WO2013154163A1 - Nouveau dérivé de 5-aryl-1,2-thiazinane - Google Patents

Nouveau dérivé de 5-aryl-1,2-thiazinane Download PDF

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WO2013154163A1
WO2013154163A1 PCT/JP2013/060953 JP2013060953W WO2013154163A1 WO 2013154163 A1 WO2013154163 A1 WO 2013154163A1 JP 2013060953 W JP2013060953 W JP 2013060953W WO 2013154163 A1 WO2013154163 A1 WO 2013154163A1
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group
formula
halogen atom
pharmaceutically acceptable
methoxy
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宗隆 大河内
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持田製薬株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/02—1,2-Thiazines; Hydrogenated 1,2-thiazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a compound that regulates the function of GPR40 (G Protein-coupled Receptor 40), in particular, 5-aryl-1,1-dioxo-1,2-thiazinan-3-one represented by the formula (I)
  • GPR40 G Protein-coupled Receptor 40
  • the present invention relates to an insulin secretagogue.
  • Type 1 diabetes is classified into type 1 diabetes (insulin-dependent diabetes) and type 2 diabetes (non-insulin-dependent diabetes), and borderline diabetes (impaired glucose tolerance), which can be regarded as a reserve army, has recently been regarded as important.
  • Type 1 diabetes is characterized by little or no production of insulin, a blood glucose regulating hormone.
  • Type 2 diabetes is characterized by peripheral insulin resistance and impaired insulin secretion.
  • Borderline type diabetes is a disease state that shows impaired glucose tolerance (IGT) and fasting blood glucose abnormality (IFG), and is a disease that is at risk of progression to type 2 diabetes and diabetic complications. Such diabetes develops due to multiple etiologies.
  • Chronic hyperglycemia control is important in clinical diabetes management and It is important for treatment.
  • type 2 diabetes and borderline diabetes a decrease in insulin secretion from pancreatic ⁇ cells causes rapid postprandial hyperglycemia.
  • suppression of such postprandial hyperglycemia in glucose intolerance is important not only for diabetes but also for suppression of the onset and progression of hypertension and cardiovascular disease ( JAMA, 290, 486-494 (2003) (non-patent document 1)).
  • Treatment of diabetes is mainly dietary / exercise therapy, but if these cannot be improved, pharmacotherapy is required.
  • drugs for the prevention and treatment of diabetes include insulin secretion promoters, sulfonylureas (such as glibenclamide and glimepiride) and rapid insulin secretion promoters that stimulate insulin secretion by stimulating pancreatic ⁇ cells (Nateglinide, mitiglinide, etc.).
  • these drugs are known to have side effects such as ineffective administration (primary ineffective / secondary ineffective) and hypoglycemia-inducing action.
  • ⁇ -glucosidase inhibitors limit the rapid increase in postprandial blood glucose level by inhibiting the degradation and digestion of carbohydrates, but it is essential to take it immediately before meals. It is known that there are cases that cause severe liver damage. Biguanides (metformin, buformin, etc.) are insulin resistance improving agents that increase insulin sensitivity and improve hyperglycemia, but are known to induce side effects such as lactic acidosis, nausea and vomiting.
  • Thiazolidinedione derivatives are peroxisome proliferator-activated receptors (PPAR) gamma agonists that increase insulin sensitivity in adipose tissue, liver and skeletal muscle, and improve chronic hyperglycemia It is known that it tends to cause edema, weight gain, and further liver damage, which is a serious side effect. Although the side effects of these drugs do not always occur, treatment satisfaction is still insufficient.
  • PPAR peroxisome proliferator-activated receptors
  • an insulin secretion enhancer that suppresses postprandial hyperglycemia without inducing hypoglycemia, which is a drug with few problems and side effects, and particularly an orally administrable drug, with the conventional preventive / therapeutic agents as described above. It has been demanded.
  • GPR40 is one of G protein-coupled receptors, belongs to the Free Fatty Acids Receptor (FFAR) family, and is activated by C6-C22 saturated fatty acids and unsaturated fatty acids. GPR40 is highly expressed in pancreatic ⁇ cells and has been reported to be involved in insulin secretion by fatty acids (Nature, 422, 173-176 (2003) (Non-patent Document 2)).
  • Patent Literature 1 WO 2004/041266 pamphlet
  • Patent Document 2 WO 2005/088661 pamphlet
  • Patent Document 3 WO 2007/123225 pamphlet
  • Patent Literature 4 WO 2009/054390 pamphlet
  • Patent Literature 6 WO 2009/054423 pamphlet
  • Patent Literature 7 WO 2005/063729 pamphlet
  • Patent Literature 8 WO 2008/130514 pamphlet
  • Patent Document 9 WO2005 / 035551 pamphlet
  • Non-patent Document 4 As a technique relating to a compound having a 5-aryl-1,1-dioxo-1,2-thiazinan-3-one ring, Synlett, 834-838 (2005) (Non-patent Document 4) can be mentioned.
  • the basic skeleton is different from the compound, and there is no disclosure or suggestion of the GPR40 agonistic action as in the present invention.
  • Recently, it has a 3-hydroxy-5-arylisoxazole group or a 3-hydroxy-5-arylisothiazole group in WO2011 / 052756 pamphlet (patent document 10) and WO2011 / 078371 pamphlet (patent document 11).
  • Compounds having GPR40 activating action have been reported.
  • GPR40 activators, insulin secretagogues, or diseases involving GPR40 that can be administered orally are highly safe, highly effective, and highly selective for other FFAR families and similar receptors And / or therapeutic agents (especially preventive and / or therapeutic agents for diabetes and obesity).
  • the pharmaceutical composition containing the compound of the present invention as an active ingredient can be administered orally, and is used for insulin secretion promoters, GPR40-related diseases, particularly diabetes (especially type 2 diabetes or borderline diabetes), obesity / obesity Expected as a preventive and / or therapeutic agent.
  • the compound group of the present invention has good solubility, high metabolic stability, excellent oral absorbability, little hERG channel inhibitory action, and little central migration. It is highly useful because it also has at least one feature.
  • the present invention relates to a compound having a 5-aryl-1,1-dioxo-1,2-thiazinan-3-one group represented by the formula (I) represented by the following embodiment or a salt thereof,
  • These solvates and pharmaceutical compositions characterized by containing them as active ingredients are GPR40 activators.
  • the first aspect of the present invention is: Formula (I) (In the formula, L represents 4- (3-hydroxy-3-methylbutoxy) -2,6-dimethylphenyl group and 4- (2-ethoxyethoxy) -2,6-dimethylphenyl group, and the following formula (A1 ), Formula (A2) and formula (A3) (Wherein p represents an integer of 0 to 4; q represents an integer of 0 to 2 (provided that p + q is an integer of 0 to 5); R 1 is, each independently, a halogen atom, -OH, a cyano group, a substituent RI with 1-5 optionally substituted C 1 to 6 alkyl groups, substituted one to five substituents RI which may C 2 - 6 alkenyl group, which may be 1-5 substituted with a substituent RI C 2 - 6 alkynyl group, a substituent RI with 1-5 optionally substitute
  • substituents RI are the same or different from each other, a halogen atom, -OH, cyano group, C 1 ⁇ 6 alkoxy group (said C 1 ⁇ 6 alkoxy group, a halogen atom, -OH, C 1 ⁇ 6 alkoxy group , an aryl group (said aryl group may be optionally 1-3 substituted with a halogen atom), a Hajime Tamaki (said heterocyclic group is optionally 1 in C 1 to 6 alkyl group or oxo group 3 may be substituted), group: —S (O) i R a (i represents an integer of 0 to 2), group: —SO 2 NR d R e , group: —CONR d R e or group: -NR b R c optionally may be 1-5 substituted with) a group: -NR b R c, and a heterocyclic oxy group (the heterocyclic oxy group, C 1 ⁇ 6 alkyl
  • R d, R e are each independently a hydrogen atom or a C 1 ⁇ 6 alkyl group (said C 1 ⁇ 6 alkyl group is optionally 1-5 substituted by a halogen atom, -OH or C 1 ⁇ 6 alkoxy group It may be)
  • R e1 is C 1 ⁇ 6 alkyl group (said C 1 ⁇ 6 alkyl group, -OH, C 1 - 6 alkoxyl group, an aryl group (said aryl group is optionally one to have three substituted by a halogen atom may be), a Hajime Tamaki (said heterocyclic group is optionally may be one to three substituents at C 1 ⁇ 6 alkyl group or oxo group), group: -S (O) i R a ( i represents an integer of 0 to 2), a
  • C 1 ⁇ 6 indicates that the number of constituent carbon atoms is 1 to 6, unless otherwise indicated, a straight-chain, the carbon atoms of branched or cyclic group Represents a number.
  • the number of constituent carbon atoms includes the total number of carbon atoms of a linear or branched group substituted with a cyclic group, or a group containing a cyclic group substituted with a linear or branched group.
  • the chain group means “straight chain or branched chain having 1 to 6 carbon atoms”.
  • the cyclic group means “a cyclic group having 1 to 6 carbon atoms in the ring”.
  • the group containing a chain group and a cyclic group means “a group having 1 to 6 total carbon atoms”.
  • alkyl group represents a linear, branched or cyclic alkyl group.
  • C 1 ⁇ 6 alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert- butyl, pentyl, isopentyl, neopentyl, tert- pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trifluoride, methyl
  • alkenyl group represents a linear, branched or cyclic alkenyl group.
  • C 2 ⁇ 6 alkenyl group are vinyl, allyl, isopropenyl, 2-methylallyl, butenyl, pentenyl, isopentenyl, hexenyl, 1-cyclopropene-1-yl, 2-cyclopropene-1-yl, 1-cyclobuten-1-yl, 1-cyclopenten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 1-cyclohexen-1-yl, 2-cyclohexen-1-yl, 3- Examples include cyclohexen-1-yl, 2,4-cyclopentadien-1-yl, 2,5-cyclohexadien-1-yl, and the like.
  • a cyclic alkenyl group is also referred to as a “cycloalkenyl group”.
  • C 5 ⁇ 7 cycloalkenyl group 1-cyclopenten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 1-cyclohexen-1-yl, 2-cyclohexen-1 Yl, 3-cyclohexen-1-yl, 1-cyclohepten-1-yl and the like.
  • the “alkynyl group” represents a linear, branched or cyclic alkynyl group. For example, as “C 2 ⁇ 6 alkynyl group”, ethynyl, 1-propynyl, 2-propynyl, butynyl, pentynyl, hexynyl and the like.
  • alkoxyl group straight chain, represents a branched or cyclic alkoxyl group
  • the comprehensive RO- (R is C 1 ⁇ 6 alkyl group listed in above in C 1 ⁇ 6 alkoxy group Represents a group represented by:
  • C 1 ⁇ 6 alkoxy group include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec- butoxy, tert- butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert- pentyloxy, 1- Methylbutoxy, 2-methylbutoxy, 1,2-dimethylpropoxy, 1-ethylpropoxy, hexyloxy, isohexyloxy, 1-methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 1,1-dimethyl Butyloxy, 1,2-dimethylbutyloxy, 2,2-dimethylbutyloxy, 1,3-dimethylbut
  • alkenyloxy group is a group in which the “alkenyl group” is substituted with an oxygen atom, and represents a straight, branched or cyclic alkenyloxy group.
  • the "C 2 ⁇ 6 alkenyloxy group” vinyloxy, allyloxy, isopropenyloxy, 2-methyl-allyloxy, butenyloxy, pentenyloxy, isopentenyl oxy, hexenyloxy, 1-cyclopropene-1-yloxy, 2- Cyclopropen-1-yloxy, 1-cyclobuten-1-yloxy, 1-cyclopenten-1-yloxy, 2-cyclopenten-1-yloxy, 3-cyclopenten-1-yloxy, 1-cyclohexen-1-yloxy, 2-cyclohexene Examples include 1-yloxy, 3-cyclohexen-1-yloxy, 2,4-cyclopentadien-1-yloxy, 2,5-cyclohexadien-1-yloxy, and
  • alkynyloxy group is a group in which the “alkynyl group” is substituted with an oxygen atom, and represents a linear, branched or cyclic alkynyloxy group.
  • alkynyloxy group ethynyloxy, 1-propynyloxy, 2-propynyloxy, butynyloxy, pentynyloxy, hexynyloxy, and the like.
  • aryl group a monocyclic or condensed cyclic C 6 ⁇ 14 aryl group, e.g., phenyl, 1-naphthyl, 2-naphthyl, anthryl, phenanthryl, acenaphthyl and the like, or (1-, 2-, 4 -Or 5-) Partially hydrogenated condensed aryl groups such as indanyl, indenyl, tetrahydronaphthyl and the like.
  • the partially hydrogenated fused aryl group means a monovalent group formed by removing any hydrogen atom from a partially hydrogenated condensed ring, and the hydrogen atom of the aromatic ring part of the condensed ring or Either hydrogen atom in the hydrogenated part may be removed.
  • the hydrogen atom of the aromatic ring part of the condensed ring or Either hydrogen atom in the hydrogenated part may be removed.
  • 1,2,3,4-tetrahydronaphthalene 1,2,3,4-tetrahydronaphthalene (-1-yl, -2-yl, -3-yl, -4-yl, -5-yl, -6-yl,- 7-yl, -8-yl) and the like.
  • heterocyclic group examples include a “heteroaryl group” and a saturated or unsaturated “non-aromatic heterocyclic group”. These rings are 3- to 14-membered, preferably 3- to 12-membered monocycles containing at least one heteroatom (preferably 1 to 4) arbitrarily selected from N, O and S in addition to carbon atoms Alternatively, it means a monovalent group formed by removing any hydrogen atom from a ring having a condensed ring.
  • the “heteroaryl group” may be monocyclic or condensed, and the monocyclic heteroaryl group preferably has 5 to 7 ring members, such as pyrrolyl, furyl, thienyl, imidazolyl.
  • the condensed heteroaryl group is preferably one having 8 to 14 ring members, which includes the 5- to 7-membered heterocycle and a monocyclic aryl group or monocyclic heteroaryl group.
  • a monovalent group formed by removing an arbitrary hydrogen atom from a condensed ring formed by condensation is included.
  • the arbitrary hydrogen atom may be removed from any condensed ring.
  • Indolinyl dihydrobenzofuranyl, dihydroisobenzofuranyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, chromanyl, isochromanyl, 3,4-dihydro-2H-1,4-benzoxazinyl, 3, 4-dihydro-2H-1,4-benzothiazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, tetrahydroquinoxalinyl, 1,3-benzodioxanyl, 1,4-benzodioxanyl, 1,3- Partially hydrogenated condensed heteroaryl groups such as benzodioxolyl, tetrahydrobenzoxazepinyl, tetrahydrobenzoazepinyl, 6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridyl, etc.
  • the partially hydrogenated condensed heteroaryl group and the like are preferably those having 8 to 14 ring members, which are a 5- to 7-membered heterocyclic ring, a monocyclic aryl group or a monocyclic heterocycle.
  • a condensed ring formed by condensation of an aryl group it means a monovalent group formed by removing any hydrogen atom from a partially hydrogenated ring.
  • the arbitrary hydrogen atom may be an aryl group, a hydrogen atom in the heterocyclic portion, or a hydrogen atom in the hydrogenated portion.
  • tetrahydroquinolyl includes 5,6,7,8-tetrahydroquinolyl or 1,2,3,4-tetrahydroquinolyl.
  • These groups may be substituted depending on the position excluding any hydrogen atom, for example, 2-yl, 3-yl, -4-yl, -5-yl in the case of 5,6,7,8-tetrahydroquinolyl.
  • Examples include -yl, -4-yl, -5-yl, -6-yl, -7-yl, -8-yl and the like.
  • non-aromatic heterocyclic group includes a 3- to 8-membered saturated or unsaturated non-aromatic heterocyclic group such as aziridinyl, azetidinyl, oxiranyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, Pyrazolinyl, pyrazolidinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl (oxanyl), tetrahydrothiopyranyl, piperazinyl, dioxanyl, oxazolinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, isothiazolinyl, oxa And diazolinyl, oxadiazolidiny
  • “Hajime Tamaki (said heterocyclic group may be optionally be 1-3, optionally substituted with C 1 ⁇ 6 alkyl group or oxo group)" is a, the groups listed in the "heterocyclic group” in addition, groups 1-3 the to the cyclic group "C 1 ⁇ 6 alkyl group” or oxo group is substituted at an arbitrary position thereof.
  • Alkyl group is a group which is substituted with an alkyl group of straight or branched chains of the "aryl group", "C 1 ⁇ 6 alkyl group", for example, benzyl, phenethyl, 3-phenylpropyl, 1 -Naphtylmethyl, 2-naphthylmethyl, 2- (1-naphthyl) ethyl, 2- (2-naphthyl) ethyl, 1-indanylmethyl, 2-indanylmethyl, 1,2,3,4-tetrahydronaphthalene- Examples include 1-ylmethyl, 1,2,3,4-tetrahydronaphthalen-2-ylmethyl and the like.
  • heterocyclic oxy group is a group in which the “heterocyclic group” is substituted with an oxygen atom, and includes “heteroaryloxy group” or “non-aromatic heterocyclic oxy group”. Specific examples include groups in which the above-mentioned “heterocyclic group” is substituted with an oxygen atom.
  • the “heteroaryloxy group” is a group in which the “heteroaryl group” is substituted with an oxygen atom, and specifically includes a group in which the group listed in the “heteroaryl group” is substituted with an oxygen atom.
  • non-aromatic heterocyclic oxy group is a group in which the “non-aromatic heterocyclic group” is substituted with an oxygen atom.
  • the groups listed in the “non-aromatic heterocyclic group” are oxygen atoms. And a substituted group.
  • a 3- to 8-membered saturated or unsaturated non-aromatic heterocyclic oxy group includes, for example, aziridinyloxy, azetidinyloxy, oxiranyloxy, oxetanyloxy, thietanyloxy, pyrrolidinyloxy, Tetrahydrofuryloxy, thiolanyloxy, pyrazolinyloxy, pyrazolidinyloxy, (1-, 2-, 3- or 4-) piperidinyloxy, dihydropyranyloxy, (2-, 3- or 4-) Tetrahydropyranyloxy ((2-, 3- or 4-) oxanyloxy), tetrahydrothiopyranyloxy, piperazinyloxy, dioxanyloxy, oxazolinyloxy, isoxazolinyloxy, oxazolidinini Ruoxy, isoxazolidinyloxy, thiazolinyloxy, isothiazoliny
  • heterocyclic oxy group examples include the above-mentioned “heterocyclic oxy group”. was added to the group, groups in which one to three of the to the cyclic group "C 1 ⁇ 6 alkyl group” or oxo group is substituted at an arbitrary position thereof.
  • the "Hajime Tamaki (said heterocyclic group may be optionally 1-3 substituted with C 1 ⁇ 6 alkyl group or oxo group)" can be also be expressed as substituted groups oxygen atom the specifically "heterocycle (the heterocyclic group, optionally 1 may be substituted to 3 to at C 1 ⁇ 6 alkyl group or oxo group)," the groups listed has been substituted with an oxygen atom Groups.
  • the “aralkyloxy group” is a group in which the “aralkyl group” is substituted with an oxygen atom, and specifically includes a group in which the group listed in the “aralkyl group” is substituted with an oxygen atom.
  • Examples include nylmethoxy, 1,2,3,4-tetrahydronaphthalen-1-ylmethoxy, 1,2,3,4-tetrahydronaphthalen-2-ylmethoxy and the like.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • the "halogenated C 1 ⁇ 6 alkyl group” denotes a group wherein the above “C 1 ⁇ 6 alkyl group” is optionally substituted with one to five halogen atoms.
  • trifluoromethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl and the like can be mentioned.
  • the "halogenated C 1 ⁇ 6 alkoxy group” denotes a group wherein the above "C 1 ⁇ 6 alkoxy group” is optionally substituted with one to five halogen atoms. Examples thereof include trifluoromethoxy, trifluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy and the like.
  • Examples of the protecting group for the “optionally protected carboxyl group” include alkyl ester protecting groups such as methyl, ethyl, tert-butyl, benzyl, diphenylmethyl and trityl, and silyl ester based groups such as trimethylsilyl and tert-butyldimethylsilyl. And protecting groups.
  • C 2 ⁇ 7 alkanoyl group refers to, R-CO- (R is the "C 1 ⁇ 6 alkyl group”
  • R is the "C 1 ⁇ 6 alkyl group”
  • Examples include carbonyl and the like.
  • heterocyclic carbonyl group means a “heterocyclic carbonyl group”, and a carbonyl group is added to the “heterocyclic group” (for example, a heteroaryl group, a saturated or unsaturated non-aromatic heterocyclic group, etc.).
  • Bound groups such as pyrrolylcarbonyl, furylcarbonyl, thienylcarbonyl, imidazolylcarbonyl, pyrazolylcarbonyl, oxazolylcarbonyl, isoxazolylcarbonyl, thiazolylcarbonyl, isothiazolylcarbonyl, 1,2,3-tria Zolylcarbonyl, 1,2,4-triazolylcarbonyl, 1,2,3-oxadiazolylcarbonyl, 1,2,4-oxadiazolylcarbonyl, 1,3,4-oxadiazolylcarbonyl, fraza Nylcarbonyl, 1,2,3-thiadiazolylcarbonyl, 1,2,4-thi Diazolylcarbonyl, 1,3,4-thiadiazolylcarbonyl, tetrazolylcarbonyl, pyridylcarbonyl, pyridazinylcarbonyl, pyrimidinylcarbonyl, pyrazinylcarbonyl, 1,
  • non-aromatic heterocyclic carbonyl group is a group in which the “heterocyclic group” of the “heterocyclic carbonyl group” is a “non-aromatic heterocyclic group”, that is, the “non-aromatic heterocyclic group” And a carbonyl group.
  • Specific examples include a carbonyl group to which the “saturated or unsaturated non-aromatic heterocyclic group” mentioned in the above “heterocyclic carbonyl group” is bonded.
  • C 1 ⁇ 6 alkylthio group means a straight chain, branched chain or cyclic alkylthio group having 1 to 6 carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec- Butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, tert-pentylthio, 1-methylbutylthio, 2-methylbutylthio, 1,2-dimethylpropylthio, 1-ethylpropylthio, hexylthio, isohexyl Thio, 1-methylpentylthio, 2-methylpentylthio, 3-methylpentylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 2,2-dimethylbutylthio,
  • halogenated C 1 ⁇ 6 alkylthio group represents a group wherein the above “C 1 ⁇ 6 alkylthio group” are optionally substituted with 1-5 halogen atoms, for example, trifluoromethylthio and the like .
  • C 1 ⁇ 6 alkylsulfinyl group straight chain C 1 -C 6 refers to branched or cyclic alkylsulfinyl group, for example methylsulfinyl, ethylsulfinyl, propyl sulfinyl, isopropyl-sulfinyl, cyclopropyl And sulfinyl, cyclopropylmethylsulfinyl, 2-methylcyclopropylsulfinyl and the like.
  • halogenated C 1 ⁇ 6 alkylsulfinyl group is a group wherein the above “C 1 ⁇ 6 alkylsulfinyl group” is optionally substituted with one to five halogen atoms, such as trifluoromethyl sulfinyl etc. Is mentioned.
  • C 1 ⁇ 6 alkylsulfonyl group straight chain C 1 -C 6 refers to branched or cyclic alkylsulfonyl groups such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, cyclopropyl Examples include sulfonyl, cyclopropylmethylsulfonyl, 2-methylcyclopropylsulfonyl and the like.
  • halogenated C 1 ⁇ 6 alkylsulfonyl group is a group wherein the above “C 1 ⁇ 6 alkylsulfonyl group” is optionally substituted with one to five halogen atoms, for example, trifluoromethylsulfonyl and the like Is mentioned.
  • group -SO 2 NR d R e ', R d and R e are each independently a hydrogen atom or a C 1 ⁇ 6 alkyl group (said C 1 ⁇ 6 alkyl group, a halogen atom, -OH or C 1-6 alkoxyl optionally may be one to five substituents in group), one or two hydrogen atoms on the nitrogen atom of the sulfamoyl group is substituted with the "C 1-6 alkyl group” in addition to the sulfamoyl group optionally, C 1 ⁇ 6 alkyl group (said C 1 ⁇ 6 alkyl group, a halogen atom, is 1-5, optionally substituted with -OH or C 1 ⁇ 6 alkoxy group) in Means a substituted sulfamoyl group; Specifically, for example, sulfamoyl group, methylsulfamoyl group, ethylsulfamoyl group, prop
  • R d and R e are each independently a hydrogen atom or a C 1 ⁇ 6 alkyl group (said C 1 ⁇ 6 alkyl group, a halogen atom, -OH or C 1 ⁇ 6 represents an alkoxy group optionally may be 1-5 substituents in), even if one or two hydrogen atoms on the nitrogen atom of the carbamoyl group is substituted with the "C 1 ⁇ 6 alkyl group” in addition to a carbamoyl group, C 1 ⁇ 6 alkyl group (said C 1 ⁇ 6 alkyl group, a halogen atom, is 1-5, optionally substituted with -OH or C 1 ⁇ 6 alkoxy group) is substituted with Carbamoyl group.
  • carbamoyl group methylcarbamoyl group, ethylcarbamoyl group, propylcarbamoyl group, isopropylcarbamoyl group, cyclopropylcarbamoyl group, butylcarbamoyl group, isobutylcarbamoyl group, pentylcarbamoyl group, isopentylcarbamoyl group, hexylcarbamoyl group , Isohexylcarbamoyl group, dimethylcarbamoyl group, diethylcarbamoyl group, dipropylcarbamoyl group, diisopropylcarbamoyl group, dibutylcarbamoyl group, dipentylcarbamoyl group, ethylmethylcarbamoyl group, methylpropylcarbamoyl group, ethy
  • R d is a hydrogen atom or a C 1 ⁇ 6 alkyl group (said C 1 ⁇ 6 alkyl group, a halogen atom, optionally with -OH or C 1 ⁇ 6 alkoxyl group 1 represents ⁇ optionally substituted five), R e1 is, C 1 ⁇ 6 alkyl group (said C 1 ⁇ 6 alkyl group, -OH, C 1 - 6 alkoxyl group, an aryl group (said aryl group is optionally may be 1-3 substituted with a halogen atom), a Hajime Tamaki (said heterocyclic group is optionally may be one to three substituents at C 1 ⁇ 6 alkyl group or oxo group ), Group: —S (O) i R a (i represents an integer of 0 to 2), group: —SO 2 NR d R e , group: —CONR d R e or group:
  • hydroxymethylcarbamoyl group 2-hydroxyethylcarbamoyl group, 3-hydroxypropylcarbamoyl group, 3-hydroxybutylcarbamoyl group, 3-hydroxy-3-methylbutylcarbamoyl group, 2,3-dihydroxypropylcarbamoyl group Group, 3-hydroxy-2-hydroxymethylpropylcarbamoyl group, 3-hydroxy-2-hydroxymethyl-2methylpropylcarbamoyl group, 2-methoxyethylcarbamoyl group, 2-ethoxyethylcarbamoyl group, 2-methoxy-3-hydroxy Propylcarbamoyl group, 3-methylsulfonyl-propylcarbamoyl group, 2- (morpholin-4-yl) ethylcarbamoyl group, 2- (4-methylpiperazin-1-yl) ethylcarbamoyl group, 2- (2 Oxopyrrolidin-1-y
  • Group: -NR b R c in, R b, and R c, each independently, a hydrogen atom, C 1 ⁇ 6 alkyl group, optionally from C 2 ⁇ 7 alkanoyl groups and C 1 ⁇ 6 alkylsulfonyl group R b and R c together with the nitrogen atom to which they are bonded may form a 3- to 8-membered cyclic group, in which one carbon atom in the ring is an oxygen atom , a sulfur atom and a nitrogen atom (said nitrogen atom, is may be substituted by C 1 ⁇ 6 alkyl group) may, be replaced by chosen atom or a carbonyl group optionally from.
  • group: -NR b R c as, amino, “mono / di C 1 ⁇ 6 alkylamino", “C 2 ⁇ 7 alkanoylamino” or “C 1 ⁇ 6 alkylsulfonylamino” and the like.
  • mono / di C 1 ⁇ 6 alkylamino refers to one or two hydrogen atoms are linear, branched, or cyclic amino group substituted by a "C 1 ⁇ 6 alkyl group” of the amino group To do.
  • halogenated mono / di C 1 ⁇ 6 alkylamino represents a group wherein "mono / di C 1 ⁇ 6 alkylamino" are optionally substituted with 1-5 halogen atoms.
  • mono / di C 1 ⁇ 6 alkylamino are optionally substituted with 1-5 halogen atoms.
  • trifluoromethylamino and the like can be mentioned.
  • the "C 2 ⁇ 7 alkanoylamino” the hydrogen atoms of the amino group means a straight chain, branched chain or cyclic amino group substituted by "C 2 ⁇ 7 alkanoyl group”.
  • the "C 1 ⁇ 6 alkylsulfonylamino" the hydrogen atoms of the amino group means a straight-chain, substituted branched chain or cyclic alkylsulfonyl group an amino group having 1 to 6 carbon atoms. Specific examples include methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, cyclopropylsulfonylamino, cyclopropylmethylsulfonylamino, 2-methylcyclopropylsulfonylamino and the like.
  • “Aromatic heterocyclic group” a hydrogen atom bonded to the nitrogen atom is removed from a ring containing a nitrogen atom in addition to the carbon atom 1 A valent cyclic group is meant.
  • the cyclic group as “when one carbon atom in the ring of the cyclic group is substituted with an oxygen atom, a sulfur atom, or a carbonyl group” means, among the cyclic groups, for example, Examples include oxazolinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, morpholinyl, thiomorpholinyl, 2-oxopyrrolidinyl and the like.
  • R b the cyclic group as "if the nitrogen atom is substituted with C 1 ⁇ 6 alkyl group" in R c is, for example, 4-methylpiperazin-1-yl, 4-ethyl-piperazin-1-yl, 4-propylpiperazin-1-yl and the like can be mentioned.
  • R a , R d , R e , R b and R c are the above-mentioned “group: —S (O) i R a ”, “group: —SO 2 NR d R e ”, “group: —CONR”.
  • d R e ”and“ group: —NR b R c ” have the same definitions as R a , R d , R e , R b and R c , respectively.
  • alkyl group having 1 to 5 halogen atoms optionally substituted with are based in, that represents the "halogenated C 1 ⁇ 6 alkyl group”.
  • the alkyl group having 1 to 5 halogen atoms optionally substituted with are based in, that represents the "halogenated C 1 ⁇ 6 alkyl group”.
  • halogenated C 1 ⁇ 6 alkyl group in addition to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, for example, trifluoromethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl and the like can be mentioned.
  • “1-5 optionally substituted C 1 ⁇ 6 alkyl group in C 1 ⁇ 6 alkoxy group” includes, in addition to the "C 1 ⁇ 6 alkyl group", the alkyl group is 1 to 5 It represents a number of said groups being optionally substituted by "C 1 ⁇ 6 alkoxy group", specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, in addition to the tert- butyl, e.g. , Methoxymethyl, methoxyethyl, methoxypropyl, ethoxyethyl and the like.
  • the alkyl group is a halogen atom, -OH, cyano group, C 1 ⁇ 6 alkoxy group (said C 1 ⁇ 6 alkoxy group, a halogen atom, -OH, C 1 ⁇ 6 alkoxy group, an aryl group (said aryl group is optionally may be 1-3 substituted with a halogen atom), a Hajime Tamaki (said heterocyclic group may be 1-3, optionally substituted with C 1 ⁇ 6 alkyl group or oxo group Group): —S (O) i R a (i represents an integer of 0 to 2), group: —NR b R c , group: —SO 2 NR d R e or group: —CONR d R e in may be 1-5 optionally substituted), group: -NR b R c, and a heterocyclic oxy group (the heterocyclic oxy group, C 1 ⁇ 1 ⁇ 3 optionally in 6 alkyl or
  • C 2 ⁇ 6 alkenyl group with a substituent RI in addition to the "C 2 ⁇ 6 alkenyl group", halogen atom, -OH, a cyano group, C 1 ⁇ 6 alkoxy group (said C 1 ⁇ 6 alkoxy group, a halogen atom, -OH, C 1 ⁇ 6 alkoxy group, an aryl group (said aryl group is optionally be optionally 1-3 substituted by a halogen atom may also), a Hajime Tamaki (said heterocyclic group may be optionally 1-3 substituted with C 1 ⁇ 6 alkyl group or oxo group), group: -S (O) i R a (i Represents an integer of 0 to 2), a group: —NR b R c , a group: —SO 2 NR d R e or a group: —CONR d R e may be optionally substituted with 1 to
  • allyl isopropenyl, 2-methylallyl, butenyl, pentenyl, hexenyl
  • trifluorovinyl 2-hydroxyvinyl, 2-methoxyvinyl, 2-trifluoromethoxyvinyl and the like can be mentioned.
  • ethynyl 1-propynyl, 2-propynyl, butynyl, pentynyl, hexynyl
  • fluoroethynyl 2-hydroxyethynyl, 2-methoxyethynyl, 2-trifluoromethoxyethynyl and the like
  • fluoroethynyl 2-hydroxyethynyl
  • 2-methoxyethynyl 2-trifluoromethoxyethynyl and the like
  • the 5-aryl-1,1-dioxo-1,2-thiazinan-3-one group may have proton tautomerism as shown in the following formula.
  • the abundance ratio of this structure can vary depending on whether the compound represented by formula (I) is in a solid state or dissolved in a liquid. Tautomers generated by this structure are included in the formula (I).
  • each R 3 is preferably independently a halogen atom, or C 1- 4 alkyl group or the like is good C 1 ⁇ 4 alkoxyl group which may be 1-5 substituted with a halogen atom,.
  • R 3 is preferably a group other than tert-butyl.
  • R 5a, R 5b is preferably independently a hydrogen atom, halogen atom or C 1 ⁇ 4 alkyl group, More specifically, a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, methyl and the like can be mentioned.
  • R 5a and R 5b is more preferably a hydrogen atom, and still more preferably, both R 5a and R 5b are hydrogen atoms.
  • R 6 is preferably a hydrogen atom, a halogen atom, C 1 ⁇ 4 alkyl groups, halogenated C 1 ⁇ 4 alkyl groups, C 2-5 alkanoyl group or a carboxyl group, more preferably a hydrogen atom or a C 1 ⁇ 4 alkyl group. More specifically, R 6 represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, acetyl, carboxyl, etc. It is. More preferably, R 6 is a hydrogen atom.
  • R 7a, R 7b are preferably each independently represent a hydrogen atom, a halogen atom, C 1 ⁇ 4 alkyl group, a halogenated C Examples thereof include 1 to 4 alkyl groups and cyano groups.
  • R 7a and R 7b are a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, cyano, etc. It is.
  • R 7a and R 7b is more preferably a hydrogen atom, and still more preferably, both R 7a and R 7b are hydrogen atoms.
  • R 5a , R 5b , R 6 , R 7a and R 7b are all hydrogen atoms. That is, a compound having a 1,1-dioxo-1,2-thiazinan-3-one group is preferable.
  • R 2 is, C 1 ⁇ 6 alkoxy group (said alkoxy group, -OH, methoxy, ethoxy, 4-hydroxy-1,1-dioxidotetrahydro--2H- Thiopyran-4-yl, 3-methyloxetane-3-yl, methylsulfonyl, ethylsulfonyl, —NH 2 , acetylamino, methylsulfonylamino, 2-oxo-1-pyrrolidinyl, 5-oxo-2-pyrrolidinyl, sulfamoyl, 1 to 5 groups optionally substituted from methylsulfamoyl, dimethylsulfamoyl, carbamoyl, methylcarbamoyl and dimethylcarbamoyl), a group: —CONR d4 R e4 (R d4 represents a hydrogen atom or C represents 1-4 alkyl group,
  • R 2 represents 2-hydroxyethoxy, 3-hydroxypropoxy, 3-hydroxybutoxy, 3-hydroxy-3-methylbutoxy, 2,3-dihydroxypropoxy, (2R) -2,3-dihydroxy Propoxy, (2S) -2,3-dihydroxypropoxy, (3S) -3-hydroxybutoxy, (3R) -3-hydroxybutoxy, 3-hydroxy-2-hydroxymethylpropoxy, 3-hydroxy-2-hydroxymethyl- 2-methylpropoxy, 2-ethoxyethoxy, (4-hydroxy-1,1-dioxidetetrahydro-2H-thiopyran-4-yl) methoxy, (3-methyloxetane-3-yl) methoxy, 2-methylsulfonyl- Ethoxy, 3-methylsulfonyl-propoxy, 2-ethylsulfonyl -Ethoxy, 3-ethylsulfonyl-propoxy, 2-aminoethoxy, 3-aminopropoxy, 2-acetylamino-ethoxy, 3-acetylamino
  • the bonding position of R 2 in the formula (A2) is preferably the 3rd or 4th position when the bonding position with the oxygen atom in the ring A ′ is the 1st position.
  • ring A, C 5 ⁇ 7 cycloalkyl group, condensed ring aryl group, condensed ring heteroaryl group or partially hydrogenated represents a condensed fused heteroaryl group.
  • ring A2 is benzene, pyrrole or 2,3-dihydrofuran. More preferably, in formula (A1) or (A1a), ring A is 1-cyclohexen-1-yl, naphthalen-1-yl, 1H-indol-4-yl or 2,3-dihydrobenzofuran-7-yl. It is.
  • ring A ′ represents a benzene ring, a pyridine ring or a pyrimidine ring, and ring A ′ is benzene or pyridine.
  • Preferred is benzene, pyridin-3-yl or pyridin-4-yl.
  • the ring A ′ is more preferably benzene or pyridin-4-yl.
  • ring A ′ is more preferably benzene or pyridin-3-yl.
  • p is preferably an integer of 0 to 3.
  • P + q is preferably an integer of 0 to 4, more preferably an integer of 0 to 3.
  • p is more preferably 0 or 1.
  • p1a is preferably 0 or 1, more preferably 0.
  • p1b is 0 or 1
  • p1c is 0 or 1
  • p1b + p1c is preferably 0 or 1
  • p1b is more preferably 0 or 1.
  • p is more preferably an integer of 1 to 3.
  • R 1 is preferably independently a halogen atom, a cyano group, C 1 ⁇ 4 alkyl group (said C 1 ⁇ 4 alkyl groups, one to five with a group selected arbitrarily from a halogen atom and -OH optionally substituted), C 2 ⁇ 4 alkenyl group, C 1 ⁇ 4 alkoxyl group (said C 1 ⁇ 4 alkoxyl group may be one to five substituted with a halogen atom), C 2 ⁇ 5 alkanoyl group, groups: -S (O) i R a (R a represents C 1 ⁇ 4 alkyl group), group: -CONR d R e (R d , R e are each independently a hydrogen atom or a C 1-4 represents an al
  • R 1 each independently, a halogen atom, a cyano group, C 1 ⁇ 4 alkyl group (said C 1 ⁇ 4 alkyl group, optionally halogen atom and -OH selected may be one to have five substituted with groups) to, C 2 - 3 alkenyl or C 1 to 4 alkoxy group (said C 1 ⁇ 4 alkoxyl groups, is 1-5 substituted by a halogen atom and may be), C 2 ⁇ 3 alkanoyl group, groups: -S (O) i R a (R a represents C 1 ⁇ 2 alkyl group), group: -CONR d R e (R d , R e are each independently a hydrogen atom or represents a C 1 ⁇ 2 alkyl group) or a group: -NR b R c (R b , R c forms a 3-6 membere
  • R 1 is, each independently, a halogen atom, a cyano group, 1-5 optionally substituted C 1 to 4 alkyl groups with a halogen atom or a halogen atom, in a 1-5 optionally substituted C 1 ⁇ 4 alkoxyl group.
  • R 1 is particularly preferably methyl.
  • R 1 is particularly preferably cyano or methoxy.
  • R 1 is particularly preferably each independently a fluorine atom, a chlorine atom, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, or trifluoromethoxy.
  • at least one R 1 is preferably a group other than methyl.
  • ring A is cyclohexene, naphthalene, indole or dihydrobenzofuran
  • p is 0 or 1
  • R 1 is a halogen atom , cyano group, C 1 ⁇ 4 alkyl group which may be 1-5 substituted with a halogen atom or one optionally be 1-5 substituted by a halogen atom is also good C 1 ⁇ 4 alkoxyl groups, is, L It is mentioned as a preferable aspect of.
  • ring A is cyclohexene, naphthalene, indol or dihydrobenzofuran, p is 0 or 1, R 1 is C 1 ⁇ 4 alkyl group. More specific examples of the formula (A1a) include 1-cyclohexen-1-yl, naphthalen-1-yl, 1-methyl-1H-indol-4-yl and 2,3-dihydrobenzofuran-7-yl. It is done.
  • ring A ′ is a benzene ring or a pyridine ring
  • p is 0 or 1
  • R 1 is a halogen atom, a cyano group or a halogen atom.
  • 1-5 optionally substituted C 1 to 4 alkyl groups or those optionally be 1-5 substituted by a halogen atom is also good C 1 ⁇ 4 alkoxyl group, it may be mentioned as a preferred embodiment of L. More preferably, Ring A 'is a benzene ring or a pyridine ring, p is 0 or 1, R 1 is a cyano group or a C 1 ⁇ 4 alkoxyl group.
  • Ring A ' is a benzene ring or pyridine-4-yl
  • p is 0 or 1
  • R 1 is a cyano group or a C 1 ⁇ 4 alkoxyl group.
  • Specific examples of the formula (A2a) include phenoxy, (2-, 3- or 4-) fluorophenoxy, (2-, 3- or 4-) chlorophenoxy, (2-, 3- or 4-) cyanophenoxy.
  • the ring A ′ is a benzene ring or a pyridine ring
  • p is an integer of 1 to 3
  • each R 1 is independently a halogen atom.
  • cyano group, C 1 ⁇ 4 alkyl group which may be 1-5 substituted with a halogen atom or one optionally be 1-5 substituted by a halogen atom is also good C 1 ⁇ 4 alkoxyl groups, is, L It is mentioned as a preferable aspect of.
  • ring A ′ is a benzene ring or a pyridine ring
  • p is an integer of 1 to 3
  • each R 1 is independently substituted with 1 to 5 halogen atoms or halogen atoms.
  • C 1 - 4 alkyl group or 1-5 optionally substituted C 1 to 4 alkoxy groups with a halogen atom,.
  • ring A ′ is a benzene ring or a pyridine ring
  • p is an integer of 1 to 3
  • each R 1 is independently substituted with 1 to 5 halogen atoms or halogen atoms.
  • R 1 is at least one of which is a group other than methyl. More specifically, as formula (A3), (2-, 3- or 4-) fluorophenyl, (2-, 3- or 4-) chlorophenyl, (2,6-, 2,5-, 2,4 -, 2,3-, 3,4- or 3,5-) difluorophenyl, (2,6-, 2,5-, 2,4-, 2,3-, 3,4- or 3,5- ) Dichlorophenyl, 4-chloro-2-fluorophenyl, (2-, 3- or 4-) methoxyphenyl, (2-, 3- or 4-) ethoxyphenyl, (2-, 3- or 4-) propoxyphenyl , (2-, 3- or 4-) isopropoxyphenyl, (2-, 3- or 4-) trifluoromethoxyphenyl, (2-, 3- or 4-) ethylphen
  • formula (A1), the formula (A1a), the formula (A1a) according to any one of the above embodiments [1-9], [1-9-a], [1-9-c], or any of their subembodiments -1
  • a preferred embodiment of the partial structure of the formula (I) -1 corresponding to the formula (A1a) -2 is the above-described embodiments [1-9], [1-9-a], [1-9-c] Or it is the same as the description in any one of those submodes.
  • a preferable compound is that q is 0, and R 5a , R 5b , R 6 , R 7a and R 7b Are both hydrogen atoms.
  • preferred compounds are those of the following formula (I) -1a (Wherein p, r, s and ring A are defined as in formula (I) in the above embodiment [1]; each of R 1-1 independently represents a halogen atom, a cyano group, or a halogen atom.
  • formula (A1a), the formula (A1a) -1, or any one of the sub-embodiments [1-9-a], [1-9-c], [1-9-g], Preferred embodiments of the partial structure of the formula (I) -1a corresponding to the formula (A1a) -2 are the above-mentioned embodiments [1-9-a], [1-9-c], [1-9-g] or It is the same as the description of any of those sub-embodiments.
  • p is preferably 0 or 1.
  • r is preferably 0 or 1, more preferably 0.
  • s is preferably 0 or 1, more preferably 0.
  • ring A is preferably cyclohexene, naphthalene, indole or dihydrobenzofuran, more preferably ring A is 1-cyclohexen-1-yl, naphthalen-1-yl, 1H-indole- 4-yl or 2,3-dihydrobenzofuran-7-yl.
  • R 1-1 include the specific groups of R 1 described in the above embodiment [1-9-f-2].
  • R 1-1 is preferably 1 to 5 amino optionally substituted C 1 to 4 alkyl groups with a halogen atom, more preferably a C 1 - 4 alkyl group, and specific examples thereof include methyl .
  • R 3-1 include the specific group of R 3 described in the above embodiment [1-2].
  • R 4-1 include the above-described embodiment [1- And specific groups for R 4 described in 4-a].
  • formula (I) -1a preferably, p is 0 or 1, r and s are 0, and ring A is cyclohexene, naphthalene, indole or dihydrobenzofuran.
  • the group corresponding to the formula (A1a) in the formula (I) -1a, that is, the ring A substituted with (R 1-1 ) p is preferably the one described in the above embodiment [1-9-g-1].
  • Specific examples include 1-cyclohexen-1-yl, naphthalen-1-yl, 1-methyl-1H-indol-4-yl and 2,3-dihydrobenzofuran-7-yl.
  • a preferable compound is q and R 5a , R 5b , R 6 , R 7a and R 7b are preferred. Are both hydrogen atoms.
  • preferred compounds are those of the following formula (I) -2a (Wherein p, r, s and ring A ′ are as defined in the formula (I) described in the above embodiment [1]; each of R 1-2 independently represents a halogen atom, a cyano group, a halogen atom, There 1-5 an optionally substituted C 1 - 4 alkyl group or 1 to 5 amino optionally substituted C 1 to 4 alkoxy groups with a halogen atom, in atom; R 3-2 are each independently to, a halogen atom, 1-5 optionally substituted C 1 - 4 alkyl group optionally or 1-5 substituted C 1 optionally
  • preferred embodiments of p, r, s, and ring A ′ are the same as those of the above embodiments [1-1], [1-3], [1-9-d], and [1-9-e]. This is the same as the preferred embodiment described in any one. Also, preferred embodiments of the partial structure of the formula (I) -2a corresponding to the formula (A2a) described in the above embodiments [1-9-a], [1-9-g] or any of their sub-embodiments Is the same as described in any one of the above-mentioned embodiments [1-9-a], [1-9-g] or sub-embodiments thereof.
  • p is preferably 0 or 1.
  • r is preferably 0 or 1, more preferably 0.
  • s is preferably 0 or 1, more preferably 0.
  • ring A ′ is preferably benzene or pyridine, more preferably ring A ′ is benzene or pyridin-4-yl.
  • R 1-2 include the specific groups of R 1 described in the above embodiment [1-9-f-2].
  • R 1-2 is preferably 1-5 substituents which may C 1 to 4 alkoxy groups with a cyano group or a halogen atom, more preferably a cyano group, or a C 1 - 4 alkoxy group, specifically Includes cyano or methoxy.
  • R 3-2 include the specific groups for R 3 described in the above embodiment [1-2], and specific groups for R 4-2 include those described in the above embodiment [1- And specific groups for R 4 described in 4-a].
  • formula (I) -2a preferably, p is 0 or 1, r and s are 0, and ring A ′ is a benzene ring or a pyridine ring.
  • the group corresponding to the formula (A2a) in the formula (I) -2a, that is, the ring A ′ substituted with (R 1-2 ) p is preferably the one described in the above embodiment [1-9-g-2] Specific examples include phenyl, (2-, 3- or 4-) cyanophenyl, (2- or 3-) methoxypyridin-4-yl, and the like.
  • preferred embodiments of p, r, s, ring A ′, R 1 , R 3 , R 4 , R 5a , R 5b , R 6 , R 7a and R 7b are the above-described embodiments [1-1 ] To [1-9] or the preferred embodiments described in any of the sub-embodiments thereof.
  • a preferred embodiment of the partial structure of the formula (I) -3 corresponding to the formula (A3) according to the above embodiment [1-9] or any of its subembodiments is the above embodiment [1-9] or It is the same as the description of any of those sub-embodiments.
  • a preferable compound is that R 5a , R 5b , R 6 , R 7a and R 7b are all hydrogen atoms.
  • preferred compounds are those of the following formula (I) -3a (Wherein p, r, s and ring A ′ are as defined in the formula (I) described in the above embodiment [1]; each of R 1-3 independently represents a halogen atom, a cyano group, a halogen atom, There 1-5 an optionally substituted C 1 - 4 alkyl group or 1 to 5 amino optionally substituted C 1 to 4 alkoxy groups with a halogen atom, in atom; R 3-3 are each independently to, a halogen atom, 1-5 optionally substituted C 1 - 4 alkyl group optionally or 1-5 substituted C 1 optionally 1-4
  • a preferred embodiment of the partial structure of the formula (I) -3a corresponding to the formula (A3) described in the above embodiments [1-9], [1-9-g] or any of the sub-embodiments thereof This is the same as the description in any one of the above embodiments [1-9], [1-9-g] or their sub embodiments.
  • p is preferably an integer of 1 to 3.
  • r is preferably 0 or 1, more preferably 0.
  • s is preferably 0 or 1, more preferably 0.
  • ring A ′ is preferably benzene or pyridine, more preferably ring A ′ is benzene or pyridin-3-yl.
  • R 1-3 include the specific groups of R 1 described in the above embodiment [1-9-f-2].
  • R 1-3 is preferably, independently, halogen atom, be 1-5 substituents with one to five substituents are C 1 optionally 1-4 alkyl group or a halogen atom with a halogen atom C 1 to 4 alkoxyl groups, and specific examples thereof include fluorine atom, chlorine atom, methyl, ethyl, trifluoromethyl, methoxy, ethoxy and trifluoromethoxy.
  • At least one R 1-3 is preferably a group other than methyl.
  • R 3-3 include the specific group of R 3 described in the above embodiment [1-2], and R 3-3 is preferably a group other than tert-butyl.
  • Specific groups for R 4-3 include the specific groups for R 4 described in the above embodiment [1-4-a].
  • p is an integer of 1 to 3
  • r and s are 0, and ring A ′ is a benzene ring or a pyridine ring.
  • the group corresponding to the formula (A3) in the formula (I) -3a, that is, the ring A ′ substituted with (R 1-3 ) p is preferably the one described in the above embodiment [1-9-g-3] Specifically, (2-, 3- or 4-) fluorophenyl, (2-, 3- or 4-) chlorophenyl, (2,6-, 2,5-, 2,4-, 2,3-, 3,4- or 3,5-) difluorophenyl, (2,6-, 2,5-, 2,4-, 2,3-, 3,4- or 3,5-) dichlorophenyl , (2-, 3- or 4-) methoxyphenyl, (2-, 3- or 4-) trifluoromethoxyphenyl, (2-, 3- or 4-) ethylphenyl, (2-, 3- or 4) -) Trifluoromethylphenyl, (4- or 5-) chloro-2-methylpheny 2-chloro- (4- or 5-) methylphenyl, 2-fluoro- (4- or 5-
  • Preferred examples of the compound of the formula (I) of the embodiment [1] include the following. 5- (4-((4 '-(3-hydroxy-3-methylbutoxy) -2', 6'-dimethyl- [1,1'-biphenyl] -3-yl) methoxy) phenyl) -1,2 -Thiazinan-3-one 1,1-dioxide (Example 1); 5- (4-((4′-fluoro- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Example 2); 5- (4-((4 '-(2-ethoxyethoxy) -2', 6'-dimethyl- [1,1'-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinane-3 -One 1,1-dioxide (Example 3); 5- (4-((4
  • a second aspect of the present invention is a compound represented by the formula (I), or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate of the compound, or the A pharmaceutical composition comprising a pharmaceutically acceptable solvate of a salt.
  • a third aspect of the present invention is the compound represented by the formula (I), or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate of the compound, or the A prophylactic and / or therapeutic agent for a disease involving GPR40, comprising at least one pharmaceutically acceptable solvate of a salt as an active ingredient.
  • the compound represented by the formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or the salt Diabetes [more specifically, type 1 diabetes (insulin-dependent diabetes), type 2 diabetes (insulin non-insulin), characterized by containing at least one pharmaceutically acceptable solvate as an active ingredient Dependent diabetes) or borderline diabetes (any or all of impaired glucose tolerance (IGT) and / or fasting glycemia (IFG))], or a prophylactic and / or therapeutic agent for each disease such as obesity and obesity It is.
  • ITT impaired glucose tolerance
  • IGF fasting glycemia
  • An example is the onset inhibitor of type 2 diabetes in impaired glucose tolerance.
  • Sulfonylurea drugs are also examples of therapeutic agents for secondary ineffective diabetes.
  • sulfonylurea drugs glibenclamide, glimepiride, etc.
  • rapid insulin secretion promoters mitiglinide, etc.
  • Insulin secretion effect and blood glucose lowering effect can be obtained even in diabetic patients.
  • diabetes is characterized by a fasting blood glucose level of 126 mg / dl or higher or an occasional blood glucose level or a 75 g oral glucose tolerance test (OGTT) 2-hour value of 200 mg / dl or higher. .
  • Borderline diabetes (also referred to as impaired glucose tolerance) is a fasting blood glucose abnormality (IFG) in which a fasting blood glucose level is 110 mg / dl or more and less than 126 mg / dl, and / or a 75 gOGTT 2 hour value is 140 mg / dl or more and 200 mg / dl.
  • IGF abnormal glucose tolerance
  • Insulin resistance refers to a pathological condition in which insulin is unable to lower blood sugar in a living body, and is clinically evaluated by a quantitative glucose clamp method or HOMA-IR. It is known that insulin resistance causes hyperinsulinemia and is a risk of hypertension and coronary artery disease.
  • “Obesity” is defined by the Japanese Society of Obesity as “a medical condition that is associated with or is expected to be associated with obesity and is a medical condition that requires medical weight loss”. . “Obesity” as defined herein is evaluated by BMI (body mass index, kg / m 2 ). Generally, a BMI of 25 or more is diagnosed as obesity. As a result of treatment, reduction of BMI can be mentioned.
  • a fourth aspect of the present invention is the compound represented by the formula (I), or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate of the compound, or the An insulin secretagogue comprising at least one pharmaceutically acceptable solvate of a salt as an active ingredient.
  • a fifth aspect of the present invention is the compound represented by the formula (I), or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate of the compound, or the A GPR40 activator comprising one or more pharmaceutically acceptable solvates of a salt.
  • the GPR40 agonistic action is measured by a method appropriately selected (for example, Pharmacological Experimental Example 1 (agonist action on human-derived GPR40) described later) It is preferable to use a compound having an EC 50 value of 3 ⁇ M or less, more preferably 1 ⁇ M or less, still more preferably 300 nM or less, particularly preferably 100 nM or less.
  • the “therapeutic agent” is intended to include not only treatment of a disease or symptom but also improvement of the disease or symptom.
  • the term “compound” when used, “a pharmaceutically acceptable salt thereof” is also referred to.
  • the compound of the present invention may have an asymmetric carbon, and the compound of the present invention includes a mixture of various stereoisomers such as geometric isomers, tautomers, optical isomers, and isolated compounds. It is.
  • the compound of the formula (I) may have axial asymmetry due to steric hindrance, and isomers generated by axial asymmetry (axial chirality) are also included in the formula (I). Isolation and purification of such stereoisomers can be carried out by those skilled in the art through conventional techniques through preferential crystallization, optical resolution using column chromatography or asymmetric synthesis.
  • salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, basic or acidic amino acids, and the like. And the like.
  • metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like.
  • salt with organic base examples include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzyl. And salts with ethylenediamine and the like.
  • salt with inorganic acid examples include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • salt with organic acid examples include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzene And salts with sulfonic acid, p-toluenesulfonic acid and the like.
  • salts with basic amino acids include, for example, salts with arginine, lysine, ornithine
  • salts with acidic amino acids include, for example, salts with aspartic acid, glutamic acid, and the like. Is mentioned.
  • an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt), an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium salt)
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid
  • organic acids such as oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, and p-toluenesulfonic acid.
  • salts can be obtained by a conventional method, for example, by mixing an equivalent amount of the compound of the present invention with a desired acid or base, and collecting the desired salt by filtration or distilling off the solvent.
  • the salt of the compound of the present invention includes a mono salt and a di salt.
  • the compound of the present invention can simultaneously form both an acid addition salt and a base salt, depending on the side chain substituent.
  • the compound of the present invention has isomers such as tautomers, optical isomers, stereoisomers, positional isomers, and rotational isomers, either one of the isomers or a mixture is included in the compound of the present invention. Is included. Furthermore, when an optical isomer exists in the compound of the present invention, an optical isomer resolved from a racemate is also encompassed in the compound of the present invention.
  • the compound of the present invention may be in the form of a crystal, and a single crystal form or a mixture of crystal forms is included in the compound of the present invention.
  • the compound of the present invention may be a pharmaceutically acceptable cocrystal or cocrystal salt.
  • co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a simple solid.
  • the cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
  • the compound of the present invention may be a solvate (for example, hydrate etc.) or a solvate, and both are included in the compound of the present invention.
  • a compound labeled or substituted with an isotope (eg, 2 H, 3 H, 11 C, 14 C, 18 F, 35 S, 125 I, etc.) is also encompassed in the compound of the present invention.
  • the compound of the present invention labeled or substituted with an isotope can be used, for example, as a tracer (PET tracer) used in Positron Emission Tomography (PET), and is useful in fields such as medical diagnosis.
  • P 1 in the production method is a protecting group for an amino group (—NH 2 ) and an imino group (—NH—) unless otherwise specified.
  • the definition of P 2 in the production method is a protecting group for an alcohol group (including a phenol group) unless otherwise specified.
  • the definition of P 3 in the production method is a protecting group for —SO 2 NHCO— group unless otherwise specified.
  • Definition of R 'in the manufacturing process, unless otherwise indicated, are H or C 1 ⁇ 6 alkyl group.
  • W 1 and W 2 in the production method are defined as follows.
  • W 2 is a boronic acid, boronic acid ester, or trifluoroborate salt.
  • W 1 is a boronic acid, boronic acid ester, or trifluoroborate salt
  • W 2 is a hydroxyl group, a halogen atom, or a trifluoromethanesulfonyloxy group.
  • the compound which has applicable boronic acid, boronic acid ester, or a trifluoroborate salt is marketed, or can be easily obtained from a commercial item by a general organic chemistry manufacturing method.
  • X 1 in the production method is a halogen atom, methanesulfonyloxy, p-toluenesulfonyloxy unless otherwise specified.
  • Definition of X 2 in the manufacturing process unless otherwise specified, a chlorine atom, OH, ONa, is OK.
  • the definition of Hal in the production method is a halogen atom unless otherwise specified.
  • the definition of * in the production method represents an asymmetric center.
  • each raw material compound used for the production of formula (I) may form a salt, and examples of such a salt include the same salts as those of formula (I). .
  • Each raw material compound used in the production of formula (I) can be used in the next reaction as a reaction liquid or as a crude product, but can also be isolated from a reaction mixture according to a conventional method. It can be easily purified by known means, for example, separation means such as extraction, concentration, neutralization, filtration, distillation, recrystallization, chromatography and the like.
  • Examples of the solvent used for the recrystallization include water; alcohols such as methanol, ethanol, 2-propanol and butanol; ethers such as diethyl ether, tetrahydrofuran and 1,4-dioxane; n-hexane, cyclohexane and heptane.
  • Hydrocarbons such as benzene, toluene, xylene, etc .; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone; chloroform Halogenated hydrocarbons such as methylene chloride and 1,2-dichloroethane; nitriles such as acetonitrile; ketones such as acetone and diphenyl ketone; esters such as methyl acetate and ethyl acetate; sulfoxides such as dimethyl sulfoxide; , Trifluoroacetic acid, methanesulfo Acid, organic acids such as p- toluenesulfonic acid; and the like.
  • solvents can be used alone, or two or more kinds of solvents can be mixed at an appropriate ratio, for example, a ratio of 1: 1 to 1:10.
  • a ratio of 1: 1 to 1:10 can be used when the compound in a formula is marketed, a commercial item can also be used as it is, and what was manufactured by the method known per se or a method according to it can also be used.
  • a hydroxyl group (alcoholic hydroxyl group, phenolic hydroxyl group, heterocyclic hydroxyl group etc.), an amino group
  • a reactive group such as a carboxyl group or a thiol group
  • Examples of the protecting group for the amino group (—NH 2 group) or imino group (—NH— group) include acetyl group (Ac group), ethylcarbonyl group (EtCO group), pivaloyl group (Piv group) and the like.
  • Alkanoyl group methoxycarbonyl group (CH 3 OCO group), ethoxycarbonyl group, (CH 3 CH 2 OCO group), ethoxycarbonyl group (CH 3 CH 2 OCO group), t-butoxycarbonyl group (t-BuOCO group) , Boc group) and the like; allyloxycarbonyl group (Alloc group); fluorenylmethoxycarbonyl group (Fmoc group); phenyloxycarbonyl group (PhOCO group); benzyloxycarbonyl group (BnOCO group, Z group), paramethoxybenzyloxycarbonyl group (p-CH 3 OPh) Arylmethoxycarbonyl group represented by CH 2 OCO group), paranitrobenzyloxycarbonyl group (p-NO 2 PhCH 2 OCO group), etc .; benzyl group (Bn group), triphenylmethyl group (trityl group, Tr group) An arylmethyl group represented by benzoyl group (B
  • Examples of the protective group for the carboxyl group include methyl group (Me group), ethyl group (Et group), n-propyl group (n-Pr group), isopropyl group (i-Pr group), n-butyl group (n- C 1-6 alkyl group, allyl group (allyl group); phenyl group (Ph group); benzyl group (Bn group), triphenylmethyl, typified by Bu group), tert-butyl group (tert-Bu group), etc.
  • Examples of the protecting group for the thiol group include methyl group (Me group), ethyl group (Et group), n-propyl group (n-Pr group), isopropyl group (i-Pr group), n-butyl group ( n 1 -Bu group), C 1-6 alkyl group represented by tert-butyl group (tert-Bu group), etc .; benzyl group (Bn group), represented by triphenylmethyl group (Ph 3 C group), etc.
  • Examples of the method for removing the protecting group include an alkanoyl group represented by an acetyl group (Ac group), an ethylcarbonyl group (EtCO group), a pivaloyl group (Piv group), and the like; a methoxycarbonyl group (CH 3 OCO group), Alkoxycarbonyl groups or benzoyl groups typified by ethoxycarbonyl group, (CH 3 CH 2 OCO group), ethoxycarbonyl group (CH 3 CH 2 OCO group), t-butoxycarbonyl group (t-BuOCO group, Boc group), etc.
  • an alkanoyl group represented by an acetyl group (Ac group), an ethylcarbonyl group (EtCO group), a pivaloyl group (Piv group), and the like
  • a methoxycarbonyl group CH 3 OCO group
  • Alkoxycarbonyl groups or benzoyl groups typified by ethoxycarbonyl
  • An acyl-type protecting group such as an aroyl group represented by (Bz group) is hydrolyzed by using an appropriate base such as an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide. Can be deprotected.
  • an appropriate base such as an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • methoxycarbonyl-type protecting groups such as carbonyl groups (p-CH 3 OPhCH 2 OCO groups), trimethylsilyl groups (Me 3 Si groups), triethylsilyl groups (Et 3 Si groups), t-butyldimethylsilyl groups (t Silyl-type protecting groups such as —Bu (CH 3 ) 2 Si group
  • suitable acids such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid or combinations thereof.
  • the silyl-type protecting group described above can also be deprotected with an appropriate fluorine ion (F ⁇ ) generating reagent such as tetrabutylammonium fluoride and hydrogen fluoride.
  • F ⁇ fluorine ion
  • Arylmethoxycarbonyl typified by benzyloxycarbonyl group (BnOCO group), paramethoxybenzyloxycarbonyl group (p-CH 3 OPhCH 2 OCO group), paranitrobenzyloxycarbonyl group (p-NO 2 PhCH 2 OCO group) and the like
  • the arylmethyl group represented by the group and benzyl group (Bn group) can be deprotected by hydrogenolysis using a palladium carbon catalyst.
  • the benzyl group can also be deprotected by Birch reduction using metallic sodium in liquid ammonia.
  • the triphenylmethyl group (Ph 3 C group) can be deprotected with a suitable acid such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid or combinations thereof.
  • deprotection can also be achieved by Birch reduction using metallic sodium or hydrogenolysis using a palladium carbon catalyst in liquid ammonia.
  • sulfonyl group in the case of a methanesulfonyl group (Ms group), sodium amalgam (Na-Hg) and HBr-AcOH can be used to form a p-toluenesulfonyl group (Ts group) and a benzenesulfonyl group (Bs group).
  • the method for introducing / removing the protecting group shown here is appropriately performed depending on the group to be protected or the type of protecting group. For example, Green et al. [Protective Groups in Organic Synthesis (Protective) Groups in Organic Synthesis, 4th edition, 2007, John Wiley & Sons].
  • reaction conditions in the production method described below are as follows unless otherwise specified.
  • the reaction temperature is in the range from ⁇ 78 ° C. to the temperature at which the solvent is refluxed. When the temperature is not described, it is room temperature (0 to 35 ° C.), and the reaction time is the time for which the reaction proceeds sufficiently.
  • each step in the production method can be performed without solvent or by dissolving or suspending the raw material compound in a solvent not involved in an appropriate reaction before the reaction.
  • the solvent not involved in the reaction include water; saturated hydrocarbon solvents such as cyclohexane and hexane; aromatic hydrocarbon solvents such as benzene, chlorobenzene, toluene and xylene; methanol, ethanol, 1-propanol, 2 Alcohol solvents such as -propanol, tert-butyl alcohol, 2-methoxyethanol; N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), hexamethylphosphoric triamide (HMPA), 1, Polar amide solvents such as 3-dimethyl-2-imidazolidinone (DMI); sulfoxide solvents such as dimethyl sulfoxide (DMSO); nitrile solvents such as acetonitrile and propionitrile; diethyl ether, diisopropyl ether, diphenyl ether, tetrahydro Ether solvents such as lofrane, 1,4-dioxan
  • One kind of these solvents may be used alone, or two or more kinds of solvents may be mixed and used at an appropriate ratio by appropriately selecting depending on the reaction conditions.
  • Specific examples of the base (or deoxidizer) used in the production method of the compound of the present invention include lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, and carbonate.
  • Inorganic bases such as cesium, calcium carbonate, sodium bicarbonate; triethylamine, N, N-diisopropylethylamine, tributylamine, cyclohexyldimethylamine, pyridine, lutidine, 4-dimethylaminopyridine (DMAP), N, N-dimethylaniline, N -Methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4.3.0] -5-nonene (DBN), 1,4-diazabicyclo [2.2.2] octane, 1, 8-diazabicyclo [5.4.0] -7-undecene (DBU) Organic bases such as imidazole; sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide and other metal alkoxides; alkali metal hydrides such as sodium hydride and potassium hydride; sodium
  • Examples of the acid or acid catalyst used in the production method of the compound of the present invention include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid and phosphoric acid; acetic acid, trifluoroacetic acid (TFA), Organic acids such as oxalic acid, phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid (CSA); boron trifluoride ether complex ( BF 3 ⁇ Et 2 O), zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride, and other Lewis acids.
  • inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid and phosphoric acid
  • TFA trifluoroacetic acid
  • Organic acids such as oxalic acid, phthalic
  • the salt of the formula (I) of the present invention is prepared according to a method known per se.
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid or phosphoric acid Mineral acids) or formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.
  • an acid By adding an acid, or when formula (I) is an acidic compound, ammonia, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N-diisopropylethylamine, N, N′-dibenzylethylenediamine, N, N— It can be produced by adding an organic base such as dialkylaniline or an inorganic base such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium bicarbonate.
  • an organic base such as dialkylaniline or an inorganic base such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium bicarbonate.
  • optical resolution method a method known per se, for example, (1) fractional recrystallization method, (2) diastereomer method, (3) chiral column method and the like are used.
  • fractional recrystallization method After obtaining a crystalline diastereomer by ion-bonding an optical resolving agent to a racemate, it is separated by a fractional recrystallization method and, if desired, a neutralization step is performed. A method for obtaining a free optically pure compound.
  • optical resolution agent examples include (+)-mandelic acid, ( ⁇ )-mandelic acid, (+)-tartaric acid, ( ⁇ )-tartaric acid, (+)-1-phenethylamine, ( ⁇ )-1-phenethylamine, There are cinchonine, ( ⁇ )-cinchonidine, brucine and the like.
  • Diastereomer method An optical resolution agent is covalently bonded (reacted) to a racemic mixture to obtain a mixture of diastereomers, which is then subjected to usual separation means (eg, fractional recrystallization, silica gel column chromatography).
  • optical isomers in the case of liquid chromatography, a mixture of optical isomers is added to a chiral column such as Daicel's CHIRAL series, and water, various buffers (eg, phosphate buffer), organic solvents (eg, ethanol, methanol,
  • buffers eg, phosphate buffer
  • organic solvents eg, ethanol, methanol
  • the optical isomers can be separated by development using isopropanol, acetonitrile, trifluoroacetic acid, diethylamine
  • separation can be performed using a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Sciences).
  • Necessary starting materials are commercially available, or can be easily obtained from commercially available products by general organic chemical production methods.
  • the compound represented by the formula (I) of the present invention can be produced using the compound represented by the formula (AI) as a starting material.
  • ⁇ Step 1> Using a compound represented by the formula (AI) and a compound represented by the formula (A-II), methods known in the literature, for example, “Journal of the American Chemical Society”, 132 ( 2) 436-437, 2010 ”, in the presence of a base such as potassium carbonate, sodium carbonate, cesium carbonate or the like in the reaction with a polar solvent such as N, N-dimethylformamide or acetonitrile.
  • the compound represented by the formula (A-III) can be produced by performing the reaction in a solvent not involved or in a mixed solvent thereof at a temperature at which the solvent is refluxed from ⁇ 78 ° C.
  • a solvent that does not participate in the reaction such as an ether solvent such as toluene, an aromatic hydrocarbon solvent such as toluene or benzene, or a polar solvent such as N, N-dimethylformamide, or a mixed solvent thereof, a solvent from ⁇ 78 ° C.
  • the compound represented by the formula (AV) can be produced by carrying out the reaction at a temperature at which is refluxed.
  • AV a compound represented by the formula (AV) and a malonic acid derivative represented by the formula (A-VI)
  • bases such as sodium hydride (NaH), tert-butoxypotassium (t-BuOK), sodium methoxide (NaOMe), sodium ethoxide (NaOEt)
  • ether solvent such as diethyl ether or tetrahydrofuran
  • aromatic hydrocarbon solvent such as toluene or benzene
  • a polar solvent such as N, N-dimethylformamide
  • the reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C., and the formula (A Can be prepared a compound represented by VII).
  • Step 4> According to a method known in the literature, for example, the method described in “Chemical & Pharmaceutical Bulletin, 33 (12), pages 5316-5327, 1985”, the formula (A-VII)
  • a compound represented by a solvent such as water, dimethyl sulfoxide, N, N-dimethylformamide or the like, which is not involved in the reaction, or a mixed solvent thereof, from 0 ° C. to the solvent
  • the compound represented by the formula (A-VIII) can be produced by performing the reaction at a temperature at which is refluxed.
  • ⁇ Step 5> Using a compound represented by the formula (A-VIII), a method known in the literature, for example, “Protective Groups in Organic Synthesis 4th Edition”, 4th edition, 2007, John Willie and In accordance with the method described in the book of John Wiley & Sons, Green et al., The P 1 group was deprotected by reacting in a method corresponding to the type of the protecting group P 1 . A compound represented by the formula (A-IX) can be produced.
  • ⁇ Step 6> Using a compound represented by the formula (A-IX), a method known in the literature, for example, a method described in “Organic Letters, 7 (22), pages 5067-5069, 2005” is used.
  • W 1 is a halogen atom or a trifluoromethanesulfonyloxy group
  • W 2 is a boronic acid, boronic acid ester, or trifluoroborate salt
  • W 1 and W 2 may be reversed.
  • a compound represented by I) can be produced. Moreover, it can manufacture by the same method using tetramethylammonium chloride, tetrabutylammonium chloride, etc. instead of a phosphine-type reagent.
  • L Formula (A2)
  • a compound represented by the formula (AX) and a compound represented by the formula (A2) -W a method known in the literature, for example, “Tetrahedron Letters, 44, 3863-3865, 2003”
  • W 1 and W 2 may be reversed] in the presence of a copper catalyst such as copper (II) acetate and copper (II) trifluoroacetate, and a base such as triethylamine,
  • Step 3> Using a compound represented by the formula (C-III) and an alkyl halide represented by, for example, R 5a X 1 or R 5b X 1 , a known method such as “Experimental Chemistry Course 5th Edition 16 Synthesis IV Carboxylic acid / amino acid / peptide, page 1-70, 2005, Maruzen ”, etc., according to the method described in sodium methoxide, sodium ethoxide, sodium hydride, lithium hydroxide, sodium hydroxide, water In the presence of a base such as potassium oxide, lithium carbonate, sodium carbonate, or potassium carbonate, a solvent that does not participate in the reaction, such as water, methanol, ethanol, N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, or a mixed solvent thereof The reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C., and the compound represented by the formula (C-IV) is used.
  • Step 4> Using the compound represented by the formula (C-IV), deprotection can be carried out in the same manner as in (Production Method A) ⁇ Step 5> to produce the compound represented by the formula (CV). .
  • Step 5> The compound represented by the formula (CV) can be produced by reacting the compound represented by the formula (CV) in the same manner as in (Production Method A) ⁇ Step 6>.
  • ⁇ Step 2> Using the compound represented by the formula (DI) and the compound represented by the formula (A-IV), the reaction is carried out in the same manner as in (Production Method A) ⁇ Step 2>, and in the formula (D-II) The compounds represented can be produced.
  • ⁇ Step 3> Using the compound represented by the formula (D-II) and the compound represented by the formula (A-VI), the reaction is carried out in the same manner as in (Production Method A) ⁇ Step 3>, and in the formula (D-III) The compounds represented can be produced.
  • Step 7> Using a compound represented by the formula (D-VI), a method known in the literature, for example, “Protective Groups in Organic Synthesis 4th Edition”, 4th edition, 2007, John Willy and Sands (John Wiley & Sons), According to the method described in the book of Green et al., The —SO 2 —NH—CO— group is converted to a P 3 group by reacting the protecting group P 3 with a method according to the type of the protecting group. A compound represented by the formula (D-VII) protected with can be produced.
  • Step 8> Using the compound represented by the formula (D-VII), deprotection can be carried out in the same manner as in (Production Method A) ⁇ Step 5> to produce the compound represented by the formula (D-VIII). .
  • Step 9> Using the compound represented by the formula (D-VIII) and the compound represented by the formula (D-IX), the reaction is carried out in the same manner as in (Production Method A) ⁇ Step 1>, followed by (Production Method A) The protecting group P 3 can be deprotected in the same manner as in ⁇ Step 5> to produce a compound represented by the formula (I).
  • the compound represented by the formula (D-IX) -A1 can be produced by reacting in the presence of a chlorinating agent such as phosphorus bromide and hydrogen bromide at a temperature at which the solvent is refluxed from 0 ° C.
  • a chlorinating agent such as phosphorus bromide and hydrogen bromide
  • the compound represented by the formula (D-IX) -A1 can be produced by reacting at a temperature at which the solvent is refluxed from 0 ° C. in the presence of an iodinating agent such as hydrofluoric acid.
  • ethers such as diethyl ether and tetrahydrofuran
  • a nucleophilic species is prepared by reacting a compound represented by the formula (I-II) with a base such as n-butyllithium or a Grignard reagent in a solvent that does not participate in the reaction such as a system solvent, and then a trifluorodiethyl ether complex (BF 3 ) Et 2 O) and the like and an ethylene oxide derivative represented by the formula (I-III) are added, and the reaction is carried out at a temperature at which the solvent is refluxed from ⁇ 78 ° C.
  • the compound represented by the formula (IV) can be produced by carrying out the reaction at a temperature at which ⁇ Step 4> Using a compound represented by the formula (IV), it was described in literature known methods such as “Justus Liebigs Annalen der Chemie, 586, 158-164, 1954”. According to the method, in the presence of a sulfur reagent such as sodium sulfite, potassium sulfite, sodium disulfite, thiourea, etc., in an alcoholic solvent such as methanol, ethanol, or a solvent not involved in the reaction such as water, or in a mixed solvent thereof
  • a sulfur reagent such as sodium sulfite, potassium sulfite, sodium disulfite, thiourea, etc.
  • an alcoholic solvent such as methanol, ethanol, or a solvent not involved in the reaction such as water, or in a mixed solvent thereof
  • the compound represented by the formula (I-VI) can be produced by conducting the reaction at a temperature at which the
  • ⁇ Step 5> Using a compound represented by the formula (I-IV) and thioacetic acid, according to a method known in the literature, for example, a method described in “Organic Reaction, 42, 1992” or the like, triphenyl In the presence of organic phosphorus compounds such as phosphine and azo compounds such as azodicarboxylic acid esters and azodicarboxylic acid amides, halogen solvents such as dichloromethane and chloroform, ether solvents such as diethyl ether and tetrahydrofuran, aromatics such as toluene and benzene It was obtained by conducting the reaction at a temperature at which the solvent refluxed from 0 ° C.
  • organic phosphorus compounds such as phosphine and azo compounds such as azodicarboxylic acid esters and azodicarboxylic acid amides
  • halogen solvents such as dichloromethane and chloroform
  • ether solvents
  • a solvent that does not participate in the reaction such as a hydrocarbon solvent, or a polar solvent such as N, N-dimethylformamide, dimethyl sulfoxide, or the like.
  • a solvent that does not participate in the reaction such as a hydrocarbon solvent, or a polar solvent such as N, N-dimethylformamide, dimethyl sulfoxide, or the like.
  • Compounds can be prepared by methods known in the literature, eg, “Canadian In accordance with a method described in Canadian of Chemistry, 62 (3), pages 610-614, 1984, etc., a compound of formula (I-VI) is obtained by reacting with chlorine in an acetic acid solvent. The compound represented by these can be manufactured.
  • the compound represented by the formula (I-VII) can be produced by further reacting the resulting sulfonyl chloride compound with ammonia (water).
  • ammonia water
  • halogen solvents such as dichloromethane and chloroform, ether solvents such as diethyl ether, tetrahydrofuran and 1,4-dioxane, aromatic hydrocarbon solvents such as toluene and benzene, polar solvents such as acetonitrile, etc.
  • Ammonia gas, water in the presence or absence of a base such as triethylamine, N, N-diisopropylethylamine, pyridine, N, N-dimethylaminopyridine, saturated aqueous sodium hydrogen carbonate, By reacting at a temperature at which the solvent refluxes from 0 ° C., it is represented by the formula (I-VII) Compounds can be produced.
  • a base such as triethylamine, N, N-diisopropylethylamine, pyridine, N, N-dimethylaminopyridine, saturated aqueous sodium hydrogen carbonate
  • Step 7> Using a compound represented by the formula (I-VII), a method known in the literature, for example, “Protective Groups in Organic Synthesis 4th Edition”, 4th edition, 2007, John Willie and Sands (John Wiley & Sons) In accordance with the method described in the book of Green et al., The compound (I-) protected with the P 1 group is reacted with the protecting group P 1 according to the type of the protecting group. VIII) can be prepared.
  • ⁇ Step 8> Using a compound represented by the formula (I-VIII), it is described in literature known methods such as “Journal of Organic Chemistry, 57 (10), 2967-2970, 1992”.
  • Step 9> Using a compound represented by the formula (I-IX) and a silyl enolate represented by the formula (IX), a method known in the literature, for example, “Tetrahedron, 65 (28), 5462- In the presence of indium bromide (InBr 3 ), the solvent is refluxed from 0 ° C. in a solvent not involved in the reaction, such as dichloromethane, n-hexane, benzene, toluene, and the like.
  • the compound represented by the formula (I-XI) can be produced by reacting at a temperature at which the reaction is performed.
  • ⁇ Step 10> Using the compound represented by the formula (I-XI), deprotection can be carried out in the same manner as in (Production Method A) ⁇ Step 5> to produce the compound represented by the formula (I-XII). .
  • a compound represented by the formula (I-XIII) can be produced by reacting the compound represented by the formula (I-XII) in the same manner as in (Production Method A) ⁇ Step 6>.
  • ⁇ Step 12> Using the compound represented by the formula (I-XIII), protecting the —SO 2 NHCO— group in the same manner as in (Production Method D) ⁇ Step 7>, and then the compound represented by the formula (I-XIV) Can be manufactured.
  • composition of the present invention can be used in combination with other drugs or drugs by a general method performed in the medical field.
  • diabetes type 1 diabetes, type 2 diabetes, borderline diabetes (abnormal glucose tolerance (IGT) and / or fasting glycemic abnormality (IFG))
  • IGF fasting glycemic abnormality
  • PPAR ⁇ agonist specifically, pioglitazone, rosiglitazone, troglitazone, ciglitazone, darglitazone, englitazone, netoglitazone, etc.
  • biguanide specifically, metformin, buformin, phenformin, etc.
  • sulfonylurea agents specifically, tolbutamide, acetohexamide, chlorpropamide, glibenclamide, gliclazide, glipizide, glimepiride, glipentide, glyquidone, glicoramide, tolazamide, etc.
  • Fast-acting insulin secretagogues specifically nateglinide, mitiglinide, repaglinide, etc.
  • ⁇ -glucosidase inhibitors specifically acarbose, voglibose, miglitol, camiglibose, adiposis
  • Insulin or insulin derivatives specifically, insulin zinc suspension, insulin lispro, insulin aspart, regular insulin, NPH insulin, insulin glargine, insulin detemir, etc.) Mixed insulin, etc.
  • GLP-1 or GLP-1 receptor agonist specifically exenatide, liraglutide, lixisenatide, taspoglutide, albiglutide, duraglutide, etc.
  • DPP-IV inhibitor specifically Sitagliptin, vildagliptin, alogliptin, saxagliptin, linagliptin, teneligliptin, ana
  • pioglitazone / metformin is included in a combination of the above two or more components (specifically, pioglitazone / metformin, pioglitazone / glimepiride, mitiglinide / voglibose, alogliptin / pioglitazone, alogliptin / metformin, etc.).
  • Other examples include lipid-lowering drugs and dyslipidemic agents.
  • ⁇ 3 fatty acids specifically ethyl icosapentate (EPA-E preparation), docosahexaenoic acid (DHA), etc.
  • HMG-CoA reductase inhibitor specifically, atorvastatin, simvastatin, Pitavastatin, itavastatin, fluvastatin, lovastatin, pravastatin, rivastatin, rosuvastatin, etc.
  • cholesterol absorption inhibitor specifically ezetimibe
  • acyl-CoA / cholesterol acyl Transferase (ACAT) inhibitor 6) CETP inhibitor, 7) squalene synthase inhibitor, 8) antioxidant (specifically, probucol, etc.), 9) PPAR ⁇ agonist (specifically, clofibrate) , Etofibrate, fenofibrate, bezafibrate, cipro Fibrates
  • CB-1 receptor antagonist specifically, rimonabant, SR-147778, BAY-6-25520, etc.
  • Monoamine reuptake inhibitor specifically sibutramine, mazindol, etc.
  • Serotonin reuptake inhibitors specifically, fluoxetine, paroxetine, etc.
  • Lipase inhibitors specifically, orlistat, cetiristat, etc.
  • Neuropeptide Y (NPY) receptor antagonist specifically, S-2367 etc.)
  • Peptide YY (PYY) receptor antagonist specifically, Adrenergic ⁇ 3 receptor agonist (specifically, KRP-204, TRK-380 / TAC-301 etc.) Can be mentioned.
  • the concomitant agent is a PPAR ⁇ agonist (more preferably pioglitazone, rosiglitazone), a biguanide agent (more preferably metformin, buformin), a sulfonylurea agent (more preferably glibenclamide, gliclazide, glimepiride), a fast-acting insulin secretagogue Agents (more preferably nateglinide, mitiglinide, repaglinide), ⁇ -glucosidase inhibitors (more preferably acarbose, voglibose, miglitol), insulin or insulin derivatives, GLP-1 or GLP-1 receptor agonists (more preferably exenatide, liraglutide) ), DPP-IV inhibitors (more preferably sitagliptin, vildagliptin, alogliptin, saxagliptin, linagliptin, teneligliptin;
  • the dosage of existing drugs can be reduced, and the side effects of existing drugs can be reduced.
  • the combination method using the said drug is not limited to the said disease, and the drug used together is not limited to the compound illustrated above.
  • the compound of the present invention when used in combination with a drug used in combination, it may be a separate preparation or a combination. Moreover, in separate preparations, both can be taken simultaneously or administered at different times.
  • excipients eg; lactose, sucrose, mannitol, crystalline cellulose, silicic acid, corn starch, potato starch
  • binders eg; celluloses (hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC)), crystalline cellulose, saccharides (lactose, mannitol, sucrose, sorbitol, erythritol, xylitol), starches (corn starch, potato starch), pregelatinized starch, dextrin, polyvinylpyrrolidone (PVP), macrogol, polyvinyl alcohol (PVA)), lubricant (eg; magnesium stearate, calcium stearate, talc, carboxymethylcellulose), disintegrant (eg; starches (corn starch, potato starch), carbox Methyl starch sodium, carmellose, carmellose calcium, croscarmellose sodium, crospovidone), coating agent (eg, cellulose
  • Various dosage forms include tablets, capsules, granules, powders, pills, aerosols, inhalants, ointments, patches, suppositories, injections, lozenges, liquids, spirits, suspensions, Examples include extract and elixir.
  • Oral subcutaneous administration, intramuscular administration, intranasal administration, transdermal administration, intravenous administration, intraarterial administration, perineural administration, epidural administration, intradural administration, intraventricular administration, intrarectal administration It can be administered to a patient by inhalation or the like.
  • the dose of the compound of the present invention is usually 0.005 mg to 3.0 g, preferably 0.05 mg to 2.5 g, more preferably 0.1 mg to 1.5 g per day for an adult.
  • Pharmacological experiment example 1 Agonist action on human-derived GPR40 The agonist action of the test compound was determined using a CHO cell line stably expressing human-derived GPR40. This cell line was seeded in a clear bottom 96-well plate at 2 ⁇ 10 4 cells / 100 ⁇ L / well, and ham F ⁇ containing 10% fetal bovine serum, 100 U / mL penicillin, 0.1 mg / mL streptomycin, 400 ⁇ g / mL geneticin. Twelve media were used and cultured overnight in a CO 2 incubator. Calcium-4 assay kit (Molecular Device) was used as a fluorescent calcium indicator reagent.
  • 77 mg / mL probenecid (Invitrogen) was added to 100 mL of the calcium indicator reagent solution, and a solution (loading solution) mixed with an equal amount of 20 mM HEPES-containing Hanks balanced salt solution (HBSS) was prepared. 200 ⁇ L of the loading solution was added to the cells from which the culture solution was removed, and the cells were cultured in a CO 2 incubator for 1 hour.
  • the test compound was diluted with 20 mM HEPES-containing HBSS, and 50 ⁇ L each was added to the cells, and the change in Ca 2+ concentration was measured with an intracellular ion analyzer.
  • the EC 50 value of the test compound was calculated from the dose response curve of changes in fluorescence intensity.
  • the EC 50 values are the compounds of the present invention of less than 0.3 [mu] M as A, also The EC 50 values are the present compounds of less than ⁇ 3 [mu] M 0.3 [mu] M as B, shown in Table 1.
  • Pharmacological Experiment Example 2 Oral Glucose Tolerance Test Male C57BL / 6J mice or SD rats fasted overnight are used to examine the blood glucose increase inhibitory effect of the test compound after glucose loading.
  • the test compound is suspended in a solvent (for example, 0.5% carboxymethyl cellulose) and administered orally before glucose loading.
  • the control group receives only the solvent.
  • Blood collection is performed before compound administration (pre-collection), immediately after glucose administration, immediately after glucose loading, after glucose loading, 15, 30, 60, and 120 minutes, and the blood glucose level is measured with the collected blood.
  • a preferred compound of the present invention has an action to suppress an increase in blood glucose by oral administration at a dose of 0.3 to 10 mg / kg.
  • DMSO Precipitation Solubility (Kinetic Solubility) A 10 mM DMSO solution of the compound of the present invention is added to 50 mM phosphate buffer (pH 7.4) to a final concentration of 100 ⁇ M. The solution was incubated at 600 rpm with stirring at room temperature for 1.5 hours, then filtered through a filter plate (4 ⁇ m, MultiScreen Solidity filter plate (Millipore)), and using a plate reader (Powerscan HT (Dainippon Pharmaceutical)). Then, the absorbance of the filtrate is measured at the maximum absorption wavelength.
  • the absorbance of each standard solution is measured using a DMSO solution to which a known concentration (1, 3, 10, 30, 100 ⁇ M) of the test compound is added as a calibration curve standard solution, and a calibration curve is created.
  • the solubility ( ⁇ M) of the compound is calculated from the absorbance values of the filtrate and standard solution.
  • Crystal solubility Thermodynamic Solubility
  • the compound of the present invention is added to water at 1 mg / mL. The solution is allowed to stand at 37 ° C. for 24 hours and then centrifuged. The obtained supernatant is analyzed by HPLC, a peak is detected at the maximum absorption wavelength, and the peak area is measured.
  • each peak area was measured using a DMSO solution to which a known concentration of a test compound (0.03, 0.1, 0.3, 1, 3, 10 ⁇ g / mL) was added as a standard curve standard solution.
  • the solubility ( ⁇ g / mL) of the compound is calculated from the peak area.
  • Pharmacological experiment example 4 Metabolic stability test Liver microsome solution (human, mouse or rat; XenoTech), NADPH generating solution ( ⁇ -NADP, Glucose-6- Phosphate, G-6-PDH (Y), water containing MgCl 2 ). The solution is incubated at 37 ° C. for 20 minutes and then quenched with acetonitrile. Similarly, sampling is performed at a predetermined time during incubation, and the reaction is stopped. These reaction solutions are centrifuged through a filter plate (MultiScreenHTS-HV plate (Millipore)), and the test compound in the filtrate is measured using high performance liquid chromatogram / mass spectrometry.
  • a filter plate MultiScreenHTS-HV plate (Millipore)
  • a sample with a reaction time of 0 minutes is measured as a control, the compound concentration in the control is set to 100%, and the residual ratio of the compound in each reaction solution is calculated. These residual rates are plotted against time, and metabolic clearance CL ( ⁇ L / mg / min) is calculated from the slope of the obtained regression line.
  • hERG-HEK human ether-a-go-related gene
  • a depolarizing pulse is periodically applied while maintaining the membrane potential at ⁇ 80 mV. After the generated current has stabilized, the test compound is added. The effect of the test compound on the hERG channel is confirmed by a change in tail current induced by a -40 mV, 0.5 second depolarizing pulse followed by a -40 mV, 0.5 second repolarizing pulse.
  • the Stimulation is performed once every 10 seconds. The measurement is performed at room temperature.
  • the hERG channel inhibition rate is calculated as a decrease rate (inhibition rate) of the tail current 2 minutes after application with respect to the maximum tail current before application of the test compound. By calculating this inhibition rate, the possibility of inducing QT prolongation by drugs and subsequent fatal side effects (ventricular tachycardia, sudden death, etc.) is shown.
  • the test compound in plasma is measured by high performance liquid chromatogram / mass spectrometry.
  • a standard solution to which a known concentration of a test compound (0.01, 0.02, 0.05, 0.1, 0.2, 0.5, 1 ⁇ g / mL) was added was measured, and a calibration curve was prepared.
  • the plasma concentration ( ⁇ g / mL) is calculated, and the maximum plasma concentration is defined as Cmax ( ⁇ g / mL).
  • Pharmacological experiment example 7 Safety test The compound of the present invention is orally administered to a mouse or rat once, and no deaths are observed, and no remarkable behavioral abnormalities are observed, indicating the safety of the compound of the present invention.
  • Pharmacological Experiment Example 8 Brain penetration test The compound of the present invention is orally administered at a dose of 1 mg / kg to male SD rats of 7 to 9 weeks old fasted overnight the day before (administration solvent is 0.5% carboxymethylcellulose aqueous solution, 10 mL / kg). Blood is collected and cerebral cortex is collected from the jugular vein 1 hour after administration.
  • the test compound in plasma is measured by high performance liquid chromatogram / mass spectrometry.
  • a standard solution to which a known concentration of a test compound (0.01, 0.02, 0.05, 0.1, 0.2, 0.5, 1 ⁇ g / mL) was added was measured, and a calibration curve was prepared.
  • the plasma concentration ( ⁇ g / mL) is calculated.
  • the cerebral cortex is homogenized by adding water, then methanol is added, and the supernatant obtained by stirring and centrifuging (14000 rpm, 10 minutes, 4 ° C.) is used for high-performance liquid chromatogram / mass spectrometry.
  • the compound of the present invention was shown to have an excellent GPR40 agonistic action, and showed a blood glucose elevation inhibitory action in a single oral glucose tolerance test using normal mice or rats. In addition, no abnormality is observed in the safety test, indicating the low toxicity of the present invention. Furthermore, it was confirmed that the compound of the present invention is good in at least one of the above-described tests, such as solubility, metabolic stability, pharmacokinetics, avoidance of hERG channel inhibitory action, and ability to enter the brain. The Therefore, the compound of the present invention is expected to be used as a GPR40 agonist for an agent for promoting insulin secretion, a preventive and / or therapeutic agent for diabetes (especially type 2 diabetes or borderline diabetes) and obesity / obesity.
  • Formulation Example 1 Compound of Tablet Example 2 100 g 137g of lactose Crystalline cellulose 30g Hydroxypropylcellulose 15g Carboxymethyl starch sodium 15g Magnesium stearate 3g The ingredients are weighed and mixed uniformly. This mixture is compressed into tablets having a weight of 150 mg.
  • Formulation Example 2 Film-coated hydroxypropylmethylcellulose 9g Macrogol 6000 1g Titanium oxide 2g After weighing the above components, hydroxypropylmethylcellulose and macrogol 6000 are dissolved in water and titanium oxide is dispersed. This liquid is film-coated on 300 g of the tablet of Preparation Example 1 to obtain film-coated tablets.
  • Example 4 Compound 100g Lactose 63g Corn starch 25g Hydroxypropylcellulose 10g Talc 2g After weighing the above components, the compound of Example 8, lactose and corn starch are uniformly mixed, an aqueous solution of hydroxypropylcellulose is added, and granules are produced by wet granulation. Talc is uniformly mixed with the granules, and 200 mg in weight is filled into suitable hard capsules to form capsules.
  • Example 6 Granules, Fine Granules Compound of Example 13 100 g Lactose 200g Crystalline cellulose 100g Partially pregelatinized starch 50g Hydroxypropylcellulose 50g After weighing the above components, the compound of Example 13, lactose, crystalline cellulose and partially pregelatinized starch were added and mixed uniformly, an aqueous solution of hydroxypropylcellulose (HPC) was added, and granules or fine granules were obtained by wet granulation. Manufacturing. The granules or fine granules are dried to obtain granules or fine granules.
  • HPC hydroxypropylcellulose
  • a Waters UPLC-ZQ MS system manufactured by Waters
  • the column was manufactured by Shiseido, MGIII-H (2.1 mm ⁇ 5 cm, 3 ⁇ m)
  • the mobile phase was methanol: 0.05% trifluoroacetic acid.
  • Gradient conditions of aqueous solution 5: 95 (0 minute) to 100: 0 (1 minute) to 100: 0 (2 minutes) were used.
  • For the preparative system gradient conditions appropriately changed depending on the compound were used.
  • ⁇ Step 2> Synthesis of 4- (4- (5,5-dimethyl-1,3,2-dioxaborin-2-yl) -3,5-dimethylphenoxy) -2-methylbutan-2-ol (Reference Example 2) )
  • Example 1 5- (4-((4 '-(3-hydroxy-3-methylbutoxy) -2', 6'-dimethyl- [1,1'-biphenyl] -3-yl) methoxy) phenyl) -1,2 Of 2-thiazinan-3-one 1,1-dioxide ⁇ Step 1> (E) -2- (4-((3-Bromobenzyl) oxy) phenyl) -N, N-bis ((2- (trimethylsilyl) Synthesis of Ethoxy) methyl) ethenesulfonamide A THF solution of the compound (13.4 g) of Reference Example 1 was replaced with nitrogen, cooled to ⁇ 43 ° C., and 1M-lithium hexamethyldisilazane (83 ml) was added dropwise.
  • Step 2> Dimethyl 2- (1- (4-((3-bromobenzyl) oxy) phenyl) -2- (N, N-bis ((2- (trimethylsilyl) ethoxy) methyl) sulfamoyl) ethyl) malonate Synthesis To a solution of dimethyl malonate (7.6 ml) in THF (60 ml), 28% sodium methoxide-methanol solution (13 g) was added at room temperature and stirred for 10 minutes, and then (Example 1) ⁇ Step 1> A solution of the compound (16 g) in THF (100 ml) was added, and the mixture was heated to reflux for 18 hours.
  • Step 3> Synthesis of methyl 3- (4-((3-bromobenzyl) oxy) phenyl) -4- (N, N-bis ((2- (trimethylsilyl) ethoxy) methyl) sulfamoyl) butanoate (Example 1) )
  • Sodium chloride (2.7 g) and water (2.1 ml) were added to a DMF (220 ml) solution of the compound of step 2 (22 g), and the mixture was heated to reflux for 9 hours.
  • ⁇ Step 4> Synthesis of methyl 3- (4-((3-bromobenzyl) oxy) phenyl) -4-sulfamoylbutanoate (Example 1)
  • Acetic acid of compound (5.0 g) in ⁇ Step 3> Water (25 ml) was added to the (50 ml) solution, and the mixture was heated and stirred at 83 degrees for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water, washed with half-saturated brine, and dried over anhydrous sodium sulfate.
  • Example 2 5- (4-((4'-Fluoro- [1,1'-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide
  • Example 3 5- (4-((4 '-(2-ethoxyethoxy) -2', 6'-dimethyl- [1,1'-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinane-3 -One 1,1-dioxide (Example 4) 5- (4-((2'-Chloro- [1,1'-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Example 5) 5- (4-((2'-methyl-4 '-(trifluoromethyl)-[1,1'-biphenyl] -3-yl) methoxy)
  • reaction mixture was filtered through celite, water was added, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate.
  • ⁇ Step 3> Synthesis of methyl 4- (N, N-bis ((2- (trimethylsilyl) ethoxy) methyl) sulfamoyl) -3- (4-((3-phenoxybenzyl) oxy) phenyl) butanoate (Example 26) )
  • methylene chloride (18 mL) phenol (46 mg), copper (II) acetate (82 mg), triethylamine (0.29 mL), molecular sieves 4A (0 .30 g) was added and stirred at room temperature for 2 days under an oxygen atmosphere.
  • ⁇ Step 5> Synthesis of 5- (4-((3-phenoxybenzyl) oxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Example 1) According to the method of ⁇ Step 5> Example 26 Using the compound (40 mg) obtained in ⁇ Step 4>, the title compound (20 mg) was obtained as a white solid.
  • Example 27 Synthesis of 3- (3-((4- (1,1-dioxide-3-oxo-1,2-thiazinan-5-yl) phenoxy) methyl) phenoxy) benzonitrile ⁇ Step 1> Methyl 3- (4- Synthesis of ((3- (3-cyanophenoxy) benzyl) oxy) phenyl) -4- (N, N-bis ((2- (trimethylsilyl) ethoxy) methyl) sulfamoyl) butanoate
  • Example 26 ⁇ Step 3> According to the method of Example 26, the title compound (0.14 g) was obtained as a colorless oil using the compound (0.30 g) obtained in ⁇ Step 2>.
  • ⁇ Step 2> Synthesis of methyl 3- (4-((3- (3-cyanophenoxy) benzyl) oxy) phenyl) -4-sulfamoylbutanoate (Example 1) According to the method of ⁇ Step 4>
  • Step 3> Synthesis of 4- (3-((4- (1,1-dioxide-3-oxo-1,2-thiazinan-5-yl) phenoxy) methyl) phenoxy) benzonitrile (Example 1) ⁇ According to the method of Step 5>, the title compound (31 mg) was obtained as a white solid using the compound (40 mg) obtained in (Example 28) ⁇ Step 2>.
  • Step 3> Synthesis of methyl 3- (4-((3-((2-methoxypyridin-4-yl) oxy) benzyl) oxy) phenyl) -4-sulfamoylbutanoate (Example 1) ⁇ According to the method of Step 4>, the title compound (5 mg) was obtained as a colorless oil using the compound (11 mg) obtained in (Example 29) ⁇ Step 2>.
  • ⁇ Step 4> Synthesis of 5- (4-((3-((2-methoxypyridin-4-yl) oxy) benzyl) oxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide ( Example 1) According to the method of ⁇ Step 5>, the title compound (1.6 mg) was obtained as a white solid using the compound (4.0 mg) obtained in (Example 29) ⁇ Step 3>. .

Abstract

L'invention concerne un agent d'activation de GPR40 comprenant un nouveau composé de formule (I) qui a une action agoniste de GPR40, un sel ou un solvate de celui-ci comme principe actif, en particulier un promoteur de sécrétion d'insuline ou un agent pour la prophylaxie et/ou le traitement du diabète, de l'obésité ou similaire. Noyau A : cycloalcényle en C5-C7, aryle condensé, hétéroaryle condensé ou hétéroaryle condensé partiellement hydrogéné, noyau A' : benzène, pyridine ou pyrimidine, R1, R3, R4 : halogène, CN, alkyle en C1-C6 ou similaires, R2 : alcoxy en C1-C6 ou similaires, R5a, R5b, R6, R7a, R7b : H, halogène, alkyle en C1-C6 ou similaires, p : 0 à 4, q : 0 à 2 et r, s : 0 à 4.
PCT/JP2013/060953 2012-04-11 2013-04-11 Nouveau dérivé de 5-aryl-1,2-thiazinane WO2013154163A1 (fr)

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US10710986B2 (en) 2018-02-13 2020-07-14 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10774071B2 (en) 2018-07-13 2020-09-15 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10899735B2 (en) 2018-04-19 2021-01-26 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11279702B2 (en) 2020-05-19 2022-03-22 Kallyope, Inc. AMPK activators
US11407768B2 (en) 2020-06-26 2022-08-09 Kallyope, Inc. AMPK activators
US11512065B2 (en) 2019-10-07 2022-11-29 Kallyope, Inc. GPR119 agonists

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Publication number Priority date Publication date Assignee Title
CN109320517A (zh) * 2017-07-31 2019-02-12 海南轩竹医药科技有限公司 Fxr受体激动剂
US10710986B2 (en) 2018-02-13 2020-07-14 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11555029B2 (en) 2018-02-13 2023-01-17 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10899735B2 (en) 2018-04-19 2021-01-26 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10774071B2 (en) 2018-07-13 2020-09-15 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11512065B2 (en) 2019-10-07 2022-11-29 Kallyope, Inc. GPR119 agonists
US11279702B2 (en) 2020-05-19 2022-03-22 Kallyope, Inc. AMPK activators
US11851429B2 (en) 2020-05-19 2023-12-26 Kallyope, Inc. AMPK activators
US11407768B2 (en) 2020-06-26 2022-08-09 Kallyope, Inc. AMPK activators

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