conducted in the same manner as described in Example 3 with -2,4-dimethyl-1-benzofuran-5-carboxylate (274 mg, 1.00 mmol) to obtain the title compound (340 mg, yield: 70%). It was.
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.81 (1H, s), 6.38 (1H, s), 5.06 (1H, s), 2.75 (2H, d, J = 17.0Hz), 2.63 (3H, s), 2.64 (2H, d, J = 17.0Hz ), 2.48 (3H, s), 2.40 (2H, d, J = 16.5Hz), 2.35 (2H, d, J = 17.0Hz), 1.80-1.90 (6H, m), 1.71-1.76 (2H, m) , 1.53-1.58 (4H, m)
MS (ESI) m / z: 487 [M + H] + .
 
（実施例７）　(2E)-3-[2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-イル]プロプ-2-エン酸
Example 7 (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] prop-2-enoic acid
Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000028
（実施例７－１）　tert-ブチル(2E)-3-[7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,4-ジメチル-1-ベンゾフラン-5-イル]プロプ-2-エノエート
　窒素雰囲気下、実施例３－４により製造される[(5-ブロモ-2,4-ジメチル-1-ベンゾフラン-7-イル)メトキシ](tert-ブチル)ジメチルシラン(12.0g, 32.4mmol)のDMF溶液(120ml)に、室温でアクリル酸t-ブチル(47.4ml, 324mmol)、トリエチルアミン45.4ml, 325mmol)、酢酸パラジウム(II)(1.46g, 6.48mmol)、トリ（o-トリル）ホスフィン(3.94g, 13.0mmol)を加え、90℃にて10時間加熱攪拌した。室温に戻した後、反応液に水を加え、ジエチルエーテルで3回抽出、得られた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン：酢酸エチル=1:0-10:1, v/v)で精製して、標記化合物(12.7g, 収率:95％)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
8.01(1H, d, J = 15.5Hz), 7.52(1H,s), 6.41(1H, d, J = 1.0Hz), 6.28(1H, d, J = 15.5Hz), 4.98(2H, s), 2.52(3H, s), 2.45(3H, d, J = 1.0Hz), 1.55(9H, s), 0.96(9H, s), 0.14(6H, s)
TOF-MS (ES-) m/z: 487[M-H]-。
（実施例７－２）　tert-ブチル(2E)-3-[7-(ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-イル]プロプ-2-エノエート
　tert-ブチル7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレートの代わりに実施例７－１により製造されるtert-ブチル(2E)-3-[7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,4-ジメチル-1-ベンゾフラン-5-イル]プロプ-2-エノエート(1.50g, 3.60mmol)を用い、 実施例３－７に記載された方法と同様に反応を行い、標記化合物(980mg, 収率:90％)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
8.00(1H, d, J = 15.5Hz), 7.47(1H, s), 6.44(1H, J = 1.0Hz), 6.31(1H, d, J = 15.5Hz), 4.94(2H, d, J = 6.5Hz), 2.53(3H,s), 2.47(3H, d, J = 1.0Hz), 1.88(1H, t, J = 6.5Hz), 1.54(9H, s)
（実施例７－３）　tert-ブチル(2E)-3-(7-ホルミル-2,4-ジメチル-1-ベンゾフラン-5-イル) プロプ-2-エノエート
　tert-ブチル 7-(ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレートの代わりに実施例７－２により製造されるtert-ブチル (2E)-3-[7-(ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-イル]プロプ-2-エノエート(980mg, 3.24mmol)を用い、実施例3-8に記載された方法と同様に反応を行い、標記化合物(718mg, 収率:74%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
10.4(1H, s), 7.97(1H, d, J = 16.0Hz), 7.93(1H, s), 6.50(1H, d, J = 1.0Hz), 6.40(1H, d, J = 16.0Hz), 2.60(3H, s), 2.55(3H, d, J = 1.0Hz), 1.55(9H, s)
（実施例７－４）　(2E)-3-[2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-イル]プロプ-2-エン酸
　tert-ブチル 7-ホルミル-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレートの代わりに実施例７－３により製造されるtert-ブチル (2E)-3-(7-ホルミル-2,4-ジメチル-1-ベンゾフラン-5-イル) プロプ-2-エノエート(450mg, 1.50mmol)を用い、実施例3に記載された方法と同様に反応を行い、標記化合物(405mg, 収率:53%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
8.13(1H, d, J = 16.0Hz), 7.50(1H, s), 6.41(2H, d, J = 16.0Hz), 6.33(1H, d, J = 1.0Hz), 5.05(1H, s), 2.51(2H, d, J = 16.0Hz), 2.46(3H, s), 2.45(2H, d, J = 16.0Hz), 2.44(3H, s), 2.23(2H, d, J = 16.5Hz), 2.12(2H, d, J = 16.5Hz), 1.10(6H,s), 0.87(1H, s)
MS (ESI) m/z: 489[M+H]+。 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. for 10 hr. After returning to room temperature, water was added to the reaction solution, extracted three times with diethyl ether, and the resulting organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0-10: 1, v / v) to give the title compound (12.7 g, yield: 95 %).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
8.01 (1H, d, J = 15.5Hz), 7.52 (1H, s), 6.41 (1H, d, J = 1.0Hz), 6.28 (1H, d, J = 15.5Hz), 4.98 (2H, s), 2.52 (3H, s), 2.45 (3H, d, J = 1.0Hz), 1.55 (9H, s), 0.96 (9H, s), 0.14 (6H, s)
TOF-MS (ES-) m / z: 487 [MH] - .
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%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
8.00 (1H, d, J = 15.5Hz), 7.47 (1H, s), 6.44 (1H, J = 1.0Hz), 6.31 (1H, d, J = 15.5Hz), 4.94 (2H, d, J = 6.5 Hz), 2.53 (3H, s), 2.47 (3H, d, J = 1.0Hz), 1.88 (1H, t, J = 6.5Hz), 1.54 (9H, s)
Example 7-3 tert-butyl (2E) -3- (7-formyl-2,4-dimethyl-1-benzofuran-5-yl) prop-2-enoate tert-butyl 7- (hydroxymethyl)- Tert-Butyl (2E) -3- [7- (hydroxymethyl) -2,4-dimethyl-1 prepared according to Example 7-2 instead of 2,4-dimethyl-1-benzofuran-5-carboxylate -Benzofuran-5-yl] prop-2-enoate (980 mg, 3.24 mmol) was used in the same manner as described in Example 3-8 to give the title compound (718 mg, yield: 74%). Obtained.
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
10.4 (1H, s), 7.97 (1H, d, J = 16.0Hz), 7.93 (1H, s), 6.50 (1H, d, J = 1.0Hz), 6.40 (1H, d, J = 16.0Hz), 2.60 (3H, s), 2.55 (3H, d, J = 1.0Hz), 1.55 (9H, s)
Example 7-4 (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] prop-2-enoic acid tert-butyl 7-formyl-2,4-dimethyl-1-benzofuran-5-carboxylate Tert-butyl (2E) -3- (7-formyl-2,4-dimethyl-1-benzofuran-5-yl) prop-2-enoate (450 mg, 1.50 mmol) prepared according to Example 7-3 The title compound (405 mg, yield: 53%) was obtained in the same manner as in Example 3.
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
8.13 (1H, d, J = 16.0Hz), 7.50 (1H, s), 6.41 (2H, d, J = 16.0Hz), 6.33 (1H, d, J = 1.0Hz), 5.05 (1H, s), 2.51 (2H, d, J = 16.0Hz), 2.46 (3H, s), 2.45 (2H, d, J = 16.0Hz), 2.44 (3H, s), 2.23 (2H, d, J = 16.5Hz), 2.12 (2H, d, J = 16.5Hz), 1.10 (6H, s), 0.87 (1H, s)
MS (ESI) m / z: 489 [M + H] < +>.
 
（実施例８）　3-[2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-イル]プロパン酸
Example 8 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
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
（実施例８－１）　tert-ブチル3-[7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,4-ジメチル-1-ベンゾフラン-5-イル]プロパノエート
　室温でメタノール(200ml)に、マグネシウム(5.06g, 208mmol)を加え、激しく攪拌しているところに、実施例７－１により製造されるtert-ブチル(2E)-3-[7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,4-ジメチル-1-ベンゾフラン-5-イル]プロプ-2-エノエート(8.67g, 20.8mmol)のメタノール溶液(30ml)を滴下した。室温で6時間攪拌した後、１規定塩酸を加え、酢酸エチルで3回抽出し、得られた有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=1:0-20:1, v/v)で精製して、標記化合物(7.42g, 収率:85%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
7.06(1H, s), 6.35(1H, d, J = 1.0Hz), 4.96(2H, s), 2.97(2H, t, J = 8.0Hz), 2.48(2H, t, J = 8.0Hz), 2.44(3H, d, J = 1.0Hz), 2.39(3H, s), 1.44(9H, s), 0.95(9H, s), 0.12(6H, s)
（実施例８－２）　tert-ブチル3-[7-(ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-イル]プロパノエート
　tert-ブチル7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレートの代わりに実施例8-1により製造されるtert-ブチル3-[7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,4-ジメチル-1-ベンゾフラン-5-イル]プロパノエート(7.42g, 17.7mmol) を用い、 実施例３－７に記載された方法と同様に反応を行い、標記化合物(4.34g, 収率:81%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
7.01(1H, s), 6.38(1H, d, J = 1.0Hz), 4.90(2H, d, J = 6.3Hz), 2.97(2H, t, J = 8.1Hz), 2.49(2H, t, J = 8.1Hz), 2.46(3H, s), 2.40(3H, s), 1.87(1H, t, J = 6.3Hz), 1.44(9H, s)
（実施例８－３）　tert-ブチル3-(7-ホルミル-2,4-ジメチル-1-ベンゾフラン-5-イル]プロパノエート
　tert-ブチル 7-(ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレートの代わりに実施例8-2により製造されるtert-ブチル 3-[7-(ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-イル]プロパノエート(1.00g, 3.29mmol) を用い、 実施例3-8に記載された方法と同様に反応を行い、標記化合物(822mg, 収率:83%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
10.3(1H, s), 7.52(1H, s), 6.45(1H, d, J = 1.0Hz), 3.03(2H, t, J = 7.8Hz), 2.54(2H, t, J = 7.8Hz), 2.53(3H, s), 2.49(3H, d, J = 1.0Hz), 1.43(9H, s)
（実施例８－４）　3-[2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-イル]プロパン酸
　tert-ブチル 7-ホルミル-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレートの代わりに実施例８－３により製造されるtert-ブチル 3-(7-ホルミル-2,4-ジメチル-1-ベンゾフラン-5-イル]プロパノエート(821mg, 2.71mmol)を用い、実施例3に記載された方法と同様に反応を行い、標記化合物(965mg, 収率:73%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
7.10(1H, s), 6.26(1H, s), 4.94(1H, s), 2.99(2H, m), 2.61(2H, m), 2.49(2H, d, J = 17.5Hz), 2.42(2H, d, J = 17.5Hz), 2.38(3H, s), 2.31(3H, s), 2.20(2H, d, J = 17.0Hz), 2.11(2H, d, J = 17.0Hz), 1.09(6H, s), 0.84(6H, s)
MS (FAB) m/z: 491[M+H]+。 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. After stirring at room temperature for 6 hours, 1N hydrochloric acid was added, and the mixture was extracted 3 times with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0-20: 1, v / v) to give the title compound (7.42 g, yield: 85 %).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.06 (1H, s), 6.35 (1H, d, J = 1.0Hz), 4.96 (2H, s), 2.97 (2H, t, J = 8.0Hz), 2.48 (2H, t, J = 8.0Hz), 2.44 (3H, d, J = 1.0Hz), 2.39 (3H, s), 1.44 (9H, s), 0.95 (9H, s), 0.12 (6H, s)
Example 8-2 tert-butyl 3- [7- (hydroxymethyl) -2,4-dimethyl-1-benzofuran-5-yl] propanoate tert-butyl 7-({[tert-butyl (dimethyl) silyl ] Oxy} methyl) hydroxymethyl) -2,4-dimethyl-1-benzofuran-5-carboxylate instead of tert-butyl 3- [7-({[tert-butyl ( Dimethyl) silyl] oxy} methyl) -2,4-dimethyl-1-benzofuran-5-yl] propanoate (7.42 g, 17.7 mmol) was used to carry out the reaction in the same manner as described in Example 3-7. The title compound (4.34 g, yield: 81%) was obtained.
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.01 (1H, s), 6.38 (1H, d, J = 1.0Hz), 4.90 (2H, d, J = 6.3Hz), 2.97 (2H, t, J = 8.1Hz), 2.49 (2H, t, J = 8.1Hz), 2.46 (3H, s), 2.40 (3H, s), 1.87 (1H, t, J = 6.3Hz), 1.44 (9H, s)
Example 8-3 tert-butyl 3- (7-formyl-2,4-dimethyl-1-benzofuran-5-yl] propanoate tert-butyl 7- (hydroxymethyl) -2,4-dimethyl-1- Tert-Butyl 3- [7- (hydroxymethyl) -2,4-dimethyl-1-benzofuran-5-yl] propanoate prepared according to Example 8-2, instead of benzofuran-5-carboxylate (1.00 g, 3.29 mmol) was used in the same manner as in Example 3-8 to give the title compound (822 mg, yield: 83%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
10.3 (1H, s), 7.52 (1H, s), 6.45 (1H, d, J = 1.0Hz), 3.03 (2H, t, J = 7.8Hz), 2.54 (2H, t, J = 7.8Hz), 2.53 (3H, s), 2.49 (3H, d, J = 1.0Hz), 1.43 (9H, s)
Example 8-4 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 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-yl] propanoate (821 mg, 2.71 mmol) prepared by To obtain the title compound (965 mg, yield: 73%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.10 (1H, s), 6.26 (1H, s), 4.94 (1H, s), 2.99 (2H, m), 2.61 (2H, m), 2.49 (2H, d, J = 17.5Hz), 2.42 (2H , d, J = 17.5Hz), 2.38 (3H, s), 2.31 (3H, s), 2.20 (2H, d, J = 17.0Hz), 2.11 (2H, d, J = 17.0Hz), 1.09 (6H , s), 0.84 (6H, s)
MS (FAB) m / z: 491 [M + H] + .
 
（実施例９）　(2E)-3-[2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-イル]プロパン酸  2-メチルプロパン-2-アミン
　2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-カルボン酸の代わりに、実施例８により製造される3-[2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-イル]プロパン酸(1.47g, 3.00mmol)を用いて実施例5と同様に行い、標記化合物(1.35g, 収率:80%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
6.94(1H, s), 6.35(1H,d, J = 1.0Hz), 4.89(1H, s), 2.90(2H, m), 2.61(2H, dd, J = 17.5, 1.0Hz), 2.50(2H, dd, J = 17.5, 1.5Hz), 2.41(3H, d, J = 1.0Hz), 2.36(2H, m), 2.33(3H, s), 2.27(2H, d, J = 16.5Hz), 2.07(2H, dd, J = 16.5, 1.5Hz), 1.33(9H, s), 1.09(6H, s), 0.84(6H, s)
 
（実施例１０）　3-[7-(1',8'-ジオキソ-1',4',5',7',8',9'-ヘキサヒドロ-2'H-ジスピロ[シクロブタン-1,3'-キサンテン-6',1''-シクロブタン]-9'-イル)-2,4-ジメチル-1-ベンゾフラン-5-イル]プロパン酸
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 same manner as in Example 5 to obtain the title compound (1.35 g, yield: 80%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
6.94 (1H, s), 6.35 (1H, d, J = 1.0Hz), 4.89 (1H, s), 2.90 (2H, m), 2.61 (2H, dd, J = 17.5, 1.0Hz), 2.50 (2H , dd, J = 17.5, 1.5Hz), 2.41 (3H, d, J = 1.0Hz), 2.36 (2H, m), 2.33 (3H, s), 2.27 (2H, d, J = 16.5Hz), 2.07 (2H, dd, J = 16.5, 1.5Hz), 1.33 (9H, s), 1.09 (6H, s), 0.84 (6H, s)

Example 10 3- [7- (1 ′, 8′-Dioxo-1 ′, 4 ′, 5 ′, 7 ′, 8 ′, 9′-Hexahydro-2′H-dispiro [cyclobutane-1,3 '-Xanthene-6', 1 ''-cyclobutane] -9'-yl) -2,4-dimethyl-1-benzofuran-5-yl] propanoic acid
Figure JPOXMLDOC01-appb-C000030
 　　　　　　　　　　　　　　　　　 
Figure JPOXMLDOC01-appb-C000030
 　　　　　　　　　　　　　　　　　 
　tert-ブチル 7-ホルミル-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレートの代わりに実施例８－３により製造されるtert-ブチル 3-(7-ホルミル-2,4-ジメチル-1-ベンゾフラン-5-イル]プロパノエート(637mg, 2.00mmol)を用い、実施例６と同様に行い、標記化合物(618mg, 収率:60%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
7.05(1H, s), 6.24(1H, d, J = 1.0Hz), 4.91(1H, s), 2.98(2H, m), 2.73(2H, d, J = 17.0Hz), 2.65(2H, d, J = 17.0Hz), 2.60(2H, m), 2.42(2H, d, J = 16.5Hz), 2.41(3H, d, J = 1.0Hz), 2.37(2H, d, J = 16.5Hz), 2.29(3H, s), 1.81-1.92(8H, m), 1.64-1.71(2H, m), 1.51-1.56(2H, m)
MS (ESI) m/z: 515[M+H]+。 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%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.05 (1H, s), 6.24 (1H, d, J = 1.0Hz), 4.91 (1H, s), 2.98 (2H, m), 2.73 (2H, d, J = 17.0Hz), 2.65 (2H, d , J = 17.0Hz), 2.60 (2H, m), 2.42 (2H, d, J = 16.5Hz), 2.41 (3H, d, J = 1.0Hz), 2.37 (2H, d, J = 16.5Hz), 2.29 (3H, s), 1.81-1.92 (8H, m), 1.64-1.71 (2H, m), 1.51-1.56 (2H, m)
MS (ESI) m / z: 515 [M + H] < +>.
 
（実施例１１）　3-[2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-イル]-2-メチルプロパン酸
Example 11 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-methylpropanoic acid
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000031
（実施例１１－１）　tert-ブチル (2E)-3-[7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,4-ジメチル-1-ベンゾフラン-5-イル]-2-メチルプロプ-2-エノエート 
　窒素雰囲気下、室温で実施例３－４により製造される[(5-ブロモ-2,4-ジメチル-1-ベンゾフラン-7-イル)メトキシ](tert-ブチル)ジメチルシラン(6.00g, 16.2mmol)のDMF溶液(60ml)に、t-ブチル メタクリレート (26.1ml, 162mmol)、トリエチルアミン22.7ml, 162mmol)、酢酸パラジウム(II)(728mg,3.24mmol)、トリ（o-トリル）ホスフィン(1.97g, 6.48mmol)を加え、90℃にて10時間加熱攪拌した。室温に冷却し、反応液に水を加え、ジエチルエーテルで3回抽出により得られた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去することにより標記化合物の粗精製物を得た。
（実施例１１－２）　tert-ブチル 3-[7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,4-ジメチル-1-ベンゾフラン-5-イル]-2-メチルプロパノエート
　tert-ブチル (2E)-3-[7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,4-ジメチル-1-ベンゾフラン-5-イル]プロプ-2-エノエートの代わりに実施例11-1により製造されるtert-ブチル (2E)-3-[7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,4-ジメチル-1-ベンゾフラン-5-イル]-2-メチルプロプ-2-エノエート(3.71g, 8.62mmol)を用いて実施例8-1に記載された方法と同様に反応を行い、標記化合物(3.05g, 収率:82%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
7.04(1H, s), 6.35(1H, d, J = 1.0Hz), 4.96(2H, s), 3.09(1H, dd, J = 13.4, 6.1Hz), 2.66(1H, dd, J = 13.4, 8.5Hz), 2.59(1H, m), 2.44(3H, d, J = 1.0Hz), 2.39(3H, s), 1.40(9H, s), 1.10(3H, d, J = 6.8Hz), 0.95(9H, s), 0.12(6H, s)
（実施例１１－３）　tert-ブチル 3-[7-(ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-イル]-2-メチルプロパノエート
　tert-ブチル7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレートの代わりに実施例11-2により製造されるtert-ブチル3-[7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,4-ジメチル-1-ベンゾフラン-5-イル]-2-メチルプロパノエート(1.98g, 4.59mmol) を用い、 実施例３－７に記載された方法と同様に反応を行い、標記化合物(1.39g, 収率:90%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
6.98(1H, s), 6.38(1H, d, J = 1.0Hz), 4.90(2H, d, J = 5.9Hz), 3.06(1H, dd, J = 13.7, 6.8Hz), 2.68(1H, dd, J = 13.7, 8.3Hz), 2.61(1H, m), 2.46(3H, d, J = 1.0Hz), 2.40(3H, s), 1.89(1H, t, J = 5.9Hz), 1.38(9H, s), 1.11(3H, d, J = 6.8Hz)
（実施例１１－４）　tert-ブチル　3-(7-ホルミル-2,4-ジメチル-1-ベンゾフラン-5-イル)-2-メチルプロパノエート
　tert-ブチル 7-(ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレートの代わりに実施例11-3により製造されるtert-ブチル 3-[7-(ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-イル]-2-メチルプロパノエート(1.39g, 4.15mmol)を用い、 実施例３－８に記載された方法と同様に反応を行い、標記化合物(1.21g, 収率:88%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
10.3(1H, s), 7.50(1H, s), 6.45(1H, d, J = 1.0Hz), 3.11(1H, dd, J = 13.9, 7.6Hz), 2.75(1H, dd, J = 13.9, 7.6Hz), 2.65(1H, m), 2.53(3H, d, J = 1.0Hz), 2.49(3H, s), 1.37(9H, s), 1.16(3H, d, J = 6.8Hz)
（実施例１１－５）　3-[2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-イル]-2-メチルプロパン酸
　tert-ブチル 7-ホルミル-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレートの代わりに実施例11-4により製造されるtert-ブチル　3-(7-ホルミル-2,4-ジメチル-1-ベンゾフラン-5-イル)-2-メチルプロパノエート(1.14g, 3.42mmol)を用い、実施例3に記載された方法と同様に反応を行い、標記化合物(1.13g, 収率:65%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
7.11(1H, s), 6.26(1H, d, J = 1.0Hz), 4.90(1H, s), 3.05(1H, dd, J = 13.7, 7.8Hz), 2.78(1H, dd, J = 13.7, 7.3Hz), 2.68(1H, m), 2.48(2H, dd, J = 17.6, 1.0Hz), 2.41(2H, dd, J = 17.6, 2.0Hz), 2.37(3H, d, J = 1.0Hz), 2.31(3H, s), 2.21(2H, dd, J = 16.6, 3.4Hz), 2.11(2H, dd, J = 16.6, 3.5Hz), 1.21(3H, d, J = 7.0Hz), 1.08(3H, s), 1.07(3H, s), 0.84(3H, s), 0.83(3H, s)
MS (ESI) m/z: 505[M+H]+。 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. for 10 hours. After cooling to room temperature, water was added to the reaction solution, and the organic layer obtained by extraction three times with diethyl ether was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of the title compound.
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%). Got.
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.04 (1H, s), 6.35 (1H, d, J = 1.0Hz), 4.96 (2H, s), 3.09 (1H, dd, J = 13.4, 6.1Hz), 2.66 (1H, dd, J = 13.4, 8.5Hz), 2.59 (1H, m), 2.44 (3H, d, J = 1.0Hz), 2.39 (3H, s), 1.40 (9H, s), 1.10 (3H, d, J = 6.8Hz), 0.95 (9H, s), 0.12 (6H, s)
Example 11-3 tert-butyl 3- [7- (hydroxymethyl) -2,4-dimethyl-1-benzofuran-5-yl] -2-methylpropanoate tert-butyl 7-({[tert Tert-butyl 3- [7- (prepared according to Example 11-2 instead of -butyl (dimethyl) silyl] oxy} methyl) hydroxymethyl) -2,4-dimethyl-1-benzofuran-5-carboxylate Using {[tert-butyl (dimethyl) silyl] oxy} methyl) -2,4-dimethyl-1-benzofuran-5-yl] -2-methylpropanoate (1.98 g, 4.59 mmol) The reaction was performed in the same manner as described in 7 to obtain the title compound (1.39 g, yield: 90%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
6.98 (1H, s), 6.38 (1H, d, J = 1.0Hz), 4.90 (2H, d, J = 5.9Hz), 3.06 (1H, dd, J = 13.7, 6.8Hz), 2.68 (1H, dd , J = 13.7, 8.3Hz), 2.61 (1H, m), 2.46 (3H, d, J = 1.0Hz), 2.40 (3H, s), 1.89 (1H, t, J = 5.9Hz), 1.38 (9H , s), 1.11 (3H, d, J = 6.8Hz)
Example 11-4 tert-butyl 3- (7-formyl-2,4-dimethyl-1-benzofuran-5-yl) -2-methylpropanoate tert-butyl 7- (hydroxymethyl) -2, Tert-Butyl 3- [7- (hydroxymethyl) -2,4-dimethyl-1-benzofuran-5-yl prepared according to Example 11-3 instead of 4-dimethyl-1-benzofuran-5-carboxylate ] -2-Methylpropanoate (1.39 g, 4.15 mmol) was used in the same manner as in Example 3-8 to give the title compound (1.21 g, yield: 88%). .
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
10.3 (1H, s), 7.50 (1H, s), 6.45 (1H, d, J = 1.0Hz), 3.11 (1H, dd, J = 13.9, 7.6Hz), 2.75 (1H, dd, J = 13.9, 7.6Hz), 2.65 (1H, m), 2.53 (3H, d, J = 1.0Hz), 2.49 (3H, s), 1.37 (9H, s), 1.16 (3H, d, J = 6.8Hz)
Example 11-5 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-methylpropanoic acid tert-butyl 7-formyl-2,4-dimethyl-1-benzofuran-5-carboxylate instead Tert-butyl 3- (7-formyl-2,4-dimethyl-1-benzofuran-5-yl) -2-methylpropanoate (1.14 g, 3.42 mmol) prepared according to Example 11-4 The reaction was carried out in the same manner as in the method described in Example 3 to obtain the title compound (1.13 g, yield: 65%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.11 (1H, s), 6.26 (1H, d, J = 1.0Hz), 4.90 (1H, s), 3.05 (1H, dd, J = 13.7, 7.8Hz), 2.78 (1H, dd, J = 13.7, 7.3Hz), 2.68 (1H, m), 2.48 (2H, dd, J = 17.6, 1.0Hz), 2.41 (2H, dd, J = 17.6, 2.0Hz), 2.37 (3H, d, J = 1.0Hz) , 2.31 (3H, s), 2.21 (2H, dd, J = 16.6, 3.4Hz), 2.11 (2H, dd, J = 16.6, 3.5Hz), 1.21 (3H, d, J = 7.0Hz), 1.08 ( 3H, s), 1.07 (3H, s), 0.84 (3H, s), 0.83 (3H, s)
MS (ESI) m / z: 505 [M + H] < +>.
 
（実施例１２）　3-[2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-イル]-2,2-ジメチルプロパン酸
Example 12 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
Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000032
（実施例１２－１）　tert-ブチル3-[7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,4-ジメチル-1-ベンゾフラン-5-イル]-2,2-ジメチルプロパノエート
　氷冷下、ジイソプロピルアミン(0.783ml, 5.55mmol)のTHF溶液(60ml)にn-ブチルリチウム(2.69Mヘキサン溶液, 1.89ml, 5.09mmol)を滴下し、同温下、10分攪拌した。-78℃に冷却した後、実施例１１－２により製造されるtert-ブチル3-[7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,4-ジメチル-1-ベンゾフラン-5-イル]-2-メチルプロパノエート(2.00g, 4.62mmol)のTHF溶液(15ml)を滴下した。-30℃で30分攪拌し、再び-78℃に冷却し、ヨードメタン(0.317ml, 5.09mmol)を加え、室温まで昇温した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで3回抽出し、得られた有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=1:0-20:1, v/v)で精製して、標記化合物(1.35g, 収率:66%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
7.06(1H, s), 6.35(1H, d, J = 1.0Hz), 4.95(2H, s), 2.97(2H, s), 2.44(3H, s), 2.39(3H, s), 1.45(9H, s), 1.12(6H, s), 0.94(9H, s), 0.11(6H, s)
（実施例１２－２）　tert-ブチル3-[7-(ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-イル]-2,2-ジメチルプロパノエート
　tert-ブチル7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレートの代わりに実施例１２－１により製造されるtert-ブチル3-[7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,4-ジメチル-1-ベンゾフラン-5-イル]-2,2-ジメチルプロパノエート(1.35g, 3.02mmol)を用い、 実施例3-7に記載された方法と同様に反応を行い、標記化合物(0.314g, 収率:20%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
7.00(1H, s), 6.38(1H, d, J = 1.0Hz), 4.88(2H, d, J = 5.9Hz), 2.97(2H, s), 2.46(3H, d, J = 1.0Hz), 2.40(3H, s), 1.84(1H, t, J = 5.9Hz), 1.46(9H, s), 1.12(6H, s)
（実施例１２－３）　tert-ブチル 3-(7-ホルミル-2,6-ジメチル-1-ベンゾフラン-5-イル)- 2,2-ジメチルプロパノエート
　tert-ブチル 7-(ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレートの代わりに実施例12-2により製造されるtert-ブチル 3-[7-(ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-イル]-2,2-ジメチルプロパノエート(318mg, 0.913mmol)を用い、 実施例３－８に記載された方法と同様に反応を行い、標記化合物(271mg, 収率:86%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
10.3(1H, s), 7.53(1H, s), 6.44(1H, d, J = 1.0Hz), 3.02(2H, s), 2.53(3H, d, J = 1.0Hz), 2.49(3H, s), 1.45(9H, s), 1.15(6H, s)
（実施例１２－４）　3-[2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-イル]-2,2-ジメチルプロパン酸
　tert-ブチル 7-ホルミル-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレートの代わりに実施例１２－３により製造されるtert-ブチル 3-(7-ホルミル-2,6-ジメチル-1-ベンゾフラン-5-イル)- 2,2-ジメチルプロパノエート(270mg, 0.780mmol)を用い、実施例3に記載された方法と同様に反応を行い、標記化合物(281mg, 収率:69%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
7.19(1H, s), 6.25(1H, d, J = 1.0Hz), 4.89(1H, s), 2.97(2H, s), 2.47(2H, m), 2.42(2H, m), 2.36(3H, d, J = 1.0Hz), 2.31(3H, s), 2.21(2H, d, J = 16.1Hz), 2.12(2H, d, J = 16.1Hz), 1.22(6H, s), 1.08(6H, s), 0.85(6H, s)
MS (ESI) m/z: 519[M+H]+。 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. After cooling to −78 ° C., tert-butyl 3- [7-({[tert-butyl (dimethyl) silyl] oxy} methyl) -2,4-dimethyl-1-benzofuran prepared according to Example 11-2 A solution of (5-yl) -2-methylpropanoate (2.00 g, 4.62 mmol) in THF (15 ml) was added dropwise. The mixture was stirred at -30 ° C for 30 minutes, cooled again to -78 ° C, iodomethane (0.317 ml, 5.09 mmol) was added, and the temperature was raised to room temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0-20: 1, v / v) to give the title compound (1.35 g, yield: 66% )
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.06 (1H, s), 6.35 (1H, d, J = 1.0Hz), 4.95 (2H, s), 2.97 (2H, s), 2.44 (3H, s), 2.39 (3H, s), 1.45 (9H , s), 1.12 (6H, s), 0.94 (9H, s), 0.11 (6H, s)
Example 12-2 tert-butyl 3- [7- (hydroxymethyl) -2,4-dimethyl-1-benzofuran-5-yl] -2,2-dimethylpropanoate tert-butyl 7-({ [tert-Butyl (dimethyl) silyl] oxy} methyl) hydroxymethyl) -2,4-dimethyl-1-benzofuran-5-carboxylate instead of tert-butyl 3- [7 -({[tert-butyl (dimethyl) silyl] oxy} methyl) -2,4-dimethyl-1-benzofuran-5-yl] -2,2-dimethylpropanoate (1.35 g, 3.02 mmol) The reaction was performed in the same manner as described in Example 3-7 to obtain the title compound (0.314 g, yield: 20%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.00 (1H, s), 6.38 (1H, d, J = 1.0Hz), 4.88 (2H, d, J = 5.9Hz), 2.97 (2H, s), 2.46 (3H, d, J = 1.0Hz), 2.40 (3H, s), 1.84 (1H, t, J = 5.9Hz), 1.46 (9H, s), 1.12 (6H, s)
Example 12-3 tert-butyl 3- (7-formyl-2,6-dimethyl-1-benzofuran-5-yl) -2,2-dimethylpropanoate tert-butyl 7- (hydroxymethyl)- Tert-Butyl 3- [7- (hydroxymethyl) -2,4-dimethyl-1-benzofuran-5 prepared according to Example 12-2 instead of 2,4-dimethyl-1-benzofuran-5-carboxylate -Il] -2,2-dimethylpropanoate (318 mg, 0.913 mmol) was used in the same manner as in Example 3-8 to give the title compound (271 mg, yield: 86%). Obtained.
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
10.3 (1H, s), 7.53 (1H, s), 6.44 (1H, d, J = 1.0Hz), 3.02 (2H, s), 2.53 (3H, d, J = 1.0Hz), 2.49 (3H, s ), 1.45 (9H, s), 1.15 (6H, s)
Example 12-4 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 tert-butyl 7-formyl-2,4-dimethyl-1-benzofuran-5-carboxylate Tert-butyl 3- (7-formyl-2,6-dimethyl-1-benzofuran-5-yl) -2,2-dimethylpropanoate (270 mg, 0.780 mmol) prepared according to Example 12-3 The title compound (281 mg, yield: 69%) was obtained in the same manner as in the method described in Example 3.
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.19 (1H, s), 6.25 (1H, d, J = 1.0Hz), 4.89 (1H, s), 2.97 (2H, s), 2.47 (2H, m), 2.42 (2H, m), 2.36 (3H , d, J = 1.0Hz), 2.31 (3H, s), 2.21 (2H, d, J = 16.1Hz), 2.12 (2H, d, J = 16.1Hz), 1.22 (6H, s), 1.08 (6H , s), 0.85 (6H, s)
MS (ESI) m / z: 519 [M + H] < +>.
 
（実施例１３）　3-[2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-イル]-2,2-ジメチルプロパン酸  2-メチルプロパン-2-アミン
　2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-カルボン酸の代わりに、実施例１２により製造される3-[2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-イル]-2,2-ジメチルプロパン酸(1.46g, 2.81mmol)を用いて実施例5と同様に行い、標記化合物(1.33g, 収率:80%)を得た。
1H-NMRスペクトル(500MHz, CD3OD）δppm：
6.98(1H, s), 6.34(1H, d, J = 1.0Hz), 4.87(1H, s), 2.95(2H, s), 2.60(2H, d, J = 17.6Hz), 2.51(2H, d, J = 17.6Hz), 2.41(3H, s), 2.34(3H, s), 2.27(2H, d, J = 16.1Hz), 2.07(2H, d, J = 16.1Hz), 1.34(9H, s), 1.09(6H, s), 1.07(6H, s), 0.84(6H, s)
 
（実施例１４）　3-[2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-イル]-3-メチルプロパン酸
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 manner as in Example 5 and the title compound (1.33 g Yield: 80%).
1 H-NMR spectrum (500 MHz, CD 3 OD) δ ppm:
6.98 (1H, s), 6.34 (1H, d, J = 1.0Hz), 4.87 (1H, s), 2.95 (2H, s), 2.60 (2H, d, J = 17.6Hz), 2.51 (2H, d , J = 17.6Hz), 2.41 (3H, s), 2.34 (3H, s), 2.27 (2H, d, J = 16.1Hz), 2.07 (2H, d, J = 16.1Hz), 1.34 (9H, s ), 1.09 (6H, s), 1.07 (6H, s), 0.84 (6H, s)

Example 14 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] -3-methylpropanoic acid
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033
（実施例１４－１）　tert-ブチル (2E)-3-[7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,4-ジメチル-1-ベンゾフラン-5-イル]ブテ-2-エノエート
　t-ブチル メタクリレートの代わりにt-ブチル　2-ブテ-2-エノエート(25ml, 156mmol)を用い、実施例3-4により製造される[(5-ブロモ-2,4-ジメチル-1-ベンゾフラン-7-イル)メトキシ](tert-ブチル)ジメチルシラン(12.5g, 30.02mmol)と、実施例１１－１と同様に反応を行い、標記化合物の粗精製物を得た。
（実施例１４－２）　tert-butyl 3-[7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,4-ジメチル-1-ベンゾフラン-5-イル]-3-メチルプロパノエート
　tert-ブチル (2E)-3-[7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,4-ジメチル-1-ベンゾフラン-5-イル]プロプ-2-エノエートの代わりに実施例１４－１により製造される
tert-ブチル (2E)-3-[7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,4-ジメチル-1-ベンゾフラン-5-イル]ブテ-2-エノエート(3.58g, 8.31mmol)を用いて実施例8-1に記載された方法と同様に反応を行い、標記化合物(2.03g, 収率:73%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
7.02(1H, s), 6.32 (1H), 4.93(2H, s), 3.09(1H, m), 2.66(1H, m), 2.59(1H, m), 2.40(3H, s), 2.37(3H, s), 1.37(9H, s), 1.06(3H, d, J = 5.9Hz), 0.95(9H, s), 0.12(6H, s)
（実施例１４－３）　tert-ブチル 3-[7-(ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-イル]-3-メチルプロパノエート
　tert-ブチル 7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレートの代わりに実施例１４－２により製造されるtert-butyl 3-[7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,4-ジメチル-1-ベンゾフラン-5-イル]-3-メチルプロパノエート(2.03g, 4.69mmol) を用い、 実施例3-7に記載された方法と同様に反応を行い、標記化合物の粗生成物を得た。
（実施例１４－４）　tert-ブチル　3-(7-ホルミル-2,4-ジメチル-1-ベンゾフラン-5-イル)-3-メチルプロパノエート
　tert-ブチル 7-(ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレートの代わりに実施例14-3により製造されるtert-ブチル 3-[7-(ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-イル]-3-メチルプロパノエート(2.03g, 6.07mmol)を用い、 実施例３－８に記載された方法と同様に反応を行い、標記化合物(1.67g, 収率:85%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
10.3(1H, s), 7.55(1H, s), 6.42(1H, s), 3.60(2H,m), 2.65(1H, m), 2.55(6H, m), 1.30(9H, s), 1.16(3H, d, J = 6.8Hz)
（実施例１４－５）　3-[2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-イル]-3-メチルプロパン酸
　tert-ブチル 7-ホルミル-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレートの代わりに実施例14-4により製造されるtert-ブチル　3-(7-ホルミル-2,4-ジメチル-1-ベンゾフラン-5-イル)-3-メチルプロパノエート(1.67g, 5.02mmol)を用い、実施例３に記載された方法と同様に反応を行い、標記化合物(2.33g, 収率:92%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
7.04(1H, s), 6.23(1H, d, J = 1.0Hz), 4.90(1H, s), 3.70(1H, m), 3.52 (1H, m), 2.62(2H, m), 2.42(5H, m), 2.31(3H, s), 2.18 (2H, m), 2.07(2H, m), 1.28(2H, dd, J = 16.6, 3.5Hz), 1.21(3H, d, J = 7.0Hz), 1.06(3H, s), 1.05(3H, s), 0.85(3H, s), 0.81(3H, s)
MS (ESI) m/z: 505[M+H]+。 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 Prepared according to Example 3-4 using tert-butyl 2-but-2-enoate (25 ml, 156 mmol) instead of 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.
tert-Butyl (2E) -3- [7-({[tert-Butyl (dimethyl) silyl] oxy} methyl) -2,4-dimethyl-1-benzofuran-5-yl] bute-2-enoate (3.58 g, 8.31 mmol) was used in the same manner as in Example 8-1 to obtain the title compound (2.03 g, yield: 73%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.02 (1H, s), 6.32 (1H), 4.93 (2H, s), 3.09 (1H, m), 2.66 (1H, m), 2.59 (1H, m), 2.40 (3H, s), 2.37 (3H , s), 1.37 (9H, s), 1.06 (3H, d, J = 5.9Hz), 0.95 (9H, s), 0.12 (6H, s)
Example 14-3 tert-butyl 3- [7- (hydroxymethyl) -2,4-dimethyl-1-benzofuran-5-yl] -3-methylpropanoate tert-butyl 7-({[tert Tert-butyl 3- [7- (prepared according to Example 14-2 instead of -butyl (dimethyl) silyl] oxy} methyl) hydroxymethyl) -2,4-dimethyl-1-benzofuran-5-carboxylate {[tert-butyl (dimethyl) silyl] oxy} methyl) -2,4-dimethyl-1-benzofuran-5-yl] -3-methylpropanoate (2.03 g, 4.69 mmol) was used to produce Example 3- Reaction was conducted in the same manner as described in 7 to obtain a crude product of the title compound.
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%). .
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
10.3 (1H, s), 7.55 (1H, s), 6.42 (1H, s), 3.60 (2H, m), 2.65 (1H, m), 2.55 (6H, m), 1.30 (9H, s), 1.16 (3H, d, J = 6.8Hz)
Example 14-5 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] -3-methylpropanoic acid tert-butyl 7-formyl-2,4-dimethyl-1-benzofuran-5-carboxylate instead Tert-butyl 3- (7-formyl-2,4-dimethyl-1-benzofuran-5-yl) -3-methylpropanoate (1.67 g, 5.02 mmol) prepared according to Example 14-4 The reaction was carried out in the same manner as in the method described in Example 3 to obtain the title compound (2.33 g, yield: 92%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.04 (1H, s), 6.23 (1H, d, J = 1.0Hz), 4.90 (1H, s), 3.70 (1H, m), 3.52 (1H, m), 2.62 (2H, m), 2.42 (5H , m), 2.31 (3H, s), 2.18 (2H, m), 2.07 (2H, m), 1.28 (2H, dd, J = 16.6, 3.5Hz), 1.21 (3H, d, J = 7.0Hz) , 1.06 (3H, s), 1.05 (3H, s), 0.85 (3H, s), 0.81 (3H, s)
MS (ESI) m / z: 505 [M + H] < +>.
 
（実施例１５）　[2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-イル]酢酸
Example 15 [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
Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000034
（実施例１５－１）　tert-ブチル 2-[7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,4-ジメチル-1-ベンゾフラン-5-イル]アセテート
　窒素雰囲気下、-10℃に冷却した酢酸パラジウム(673mg, 3.00mmol)、2-ジシクロヘキシルホスフィノ-2’-(N,N-ジメチルアミノ)ビフェニル(2.48g, 6.30mmol)のトルエン溶液(80ml)にリチウム　ビス(トリメチルシリル)アミド (1.0M トルエン溶液, 196ml, 196mmol)を滴下した。同温下、酢酸t-ブチル(24.0ml, 180mmol)を加え、10分攪拌した後に、実施例３－４により製造される[(5-ブロモ-2,4-ジメチル-1-ベンゾフラン-7-イル)メトキシ](tert-ブチル)ジメチルシラン(22.1g, 60.0mmol)のトルエン溶液(20ml)を加えた。85℃で6時間攪拌を行った後、室温にまで冷却し、反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで３回抽出し、得られた有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥し、減圧下にて溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=1:0-20:1, v/v)で精製して、標記化合物(8.18g, 収率:34%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
7.10(1H, s), 6.36(1H, d, J = 1.0Hz), 4.97(2H, s), 3.61(2H, s), 2.44(3H, d, J = 1.0Hz), 2.38(3H, s), 1.42(9H, s), 0.95(9H, s), 0.11(6H, s)
（実施例１５－２）　tert-ブチル[7-(ヒドロキシメチル) -2,4-ジメチル-1-ベンゾフラン-5-イル]アセテート
　tert-ブチル7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレートの代わりに実施例１５－１により製造されるtert-ブチル [7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,4-ジメチル-1-ベンゾフラン-5-イル]アセテート(8.18g, 20.2mmol) を用い、 実施例3-7に記載された方法と同様に反応を行い、標記化合物(4.80g, 収率:82%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
7.04(1H, s), 6.39(1H, d, J = 1.0Hz), 4.91(2H, d, J = 6.3Hz), 3.61(2H, s), 2.46(3H, d, J = 1.0Hz), 2.39(3H, s), 1.89(1H, t, J = 6.3Hz), 1.43(9H, s)
（実施例１５－３）　tert-ブチル (7-ホルミル-2,4-ジメチル-1-ベンゾフラン-5-イル)アセテート
　tert-ブチル 7-(ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレートの代わりに実施例15-2により製造されるtert-ブチル [7-(ヒドロキシメチル) -2,4-ジメチル-1-ベンゾフラン-5-イル]アセテート(4.80g, 16.5mmol)を用い、 実施例３－８に記載された方法と同様に反応を行い、標記化合物(3.84g, 収率:81％)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
10.3(1H, s), 7.54(1H, s), 6.46(1H, d, J = 1.0Hz), 3.67(2H, s), 2.53(3H, d, J = 1.0Hz), 2.47(3H, s), 1.44(9H, s)
（実施例１５－４）　[2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-イル]酢酸
　tert-ブチル 7-ホルミル-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレートの代わりに実施例15-3により製造されるtert-ブチル (7-ホルミル-2,4-ジメチル-1-ベンゾフラン-5-イル)アセテート(5.00g, 17.3mmol)を用い、実施例３に記載された方法と同様に反応を行い、標記化合物(4.94g, 収率:60％)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm： 
7.08(1H, s), 6.28(1H, d, J = 1.0Hz), 4.99(1H, s), 3.69(2H, s), 2.48(2H, d, J = 17.5Hz), 2.42(2H, d, J = 17.5Hz), 2.41(3H, s), 2.31(3H, s), 2.20(2H, d, J = 16.1Hz), 2.11(2H, d, J = 16.1Hz), 1.08(6H, s), 0.85(6H, s)
MS (ESI) m/z: 477[M+H]+。 Example 15-1 tert-butyl 2- [7-({[tert-butyl (dimethyl) silyl] oxy} methyl) -2,4-dimethyl-1-benzofuran-5-yl] acetate under nitrogen atmosphere To a toluene solution (80 ml) of palladium acetate (673 mg, 3.00 mmol), 2-dicyclohexylphosphino-2 ′-(N, N-dimethylamino) biphenyl (2.48 g, 6.30 mmol) cooled to −10 ° C., lithium bis ( Trimethylsilyl) amide (1.0 M toluene solution, 196 ml, 196 mmol) was added dropwise. At the same temperature, t-butyl acetate (24.0 ml, 180 mmol) was added, and the mixture was stirred for 10 minutes, and then prepared according to Example 3-4 [(5-bromo-2,4-dimethyl-1-benzofuran-7- (Il) methoxy] (tert-butyl) dimethylsilane (22.1 g, 60.0 mmol) in toluene (20 ml) was added. After stirring at 85 ° C. for 6 hours, the mixture was cooled to room temperature, saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. And the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0-20: 1, v / v) to obtain the title compound (8.18 g, yield: 34%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.10 (1H, s), 6.36 (1H, d, J = 1.0Hz), 4.97 (2H, s), 3.61 (2H, s), 2.44 (3H, d, J = 1.0Hz), 2.38 (3H, s ), 1.42 (9H, s), 0.95 (9H, s), 0.11 (6H, s)
Example 15-2 tert-butyl [7- (hydroxymethyl) -2,4-dimethyl-1-benzofuran-5-yl] acetate tert-butyl 7-({[tert-butyl (dimethyl) silyl] oxy } Methyl) hydroxymethyl) -2,4-dimethyl-1-benzofuran-5-carboxylate instead of tert-butyl [7-({[tert-butyl (dimethyl) silyl]] prepared according to Example 15-1 Oxy} methyl) -2,4-dimethyl-1-benzofuran-5-yl] acetate (8.18 g, 20.2 mmol) was used in the same manner as described in Example 3-7 to give the title compound ( 4.80 g, yield: 82%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.04 (1H, s), 6.39 (1H, d, J = 1.0Hz), 4.91 (2H, d, J = 6.3Hz), 3.61 (2H, s), 2.46 (3H, d, J = 1.0Hz), 2.39 (3H, s), 1.89 (1H, t, J = 6.3Hz), 1.43 (9H, s)
Example 15-3 tert-butyl (7-formyl-2,4-dimethyl-1-benzofuran-5-yl) acetate tert-butyl 7- (hydroxymethyl) -2,4-dimethyl-1-benzofuran- Instead of 5-carboxylate tert-butyl [7- (hydroxymethyl) -2,4-dimethyl-1-benzofuran-5-yl] acetate (4.80 g, 16.5 mmol) prepared according to Example 15-2 was used. And the reaction was conducted in the same manner as described in Example 3-8 to obtain the title compound (3.84 g, yield: 81%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
10.3 (1H, s), 7.54 (1H, s), 6.46 (1H, d, J = 1.0Hz), 3.67 (2H, s), 2.53 (3H, d, J = 1.0Hz), 2.47 (3H, s ), 1.44 (9H, s)
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-yl) acetate (5.00 g, 17.3 mmol) produced, the reaction was carried out in the same manner as described in Example 3. The title compound (4.94 g, yield: 60%) was obtained.
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.08 (1H, s), 6.28 (1H, d, J = 1.0Hz), 4.99 (1H, s), 3.69 (2H, s), 2.48 (2H, d, J = 17.5Hz), 2.42 (2H, d , J = 17.5Hz), 2.41 (3H, s), 2.31 (3H, s), 2.20 (2H, d, J = 16.1Hz), 2.11 (2H, d, J = 16.1Hz), 1.08 (6H, s ), 0.85 (6H, s)
MS (ESI) m / z: 477 [M + H] < +>.
 
（実施例１６）　エチル　[2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-イル]アセテート
Example 16 Ethyl [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] acetate
Figure JPOXMLDOC01-appb-C000035
Figure JPOXMLDOC01-appb-C000035
　実施例15により製造される[2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-イル]酢酸(200mg, 0.420mmol)と炭酸カリウム(138mg, 1.00mmol)のDMF懸濁液(5.00ml)に、室温でヨードエタン(0.040ml, 0.504mmol)を加え、50℃にて3時間加熱攪拌した。室温に戻した後、反応液に水を加え、酢酸エチルで3回抽出し、得られた有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=10:1-1:1, v/v)で精製して、標記化合物(147mg, 収率:70％）を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm :
7.07(1H, s), 6.27(1H, d, J = 1.0Hz), 5.00(1H, s), 4.10(2H, q, J = 7.1Hz), 3.64(2H, s), 2.48(2H, d, J = 16.5Hz), 2.42(2H, d, J = 16.5Hz), 2.41(3H, d, J = 1.0Hz), 2.31(3H, s), 2.20(2H, d, J = 16.6Hz), 2.10(2H, dd, J = 16.5, 1.0Hz), 1.23(3H, t, J = 7.1Hz), 1.08(6H, s), 0.86(6H, s)
MS (ESI) m/z: 505[M+H]+。 [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 (200 mg, 0.420 mmol) and potassium carbonate (138 mg, 1.00 mmol) in DMF suspension (5.00 ml) at room temperature with iodoethane ( 0.040 ml, 0.504 mmol) was added, and the mixture was stirred with heating at 50 ° C. for 3 hours. After returning to room temperature, water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1-1: 1, v / v) to give the title compound (147 mg, yield: 70%) Got.
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.07 (1H, s), 6.27 (1H, d, J = 1.0Hz), 5.00 (1H, s), 4.10 (2H, q, J = 7.1Hz), 3.64 (2H, s), 2.48 (2H, d , J = 16.5Hz), 2.42 (2H, d, J = 16.5Hz), 2.41 (3H, d, J = 1.0Hz), 2.31 (3H, s), 2.20 (2H, d, J = 16.6Hz), 2.10 (2H, dd, J = 16.5, 1.0Hz), 1.23 (3H, t, J = 7.1Hz), 1.08 (6H, s), 0.86 (6H, s)
MS (ESI) m / z: 505 [M + H] < +>.
 
（実施例１７）　2-[2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-イル]ブタン酸
Example 17 2- [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] butanoic acid
Figure JPOXMLDOC01-appb-C000036
Figure JPOXMLDOC01-appb-C000036
（実施例１７－１）　tert-ブチル2-[7-(ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-イル]ブタノエート
　-78℃冷却下、実施例１５－１により製造されるtert-ブチル [7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,4-ジメチル-1-ベンゾフラン-5-イル]アセテート(2.02g, 5.00mmol)のTHF溶液(50ml)にリチウム　ビス（トリメチルシリル）アミド(1.10M ヘキサン溶液, 5.45ml, 6.00mmol)を滴下し、20分攪拌した。ヨードエタン(0.402ml, 5.00mmol)を加えた後、室温まで徐々に昇温した後、飽和塩化アンモニウム水溶液を加え、ジエチルエーテルで2回抽出し、得られた有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し得られた残渣をTHF(10ml)に溶かし、氷冷下、フッ化テトラブチルアンモニウム(1.0M THF溶液, 15.0ml, 15.0mmol)と酢酸(0.944ml, 16.5mmol)との混合物に滴下し、室温で12時間攪拌を行った。反応液に水を加え、酢酸エチルで3回抽出し、得られた有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥し、減圧下にて溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=20:1-3:1, v/v)で精製して、標記化合物(850mg, 収率:54％)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm :
7.16(1H, s), 6.40(1H, d, J = 1.0Hz), 4.91(2H, m), 2.46(3H, d, J = 1.0Hz), 2.45(3H, s), 2.11(1H, m), 1.90(1H, t, J = 6.1Hz), 1.73(1H, m), 1.38(9H, s), 0.90(3H, t, J = 7.6Hz)
（実施例１７－２）　tert-ブチル2-(7-ホルミル-2,4-ジメチル-1-ベンゾフラン-5-イル)ブタノエート
　tert-ブチル 7-(ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレートの代わりに実施例17-1により製造されるtert-ブチル2-[7-(ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-イル]ブタノエート(850mg, 2.67mmol)を用い、 実施例３－８に記載された方法と同様に反応を行い、標記化合物(600mg, 収率:73％)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm :
10.3(1H, s), 7.69(1H, s), 6.47(1H, d, J = 1.0Hz), 3.75(1H, t, J = 7.8Hz), 2.54(6H, s), 2.17(1H, m), 1.79(1H, m), 1.38(9H, s), 0.92(3H, t, J = 7.3Hz)
（実施例１７－３）　tert-ブチル2-[2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-イル]ブタノエート
　実施例１７－２により製造されるtert-ブチル2-(7-ホルミル-2,4-ジメチル-1-ベンゾフラン-5-イル)ブタノエート(600mg, 1.89mmol)、5, 5-ジメチル-1,3-ヘキサンジオン(530mg, 3.78mmol)、ドデシルベンゼンスルホン酸(5滴)を室温で混合し、水(50ml)中、一昼夜加熱還流した。生じた固体をろ取し、シリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=1:0-3:1, v/v)で精製して、標記化合物(912mg, 収率:55％)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm :
6.91(1H, s), 6.33(1H, d, J = 1.0Hz), 5.77(1H, s), 3.72(1H, q, J = 6.8Hz), 2.26-2.51(8H, m), 2.40(3H, s), 2.32(3H, d, J = 1.0Hz), 2.01(1H, m), 1.65(1H, m),, 1.35(9H, s), 1.24(3H, t, J = 6.8Hz), 0.80-1.10(12H, m)
（実施例１７－４）　2-[2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-イル]ブタン酸
　氷冷下、トリフルオロ酢酸(15.0ml)に実施例１７－３により製造されるtert-ブチル 2-[2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-イル]ブタノエート(912mg, 1.63mmol)のジクロロメタン溶液(5ml)を滴下した。室温で１時間攪拌した後、減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製して、標記化合物(821mg, 収率:100％)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm :
7.00(1H, s), 6.29(1H, d, J = 1.0Hz), 5.07(1H, s), 3.74(1H, t, J = 7.6Hz), 2.46(3H, s), 2.37(3H, s), 2.35-2.51(4H, m), 2.05-2.24(5H, m), 1.73(1H, m), 1.08(3H, s), 0.98(3H, s), 0.88(3H, s), 0.84(3H, t, J = 7.3Hz), 0.72(3H, s)
MS (ESI) m/z: 505[M+H]+。 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. tert-Butyl [7-({[tert-Butyl (dimethyl) silyl] oxy} methyl) -2,4-dimethyl-1-benzofuran-5-yl] acetate (2.02 g, 5.00 mmol) in THF (50 ml) To the solution, lithium bis (trimethylsilyl) amide (1.10 M hexane solution, 5.45 ml, 6.00 mmol) was added dropwise and stirred for 20 minutes. After iodoethane (0.402 ml, 5.00 mmol) was added, the temperature was gradually raised to room temperature, saturated aqueous ammonium chloride solution was added, extracted twice with diethyl ether, and the resulting organic layer was washed with saturated brine, anhydrous Dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in THF (10 ml) .Under ice cooling, tetrabutylammonium fluoride (1.0 M THF solution, 15.0 ml, 15.0 mmol) and acetic acid (0.944 ml, 16.5 mmol) were added. The mixture was added dropwise to the mixture and stirred at room temperature for 12 hours. Water was added to the reaction mixture, 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 purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1-3: 1, v / v) to obtain the title compound (850 mg, yield: 54%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.16 (1H, s), 6.40 (1H, d, J = 1.0Hz), 4.91 (2H, m), 2.46 (3H, d, J = 1.0Hz), 2.45 (3H, s), 2.11 (1H, m ), 1.90 (1H, t, J = 6.1Hz), 1.73 (1H, m), 1.38 (9H, s), 0.90 (3H, t, J = 7.6Hz)
Example 17-2 tert-butyl 2- (7-formyl-2,4-dimethyl-1-benzofuran-5-yl) butanoate tert-butyl 7- (hydroxymethyl) -2,4-dimethyl-1- Tert-Butyl 2- [7- (hydroxymethyl) -2,4-dimethyl-1-benzofuran-5-yl] butanoate prepared according to Example 17-1 instead of benzofuran-5-carboxylate (850 mg, 2.67 The title compound (600 mg, yield: 73%) was obtained in the same manner as in Example 3-8.
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
10.3 (1H, s), 7.69 (1H, s), 6.47 (1H, d, J = 1.0Hz), 3.75 (1H, t, J = 7.8Hz), 2.54 (6H, s), 2.17 (1H, m ), 1.79 (1H, m), 1.38 (9H, s), 0.92 (3H, t, J = 7.3Hz)
Example 17-3 tert-butyl 2- [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] butanoate tert-butyl 2- (7-formyl-2,4-dimethyl-, prepared according to Example 17-2 1-benzofuran-5-yl) butanoate (600 mg, 1.89 mmol), 5,5-dimethyl-1,3-hexanedione (530 mg, 3.78 mmol), dodecylbenzenesulfonic acid (5 drops) are mixed at room temperature, (50 ml) was heated to reflux for a whole day and night. The resulting solid was collected by filtration and purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0-3: 1, v / v) to obtain the title compound (912 mg, yield: 55%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
6.91 (1H, s), 6.33 (1H, d, J = 1.0Hz), 5.77 (1H, s), 3.72 (1H, q, J = 6.8Hz), 2.26-2.51 (8H, m), 2.40 (3H , s), 2.32 (3H, d, J = 1.0Hz), 2.01 (1H, m), 1.65 (1H, m), 1.35 (9H, s), 1.24 (3H, t, J = 6.8Hz), 0.80-1.10 (12H, m)
Example 17-4 2- [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] butanoic acid tert-butyl 2- [ 2,4-Dimethyl-7- (3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthene-9- (Il) -1-benzofuran-5-yl] butanoate (912 mg, 1.63 mmol) in dichloromethane (5 ml) was added dropwise. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (821 mg, yield: 100%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.00 (1H, s), 6.29 (1H, d, J = 1.0Hz), 5.07 (1H, s), 3.74 (1H, t, J = 7.6Hz), 2.46 (3H, s), 2.37 (3H, s ), 2.35-2.51 (4H, m), 2.05-2.24 (5H, m), 1.73 (1H, m), 1.08 (3H, s), 0.98 (3H, s), 0.88 (3H, s), 0.84 ( 3H, t, J = 7.3Hz), 0.72 (3H, s)
MS (ESI) m / z: 505 [M + H] < +>.
 
（実施例１８）　3-[2,6-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-イル]プロパン酸
Example 18 3- [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
Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000037
（実施例１８－１）　エチル 3-ブロモ-2-メチル-6-(プロプ-2-エン-1-イルオキシ)ベンゾエート
　エチル 3-ブロモ-6-ヒドロキシ-2-メチル-5-(プロプ-2-エン-1-イル)ベンゾエート(US 6127570A 記載化合物、36.8g, 142mmol)のDMF溶液(200ml)に室温で炭酸カリウム(31.5g, 227mmol)を加え、激しく攪拌した。更に3-ブロモ-1-プロペン(17.6ml, 208mmol)を加え、室温で6時間激しく攪拌した。反応液をろ過した後、水を加え、酢酸エチルで2回抽出し、得られた有機層を水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=1:0-10:1, v/v)で精製して、標記化合物(37.8g, 収率89%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm :
7.47(1H, d, J = 8.8Hz), 6.65(1H, d, J = 8.8Hz), 5.97(1H, m), 5.37(1H, m), 5.26(1H, dd, J = 10.7, 0.7Hz), 4.53(2H, dd, J = 5.1, 1.7Hz), 4.40(2H, q, J = 7.1Hz), 2.33(3H, s), 1.38(3H, t, J = 7.1Hz)
（実施例１８－２）　エチル 5-ブロモ-2,6-ジメチル-2,3-ジヒドロ-1-ベンゾフラン-7-カルボキシレート
　実施例18-1により製造されるエチル 3-ブロモ-2-メチル-6-(プロプ-2-エン-1-イルオキシ)ベンゾエート(37.8g, 126mmol)のトルエン溶液(600ml)に、室温でイッテルビウム(III)トリフルオロメタンスルホナート水和物(3.91g, 6.30mmol)を加え、6時間加熱還流した。反応液に水を加え、ジエチルエーテルで3回抽出し、得られた有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥し、減圧下にて溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=1:0-10:1, v/v)で精製して、標記化合物(15.0g, 収率:40%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm :
7.36(1H, s), 4.99(1H, m), 4.39(1H, qd, J = 7.2, 1.2Hz), 3.28(1H, m), 2.78(1H, dd, J = 15.7, 7.4Hz), 2.38(3H, s), 1.45(3H, d, J = 6.3Hz), 1.38(3H, t, J = 7.2Hz)
（実施例１８－３）　エチル 5-ブロモ-2,6-ジメチル-1-ベンゾフラン-7-カルボキシレート
　実施例18-2により製造されるエチル 5-ブロモ-2,6-ジメチル-2,3-ジヒドロ-1-ベンゾフラン-7-カルボキシレート(8.97g, 30.0mmol)のトルエン溶液(100ml)に、室温で2,3-ジクロロ-5,6-ジシアノ-1,4-ベンゾキノン(13.6g, 60.0mmol)を加え、110度で2日間加熱攪拌した。室温に戻した後、1規定水酸化ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=1:0-15:1, v/v)で精製して、標記化合物(7.49g, 収率:84%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm :
7.73(1H, s), 6.30(1H, d, J = 1.0Hz), 4.49(2H, q, J = 7.2Hz), 2.54(3H, s), 2.45(3H, d, J = 1.0Hz), 1.44(3H, t, J = 7.2Hz)
（実施例１８－４）　(5-ブロモ-2,6-ジメチル-1-ベンゾフラン-7-イル)メタノール
　-78℃冷却下、実施例18-3により製造されるエチル 5-ブロモ-2,6-ジメチル-1-ベンゾフラン-7-カルボキシレート(8.94g, 30.1mmol)のジクロロメタン溶液(200ml)にジイソブチルアルミニウムヒドリド(1.06M, ヘキサン溶液, 71.0ml, 75.3mmol)を滴下した。反応液を室温で3時間攪拌し、再び-78℃に冷却した。酒石酸カリウムナトリウム水溶液を加え、室温で30分攪拌した後、反応液をジクロロメタンで2回抽出し、有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥した。、減圧下溶媒を留去し得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=10:1-3:1, v/v)で精製して、標記化合物(7.24g, 収率:95%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm :
7.63(1H, s), 6.29(1H, d, J = 1.0Hz), 5.03(2H, d, J = 5.9Hz), 2.56(3H, s), 2.45(3H, br s), 1.77(1H, t, J = 5.9Hz)
（実施例１８－５）　[(5-ブロモ-2,6-ジメチル-1-ベンゾフラン-7-イル)メトキシ]( tert-ブチル)ジメチルシラン
　(5-ブロモ-2,4-ジメチル-1-ベンゾフラン-7-イル)メタノールの代わりに実施例18-4により製造される(5-ブロモ-2,6-ジメチル-1-ベンゾフラン-7-イル)メタノール(7.24g, 28.4mmol)を用い、実施例3-4に記載された方法と同様に反応を行い、標記化合物 (10.7g, 収率:100%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm :
7.59(1H, s), 6.26(1H, d, J = 1.0Hz), 5.01(2H, s), 2.54(3H, s), 2.44(3H, d, J = 1.0Hz), 0.89(9H, s), 0.06(6H, s)
（実施例１８－６）　tert-ブチル(2E)-3-[7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,6-ジメチル-1-ベンゾフラン-5-イル]プロプ-2-エノエート
　[(5-ブロモ-2,4-ジメチル-1-ベンゾフラン-7-イル)メトキシ](tert-ブチル)ジメチルシランの代わりに実施例18-5により製造される[(5-ブロモ-2,6-ジメチル-1-ベンゾフラン-7-イル)メトキシ]( tert-ブチル)ジメチルシラン(10.7g, 29.0mmol) を用い、実施例7-1に記載された方法と同様に反応を行い、標記化合物標記化合物(12.5g, 収率:100%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm :
8.04(1H, d, J = 15.6Hz), 7.59(1H, s), 6.31(1H, d, J = 1.0Hz), 6.24(1H, d, J = 15.6Hz), 5.01(2H, s), 2.53(3H, s), 2.44(3H, d, J = 1.0Hz), 1.54(9H, s), 0.89(9H, s), 0.06(6H, s)
（実施例１８－７）　tert-ブチル3-[7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,6-ジメチル-1-ベンゾフラン-5-イル]プロパノエート
　tert-ブチル(2E)-3-[7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,4-ジメチル-1-ベンゾフラン-5-イル]プロプ-2-エノエートの代わりに実施例18-6により製造されるtert-ブチル(2E)-3-[7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,6-ジメチル-1-ベンゾフラン-5-イル]プロプ-2-エノエート(7.84g, 18.8mmol) を用い、実施例8-1に記載された方法と同様に反応を行い、標記化合物(6.36g, 収率:84%）を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm :
7.19(1H, s), 6.25(1H, d, J = 1.0Hz), 5.02(2H, s), 2.97(2H, m), 2.49(2H, m), 2.42(6H, s), 1.43(9H, s), 0.89(9H, s), 0.04(6H, s)
（実施例１８－８）　tert-ブチル3-[7-(ヒドロキシメチル)-2,6-ジメチル-1-ベンゾフラン-5-イル]プロパノエート
　tert-ブチル7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレートの代わりに実施例18-7により製造されるtert-ブチル3-[7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,6-ジメチル-1-ベンゾフラン-5-イル]プロパノエート(3.00g, 7.17mmol)を用い、 実施例3-7に記載された方法と同様に反応を行い、標記化合物(1.72g, 収率:79%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm :
7.23(1H, s), 6.28(1H, d, J = 1.0Hz), 5.03(2H, d, J = 5.9Hz), 2.98(2H, m), 2.50(2H, m), 2.44(3H, s), 2.43(3H, d, J = 1.0Hz), 1.74(1H, t, J = 5.9Hz), 1.44(9H, s)
（実施例１８－９）　tert-ブチル3-(7-ホルミル-2,6-ジメチル-1-ベンゾフラン-5-イル)プロパノエート
　tert-ブチル 7-(ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレートの代わりに実施例18-8により製造されるtert-ブチル 3-[7-(ヒドロキシメチル)-2,6-ジメチル-1-ベンゾフラン-5-イル]プロパノエート(1.72g, 5.65mmol)を用い、 実施例3-8に記載された方法と同様に反応を行い、標記化合物(1.18g, 収率:70%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm :
10.8(1H, s), 7.51(1H, s), 6.33 (1H, d, J = 1.0Hz), 3.02(2H,m), 2.69(3H, s), 2.51(2H, m), 2.49(3H, s), 1.42(9H, s)
（実施例１８－１０）　3-[2,6-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-イル]プロパン酸
　tert-ブチル 7-ホルミル-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレートの代わりに実施例18-9により製造されるtert-ブチル 3-(7-ホルミル-2,6-ジメチル-1-ベンゾフラン-5-イル)プロパノエート(1.18g, 3.90mmol)を用い、実施例3に記載された方法と同様に反応を行い、標記化合物(1.34g, 収率:70%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm :
7.07(1H, s), 6.14(1H, d, J = 1.0Hz), 5.15(1H, s), 3.05(2H, m), 2.85(3H, s), 2.65(2H, m), 2.50(2H, d, J = 17.1Hz), 2.38(2H, d, J = 17.1Hz), 2.32(3H, s), 2.20(2H, d, J = 16.6Hz), 2.09(2H, d, J = 16.6Hz), 1.08(6H, s), 0.75(6H, s)
MS (ESI) m/z: 491[M+H]+。 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. The obtained organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0-10: 1, v / v) to give the title compound (37.8 g, yield 89%) Got.
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.47 (1H, d, J = 8.8Hz), 6.65 (1H, d, J = 8.8Hz), 5.97 (1H, m), 5.37 (1H, m), 5.26 (1H, dd, J = 10.7, 0.7Hz ), 4.53 (2H, dd, J = 5.1, 1.7Hz), 4.40 (2H, q, J = 7.1Hz), 2.33 (3H, s), 1.38 (3H, t, J = 7.1Hz)
Example 18-2 Ethyl 5-bromo-2,6-dimethyl-2,3-dihydro-1-benzofuran-7-carboxylate Ethyl 3-bromo-2-methyl-produced according to Example 18-1 To a toluene solution (600 ml) of 6- (prop-2-en-1-yloxy) benzoate (37.8 g, 126 mmol), ytterbium (III) trifluoromethanesulfonate hydrate (3.91 g, 6.30 mmol) was added at room temperature. And refluxed for 6 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with diethyl ether. 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 purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0-10: 1, v / v) to obtain the title compound (15.0 g, yield: 40%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.36 (1H, s), 4.99 (1H, m), 4.39 (1H, qd, J = 7.2, 1.2Hz), 3.28 (1H, m), 2.78 (1H, dd, J = 15.7, 7.4Hz), 2.38 (3H, s), 1.45 (3H, d, J = 6.3Hz), 1.38 (3H, t, J = 7.2Hz)
Example 18-3 Ethyl 5-bromo-2,6-dimethyl-1-benzofuran-7-carboxylate Ethyl 5-bromo-2,6-dimethyl-2,3-produced according to Example 18-2 To a toluene solution (100 ml) of dihydro-1-benzofuran-7-carboxylate (8.97 g, 30.0 mmol) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (13.6 g, 60.0 mmol) at room temperature. ) And heated and stirred at 110 degrees for 2 days. After returning to room temperature, the mixture was washed with 1N aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0-15: 1, v / v) to give the title compound (7.49 g, yield: 84% )
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.73 (1H, s), 6.30 (1H, d, J = 1.0Hz), 4.49 (2H, q, J = 7.2Hz), 2.54 (3H, s), 2.45 (3H, d, J = 1.0Hz), 1.44 (3H, t, J = 7.2Hz)
Example 18-4 (5-Bromo-2,6-dimethyl-1-benzofuran-7-yl) methanol Ethyl 5-bromo-2,6 prepared according to Example 18-3 under cooling at -78 ° C Diisobutylaluminum hydride (1.06 M, hexane solution, 71.0 ml, 75.3 mmol) was added dropwise to a dichloromethane solution (200 ml) of -dimethyl-1-benzofuran-7-carboxylate (8.94 g, 30.1 mmol). The reaction was stirred at room temperature for 3 hours and cooled again to -78 ° C. Aqueous potassium sodium tartrate solution was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted twice with dichloromethane, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1-3: 1, v / v) to give the title compound (7.24 g, yield: 95 %).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.63 (1H, s), 6.29 (1H, d, J = 1.0Hz), 5.03 (2H, d, J = 5.9Hz), 2.56 (3H, s), 2.45 (3H, br s), 1.77 (1H, t, J = 5.9Hz)
Example 18-5 [(5-Bromo-2,6-dimethyl-1-benzofuran-7-yl) methoxy] (tert-butyl) dimethylsilane (5-bromo-2,4-dimethyl-1-benzofuran Example using (5-bromo-2,6-dimethyl-1-benzofuran-7-yl) methanol (7.24 g, 28.4 mmol) prepared according to Example 18-4 in place of methanol The reaction was performed in the same manner as described in 3-4 to obtain the title compound (10.7 g, yield: 100%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.59 (1H, s), 6.26 (1H, d, J = 1.0Hz), 5.01 (2H, s), 2.54 (3H, s), 2.44 (3H, d, J = 1.0Hz), 0.89 (9H, s ), 0.06 (6H, s)
Example 18-6 tert-butyl (2E) -3- [7-({[tert-butyl (dimethyl) silyl] oxy} methyl) -2,6-dimethyl-1-benzofuran-5-yl] prop 2-Enoate [(5-Bromo-2,4-dimethyl-1-benzofuran-7-yl) methoxy] (tert-butyl) prepared by Example 18-5 instead of dimethylsilane [(5-bromo -2,6-dimethyl-1-benzofuran-7-yl) methoxy] (tert-butyl) dimethylsilane (10.7 g, 29.0 mmol) was used in the same manner as described in Example 7-1. The title compound (12.5 g, yield: 100%) was obtained.
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
8.04 (1H, d, J = 15.6Hz), 7.59 (1H, s), 6.31 (1H, d, J = 1.0Hz), 6.24 (1H, d, J = 15.6Hz), 5.01 (2H, s), 2.53 (3H, s), 2.44 (3H, d, J = 1.0Hz), 1.54 (9H, s), 0.89 (9H, s), 0.06 (6H, s)
Example 18-7 tert-butyl 3- [7-({[tert-butyl (dimethyl) silyl] oxy} methyl) -2,6-dimethyl-1-benzofuran-5-yl] propanoate tert-butyl ( 2E) -3- [7-({[tert-Butyl (dimethyl) silyl] oxy} methyl) -2,4-dimethyl-1-benzofuran-5-yl] prop-2-enoate Example 18- Tert-butyl (2E) -3- [7-({[tert-butyl (dimethyl) silyl] oxy} methyl) -2,6-dimethyl-1-benzofuran-5-yl] prop-2 -Enoate (7.84 g, 18.8 mmol) was used in the same manner as described in Example 8-1 to obtain the title compound (6.36 g, yield: 84%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.19 (1H, s), 6.25 (1H, d, J = 1.0Hz), 5.02 (2H, s), 2.97 (2H, m), 2.49 (2H, m), 2.42 (6H, s), 1.43 (9H , s), 0.89 (9H, s), 0.04 (6H, s)
Example 18-8 tert-butyl 3- [7- (hydroxymethyl) -2,6-dimethyl-1-benzofuran-5-yl] propanoate tert-butyl 7-({[tert-butyl (dimethyl) silyl ] Oxy} methyl) hydroxymethyl) -2,4-dimethyl-1-benzofuran-5-carboxylate instead of tert-butyl 3- [7-({[tert-butyl ( Dimethyl) silyl] oxy} methyl) -2,6-dimethyl-1-benzofuran-5-yl] propanoate (3.00 g, 7.17 mmol) was used to carry out the reaction in the same manner as described in Example 3-7. The title compound (1.72 g, yield: 79%) was obtained.
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.23 (1H, s), 6.28 (1H, d, J = 1.0Hz), 5.03 (2H, d, J = 5.9Hz), 2.98 (2H, m), 2.50 (2H, m), 2.44 (3H, s ), 2.43 (3H, d, J = 1.0Hz), 1.74 (1H, t, J = 5.9Hz), 1.44 (9H, s)
Example 18-9 tert-butyl 3- (7-formyl-2,6-dimethyl-1-benzofuran-5-yl) propanoate tert-butyl 7- (hydroxymethyl) -2,4-dimethyl-1- Tert-Butyl 3- [7- (hydroxymethyl) -2,6-dimethyl-1-benzofuran-5-yl] propanoate prepared according to Example 18-8 instead of benzofuran-5-carboxylate (1.72 g, 5.65 mmol) was used in the same manner as described in Example 3-8 to obtain the title compound (1.18 g, yield: 70%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
10.8 (1H, s), 7.51 (1H, s), 6.33 (1H, d, J = 1.0Hz), 3.02 (2H, m), 2.69 (3H, s), 2.51 (2H, m), 2.49 (3H , s), 1.42 (9H, s)
Example 18-10 3- [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, 3.90 mmol) prepared by Reaction was performed to obtain the title compound (1.34 g, yield: 70%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.07 (1H, s), 6.14 (1H, d, J = 1.0Hz), 5.15 (1H, s), 3.05 (2H, m), 2.85 (3H, s), 2.65 (2H, m), 2.50 (2H , d, J = 17.1Hz), 2.38 (2H, d, J = 17.1Hz), 2.32 (3H, s), 2.20 (2H, d, J = 16.6Hz), 2.09 (2H, d, J = 16.6Hz ), 1.08 (6H, s), 0.75 (6H, s)
MS (ESI) m / z: 491 [M + H] < +>.
 
（実施例１９）　2-[2,6-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-イル] シクロペンタンカルボン酸
Example 19 2- [2,6-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] cyclopentanecarboxylic acid
Figure JPOXMLDOC01-appb-C000038
Figure JPOXMLDOC01-appb-C000038
（実施例１９-１）　tert-ブチル2-[7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,6-ジメチル-1-ベンゾフラン-5-イル]シクロプロパンカルボキシレート
　ヨウ化トリメチルスルホニウム (8.80g, 40.0mmol)のジメチルスルホキシド溶液(50ml)に室温でtert-ブトキシカリウム(4.49g, 40.0mmol)を徐々に加えた。この溶液に実施例18-6により製造されるtert-ブチル(2E)-3-[7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,6-ジメチル-1-ベンゾフラン-5-イル]プロプ-2-エノエート(4.16g, 10.0mmol)のジメチルスルホキシド溶液(10ml)を滴下し、60度にて1時間攪拌した。冷却後、反応液に水を加え、酢酸エチルで3回抽出し、得られた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥、減圧下にて溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=20:1, v/v)で精製して、標記化合物(2.58g, 収率:60%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm :
7.10(1H, s), 6.25(1H, d, J = 1.0Hz), 5.03(1H, d, J = 11.5Hz), 5.01(1H, d, J = 1.0Hz), 2.49(3H, s), 2.47(1H, m), 2.42(3H, d, J = 1.0Hz), 1.64(1H, dt, J = 9.3, 4.1Hz), 1.52(1H, m), 1.50(9H, s), 1.27(1H, m), 0.90(9H, s), 0.06(3H, s), 0.05(3H, s)
（実施例１９－２）　tert-ブチル2-[7-(ヒドロキシメチル)-2,6-ジメチル-1-ベンゾフラン-5-イル]シクロペンタンカルボキシレート
　tert-ブチル7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレートの代わりに実施例19-1により製造されるtert-ブチル 2-[7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,6-ジメチル-1-ベンゾフラン-5-イル]シクロプロパンカルボキシレート(2.58g, 6.00mmol)を用い、 実施例3-7に記載された方法と同様に反応を行い、標記化合物(11.70g, 収率:90%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm :
7.14(1H, s), 6.28(1H, d, J = 1.0Hz), 5.03(2H, s), 2.50(3H, s), 2.47(1H, ddd, J = 9.9, 5.7, 3.5Hz), 2.43(3H, d, J = 1.0Hz), 1.83(1H, br s), 1.63(1H, m), 1.52(1H, m), 1.50(9H, s), 1.28(1H, ddd, J = 8.5, 7.0, 4.5Hz)
（実施例１９－３）　tert-ブチル2-(7-ホルミル-2,6-ジメチル-1-ベンゾフラン-5-イル)シクロペンタンカルボキシレート
　tert-ブチル 7-(ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレートの代わりに実施例19-2により製造されるtert-ブチル tert-ブチル 2-[7-(ヒドロキシメチル)-2,6-ジメチル-1-ベンゾフラン-5-イル]シクロペンタンカルボキシレート(1.70g, 5.37mmol)を用い、 実施例3-8に記載された方法と同様に反応を行い、標記化合物(1.26g, 収率:75%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm :
10.8(1H, s), 7.49(1H, s), 6.34 (1H, s), 2.77(3H, s), 2.50(4H, m), 1.65(1H, m), 1.56(1H, m), 1.50(9H, s), 1.27(1H, m)
（実施例１９－４）　tert-ブチル2-[2,6-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-イル] シクロペンタンカルボキシレート
　tert-ブチル2-(7-ホルミル-2,4-ジメチル-1-ベンゾフラン-5-イル)ブタノエートの代わりに実施例19-3により製造されるtert-ブチル 2-(7-ホルミル-2,6-ジメチル-1-ベンゾフラン-5-イル)シクロペンタンカルボキシレート(1.04g,3.29mmol)を用い、 実施例17-3に記載された方法と同様に反応を行い、標記化合物(1.20g, 収率:66%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm :
6.98(1H, s), 6.13(1H, s), 5.18(1H, s), 2.92(3H, s), 2.48-2.56(3H, m), 2.37(2H, m), 2.31(3H, s), 2.20(2H, dd, J = 16.6, 5.9Hz), 2.08(2H, ddd, J = 16.6, 4.9, 1.5Hz), 1.73(1H, m), 1.50(9H, s), 1.47(1H, m), 1.22(1H, m), 1.08(3H, s), 1.07(3H, s), 0.74(3H,s), 0.73(3H, s)
（実施例１９－５）　2-[2,6-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-イル] シクロペンタンカルボン酸
　tert-ブチル 2-[2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-イル]ブタノエートの代わりに実施例19-4により製造されるtert-ブチル 2-[2,6-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-イル] シクロペンタンカルボキシレート(1.20g, 2.15mmol)を用い、 実施例17に記載された方法と同様に反応を行い、標記化合物(1.08g, 収率:100%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm :
7.01(1H, s), 6.14(1H, d, J = 1.0Hz), 5.18(1H, s), 2.94(1H, s), 2.71(1H, m), 2.50(2H, d, J = 17.5Hz), 2.37(2H, d, J = 17.5Hz), 2.32(3H, s), 2.20(2H, dd, J = 16.6, 2.4Hz), 2.08(2H, m), 1.63(1H, m), 1.37(1H, m), 1.25(1H, m), 1.08(6H, s), 0.74(6H, s)
MS (ESI) m/z: 503[M+H]+。 Example 19-1 tert-butyl 2- [7-({[tert-butyl (dimethyl) silyl] oxy} methyl) -2,6-dimethyl-1-benzofuran-5-yl] cyclopropanecarboxylate iodine Tert-Butoxy potassium (4.49 g, 40.0 mmol) was gradually added to a dimethyl sulfoxide solution (50 ml) of trimethylsulfonium fluoride (8.80 g, 40.0 mmol) at room temperature. To this solution was prepared tert-butyl (2E) -3- [7-({[tert-butyl (dimethyl) silyl] oxy} methyl) -2,6-dimethyl-1-benzofuran- A dimethyl sulfoxide solution (10 ml) of 5-yl] prop-2-enoate (4.16 g, 10.0 mmol) was added dropwise, and the mixture was stirred at 60 ° C. for 1 hour. After cooling, water was added to the reaction mixture, 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 purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1, v / v) to obtain the title compound (2.58 g, yield: 60%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.10 (1H, s), 6.25 (1H, d, J = 1.0Hz), 5.03 (1H, d, J = 11.5Hz), 5.01 (1H, d, J = 1.0Hz), 2.49 (3H, s), 2.47 (1H, m), 2.42 (3H, d, J = 1.0Hz), 1.64 (1H, dt, J = 9.3, 4.1Hz), 1.52 (1H, m), 1.50 (9H, s), 1.27 (1H , m), 0.90 (9H, s), 0.06 (3H, s), 0.05 (3H, s)
Example 19-2 tert-butyl 2- [7- (hydroxymethyl) -2,6-dimethyl-1-benzofuran-5-yl] cyclopentanecarboxylate tert-butyl 7-({[tert-butyl ( Dimethyl) silyl] oxy} methyl) hydroxymethyl) -2,4-dimethyl-1-benzofuran-5-carboxylate instead of tert-butyl 2- [7-({[tert -Butyl (dimethyl) silyl] oxy} methyl) -2,6-dimethyl-1-benzofuran-5-yl] cyclopropanecarboxylate (2.58 g, 6.00 mmol) using the method described in Example 3-7 The title compound (11.70 g, yield: 90%) was obtained in the same manner as above.
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.14 (1H, s), 6.28 (1H, d, J = 1.0Hz), 5.03 (2H, s), 2.50 (3H, s), 2.47 (1H, ddd, J = 9.9, 5.7, 3.5Hz), 2.43 (3H, d, J = 1.0Hz), 1.83 (1H, br s), 1.63 (1H, m), 1.52 (1H, m), 1.50 (9H, s), 1.28 (1H, ddd, J = 8.5, (7.0, 4.5Hz)
Example 19-3 tert-butyl 2- (7-formyl-2,6-dimethyl-1-benzofuran-5-yl) cyclopentanecarboxylate tert-butyl 7- (hydroxymethyl) -2,4-dimethyl Tert-Butyl tert-butyl 2- [7- (hydroxymethyl) -2,6-dimethyl-1-benzofuran-5-yl prepared according to Example 19-2 instead of -1-benzofuran-5-carboxylate The reaction was carried out in the same manner as described in Example 3-8 using cyclopentanecarboxylate (1.70 g, 5.37 mmol) to obtain the title compound (1.26 g, yield: 75%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
10.8 (1H, s), 7.49 (1H, s), 6.34 (1H, s), 2.77 (3H, s), 2.50 (4H, m), 1.65 (1H, m), 1.56 (1H, m), 1.50 (9H, s), 1.27 (1H, m)
Example 19-4 tert-butyl 2- [2,6-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] cyclopentanecarboxylate tert-butyl 2- (7-formyl-2,4-dimethyl-1-benzofuran-5- Yl) tert-Butyl 2- (7-formyl-2,6-dimethyl-1-benzofuran-5-yl) cyclopentanecarboxylate (1.04 g, 3.29 mmol) prepared according to Example 19-3 instead of yl) butanoate Was used in the same manner as in Example 17-3 to give the title compound (1.20 g, yield: 66%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
6.98 (1H, s), 6.13 (1H, s), 5.18 (1H, s), 2.92 (3H, s), 2.48-2.56 (3H, m), 2.37 (2H, m), 2.31 (3H, s) , 2.20 (2H, dd, J = 16.6, 5.9Hz), 2.08 (2H, ddd, J = 16.6, 4.9, 1.5Hz), 1.73 (1H, m), 1.50 (9H, s), 1.47 (1H, m ), 1.22 (1H, m), 1.08 (3H, s), 1.07 (3H, s), 0.74 (3H, s), 0.73 (3H, s)
Example 19-5 2- [2,6-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] cyclopentanecarboxylic acid tert-butyl 2- [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] butanoate instead of Example 19- Tert-butyl 2- [2,6-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] The reaction was carried out in the same manner as described in Example 17 using cyclopentanecarboxylate (1.20 g, 2.15 mmol). The title compound (1.08 g, yield: 100%) was obtained.
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.01 (1H, s), 6.14 (1H, d, J = 1.0Hz), 5.18 (1H, s), 2.94 (1H, s), 2.71 (1H, m), 2.50 (2H, d, J = 17.5Hz ), 2.37 (2H, d, J = 17.5Hz), 2.32 (3H, s), 2.20 (2H, dd, J = 16.6, 2.4Hz), 2.08 (2H, m), 1.63 (1H, m), 1.37 (1H, m), 1.25 (1H, m), 1.08 (6H, s), 0.74 (6H, s)
MS (ESI) m / z: 503 [M + H] < +>.
 
（実施例２０）　2-[2,6-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-イル]プロパン酸
Example 20 2- [2,6-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] propanoic acid
Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000039
（実施例２０－１）　tert-ブチル 2-[7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,6-ジメチル-1-ベンゾフラン-5-イル]アセテート
　[(5-ブロモ-2,4-ジメチル-1-ベンゾフラン-7-イル)メトキシ](tert-ブチル)ジメチルシランの代わりに実施例18-5により製造される[(5-ブロモ-2,6-ジメチル-1-ベンゾフラン-7-イル)メトキシ]( tert-ブチル)ジメチルシラン(4.75g, 12.8mmol)を用い、実施例15-1に記載された方法と同様に反応を行い、標記化合物(4.77g, 収率:92%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm :
7.22(1H, s), 6.26(1H, d, J = 1.0Hz), 5.02(2H, s), 3.61(2H, s), 2.42(3H, d, J = 1.0Hz), 2.39(3H, s), 1.43(9H, s), 0.88(9H, s), 0.04(6H, s)
（実施例２０－２）　tert-ブチル 2-[7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,6-ジメチル-1-ベンゾフラン-5-イル]プロパノエート
　-78℃冷却下、実施例20-1により製造されるtert-ブチル 2-[7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,6-ジメチル-1-ベンゾフラン-5-イル]アセテート(2.00g, 4.94mmol)のTHF溶液(50.0ml)にリチウム　ビス(トリメチルシリル)アミド(1.1M ヘキサン溶液, 5.38ml, 5.92mmol)を滴下し、20分攪拌した。ヨードメタン(0.338ml, 5.43mmol)を加え、室温まで昇温した後、反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで3回抽出し、得られた有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=1:0-20:1, v/v)で精製して、標記化合物(1.81g, 収率:88%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm :
7.31(1H, s), 6.27(1H, d, J = 1.0Hz), 5.09(1H, s), 3.95(1H, d, J = 7.0Hz), 2.46(3H, s), 2.42(3H, d, J = 1.0Hz), 1.44(3H, d, J = 7.0Hz), 1.37(9H, s), 0.88(9H, s), 0.03(3H, s), 0.02(3H, s)
（実施例２０－３）　tert-ブチル 2-[7-(ヒドロキシメチル)-2,6-ジメチル-1-ベンゾフラン-5-イル]プロパノエート
　tert-ブチル7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレートの代わりに実施例20-2により製造されるtert-ブチル 2-[7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,6-ジメチル-1-ベンゾフラン-5-イル]プロパノエート(1.81g, 4.32mmol)を用い、 実施例3-7に記載された方法と同様に反応を行い、標記化合物(1.18g, 収率:90%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm :
7.35(1H, s), 6.30(1H, d, J = 1.0Hz), 5.06(1H, dd, J = 11.0, 5.0Hz), 5.02(1H, dd, J = 11.0, 5.0Hz), 3.95(1H, q, J = 7.0Hz), 2.47(3H, s), 2.43(1H, d, J = 1.0Hz), 1.75(1H, t, J = 5.0Hz), 1.46(3H, d, J = 7.0Hz), 1.39(9H, s)
（実施例２０－４）　tert-ブチル 2-(7-ホルミル-2,6-ジメチル-1-ベンゾフラン-5-イル)プロパノエート
　tert-ブチル 7-(ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレートの代わりに実施例20-3により製造されるtert-ブチル 2-[7-(ヒドロキシメチル)-2,6-ジメチル-1-ベンゾフラン-5-イル]プロパノエート(1.34g, 4.40mmol)を用い、 実施例3-8に記載された方法と同様に反応を行い、標記化合物(628mg, 収率:47%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm :
10.8(1H, s), 7.63(1H, s), 6.36(1H, d, J = 1.0Hz), 4.02(1H, q, J = 6.8Hz), 2.73(3H, s), 2.49(3H, d, J = 1.0Hz), 1.48(3H, d, J = 6.8Hz), 1.39(9H, s)
（実施例２０－５）　2-[2,6-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-イル]プロパン酸
　tert-ブチル 7-ホルミル-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレートの代わりに実施例20-4により製造されるtert-ブチル 2-(7-ホルミル-2,6-ジメチル-1-ベンゾフラン-5-イル)プロパノエート(628mg, 2.07mmol)を用い、実施例3に記載された方法と同様に反応を行い、標記化合物(861mg, 収率:85%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm :
7.21(1H, s), 6.17(1H, d, J = 1.0Hz), 5.17(1H, s), 4.15(1H, q, J = 6.8Hz), 2.86(3H, s), 2.51(2H, dd, J = 17.6, 1.0Hz), 2.39(2H, J = 17.6, 1.0Hz), 2.32(3H, d, J = 1.0Hz), 2.22(2H, dd, J = 16.4, 3.2Hz), 2.12(2H, m), 1.50(3H, d, J = 6.8Hz), 1.09(3H, s), 1.08(3H, s), 0.77(3H, s), 0.76(3H, s)
MS (ESI) m/z: 491[M+H]+。 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). Rate: 92%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.22 (1H, s), 6.26 (1H, d, J = 1.0Hz), 5.02 (2H, s), 3.61 (2H, s), 2.42 (3H, d, J = 1.0Hz), 2.39 (3H, s ), 1.43 (9H, s), 0.88 (9H, s), 0.04 (6H, s)
Example 20-2 tert-butyl 2- [7-({[tert-butyl (dimethyl) silyl] oxy} methyl) -2,6-dimethyl-1-benzofuran-5-yl] propanoate -78 ° C cooling Below, tert-butyl 2- [7-({[tert-butyl (dimethyl) silyl] oxy} methyl) -2,6-dimethyl-1-benzofuran-5-yl] acetate prepared according to Example 20-1 Lithium bis (trimethylsilyl) amide (1.1M hexane solution, 5.38 ml, 5.92 mmol) was added dropwise to a THF solution (50.0 ml) of (2.00 g, 4.94 mmol) and stirred for 20 minutes. After adding iodomethane (0.338 ml, 5.43 mmol) and warming to room temperature, a saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction three times with ethyl acetate, and the resulting organic layer was washed with saturated brine, and anhydrous sulfuric acid. Dried with magnesium. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0-20: 1, v / v) to give the title compound (1.81 g, yield: 88% )
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.31 (1H, s), 6.27 (1H, d, J = 1.0Hz), 5.09 (1H, s), 3.95 (1H, d, J = 7.0Hz), 2.46 (3H, s), 2.42 (3H, d , J = 1.0Hz), 1.44 (3H, d, J = 7.0Hz), 1.37 (9H, s), 0.88 (9H, s), 0.03 (3H, s), 0.02 (3H, s)
Example 20-3 tert-butyl 2- [7- (hydroxymethyl) -2,6-dimethyl-1-benzofuran-5-yl] propanoate tert-butyl 7-({[tert-butyl (dimethyl) silyl ] Oxy} methyl) hydroxymethyl) -2,4-dimethyl-1-benzofuran-5-carboxylate instead of tert-butyl 2- [7-({[tert-butyl ( Dimethyl) silyl] oxy} methyl) -2,6-dimethyl-1-benzofuran-5-yl] propanoate (1.81 g, 4.32 mmol) was used in the same manner as described in Example 3-7. The title compound (1.18 g, yield: 90%) was obtained.
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.35 (1H, s), 6.30 (1H, d, J = 1.0Hz), 5.06 (1H, dd, J = 11.0, 5.0Hz), 5.02 (1H, dd, J = 11.0, 5.0Hz), 3.95 (1H , q, J = 7.0Hz), 2.47 (3H, s), 2.43 (1H, d, J = 1.0Hz), 1.75 (1H, t, J = 5.0Hz), 1.46 (3H, d, J = 7.0Hz ), 1.39 (9H, s)
Example 20-4 tert-butyl 2- (7-formyl-2,6-dimethyl-1-benzofuran-5-yl) propanoate tert-butyl 7- (hydroxymethyl) -2,4-dimethyl-1- Tert-Butyl 2- [7- (hydroxymethyl) -2,6-dimethyl-1-benzofuran-5-yl] propanoate prepared according to Example 20-3 instead of benzofuran-5-carboxylate (1.34 g, 4.40 mmol) was used in the same manner as described in Example 3-8 to obtain the title compound (628 mg, yield: 47%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
10.8 (1H, s), 7.63 (1H, s), 6.36 (1H, d, J = 1.0Hz), 4.02 (1H, q, J = 6.8Hz), 2.73 (3H, s), 2.49 (3H, d , J = 1.0Hz), 1.48 (3H, d, J = 6.8Hz), 1.39 (9H, s)
Example 20-5 2- [2,6-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] propanoic acid tert-butyl 7-formyl-2,4-dimethyl-1-benzofuran-5-carboxylate instead of Example 20 Tert-Butyl 2- (7-formyl-2,6-dimethyl-1-benzofuran-5-yl) propanoate (628 mg, 2.07 mmol) prepared by -4, similar to the method described in Example 3 The title compound (861 mg, yield: 85%) was obtained.
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.21 (1H, s), 6.17 (1H, d, J = 1.0Hz), 5.17 (1H, s), 4.15 (1H, q, J = 6.8Hz), 2.86 (3H, s), 2.51 (2H, dd , J = 17.6, 1.0Hz), 2.39 (2H, J = 17.6, 1.0Hz), 2.32 (3H, d, J = 1.0Hz), 2.22 (2H, dd, J = 16.4, 3.2Hz), 2.12 (2H , m), 1.50 (3H, d, J = 6.8Hz), 1.09 (3H, s), 1.08 (3H, s), 0.77 (3H, s), 0.76 (3H, s)
MS (ESI) m / z: 491 [M + H] < +>.
 
（実施例２１）　2-{[2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-イル]オキシ}-2-メチルプロパン酸
Example 21 2-{[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] oxy} -2-methylpropanoic acid
Figure JPOXMLDOC01-appb-C000040
  
Figure JPOXMLDOC01-appb-C000040
  
（実施例２１－１）　tert-ブチル{[2,4-ジメチル-5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1-ベンゾフラン-7-イル]メトキシ}ジメチルシラン
　実施例3-4により製造される[(5-ブロモ-2,4-ジメチル-1-ベンゾフラン-7-イル)メトキシ](tert-ブチル)ジメチルシラン(22.6g, 61.2mmol)のジメチルスルホキシド溶液(200ml)に、室温でビス(ピナコラト)ジボラン(17.1g, 67.3mmol)、酢酸カリウム(18.1g, 184mmol)、塩化パラジウム(II)ビス（ジフェニルホスフィノ）フェロセン・ジクロロメタン錯体(7.50g, 9.18mmol)を加えた後、窒素雰囲気下、90℃にて10時間加熱攪拌を行った。室温に戻した後、反応液に水を加え、酢酸エチルで3回抽出し、得られた有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=1:0-20:1, v/v)で精製して、標記化合物(24.2g, 収率:95%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm :
7.68(1H, s), 6.40(1H, d, J = 1.0Hz), 4.97(2H, s), 2.64(3H, s), 2.45(3H, s), 1.26(12H, s), 0.95(9H, s), 0.12(6H, s)
（実施例２１－２）　7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,4-ジメチル-1-ベンゾフラン-5-オール
　室温で水酸化カリウム(8.42g, 150mmol)の水溶液(100ml)に実施例21-1により製造されるtert-ブチル{[2,4-ジメチル-5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1-ベンゾフラン-7-イル]メトキシ}ジメチルシラン(20.8g, 49.8mmol)を加えた。この溶液に硫酸銅(II)(1.20g, 7.50mmol)、1,10-フェナントロリン(2.70g, 15.0mmol)を加え、室温で20時間攪拌を行った。反応液に2規定塩酸を加え、酢酸エチルで3回抽出し、得られた有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、減圧下にて溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=1:0-10:1, v/v)で精製して、標記化合物(5.94g, 収率:39%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm :
6.78(1H, s), 6.31(1H, d, J = 1.0Hz), 4.95(2H, s), 4.58(1H, s), 2.42(3H, d, J = 1.0Hz), 2.31(3H, s), 0.98(9H, s), 0.13(6H, s)
（実施例２１－３）　tert-ブチル2-{[7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,4-ジメチル-1-ベンゾフラン-5-イル]オキシ}-2-メチルプロパノエート
　実施例21-2により製造される7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,4-ジメチル-1-ベンゾフラン-5-オール(5.54g, 18.2mmol)のDMF溶液(40ml)に、室温で炭酸セシウム(7.76g, 23.5mmol)、2-ブロモイソ酪酸t-ブチル(6.75ml, 36.2mmol)を加え、80℃にて12時間加熱攪拌を行った。室温にまで冷却した後、反応液に水を加え、酢酸エチルで3回抽出し、得られた有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=1:0-20:1, v/v)で精製して、標記化合物(6.86g, 収率:85%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm :
6.90(1H, s), 6.32(1H, d, J = 1.0Hz), 4.92(2H, s), 2.43(3H, s), 2.32(3H, s), 1.51(6H, s), 1.47(9H, s), 0.93(9H, s), 0.10(6H, s),
（実施例２１－４）　tert-ブチル2-{[7-(ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-イル]オキシ}-2-メチルプロパノエート
　tert-ブチル7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレートの代わりに実施例21-3により製造されるtert-ブチル2-{[7-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2,4-ジメチル-1-ベンゾフラン-5-イル]オキシ}-2-メチルプロパノエート(6.86g, 15.3mmol)を用い、 実施例3-7に記載された方法と同様に反応を行い、標記化合物(4.90g, 収率:96%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm :
6.82(1H, s), 6.35(1H, d, J = 1.0Hz), 4.85(2H, d, J = 5.9Hz), 2.33(3H, s), 1.83(1H, t, J = 5.9Hz), 1.51(6H, s), 1.50(9H, s)
（実施例２１－５）　tert-ブチル2-[(7-ホルミル-2,4-ジメチル-1-ベンゾフラン-5-イル)オキシ]-2-メチルプロパノエート
　tert-ブチル 7-(ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレートの代わりに実施例21-4により製造されるtert-ブチル 2-{[7-(ヒドロキシメチル)-2,4-ジメチル-1-ベンゾフラン-5-イル]オキシ}-2-メチルプロパノエート(4.90g, 14.6mmol)を用い、 実施例3-8に記載された方法と同様に反応を行い、標記化合物(3.82g, 収率:79%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm :
10.3(1H, s), 7.23(1H, s), 6.42(1H, d, J = 1.0Hz), 2.51(3H, d, J = 1.0Hz), 2.41(3H, s), 1.57(6H, s), 1.50(9H, s)
（実施例２１－６）　2-{[2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-イル]オキシ}-2-メチルプロパン酸
　tert-ブチル 7-ホルミル-2,4-ジメチル-1-ベンゾフラン-5-カルボキシレートの代わりに実施例21-5により製造されるtert-ブチル 2-[(7-ホルミル-2,4-ジメチル-1-ベンゾフラン-5-イル)オキシ]-2-メチルプロパノエート(3.82g,11.5mmol)を用い、実施例3に記載された方法と同様に反応を行い、標記化合物(2.71g, 収率:46%)を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm :
6.96(1H, s), 6.26(1H, d, J = 1.0Hz), 4.89(1H, s), 2.50(2H, dd, J = 17.5, 1.0Hz), 2.42(2H, d, J = 17.5Hz), 2.39(3H, d, J = 1.0Hz), 2.25(3H, s), 2.22(2H, d, J = 16.1Hz), 2.11(2H, dd, J = 16.1, 1.0Hz), 1.56(6H, s), 1.09(6H, s), 0.85(6H, s)
MS (ESI) m/z: 521[M+H]+。 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. for 10 hours under a nitrogen atmosphere. After returning to room temperature, water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0-20: 1, v / v) to give the title compound (24.2 g, yield: 95% )
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.68 (1H, s), 6.40 (1H, d, J = 1.0Hz), 4.97 (2H, s), 2.64 (3H, s), 2.45 (3H, s), 1.26 (12H, s), 0.95 (9H , s), 0.12 (6H, s)
Example 21-2 7-({[tert-butyl (dimethyl) silyl] oxy} methyl) -2,4-dimethyl-1-benzofuran-5-ol Potassium hydroxide (8.42 g, 150 mmol) at room temperature Tert-butyl {[2,4-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) prepared according to Example 21-1 in an aqueous solution (100 ml) ) -1-Benzofuran-7-yl] methoxy} dimethylsilane (20.8 g, 49.8 mmol) was added. Copper (II) sulfate (1.20 g, 7.50 mmol) and 1,10-phenanthroline (2.70 g, 15.0 mmol) were added to this solution, and the mixture was stirred at room temperature for 20 hours. 2N Hydrochloric acid was added to the reaction mixture, 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 purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0-10: 1, v / v) to obtain the title compound (5.94 g, yield: 39%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
6.78 (1H, s), 6.31 (1H, d, J = 1.0Hz), 4.95 (2H, s), 4.58 (1H, s), 2.42 (3H, d, J = 1.0Hz), 2.31 (3H, s ), 0.98 (9H, s), 0.13 (6H, s)
Example 21-3 tert-butyl 2-{[7-({[tert-butyl (dimethyl) silyl] oxy} methyl) -2,4-dimethyl-1-benzofuran-5-yl] oxy} -2 -Methylpropanoate 7-({[tert-butyl (dimethyl) silyl] oxy} methyl) -2,4-dimethyl-1-benzofuran-5-ol (5.54 g, 18.2) prepared according to Example 21-2 mmol) in DMF solution (40 ml), cesium carbonate (7.76 g, 23.5 mmol) and t-butyl 2-bromoisobutyrate (6.75 ml, 36.2 mmol) were added at room temperature, followed by heating and stirring at 80 ° C. for 12 hours. . After cooling to room temperature, water was added to the reaction solution, followed by extraction three times with ethyl acetate, and the resulting organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0-20: 1, v / v) to give the title compound (6.86 g, yield: 85% )
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
6.90 (1H, s), 6.32 (1H, d, J = 1.0Hz), 4.92 (2H, s), 2.43 (3H, s), 2.32 (3H, s), 1.51 (6H, s), 1.47 (9H , s), 0.93 (9H, s), 0.10 (6H, s),
Example 21-4 tert-butyl 2-{[7- (hydroxymethyl) -2,4-dimethyl-1-benzofuran-5-yl] oxy} -2-methylpropanoate tert-butyl 7- ( {[tert-Butyl (dimethyl) silyl] oxy} methyl) hydroxymethyl) -2,4-dimethyl-1-benzofuran-5-carboxylate tert-butyl 2- {prepared according to Example 21-3 [7-({[tert-Butyl (dimethyl) silyl] oxy} methyl) -2,4-dimethyl-1-benzofuran-5-yl] oxy} -2-methylpropanoate (6.86 g, 15.3 mmol) And the reaction was carried out in the same manner as described in Example 3-7 to obtain the title compound (4.90 g, yield: 96%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
6.82 (1H, s), 6.35 (1H, d, J = 1.0Hz), 4.85 (2H, d, J = 5.9Hz), 2.33 (3H, s), 1.83 (1H, t, J = 5.9Hz), 1.51 (6H, s), 1.50 (9H, s)
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 to give the title compound (3.82 g, yield: 79%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
10.3 (1H, s), 7.23 (1H, s), 6.42 (1H, d, J = 1.0Hz), 2.51 (3H, d, J = 1.0Hz), 2.41 (3H, s), 1.57 (6H, s ), 1.50 (9H, s)
Example 21-6 2-{[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] oxy} -2-methylpropanoic acid tert-butyl 7-formyl-2,4-dimethyl-1-benzofuran-5-carboxy Tert-Butyl 2-[(7-formyl-2,4-dimethyl-1-benzofuran-5-yl) oxy] -2-methylpropanoate (3.82 g) prepared according to Example 21-5 instead of the rate 11.5 mmol), and the reaction was carried out in the same manner as described in Example 3 to obtain the title compound (2.71 g, yield: 46%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
6.96 (1H, s), 6.26 (1H, d, J = 1.0Hz), 4.89 (1H, s), 2.50 (2H, dd, J = 17.5, 1.0Hz), 2.42 (2H, d, J = 17.5Hz ), 2.39 (3H, d, J = 1.0Hz), 2.25 (3H, s), 2.22 (2H, d, J = 16.1Hz), 2.11 (2H, dd, J = 16.1, 1.0Hz), 1.56 (6H , s), 1.09 (6H, s), 0.85 (6H, s)
MS (ESI) m / z: 521 [M + H] + .
 
（実施例２２）　N-(2-ヒドロキシプロピル)-2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-カルボキサミド
Example 22 N- (2-hydroxypropyl) -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-carboxamide
Figure JPOXMLDOC01-appb-C000041
Figure JPOXMLDOC01-appb-C000041
　実施例3により製造される2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-カルボン酸(200mg,0.432mmol)のジクロロメタン溶液(10ml)に、室温で1-アミノプロパン-2-オール(39.0mg, 0.519mmol)、（ベンゾトリアゾール-1-イルオキシ）トリピロリジノホスホニウム　ヘキサフルオロホスフェート(270mg, 0.519mmol)、ジイソプロピルエチルアミン(0.088ml, 0.519mmol)を加え一晩攪拌した。反応液に水を加え、ジクロロメタンで３回抽出し、得られた有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製して、標記化合物(180mg, 収率：80%）を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
7.41(1H, s), 6.68(1H, t, J = 5.6Hz), 6.33(1H, d, J = 1.0Hz), 4.94(1H, s), 4.05(1H, m), 3.60(1H, m), 3.30(1H, m), 2.48-2.52(5H, m), 2.39-2.48(5H, m), 2.21(2H, d, J = 16.6Hz), 2.09(2H, dd, J = 16.6, 1.0Hz), 1.25(3H, d, J =5.9Hz), 1.09(6H, s), 0.82(6H, s)
MS (ESI) m/z: 520[M+H]+。 2,4-Dimethyl-7- (3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8-octahydro-1H prepared according to Example 3 -Xanthen-9-yl) -1-benzofuran-5-carboxylic acid (200 mg, 0.432 mmol) in dichloromethane (10 ml) at room temperature with 1-aminopropan-2-ol (39.0 mg, 0.519 mmol), (benzo Triazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (270 mg, 0.519 mmol) and diisopropylethylamine (0.088 ml, 0.519 mmol) were added and stirred overnight. Water was added to the reaction mixture, and the mixture was extracted 3 times with dichloromethane. The obtained organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (180 mg, yield: 80%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.41 (1H, s), 6.68 (1H, t, J = 5.6Hz), 6.33 (1H, d, J = 1.0Hz), 4.94 (1H, s), 4.05 (1H, m), 3.60 (1H, m ), 3.30 (1H, m), 2.48-2.52 (5H, m), 2.39-2.48 (5H, m), 2.21 (2H, d, J = 16.6Hz), 2.09 (2H, dd, J = 16.6, 1.0 Hz), 1.25 (3H, d, J = 5.9Hz), 1.09 (6H, s), 0.82 (6H, s)
MS (ESI) m / z: 520 [M + H] + .
 
（実施例２３）　N-(2-ヒドロキシ-2-メチルプロピル)-2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-カルボキサミド
Example 23 N- (2-hydroxy-2-methylpropyl) -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-carboxamide
Figure JPOXMLDOC01-appb-C000042
Figure JPOXMLDOC01-appb-C000042
　1-アミノプロパン-2-オールの代わりに1-アミノ-2-メチルプロパン-2-オール (62.6mg, 0.702mmol)を用い、実施例3により製造される2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-カルボン酸(250mg,0.540mmol)と、実施例22に記載された方法と同様に反応を行い、標記化合物(226mg, 収率：78％）を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
7.41(1H, s), 6.63(1H, t, J = 6.3Hz), 6.34(1H, d, J = 1.0Hz), 4.96(1H, s), 3.46(2H, d, J = 6.3Hz), 2.50(2H, d, J = 17.5Hz), 2.49(3H, s), 2.42(2H, d, J = 17.5Hz), 2.40(3H, s), 2.21(2H, d, J = 16.6Hz), 2.10(2H, d, J = 16.6Hz), 1.30(6H, s), 1.09(6H, s), 0.82(6H, s)
MS (ESI) m/z: 534[M+H]+。 2,4-Dimethyl-7- (3 prepared according to Example 3 using 1-amino-2-methylpropan-2-ol (62.6 mg, 0.702 mmol) instead of 1-aminopropan-2-ol , 3,6,6-Tetramethyl-1,8-dioxo-2,3,4,5,6,7,8-octahydro-1H-xanthen-9-yl) -1-benzofuran-5-carboxylic acid ( The title compound (226 mg, yield: 78%) was obtained by reacting with 250 mg, 0.540 mmol) in the same manner as described in Example 22.
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.41 (1H, s), 6.63 (1H, t, J = 6.3Hz), 6.34 (1H, d, J = 1.0Hz), 4.96 (1H, s), 3.46 (2H, d, J = 6.3Hz), 2.50 (2H, d, J = 17.5Hz), 2.49 (3H, s), 2.42 (2H, d, J = 17.5Hz), 2.40 (3H, s), 2.21 (2H, d, J = 16.6Hz), 2.10 (2H, d, J = 16.6Hz), 1.30 (6H, s), 1.09 (6H, s), 0.82 (6H, s)
MS (ESI) m / z: 534 [M + H] < +>.
 
（実施例２４）　2-[2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-イル]-N-(メチルスルホニル)プロパナミド
Example 24 2- [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] -N- (methylsulfonyl) propanamide
Figure JPOXMLDOC01-appb-C000043
Figure JPOXMLDOC01-appb-C000043
　実施例３により製造される2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-カルボン酸(491mg,1.00mmol)のジクロロメタン溶液(10ml)に、室温で塩化亜鉛(40.9mg, 0.300mmol)、安息香酸無水物(272mg, 1.20mmol)を加え20分攪拌した。室温でメタンスルホンアミド(272mg, 2.86mmol)のジクロロメタン溶液(40ml)を加え、一晩攪拌した。反応液に水を加え、ジクロロメタンで３回抽出し、得られた有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル=1:0-1:1, v/v）で精製して、標記化合物(113mg, 収率：20％）を得た。
1H-NMRスペクトル(500MHz, CDCl3）δppm：
7.82(1H, brs), 7.12(1H, s), 6.31(1H, d, J = 1.0Hz), 4.87(1H, s), 3.93(1H, q, J = 7.0Hz), 3.41(3H, s), 2.38-2.51(4H, m), 2.40(3H, d, J = 1.0Hz), 2.34(3H, s), 2.05-2.23(4H, m), 1.55(3H, d, J = 7.0Hz), 1.09(3H, s), 1.08(3H, s), 0.87(3H, s), 0.81(3H, s)
MS (ESI) m/z: 568[M+H]+。 2,4-Dimethyl-7- (3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8-octahydro-1H prepared according to Example 3 -Xanthen-9-yl) -1-benzofuran-5-carboxylic acid (491 mg, 1.00 mmol) in dichloromethane (10 ml) at room temperature with zinc chloride (40.9 mg, 0.300 mmol), benzoic anhydride (272 mg, 1.20 mmol) was added and stirred for 20 minutes. Methanesulfonamide (272 mg, 2.86 mmol) in dichloromethane (40 ml) was added at room temperature, and the mixture was stirred overnight. Water was added to the reaction mixture, and the mixture was extracted 3 times with dichloromethane. The obtained organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0-1: 1, v / v) to give the title compound (113 mg, yield: 20%) Got.
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.82 (1H, brs), 7.12 (1H, s), 6.31 (1H, d, J = 1.0Hz), 4.87 (1H, s), 3.93 (1H, q, J = 7.0Hz), 3.41 (3H, s ), 2.38-2.51 (4H, m), 2.40 (3H, d, J = 1.0Hz), 2.34 (3H, s), 2.05-2.23 (4H, m), 1.55 (3H, d, J = 7.0Hz) , 1.09 (3H, s), 1.08 (3H, s), 0.87 (3H, s), 0.81 (3H, s)
MS (ESI) m / z: 568 [M + H] < +>.
 
（実施例２５）　6-メトキシ-5-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)ナフタレン-2-カルボン酸
Example 25 6-Methoxy-5- (3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthene -9-yl) naphthalene-2-carboxylic acid
Figure JPOXMLDOC01-appb-C000044
Figure JPOXMLDOC01-appb-C000044
（実施例２５－１）　メチル　6-メトキシ-5-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)ナフタレン-2-カルボキシレート
　メチル 5-ホルミル-6-メトキシナフタレン-2-カルボキシレート(4.8g, 19.7mmol)のエタノール溶液(100ml)に、室温で5, 5-ジメチル-1,3-ヘキサンジオン(6.0g, 42.9mmol)、ピロリジン(30μl)を加え、90℃で加熱した。室温に戻した後、反応液を濃縮した。得られた残渣をクロロホルム(100ml)に溶解し、p-トルエンスルホン酸1水和物(0.1g, 0.5mmol)を加え、70℃で加熱した。室温に戻した後、p-トルエンスルホン酸1水和物(1.0g, 5.0mmol)を加え、80℃で加熱した。室温に戻した後、反応液を濃縮し、得られた残渣を酢酸エチル、ヘキサン混合溶媒を用いて結晶化し、不純物を含む結晶(9.0g)を得た。さらに、シリカゲルカラムクロマトグラフィー(塩基性シリカゲル使用、酢酸エチル:ジクロロメタン=1:100-1:10, v/v)で精製して、標記化合物（5.0g, 収率：52％）を得た。
MS (ESI/APCI) m/z: 511 [M+Na]+
（実施例２５－２）　6-メトキシ-5-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)ナフタレン-2-カルボン酸
　実施例２５－１により製造されるメチル　6-メトキシ-5-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)ナフタレン-2-カルボキシレート（5.0g, 10.2mmol）をジクロロメタン(20ml)、THF(100ml)、メタノール(100ml)に溶解し、室温で1規定水酸化ナトリウム水溶液(50ml, 50mmol)を加え、50℃で90分間、室温で一晩攪拌した。減圧下濃縮し、得られた残渣へ、5規定塩酸(11ml)、ジクロロメタン、酢酸エチル、水を加え、攪拌した。析出した結晶をろ取し、水、メタノール、酢酸エチル、ヘキサンで洗浄した。結晶は風乾し、標記化合物（3.33g, 収率：69%）を得た。
MS (ESI/APCI) m/z: 497 [M+Na]+
 
（実施例２６）　6-メトキシ-1-メチル-5-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)ナフタレン-2-カルボン酸 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 μl) 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. Further, the residue was purified by silica gel column chromatography (using basic silica gel, ethyl acetate: dichloromethane = 1: 100-1: 10, v / v) to obtain the title compound (5.0 g, yield: 52%).
MS (ESI / APCI) m / z: 511 [M + Na] +
Example 25-2 6-methoxy-5- (3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H -Xanthen-9-yl) naphthalene-2-carboxylic acid Methyl 6-methoxy-5- (3,3,6,6-tetramethyl-1,8-dioxo-2,3 prepared according to Example 25-1 , 4,5,6,7,8,9-octahydro-1H-xanthen-9-yl) naphthalene-2-carboxylate (5.0 g, 10.2 mmol) in dichloromethane (20 ml), THF (100 ml), methanol (100 ml 1N aqueous sodium hydroxide solution (50 ml, 50 mmol) was added at room temperature, and the mixture was stirred at 50 ° C. for 90 minutes and at room temperature overnight. After concentration under reduced pressure, 5N hydrochloric acid (11 ml), dichloromethane, ethyl acetate, and water were added to the resulting residue and stirred. The precipitated crystals were collected by filtration and washed with water, methanol, ethyl acetate, and hexane. The crystals were air-dried to obtain the title compound (3.33 g, yield: 69%).
MS (ESI / APCI) m / z: 497 [M + Na] +

Example 26 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
Figure JPOXMLDOC01-appb-C000045
Figure JPOXMLDOC01-appb-C000045
（実施例２６－１）　メチル　6-メトキシ-1-{[(トリフルオロメチル)スルホニル]オキシ}ナフタレン-2-カルボキシレート
　メチル 1-ヒドロキシ-6-メトキシナフタレンカルボキシレート(3.48g, 15.0mmol)のDMF溶液(15ml)に、室温で炭酸カリウム(6.22g, 45.0mmol)、N-フェニルビス（トリフルオロメタンスルホンイミド）(5.36g, 15.0mmol)を加え、70℃にて2時間加熱した。反応液を室温に戻した後、水、酢酸エチルを加え、分液をし、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=1:3-1:1, v/v)で精製して、標記化合物（5.55g, 収率：100%）を得た。
1H-NMRスペクトル(500MHz，CDCl3)δppm:
8.10 (1H, d, J = 9.3 Hz), 8.00 (1H, d, J = 8.5 Hz), 7.80 (1H, d, J = 8.8 Hz), 7.35 (1H, dd, J = 9.3, 2.4 Hz), 7.21 (1H, d, J = 2.4 Hz), 4.03 (3H, s), 3.99 (3H, s).
（実施例２６－２）　メチル　6-メトキシ-1-メチルナフタレン-2-カルボキシレート
　窒素雰囲気下、実施例２６－１により製造されるメチル　6-メトキシ-1-{[(トリフルオロメチル)スルホニル]オキシ}ナフタレン-2-カルボキシレート(1.82g, 5.00mmol)のジオキサン溶液(10ml)に、室温でリン酸カリウム(3.29g, 15.5mmol)、トリメチルボロキシン(3.5MTHF溶液, 0.86ml, 3.0mmol)、1,1′-ビス(ジフェニルホスフィノ)フェロセン-パラジウム(II)ジクロリド-ジクロロメタン錯体(81.7mg, 0.1mmol)を加え、110℃で90分間加熱した。反応液を室温に戻した後、セライトろ過により不溶物をろ去し、水で洗浄後、無水硫酸ナトリウムにて乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=1:3-1:1, v/v)で精製して、標記化合物（0.598g, 収率：52%）を得た。
1H-NMRスペクトル(500MHz，CDCl3)δppm:
8.14 (1H, d, J= 9.3 Hz), 7.85 (1H, d, J = 8.5 Hz), 7.63 (1H, d, J = 8.5 Hz), 7.25 (1H, dd, J = 9.3, 2.7 Hz), 7.16 (1H, d, J = 2.7 Hz), 3.97 (6H, s), 2.95 (3H, s).
（実施例２６－３）　メチル 5-ホルミル-6-メトキシ-1-メチルナフタレン-2-カルボキシレート
　実施例２６－２により製造されるメチル　6-メトキシ-1-メチルナフタレン-2-カルボキシレート(15.4g, 67.0mmol)、N-メチルホルムアニリド(27.0g, 199mmol)に、氷水冷下、オキシ塩化リン(42.7g, 278mmol)を加え、85℃で6時間加熱した。反応液を室温に戻した後、水を加え、酢酸エチルにて抽出し、有機層を無水硫酸ナトリウムにて乾燥した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=1:3-1:1, v/v)で精製して、標記化合物（14.5g, 収率：84%）を得た。
（実施例２６－４）　メチル　6-メトキシ-1-メチル-5-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)ナフタレン-2-カルボキシレート
　実施例２６－３により製造されるメチル 5-ホルミル-6-メトキシ-1-メチルナフタレン-2-カルボキシレート(12.0g, 47.0mmol)のメタノール溶液(190ml)に、室温で5, 5-ジメチル-1,3-ヘキサンジオン(15.0g, 199mmol)、ピロリジン(3.67g, 51.6mmol)を加え、70℃で90分間加熱した。室温に戻した後、反応液を濃縮した。得られた残渣をクロロホルム(190ml)に溶解し、p-トルエンスルホン酸1水和物(11.2g, 58.9mmol)を加え、70℃で30分間加熱した。室温に戻した後、反応液を濃縮し、得られた残渣を、シリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=1:3-1:1, v/v)で精製して、標記化合物（18.0g, 収率：76%）を得た。
1H-NMRスペクトル(400MHz，CDCl3)δppm:
8.75 (1H, d, J = 9.8 Hz), 8.06 (1H, d, J = 9.8 Hz), 7.97 (1H, d, J = 9.3 Hz), 7.14 (1H, d, J = 9.3 Hz), 5.60 (1H, s), 3.90 (3H, s), 3.81 (3H, s), 2.85 (3H, s), 2.47 (2H, d, J= 17.6 Hz), 2.38 (2H, d, J = 18.1 Hz), 2.15 (2H, d, J = 16.6 Hz), 2.03 (2H, d, J = 16.6 Hz), 1.06 (6H, s), 0.90 (6H, s).
（実施例２６－５）　6-メトキシ-1-メチル-5-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)ナフタレン-2-カルボン酸
　実施例２６－４により製造されるメチル　6-メトキシ-1-メチル-5-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)ナフタレン-2-カルボキシレート（19.6g, 39mmol）をジクロロメタン(40ml)、THF(60ml)、メタノール(120ml)に溶解し、室温で2規定水酸化ナトリウム水溶液(40ml, 80mmol)を加え、40℃で７時間、75℃で12時間攪拌した。反応液を室温に戻した後、減圧下濃縮した。得られた残渣を、THF(100ml)、水(80ml)、メタノール(5ml)に溶解し、2規定塩酸（2N, 45ml, 90mmol）を加え、室温で中和晶析した。得られた結晶をエタノール(22ml)-水(200ml)に懸濁させ、7時間加熱還流した。室温に戻し、結晶をろ取し、含水エタノール(10%, 50ml)で洗浄し、50℃、7時間減圧乾燥することにより標記化合物を1水和物（19.0g, 収率：100%）として得た。
1H-NMRスペクトル(400MHz，CDCl3)δppm:
8.75 (1H, d, J = 9.8 Hz), 8.08 (1H, d, J = 9.8 Hz), 8.02 (1H, d, J = 9.3 Hz), 7.16 (1H, d, J = 9.3 Hz), 5.60 (1H, s), 3.82 (3H, s), 2.88 (3H, s), 2.49 (2H, d, J = 17.6 Hz), 2.38 (2H, d, J = 17.6 Hz), 2.17 (2H, d, J = 16.6 Hz), 2.04 (2H, d, J = 16.6 Hz), 1.07 (6H, s), 0.90 (6H, s).
TOF-MS (ES-) m/z: 488 [M+]
 
（実施例２７）　1,6-ジメトキシ-5-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)ナフタレン-2-カルボン酸 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. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3-1: 1, v / v) to give the title compound (5.55 g, yield: 100). %).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
8.10 (1H, d, J = 9.3 Hz), 8.00 (1H, d, J = 8.5 Hz), 7.80 (1H, d, J = 8.8 Hz), 7.35 (1H, dd, J = 9.3, 2.4 Hz), 7.21 (1H, d, J = 2.4 Hz), 4.03 (3H, s), 3.99 (3H, s).
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. for 90 minutes. After returning the reaction solution to room temperature, insolubles were removed by filtration through celite, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3-1: 1, v / v) to give the title compound (0.598 g, yield: 52 %).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
8.14 (1H, d, J = 9.3 Hz), 7.85 (1H, d, J = 8.5 Hz), 7.63 (1H, d, J = 8.5 Hz), 7.25 (1H, dd, J = 9.3, 2.7 Hz), 7.16 (1H, d, J = 2.7 Hz), 3.97 (6H, s), 2.95 (3H, s).
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. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3-1: 1, v / v) to give the title compound (14.5 g, yield: 84). %).
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. After returning to room temperature, the reaction solution was concentrated. The obtained residue was dissolved in chloroform (190 ml), p-toluenesulfonic acid monohydrate (11.2 g, 58.9 mmol) was added, and the mixture was heated at 70 ° C. for 30 min. After returning to room temperature, the reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3-1: 1, v / v) to give the title compound (18.0 g Yield: 76%).
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ ppm:
8.75 (1H, d, J = 9.8 Hz), 8.06 (1H, d, J = 9.8 Hz), 7.97 (1H, d, J = 9.3 Hz), 7.14 (1H, d, J = 9.3 Hz), 5.60 ( 1H, s), 3.90 (3H, s), 3.81 (3H, s), 2.85 (3H, s), 2.47 (2H, d, J = 17.6 Hz), 2.38 (2H, d, J = 18.1 Hz), 2.15 (2H, d, J = 16.6 Hz), 2.03 (2H, d, J = 16.6 Hz), 1.06 (6H, s), 0.90 (6H, s).
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. for 7 hours and 75 ° C. for 12 hours. The reaction solution was returned to room temperature and then concentrated under reduced pressure. The obtained residue was dissolved in THF (100 ml), water (80 ml) and methanol (5 ml), 2N hydrochloric acid (2N, 45 ml, 90 mmol) was added, and neutralized crystallization was performed at room temperature. The obtained crystals were suspended in ethanol (22 ml) -water (200 ml) and heated to reflux for 7 hours. After returning to room temperature, the crystals were collected by filtration, washed with aqueous ethanol (10%, 50 ml), and dried under reduced pressure at 50 ° C. for 7 hours to give the title compound as a monohydrate (19.0 g, yield: 100%). Obtained.
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ ppm:
8.75 (1H, d, J = 9.8 Hz), 8.08 (1H, d, J = 9.8 Hz), 8.02 (1H, d, J = 9.3 Hz), 7.16 (1H, d, J = 9.3 Hz), 5.60 ( 1H, s), 3.82 (3H, s), 2.88 (3H, s), 2.49 (2H, d, J = 17.6 Hz), 2.38 (2H, d, J = 17.6 Hz), 2.17 (2H, d, J = 16.6 Hz), 2.04 (2H, d, J = 16.6 Hz), 1.07 (6H, s), 0.90 (6H, s).
TOF-MS (ES-) m / z: 488 [M + ]

Example 27 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
Figure JPOXMLDOC01-appb-C000046
Figure JPOXMLDOC01-appb-C000046
（実施例２７－１）　メチル 5-ホルミル-1,6-ジメトキシナフタレン-2-カルボキシレート
　6-メトキシ-1-メチルナフタレン-2-カルボキシレートの代わりに公知化合物であるメチル　1,6-ジメトキシナフタレン-2-カルボキシレート(7.8g, 31.7mmol)を用い、実施例２６－３に記載された方法と同様に反応を行い、標記化合物（3.2g, 収率：37%）を得た。
1H-NMRスペクトル(400MHz，CDCl3)δppm:
10.82 (1H, d, J = 0.8 Hz), 8.99 (1H, d, J = 9.0 Hz), 8.53 (1H, d, J = 9.8 Hz), 7.97 (1H, d, J = 9.4 Hz), 7.33 (1H, d, J = 9.4 Hz), 4.06 (3H, s), 4.00 (3H, s), 3.94 (3H, s).
（実施例２７－２）　メチル　 1,6-ジメトキシ-5-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)ナフタレン-2-カルボキシレート
　メチル 5-ホルミル-6-メトキシ-1-メチルナフタレン-2-カルボキシレートの代わりに、実施例２７－１により製造されるメチル 5-ホルミル-1,6-ジメトキシナフタレン-2-カルボキシレート(7.14g, 26.1mmol)を用い、実施例26-4に記載された方法と同様に反応を行い、標記化合物（8.68g, 収率：64%）を得た。
1H-NMRスペクトル(500MHz，CDCl3)δppm:
8.65 (1H, d, J= 9.5 Hz), 8.21 (1H, d, J = 9.3 Hz), 8.05 (1H, d, J = 9.3 Hz), 7.18 (1H, d, J = 9.3 Hz), 5.33 (1H, s), 4.03 (3H, s), 3.98 (3H, s), 3.87 (3H, s), 2.53 (2H, d, J = 17.6 Hz), 2.43 (2H, d, J = 18.3 Hz), 2.22 (2H, d, J = 16.6 Hz), 2.11 (2H, d, J = 16.6 Hz), 1.13 (6H, s), 0.96 (6H, s).
（実施例２７－３）　1,6-ジメトキシ-5-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)ナフタレン-2-カルボン酸
　実施例２７－２により製造されるメチル　 1,6-ジメトキシ-5-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)ナフタレン-2-カルボキシレート（9.99g, 19.3mmol）をTHF(100ml)、メタノール(200ml)に溶解し、室温で2規定水酸化ナトリウム水溶液(100ml, 200mmol)を加え、86℃で3時間攪拌した。反応液を室温に戻した後、2規定塩酸水溶液（200ml, 400mmol）を加え、酢酸エチルにて抽出し、無水硫酸ナトリウムにて乾燥した。減圧下溶媒を留去し、酢酸エチル－ヘキサンより再結晶を行うことにより標記化合物（9.00g, 収率：93%）を得た。
1H-NMRスペクトル(400MHz，CD3OD)δppm:
8.51 (1H, d, J = 9.4 Hz), 8.16 (1H, d, J = 9.4 Hz), 7.89 (1H, d, J = 9.4 Hz), 7.32 (1H, d, J = 9.4 Hz), 5.49 (1H, s), 3.95 (3H, s), 3.86 (3H, s), 2.58 (2H, d, J= 17.6 Hz), 2.45 (2H, d, J = 18.0 Hz), 2.23 (2H, d, J = 16.4 Hz), 1.97 (2H, d, J = 16.4 Hz), 1.06 (6H, s), 0.89 (6H, s).
MS (ESI) m/z: 527 [M+Na]+
 
（実施例２８）　[6-メトキシ-5-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)ナフタレン-2-イル]酢酸 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%).
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ ppm:
10.82 (1H, d, J = 0.8 Hz), 8.99 (1H, d, J = 9.0 Hz), 8.53 (1H, d, J = 9.8 Hz), 7.97 (1H, d, J = 9.4 Hz), 7.33 ( 1H, d, J = 9.4 Hz), 4.06 (3H, s), 4.00 (3H, s), 3.94 (3H, s).
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. %).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
8.65 (1H, d, J = 9.5 Hz), 8.21 (1H, d, J = 9.3 Hz), 8.05 (1H, d, J = 9.3 Hz), 7.18 (1H, d, J = 9.3 Hz), 5.33 ( 1H, s), 4.03 (3H, s), 3.98 (3H, s), 3.87 (3H, s), 2.53 (2H, d, J = 17.6 Hz), 2.43 (2H, d, J = 18.3 Hz), 2.22 (2H, d, J = 16.6 Hz), 2.11 (2H, d, J = 16.6 Hz), 1.13 (6H, s), 0.96 (6H, s).
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. for 3 hours. After returning the reaction solution to room temperature, 2N aqueous hydrochloric acid solution (200 ml, 400 mmol) was added, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and recrystallization from ethyl acetate-hexane gave the title compound (9.00 g, yield: 93%).
1 H-NMR spectrum (400 MHz, CD 3 OD) δ ppm:
8.51 (1H, d, J = 9.4 Hz), 8.16 (1H, d, J = 9.4 Hz), 7.89 (1H, d, J = 9.4 Hz), 7.32 (1H, d, J = 9.4 Hz), 5.49 ( 1H, s), 3.95 (3H, s), 3.86 (3H, s), 2.58 (2H, d, J = 17.6 Hz), 2.45 (2H, d, J = 18.0 Hz), 2.23 (2H, d, J = 16.4 Hz), 1.97 (2H, d, J = 16.4 Hz), 1.06 (6H, s), 0.89 (6H, s).
MS (ESI) m / z: 527 [M + Na] +

Example 28 [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
Figure JPOXMLDOC01-appb-C000047
Figure JPOXMLDOC01-appb-C000047
（実施例２８－１）　メチル [6-メトキシ-5-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)ナフタレン-2-イル]アセテート
　メチル 5-ホルミル-6-メトキシ-1-メチルナフタレン-2-カルボキシレートの代わりに、公知化合物であるメチル (5-ホルミル-6-メトキシナフタレン-2-イル)アセテート (308.1mg, 1.19mmol) を用い、実施例２６－４に記載された方法と同様に反応を行い、標記化合物（376.1mg, 収率：63%）を得た。
1H-NMRスペクトル(500MHz，CDCl3)δppm:
8.85 (1H, d, J = 8.8 Hz), 7.67-7.58 (3H, m), 7.12 (1H, d, J = 9.0 Hz), 5.63 (1H, s), 3.83 (3H, s), 3.76 (2H, s), 3.71 (3H, s), 2.52 (2H, d, J = 17.6 Hz), 2.42 (2H, d, J = 18.1 Hz), 2.21 (2H, d, J = 16.4 Hz), 2.09 (2H, d, J = 16.1 Hz), 1.12 (6H, s), 0.96 (6H, s).
（実施例２８－２）　[6-メトキシ-5-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)ナフタレン-2-イル]酢酸
　1,6-ジメトキシ-5-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)ナフタレン-2-カルボキシレートの代わりに、実施例28-1により製造されるメチル [6-メトキシ-5-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)ナフタレン-2-イル]アセテート(376.1mg, 0.749mmol)を用い、実施例２７に記載された方法と同様に反応を行い、標記化合物（301.2mg, 収率：82%）を得た。
1H-NMRスペクトル(500MHz，CD3OD)δppm:
8.71 (1H, d, J= 9.0 Hz), 7.69 (1H, d, J = 9.0 Hz), 7.60 (1H, s), 7.50-7.49 (1H, m), 7.25 (1H, d, J = 9.0 Hz), 5.54 (1H, s), 3.85 (3H, s), 3.72 (2H, s), 2.61 (2H, d, J = 17.8 Hz), 2.49 (2H, d, J = 17.8 Hz), 2.25 (2H, d, J = 16.4 Hz), 2.00 (2H, d, J = 16.4 Hz), 1.09 (6H, s), 0.93 (6H, s).
MS (ESI) m/z: 511 [M+Na]+
 
（実施例２９）　(2E)-3-[6-メトキシ-5-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)ナフタレン-2-イル]プロプ-2-エン酸 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%). .
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
8.85 (1H, d, J = 8.8 Hz), 7.67-7.58 (3H, m), 7.12 (1H, d, J = 9.0 Hz), 5.63 (1H, s), 3.83 (3H, s), 3.76 (2H , s), 3.71 (3H, s), 2.52 (2H, d, J = 17.6 Hz), 2.42 (2H, d, J = 18.1 Hz), 2.21 (2H, d, J = 16.4 Hz), 2.09 (2H , d, J = 16.1 Hz), 1.12 (6H, s), 0.96 (6H, s).
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.
1 H-NMR spectrum (500 MHz, CD 3 OD) δ ppm:
8.71 (1H, d, J = 9.0 Hz), 7.69 (1H, d, J = 9.0 Hz), 7.60 (1H, s), 7.50-7.49 (1H, m), 7.25 (1H, d, J = 9.0 Hz ), 5.54 (1H, s), 3.85 (3H, s), 3.72 (2H, s), 2.61 (2H, d, J = 17.8 Hz), 2.49 (2H, d, J = 17.8 Hz), 2.25 (2H , d, J = 16.4 Hz), 2.00 (2H, d, J = 16.4 Hz), 1.09 (6H, s), 0.93 (6H, s).
MS (ESI) m / z: 511 [M + Na] +

Example 29 (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
Figure JPOXMLDOC01-appb-C000048
Figure JPOXMLDOC01-appb-C000048
（実施例２９－１）　エチル (2E)-3-(5-ホルミル-6-メトキシナフタレン-2-イル)プロプ-2-エノエート
　メチル　1,6-ジメトキシナフタレン-2-カルボキシレートの代わりに、公知化合物であるメチル (6-メトキシナフタレン-2-イル)アセテート（1.28g, 5.00mmol）を用い実施例２７－１に記載された方法と同様に反応を行い、標記化合物（301.2mg, 収率：82%）を得た。
1H-NMRスペクトル(400MHz，CDCl3)δppm:
10.87 (1H, s), 9.26 (1H, d, J = 9.4 Hz), 8.07 (1H, d, J = 9.0 Hz), 7.85-7.77 (3H, m), 7.33 (1H, d, J= 9.4 Hz), 6.54 (1H, d, J = 16.0 Hz), 4.29 (2H, q, J = 7.0 Hz), 4.07 (3H, s), 1.36 (3H, t, J= 7.2 Hz).
（実施例２９－２）　エチル (2E)-3-[6-メトキシ-5-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)ナフタレン-2-イル]プロプ-2-エノエート
　メチル 5-ホルミル-6-メトキシ-1-メチルナフタレン-2-カルボキシレートの代わりに、実施例29-1により製造されるエチル (2E)-3-(5-ホルミル-6-メトキシナフタレン-2-イル)プロプ-2-エノエート(487.3mg, 1.72mmol)を用い、実施例２６－４に記載された方法と同様に反応を行い、標記化合物（597.3mg, 収率：66%）を得た。
1H-NMRスペクトル(500MHz，CDCl3)δppm:
8.88 (1H, d, J = 9.0 Hz), 7.83-7.75 (4H, m), 7.15 (1H, d, J = 9.0 Hz), 6.54 (1H, d, J = 15.9 Hz), 5.63 (1H, s), 4.31 (2H, q, J = 7.1 Hz), 3.86 (3H, s), 2.53 (2H, d, J = 17.8 Hz), 2.43 (2H, d, J = 17.6 Hz), 2.22 (2H, d, J = 16.6 Hz), 2.10 (2H, d, J = 16.4 Hz), 1.39 (3H, t, J = 7.2 Hz), 1.13 (6H, s), 0.96 (6H, s).
（実施例２９－３）　(2E)-3-[6-メトキシ-5-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)ナフタレン-2-イル]プロプ-2-エン酸
　1,6-ジメトキシ-5-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)ナフタレン-2-カルボキシレートの代わりに、実施例２９－２により製造されるエチル (2E)-3-[6-メトキシ-5-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)ナフタレン-2-イル]プロプ-2-エノエート(237.3mg, 0.449mmol)を用い、実施例27に記載された方法と同様に反応を行い、標記化合物（172.6mg, 収率：77%）を得た。
1H-NMRスペクトル(400MHz，CD3OD)δppm:
8.77 (1H, d, J= 9.0 Hz), 7.85-7.80 (4H, m), 7.30 (1H, d, J = 9.4 Hz), 6.57 (1H, d, J= 15.6 Hz), 5.55 (1H, s), 3.88 (3H, s), 2.62 (2H, d, J = 17.6 Hz), 2.49 (2H, d, J = 17.6 Hz), 2.27 (2H, d, J = 16.4 Hz), 2.01 (2H, d, J = 16.4 Hz), 1.10 (6H, s), 0.93 (6H, s).
MS (ESI) m/z: 523 [M+Na]+
 
（実施例３０）　3-[6-メトキシ-5-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)ナフタレン-2-イル]プロパン酸 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%).
1 H-NMR spectrum (400 MHz, CDCl 3 ) δ ppm:
10.87 (1H, s), 9.26 (1H, d, J = 9.4 Hz), 8.07 (1H, d, J = 9.0 Hz), 7.85-7.77 (3H, m), 7.33 (1H, d, J = 9.4 Hz) ), 6.54 (1H, d, J = 16.0 Hz), 4.29 (2H, q, J = 7.0 Hz), 4.07 (3H, s), 1.36 (3H, t, J = 7.2 Hz).
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. The reaction was carried out in the same manner as described above to obtain the title compound (597.3 mg, yield: 66%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
8.88 (1H, d, J = 9.0 Hz), 7.83-7.75 (4H, m), 7.15 (1H, d, J = 9.0 Hz), 6.54 (1H, d, J = 15.9 Hz), 5.63 (1H, s ), 4.31 (2H, q, J = 7.1 Hz), 3.86 (3H, s), 2.53 (2H, d, J = 17.8 Hz), 2.43 (2H, d, J = 17.6 Hz), 2.22 (2H, d , J = 16.6 Hz), 2.10 (2H, d, J = 16.4 Hz), 1.39 (3H, t, J = 7.2 Hz), 1.13 (6H, s), 0.96 (6H, s).
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 manner as described in Example 27 to give the title compound (172.6 mg, yield: 77%).
1 H-NMR spectrum (400 MHz, CD 3 OD) δ ppm:
8.77 (1H, d, J = 9.0 Hz), 7.85-7.80 (4H, m), 7.30 (1H, d, J = 9.4 Hz), 6.57 (1H, d, J = 15.6 Hz), 5.55 (1H, s ), 3.88 (3H, s), 2.62 (2H, d, J = 17.6 Hz), 2.49 (2H, d, J = 17.6 Hz), 2.27 (2H, d, J = 16.4 Hz), 2.01 (2H, d , J = 16.4 Hz), 1.10 (6H, s), 0.93 (6H, s).
MS (ESI) m / z: 523 [M + Na] +

Example 30 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
Figure JPOXMLDOC01-appb-C000049
Figure JPOXMLDOC01-appb-C000049
（実施例３０－１）　エチル 3-[6-メトキシ-5-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)ナフタレン-2-イル]プロパノエート
　実施例29-2により製造されるエチル (2E)-3-[6-メトキシ-5-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)ナフタレン-2-イル]プロプ-2-エノエートをエタノール(20ml)、酢酸エチル(100ml)に溶解し、室温で10％パラジウム－炭素(360.0mg)を加え、水素雰囲気下、室温で3時間攪拌した。窒素置換した後、触媒をセライトろ過により除去し、濃縮後得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=1:3-1:1, v/v)で精製して、標記化合物（259.9mg, 収率：90%）を得た。
1H-NMRスペクトル(500MHz，CDCl3)δppm:
8.82 (1H, d, J= 9.5 Hz), 7.63 (1H, d, J = 9.0 Hz), 7.52-7.51 (2H, m), 7.10 (1H, d, J= 8.8 Hz), 5.63 (1H, s), 4.19 (2H, q, J= 7.2 Hz), 3.83 (3H, s), 3.09 (2H, t, J= 8.1 Hz), 2.73 (2H, t, J = 8.1 Hz), 2.52 (2H, d, J = 17.6 Hz), 2.42 (2H, d, J = 17.6 Hz), 2.21 (2H, d, J = 16.6 Hz), 2.09 (2H, d, J = 16.1 Hz), 1.30 (4H, t, J = 7.1 Hz), 1.12 (6H, s), 0.96 (6H, s).
（実施例３０－２）　3-[6-メトキシ-5-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)ナフタレン-2-イル]プロパン酸
　1,6-ジメトキシ-5-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)ナフタレン-2-カルボキシレートの代わりに、実施例３０－１により製造されるエチル3-[6-メトキシ-5-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)ナフタレン-2-イル]プロパノエート(284.3mg, 0.537mmol)を用い、実施例27に記載された方法と同様に反応を行い、標記化合物（259.9mg, 収率：96%）を得た。
1H-NMRスペクトル(400MHz，CD3OD)δppm:
8.68 (1H, d, J= 9.0 Hz), 7.65 (1H, d, J = 9.0 Hz), 7.53 (1H, s), 7.45-7.43 (1H, m), 7.22 (1H, d, J = 9.0 Hz), 5.53 (1H, s), 3.84 (3H, s), 3.05 (2H, t, J = 7.6 Hz), 2.69 (2H, t, J = 7.6 Hz), 2.60 (2H, d, J = 17.6 Hz), 2.48 (2H, d, J = 17.6 Hz), 2.25 (2H, d, J = 16.4 Hz), 2.00 (2H, d, J = 16.4 Hz), 1.09 (6H, s), 0.93 (6H, s).
MS (ESI) m/z: 525 [M+Na]+
 
（実施例３１）　[5-メトキシ-4-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)-2,3-ジヒドロ-1H-インデン-1-イル]酢酸 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 Ethyl (2E) -3- [6-methoxy-5- (3,3,6,6-) prepared according to Example 29-2 Tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl) naphthalen-2-yl] prop-2-enoate with ethanol (20 ml ) And ethyl acetate (100 ml), 10% palladium-carbon (360.0 mg) was added at room temperature, and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. After purging with nitrogen, the catalyst was removed by Celite filtration, and the residue obtained after concentration was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3-1: 1, v / v) to give the title compound ( 259.9 mg, yield: 90%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
8.82 (1H, d, J = 9.5 Hz), 7.63 (1H, d, J = 9.0 Hz), 7.52-7.51 (2H, m), 7.10 (1H, d, J = 8.8 Hz), 5.63 (1H, s ), 4.19 (2H, q, J = 7.2 Hz), 3.83 (3H, s), 3.09 (2H, t, J = 8.1 Hz), 2.73 (2H, t, J = 8.1 Hz), 2.52 (2H, d , J = 17.6 Hz), 2.42 (2H, d, J = 17.6 Hz), 2.21 (2H, d, J = 16.6 Hz), 2.09 (2H, d, J = 16.1 Hz), 1.30 (4H, t, J = 7.1 Hz), 1.12 (6H, s), 0.96 (6H, s).
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: 96%).
1 H-NMR spectrum (400 MHz, CD 3 OD) δ ppm:
8.68 (1H, d, J = 9.0 Hz), 7.65 (1H, d, J = 9.0 Hz), 7.53 (1H, s), 7.45-7.43 (1H, m), 7.22 (1H, d, J = 9.0 Hz ), 5.53 (1H, s), 3.84 (3H, s), 3.05 (2H, t, J = 7.6 Hz), 2.69 (2H, t, J = 7.6 Hz), 2.60 (2H, d, J = 17.6 Hz) ), 2.48 (2H, d, J = 17.6 Hz), 2.25 (2H, d, J = 16.4 Hz), 2.00 (2H, d, J = 16.4 Hz), 1.09 (6H, s), 0.93 (6H, s ).
MS (ESI) m / z: 525 [M + Na] +

Example 31 [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
Figure JPOXMLDOC01-appb-C000050
Figure JPOXMLDOC01-appb-C000050
（実施例３１－１）　エチル (4-ホルミル-5-メトキシ-2,3-ジヒドロ-1H-インデン-1-イル)アセテート及び、エチル (6-ホルミル-5-メトキシ-2,3-ジヒドロ-1H-インデン-1-イル)アセテート
　エチル　2-(5-メトキシ-2，3-ジヒドロ-1H-インデン-1-イル）アセテート(21.2g, 90.4mmol)、ジクロロメチルメチルエーテル(25ml, 282.7mmol) のジクロロメタン溶液(400ml)に、氷冷下、四塩化チタン(1.0M ジクロロメタン溶液, 400ml, 400mmol)を加えた。10分後、反応溶液に水(300ml)と重曹を加え反応を終了させた後、ジクロロメタンで２回抽出した。硫酸マグネシウムで乾燥後ジクロロメタンを減圧留去した。粗成生物のまま次の工程に付した。
（実施例３１－２）　エチル [5-メトキシ-4-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)-2,3-ジヒドロ-1H-インデン-1-イル]アセテート
　実施例３１－１－１，２により得られた粗精製物をエタノール(100ml)に溶かし、室温でピロリジン(0.5ml, 6.12mmol)と5,5-ジメチルシクロヘキサン-1,3-ジオン(26.6g, 190mmol)を加えた後、2時間加熱還流した。エタノールを減圧留去し、クロロホルム(200ml)に溶解させ、パラトルエンスルホン酸一水和物(11.0g, 57.8mmol)を加えた後、2時間加熱還流した。反応溶液に飽和重曹水を加えた後、ジクロロメタンで2回抽出を行った。硫酸マグネシウムで乾燥後、ジクロロメタンを減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=1:2-1:1, v/v) で精製して、標記化合物(4.40g, 収率：10%）、を得た。
1H-NMRスペクトル(500MHz，CDCl3)δppm:
6.89(1H, d, J = 7.8 Hz), 6.52(1H, d, J = 7.8 Hz), 4.77 (1H, s), 4.14-4.19(2H, m), 3.64(3H,s), 3.40-3.64(3H, m), 2.69(1H, dd, J = 5.9, 15.1 Hz), 2.40-2.47(4H, m), 2.34(2H, dd, J = 3.4, 17.6 Hz), 2.19(2H, dd, J = 2.2, 16.4 Hz), 2.12(2H, ddd, J = 1.1, 8.2, 16.5 Hz),1.82(1H,m), 1.27(3H, t, J = 7.0 Hz), 1.09(3H, s), 1.08(3H, s), 0.95(3H, s), 0.93(3H, s) 
MS (ESI) m/z: 529 [M+Na]+。
（実施例３１－３）　[5-メトキシ-4-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)-2,3-ジヒドロ-1H-インデン-1-イル]酢酸
　実施例３１－２により製造されるエチル [5-メトキシ-4-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)-2,3-ジヒドロ-1H-インデン-1-イル]アセテート(4.40g, 8.70mmol)のジオキサン溶液(50ml)に、室温で2規定塩酸(50ml, 100mmol)を加え、３時間加熱還流した。室温に戻した後、ヘキサンを加え、有機層を分離した。水層に対し、酢酸エチルによる抽出操作を一回行い、得られた有機層を併せ、硫酸マグネシウムで乾燥した。有機層を減圧留去した後、シリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=1:2-1:0, v/v) で精製して、標記精製物 (3.0g, 収率：66%）を得た。
1H-NMRスペクトル(500MHz，CDCl3)δppm:
6.93(1H, d, J = 7.8 Hz), 6.54(1H, d, J = 7.8 Hz), 4.77 (1H, s), 3.65(3H, s), 3.51-3.69(2H, m), 3.40-3.51(1H, m), 2.75(1H,dd, J = 5,6 Hz, 15.9 Hz), 2.29-2.57(6H, m), 2.20(2H, dd, 3.4, 16.1 Hz), 2.09-2.16(2H, m), 1.85(1H, m), 1.09(3H, s), 1.08(3H, s) 0.95(3H, s), 0.93(3H, s) 
MS (ESI) m/z: 501 [M+Na]+。 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. After 10 minutes, water (300 ml) and sodium bicarbonate were added to the reaction solution to terminate the reaction, followed by extraction with dichloromethane twice. After drying with magnesium sulfate, dichloromethane was distilled off under reduced pressure. The crude product was used for the next step.
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. After adding pyrrolidine (0.5 ml, 6.12 mmol) and 5,5-dimethylcyclohexane-1,3-dione (26.6 g, 190 mmol), the mixture was heated to reflux for 2 hours. Ethanol was distilled off under reduced pressure, dissolved in chloroform (200 ml), paratoluenesulfonic acid monohydrate (11.0 g, 57.8 mmol) was added, and the mixture was heated to reflux for 2 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted twice with dichloromethane. After drying with magnesium sulfate, dichloromethane was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2-1: 1, v / v) to obtain the title compound (4.40 g, yield: 10%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
6.89 (1H, d, J = 7.8 Hz), 6.52 (1H, d, J = 7.8 Hz), 4.77 (1H, s), 4.14-4.19 (2H, m), 3.64 (3H, s), 3.40-3.64 (3H, m), 2.69 (1H, dd, J = 5.9, 15.1 Hz), 2.40-2.47 (4H, m), 2.34 (2H, dd, J = 3.4, 17.6 Hz), 2.19 (2H, dd, J = 2.2, 16.4 Hz), 2.12 (2H, ddd, J = 1.1, 8.2, 16.5 Hz), 1.82 (1H, m), 1.27 (3H, t, J = 7.0 Hz), 1.09 (3H, s), 1.08 (3H, s), 0.95 (3H, s), 0.93 (3H, s)
MS (ESI) m / z: 529 [M + Na] +.
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. After returning to room temperature, hexane was added and the organic layer was separated. The aqueous layer was extracted once with ethyl acetate, and the resulting organic layers were combined and dried over magnesium sulfate. After evaporating the organic layer under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2-1: 0, v / v) to give the title purified product (3.0 g, yield: 66%). Obtained.
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
6.93 (1H, d, J = 7.8 Hz), 6.54 (1H, d, J = 7.8 Hz), 4.77 (1H, s), 3.65 (3H, s), 3.51-3.69 (2H, m), 3.40-3.51 (1H, m), 2.75 (1H, dd, J = 5,6 Hz, 15.9 Hz), 2.29-2.57 (6H, m), 2.20 (2H, dd, 3.4, 16.1 Hz), 2.09-2.16 (2H, m), 1.85 (1H, m), 1.09 (3H, s), 1.08 (3H, s) 0.95 (3H, s), 0.93 (3H, s)
MS (ESI) m / z: 501 [M + Na] < +>.
 
（実施例３２）　[5-メトキシ-6-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)-2,3-ジヒドロ-1H-インデン-1-イル]酢酸
Example 32 [5-Methoxy-6- (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
Figure JPOXMLDOC01-appb-C000051
Figure JPOXMLDOC01-appb-C000051
（実施例３２－１）　エチル (4-ホルミル-5-メトキシ-2,3-ジヒドロ-1H-インデン-1-イル)アセテート及び、エチル (6-ホルミル-5-メトキシ-2,3-ジヒドロ-1H-インデン-1-イル)アセテート
　エチル　2-(5-メトキシ-2，3-ジヒドロ-1H-インデン-1-イル）アセテート(21.2g, 90.4mmol)、ジクロロメチルメチルエーテル(25ml, 282.7mmol) のジクロロメタン溶液(400ml)に、氷水冷下、四塩化チタン(1.0M ジクロロメタン溶液, 400ml, 400mmol)を加えた。10分後、反応溶液に水(300ml)と重曹を加え反応を終了させた後、ジクロロメタンで２回抽出した。硫酸マグネシウムで乾燥後ジクロロメタンを減圧留去した。粗成生物のまま次の工程に付した。
（実施例３２－２）
　エチル [5-メトキシ-6-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)-2,3-ジヒドロ-1H-インデン-1-イル]アセテート
　実施例３２－１により得られた粗精製物をエタノール(100ml)に溶かし、室温でピロリジン(0.5ml, 6.12mmol)と5,5-ジメチルシクロヘキサン-1,3-ジオン(26.6g, 190mmol)を加えた後、2時間加熱還流した。エタノールを減圧留去し、クロロホルム(200ml)に溶解させ、パラトルエンスルホン酸一水和物(11.0g, 57.8mmol)を加えた後、2時間加熱還流した。反応溶液に飽和重曹水を加えた後、ジクロロメタンで2回抽出を行った。硫酸マグネシウムで乾燥後、ジクロロメタンを減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=1:2-1:1, v/v) で精製して標記化合物(30.0g, 収率：70%）を得た。
1H-NMRスペクトル(500MHz，CDCl3)δppm:
 7.13(1H, s), 6.63 (1H, s), 4.83 (1H, s), 4.18 (2H, q, J = 7.2 Hz), 3.76 (3H, s), 3.45-3.53(1H, m), 2.69-2.85(3H, m), 2.27-2.49(6H, m), 2.20 (2H, dd, J =  4.9, 16.6 Hz), 2.10-2.14 (2H, m), 1.68(1H, ddd, J = 5.4, 10.3, 18.1 Hz), 1.28(3H, t, J = 7.2 Hz), 1.08(6H, s), 0.96(3H, s), 0.95(3H, s)
MS (ESI) m/z: 529 [M+Na]+
（実施例３２－３）　[5-メトキシ-6-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)-2,3-ジヒドロ-1H-インデン-1-イル]酢酸
　エチル [5-メトキシ-4-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)-2,3-ジヒドロ-1H-インデン-1-イル]アセテートの代わりに、実施例３１－２－２で得られるエチル [5-メトキシ-6-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)-2,3-ジヒドロ-1H-インデン-1-イル]アセテート(2.17g, 4.15mmol)を用い、実施例31に記載された方法と同様に反応を行い、標記化合物(1.81g, 収率：88％）を得た。
1H-NMRスペクトル(500MHz，CDCl3)δppm:
7.18(1H, s), 6.64(1H, s), 4.83(1H, s), 3.76(3H, s), 3.48-3.56(1H, m), 2.72-2.90(3H, m), 2.32-2.50(6H, m), 2.21(2H, 3.7, J = 16.4 Hz), 2.11-2.15 (2H, m), 1.72(1H, ddd, J = 5.4, 10.2, 18.1 Hz), 1.09(3H, s), 1.08(3H,s), 0.96(3H, s), 0.95(3H, s)
MS (ESI) m/z: 501[M+Na]+。 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. After 10 minutes, water (300 ml) and sodium bicarbonate were added to the reaction solution to terminate the reaction, followed by extraction with dichloromethane twice. After drying with magnesium sulfate, dichloromethane was distilled off under reduced pressure. The crude product was used for the next step.
(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. Ethanol was distilled off under reduced pressure, dissolved in chloroform (200 ml), paratoluenesulfonic acid monohydrate (11.0 g, 57.8 mmol) was added, and the mixture was heated to reflux for 2 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted twice with dichloromethane. After drying with magnesium sulfate, dichloromethane was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2-1: 1, v / v) to obtain the title compound (30.0 g, yield: 70%).
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.13 (1H, s), 6.63 (1H, s), 4.83 (1H, s), 4.18 (2H, q, J = 7.2 Hz), 3.76 (3H, s), 3.45-3.53 (1H, m), 2.69 -2.85 (3H, m), 2.27-2.49 (6H, m), 2.20 (2H, dd, J = 4.9, 16.6 Hz), 2.10-2.14 (2H, m), 1.68 (1H, ddd, J = 5.4, 10.3, 18.1 Hz), 1.28 (3H, t, J = 7.2 Hz), 1.08 (6H, s), 0.96 (3H, s), 0.95 (3H, s)
MS (ESI) m / z: 529 [M + Na] +
Example 32-3 [5-Methoxy-6- (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- Instead of 2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl) -2,3-dihydro-1H-inden-1-yl] acetate, Example 31- Ethyl obtained in 2-2 [5-methoxy-6- (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 (2.17 g, 4.15 mmol) was used in the same manner as described in Example 31 to give the title A compound (1.81 g, yield: 88%) was obtained.
1 H-NMR spectrum (500 MHz, CDCl 3 ) δ ppm:
7.18 (1H, s), 6.64 (1H, s), 4.83 (1H, s), 3.76 (3H, s), 3.48-3.56 (1H, m), 2.72-2.90 (3H, m), 2.32-2.50 ( 6H, m), 2.21 (2H, 3.7, J = 16.4 Hz), 2.11-2.15 (2H, m), 1.72 (1H, ddd, J = 5.4, 10.2, 18.1 Hz), 1.09 (3H, s), 1.08 (3H, s), 0.96 (3H, s), 0.95 (3H, s)
MS (ESI) m / z: 501 [M + Na] < +>.
 
＜試験例＞　経口糖負荷試験
（1）使用動物
　市販のマウス（C57BL/6Jマウス、雄、使用時8～12週齡、日本チャールス・リバー(株)販売）
（２）実験方法・結果
　マウスに飼料（FR-2、株式会社船橋農場）を1週間以上自由摂取させ予備飼育した後、一晩絶食し、供試動物として用いた。被験化合物を1 mg/mlの濃度になるように0.5％メチルセルロース（和光純薬工業(株)）溶液(0.5％MC)を用いて、あるいは2 mg/mlの濃度になるようにプロピレングリコール（80v/v％, ナカライテスク（株））・Tween80（20v/v％、ナカライテスク（株)）混合溶液(PG:Tween)を用いて、投与液を調製した。投与液は、各群4～5匹のマウスに10 mg/kgの用量で強制経口投与した。対照群は、0.5％メチルセルロース溶液あるいはプロピレングリコール・Tween80混合液をそれぞれ10 ml/kgあるいは5ml/kgの容量にて経口投与した。経口糖負荷は、被験化合物投与30分後にグルコース溶液（大塚糖液50％:(株)大塚製薬工業）を3g/kgの用量で経口投与して行った。
<Test example> Oral glucose tolerance test (1) Animals used Commercially available mice (C57BL / 6J mice, male, 8-12 weeks old when used, sold by Charles River Japan Co., Ltd.)
(2) Experimental method / results Mice were allowed free intake of feed (FR-2, Funabashi Farm Co., Ltd.) for 1 week or longer, preliminarily raised, fasted overnight, and used as test animals. Use 0.5% methylcellulose (Wako Pure Chemical Industries, Ltd.) solution (0.5% MC) to a test compound concentration of 1 mg / ml, or propylene glycol (80v to a concentration of 2 mg / ml). 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. In the control group, 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.
　被験化合物投与直前（T0）、被験化合物投与25分後(T1)、経口糖負荷30分後(T2)および90分後(T3)に、マウスの尾静脈より採血を行い、血糖測定器（アキュチェックアビバ：ロシュ・ダイアグノスティックス（株））にて血糖値を測定した。また、T1血糖値は化合物投与30分後の糖負荷直前値として解析した。下記式より、血糖値曲線下面積を求め、対象群からの血糖低下率（％）を算出し、表１に示した。 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.
　血糖値曲線下面積＝[（T0血糖値＋T1血糖値）×30]÷2 ＋[（T1血糖値＋T2血糖値）×30]÷2 
＋[（T2血糖値＋T3血糖値）×60]÷2
　血糖低下率（％）＝[１－(被験化合物投与群血糖値曲線下面積／対照群血糖値曲線下面積)]×100
  Area under the blood glucose level curve = [(T0 blood sugar level + T1 blood sugar level) x 30] ÷ 2 + [(T1 blood sugar level + T2 blood sugar level) x 30] ÷ 2
+ [((T2 blood sugar level + T3 blood sugar level) x 60] ÷ 2
Blood glucose reduction rate (%) = [1- (Area under test compound administration group blood glucose level curve / Area under control group blood glucose level curve)] × 100
Figure JPOXMLDOC01-appb-T000052
  
Figure JPOXMLDOC01-appb-T000052
  
　上記の試験より、本発明化合物は、優れた血糖低下作用、食後血糖抑制作用、耐糖能不全改善作用等を有することがわかる。従って、本発明の化合物は、高血糖症、糖尿病及びそれら疾病に関連する病態または疾患の予防・治療薬として有用であると考えられる。
＜製剤例＞
　（製剤例１）カプセル剤
実施例１又は２の化合物　　５０ｍｇ
乳糖　　　　　　　　　　１２８ｍｇ
トウモロコシデンプン　　　７０ｍｇ
ステアリン酸マグネシウム　　２ｍｇ
－－－－－－－－－－－－－－－－－
　　　　　　　　　　　　２５０ｍｇ
上記処方の粉末を混合し、60メッシュのふるいを通した後、この粉末を250mgのゼラチンカプセルに入れ、カプセル剤とする。 From the above test, it can be seen that 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.
　（製剤例２）錠剤
実施例１又は２の化合物　　５０ｍｇ
乳糖　　　　　　　　　　１２６ｍｇ
トウモロコシデンプン　　　２３ｍｇ
ステアリン酸マグネシウム　　１ｍｇ
－－－－－－－－－－－－－－－－－
　　　　　　　　　　　　２００ｍｇ
上記処方の粉末を混合し、トウモロコシデンプン糊を用いて造粒、乾燥した後、打錠機により打錠して、１錠200mgの錠剤とする。この錠剤は必要に応じて糖衣を施すことができる。 (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.
　本発明の一般式（I）で表される新規なキサンテン誘導体又はその薬理上許容される塩は、優れた血糖降下作用を有し、医薬として有用である。 The 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.

Claims (24)

  1. 　下記一般式（I）
    Figure JPOXMLDOC01-appb-C000001
      
    ［式中、
    Figure JPOXMLDOC01-appb-C000002
     は二重結合又は単結合を示し、
    Xは、=C(-R8)-、-CH(-R8)-、 =N- 又は -O- を示し、
    Yは、=C(-R9)- 、 -CH(-R9)-又は =N- を示し、
    Zは、=C(-R10)- 、 -CH(-R9)-又は =N- を示し、
    R1は、水素原子、置換基群αから選ばれる1若しくは2個の基に置換されていてもよいC1-C3アルキル基、置換基群αから選ばれる1若しくは2個の基に置換されていてもよいC1-C3アルコキシ基、置換基群αから選ばれる1若しくは2個の基に置換されていてもよいC2-C3アルケニル基、置換基群αから選ばれる1若しくは2個の基に置換されていてもよいC3-C6シクロアルキル基、C1-C3アルコキシカルボニル基、置換基群αから選ばれる1又は2個の基に置換されていてもよいアミノカルボニル基、窒素、酸素及び硫黄から選択される同一若しくは異なった1-3個のヘテロ原子を含む3-10員複素環カルボニル基、カルボキシル基又はハロゲン原子を示し、
    R2は、同一又は異なって、水素原子、C1-C3アルキル基、C3-C6シクロアルキル基、C1-C3アルコキシ基、カルボキシル基若しくはハロゲン原子を示し、
    R3は、水素原子、C1-C3アルキル基（該アルキル基は、カルボキシル基で1個置換されていても良い）、C3-C6シクロアルキル基、C1-C3アルコキシ基（該アルコキシ基は、C1-C3アルコキシ基で1個置換されていても良い）、カルボキシル基、を示し、
    R4及びR5は、それぞれ同一若しくは異なって、C1-C3アルキル基を示すか又は、R4及びR5が結合して3-6員飽和炭素環を形成していてもよく、
    R6及びR7は、それぞれ同一若しくは異なって、C1-C3アルキル基を示すか又は、R6及びR7が結合して3-6員飽和炭素環を形成していてもよく、
    R8は、水素原子、C1-C3アルキル基（該アルキル基は、カルボキシル基で1個置換されていても良い）を示し、
    R9は、水素原子、C1-C3アルキル基（該アルキル基は、カルボキシル基で1個置換されていても良い）、C1-C3アルコキシカルボニル基、カルボキシル基、カルボキシル基で1個置換されたC2-C3アルケニル基を示し、
    R10は、水素原子、C1-C3アルコキシ基、置換基群αから選ばれる1又は2個の基に置換されていてもよいC1-C3アルキル基、C6-C10アリール基、窒素、酸素及び硫黄から選択される同一若しくは異なった1-3個のヘテロ原子を含む3-10員複素環基、C1-C3アルコキシカルボニル基、置換基群αから選ばれる基に1又は2個の基に置換されていてもよいアミノカルボニル基、カルボキシル基で1個置換されたC2-C3アルケニル基、若しくはカルボキシル基を示し、
    nは、0又は1を示し、
    mは、0又は1を示し、
    tは、1又は2を示し、
    ただし、Xが=C(-R8)-、Yが=C(-R9)- 及びZが=C(-R10)- を示す場合、R9又はR10のいずれか一つが、C1-C3アルコキシカルボニル基、カルボキシル基、カルボキシル基で1個置換されたC1-C3アルキル基若しくはカルボキシル基で1個置換されたC2-C3アルケニル基を示し、
    Xが-O- を示す場合、Zは=C(-R10)-を示す。
    　（置換基群α）
    水酸基、C1-C3アルキル基（該アルキル基は、カルボキシル基、C1-C3アルキルスルホニル基で1若しくは2個置換されていてもよいアミノカルボニル基、C3-C6シクロアルキル基又は水酸基で、1若しくは2個置換されていても良い）、C3-C6シクロアルキル基（該シクロアルキル基は、水酸基で1又は2個置換されていても良い）、アミノカルボニル基、カルボキシル基、
    C1-C3アルキルスルホニル基、窒素、酸素及び硫黄から選択される同一若しくは異なった1-3個のヘテロ原子を含む3-10員複素環基（該複素環基は、カルボキシル基で1個置換されていても良い）、窒素、酸素及び硫黄から選択される同一若しくは異なった1-3個のヘテロ原子を含む3-10員複素環C1-C3アルキル基（該複素環C1-C3アルキル基は、C1-C3ヒドロキシアルキル基又はカルボキシル基で1若しくは2個置換されていても良い）］で表される化合物又はその薬理上許容される塩。
          The following general formula (I)
    Figure JPOXMLDOC01-appb-C000001
    [Where:
    Figure JPOXMLDOC01-appb-C000002
     Represents a double bond or a single bond,
    X represents = C (-R 8 )-, -CH (-R 8 )-, = N- or -O-
    Y represents = C (-R 9 )-, -CH (-R 9 )-or = N-
    Z represents = C (-R 10 )-, -CH (-R 9 )-or = N-
    R 1 is a hydrogen atom, a C1-C3 alkyl group which may be substituted with one or two groups selected from substituent group α, and one or two groups selected from substituent group α. C1-C3 alkoxy group which may be substituted, 1 or 2 groups selected from substituent group α may be substituted with C2-C3 alkenyl group which may be substituted, 1 or 2 groups selected from substituent group α 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 α, nitrogen, oxygen and sulfur A 3- to 10-membered heterocyclic carbonyl group containing the same or different 1-3 heteroatoms, a carboxyl group or a halogen atom,
    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 (the alkyl group may be substituted with one carboxyl group), a C3-C6 cycloalkyl group, a C1-C3 alkoxy group (the alkoxy group is C1 -Optionally substituted with a -C3 alkoxy group), a carboxyl group,
    R 4 and R 5 are the same or different and each represents a C1-C3 alkyl group, or R 4 and R 5 may be bonded to form a 3-6 membered saturated carbocycle,
    R 6 and R 7 are the same or different and each represents a C1-C3 alkyl group, or R 6 and R 7 may be bonded to form a 3-6 membered saturated carbocycle,
    R 8 represents a hydrogen atom or a C1-C3 alkyl group (the alkyl group may be substituted with one carboxyl group),
    R 9 is a hydrogen atom, a C1-C3 alkyl group (the alkyl group may be substituted with one carboxyl group), a C1-C3 alkoxycarbonyl group, a carboxyl group, or a C2 substituted with one carboxyl group. -C3 represents an alkenyl 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 α, 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 α is substituted with 1 or 2 groups An aminocarbonyl group, a C2-C3 alkenyl group substituted with one carboxyl group, or a carboxyl group,
    n represents 0 or 1,
    m represents 0 or 1,
    t represents 1 or 2,
    However, when X is = C (-R 8 )-, Y is = C (-R 9 )-and Z is = C (-R 10 )-, 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,
    When X represents -O-, Z represents = C (-R 10 )-.
    (Substituent group α)
    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 alkyl group is Or a pharmacologically acceptable salt thereof. The compound may be substituted with one or two C1-C3 hydroxyalkyl groups or carboxyl groups)].
  2. 　Xが=C(-R8)- 又は -O- である、請求項１に記載の化合物又はその薬理上許容される塩。
          The compound or pharmacologically acceptable salt thereof according to claim 1, wherein X is = C (-R 8 )-or -O-.
  3. 　Zが=C(-R10)- である、請求項１又は２に記載の化合物又はその薬理上許容される塩。
          The compound or pharmacologically acceptable salt thereof according to claim 1 or 2, wherein Z is = C (-R 10 )-.
  4. 　下記一般式（IA）
    Figure JPOXMLDOC01-appb-C000003
     ［式中、
    R1は、水素原子、置換基群αから選ばれる1若しくは2個の基に置換されていてもよいC1-C3アルキル基、置換基群αから選ばれる1若しくは2個の基に置換されていてもよいC1-C3アルコキシ基、置換基群αから選ばれる1若しくは2個の基に置換されていてもよいC2-C3アルケニル基、置換基群αから選ばれる1若しくは2個の基に置換されていてもよいC3-C6シクロアルキル基、C1-C3アルコキシカルボニル基、置換基群αから選ばれる1又は2個の基に置換されていてもよいアミノカルボニル基、窒素、酸素及び硫黄から選択される同一若しくは異なった1-3個のヘテロ原子を含む3-10員複素環カルボニル基、カルボキシル基又はハロゲン原子を示し、
    R2は、同一又は異なって、水素原子、C1-C3アルキル基、C3-C6シクロアルキル基、C1-C3アルコキシ基、カルボキシル基若しくはハロゲン原子を示し、
    R4及びR5は、それぞれ同一若しくは異なって、C1-C3アルキル基を示すか又は、R4及びR5が結合して3-6員飽和炭素環を形成していてもよく、
    R6及びR7は、それぞれ同一若しくは異なって、C1-C3アルキル基を示すか又は、R6及びR7が結合して3-6員飽和炭素環を形成していてもよく、
    R10は、水素原子、C1-C3アルコキシ基、置換基群αから選ばれる1又は2個の基に置換されていてもよいC1-C3アルキル基、C6-C10アリール基、窒素、酸素及び硫黄から選択される同一若しくは異なった1-3個のヘテロ原子を含む3-10員複素環基、C1-C3アルコキシカルボニル基、置換基群αから選ばれる基に1又は2個の基に置換されていてもよいアミノカルボニル基カルボキシル基で1個置換されたC2-C3アルケニル基、若しくはカルボキシル基を示し、
    tは、1又は2を示す。
    　（置換基群α）
    水酸基、C1-C3アルキル基（該アルキル基は、カルボキシル基、C1-C3アルキルスルホニル基で1若しくは2個置換されていてもよいアミノカルボニル基、C3-C6シクロアルキル基又は水酸基で、1若しくは2個置換されていても良い）、C3-C6シクロアルキル基（該シクロアルキル基は、水酸基で1又は2個置換されていても良い）、アミノカルボニル基、カルボキシル基、
    C1-C3アルキルスルホニル基、窒素、酸素及び硫黄から選択される同一若しくは異なった1-3個のヘテロ原子を含む3-10員複素環基（該複素環基は、カルボキシル基で1個置換されていても良い）、窒素、酸素及び硫黄から選択される同一若しくは異なった1-3個のヘテロ原子を含む3-10員複素環C1-C3アルキル基（該複素環C1-C3アルキル基は、C1-C3ヒドロキシアルキル基又はカルボキシル基で1若しくは2個置換されていても良い）］で表される化合物又はその薬理上許容される塩。
          The following general formula (IA)
    Figure JPOXMLDOC01-appb-C000003
     [Where:
    R 1 is a hydrogen atom, a C1-C3 alkyl group which may be substituted with one or two groups selected from substituent group α, and one or two groups selected from substituent group α. C1-C3 alkoxy group which may be substituted, 1 or 2 groups selected from substituent group α may be substituted with C2-C3 alkenyl group which may be substituted, 1 or 2 groups selected from substituent group α 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 α, nitrogen, oxygen and sulfur A 3- to 10-membered heterocyclic carbonyl group containing the same or different 1-3 heteroatoms, a carboxyl group or a halogen atom,
    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 4 and R 5 are the same or different and each represents a C1-C3 alkyl group, or R 4 and R 5 may be bonded to form a 3-6 membered saturated carbocycle,
    R 6 and R 7 are the same or different and each represents a C1-C3 alkyl group, or R 6 and R 7 may be bonded to form a 3-6 membered saturated carbocycle,
    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 α, 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 α 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 α)
    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 alkyl group is Or a pharmacologically acceptable salt thereof. The compound may be substituted with one or two C1-C3 hydroxyalkyl groups or carboxyl groups)].
  5. 　R1が置換基群αから選ばれる1若しくは2個の基に置換されていてもよいC1-C3アルキル基又はカルボキシル基である、請求項４に記載の化合物又はその薬理上許容される塩。
          The compound or pharmacologically acceptable salt thereof according to claim 4, wherein R 1 is a C1-C3 alkyl group or a carboxyl group which may be substituted with one or two groups selected from substituent group α.
  6. 　R2が、同一又は異なって、水素原子若しくはC1-C3アルキル基である、請求項４又は５に記載の化合物若しくはその薬理上許容される塩。
          R 2 are the same or different, it is a hydrogen atom or a C1-C3 alkyl group, compound or a pharmacologically acceptable salt thereof according to claim 4 or 5.
  7. 　R10が置換基群αから選ばれる1又は2個の基に置換されていてもよいC1-C3アルキル基である、請求項１乃至６から選択されるいずれか１項に記載の化合物若しくはその薬理上許容される塩。
          The compound according to any one of claims 1 to 6 or a compound thereof, wherein R 10 is a C1-C3 alkyl group optionally substituted by 1 or 2 groups selected from substituent group α Pharmacologically acceptable salt.
  8. 　R4、R5、R6及びR7がC1-C3アルキル基である請求項１乃至７から選択されるいずれか１項に記載の化合物又はその薬理上許容される塩。
          R 4, R 5, compound or a pharmacologically acceptable salt thereof according to any one of R 6 and R 7 are selected from claims 1 to 7 is a C1-C3 alkyl group.
  9. 　下記式
    Figure JPOXMLDOC01-appb-C000004
     で表される、2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-カルボン酸。
          Following formula
    Figure JPOXMLDOC01-appb-C000004
     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-carboxylic acid.
  10. 　下記式
    Figure JPOXMLDOC01-appb-C000005
     で表される、7-(1’,8’-ジオキソ-1’,4’,5’,7’,8’,9’-ヘキサヒドロ-2’H-ジスピロ[シクロブタン-1,3’-キサンテン-6’,1”-シクロブタン]-9’-イル)-2,4-ジメチル-1-ベンゾフラン-5-カルボン酸。
          Following formula
    Figure JPOXMLDOC01-appb-C000005
     7- (1 ′, 8′-dioxo-1 ′, 4 ′, 5 ′, 7 ′, 8 ′, 9′-hexahydro-2′H-dispiro [cyclobutane-1,3′-xanthene -6 ', 1 "-cyclobutane] -9'-yl) -2,4-dimethyl-1-benzofuran-5-carboxylic acid.
  11. 　下記式
    Figure JPOXMLDOC01-appb-C000006
     で表される、3-[2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-イル]-2-メチルプロパン酸。
          Following formula
    Figure JPOXMLDOC01-appb-C000006
     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-methylpropanoic acid.
  12. 　下記式
    Figure JPOXMLDOC01-appb-C000007
     で表される、2-[2,4-ジメチル-7-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)-1-ベンゾフラン-5-イル]ブタン酸。
          Following formula
    Figure JPOXMLDOC01-appb-C000007
     2- [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] butanoic acid.
  13. 　下記式
    Figure JPOXMLDOC01-appb-C000008
     で表される、6-メトキシ-1-メチル-5-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)ナフタレン-2-カルボン酸。
          Following formula
    Figure JPOXMLDOC01-appb-C000008
     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.
  14. 　下記式
    Figure JPOXMLDOC01-appb-C000009
     で表される、1,6-ジメトキシ-5-(3,3,6,6-テトラメチル-1,8-ジオキソ-2,3,4,5,6,7,8,9-オクタヒドロ-1H-キサンテン-9-イル)ナフタレン-2-カルボン酸。
          Following formula
    Figure JPOXMLDOC01-appb-C000009
     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.
  15. 　請求項９乃至１４から選択されるいずれか１項に記載の化合物若しくはその薬理上許容される塩。
          The compound according to any one of claims 9 to 14, or a pharmacologically acceptable salt thereof.
  16. 　請求項９乃至１４から選択されるいずれか１項に記載の化合物の2-メチルプロパン-2-アミン塩。
          The 2-methylpropan-2-amine salt of the compound according to any one of claims 9 to 14.
  17. 　請求項９乃至１４から選択されるいずれか１項に記載の化合物のナトリウム塩。
          The sodium salt of the compound according to any one of claims 9 to 14.
  18. 　請求項１乃至１７から選択されるいずれか１項に記載の化合物又はその薬理上許容される塩を有効成分として含有する血糖降下剤。
          A hypoglycemic agent comprising the compound according to any one of claims 1 to 17 or a pharmacologically acceptable salt thereof as an active ingredient.
  19. 　請求項１乃至１７から選択されるいずれか１項に記載の化合物又はその薬理上許容される塩を有効成分として含有する医薬。
          A medicament comprising the compound according to any one of claims 1 to 17 or a pharmacologically acceptable salt thereof as an active ingredient.
  20. 　糖尿病、食後過血糖症、耐糖能障害、糖尿病性神経障害、糖尿病性腎症、糖尿病性網膜症、高脂血症、動脈硬化症、血栓性疾患、肥満、高血圧、浮腫、インスリン抵抗性、不安定糖尿病、インスリノーマ又は高インスリン血症の治療若しくは予防のための、請求項１９に記載の医薬。
          Diabetes, postprandial hyperglycemia, glucose intolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, hyperlipidemia, arteriosclerosis, thrombotic disease, obesity, hypertension, edema, insulin resistance, non The medicament according to claim 19, for the treatment or prevention of stable diabetes, insulinoma or hyperinsulinemia.
  21. 　糖尿病、食後過血糖症、耐糖能障害又はインスリン抵抗性の治療若しくは予防のための、請求項１９に記載の医薬。
          The medicament according to claim 19, for the treatment or prevention of diabetes, postprandial hyperglycemia, impaired glucose tolerance or insulin resistance.
  22. 　2型糖尿病の治療のための、請求項１９に記載の医薬。
          20. A medicament according to claim 19 for the treatment of type 2 diabetes.
  23. 　医薬組成物を製造するための、請求項１乃至１７から選択されるいずれか一項に記載された化合物又はその薬理上許容される塩の使用。
          Use of a compound according to any one of claims 1 to 17 or a pharmacologically acceptable salt thereof for the manufacture of a pharmaceutical composition.
  24. 　請求項１乃至１７から選択されるいずれか一項に記載された化合物又はその薬理上許容される塩の薬理的な有効量を温血動物に投与することを含む、2型糖尿病の治療又は予防方法。 The treatment or prevention of type 2 diabetes, comprising administering to a warm-blooded animal a pharmacologically effective amount of the compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 17. Method.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016204134A1 (en) * 2015-06-15 2016-12-22 第一三共株式会社 Six-membered-heterocycle derivative
WO2016204135A1 (en) * 2015-06-15 2016-12-22 第一三共株式会社 Five-membered-heterocycle derivative

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998047505A1 (en) * 1997-04-23 1998-10-29 Banyu Pharmaceutical Co., Ltd. Neuropeptide y receptor antagonist
WO1999015516A1 (en) * 1997-09-25 1999-04-01 Banyu Pharmaceutical Co., Ltd. Novel neuropeptide y receptor antagonists
WO2006065842A2 (en) * 2004-12-13 2006-06-22 Synta Pharmaceuticals Corp. 5,6,7,8-tetrahydroquinolines and related compounds and uses thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998047505A1 (en) * 1997-04-23 1998-10-29 Banyu Pharmaceutical Co., Ltd. Neuropeptide y receptor antagonist
WO1999015516A1 (en) * 1997-09-25 1999-04-01 Banyu Pharmaceutical Co., Ltd. Novel neuropeptide y receptor antagonists
WO2006065842A2 (en) * 2004-12-13 2006-06-22 Synta Pharmaceuticals Corp. 5,6,7,8-tetrahydroquinolines and related compounds and uses thereof

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 (en) * 2015-06-15 2016-12-22 第一三共株式会社 Six-membered-heterocycle derivative
WO2016204135A1 (en) * 2015-06-15 2016-12-22 第一三共株式会社 Five-membered-heterocycle derivative

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