WO2016204135A1 - Dérivé hétérocyclique à cinq chaînons - Google Patents

Dérivé hétérocyclique à cinq chaînons Download PDF

Info

Publication number
WO2016204135A1
WO2016204135A1 PCT/JP2016/067618 JP2016067618W WO2016204135A1 WO 2016204135 A1 WO2016204135 A1 WO 2016204135A1 JP 2016067618 W JP2016067618 W JP 2016067618W WO 2016204135 A1 WO2016204135 A1 WO 2016204135A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
mmol
methoxy
methyl
propan
Prior art date
Application number
PCT/JP2016/067618
Other languages
English (en)
Japanese (ja)
Inventor
篠塚　剛
秀紀 双木
大川　信幸
麻都佳 星野
薫 松下
茂雄 山野井
朋子 荻山
祐介 朝生
鶴岡　弘幸
Original Assignee
第一三共株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 第一三共株式会社 filed Critical 第一三共株式会社
Publication of WO2016204135A1 publication Critical patent/WO2016204135A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/535—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 oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to a novel compound having an action such as lowering blood sugar and useful as a therapeutic and / or prophylactic agent for diabetes and the like and a pharmacologically acceptable salt thereof.
  • the present invention includes diabetes (type 1 diabetes, type 2 diabetes, gestational diabetes, etc.), postprandial hyperglycemia, impaired glucose tolerance, diabetic neuropathy, diabetes containing the above compound or a pharmacologically acceptable salt thereof as an active ingredient Therapeutic and / or prevention for diabetic nephropathy, diabetic retinopathy, hyperlipidemia, arteriosclerosis, thrombotic disease, obesity, hypertension, edema, insulin resistance, unstable diabetes, insulinoma, hyperinsulinemia, etc.
  • the present invention relates to a drug (preferably a therapeutic and / or preventive for diabetes).
  • the present invention provides a composition for preventing or treating the above-mentioned disease containing the above compound or a pharmacologically acceptable salt thereof as an active ingredient, and the above-mentioned pharmaceutical composition for producing a medicament for preventing or treating the above-mentioned disease.
  • the present invention relates to the use of a compound, or a method for preventing or treating the above disease, wherein a pharmacologically effective amount of the above compound is administered to a mammal (preferably a human).
  • Diabetes is a disease whose main feature is chronic hyperglycemia, and develops due to an absolute or relative lack of insulin action. In clinical practice, it is roughly divided into insulin-dependent diabetes (type 1 diabetes) and non-insulin-dependent diabetes (type 2 diabetes).
  • diabetes treatment is basically diet therapy and exercise therapy.
  • a drug is administered. Therefore, there is a demand for safer and more effective drugs.
  • Patent Documents 1 and 2 disclose compounds having a partial structure partially in common with the compound of the present invention.
  • the present inventors have found that the compound represented by the formula (I) described below has excellent properties in terms of pharmacokinetics based on its specific chemical structure, resulting in extremely excellent blood glucose. It has an activity such as lowering, and has excellent physical properties as a pharmaceutical product such as stability, and is safe as a prophylactic / therapeutic agent for hyperglycemia, diabetes and pathologies or diseases related to those diseases.
  • the present invention was completed based on these findings.
  • the compound of the present invention has a hypoglycemic action and the like, such as diabetes (type 1 diabetes, type 2 diabetes, gestational diabetes, etc.), postprandial hyperglycemia, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, diabetes Prevention, treatment for diseases such as retinopathy, hyperlipidemia, arteriosclerosis, thrombotic disease, obesity, hypertension, edema, insulin resistance, unstable diabetes, insulinoma, hyperinsulinemia, especially type 2 diabetes Useful as an agent.
  • diabetes type 1 diabetes, type 2 diabetes, gestational diabetes, etc.
  • postprandial hyperglycemia impaired glucose tolerance
  • diabetic neuropathy diabetic nephropathy
  • diabetes Prevention treatment for diseases such as retinopathy, hyperlipidemia, arteriosclerosis, thrombotic disease, obesity, hypertension, edema, insulin resistance, unstable diabetes, insulinoma, hyperinsulinemia, especially type 2 diabetes Useful as an agent.
  • R 1 represents a hydrogen atom, a C1-C3 alkyl group or a C3-C6 cycloalkyl group
  • R 2 represents a hydrogen atom or a C1-C3 alkyl group, or may combine with the C1-C3 alkyl group of R 1 to form a 3-6 membered saturated carbocycle
  • R 3 represents a hydrogen atom, a C1-C6 alkyl group or a C3-C6 cycloalkyl group
  • R 4 represents a hydrogen atom or a C1-C6 alkyl group, or may combine with the C1-C6 alkyl group of R 3 to form a 3-6 membered saturated carbocycle
  • X represents —CH 2 — or —C ( ⁇ O) —
  • Y represents -N (-R 5 )-or -O- R 5 is a hydrogen atom, a C1-C6 alkyl group, a hydroxy C1-C3 alkyl group,
  • ⁇ Substituent group ⁇ > C1-C3 alkyl group (the alkyl group may be substituted with one hydroxyl group), C3-C6 cycloalkyl group (the cycloalkyl group is substituted with one C1-C3 alkyl group or carboxyl group) Or a C1-C3 alkoxy group, a carbamoyl group (the C1-C3 alkylsulfonyl group, C3-C6 cycloalkylsulfonyl group or hydroxy group optionally substituted by one C1-C3 alkoxy group) One optionally substituted with a C1-C3 alkyl group), A 3-10 membered heterocyclyl group containing 1-4 identical or different heteroatoms selected from nitrogen, oxygen and sulfur; A 3-10 membered heterocyclylcarbonyl group containing the same or different 1-4 heteroatoms selected from nitrogen, oxygen and sulfur; An amino group (the amino group may be substituted by a C1-C3
  • R 1 represents a hydrogen atom, a C1-C3 alkyl group or a C3-C6 cycloalkyl group
  • R 2 represents a hydrogen atom or a C1-C3 alkyl group, or may combine with the C1-C3 alkyl group of R 1 to form a 3-6 membered saturated carbocycle
  • W represents a phenyl group (the phenyl group may be substituted with 1-4 identical or different substituents selected from the substituent group ⁇ );
  • a biphenyl group (the biphenyl group may be substituted with the same or different 1-8 substituents selected from the substituent group ⁇ ), 5- to 10-membered heteroarylphenyl group containing 1-4 heteroatoms selected from nitrogen, oxygen and sulfur (the heteroarylphenyl groups are the same or different selected from substituent group ⁇ )
  • 7-benzofuranyl group the 7-benzofuranyl group may be substituted with the same or different 1-4 substitu
  • ⁇ Substituent group ⁇ > C1-C3 alkyl group (the alkyl group may be substituted with one hydroxyl group), C3-C6 cycloalkyl group (the cycloalkyl group is substituted with one C1-C3 alkyl group or carboxyl group) Or a C1-C3 alkoxy group, a carbamoyl group (the C1-C3 alkylsulfonyl group, C3-C6 cycloalkylsulfonyl group or hydroxy group optionally substituted by one C1-C3 alkoxy group) One optionally substituted with a C1-C3 alkyl group), A 3-10 membered heterocyclyl group containing 1-4 identical or different heteroatoms selected from nitrogen, oxygen and sulfur; A 3-10 membered heterocyclylcarbonyl group containing the same or different 1-4 heteroatoms selected from nitrogen, oxygen and sulfur; An amino group (the amino group may be substituted by a C1-C3
  • R 6 represents a carboxyl group or a carbamoyl group optionally substituted by one methylsulfonyl group
  • R 7 represents a hydrogen atom or a methyl group
  • R 8 represents a hydrogen atom or a methyl group
  • R 9 represents a methyl group or a methoxy group.
  • a pharmacologically acceptable salt thereof according to any one of the above (1) to (5-4), (7-1) The compound according to the above (7) or a pharmacologically acceptable salt thereof, wherein R 6 is a carboxyl group, (7-2) The compound according to (7) or a pharmacologically acceptable salt thereof, wherein R 7 is a methyl group, (7-3) The compound according to (7) or a pharmacologically acceptable salt thereof, wherein R 9 is a methyl group, (8) 2,4-Dimethyl-7-[(3R, 9S) -2,6,6-trimethyl-1,8-dioxo-3- (propan-2-yl) -1,2,3,5, 6,7,8,9-octahydrochromeno [2,3-c] pyrrol-9-yl] -1-benzofuran-5-carboxylic acid, 6- ⁇ 4-Methoxy-2-methyl-3-[(3R, 9S) -2-methyl-1,8-dioxo-3- (prop
  • the disease is diabetes, postprandial hyperglycemia, glucose intolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, hyperlipidemia, arteriosclerosis, thrombotic disease, obesity, hypertension , Edema, insulin resistance, unstable diabetes, insulinoma or hyperinsulinemia, or a pharmacologically acceptable salt thereof according to (18) above.
  • (18-2) The compound or pharmacologically acceptable salt thereof described in (18) above, wherein the disease is type 2 diabetes. (19) The following general formula (I)
  • R 1 represents a hydrogen atom, a C1-C3 alkyl group or a C3-C6 cycloalkyl group
  • R 2 represents a hydrogen atom or a C1-C3 alkyl group, or may combine with the C1-C3 alkyl group of R 1 to form a 3-6 membered saturated carbocycle
  • R 3 represents a hydrogen atom, a C1-C6 alkyl group or a C3-C6 cycloalkyl group
  • R 4 represents a hydrogen atom or a C1-C6 alkyl group, or may combine with the C1-C6 alkyl group of R 3 to form a 3-6 membered saturated carbocycle
  • X represents —CH 2 — or —C ( ⁇ O) —
  • Y represents -N (-R 5 )-or -O- R 5 represents a hydrogen atom, a C1-C6 alkyl group, a hydroxy C1-C3 alkyl group,
  • ⁇ Substituent group ⁇ > C1-C3 alkyl group (the alkyl group may be substituted with one hydroxyl group), C3-C6 cycloalkyl group (the cycloalkyl group is substituted with one C1-C3 alkyl group or carboxyl group) Or a C1-C3 alkoxy group, a carbamoyl group (the C1-C3 alkylsulfonyl group, C3-C6 cycloalkylsulfonyl group or hydroxy group optionally substituted by one C1-C3 alkoxy group) One optionally substituted with a C1-C3 alkyl group), A 3-10 membered heterocyclyl group containing 1-4 identical or different heteroatoms selected from nitrogen, oxygen and sulfur; A 3-10 membered heterocyclylcarbonyl group containing the same or different 1-4 heteroatoms selected from nitrogen, oxygen and sulfur; An amino group (the amino group may be substituted by a C1-C3
  • the “C1-C3 alkyl group” is a linear or branched alkyl group having 1 to 3 carbon atoms, for example, a methyl, ethyl, n-propyl or isopropyl group. Can be mentioned.
  • the substituent of R 1 , R 2 , substituent group ⁇ and “C3-C6 cycloalkyl group” in substituent group ⁇ is preferably a methyl group.
  • the “C1-C6 alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms.
  • C1-3 alkyl group Listed groups or n-butyl, isobutyl, s-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methyl Pentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3 Mention may be made of -dimethylbutyl or 2-ethylbutyl groups.
  • R 3 and R 4 are preferably a t-butyl,
  • examples of the “3-6 membered saturated carbocycle” include cyclopropane, cyclobutane, cyclopentane, and cyclohexane.
  • R 1 , R 2 , R 3 and R 4 are preferably cyclopropane or cyclobutane.
  • the “C3-C6 cycloalkyl group” is a 3- to 6-membered saturated cyclic hydrocarbon group, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.
  • R 1 and R 3 are preferably a cyclopropyl group
  • R 5 and the substituent group ⁇ are preferably a cyclopropyl group or a cyclobutyl group.
  • the “hydroxy C1-C3 alkyl group” is a group in which a hydroxyl group is substituted on the “C1-C3 alkyl group”, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl.
  • Examples of the substituent of R 5 and the “carbamoyl group” of the substituent group ⁇ are preferably a hydroxymethyl group or a 1-hydroxyethyl group.
  • the “C1-C3 alkoxy group” is a group in which the “C1-C3 alkyl group” is bonded to an oxygen atom, and has, for example, a carbon number such as methoxy, ethoxy, n-propoxy, isopropoxy group. Mention may be made of 1 to 3 straight-chain or branched alkoxy groups.
  • the substituent of the substituent group ⁇ and the substituent of the “carbamoyl group” in the substituent group ⁇ is preferably a methoxy or ethoxy group.
  • the “C1-C3 alkoxy C1-C3 alkyl group” is a group in which the “C1-C3 alkoxy group” is substituted on the “C1-C3 alkyl group”.
  • n-butoxymethyl, isobutoxy Methyl, s-butoxymethyl, tert-butoxymethyl, n-pentoxymethyl isopentoxymethyl, 2-methylbutoxymethyl, neopentoxymethyl, n-hexyloxymethyl, 4-methylpentoxymethyl, 3-methyl Pentoxymethyl, 2-methylpentoxymethyl, 3,3-dimethylbutoxymethyl, 2,2-dimethylbutoxymethyl, 1,1-dimethylbutoxymethyl, 1,2-dimethylbutoxymethyl, 1,3-dimethylbutoxymethyl 2,3-dimethylbutoxymethyl group
  • R 5 is preferably a methoxyethyl group.
  • the “C2-C6 alkenyl group” is a straight chain or branched alkenyl group having 2 to 6 carbon atoms containing one double bond, such as ethenyl, 1-propenyl, 2-propenyl.
  • C2-C6 alkynyl group is a straight chain or branched alkynyl group having 2 to 6 carbon atoms containing one triple bond, such as ethynyl, prop-2-yne-1 -Yl group may be mentioned.
  • R 5 is preferably a prop-2-yn-1-yl group.
  • the “3- to 10-membered heterocyclyl group containing 1-4 heteroatoms which are the same or different and selected from nitrogen, oxygen and sulfur” refers to 3 to 4 containing 1 to 4 nitrogen, oxygen or sulfur 10-membered heterocyclic group such as furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl (for example , 2-pyridylphenyl, 3-pyridylphenyl, 4-pyridylphenyl), aromatic heterocyclic groups such as pyridazinyl, pyrimidinyl, pyrazinyl and oxetanyl, morpholiny
  • the above “4- to 10-membered heterocyclic group” may be condensed with other cyclic groups, such as benzofuranyl, chromenyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolidinyl, isoquinolyl, quinolyl, Phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, isoindolinyl, 2,3-dihydro-1-benzofuranyl, 3,4-dihydro-1H-isochromenyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4 -A tetrahydroisoquinolinyl group can be mentioned.
  • other cyclic groups such as benzofuranyl, chromenyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl,
  • Preferred examples of the substituent group ⁇ include triazolyl, tetrazolyl, morpholinyl, pyrrolidinyl, piperidinyl, and 5-oxo-4,5-dihydro-1,2,4-oxadiazolyl groups.
  • the “3- to 10-membered heterocyclic carbonyl group containing the same or different 1-4 heteroatoms selected from nitrogen, oxygen and sulfur” is selected from the above “nitrogen, oxygen and sulfur”
  • a morpholinylcarbonyl group is preferable.
  • the “5- to 10-membered heteroaryl group containing 1-4 heteroatoms which are the same or different from nitrogen, oxygen and sulfur” includes 1 to 4 nitrogen, oxygen or sulfur.
  • To 10-membered heteroaromatic group such as furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl , Pyridazinyl, pyrimidinyl and pyrazinyl groups.
  • the “5- to 10-membered heteroarylphenyl group containing 1-4 identical or different heteroatoms selected from nitrogen, oxygen and sulfur” is selected from the above “nitrogen, oxygen and sulfur” ⁇ 5- to 10-membered heteroaryl group containing the same or different 1-4 heteroatoms '' is a group bonded to a phenyl group, such as furylphenyl, thienylphenyl, pyrrolylphenyl, azepinylphenyl, pyrazolylphenyl, Imidazolylphenyl, oxazolylphenyl, oxadiazolylphenyl, isoxazolylphenyl, thiazolylphenyl, isothiazolylphenyl, 1,2,3-oxadiazolylphenyl, triazolylphenyl, tetrazolylphenyl, Thiadiazolylphenyl, pyranylphenyl, 2-pyridylphenyl
  • the “C1-C3 alkylcarbonyl group” is a group in which the “C1-C3 alkyl group” is bonded to a carbonyl group.
  • a carbon such as acetyl, propionyl, n-propylcarbonyl, isopropylcarbonyl, etc.
  • examples thereof include a linear or branched alkoxycarbonyl group having a number of 1 to 3, and the substituent of the “amino group” in the substituent group ⁇ is preferably an acetyl or propionyl group.
  • the “C1-C3 alkylsulfonyl group” is a group to which the “C1-3 alkyl group” is bonded via a sulfonyl group, such as methanesulfonyl, ethanesulfonyl, n-propanesulfonyl, isopropane.
  • a sulfonyl group can be mentioned.
  • the substituent of the substituent group ⁇ “carbamoyl group” and the substituent of the “amino group” of the substituent group ⁇ are preferably a methanesulfonyl group.
  • the “C3-C6 cycloalkylsulfonyl group” is a group to which the “C3-C6 cycloalkyl” is bonded via a sulfonyl group, such as cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexyl.
  • a sulfonyl group can be mentioned.
  • the substituent of the substituent group ⁇ “carbamoyl group” is preferably a cyclopropylsulfonyl group.
  • the “carboxy C1-C3 alkyl group” is a group in which a carboxylic acid is bonded to the “C1-3 alkyl group”. There may be mentioned three straight-chain or branched alkoxycarbonyl groups.
  • R 5 and the substituent of the “amino group” in the substituent group ⁇ are preferably ethanoic acid.
  • the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and in R 8 and the substituent group ⁇ , preferably a chlorine atom or a fluorine atom.
  • the “naphthyl group” is a 1-naphthyl group or a 2-naphthyl group, and W is preferably a 1-naphthyl group.
  • the “C1-C3 haloalkyl group” is a group obtained by substituting the “halogen atom” for the “C1-C3 alkyl group”.
  • the ⁇ C1-C3 haloalkyl group '' for example, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, Examples include 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-chloropropyl, and 2,2-dibromoethyl group.
  • R 5 is preferably a 2-fluoroethyl group. .
  • examples of the “biphenyl group” include 2-biphenyl, 3-biphenyl, and 4-biphenyl groups, and W is preferably a 3-biphenyl group.
  • the term “pharmacologically acceptable salt” refers to a case where a basic group such as an amino group is reacted with an acid, and a case where an acidic group such as a carboxyl group is present. By reacting with a base, it can be converted into a salt, so that salt is shown.
  • the salt based on the basic group is preferably a hydrohalide such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfuric acid.
  • Inorganic acid salts such as salts and phosphates; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate, aryl sulfones such as benzene sulfonate and p-toluene sulfonate Acid salt, acetate salt, malate salt, fumarate salt, succinate salt, citrate salt, ascorbate salt, tartrate salt, succinate salt, maleate salt, etc .; and glycine salt, lysine salt And amino acid salts such as arginine salt, ornithine salt, glutamate and aspartate.
  • it is a hydrohalide salt or an inorgan
  • the salt based on an acidic group is preferably an alkali metal salt such as a sodium salt, potassium salt or lithium salt, an alkaline earth metal salt such as a calcium salt or magnesium salt, an aluminum salt or an iron salt.
  • Metal salt such as ammonium salt, tert-butylamine salt, t-octylamine salt, diisopropylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglu Camine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt Salt, tris (hydro Shimechir
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof includes all isomers (keto-enol isomer, stereoisomer, etc.).
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has various isomers when an asymmetric carbon atom is present in the molecule.
  • these isomers and mixtures of these isomers are all represented by a single formula, that is, the general formula (I). Therefore, the present invention includes all of these isomers and a mixture of these isomers in an arbitrary ratio.
  • stereoisomers as described above can be obtained by isolating the synthesized compound according to the present invention, if desired, using a conventional optical resolution method or separation method.
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof may also contain an unnatural ratio of atomic isotopes at one or more of atoms constituting such a compound.
  • atomic isotopes include deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), and carbon-14 ( 14 C).
  • the compound may also be radiolabeled with a radioisotope such as, for example, tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is left in the air or recrystallized to absorb moisture and adsorb water. It may become a hydrate, and such a hydrate is also included in the salt of the present invention.
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof may absorb a certain other solvent and become a solvate, and such a solvate is also present. Included in the salts of the invention.
  • the present invention provides a compound that is metabolized in vivo and converted to a 5-membered heterocyclic derivative having the general formula (I) or a salt thereof (for example, the carboxylic acid moiety of the general formula (I) is esterified. Derivatives etc.) are all included.
  • R 1 in the present invention is preferably a C1-C3 alkyl group, and more preferably a methyl group.
  • R 2 is preferably bonded to the C1-C3 alkyl group of R 1 to form a 3-6 membered saturated carbocycle, or is a methyl group, more preferably a methyl group. . .
  • R 3 in the present invention is preferably a C1-C6 alkyl group, and more preferably an isopropyl group.
  • R 4 in the present invention is preferably a hydrogen atom.
  • R 5 in the present invention is preferably a C1-C6 alkyl group, and more preferably an ethyl group or a methyl group.
  • Y in the present invention is preferably —N (—R 5 ) —.
  • W of the present invention is preferably a 7-benzofuranyl group (the 7-benzofuranyl group may be substituted with 1-4 identical or different substituents selected from the substituent group ⁇ ) or A 5- to 10-membered heteroarylphenyl group containing 1-4 heteroatoms selected from the same, or different, selected from nitrogen, oxygen and sulfur (the heteroarylphenyl groups are the same or selected from the substituent group ⁇ ) Which may be substituted with 1 to 8 different substituents), and more preferably the following general formula (Ii)
  • R 6 represents a carboxyl group or a carbamoyl group optionally substituted by one methylsulfonyl group
  • R 7 represents a hydrogen atom or a methyl group
  • R 8 represents a hydrogen atom or a methyl group
  • R 9 represents a methyl group or a methoxy group.
  • R 10 represents a hydrogen atom or a methyl group.
  • the substituent group ⁇ of the present invention is preferably a C3-C6 cycloalkyl group, a C1-C3 alkoxy group and a carboxyl group in the substituent of the phenyl group of W.
  • the substituent group ⁇ of the present invention is preferably a C1-C3 alkyl group, a C1-C3 alkoxy group and a carboxyl group in the substituent of the biphenyl group of W.
  • the substituent group ⁇ of the present invention is preferably a carbamoyl group in a substituent of a 5- to 10-membered heteroarylphenyl group containing 1-4 heteroatoms selected from nitrogen, oxygen and sulfur of W.
  • the carbamoyl group may be substituted with a C1-C3 alkylsulfonyl group, a C3-C6 cycloalkylsulfonyl group, or a hydroxy C1-C3 alkyl group, which may be substituted with a C1-C3 alkoxy group.
  • C1-C3 alkyl group C1-C3 alkoxy group or carboxyl group, and more preferably a carbamoyl group (the carbamoyl group may be substituted with one methylsulfonyl group), a methyl group, A methoxy group and a carboxyl group;
  • the general formula (I) of the present invention is preferably the following formula (Ib), (Ic) or (Id),
  • the compound having the general formula (I) of the present invention can be produced, for example, by the following method.
  • Method A Among the compounds having the general formula (I), Y is —N (—R 5 ) —.
  • Compound (Ib) in which X is —C ( ⁇ O) — can be produced by carrying out Steps A-1 to A-3.
  • the compound (Ic) in which Y is —N (—R 5 ) — and X is —CH 2 — is subjected to steps A-1 to A-5. Can be manufactured.
  • Method B Among the compounds having the general formula (I), the compound (Id) in which Y is —O— and X is —C ( ⁇ O) — is obtained after steps A-1 and B-1 to B— It can be manufactured by carrying out 4 steps.
  • Compound (Ie) in which Y is —O— and X is —CH 2 — can be produced by performing steps B-1 to B-6 after steps A-1 to A-5.
  • W, X, Y, R 1 , R 2 , R 3 , R 4 and R 5 have the same meaning as described above.
  • P 1 is not particularly limited as long as it is a protecting group used for protecting a carboxyl group.
  • P 2 is not particularly limited as long as it is a protecting group used for protecting a hydroxyl group, but benzyl group, trimethylsilyl group, triethylsilyl group, isopropyldimethylsilyl group, t-butyldimethylsilyl group A methyldiisopropylsilyl group, a methyldi-t-butylsilyl group or a triisopropylsilyl group is preferred.
  • Protecting and deprotecting hydroxyl groups, amino groups and carboxyl groups during the above steps and in the following description can be carried out by conventional methods in the field of synthetic organic chemistry.
  • the methods and protecting groups described in Green Watts, "Protective groups in organic synthesis 4th edition” (Wiley-Interscience, USA) can be mentioned, but are not limited thereto. Is not to be done.
  • Raw material compound (1), compound (2), and cocoon compound (4) are commercially available or can be synthesized by methods in accordance with literature.
  • Raw material compound (7) is commercially available or can be synthesized according to literature.
  • This step is a step for producing the intermediate compound (3) by reacting the starting compound (1) with the compound (2) in the presence of a base in a solvent.
  • the solvent is preferably an ether or an amide, more preferably acetonitrile, tetrahydrofuran or N, N-dimethylformamide.
  • the base is preferably an organic base or an inorganic base, more preferably an amino acid, an amine, an alkali metal carbonate or an alkaline earth metal carbonate, and more preferably proline, pyrrolidine, or piperidine. Morpholine, triethylamine, diisopropylethylamine, cesium carbonate or potassium carbonate.
  • the reaction temperature is usually 0 ° C. to 100 ° C., preferably 0 ° C. to 60 ° C.
  • the reaction time is usually 0.5 to 72 hours, preferably 1 to 30 hours.
  • step A-2 may be directly performed without isolating the compound (3).
  • This step is a step for producing intermediate compound (5) by reacting compound (3) with compound (4) in the presence of a base in a solvent.
  • the solvent is preferably an ether or an amide, more preferably acetonitrile, tetrahydrofuran or N, N-dimethylformamide.
  • the base is preferably an organic base or an inorganic base, more preferably amines, alkali metal carbonates or alkaline earth metal carbonates, and more preferably pyrrolidine, piperidine, morpholine, triethylamine. Diisopropylethylamine, cesium carbonate or potassium carbonate.
  • the reaction temperature is usually 0 ° C. to 100 ° C., preferably 0 ° C. to room temperature.
  • the reaction time is usually 0.5 to 48 hours, preferably 1 to 30 hours.
  • step A-3 may be directly performed without isolating the compound (5).
  • This step is a step of producing the target compound (Ib) by activating the enolic hydroxyl group of the compound (5) in a solvent.
  • Methanesulfonylation or trifluoromethanesulfonylation is used as a method for activating the enolic hydroxyl group.
  • the solvent is preferably ethers, halogenated hydrocarbons or amides, more preferably tetrahydrofuran, dichloromethane or N, N-dimethylformamide.
  • the base is preferably an organic base or an alkaline earth metal carbonate, and more preferably triethylamine, diisopropylethylamine, cesium carbonate or potassium carbonate.
  • methanesulfonylating agent or trifluoromethanesulfonylating agent examples include methanesulfonyl chloride, methanesulfonic anhydride, N-phenylbis (trifluoromethanesulfonimide), and trifluoromethanesulfonic anhydride.
  • the reaction temperature is usually 0 ° C. to 100 ° C., preferably 0 ° C. to room temperature.
  • the reaction time is usually 0.5 to 48 hours, preferably 1 to 30 hours.
  • This step is a step for producing intermediate compound (6) by reacting compound (Ib) with a thiocarbonylating agent in a solvent.
  • the solvent is preferably an ether or hydrocarbon, and more preferably tetrahydrofuran, 1,4-dioxane or toluene.
  • the thiocarbonylating agent is preferably Lawesson's reagent or diphosphorus pentasulfide.
  • the reaction temperature is usually 0 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is usually 0.5 to 48 hours, preferably 1 to 30 hours.
  • This step is a step of producing compound (Ic) by reacting intermediate compound (6) with a reducing agent in a solvent.
  • the solvent is preferably an ether or an alcohol, and more preferably tetrahydrofuran or ethanol.
  • the reducing agent is preferably a transition metal, a mixture of a reducing agent and a transition metal, and more preferably a mixture of Raney nickel, sodium borohydride and nickel chloride.
  • the reaction temperature is usually 0 ° C. to 100 ° C., preferably 0 ° C. to room temperature.
  • the reaction time is usually 0.5 to 48 hours, preferably 1 to 30 hours.
  • This step is a step for producing the intermediate compound (8) by reacting the intermediate compound (3) with the compound (7) in the presence of a base in a solvent.
  • the solvent is preferably ethers or amides, more preferably acetonitrile, tetrahydrofuran or N, N-dimethylformamide.
  • the base is preferably an organic base or an inorganic base, more preferably amines, alkali metal carbonates or alkaline earth metal carbonates, more preferably pyrrolidine, piperidine, morpholine, triethylamine, Diisopropylethylamine, cesium carbonate or potassium carbonate.
  • the reaction temperature is usually 0 ° C. to 100 ° C., preferably 0 ° C. to room temperature.
  • the reaction time is usually 0.5 to 48 hours, preferably 1 to 30 hours.
  • Step B-2 may be carried out without isolating compound (8).
  • This step is a step of producing the intermediate compound (9) by activating the enolic hydroxyl group of the intermediate compound (8) in a solvent by Mitsunobu reaction.
  • the solvent is preferably an ether, a hydrocarbon or a halogenated hydrocarbon, and more preferably tetrahydrofuran, toluene or dichloromethane.
  • the azo reagent used in the Mitsunobu reaction is preferably diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, 1,1 ′-(azodicarbonyl) dipiperidine.
  • the phosphine reagent used for the Mitsunobu reaction is preferably triphenylphosphine, tributylphosphine, or tricyclohexylphosphine.
  • the reaction temperature is usually 0 ° C. to 100 ° C., preferably 0 ° C. to room temperature.
  • the reaction time is usually 0.5 to 48 hours, preferably 1 to 30 hours.
  • step B-3 may be directly performed without isolating compound (9).
  • This step is a deprotection step of the protecting group P 2 of the intermediate compound (9), and the deprotection can be performed by a conventional method in the field of organic synthetic chemistry.
  • P 2 is a substituted benzyl group, for example, the following hydrogenolysis conditions can be applied.
  • the solvent is preferably an ether or an alcohol, and more preferably tetrahydrofuran or ethanol.
  • the catalyst is preferably a palladium catalyst, and more preferably palladium hydroxide carbon or palladium carbon.
  • the reaction temperature is usually 0 ° C. to 100 ° C., preferably 0 ° C. to room temperature.
  • the reaction time is usually 0.5 to 48 hours, preferably 1 to 30 hours.
  • This step is a step of producing the target compound (Id) by a ring-closing reaction to a lactone with an acid, and the ester can be hydrolyzed as necessary.
  • the solvent is preferably ethers, halogenated hydrocarbons or hydrocarbons, and more preferably tetrahydrofuran, 1,4-dioxane, dichloromethane or toluene.
  • the acid is preferably trifluoroacetic acid.
  • the reaction temperature is usually 0 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is usually 0.5 to 48 hours, preferably 1 to 30 hours.
  • Step B-5 This step is a step of producing intermediate compound (11) by reacting compound (Id) with a thiocarbonylating agent in a solvent, and can be carried out according to the step described in Step A-4. it can.
  • Step B-6 This step is a step of producing compound (Ie) by reacting intermediate compound (11) with a reducing agent in a solvent, and can be carried out according to the step described in Step A-5.
  • the target compound can also be produced by appropriately adding a step of introducing a substituent R 5 onto the nitrogen atom in any of the steps of Method A and Method B.
  • Introduction of the substituent R 5 onto the nitrogen atom can be achieved, for example, by reacting a halide of R 5 (chloride, bromide, etc.) in a solvent in the presence of a base.
  • the solvent used is preferably an ether or an amide, more preferably tetrahydrofuran or N, N-dimethylformamide.
  • the base is preferably an inorganic base, more preferably an alkali metal hydride or alkaline earth metal hydride, and more preferably sodium hydride.
  • the reaction temperature is usually 0 ° C. to 100 ° C., preferably 0 ° C. to room temperature.
  • the reaction time is usually 0.5 to 48 hours, preferably 1 to 30 hours.
  • the solvent is preferably ethers, halogenated hydrocarbons or alcohols, and more preferably tetrahydrofuran, dichloromethane, methanol or ethanol.
  • the base is preferably a metal hydroxide, and more preferably sodium hydroxide, lithium hydroxide, or potassium hydroxide.
  • the acid is preferably hydrochloric acid or trifluoroacetic acid.
  • the reaction temperature is usually 0 ° C. to 100 ° C., preferably 0 ° C. to room temperature.
  • the reaction time is usually 0.5 to 48 hours, preferably 1 to 30 hours.
  • the solvent is preferably a halogenated hydrocarbon, ether or amide, more preferably dichloromethane, tetrahydrofuran or N, N-dimethylformamide.
  • the condensing agent is preferably carbonyldiimidazole.
  • the reaction temperature is usually 0 ° C. to 100 ° C., preferably 0 ° C. to room temperature.
  • the reaction time is usually 0.5 to 48 hours, preferably 1 to 30 hours.
  • the solvent is preferably an ether or an amide, more preferably 1,4-dioxane or tetrahydrofuran.
  • the catalyst is, for example, a divalent palladium catalyst or a zero-valent palladium catalyst, and more preferably PdCl 2 (dppe), PdCl 2 (dppf), or PdCl 2 (Ph 3 P) 2 .
  • the reaction temperature is usually 0 ° C. to 150 ° C., preferably room temperature to 120 ° C.
  • the reaction time is usually 0.5 to 60 hours, preferably 1 to 48 hours.
  • the solvent is preferably an ether or an amide, more preferably 1,4-dioxane or tetrahydrofuran.
  • the catalyst is, for example, a divalent palladium catalyst or a zero-valent palladium catalyst, more preferably PdCl 2 (dppe), PdCl 2 (dppf), Pd (Ph 3 P) 4 or 2nd Generation X-Phos Precatalyst. It is.
  • the reaction temperature is usually 0 ° C. to 150 ° C., preferably room temperature to 120 ° C.
  • the reaction time is usually 0.5 to 60 hours, preferably 1 to 48 hours.
  • the target compound is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added, washed with water, and the target compound is then contained.
  • the organic layer is separated, dried over anhydrous magnesium sulfate and the like, and then the solvent is distilled off.
  • the obtained target product can be obtained by a conventional method such as recrystallization, reprecipitation, or a method usually used for separation and purification of organic compounds, such as adsorption column chromatography, distribution column chromatography, etc. Separation and purification by eluting with an appropriate eluent by combining a method using a synthetic adsorbent, a method using ion exchange chromatography, or a normal phase / reverse phase column chromatography method using silica gel or alkylated silica gel. can do.
  • the optically active substance can be separated and purified by a chiral column.
  • the 5-membered heterocyclic derivative having the general formula (I) of the present invention and a pharmacologically acceptable salt thereof are administered in various forms.
  • the administration form is not particularly limited, and is determined according to various preparation forms, patient age, sex and other conditions, the degree of disease, and the like.
  • tablets, pills, powders, granules, syrups, solutions, suspensions, emulsions and capsules they are administered orally.
  • a normal replacement fluid such as glucose or amino acid
  • it is administered intramuscularly, intradermally, subcutaneously or intraperitoneally as necessary.
  • a suppository it is administered intrarectally. Oral administration is preferred.
  • compositions are prepared by using known adjuvants that can be generally used in the field of known pharmaceutical preparations such as excipients, binders, disintegrants, lubricants, solubilizers, flavoring agents, and coating agents according to conventional methods. It can be formulated.
  • conventionally known carriers can be widely used as carriers, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and the like.
  • carriers such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and the like.
  • Form water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders, dry starch, sodium alginate, agar powder, laminaran powder Sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose and other disintegrants, sucrose, stearin, cacao butter, hydrogenated oil and other
  • the tablets can be made into tablets with ordinary coatings as necessary, for example, sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multilayer tablets.
  • those conventionally known in this field can be widely used as carriers, for example, glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc and other excipients, gum arabic powder, Examples thereof include binders such as tragacanth powder, gelatin and ethanol, and disintegrants such as lamina lankanten.
  • conventionally known carriers can be widely used as carriers, such as polyethylene glycol, cacao butter, higher alcohols, higher alcohol esters, gelatin, semi-synthetic glycerides and the like. it can.
  • the solutions and suspensions are preferably sterilized and isotonic with blood, and in the form of these solutions, emulsions and suspensions, this is used as a diluent.
  • Any of those commonly used in the field can be used, and examples thereof include water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters.
  • a sufficient amount of sodium chloride, glucose, or glycerin to prepare an isotonic solution may be contained in the pharmaceutical preparation.
  • Ordinary solubilizers, buffers, soothing agents, etc. may be added. It may be added.
  • colorants may be included.
  • preservatives may be included.
  • fragrances may be included.
  • flavors may be included.
  • sweeteners may be included.
  • the amount of the active ingredient compound contained in the pharmaceutical preparation is not particularly limited and is appropriately selected within a wide range, but is usually 1 to 70% by weight, preferably 1 to 30% by weight in the total composition. Is appropriate.
  • the dosage varies depending on symptoms, age, body weight, administration method, dosage form, etc., but is usually 0.001 mg / kg (preferably 0.01 mg / kg, more preferably 0.1 mg as a lower limit for adults per day) / mg), and 200 mg / kg (preferably 20 mg / kg, more preferably 10 mg / kg) as the upper limit can be administered once to several times.
  • the compound of the present invention can be used in combination with various therapeutic or prophylactic agents for the diseases for which the present invention is considered to be effective.
  • the combination may be administered simultaneously or separately in succession or at desired time intervals.
  • the simultaneous administration preparation may be a compounding agent or may be separately formulated.
  • antidiabetic agents that can be used in combination include insulin preparations, sulfonylureas, thiazolidines, biguanides, ⁇ -glucosidase inhibitors, fast-acting insulin secretagogues, GLP-1 receptor agonists, SGLT2 inhibitors And DPPIV inhibitors and the like.
  • the 5-membered heterocyclic derivative and the pharmacologically acceptable salt thereof, which are the compounds of the present invention, have an excellent hypoglycemic action, such as diabetes (type 1 diabetes, type 2 diabetes, gestational diabetes, etc.), postprandial hyperglycemia.
  • diabetes type 1 diabetes, type 2 diabetes, gestational diabetes, etc.
  • postprandial hyperglycemia Impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, hyperlipidemia, arteriosclerosis, thrombotic disease, obesity, hypertension, edema, insulin resistance, unstable diabetes, insulinoma, high
  • it since it is low in toxicity and excellent in safety, it can be said that it is extremely useful as a medicine.
  • silica gel SK-85 230-400 mesh
  • silica gel SK-34 70-230 mesh
  • Fuji Silysia Chemical Chromatorex NH 200-350 mesh
  • Merck & Co., Inc. was used.
  • SP-1 Biotage's automated chromatography device
  • Yamazen's automated chromatography device Yamazen's automated chromatography device
  • Teledyne Isco's automated chromatography device CombiFlash Rf
  • Hexane represents n-hexane
  • THF represents tetrahydrofuran
  • DME represents 1,2-dimethoxyethane
  • DMA represents N, N-dimethylacetamide
  • DMF represents N, N-dimethylformamide
  • DBU represents 1,8-diazabicyclo [5.4.0] undec-7-ene
  • 2nd generation X-phos precatalyst is chloro (2-dicyclohexylphosphino-2 ', 4', 6'-triisopropyl-1,1'- Biphenyl) [2- (2′-amino-1,1′-biphenyl)] palladium (II)
  • WSC ⁇ HCl represents N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride.
  • the first peak was shown as a low polarity compound, and the second peak was shown as a high polarity compound.
  • Cesi Beam (263 mg, 0.807 mmol) was added.
  • the reaction solution was stirred at room temperature for 30 minutes, methanesulfonyl chloride (38 ⁇ L, 0.484 mmol) was added, and the reaction solution was further stirred at room temperature for 8 hours.
  • Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate.
  • reaction solution was concentrated, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted twice with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (24.1 mg, 16%).
  • Example 2 6- [3-[(3R * , 9R * )-3-Isopropyl-2,6,6-trimethyl-1,8-dioxo-3,5,7,9-tetrahydrochromeno [2,3-c] Pyrrole-9-yl] -4-methoxy-2-methyl-phenyl] pyridine-2-carboxylic acid (2a) Benzyl 6- ⁇ 4-methoxy-2-methyl-3-[(3R *, 9R *)-2,6,6-trimethyl-1,8-dioxo-3- (propan-2-yl)- 1,2,3,5,6,7,8,9-Octahydrochromeno [2,3-c] pyrrol-9-yl] phenyl ⁇ pyridine-2-carboxylate Benzyl by-produced in Example 1f 6 - ⁇ 3-[(3R *, 9R *)-6,6-dimethyl-1,8-dioxo-3- (propan-2-yl)
  • Example 3 6- ⁇ 3-[(3R *, 9S *)-6,6-dimethyl-1,8-dioxo-3- (propan-2-yl) -1,2,3,5,6,7,8, 9-Octahydrochromeno [2,3-c] pyrrol-9-yl] -4-methoxy-2-methylphenyl ⁇ pyridine-2-carboxylic acid (3a) 2- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene] -5,5-dimethylcyclohexane- 1,3-dione 6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzaldehyde prepared in Example 1b (1.00 g, 3.62 mmol) and pyrrolidine (30 ⁇ L, 0.362 mmol) in DMF (3.6
  • reaction solution was stirred at 0 ° C. for 2 hours, methanesulfonyl chloride (70 ⁇ L, 0.904 mmol) was added, and the reaction solution was further stirred at room temperature for 22 hours.
  • Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate; 7: 3) to obtain the title compound (120 mg, 26%).
  • Example 4 6- [3-[(3R, 9S) -3-Isopropyl-2,6,6-trimethyl-1,8-dioxo-3,5,7,9-tetrahydrochromeno [2,3-c] pyrrole- 9-yl] -4-methoxy-2-methyl-phenyl] pyridine-2-carboxylic acid (4a) benzyl 6- ⁇ 3-[(3R, 9S) -6,6-dimethyl-1,8-dioxo-3- (propan-2-yl) -1,2,3,5,6,7, 8,9-Octahydrochromeno [2,3-c] pyrrol-9-yl] -4-methoxy-2-methylphenyl ⁇ pyridine-2-carboxylate and benzyl 6- ⁇ 3-[(3R, 9R) -6,6-Dimethyl-1,8-dioxo-3- (propan-2-yl) -1,2,3,5,6,7
  • reaction solution was stirred at 0 ° C. for 2 hours, methanesulfonyl chloride (35 ⁇ L, 0.455 mmol) was added, and the reaction solution was further stirred at room temperature for 22 hours.
  • Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate; 7: 3) to obtain the title compound (174 mg, 69%) as a diastereomer mixture.
  • Example 5 6- [3-[(3R, 9S) -3-Isopropyl-2,6,6-trimethyl-1,8-dioxo-3,5,7,9-tetrahydrochromeno [2,3-c] pyrrole- 9-yl] -4-methoxy-2-methyl-phenyl] pyridine-2-carboxylic acid (5a) (3R, 9S) -9- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -6 , 6-Dimethyl-3- (propan-2-yl) -2,3,5,6,7,9-hexahydrochromeno [2,3-c] pyrrole-1,8-dione prepared in Example 3a 2- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylidene]
  • Example 6 6- [3-[(3S, 9R) -3-Isopropyl-2,6,6-trimethyl-1,8-dioxo-3,5,7,9-tetrahydrochromeno [2,3-c] pyrrole- 9-yl] -4-methoxy-2-methyl-phenyl] pyridine-2-carboxylic acid tert-butylamine salt (6a) benzyl 6- ⁇ 3-[(3S, 9R) -6,6-dimethyl-1,8-dioxo-3- (propan-2-yl) -1,2,3,5,6,7, 8,9-Octahydrochromeno [2,3-c] pyrrol-9-yl] -4-methoxy-2-methylphenyl ⁇ pyridine-2-carboxylate and benzyl 6- ⁇ 3-[(3S, 9S) -6,6-Dimethyl-1,8-dioxo-3- (propan-2-yl)
  • Example 7 6- ⁇ 3-[(3R *, 9R *)-6,6-dimethyl-1,8-dioxo-3- (propan-2-yl) -1,2,3,5,6,7,8, 9-Octahydrochromeno [2,3-c] pyrrol-9-yl] -4-methoxy-2-methylphenyl ⁇ pyridine-2-carboxylic acid (7a) tert-butyl (3R *, 9R *)-9- ⁇ 3- [6- (tert-butoxycarbonyl) pyridin-2-yl] -6-methoxy-2-methylphenyl ⁇ -6,6-dimethyl -1,8-Dioxo-3- (propan-2-yl) -3,5,6,7,8,9-hexahydrochromeno [2,3-c] pyrrole-2 (1H) -carboxylate (3R *, 9R *)-9- [6-methoxy-2-methyl-3- (4,4,5,
  • Example 9 6- ⁇ 4-Methoxy-2-methyl-3-[(3R *, 9S *)-2,6,6-trimethyl-1,8-dioxo-3- (propan-2-yl) -1,2, 3,5,6,7,8,9-Octahydrochromeno [2,3-c] pyrrol-9-yl] phenyl ⁇ -N- (methylsulfonyl) pyridine-2-carboxamide Prepared in Example 1h 6 -[3-[(3R *, 9S *)-3-Isopropyl-2,6,6-trimethyl-1,8-dioxo-3,5,7,9-tetrahydrochromeno [2,3-c] pyrrole -9-yl] -4-methoxy-2-methyl-phenyl] pyridine-2-carboxylic acid (60.0 mg, 0.113 mmol) and carbonyldiimidazole (22.0 mg, 0.136 mmol) in DMF (1.2 mL
  • Example 10 6- ⁇ 4-Methoxy-2-methyl-3-[(3R *, 9S *)-2,6,6-trimethyl-1,8-dioxo-3- (propan-2-yl) -1,2, 3,5,6,7,8,9-octahydrochromeno [2,3-c] pyrrol-9-yl] phenyl ⁇ -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide tert-butylamine salt (10a) 6- ⁇ 4-Methoxy-2-methyl-3-[(3R *, 9S *)-2,6,6-trimethyl-1,8-dioxo-3- (propan-2-yl) -1 , 2,3,5,6,7,8,9-Octahydrochromeno [2,3-c] pyrrol-9-yl] phenyl ⁇ -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide 6- ⁇ 4-Methoxy-2-methyl-3-
  • Methanesulfonamide (45.4 mg, 0.477 mmol) and DBU (71 ⁇ L, 0.477 mmol) were added to the reaction solution, and the reaction solution was further stirred at room temperature for 3 hours. 1 M hydrochloric acid was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was recrystallized from octane and hexane to obtain the title compound (134 mg, 59%).
  • Example 11 6- ⁇ 4-Methoxy-2-methyl-3-[(3R, 9S) -2,6,6-trimethyl-1,8-dioxo-3- (propan-2-yl) -1,2,3, 5,6,7,8,9-Octahydrochromeno [2,3-c] pyrrol-9-yl] phenyl ⁇ -3-methylpyridine-2-carboxylic acid tert-butylamine salt
  • 11a tert-butyl 6- ⁇ 4-methoxy-2-methyl-3-[(3R, 9S) -2,6,6-trimethyl-1,8-dioxo-3- (propan-2-yl)- 1,2,3,5,6,7,8,9-octahydrochromeno [2,3-c] pyrrol-9-yl] phenyl ⁇ -3-methylpyridine-2-carboxylate prepared in Example 5b (3R, 9S) -9- [6-Methoxy-2-methyl-3- (4,4,5,
  • Example 13 6- ⁇ 4-Methoxy-2-methyl-3-[(3S, 9R) -2,6,6-trimethyl-1,8-dioxo-3- (propan-2-yl) -1,2,3, 5,6,7,8,9-Octahydrochromeno [2,3-c] pyrrol-9-yl] phenyl ⁇ -3-methylpyridine-2-carboxylic acid tert-butylamine salt
  • 13a (3S, 9R) -9- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -6 , 6-Dimethyl-3- (propan-2-yl) -2,3,5,6,7,9-hexahydrochromeno [2,3-c] pyrrole-1,8-dione prepared in Example 3a 2- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-
  • Example 15 6- ⁇ 4-Methoxy-2-methyl-3-[(3R, 9S) -2,6,6-trimethyl-1,8-dioxo-3- (propan-2-yl) -1,2,3, 5,6,7,8,9-Octahydrochromeno [2,3-c] pyrrol-9-yl] phenyl ⁇ -N- (methylsulfonyl) pyridine-2-carboxamide tert-butylamine salt
  • Example 15a 6- ⁇ 4-Methoxy-2-methyl-3-[(3R, 9S) -2,6,6-trimethyl-1,8-dioxo-3- (propan-2-yl) -1,2 , 3,5,6,7,8,9-Octahydrochromeno [2,3-c] pyrrol-9-yl] phenyl ⁇ -N- (methylsulfonyl) pyridine-2-carboxamide Prepared in Example 4c 6- [3-[(3R, 9S)
  • Example 17 6- ⁇ 4-Methoxy-2-methyl-3-[(3S, 9R) -2,6,6-trimethyl-1,8-dioxo-3- (propan-2-yl) -1,2,3, 5,6,7,8,9-Octahydrochromeno [2,3-c] pyrrol-9-yl] phenyl ⁇ -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide tert-butylamine salt (17a) 6- ⁇ 4-Methoxy-2-methyl-3-[(3S, 9R) -2,6,6-trimethyl-1,8-dioxo-3- (propan-2-yl) -1,2 , 3,5,6,7,8,9-Octahydrochromeno [2,3-c] pyrrol-9-yl] phenyl ⁇ -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide Examples 6- ⁇ 4-Methoxy-2-methyl-3-
  • Example 18 6- ⁇ 3-[(3R, 9S) -6,6-Dimethyl-1,8-dioxo-3- (propan-2-yl) -2- (prop-2-yn-1-yl) -1, 2,3,5,6,7,8,9-octahydrochromeno [2,3-c] pyrrol-9-yl] -4-methoxy-2-methylphenyl ⁇ pyridine-2-carboxylic acid (18a) tert-butyl 6- ⁇ 3-[(3R, 9S) -6,6-dimethyl-1,8-dioxo-3- (propan-2-yl) -1,2,3,5,6, 7,8,9-Octahydrochromeno [2,3-c] pyrrol-9-yl] -4-methoxy-2-methylphenyl ⁇ pyridine-2-carboxylate prepared in Example 5a (3R, 9S) -9- [6-Methoxy-2-methyl-3- (4,4,5,5-
  • Example 20 6- ⁇ 3-[(3R, 9S) -6,6-Dimethyl-1,8-dioxo-3- (propan-2-yl) -2-propyl-1,2,3,5,6,7, 8,9-Octahydrochromeno [2,3-c] pyrrol-9-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxylic acid (20a) tert-butyl 6- ⁇ 3-[(3R, 9S) -6,6-dimethyl-1,8-dioxo-3- (propan-2-yl) -2-propyl-1,2,3, 5,6,7,8,9-Octahydrochromeno [2,3-c] pyrrol-9-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxylate under hydrogen atmosphere Tert-butyl 6- ⁇ 3-[(3R, 9S) -6,6-dimethyl-1
  • Example 23 6- ⁇ 3-[(3R, 9S) -6,6-Dimethyl-1,8-dioxo-3- (propan-2-yl) -2-propyl-1,2,3,5,6,7, 8,9-Octahydrochromeno [2,3-c] pyrrol-9-yl] -4-methoxy-2-methylphenyl ⁇ -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide
  • Example 20b 6- ⁇ 3-[(3R, 9S) -6,6-Dimethyl-1,8-dioxo-3- (propan-2-yl) -2-propyl-1,2,3,5,6 , 7,8,9-Octahydrochromeno [2,3-c] pyrrol-9-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxylic acid (50.6 mg, 0.0884 mmol ), Carbonyldiimidazole (1
  • Example 26 6- ⁇ 3-[(3R, 9S) -2-ethyl-6,6-dimethyl-1,8-dioxo-3- (propan-2-yl) -1,2,3,5,6,7, 8,9-Octahydrochromeno [2,3-c] pyrrol-9-yl] -4-methoxy-2-methylphenyl ⁇ -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide tert-butylamine salt (26a) 6- ⁇ 3-[(3R, 9S) -2-ethyl-6,6-dimethyl-1,8-dioxo-3- (propan-2-yl) -1,2,3,5,6 , 7,8,9-Octahydrochromeno [2,3-c] pyrrol-9-yl] -4-methoxy-2-methylphenyl ⁇ -3-methyl-N- (methylsulfonyl) pyridine-2-carboxamide ter
  • Example 28 6- ⁇ 3-[(3R, 9S) -3-tert-butyl-2-ethyl-6,6-dimethyl-1,8-dioxo-1,2,3,5,6,7,8,9- Octahydrochromeno [2,3-c] pyrrol-9-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxylic acid (28a) (3R, 9S) -3-tert-Butyl-2-ethyl-9- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl) phenyl] -6,6-dimethyl-2,3,5,6,7,9-hexahydrochromeno [2,3-c] pyrrole-1,8-dione prepared in Example 27c (3R, 9S) -3-tert-butyl-9- [6-methoxy-2-methyl-3- (4,4,5,
  • Example 32 6- ⁇ 3-[(3R, 9S) -2-ethyl-6,6-dimethyl-1,8-dioxo-3- (propan-2-yl) -1,2,3,5,6,7, 8,9-Octahydrochromeno [2,3-c] pyrrol-9-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxamide 6- ⁇ 3 prepared in Example 12c -[(3R, 9S) -2-ethyl-6,6-dimethyl-1,8-dioxo-3- (propan-2-yl) -1,2,3,5,6,7,8,9- Octahydrochromeno [2,3-c] pyrrol-9-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxylic acid (100 mg, 0.179 mmol) in DMF (1.0 mL) Carbonyldiimidazole (34.8 mg,
  • Aqueous ammonia solution (28%, 0.50 mL) was added to the reaction solution, and the reaction solution was further stirred at room temperature for 30 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 10% aqueous citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was crystallized from hexane and ether to obtain the title compound (88.4 mg, 89%).
  • Example 33 6- ⁇ 4-Methoxy-2-methyl-3-[(3R, 9S) -2,6,6-trimethyl-1,8-dioxo-3- (propan-2-yl) -1,2,3, 5,6,7,8,9-Octahydrochromeno [2,3-c] pyrrol-9-yl] phenyl ⁇ -3,4-dimethylpyridine-2-carboxylic acid tert-butylamine salt
  • 33a 3,4-Dimethylpyridine-2-carbonitrile 1-oxide 3,4-Dimethylpyridine-2-carbonitrile (30.0 g, 227 mmol), Oxone (101 g, 363 mmol) in methanol (150 mL) And the water (150 mL) solution was stirred at room temperature for 48 hours.
  • Example 34 6- ⁇ 3-[(3R, 9S) -2-ethyl-6,6-dimethyl-1,8-dioxo-3- (propan-2-yl) -1,2,3,5,6,7, 8,9-Octahydrochromeno [2,3-c] pyrrol-9-yl] -4-methoxy-2-methylphenyl ⁇ -3,4-dimethylpyridine-2-carboxylic acid tert-butylamine salt (34a) tert-butyl 6- ⁇ 3-[(3R, 9S) -2-ethyl-6,6-dimethyl-1,8-dioxo-3- (propan-2-yl) -1,2,3, 5,6,7,8,9-octahydrochromeno [2,3-c] pyrrol-9-yl] -4-methoxy-2-methylphenyl ⁇ -3,4-dimethylpyridine-2-carboxylate (3R, 9S) -2-Eth
  • Example 36 (3R, 9S) -9- [3- (2-Aminopyrimidin-4-yl) -6-methoxy-2-methylphenyl] -6,6-dimethyl-3- (propan-2-yl) -2, 3,5,6,7,9-Hexahydrochromeno [2,3-c] pyrrole-1,8-dione (36a) Di-tert-butyl (4- ⁇ 3-[(3R, 9S) -6,6-dimethyl-1,8-dioxo-3- (propan-2-yl) -1,2,3,5 , 6,7,8,9-Octahydrochromeno [2,3-c] pyrrol-9-yl] -4-methoxy-2-methylphenyl ⁇ pyrimidin-2-yl) imide dicarbonate Prepared in Example 5a (3R, 9S) -9- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-diox
  • the reaction solution was diluted with ethyl acetate, and the organic layer was washed with water and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate; 1: 4) to obtain the title compound (406 mg, 43%).
  • Example 38 1- (6- ⁇ 3-[(3R, 9S) -6,6-Dimethyl-1,8-dioxo-3- (propan-2-yl) -1,2,3,5,6,7,8 , 9-Octahydrochromeno [2,3-c] pyrrol-9-yl] -4-methoxy-2-methylphenyl ⁇ pyridin-2-yl) urea (3R, 9S) -9 prepared in Example 35 -[3- (6-Aminopyridin-2-yl) -6-methoxy-2-methylphenyl] -6,6-dimethyl-3- (propan-2-yl) -2,3,5,6,7 , 9-hexahydrochromeno [2,3-c] pyrrole-1,8-dione (41.9 mg, 0.0859 mmol) and triethylamine (29.9 mg, 0.215 mmol) in THF (1.0 mL) at 0 ° C with trip
  • Example 40 (3R, 9S) -9- ⁇ 3- [6- (2-Hydroxypropan-2-yl) -5-methylpyridin-2-yl] -6-methoxy-2-methylphenyl ⁇ -6,6-dimethyl -3- (propan-2-yl) -2,3,5,6,7,9-hexahydrochromeno [2,3-c] pyrrole-1,8-dione prepared in Example 5a (3R, 9S) -9- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -6,6-dimethyl-3 -(Propan-2-yl) -2,3,5,6,7,9-hexahydrochromeno [2,3-c] pyrrole-1,8-dione (200 mg, 0.384 mmol), Example 39a 2- (6-Chloro-3-methylpyridin-2-yl
  • Example 45 6- ⁇ 3-[(3R, 9S) -2-Ethyl-1,8-dioxo-3- (propan-2-yl) -2,3,5,7,8,9-hexahydro-1H-spiro [ Chromeno [2,3-c] pyrrole-6,1'-cyclobutane] -9-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxylic acid (45a) tert-butyl 6- ⁇ 3-[(3R, 9S) -2-ethyl-1,8-dioxo-3- (propan-2-yl) -2,3,5,7,8,9- Hexahydro-1H-spiro [chromeno [2,3-c] pyrrole-6,1′-cyclobutane] -9-yl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-carboxylate Examples (3R, 9S)
  • Example 48 6- (3- ⁇ (3R, 9S) -3-[(2R) -butan-2-yl] -2,6,6-trimethyl-1,8-dioxo-1,2,3,5,6, 7,8,9-Octahydrochromeno [2,3-c] pyrrol-9-yl ⁇ -4-methoxy-2-methylphenyl) -3-methylpyridine-2-carboxylic acid (48a) (3R, 9S ) -3-[(2R) -Butan-2-yl] -9- [6-methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2) -Yl) phenyl] -6,6-dimethyl-2,3,5,6,7,9-hexahydrochromeno [2,3-c] pyrrole-1,8-dione 2-prepared in Example 3a [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-
  • reaction solution was stirred at room temperature for 30 minutes, 2-bromo-6-fluoropyridine (500 mg, 2.84 mmol) was added to the reaction solution at 0 ° C., and the reaction solution was stirred at 50 ° C. for 1 hour.
  • water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate.
  • the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate; 1: 1) to obtain the title compound (543 mg, 71%).
  • Example 54 5- ⁇ 4-methoxy-2-methyl-3-[(3R, 9S) -2,6,6-trimethyl-1,8-dioxo-3- (propan-2-yl) -1,2,3, 5,6,7,8,9-Octahydrochromeno [2,3-c] pyrrol-9-yl] phenyl ⁇ -1-methyl-1H-pyrazole-3-carboxylic acid (54a) Benzyl 5-chloro-1-methyl-1H-pyrazole-3-carboxylate 5-chloro-1-methyl-1H-pyrazole-3-carboxylic acid (1.00 g, 6.23 mmol), benzyl alcohol (967 ⁇ L, 9.34 mmol), WSC ⁇ HCl (1.79 g, 9.34 mmol), HOBt (1.43 g, 7.34 mmol) and triethylamine (1.30 mL, 9.34 mmol) in DMF (10 mL) were stirred at room temperature for 22 hours.
  • Example 55 (3R, 9S) -9- ⁇ 3- [3- (Hydroxymethyl) -1-methyl-1H-pyrazol-5-yl] -6-methoxy-2-methylphenyl ⁇ -2,6,6-trimethyl- 3- (propan-2-yl) -2,3,5,6,7,9-hexahydrochromeno [2,3-c] pyrrole-1,8-dione 5- ⁇ 4 prepared in Example 54c -Methoxy-2-methyl-3-[(3R, 9S) -2,6,6-trimethyl-1,8-dioxo-3- (propan-2-yl) -1,2,3,5,6, 7,8,9-octahydrochromeno [2,3-c] pyrrol-9-yl] phenyl ⁇ -1-methyl-1H-pyrazole-3-carboxylic acid (123 mg, 0.231 mmol) and 1,1 ′ A solution of -carbonyldiimidazole (44.9 mg, 0.277
  • Example 56 1- ⁇ 4-methoxy-2-methyl-3-[(3R, 9S) -2,6,6-trimethyl-1,8-dioxo-3- (propan-2-yl) -1,2,3, 5,6,7,8,9-octahydrochromeno [2,3-c] pyrrol-9-yl] phenyl ⁇ -1H-pyrazole-4-carboxylic acid (56a) benzyl 1H-pyrazole-4-carboxylate 1H-pyrazole-4-carboxylic acid (2.00 g, 17.8 mmol), benzyl alcohol (2.77 mL, 26.8 mmol), WSCHCl (5.13 g, 26.8 mmol), HOBt (4.10 g, 26.8 mmol), 4-methylmorpholine (2.94 mL, 26.8 mmol) and DMF (20 mL) were used for the reaction and workup according to Example 54a to give the title compound (838 mg, 23 %).
  • reaction mixture was diluted with ethyl acetate and washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine.
  • the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (1.23 g, 96%).
  • Example 60 3-Methoxy-6- (pyridin-2-yl) -2-[(3R, 9S) -2,6,6-trimethyl-1,8-dioxo-3- (propan-2-yl) -1,2 , 3,5,6,7,8,9-Octahydrochromeno [2,3-c] pyrrol-9-yl] benzoic acid (60a) Ethyl 3-bromo-2- (bromomethyl) -6-methoxybenzoate Ethyl 3-bromo-6-methoxy-2-methylbenzoate (12.1 g, 44.2 mmol), 2,2'-azobis (isobutyronitrile ) (182 mg, 1.11 mmol) and N-bromosuccinimide (9.45 g, 53.1 mmol) in benzene (180 mL) were stirred at 95 ° C.
  • reaction solution was diluted with dichloromethane, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (2.05 g, 99%).
  • Example 62 7-[(3R, 9S) -6,6-Dimethyl-1,8-dioxo-3- (propan-2-yl) -2-propyl-1,2,3,5,6,7,8,9 -Octahydrochromeno [2,3-c] pyrrol-9-yl] -2,6-dimethyl-1-benzofuran-5-carboxylic acid (62a) 7-( ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ Methyl) -2,6-dimethyl-1-benzofuran-5-carboxylic acid [(5-bromo-2,6-dimethyl-1-benzofuran-7-yl) methoxy] (tert-butyl) dimethylsilane (WO2014 / 061764; 1.48 g, 4.01 mmol) in THF (15 mL) was added n-butyllithium (1.6 M in hexane; 3.01 mL
  • Example 65 [4-Methoxy-2-methyl-3- (3,6,6-trimethyl-1,8-dioxo-3,5,6,7,8,9-hexahydro-1H-furo [3,4- b] chromen-9-yl) phenyl] pyridine-2-carboxylic acid (65a) Methyl 4- (benzyloxy) -3-oxopentanoate Sodium hydride (60%, 230 mg, 5.75 mmol) in THF (6 mL) at room temperature with benzyl bromide (310 mg, 2.87 mmol) added.
  • reaction solution was stirred at room temperature for 20 minutes, and then a solution of methyl 4-bromo-3-oxopentanoate (600 mg, 2.87 mmol) in THF (2 mL) was added.
  • the reaction solution was stirred at 60 ° C. for 2 hours, saturated aqueous ammonium chloride solution was added, and the mixture was extracted twice with ethyl acetate.
  • the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate; 10: 1) to obtain the title compound (384 mg, 57%).
  • reaction solution was stirred at room temperature for 30 minutes, saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate; 2: 3) to obtain the title compound (732 mg, 92%) as a diastereomer mixture.
  • reaction solution was filtered (celite), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate; 2: 3) to give the title compound (98.9 mg, 60%) as a diastereomeric mixture. .
  • Benzyl 6-chloro-4-methylpyridine-2-carboxylate 6-chloro-4-methylpyridine-2-carboxylic acid (1.00 g, 5.85 mmol), benzyl bromide (764 ⁇ L, 6.43 mmol), cesium carbonate (3.81 g, 11.7 mmol) and DMF (10 mL) were used for the reaction and post-treatment according to Example 59a to obtain the title compound (1.53 g, 99%).
  • Example 70 6- ⁇ 3-[(3R, 9S) -2-ethyl-6,6-dimethyl-1,8-dioxo-3- (propan-2-yl) -1,2,3,5,6,7, 8,9-Octahydrochromeno [2,3-c] pyrrol-9-yl] -4-methoxy-2-methylphenyl ⁇ -4-methylpyridine-2-carboxylic acid (70a) Benzyl 6- ⁇ 3-[(3R, 9S) -2-ethyl-6,6-dimethyl-1,8-dioxo-3- (propan-2-yl) -1,2,3,5, 6,7,8,9-Octahydrochromeno [2,3-c] pyrrol-9-yl] -4-methoxy-2-methylphenyl ⁇ -4-methylpyridine-2-carboxylate prepared in Example 12a (3R, 9S) -2-ethyl-9- [6-methoxy-2-methyl-3-
  • Example 71 6- ⁇ 3-[(3R, 9S) -2-ethyl-6,6-dimethyl-1,8-dioxo-3- (propan-2-yl) -1,2,3,5,6,7, 8,9-Octahydrochromeno [2,3-c] pyrrol-9-yl] -4-methoxy-2-methylphenyl ⁇ -3,4-dimethyl-N- (methylsulfonyl) pyridine-2-carboxamide 6- ⁇ 3-[(3R, 9S) -2-ethyl-6,6-dimethyl-1,8-dioxo-3- (propan-2-yl) -1,2,3,5 prepared in Example 34b , 6,7,8,9-octahydrochromeno [2,3-c] pyrrol-9-yl] -4-methoxy-2-methylphenyl ⁇ -3,4-dimethylpyridine-2-carboxylic acid (90.0 mg, 0.161 mmol),
  • Example 72 4-Methoxy-6- ⁇ 4-methoxy-2-methyl-3-[(3R, 9S) -2,6,6-trimethyl-1,8-dioxo-3- (propan-2-yl) -1, 2,3,5,6,7,8,9-octahydrochromeno [2,3-c] pyrrol-9-yl] phenyl ⁇ pyridine-2-carboxylic acid
  • 72a Benzyl 6-chloro-4-methoxypyridine-2-carboxylate 6-chloro-4-methoxypyridine-2-carboxylic acid (91.0 mg, 0.487 mmol), benzyl bromide (100 ⁇ L, 0.584 mmol), cesium carbonate (317 mg, 0.974 mmol) and DMF (1.0 mL) were used for the reaction and post-treatment according to Example 59a to obtain the title compound (107 mg, 79%).
  • Example 73 6- ⁇ 3-[(3R, 9S) -6,6-Dimethyl-1,8-dioxo-3- (propan-2-yl) -2-propyl-1,2,3,5,6,7, 8,9-Octahydrochromeno [2,3-c] pyrrol-9-yl] -4-methoxy-2-methylphenyl ⁇ pyridine-2-carboxylic acid (73a) (3R, 9S) -9- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -6 , 6-Dimethyl-3- (propan-2-yl) -2-propyl-2,3,5,6,7,9-hexahydrochromeno [2,3-c] pyrrole-1,8-dione (3R, 9S) -9- [6-Methoxy-2-methyl-3- (4,4,5,5-tetramethyl-1,
  • Example 74b 6- ⁇ 3-[(3R, 9S) -6,6-Dimethyl-1,8-dioxo-3- (propan-2-yl) -2-propyl-1,2,3,5,6 , 7,8,9-Octahydrochromeno [2,3-c] pyrrol-9-yl] -4-methoxy-2-methylphenyl ⁇ -3,4-dimethylpyridine-2-carboxylic acid
  • Example 74a Prepared tert-butyl 6- ⁇ 3-[(3R, 9S) -6,6-dimethyl-1,8-dioxo-3- (propan-2-yl) -2-propyl-1,2,3,5 , 6,7,8,9-octahydrochromeno [2,3-c] pyrrol-9-yl] -4-methoxy-2-methylphenyl ⁇ -3,4-dimethylpyridine-2-carboxylate (150 mg, 0.233 mmol), dichlorome
  • reaction solution was filtered (celite) and concentrated under reduced pressure.
  • residue was purified by silica gel column chromatography (hexane / ethyl acetate; 65:35) to give the title compound (365 mg, 73%) as a mixture of conformers.
  • Example 76 4'-methoxy-2 ', 4-dimethyl-3'-[(3R, 9S) -2,6,6-trimethyl-1,8-dioxo-3- (propan-2-yl) -1,2, 3,5,6,7,8,9-octahydrochromeno [2,3-c] pyrrol-9-yl] biphenyl-3-carboxylic acid
  • 76a Benzyl 5-chloro-2-methylbenzoate 5-chloro-2-methylbenzoic acid (1.00 g, 5.86 mmol), benzyl bromide (731 ⁇ L, 6.16 mmol), cesium carbonate (2.29 g, 7.03 mmol) and DMF (5.0 mL) was used for the reaction and workup according to Example 59a to give the title compound (1.50 g, 98%).
  • Example 78 6- ⁇ 4-Methoxy-2-methyl-3-[(3R, 9S) -2-methyl-1,8-dioxo-3- (propan-2-yl) -2,3,5,7,8, 9-Hexahydro-1H-spiro [chromeno [2,3-c] pyrrole-6,1'-cyclopropane] -9-yl] phenyl ⁇ -3-methylpyridine-2-carboxylic acid (78a) tert-butyl 6- ⁇ 4-methoxy-2-methyl-3-[(3R, 9S) -2-methyl-1,8-dioxo-3- (propan-2-yl) -2,3, 5,7,8,9-Hexahydro-1H-spiro [chromeno [2,3-c] pyrrole-6,1'-cyclopropane] -9-yl] phenyl ⁇ -3-methylpyridine-2-carboxylate (3R, 9S) -9- [
  • Example 80 5-[(3R) -6,6-Dimethyl-1,8-dioxo-3- (propan-2-yl) -2-propyl-1,2,3,5,6,7,8,9-octa Hydrochromeno [2,3-c] pyrrol-9-yl] -6-methoxy-1-methylnaphthalene-2-carboxylic acid (80a) Benzyl 5-formyl-6-methoxy-1-methylnaphthalene-2-carboxylate A known compound, methyl 5-formyl-6-methoxy-1-methylnaphthalene-2-carboxylate (8.60 g, 33.3 mmol) A solution of 2 M aqueous sodium hydroxide (83 mL, 166 mmol) in THF / methanol solution (1: 1, v / v; 340 mL) was stirred at 80 ° C.
  • Example 82 6- [4-Methoxy-2-methyl-3- (4,4,8,8-tetramethyl-1,10-dioxo-1,2,3,4,5,7,8,9,10,11 -Decahydrochromeno [3,2-c] azepin-11-yl) phenyl] -3-methylpyridine-2-carboxylic acid (82a) tert-butyl 6- [4-methoxy-2-methyl-3- (4,4,8,8-tetramethyl-1,10-dioxo-1,2,3,4,5,7,8 , 9,10,11-Decahydrochromeno [3,2-c] azepin-11-yl) phenyl] -3-methylpyridine-2-carboxylate tert-butyl 6- ⁇ 3- prepared in Example 66b [(4,4-dimethyl-2,6-dioxocyclohexylidene) methyl] -4-methoxy-2-methylphenyl ⁇ -3-methylpyridine-2-car
  • the reaction solution was stirred at 0 ° C. for 60 minutes, water was added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude adduct.
  • Di-tert-butyl azodicarboxylate (596 mg, 2.59 mmol) was added to the crude adduct and triphenylphosphine (679 mg, 2.59 mmol) in THF (13 mL) at room temperature, and the reaction solution was added at room temperature to 3 mL. Stir for hours.
  • mice Oral glucose tolerance test
  • Animal used Commercially available mouse C57BL / 6J mouse, male, 8-12 weeks old when used, sold by Charles River Japan Co., Ltd.
  • Experimental method / results Mice were allowed to freely ingest feed (FR-2, Funabashi Farm Co., Ltd.) for 1 week or longer and pre-bred, then fasted overnight and used for the test.
  • FR-2 Ratio Farm Co., Ltd.
  • MC 0.5% methylcellulose
  • the prepared dosing solution was orally administered by gavage so that the dose of the test compound was 10 mg / kg to 4 to 5 mice in each group.
  • methylcellulose solution (dose: 10 mL / kg) was orally administered.
  • the oral glucose load was performed 30 minutes after administration of the test compound by oral administration of a glucose solution (Otsuka sugar solution 50%: Otsuka Pharmaceutical Co., Ltd.) at a dose of 3 g / kg.
  • Blood was collected from the tail vein of the mouse immediately before administration of the test compound (T0), 25 minutes after administration of the test compound (T1), 30 minutes after oral glucose load (T2) and 90 minutes (T3). Blood glucose level was measured with Check Aviva: Roche Diagnostics Co., Ltd. The T1 blood glucose level was analyzed as the value immediately before glucose load 30 minutes after compound administration. The area under the blood glucose level curve was determined from the following formula, and the blood glucose reduction rate (%) from the control group was calculated.
  • methylcellulose solution (dose: 4 mL / kg) was orally administered.
  • the oral glucose load was performed 30 minutes after administration of the test compound by orally administering a glucose solution (Otsuka sugar solution 50%: Otsuka Pharmaceutical Co., Ltd.) at a dose of 2.5 g / kg.
  • T5 Immediately before test compound administration (T0), 25 minutes after test compound administration (T1), 30 minutes after oral glucose load (T2), 60 minutes (T3), 120 minutes (T4) and 180 minutes (T5), Blood was collected from the tail vein of the rat, and the blood glucose level was measured with a blood glucose meter (Accu Check Aviva: Roche Diagnostics Co., Ltd.). The T1 blood glucose level was analyzed as the value immediately before glucose load 30 minutes after compound administration. From the following formula, the area under the blood glucose level curve was determined, and the blood glucose reduction rate (%) from the control group was calculated.
  • the compound of the present invention has an excellent blood glucose lowering effect, postprandial blood glucose inhibitory effect, glucose tolerance deficiency improving effect and the like. Therefore, the compound of the present invention is considered to be useful as a prophylactic / therapeutic agent for hyperglycemia, diabetes, and pathological conditions or diseases associated with these diseases.
  • this powder After mixing the powder of the above formulation and passing through a 60 mesh sieve, this powder is put into a 250 mg gelatin capsule to form a capsule.
  • the powder of the above formulation is mixed, granulated and dried using corn starch paste, and then tableted by a tableting machine to make one tablet of 200 mg.
  • This tablet can be sugar-coated if necessary.
  • novel 5-membered heterocyclic derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof according to the present invention has an excellent hypoglycemic action and is useful as a medicine.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé, ou un sel pharmacologiquement acceptable de celui-ci, ayant une excellente action hypoglycémique, ledit composé étant représenté par la formule générale (I). [Dans la formule, R1 est un atome d'hydrogène, un groupe alkyle en C1-3, ou un groupe cycloalkyle en C3-6, R2 est un atome d'hydrogène, un groupe alkyle en C1-3, ou est lié à un groupe alkyle en C1-3 qui est en R1 de façon à former un cycle carbone saturé ayant de 3 à 6 chaînons, R3 est un atome d'hydrogène, un groupe alkyle en C1-6, ou un groupe cycloalkyle en C3-6, R4 est un atome d'hydrogène, un groupe alkyle en C1-6, ou est lié à un groupe alkyle en C1-6 qui est en R3 de façon à former un carbone saturé ayant de 3 à 6 chaînons, X est -CH2- ou -C(=O)-, Y est -N(-R5)-, ou -O-, R5 est un atome d'hydrogène, un groupe alkyle en C1-6, un groupe hydroxyalkyle en C1-3, un groupe alcoxy(en C1-3)alkyle en C1-3, un groupe carboxyalkyle en C1-3, un groupe haloalkyle en C1-3, un groupe alcényle en C2-6, un groupe alcynyle en C2-6, ou un groupe cycloalkyle en C3-6, W est un groupe phényle éventuellement substitué, un groupe biphényle éventuellement substitué, un groupe hétéroarylphényle ayant de 5 à 10 chaînons éventuellement substitué qui comprend de 1 à 4 hétéroatomes identiques ou différents choisis parmi azote, oxygène et soufre, un groupe 7-benzofuranyle éventuellement substitué, ou un groupe naphtyle éventuellement substitué].
PCT/JP2016/067618 2015-06-15 2016-06-14 Dérivé hétérocyclique à cinq chaînons WO2016204135A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2015-119978 2015-06-15
JP2015119978 2015-06-15

Publications (1)

Publication Number Publication Date
WO2016204135A1 true WO2016204135A1 (fr) 2016-12-22

Family

ID=57545460

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2016/067618 WO2016204135A1 (fr) 2015-06-15 2016-06-14 Dérivé hétérocyclique à cinq chaînons

Country Status (2)

Country Link
TW (1) TW201710264A (fr)
WO (1) WO2016204135A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113149826A (zh) * 2021-04-08 2021-07-23 台州市源众药业有限公司 一种培比洛芬的制备工艺

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001039984A (ja) * 1999-07-30 2001-02-13 Meiji Seika Kaisha Ltd チオフェン化合物
US20130324525A1 (en) * 2007-07-05 2013-12-05 Gilead Sciences, Inc. Substituted heterocyclic compounds
WO2014061764A1 (fr) * 2012-10-19 2014-04-24 第一三共株式会社 Dérivé de xanthène
WO2014142127A1 (fr) * 2013-03-12 2014-09-18 第一三共株式会社 Dérivé de phénylxanthène

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001039984A (ja) * 1999-07-30 2001-02-13 Meiji Seika Kaisha Ltd チオフェン化合物
US20130324525A1 (en) * 2007-07-05 2013-12-05 Gilead Sciences, Inc. Substituted heterocyclic compounds
WO2014061764A1 (fr) * 2012-10-19 2014-04-24 第一三共株式会社 Dérivé de xanthène
WO2014142127A1 (fr) * 2013-03-12 2014-09-18 第一三共株式会社 Dérivé de phénylxanthène

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113149826A (zh) * 2021-04-08 2021-07-23 台州市源众药业有限公司 一种培比洛芬的制备工艺

Also Published As

Publication number Publication date
TW201710264A (zh) 2017-03-16

Similar Documents

Publication Publication Date Title
AU2021237841B2 (en) Biaryl derivatives as YAP/TAZ-TEAD protein-protein interaction inhibitors
AU2018212593B2 (en) Tyrosine amide derivatives as Rho- kinase inhibitors
EP3381896B1 (fr) Composé de biphényle ou un sel de celui-ci
JP6305510B2 (ja) ヤヌスキナーゼ阻害剤としての非環式シアノエチルピラゾロピリドン
US20170015675A1 (en) Substituted tricyclics and method of use
BR112014015669B1 (pt) Compostos derivados de piridinona e pirimidinona, composição farmacêutica que compreende os ditos compostos e uso dos mesmos para o tratamento ou prevenção de uma doença tromboembólica
JP6158193B2 (ja) 新規レニン阻害薬
ES2949357T3 (es) Inhibidores de 3-fosfoglicerato deshidrogenasa y usos de los mismos
EA027569B1 (ru) Производные пиридина
WO2017156165A1 (fr) Inhibiteurs de la 3-phosphoglycérate déshydrogénase et leurs utilisations
TW202137979A (zh) 使用有新穎聯苯化合物之抗腫瘤效果增強劑
JP2016514709A (ja) ヤヌスキナーゼ阻害剤としてのジェミナル置換シアノエチルピラゾロピリドン
KR20220097438A (ko) 암, 자가면역, 및 염증성 질환의 치료를 위한 다이하이드로오로테이트 데하이드로게나제(dhodh) 억제제로서의 플루오르화 퀴놀린 및 퀴녹살린 유도체
JP6219817B2 (ja) フェニルキサンテン誘導体
WO2016204135A1 (fr) Dérivé hétérocyclique à cinq chaînons
US20240116917A1 (en) Iso-citrate dehydrogenase (idh) inhibitor
JP2024513988A (ja) Ｌｔａ４ｈの阻害剤としてのヘテロアリールアミノプロパノール誘導体
EP3189060A1 (fr) Derives de n-aryl-2-amino-4-aryl-pyrimidines polyethers macrocycliques comme inhibiteurs de la ftl3 and jak
IL310872A (en) SOS1 inhibitor and its use
TW202409010A (zh) 人類呼吸道融合病毒及人類間質肺炎病毒之抑制劑
WO2016204134A1 (fr) Dérivé hétérocyclique à six chaînons
WO2023077070A1 (fr) Agonistes de rxfp1
WO2023220225A1 (fr) Inhibiteurs du virus respiratoire syncytial humain et du métapneumovirus humain
TW202409011A (zh) 人類呼吸道融合病毒及間質肺病毒抑制劑
JP2019182805A (ja) リンカー部位を持つ縮環ピラゾール誘導体およびその医薬用途

Legal Events

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

Ref document number: 16811609

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16811609

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP