WO2013147214A1 - Dérivé de 5-hydroxypyrimidine-4-carboxamide - Google Patents

Dérivé de 5-hydroxypyrimidine-4-carboxamide Download PDF

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WO2013147214A1
WO2013147214A1 PCT/JP2013/059655 JP2013059655W WO2013147214A1 WO 2013147214 A1 WO2013147214 A1 WO 2013147214A1 JP 2013059655 W JP2013059655 W JP 2013059655W WO 2013147214 A1 WO2013147214 A1 WO 2013147214A1
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group
methyl
amino
carbonyl
piperidin
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Japanese (ja)
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田中　直樹
崇 石山
力 後藤
福田　剛
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第一三共株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention relates to a low molecular compound having erythropoietin production enhancing activity.
  • Erythropoietin (hereinafter referred to as EPO) is a glycoprotein hormone essential for erythropoiesis, and is usually secreted from the kidney and promotes erythrocyte production by acting on erythroid stem cells of the bone marrow. In diseases accompanied by a decrease in endogenous EPO production (for example, chronic renal failure) and the like, erythrocyte production is reduced and anemia appears, so replacement therapy with recombinant human EPO is performed.
  • genetically-recombinant human EPO has been pointed out to be disadvantageous in that it is a biopharmaceutical and expensive medical care, it is an injectable agent, is not convenient, and has antigenicity.
  • examples of low molecular weight EPO inducers include pyridine derivatives, cinnoline derivatives, quinoline derivatives and isoquinoline derivatives (see Patent Documents 1 to 6 and 8), 6-hydroxy-2,4-dioxotetrahydropyrimidine derivatives (Patent Document 7).
  • Compounds) such as 4-hydroxypyrimidine-5-carboxamide derivatives (see Patent Document 9) and 5-hydroxypyrimidine-4-carboxamide derivatives (see Patent Documents 10 to 14) are known.
  • the present inventors provide a novel low-molecular compound that has an excellent EPO production enhancing activity and is useful for the treatment of diseases caused by a decrease in EPO, and further provides a medicament containing these compounds. Researched for the purpose.
  • the present inventors have a novel compound having a 5-hydroxypyrimidine-4-carboxamide structure that has an excellent EPO production enhancing activity and is effective in treating a disease caused by a decrease in EPO. As a result, the present invention has been completed.
  • a novel 5-hydroxypyrimidine-4-carboxamide compound represented by the following general formula (1) or a pharmacologically acceptable salt thereof (hereinafter referred to as the compound of the present invention) is provided. .
  • R 1 represents the following general formula (1A)
  • R 4 and R 5 each independently represents a hydrogen atom, a halogen atom, or a C 1 -C 6 alkyl group
  • R 6 represents a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, a carbamoyl group, a C 1 -C 6 alkylcarbamoyl group, or a (C 1 -C 6 alkyl) (C 1 -C 6 alkyl) carbamoyl group.
  • Show R 7 is a C 2 to C 7 alkanoyl C 1 to C 6 alkyl group which may have one or two substituents independently selected from the substituent group ⁇ , independently from the substituent group ⁇ .
  • a C 2 -C 7 alkanoyl C 2 -C 6 alkenyl group optionally having one or two selected substituents, independently having one or two substituents selected from substituent group ⁇ which may be C 1 ⁇ C 6 alkylcarbamoyloxy C 1 ⁇ C 6 alkyl group, independently 1 substituent selected from ⁇ substituent group with or two has good C 1 even if ⁇ C 6 alkyl
  • a C 1 -C 6 alkylthiocarbonylamino C 1 -C 6 alkyl group optionally having 1 or 2 substituents, or 1 or 2 substituents independently selected from the substituent group ⁇ C 1 -C 6 alkylsulfonylamino which may
  • R 2 represents a C 1 -C 3 alkyl group or a methylsulfanyl group
  • R 3 represents a hydrogen atom or a methyl group.
  • R 1 is represented by the following general formula (1B)
  • R 7 represents a C 2 -C 7 alkanoyl C 1 -C 6 alkyl group, a C 2 -C 7 alkanoyl C 2 -C 6 alkenyl group, a C 1 -C 6 alkylcarbamoyloxy C 1 -C 6 alkyl group, C 1 -C 6 alkylcarbamoylamino C 1 -C 6 alkyl group, C 1 -C 6 alkoxycarbonylamino C 1 -C 6 alkyl group, C 1 -C 6 alkylthiocarbonylamino C 1 -C 6 alkyl group, or C 1- C 6 alkylsulfonylamino represents a C 1 -C 6 alkyl group,
  • X represents a single bond or methylene;
  • R 1 is represented by the following general formula (1B-1), general formula (1B-2), general formula (1B-3), or general formula (1B-4)
  • R 7 is a C 2 -C 7 alkanoyl C 1 -C 6 alkyl group, a C 2 -C 7 alkanoyl C 2 -C 6 alkenyl group, a C 1 -C 6 alkylcarbamoyloxy C 1 -C 6 alkyl group, C 1 -C 6 alkylcarbamoylamino C 1 -C 6 alkyl group, C 1 -C 6 alkoxycarbonylamino C 1 -C 6 alkyl group, C 1 -C 6 alkylthiocarbonylamino C 1 -C 6 alkyl group, or C 1- C 6 alkylsulfonylamino represents a C 1 -C 6 alkyl group.
  • R 7 is a 2-oxopropyl group, 2-oxobutyl group, 3-oxobutyl group, 2-oxopentyl group, 3-oxo-1-butenyl group, [(methoxycarbonyl) amino] methyl group, [( Ethoxycarbonyl) amino] methyl group, [(tert-butoxycarbonyl) amino] methyl group, ( ⁇ [(ethylthio) carbonyl] amino ⁇ methyl group, [(ethylcarbamoyl) amino] methyl group, [(ethylcarbamoyl) oxy]
  • the pharmaceutical composition according to [12] The pharmaceutical composition according to the above [10], wherein the anemia is anemia associated with chronic kidney disease, [13] The pharmaceutical composition according to [9] above for producing erythropoietin, [14] Use of the compound according to any one of [1] to [8] above, or a pharmacologically acceptable salt thereof, for producing a medicament, [15] The use according to [14] above, wherein the medicament is a medicament for the prevention and / or treatment of anemia, [16] The above [15], wherein the anemia is renal anemia, premature infant anemia, anemia associated with chronic disease, anemia associated with cancer chemotherapy, cancer anemia, inflammation-related anemia, or anemia associated with congestive heart failure.
  • the compound of the present invention represented by the general formula (1) has a 5-hydroxypyrimidine-4-carboxamide skeleton, the substituent at the 2-position of the pyrimidine ring has three cyclic groups, Groups have specific substituents.
  • the compound of the present invention or a pharmacologically acceptable salt thereof has an excellent EPO production enhancing activity.
  • halogen atom in the definitions of R 4 , R 5 and R 6 is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and preferably a fluorine atom.
  • the “C 1 -C 3 alkyl group” in the definition of R 2 represents a linear or branched alkyl group having 1 to 3 carbon atoms. Examples thereof include a methyl group, an ethyl group, a propyl group, and an isopropyl group.
  • the “C 1 -C 6 alkyl group” in the definitions of R 4 , R 5 , and R 6 represents a linear or branched alkyl group having 1 to 6 carbon atoms.
  • the “C 1 -C 6 alkoxy group” in the definition of the substituent group ⁇ represents a group in which the above “C 1 -C 6 alkyl group” is bonded to an oxygen atom. Examples thereof include a methoxy group, an ethoxy group, an n-propoxy group, an n-butoxy group, an s-butoxy group, a tert-butoxy group, and an n-pentoxy group.
  • the C 1 -C 6 alkoxy group is preferably a C 1 -C 4 alkoxy group, and more preferably a C 1 -C 2 alkoxy group.
  • the “halogeno C 1 -C 6 alkoxy group” in the definition of the substituent group ⁇ means that one or two hydrogen atoms of the above “C 1 -C 6 alkoxy group” are substituted with the above “halogen atom”. Indicates a group. Examples thereof include a fluoromethoxy group, a chloromethoxy group, a 1-fluoroethoxy group, a 1-chloroethoxy group, a 2-fluoroethoxy group, and a 1,2-difluoropropoxy group.
  • the halogeno C 1 -C 6 alkoxy group is preferably a halogeno C 1 -C 4 alkoxy group, and more preferably a halogeno C 1 -C 3 alkoxy group.
  • the “C 1 -C 6 alkoxyimino group” in the definition of the substituent group ⁇ represents a group in which the above “C 1 -C 6 alkoxyimino group” is bonded to an imino group.
  • methoxyimino group, ethoxyimino group, n-propoxyimino group, isopropoxyimino group, n-butoxyimino group, isobutoxyimino group, s-butoxyimino group, tert-butoxyimino group, n-pentoxyimino group iso Examples thereof include a pentoxyimino group and a 2-methylbutoxyimino group.
  • the C 1 -C 6 alkoxyimino group is preferably a C 1 -C 4 alkoxyimino group, and more preferably a C 1 -C 3 alkoxyimino group.
  • C 1 ⁇ C 6 alkoxycarbonylamino C 1 ⁇ C 6 alkyl group in the definition of R 7, attached to the nitrogen atom and the "C 1 ⁇ C 6 alkyl group", "amino C 1 ⁇ C 6 alkyl group "(e.g., aminomethyl group, aminoethyl group, an amino isopropyl group) nitrogen atoms
  • C 1 ⁇ C 6 alkoxycarbonyl is a group in which the carbon atom of the carbonyl and the" C 1 ⁇ C 6 alkoxy group "is bonded Bonded to the carbon atom of the carbonyl of the group (eg, methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, etc.) Indicates a group.
  • the C 1 -C 6 alkoxycarbonylamino C 1 -C 6 alkyl group is preferably a C 1 -C 4 alkoxycarbonylamino C 1 -C 4 alkyl group, more preferably a C 1 -C 3 alkoxy group. Carbonylamino C 1 -C 3 alkyl group.
  • the “C 1 -C 6 alkylthiocarbonylamino C 1 -C 6 alkyl group” in the definition of R 7 means that the nitrogen atom of the above “amino C 1 -C 6 alkyl group” is the above “C 1 -C 6 alkyl group” C 1 -C 6 alkylthiocarbonyl group (for example, (methylthio) carbonyl group, (ethylthio) carbonyl group, (n-propylthio) carbonyl group, (isopropylthio) carbonyl group, which is a group in which the sulfur atom of thiocarbonyl group is bonded) A group bonded to a carbon atom of a carbonyl of a group, (n-butylthio) carbonyl group, (sec-butylthio) carbonyl group, (tert-butylthio) carbonyl group and the like).
  • the C 1 -C 6 alkylthiocarbonylamino C 1 -C 6 alkyl group is preferably a C 1 -C 4 alkylthiocarbonylamino C 1 -C 4 alkyl group, more preferably a C 1 -C 3 alkylthio group. Carbonylamino C 1 -C 3 alkyl group.
  • the “C 1 -C 6 alkylsulfonylamino C 1 -C 6 alkyl group” in the definition of R 7 means that the nitrogen atom of the above “amino C 1 -C 6 alkyl group” is the above “C 1 -C 6 alkyl group”
  • a C 1 -C 6 alkylsulfonyl group (for example, methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, isopropylsulfonyl group, n-butylsulfonyl group, sec- A butylsulfonyl group, a tert-butylsulfonyl group and the like).
  • the C 1 -C 6 alkylsulfonylamino C 1 -C 6 alkyl group is preferably a C 1 -C 4 alkylsulfonylamino C 1 -C 4 alkyl group, more preferably a C 1 -C 3 alkyl group.
  • the “C 1 -C 6 alkylcarbamoyl group” in the definition of R 6 represents a group in which one hydrogen atom of the carbamoyl group is substituted with the above “C 1 -C 6 alkyl group”.
  • a methylcarbamoyl group, an ethylcarbamoyl group, an n-propylcarbamoyl group, and the like can be given.
  • the C 1 -C 6 alkylcarbamoyl group is preferably a C 1 -C 4 alkylcarbamoyl group, and more preferably a C 1 -C 3 alkylcarbamoyl group.
  • (C 1 -C 6 alkyl) (C 1 -C 6 alkyl) carbamoyl group” in the definition of R 6 means that two hydrogen atoms of the carbamoyl group are each substituted with the above “C 1 -C 6 alkyl group”.
  • the (C 1 -C 6 alkyl) (C 1 -C 6 alkyl) carbamoyl group is preferably a (C 1 -C 4 alkyl) (C 1 -C 4 alkyl) carbamoyl group, more preferably (C 1 -C 2 alkyl) (C 1 -C 2 alkyl) carbamoyl group.
  • the C 1 -C 6 alkylcarbamoyloxy C 1 -C 6 alkyl group is preferably a C 1 -C 4 alkylcarbamoyloxy C 1 -C 4 alkyl group, more preferably a C 1 -C 2 alkyl group.
  • the C 1 -C 6 alkylcarbamoylamino C 1 -C 6 alkyl group is preferably a C 1 -C 4 alkylcarbamoylamino C 1 -C 4 alkyl group, more preferably a C 1 -C 2 alkyl group.
  • the “C 2 -C 7 alkanoylamino group” in the definition of the substituent group ⁇ is a C 2 -C 7 alkanoyl group (for example, an acetyl group, which is a linear or branched alkanoyl group having 2 to 7 carbon atoms).
  • the C 2 -C 7 alkanoylamino group is preferably a C 2 -C 5 alkanoylamino group, and more preferably a C 2 -C 4 alkanoylamino group.
  • C 2 -C 7 alkanoyl C 1 -C 6 alkyl group in the definition of R 7 means that one hydrogen atom of the above “C 1 -C 6 alkyl group” is the above “C 2 -C 7 alkanoyl group”.
  • the group substituted by is shown.
  • 2-oxopropyl group, 2-oxobutyl group, 3-oxobutyl group, 2-oxopentyl group, 3-oxopentyl group, 4-oxopentyl group and the like can be mentioned.
  • the C 2 -C 7 alkanoyl C 1 -C 6 alkyl group is preferably a C 2 -C 5 alkanoyl C 1 -C 4 alkyl group, more preferably a C 2 -C 3 alkanoyl C 1 -C 2 is an alkyl group.
  • the “C 2 -C 7 alkanoyl C 2 -C 6 alkenyl group” in the definition of R 7 is a C 2 -C 6 alkenyl group which is a straight or branched alkenyl group having 2 to 6 carbon atoms (eg, , Vinyl group, 1-propenyl group, 2-propenyl group, isopropenyl group, 1-methyl-2-propenyl group, 2-methyl-2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group , 2-methyl-1-propenyl group, 1-pentenyl group, 4-pentenyl group, 1-methyl-4-pentenyl group, 5-hexenyl group, etc.) are substituted with the above-mentioned “C 2 -C 7 alkanoyl” The group substituted by "group” is shown.
  • a 3-oxo-1-butenyl group, a 3-oxo-1-pentenyl group, a 4-oxo-1-pentenyl group, a 4-oxo-2-pentenyl group, and the like can be given.
  • a C 2 -C 7 alkanoyl C 2 -C 6 alkenyl group is preferably a C 2 -C 4 alkanoyl C 2 -C 4 alkenyl group.
  • the “monocyclic hydrocarbon ring group” in the definition of ring Q 2 and ring Q 3 represents a saturated, partially unsaturated or unsaturated 5- to 7-membered monocyclic hydrocarbon group.
  • a monocyclic aromatic hydrocarbon ring group such as a phenyl group
  • a monocyclic non-aromatic hydrocarbon ring group such as a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclopentenyl group, a cyclohexenyl group, and a cycloheptenyl group
  • a 6-membered aromatic hydrocarbon ring group or a non-aromatic hydrocarbon ring group is preferable, and a 6-membered aromatic hydrocarbon ring group is more preferable.
  • “Monocyclic heterocyclic group” in the definition of ring Q 1 , ring Q 2 and ring Q 3 is a saturated, partially containing one or two atoms selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom An unsaturated or unsaturated 5- to 7-membered monocyclic heterocyclic group is shown.
  • tetrahydrofuranyl group tetrahydropyranyl group, dioxolanyl group, dioxanyl group, dioxepanyl group, pyrrolidinyl group, piperidyl group, azepanyl group, dihydropyrrolyl group, dihydropyridyl group, tetrahydropyridyl group, piperazinyl group, morpholinyl group, dihydrooxa Monocyclic non-aromatic heterocyclic group such as zolyl group and dihydrothiazolyl group; pyrrolyl group, pyridyl group, thienyl group, furyl group, pyrimidinyl group, pyranyl group, pyridazinyl group, pyrazinyl group, pyrazolyl group, imidazolyl A monocyclic aromatic heterocyclic group such as a group, a thiazolyl group, an isothiazolyl
  • the “monocyclic heterocyclic group” in the present invention is preferably a 6-membered aromatic heterocyclic group or a non-aromatic heterocyclic group containing 1 or 2 nitrogen atoms, and a 6-membered heterocyclic group containing 1 nitrogen atom.
  • An aromatic heterocyclic group or a non-aromatic heterocyclic group is more preferable.
  • the monocyclic heterocyclic group in ring Q 1 is more preferably a 6-membered non-aromatic heterocyclic group containing one nitrogen atom.
  • R 1 in the compound of the present invention will be described below.
  • R 1 represents a group represented by the following general formula (1A).
  • R 4 and R 5 each independently represent a hydrogen atom, a halogen atom or a C 1 -C 6 alkyl group
  • R 6 represents a hydrogen atom, a halogen atom, C 1 -C 6 An alkyl group, a carbamoyl group, a C 1 -C 6 alkylcarbamoyl group, or a (C 1 -C 6 alkyl) (C 1 -C 6 alkyl) carbamoyl group;
  • R 4 preferably represents a hydrogen atom.
  • R 5 preferably represents a hydrogen atom, a halogen atom or a methyl group, more preferably a hydrogen atom.
  • R 6 preferably represents a hydrogen atom, a halogen atom, or a methyl group, more preferably represents a hydrogen atom, a chlorine atom, or a methyl group, and further preferably represents a hydrogen atom.
  • R 7 is a C 2 -C 7 alkanoyl C 1 -C 6 alkyl group which may have one or two substituents independently selected from the substituent group ⁇ , independently substituted A C 2 to C 7 alkanoyl C 2 to C 6 alkenyl group which may have one or two substituents selected from the group ⁇ , and one or more substituents independently selected from the substituent group ⁇ C 1 -C 6 alkylcarbamoyloxy C 1 -C 6 alkyl group which may have two, C 1 which may have one or two substituents independently selected from the substituent group ⁇ -C 6 alkylcarbamoylamino C 1 -C 6 alkyl group, which may have 1 or 2 substituents independently selected from the substituent group ⁇ , C 1 -C 6 alkoxycarbonylamino C 1 -C 6 alkyl group, independently location One or two have C 1 optionally ⁇ C 6 alkyl thiocarbonyl amino C 1 ⁇
  • the substituent group ⁇ in the present invention is preferably a group consisting of a hydroxy group, a C 1 -C 6 alkoxy group, a halogeno C 1 -C 6 alkoxy group, and a C 2 -C 7 alkanoylamino group, More preferred is a group consisting of C 1 -C 2 alkoxy groups.
  • R 7 represents a C 2 -C 7 alkanoyl C 1 -C 6 alkyl group, a C 2 -C 7 alkanoyl C 2 -C 6 alkenyl group, a C 1 -C 6 alkylcarbamoyloxy C 1 -C 6 alkyl group.
  • X preferably represents a single bond or methylene, and more preferably represents a single bond.
  • R 1 is preferably a group represented by the following general formula (1B).
  • Y and Z each independently represent a carbon atom (having one hydrogen atom) or a nitrogen atom
  • X represents a single bond or methylene
  • R 7 represents 2-oxo Propyl group, 2-oxobutyl group, 3-oxobutyl group, 2-oxopentyl group, 3-oxo-1-butenyl group, [(methoxycarbonyl) amino] methyl group, [(ethoxycarbonyl) amino] methyl group, [( tert-butoxycarbonyl) amino] methyl group, ( ⁇ [(ethylthio) carbonyl] amino ⁇ methyl group, [(ethylcarbamoyl) amino] methyl group, [(ethylcarbamoyl) oxy] methyl group, or [(methylsulfonyl) amino ] represents a methyl group.
  • R 7 represents, 2-oxopropyl group, 2-oxobutyl group, 3-oxobutyl group, 2- Okisopen Group, 3-oxo-1-butenyl group, [(methoxycarbonyl) amino] methyl group, [(ethoxycarbonyl) amino] methyl group, [(tert-butoxycarbonyl) amino] methyl group, or [(ethylcarbamoyl) It preferably represents an oxy] methyl group.
  • R 1 is more preferably a group represented by the following general formula (1B-1) to general formula (1B-4).
  • R 7 represents a 2-oxopropyl group, a 2-oxobutyl group, a 3-oxobutyl group, a 2-oxopentyl group, a 3-oxo-1- Butenyl, [(methoxycarbonyl) amino] methyl, [(ethoxycarbonyl) amino] methyl, [(tert-butoxycarbonyl) amino] methyl, ( ⁇ [(ethylthio) carbonyl] amino ⁇ methyl, [( Ethylcarbamoyl) amino] methyl group, [(ethylcarbamoyl) oxy] methyl group, or [(methylsulfonyl) amino] methyl group, wherein R 7 represents a 2-oxopropyl group, a 2-oxobutyl group, a 3-oxobutyl group.
  • R 2 represents a C 1 -C 3 alkyl group or a methylsulfanyl group, preferably a methyl group or a methylsulfanyl group, and more preferably a methyl group.
  • R 3 represents a hydrogen atom or a methyl group, preferably a hydrogen atom.
  • the compound of the present invention is preferably one selected from the following compounds or pharmacologically acceptable salts thereof: ⁇ [(2- ⁇ [1- (4 ′- ⁇ [(Ethoxycarbonyl) amino] methyl ⁇ biphenyl-4-yl) piperidin-4-yl] methyl ⁇ -5-hydroxy-6-methylpyrimidin-4-yl ) Carbonyl] amino ⁇ acetic acid, ( ⁇ [2-( ⁇ 1- [4 ′-( ⁇ [(Ethylthio) carbonyl] amino ⁇ methyl) biphenyl-4-yl] piperidin-4-yl ⁇ methyl) -5-hydroxy-6-methylpyrimidine-4 -Yl] carbonyl ⁇ amino) acetic acid, ( ⁇ [2-( ⁇ 1- [4- (6- ⁇ [(tert-butoxycarbonyl) amino] methyl ⁇ pyridin-3-yl) phenyl] piperidin-4-yl ⁇ methyl) -5-hydroxy-6- Methylpyrimidin-4-yl]
  • geometric isomers or tautomers may exist depending on the type of substituent.
  • optical isomers may exist.
  • the present invention includes separated (for example, enantiomers or diastereomers) of these isomers or mixtures (for example, racemates or diastereomeric mixtures).
  • a label compound that is, a compound in which one or more atoms of the compound of the present invention are substituted with the corresponding radioisotope or non-radioisotope in an arbitrary ratio is also included in the present invention.
  • acid addition salts include, for example, hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide; nitrate, perchlorate, sulfate, phosphate Inorganic acid salts such as methane sulfonate, trifluoromethane sulfonate, ethane sulfonate, etc. Lower alkane sulfonates; benzene sulfonate, p-toluene sulfonate, etc.
  • aryl sulfonates such as malate, fumarate, succinate, citrate, tartrate, succinate, maleate; or amino acid salts such as ornithate, glutamate, aspartate Hydrohalide and organic acid salts are preferred.
  • base addition salts include alkali metal salts such as sodium salt, potassium salt and lithium salt; alkaline earth metal salts such as calcium salt and magnesium salt; inorganic salts such as ammonium salt; or dibenzylamine salt, Morpholine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, diethylamine salt, triethylamine salt, cyclohexylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, diethanolamine salt, N-benzyl- Examples thereof include organic amine salts such as N- (2-phenylethoxy) amine salt, piperazine salt, tetramethylammonium salt, and tris (hydroxymethyl) aminomethane salt.
  • the compound of the present invention may exist as a non-solvate or a solvate.
  • the solvate is not particularly limited as long as it is pharmacologically acceptable, and specifically, a hydrate, an ethanolate, and the like are preferable.
  • a nitrogen atom is present in the compound represented by the general formula (1), it may be an N-oxide form, and these solvates and N-oxide forms are also included in the scope of the present invention. .
  • various isomers such as geometric isomers such as cis isomers and trans isomers, tautomers or optical isomers such as d isomers and l isomers may exist depending on the type and combination of substituents.
  • the compounds of the present invention include all isomers and mixtures of these isomers in any ratio.
  • the compounds of the present invention may also contain unnatural proportions of isotopes at one or more of the atoms that constitute such compounds.
  • isotope examples include deuterium ( 2 H; D), tritium ( 3 H; T), iodine-125 ( 125 I), carbon-14 ( 14 C), and the like.
  • the compounds of the present invention can also be radiolabeled with radioisotopes 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 (eg, assay reagents), and diagnostic agents (eg, in vivo diagnostic imaging agents). Compounds of the invention that contain all proportions of radioactive or non-radioactive isotopes are included within the scope of the invention.
  • the compound of the present invention can also be produced by applying various known synthesis methods depending on the basic skeleton or the type of substituent.
  • the functional group can be protected with an appropriate protective group at the raw material or intermediate stage, or can be replaced with a group that can be easily converted into the functional group.
  • Examples of such a functional group such as amino group, hydroxyl group, there are carboxyl group and the like, as their protecting groups, for example, Protective Groups in Organic Synthesis, 3 rd ed., Greene, TW, Wuts, PGM, John Wiley & Sons, Inc., New York, 1999, and the like, and can be appropriately selected depending on the reaction conditions.
  • the desired compound after carrying out the reaction by introducing the protecting group, the desired compound can be obtained by removing the protecting group as necessary or converting it to a desired group.
  • the resulting compounds of the present invention can be identified and analyzed for their composition or purity by standard analytical techniques such as elemental analysis, NMR, mass spectroscopy, IR analysis and the like.
  • Raw materials and reagents used in the production of the compounds of the present invention can be purchased from commercial suppliers, or can be synthesized by methods described in the literature.
  • anemia refers to renal anemia, premature infant anemia, anemia associated with chronic diseases, anemia associated with cancer chemotherapy, cancer anemia, inflammation-related anemia, and anemia associated with congestive heart failure (congestive heart failure).
  • Anemia associated with chronic disease includes anemia associated with chronic kidney disease, and chronic kidney disease includes chronic renal failure.
  • a patient to whom a compound of the invention is administered can also be a patient who has or has not undergone dialysis.
  • the compound of the present invention or a pharmacologically acceptable salt thereof exhibits excellent EPO production enhancing activity in an assay system using Hep3B cells and is excellent in safety. That is, by administering a pharmaceutical composition containing the compound of the present invention or a pharmacologically acceptable salt thereof to a mammal (human, cow, horse, pig, etc.) or a bird (chicken, etc.), EPO production Can be strengthened. Therefore, the pharmaceutical composition containing the compound of the present invention, or a pharmacologically acceptable salt thereof, can prevent and / or prevent diseases or pathological conditions in which EPO is decreased, such as diseases caused by a decrease in EPO, ischemic brain diseases and the like.
  • EPO embolism originating from EPO decline
  • diseases resulting from EPO decline include, for example, anemia, especially renal anemia (dialysis phase, preservation phase), premature infant anemia, anemia associated with chronic disease, anemia associated with cancer chemotherapy, cancerous anemia, inflammation-related Mention may be made of anemia or anemia associated with congestive heart failure.
  • anemia especially renal anemia (dialysis phase, preservation phase)
  • premature infant anemia anemia associated with chronic disease
  • anemia associated with cancer chemotherapy cancerous anemia
  • inflammation-related Mention may be made of anemia or anemia associated with congestive heart failure.
  • the compound having the general formula (1) of the present invention can be obtained by the method described below.
  • the first step is a step of producing a compound having the general formula (1) from a compound having the general formula (2) described later.
  • R 1 to R 3 are as defined above
  • R 8 is a substituted or unsubstituted aryl group or heteroaryl group
  • R 1a and R 1b are the above R 1 or a precursor thereof.
  • R 2a represents the aforementioned R 2 or a group serving as a precursor thereof
  • R 7a and R 7b represent the aforementioned R 7 or a group serving as a precursor thereof
  • Pro 1 to Pro 4 are known protection groups. indicating groups (e.g., protective groups in Organic Synthesis, 3 rd ed., Greene, TW, Wuts, PGM, John Wiley & Sons, Inc., New York, 1999 , etc.) the protecting group is selected from the respective functional groups .
  • Pro 1 to Pro 4 are not particularly limited as long as they exist stably during the reaction and do not inhibit the reaction.
  • Pro 1 represents a benzyl group
  • Pro 2 represents a tert-butyl group
  • Pro 1 3 represents a methyl group, an ethyl group, a tert-butyl group, or a benzyl group
  • Pro 4 represents a tert-butoxycarbonyl group.
  • X 1 in the step 1-1c, step 1-1d, or step 1-1e is not particularly limited as long as it is a substituent that forms a leaving group together with the bonded oxygen, but is preferably a trifluoromethanesulfonyl group.
  • Step 1-1 is a step of producing a compound having the general formula (3) from a compound having the general formula (2) described later.
  • Step 1-1a Deprotection reaction of protecting group Pro 2
  • Step 1-1b condensation reaction with an amino acid or amino acid salt having the general formula H 2 NCH (R 3 ) CO 2 Pro 3
  • Step 1-1c Reaction of introducing a leaving group (—OX 1 ) into the 6-position hydroxyl group
  • Step 1-1d A reaction for converting a leaving group (—OX 1 ) into a substituent R 2a is exemplified.
  • Step 1-1e a reaction for converting R 1a to R 1b can be added.
  • the steps 1-1a to 1-1e may be performed in any order.
  • Step 1-1a This step is a step of deprotection of the protecting group Pro 2. Depending on the Pro 2 using, for example, Protective Groups in Organic Synthesis, 3 rd ed., Greene, TW, Wuts, PGM, John Wiley & Sons, Inc., known methods which are described, for example, New York, 1999 Appropriately selected, this step is performed accordingly.
  • step 1-1a1 a method of converting Pro 2 to a hydrogen atom using a base in an inert solvent by selecting a tert-butyl group as a suitable Pro 2 (step 1-1a1), or using an acid in an inert solvent
  • step 1-1a2 a method of converting Pro 2 to a hydrogen atom using a base in an inert solvent by selecting a tert-butyl group as a suitable Pro 2 (step 1-1a2) is described, but this step is not limited thereto.
  • step 1-1a1 process This step is a step of converting Pro 2 to a hydrogen atom using an appropriate base in an inert solvent.
  • the solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably an aromatic hydrocarbon such as benzene, toluene, xylene; Halogenated hydrocarbons; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; alcohols such as methanol, ethanol and tert-butanol; such as ethyl acetate and propyl acetate Nitriles such as acetonitrile; amides such as formamide and N, N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; a mixed solvent in any ratio of a plurality of organic solvents; or these and water And a mixed solvent in any ratio with That.
  • aromatic hydrocarbon such as benzene, toluene, xylene
  • Halogenated hydrocarbons such as diethyl ether
  • the base used is not particularly limited as long as it is used as a base in ordinary reactions, but organic bases such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, lutidine, pyridine; sodium carbonate Alkali metal carbonates such as potassium carbonate; Alkaline earth metal carbonates such as calcium carbonate; Alkali metal hydrogen carbonates such as potassium hydrogen carbonate; Alkaline earth metal hydrogen carbonates such as calcium hydrogen carbonate; Water Examples include alkali metal hydroxides such as sodium oxide and potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide; and alkali metal phosphates such as tripotassium phosphate. it can.
  • the reaction temperature varies depending on the raw material compounds, reagents and the like, but is usually ⁇ 10 ° C. to 150 ° C., preferably 10 ° C. to 90 ° C.
  • the reaction time varies depending on the raw material compounds, reagents and the like, but is usually 1 minute to 24 hours, preferably 10 minutes to 6 hours.
  • the target compound can be obtained as a solid by distilling off the organic solvent and adding an acid.
  • the organic compound is extracted with an organic solvent such as ethyl acetate, and the organic layer is dried by a procedure usually used, and then concentrated under reduced pressure to obtain the target compound. Obtainable.
  • This step is a step of converting Pro 2 to a hydrogen atom using an appropriate acid in an inert solvent.
  • the solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably an aromatic hydrocarbon such as benzene, toluene, xylene; Halogenated hydrocarbons; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; alcohols such as methanol and ethanol; Nitriles such as acetonitrile; Amides such as formamide, N, N-dimethylformamide; Sulfoxides such as dimethyl sulfoxide; Mixed solvents in any ratio of a plurality of organic solvents; or any of these and water A mixed solvent having a ratio can be used.
  • an aromatic hydrocarbon such as benzene, toluene, xylene
  • Halogenated hydrocarbons esters such as ethyl acetate and prop
  • the acid to be used is not particularly limited as long as it is used as an acid in a normal reaction, but inorganic acids such as hydrochloric acid and sulfuric acid; boron trifluoride, boron trichloride, boron tribromide, trimethylsilane iodide Or an organic acid such as trifluoroacetic acid.
  • the reaction temperature varies depending on the raw material compounds, reagents and the like, but is usually ⁇ 100 ° C. to 150 ° C., preferably ⁇ 78 ° C. to 100 ° C.
  • the reaction time varies depending on the raw material compound, reagent, etc., but is usually 5 minutes to 24 hours, preferably 10 minutes to 6 hours.
  • the target compound can be obtained as a solid by distilling off the organic solvent and adding a base.
  • the organic compound is extracted with an organic solvent such as ethyl acetate, and the organic layer is dried by a procedure usually used, and then concentrated under reduced pressure to obtain the target compound. Obtainable.
  • Step 1-1b This step is a step of condensing the carboxylic acid obtained in Step 1-1a with an amino acid or an amino acid salt having the general formula H 2 NCH (R 3 ) CO 2 Pro 3 . It is carried out using a condensing agent in the presence or absence.
  • the solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably an aromatic hydrocarbon such as benzene, toluene, xylene; Halogenated hydrocarbons; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; methanol, ethanol, tert-butanol and the like Alcohols; nitriles such as acetonitrile; amides such as formamide, N, N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; mixed solvents in any ratio of a plurality of organic solvents; And a mixed solvent in any ratio with That.
  • aromatic hydrocarbon such as benzene, toluene, xylene
  • Halogenated hydrocarbons esters such as eth
  • the base used is not particularly limited as long as it is used as a base in a normal reaction, but preferably organic bases such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, lutidine, pyridine.
  • Alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as calcium carbonate; alkali metal bicarbonates such as potassium hydrogen carbonate; alkaline earth metal hydrogen carbonates such as calcium hydrogen carbonate; Salts; alkali metal hydroxides such as sodium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide; or alkali metal phosphates such as tripotassium phosphate. .
  • condensing agent to be used those used as condensing agents that form amide bonds (for example, the 4th edition Sakai Experimental Science Course (22. Organic Synthesis IV oxalic acid, amino acid, peptide), Shoichi Enomoto et al. Maruzen Co., Ltd., 1990; Nobuo Izumiya et al., Peptide Synthesis Fundamentals and Experiments, Maruzen, 1985, etc.), but is not particularly limited.
  • Tetramethyluronium hexafluorophosphate HBTU
  • 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate TBTU
  • 1- (3-dimethylamino Propyl) -3-ethylcarbodiimide hydrochloride EDCI
  • the reaction temperature varies depending on the raw material compounds, reagents and the like, but is usually ⁇ 10 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time varies depending on the raw material compounds, reagents and the like, but is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours.
  • the target compound of this reaction is, for example, concentrating the reaction mixture, adding an organic solvent such as ethyl acetate, washing with water, separating the organic layer containing the target compound, drying over anhydrous sodium sulfate, etc. Obtained by distilling off the solvent.
  • Step 1-1c This step is a step of converting the hydroxyl group at the 6-position to a leaving group (—OX 1 ), which is carried out by reacting with an acid chloride or acid anhydride in an inert solvent in the presence or absence of a base. Is called.
  • the solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably an aromatic hydrocarbon such as benzene, toluene, xylene; Halogenated hydrocarbons; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; nitriles such as acetonitrile; formamide, Examples thereof include amides such as N, N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; or a mixed solvent in an arbitrary ratio of a plurality of organic solvents.
  • aromatic hydrocarbon such as benzene, toluene, xylene
  • Halogenated hydrocarbons esters such as ethyl acetate and propyl acetate
  • ethers such as diethyl ether
  • the acid chloride or acid anhydride to be used is not particularly limited as long as it is an acid chloride or acid anhydride having X 1 in which —OX 1 group becomes a known leaving group.
  • Substituted or unsubstituted alkyl sulfonic acid anhydride or aryl sulfonic acid anhydride such as methane sulfonic acid anhydride; substituted or unsubstituted alkyl sulfonyl chloride or aryl sulfonyl chloride such as methane sulfonyl chloride, p-toluene sulfonyl chloride Or substituted or unsubstituted alkyl phosphate chlorides or aryl phosphate chlorides.
  • the base used is not particularly limited as long as it is used as a base in a normal reaction, but preferably organic bases such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, lutidine, pyridine.
  • Alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as calcium carbonate; alkali metal bicarbonates such as potassium hydrogen carbonate; alkaline earth metal hydrogen carbonates such as calcium hydrogen carbonate; Salts; alkali metal hydroxides such as sodium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide; or alkali metal phosphates such as tripotassium phosphate. .
  • the reaction temperature varies depending on the raw material compounds, reagents and the like, but is usually ⁇ 100 ° C. to 150 ° C., preferably ⁇ 80 ° C. to 40 ° C.
  • the reaction time varies depending on the raw material compound, reagent, etc., but is usually 5 minutes to 24 hours, preferably 10 minutes to 6 hours.
  • the target compound of this reaction is, for example, concentrating the reaction mixture, adding an organic solvent such as ethyl acetate, washing with water, separating the organic layer containing the target compound, drying over anhydrous sodium sulfate, etc. Obtained by distilling off the solvent.
  • Step 1-1d This step is a step of converting the leaving group (—OX 1 ) into the substituent R 2a .
  • R 2a is an alkyl group or an alkenyl group, in an inert solvent, in the presence or absence of a base, in the presence or absence of an additive, in the presence of a metal catalyst, an alkyl boron compound or an alkenyl boron compound and This is carried out by reacting (step 1-1d1).
  • step 1-1d2 When R 2a is a methylsulfanyl group, the reaction is carried out by reacting with methanethiol or a metal salt of methanethiol in an inert solvent in the presence or absence of a base (step 1-1d2).
  • This step is a step of converting a leaving group (—OX 1 ) into an alkyl group or an alkenyl group.
  • a metal In an inert solvent, in the presence or absence of a base, in the presence or absence of an additive, a metal The reaction is carried out by reacting with an alkyl boron compound or an alkenyl boron compound in the presence of a catalyst.
  • the reaction conditions are, for example, Zou, G., Reddy, YK, Falck, JR, Tetrahedron Lett., 2001, 42, 7213; Molander, GA, Yun, C.-S., Tetrahedron, 2002, 58, 1465; Tsuji, J., Palladium Reagents and Catalysts, John Wiley & Sons, Inc., England, 2004; Metal-Catalyzed Cross-Coupling Reactions, de Meijere, A., Diederich, F., Wiley-VCH, Weinheim, 2004, etc. Appropriately selected from the known methods described, this step is carried out accordingly.
  • the reaction conditions in this step are preferably as follows, but are not limited thereto.
  • the solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably an aromatic hydrocarbon such as benzene, toluene, xylene; Halogenated hydrocarbons; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; methanol, ethanol, tert-butanol and the like Alcohols; nitriles such as acetonitrile; amides such as formamide, N, N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; mixed solvents in any ratio of a plurality of organic solvents; And a mixed solvent in any ratio with That.
  • aromatic hydrocarbon such as benzene, toluene, xylene
  • Halogenated hydrocarbons esters such as eth
  • the base used is not particularly limited as long as it is used as a base in a normal reaction, but preferably organic bases such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, lutidine, pyridine.
  • Alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as calcium carbonate; alkali metal bicarbonates such as potassium hydrogen carbonate; alkaline earth metal hydrogen carbonates such as calcium hydrogen carbonate; Salts; alkali metal hydroxides such as sodium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide; alkali metal phosphates such as tripotassium phosphate; or sodium tert-butoxide; Metal alkoxides such as potassium tert-butoxide It is possible.
  • the additive used is not particularly limited as long as it is used in a known method, but preferably metal oxides such as silver oxide and alumina; triphenylphosphine, tri-tert-butylphosphine, Cyclohexylphosphine, tri (o-toluyl) phosphine, diphenylphosphinoferrocene, 2-dicyclohexylphosphino-2 ′, 6′-dimethoxy-1,1′-biphenyl (S-PHOS), 2-dicyclohexylphosphino-2 ′ Phosphines such as 2,4 ′, 6′-triisopropyl-1,1′-biphenyl (X-PHOS), 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP); Phosphine oxides such as phenylphosphine oxide; lithium chloride, potassium fluoride, fluorine Metal salts such
  • the metal catalyst used is not particularly limited as long as it is used in a known method, but preferably tetrakis (triphenylphosphine) palladium, bis (tri-tert-butylphosphine) palladium, palladium acetate, Palladium dichloride diphenylphosphinoferrocene complex, palladium chloride benzonitrile complex, palladium chloride acetonitrile complex, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium, bis [1,2-bis (diphenylphosphino) And palladium catalysts such as ethane] palladium, 3-chloropyridine [1,3-bis (2,6-diisopropylphenyl) imidazo-2-ylidene] palladium, and palladium-activated carbon.
  • the alkyl boron compound or alkenyl boron compound to be used is not particularly limited as long as it is used as a known reaction reagent.
  • R 2a is an alkyl group, methyl boric acid, methyl boric acid ester, trifluoro (methyl) boraneoid A metal salt, ethyl boric acid, ethyl borate ester or ethyl trifluoroborane metal salt, etc.
  • R 2a is an alkenyl group, vinyl boric acid, 4,4,5,5-tetramethyl-2-vinyl-1,3, Examples thereof include 2-dioxaborolane, vinyl borate ester, vinyl trifluoroboronoid metal salt, allyl boric acid, allyl borate ester, and allyl (trifluoro) boraneoid metal salt.
  • alkyl borate ester part trifluoro (alkyl) boranoid metal salt metal, alkenyl borate ester part, and trifluoro (alkenyl) boranoid metal salt metal used as known compounds? Or as long as it is synthesized according to a known method.
  • the reaction temperature varies depending on the raw material compounds, reagents and the like, but is usually ⁇ 10 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C.
  • the reaction time varies depending on the raw material compound, reagent, etc., but is usually 5 minutes to 48 hours, preferably 10 minutes to 12 hours.
  • the target compound of this reaction is, for example, concentrating the reaction mixture, adding an organic solvent such as ethyl acetate, washing with water, separating the organic layer containing the target compound, drying over anhydrous sodium sulfate, etc. Obtained by distilling off the solvent.
  • the obtained compound can be further purified by a conventional method such as recrystallization, reprecipitation, silica gel column chromatography and the like, if necessary.
  • Step 1-1d2 This step is a step of converting a leaving group (—OX 1 ) into a methylsulfanyl group, by reacting methanethiol or a metal salt of methanethiol in an inert solvent in the presence or absence of a base. Done.
  • the solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably an aromatic hydrocarbon such as benzene, toluene, xylene; Halogenated hydrocarbons; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; nitriles such as acetonitrile; formamide, Amides such as N, N-dimethylformamide; alcohols such as methanol and ethanol; sulfoxides such as dimethyl sulfoxide; a mixed solvent in an arbitrary ratio of a plurality of organic solvents; or any of these and water A mixed solvent having a ratio can be used.
  • an aromatic hydrocarbon such as benzene, toluene, xylene
  • Halogenated hydrocarbons esters such as ethy
  • the metal in the metal salt of methanethiol to be used is not particularly limited, but preferred examples include an alkali metal such as sodium or an alkaline earth metal such as magnesium.
  • the base used is not particularly limited as long as it is used as a base in a normal reaction, but preferably organic bases such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, lutidine, pyridine.
  • Alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as calcium carbonate; alkali metal bicarbonates such as potassium hydrogen carbonate; alkaline earth metal hydrogen carbonates such as calcium hydrogen carbonate; Salts; alkali metal hydroxides such as sodium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide; alkali metal phosphates such as tripotassium phosphate; or sodium tert-butoxide; Metal alkoxides such as potassium tert-butoxide It is possible.
  • the reaction temperature varies depending on the raw material compounds, reagents and the like, but is usually ⁇ 10 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time varies depending on the raw material compound, reagent, etc., but is usually 5 minutes to 48 hours, preferably 10 minutes to 12 hours.
  • the target compound of this reaction is, for example, concentrating the reaction mixture, adding an organic solvent such as ethyl acetate, washing with water, separating the organic layer containing the target compound, drying over anhydrous sodium sulfate, etc. Obtained by distilling off the solvent.
  • Step 1-1e This step is a step of converting R 1a to R 1b , and the synthesis method differs depending on the type of heterocyclic ring of ring Q 1 .
  • R 1a has a ring Q 1 and the ring Q 1 is a heterocyclic ring containing a nitrogen atom and has a protecting group Pro 4 on the nitrogen atom will be described below.
  • 1-1e1 step deprotection reaction of protecting group Pro 4
  • Step 1-1e2 An introduction reaction of the substituent R 8 can be mentioned.
  • a step 1-1e3 a reaction for converting the substituent R 7a on the ring Q 3 into R 7b can be added.
  • the reaction formulas of the above steps 1-1e1 and 1-1e2 show the case where R 1a is a piperidin-4-yl group having a protecting group Pro 4 at the 1-position. Although the case where 4 is a tert-butoxycarbonyl group is shown, the step 1-1e is not limited thereto.
  • This step is a step of producing a compound having the general formula (5) or (8).
  • Pro 4 is used as the protecting group, for example, Protective Groups in Organic Synthesis, 3 rd ed., Greene, TW, Wuts, PGM, John Wiley & Sons, Inc., are described, for example, New York, 1999 known Are appropriately selected, and this step is performed accordingly.
  • this step is performed by adding an appropriate reagent to the compound having the general formula (4) or (7) in an inert solvent.
  • the solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably an aromatic hydrocarbon such as benzene, toluene, xylene; Halogenated hydrocarbons; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane; esters such as ethyl acetate and propyl acetate; nitriles such as acetonitrile; formamide, Examples thereof include amides such as N, N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; or a mixed solvent in an arbitrary ratio of a plurality of organic solvents.
  • aromatic hydrocarbon such as benzene, toluene, xylene
  • Halogenated hydrocarbons such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dime
  • the reagent to be used is not particularly limited as long as it is used as a reagent for deprotecting the tert-butoxycarbonyl group in a normal reaction, but preferably an inorganic acid such as hydrochloric acid or sulfuric acid; acetic acid, trifluoro Organic acids such as acetic acid; Lewis acids such as trimethylsilyl iodide, boron trifluoride; acid chlorides such as acetyl chloride; or alkali metal hydroxides such as sodium hydroxide. .
  • the reaction temperature varies depending on the raw material compounds, reagents and the like, but is usually ⁇ 10 ° C. to 100 ° C., preferably 10 ° C. to 50 ° C.
  • the reaction time varies depending on the raw material compound, reagent, etc., but is usually 5 minutes to 24 hours, preferably 10 minutes to 6 hours.
  • the solvent is distilled off, and n-hexane or the like is added to the resulting residue to obtain a solid substance.
  • the salt of the compound which has general formula (5) or (8) is obtained.
  • the organic substance is extracted with an organic solvent such as ethyl acetate, and then the organic layer is dried by a procedure usually used, or concentrated.
  • the target compound can be obtained by concentrating under reduced pressure.
  • This step comprises (i) 1-1e2-1 step; (ii) a combination of 1-1e2-2 and 1-1e2-3 steps; or (iii) 1-1e2-2, 1-1e2-4 and 1 1e2-5 can be performed according to a combination of steps.
  • (1-1e2-1 process) This step is a step for producing a compound having the general formula (6) or (9). In the inert solvent, in the presence or absence of a base, in the presence or absence of an additive, the metal catalyst.
  • heteroaryl pseudohalide ring Q 2 and ring Q 3 a substituted or unsubstituted containing aryl halide or Previous or hetero aryl halides or aryl pseudohalide, general formula (5) or (8) It is carried out by reacting with a compound having it.
  • the reaction conditions are, for example, Tsuji, J.
  • the solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably an aromatic hydrocarbon such as benzene, toluene, xylene; Halogenated hydrocarbons; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; methanol, ethanol, tert-butanol and the like Alcohols; nitriles such as acetonitrile; amides such as formamide, N, N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; mixed solvents in any ratio of a plurality of organic solvents; And a mixed solvent in any ratio with That.
  • aromatic hydrocarbon such as benzene, toluene, xylene
  • Halogenated hydrocarbons esters such as eth
  • the base used is not particularly limited as long as it is used as a base in a normal reaction, but preferably organic bases such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, lutidine, pyridine.
  • Alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as calcium carbonate; alkali metal bicarbonates such as potassium hydrogen carbonate; alkaline earth metal hydrogen carbonates such as calcium hydrogen carbonate; Salts; alkali metal hydroxides such as sodium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide; alkali metal acetates such as sodium acetate and potassium acetate; such as tripotassium phosphate Alkali metal phosphates; sodium tert-butoxide, potassium te metal alkoxides such as t-butoxide; organometallic amides such as lithium diisopropylamide, sodium hexamethyldisilazide; or organometallic compounds such as tert-butyllithium; metal hydrides such as potassium hydride And the like.
  • the additive used is not particularly limited as long as it is used in a known method, but preferably metal oxides such as silver oxide and alumina; triphenylphosphine, tri-tert-butylphosphine, Cyclohexylphosphine, tri (o-toluyl) phosphine, diphenylphosphinoferrocene, 2-dicyclohexylphosphino-2 ′, 6′-dimethoxy-1,1′-biphenyl (S-PHOS), 2-dicyclohexylphosphino-2 ′ Phosphines such as 2,4 ′, 6′-triisopropyl-1,1′-biphenyl (X-PHOS), 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP); Phosphine oxides such as phenylphosphine oxide; lithium chloride, potassium fluoride, fluorine Metal salts such
  • the metal catalyst used is not particularly limited as long as it is used in a known method, but preferably tetrakis (triphenylphosphine) palladium, bis (tri-tert-butylphosphine) palladium, palladium acetate, Palladium dichloride diphenylphosphinoferrocene complex, palladium chloride benzonitrile complex, palladium chloride acetonitrile complex, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium, bis [1,2-bis (diphenylphosphino) ) Ethane] palladium, 3-chloropyridine [1,3-bis (2,6-diisopropylphenyl) imidazo-2-ylidene] palladium, palladium catalysts such as palladium-activated carbon, and the like.
  • Pseudohalide refers to a compound having a pseudohalogen group, which is known to oxidatively add to a low-valent transition metal catalyst in the same manner as a halogen atom in a coupling reaction using a transition metal catalyst. Indicates a group.
  • the pseudohalogen group is not particularly limited as long as the oxidative addition reaction is known to occur, but a sulfonyloxy group such as a trifluoromethanesulfonyloxy group, a methanesulfonyloxy group, or a p-toluenesulfonyloxy group.
  • An acyloxy group such as an acetyloxy group; a diazonium group; or a phosphonyloxy group.
  • the substituted or unsubstituted aryl halide or heteroaryl halide or aryl pseudohalide or heteroaryl pseudohalide used is a known compound or synthesized according to a known method. If it does not specifically limit.
  • the reaction temperature varies depending on the raw material compounds, reagents and the like, but is usually ⁇ 10 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C.
  • the reaction time varies depending on the raw material compound, reagent, etc., but is usually 5 minutes to 48 hours, preferably 10 minutes to 12 hours.
  • the target compound of this reaction is, for example, concentrating the reaction mixture, adding an organic solvent such as ethyl acetate, washing with water, separating the organic layer containing the target compound, drying over anhydrous sodium sulfate, etc. Obtained by distilling off the solvent.
  • Step 1-1e2-2 This step is carried out in an inert solvent in the presence or absence of a base, in the presence or absence of an additive, in the presence of a metal catalyst, containing ring Q 2 and not containing ring Q 3.
  • This is a step of reacting a substituted aryl halide, heteroaryl halide, aryl pseudohalide or heteroaryl pseudohalide with a compound having the general formula (5) or (8).
  • This step can be performed according to a method according to step 1-1e2-1.
  • (1-1e2-3 process) the compound obtained in Step 1-1e2-2 and having a leaving group such as a halogen atom or —OX 1 group in ring Q 2 is present in an inert solvent in the presence or absence of a base.
  • the compound having the general formula (6) or (9) is produced by reacting with a substituted or unsubstituted arylboric acid or heteroarylboric acid in the presence or absence of an additive and in the presence of a metal catalyst. It is a process.
  • This reaction condition is, for example, Miyaura, N., Yamada, K., Suzuki, A., Tetrahedron Lett., 1979, 36, 3437; Miyaura, N., Suzuki, A., Chem. Rev., 1995, 95. , 2457 and the like, and this step is performed accordingly.
  • the reaction conditions in this step are preferably as follows, but are not limited thereto.
  • the solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably an aromatic hydrocarbon such as benzene, toluene, xylene; Halogenated hydrocarbons; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; methanol, ethanol, tert-butanol and the like Alcohols; nitriles such as acetonitrile; amides such as formamide, N, N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; mixed solvents in any ratio of a plurality of organic solvents; And a mixed solvent in any ratio with That.
  • aromatic hydrocarbon such as benzene, toluene, xylene
  • Halogenated hydrocarbons esters such as eth
  • the base used is not particularly limited as long as it is used as a base in a normal reaction, but preferably organic bases such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, lutidine, pyridine.
  • Alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as calcium carbonate; alkali metal bicarbonates such as potassium hydrogen carbonate; alkaline earth metal hydrogen carbonates such as calcium hydrogen carbonate; Salts; alkali metal hydroxides such as sodium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide; alkali metal acetates such as sodium acetate and potassium acetate; such as tripotassium phosphate Alkali metal phosphates; sodium tert-butoxide, potassium te metal alkoxides such as t-butoxide; organometallic amides such as lithium diisopropylamide, sodium hexamethyldisilazide; organometallic compounds such as tert-butyllithium; or metal hydrides such as potassium hydride And the like.
  • the additive used is not particularly limited as long as it is used in a known method, but preferably metal oxides such as silver oxide and alumina; triphenylphosphine, tri-tert-butylphosphine, Cyclohexylphosphine, tri (o-toluyl) phosphine, diphenylphosphinoferrocene, 2-dicyclohexylphosphino-2 ′, 6′-dimethoxy-1,1′-biphenyl (S-PHOS), 2-dicyclohexylphosphino-2 ′ Phosphines such as 2,4 ′, 6′-triisopropyl-1,1′-biphenyl (X-PHOS), 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP); Phosphine oxides such as phenylphosphine oxide; lithium chloride, potassium fluoride, fluorine Metal salts such
  • the metal catalyst used is not particularly limited as long as it is used in a known method, but preferably tetrakis (triphenylphosphine) palladium, bis (tri-tert-butylphosphine) palladium, palladium acetate, Palladium dichloride diphenylphosphinoferrocene complex, palladium chloride benzonitrile complex, palladium chloride acetonitrile complex, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium, bis [1,2-bis (diphenylphosphino) ) Ethane] palladium, 3-chloropyridine [1,3-bis (2,6-diisopropylphenyl) imidazo-2-ylidene] palladium, palladium catalysts such as palladium-activated carbon, and the like.
  • the reaction temperature varies depending on the raw material compounds, reagents and the like, but is usually ⁇ 10 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C.
  • the reaction time varies depending on the raw material compound, reagent, etc., but is usually 5 minutes to 48 hours, preferably 10 minutes to 12 hours.
  • the target compound of this reaction is, for example, concentrating the reaction mixture, adding an organic solvent such as ethyl acetate, washing with water, separating the organic layer containing the target compound, drying over anhydrous sodium sulfate, etc. Obtained by distilling off the solvent.
  • the obtained compound can be further purified by conventional methods such as recrystallization, reprecipitation, silica gel column chromatography and the like.
  • (1-1e2-4 process) In this step, the compound obtained in Step 1-1e2-2 and having a leaving group such as a halogen atom or —OX 1 group in ring Q 2 is present in an inert solvent in the presence or absence of a base.
  • a boron reagent in the presence or absence of an additive and in the presence of a metal catalyst.
  • This reaction condition is, for example, Ishiyama, T., Murata, M., Miyaura, N., J. Org.
  • the solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably an aromatic hydrocarbon such as benzene, toluene, xylene; Halogenated hydrocarbons; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; methanol, ethanol, tert-butanol and the like Alcohols; nitriles such as acetonitrile; amides such as formamide, N, N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; mixed solvents in any ratio of a plurality of organic solvents; And a mixed solvent in any ratio with That.
  • aromatic hydrocarbon such as benzene, toluene, xylene
  • Halogenated hydrocarbons esters such as eth
  • the boron reagent to be used is not particularly limited as long as it is used in a known method.
  • 4,4,4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl- Examples include 2,2′-bi-1,3,2-dioxaborolane.
  • the base used is not particularly limited as long as it is used as a base in a normal reaction, but preferably organic bases such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, lutidine, pyridine.
  • Alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as calcium carbonate; alkali metal bicarbonates such as potassium hydrogen carbonate; alkaline earth metal hydrogen carbonates such as calcium hydrogen carbonate; Salts; alkali metal hydroxides such as sodium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide; alkali metal acetates such as sodium acetate and potassium acetate; such as tripotassium phosphate Alkali metal phosphates; sodium tert-butoxide, potassium te metal alkoxides such as t-butoxide; organometallic amides such as lithium diisopropylamide, sodium hexamethyldisilazide; or organometallic compounds such as tert-butyllithium; metal hydrides such as potassium hydride And the like.
  • the additive used is not particularly limited as long as it is used in a known method, but preferably metal oxides such as silver oxide and alumina; triphenylphosphine, tri-tert-butylphosphine, Cyclohexylphosphine, tri (o-toluyl) phosphine, diphenylphosphinoferrocene, 2-dicyclohexylphosphino-2 ′, 6′-dimethoxy-1,1′-biphenyl (S-PHOS), 2-dicyclohexylphosphino-2 ′ Phosphines such as 2,4 ′, 6′-triisopropyl-1,1′-biphenyl (X-PHOS), 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP); Phosphine oxides such as phenylphosphine oxide; lithium chloride, potassium fluoride, fluorine Metal salts such
  • the metal catalyst used is not particularly limited as long as it is used in a known method, but preferably tetrakis (triphenylphosphine) palladium, bis (tri-tert-butylphosphine) palladium, palladium acetate, Palladium dichloride diphenylphosphinoferrocene complex, palladium chloride benzonitrile complex, palladium chloride acetonitrile complex, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium, bis [1,2-bis (diphenylphosphino) ) Ethane] palladium, 3-chloropyridine [1,3-bis (2,6-diisopropylphenyl) imidazo-2-ylidene] palladium, palladium catalysts such as palladium-activated carbon, and the like.
  • the reaction temperature varies depending on the raw material compounds, reagents and the like, but is usually ⁇ 10 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C.
  • the reaction time varies depending on the raw material compound, reagent, etc., but is usually 5 minutes to 48 hours, preferably 10 minutes to 12 hours.
  • the target compound of this reaction is, for example, concentrating the reaction mixture, adding an organic solvent such as ethyl acetate, washing with water, separating the organic layer containing the target compound, drying over anhydrous sodium sulfate, etc. Obtained by distilling off the solvent.
  • the obtained compound can be further purified by conventional methods such as recrystallization, reprecipitation, silica gel column chromatography and the like.
  • (1-1e2-5 process) In this step, the boron compound obtained in step 1-1e2-4 is reacted with ring Q in an inert solvent in the presence or absence of a base, in the presence or absence of an additive, in the presence of a metal catalyst.
  • a compound having the general formula (6) or (9) by reacting with a substituted or unsubstituted aryl halide or heteroaryl halide containing 3 or aryl pseudohalide or heteroaryl pseudohalide It is a process. This step can be performed according to a method according to step 1-1e2-3.
  • This step is a step of converting the substituent R 7a on the ring Q 3 into R 7b , and the synthesis method varies depending on the type of the substituent of R 7b .
  • R 7b is an alkylcarbamoyloxyalkyl group, an alkylcarbamoylaminoalkyl group, an alkoxycarbonylaminoalkyl group, an alkylthiocarbonylaminoalkyl group, or an alkylsulfonylaminoalkyl group
  • step 1-1e3-1 is used
  • R 7b is an alkanoyl In the case of an alkyl group or an alkanoylalkenyl group, it is carried out by the 1-1e3-2 step. (Step 1-1e3-1).
  • This step from a compound having a hydroxyalkyl group or an aminoalkyl group as R 7a , (a) an alkylcarbamoyloxyalkyl group or (b) an alkylcarbamoylaminoalkyl group, an alkoxycarbonylaminoalkyl group as R 7b ,
  • This step leads to a compound having an alkylthiocarbonylaminoalkyl group or an alkylsulfonylaminoalkyl group.
  • R 7b is (a) a compound having a hydroxyalkyl group as R 7a, also, if R 7b is (b) a compound having an aminoalkyl group as R 7a, in an inert solvent, a base By reacting with an appropriate reactive agent in the presence or absence of.
  • the solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably an aromatic hydrocarbon such as benzene, toluene, xylene; Halogenated hydrocarbons; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; nitriles such as acetonitrile; formamide, Examples thereof include amides such as N, N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; or a mixed solvent in an arbitrary ratio of a plurality of organic solvents.
  • aromatic hydrocarbon such as benzene, toluene, xylene
  • Halogenated hydrocarbons esters such as ethyl acetate and propyl acetate
  • ethers such as diethyl ether
  • the reaction agent used varies depending on the kind of substituents R 7b, not particularly limited as long as it is used as a reaction agent corresponding to R 7b.
  • R 7b is an alkylcarbamoyloxyalkyl group and an alkylcarbamoylaminoalkyl group
  • an alkyl isocyanate is used
  • alkoxycarbonylaminoalkyl group is used
  • alkoxycarbonyl chloride is used
  • alkylsulfonylaminoalkyl group alkylsulfonyl chloride can be mentioned.
  • the base used is not particularly limited as long as it is used as a base in a normal reaction, but preferably organic bases such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, lutidine, pyridine.
  • Alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as calcium carbonate; alkali metal bicarbonates such as potassium hydrogen carbonate; alkaline earth metal hydrogen carbonates such as calcium hydrogen carbonate; Salts; alkali metal hydroxides such as sodium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide; or alkali metal phosphates such as tripotassium phosphate. .
  • the reaction temperature varies depending on the raw material compounds, reagents and the like, but is usually ⁇ 100 ° C. to 150 ° C., preferably 0 ° C. to 50 ° C.
  • the reaction time varies depending on the raw material compound, reagent, etc., but is usually 5 minutes to 24 hours, preferably 10 minutes to 6 hours.
  • the target compound of this reaction is, for example, concentrating the reaction mixture, adding an organic solvent such as ethyl acetate, washing with water, separating the organic layer containing the target compound, drying over anhydrous sodium sulfate, etc. Obtained by distilling off the solvent.
  • Step 1-1e3-2 This step is a step leading from a compound having a hydroxyalkyl group as R 7a to a compound having an alkanoylalkyl group or alkanoylalkenyl group as R 7b , and using an appropriate oxidizing agent for the secondary alcohol compound Is done.
  • the oxidizing agent to be used is not particularly limited. For example, it is described in the 4th edition, Experimental Science Course (21.
  • oxidation reactions include chromic anhydride, chromium (VI) oxide-pyridine complex (Collins reagent), pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), chromium oxide (VI) -sulfuric acid- Oxidation reaction using chromic acid such as acetone (Jones reagent), oxidation reaction using activated manganese dioxide, dicyclohexylcarbodiimide (DCC), acetic anhydride, phosphorus pentoxide, sulfur trioxide-pyridine complex, or oxalyl chloride and dimethyl
  • DMSO sulfoxide
  • hyperatom oxidation reaction using a hyperatom
  • R 7a has a protecting group at 1-1e3 step further comprises the step of the deprotection, depending on the protecting group used, for example, Protective Groups in Organic Synthesis, 3 rd ed., Greene, TW , Wuts, PGM, John Wiley & Sons, Inc., New York, 1999, and the like are appropriately selected, and this step is performed accordingly.
  • the protecting group used for example, Protective Groups in Organic Synthesis, 3 rd ed., Greene, TW , Wuts, PGM, John Wiley & Sons, Inc., New York, 1999, and the like are appropriately selected, and this step is performed accordingly.
  • a methoxymethyl group, a tert-butyl (dimethyl) silyl group or a triisopropylsilyl group is selected as a suitable protecting group, and the deprotection of the methoxymethyl group using an acid in an inert solvent (1- 1e3-3 step), a method of deprotecting a tert-butyl (dimethyl) silyl group or triisopropylsilyl group using an acid in an inert solvent (step 1-1e3-4), or in an inert solvent ,
  • a method for deprotecting a tert-butyl (dimethyl) silyl group or a triisopropylsilyl group using a fluorine compound is described, but this step is not limited thereto.
  • This step is a step of deprotecting the methoxymethyl group, and can be performed according to a method according to step 1-1a2.
  • (1-1e3-4 process) This step is a step of deprotecting the tert-butyl (dimethyl) silyl group or the triisopropylsilyl group, and can be performed according to a method according to step 1-1a2.
  • (1-1e3-5 process) This step is a step of deprotecting the tert-butyl (dimethyl) silyl group or triisopropylsilyl group, and is performed using a fluorine compound in an inert solvent.
  • the solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably an aromatic hydrocarbon such as benzene, toluene, xylene; Halogenated hydrocarbons; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; methanol, ethanol, tert-butanol and the like Alcohols; nitriles such as acetonitrile; amides such as formamide, N, N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; mixed solvents in any ratio of a plurality of organic solvents; And a mixed solvent in any ratio with That.
  • aromatic hydrocarbon such as benzene, toluene, xylene
  • Halogenated hydrocarbons esters such as eth
  • the fluorine compound to be used is not particularly limited as long as it is used for deprotection of a silyl group, but preferably tetrabutylammonium fluoride, hydrogen fluoride-pyridine, tris (dimethylamino) difluorotrimethylsilicate. ) Sulfonium and the like.
  • the reaction temperature varies depending on the raw material compounds, reagents and the like, but is usually ⁇ 100 ° C. to 150 ° C., preferably ⁇ 20 ° C. to 100 ° C.
  • the reaction time varies depending on the raw material compound, reagent, etc., but is usually 5 minutes to 24 hours, preferably 10 minutes to 6 hours.
  • the target compound of this reaction is, for example, concentrating the reaction mixture, adding an organic solvent such as ethyl acetate, washing with water, separating the organic layer containing the target compound, drying over anhydrous sodium sulfate, etc. Obtained by distilling off the solvent.
  • Step 1-2 is a step of producing a compound having the general formula (1) from a compound having the general formula (3).
  • Step 1-2a Deprotection reaction of protecting group Pro 1
  • Step 1-2b Deprotection reaction of protecting group Pro 3
  • step 1-2c reaction for converting R 1b to R 1
  • Step 1-2d A reaction for converting R 2a to R 2 can be added.
  • the steps 1-2a to 1-2d may be performed in any order.
  • Step 1-2a) This step is a step of deprotecting the protecting group Pro 1 .
  • a benzyl group as a preferable Pro 1, under a hydrogen atmosphere in an inert solvent in the presence or absence of an additive, with a catalyst, a method for converting Pro 1 to the hydrogen atom (1-2A1 Step), a method of converting Pro 1 to a hydrogen atom using a catalyst in the presence of an organic compound that can be a hydrogen source, in an atmosphere of nitrogen or argon, in an inert solvent, in the presence or absence of an additive (1- Step 2a2) or a method of converting Pro 1 to a hydrogen atom using an appropriate acid in an inert solvent (step 1-2a3) is described, but this step is not limited thereto.
  • This step is a step of converting Pro 1 to a hydrogen atom using a catalyst in a hydrogen atmosphere, in an inert solvent, in the presence or absence of an additive.
  • the solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably an aromatic hydrocarbon such as benzene, toluene, xylene; Halogenated hydrocarbons; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; alcohols such as methanol and ethanol; Nitriles such as acetonitrile; Amides such as formamide, N, N-dimethylformamide; Sulfoxides such as dimethyl sulfoxide; Mixed solvents in any ratio of a plurality of organic solvents; or any of these and water A mixed solvent having a ratio can be used.
  • an aromatic hydrocarbon such as benzene, toluene, xylene
  • Halogenated hydrocarbons esters such as ethyl acetate and prop
  • the additive used is not particularly limited as long as it is used in a known method, and examples thereof include hydrochloric acid.
  • the metal catalyst to be used is not particularly limited as long as it is used in a known method.
  • Preferable examples include palladium-activated carbon, tris (triphenylphosphine) rhodium chloride, palladium hydroxide and the like. it can.
  • the reaction temperature varies depending on the raw material compounds, reagents and the like, but is usually ⁇ 100 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time varies depending on the raw material compounds, reagents and the like, but is usually 1 minute to 24 hours, preferably 5 minutes to 10 hours.
  • the target compound of this reaction can be obtained, for example, by filtering insolubles and concentrating the filtrate under reduced pressure. If necessary, the obtained compound can be further purified by conventional methods such as recrystallization, reprecipitation, silica gel column chromatography and the like.
  • Step 1-2a2 is a step of converting Pro 1 to a hydrogen atom using a catalyst in the presence of an organic compound that can be a hydrogen source, in an atmosphere of nitrogen or argon, in an inert solvent, in the presence or absence of an additive. .
  • the solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably an aromatic hydrocarbon such as benzene, toluene, xylene; Halogenated hydrocarbons; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; alcohols such as methanol and ethanol; Nitriles such as acetonitrile; Amides such as formamide, N, N-dimethylformamide; Sulfoxides such as dimethyl sulfoxide; Mixed solvents in any ratio of a plurality of organic solvents; or any of these and water A mixed solvent having a ratio can be used.
  • an aromatic hydrocarbon such as benzene, toluene, xylene
  • Halogenated hydrocarbons esters such as ethyl acetate and prop
  • the organic compound to be used is not particularly limited as long as it is used in a known method.
  • formic acid can be mentioned.
  • the additive used is not particularly limited as long as it is used in a known method, and examples thereof include hydrochloric acid.
  • the metal catalyst to be used is not particularly limited as long as it is used in a known method.
  • Preferable examples include palladium-activated carbon, tris (triphenylphosphine) rhodium chloride, palladium hydroxide and the like. it can.
  • the reaction temperature varies depending on the raw material compounds, reagents and the like, but is usually ⁇ 100 ° C. to 150 ° C., preferably ⁇ 78 ° C. to 100 ° C.
  • the reaction time varies depending on the raw material compound, reagent, etc., but is usually 5 minutes to 24 hours, preferably 10 minutes to 6 hours.
  • the target compound of this reaction is, for example, concentrating the reaction mixture, adding an organic solvent such as ethyl acetate, washing with water, separating the organic layer containing the target compound, drying over anhydrous sodium sulfate, etc. Obtained by distilling off the solvent.
  • Step 1-2a3 This step is a step of converting Pro 1 to a hydrogen atom using an appropriate acid in an inert solvent. This step can be performed according to a method according to step 1-1a2.
  • Step 1-2b This step is a step of deprotecting the protecting group Pro 3 . This step can be performed according to a method according to step 1-1a. When Pro 3 is a benzyl group, this step can also be performed according to a method according to Step 1-2a1.
  • Step 1-2c This step is a step of converting R 1b to R 1 .
  • This step can be performed according to a method according to step 1-1e2. Further, it can be carried out according to a method according to step 1-1e3, including a step of converting substituent R 7b on ring Q 3 to R 7 as necessary.
  • Step 1-2d This step is a step of converting R 2a to R 2.
  • R 2a is an alkenyl group
  • the alkenyl group can be converted to a corresponding alkyl group according to a method according to step 1-2a1.
  • the second step is a step for producing the compound (2) used in the first step.
  • R 1a represents the same meaning as above, Pro 5 is known protecting groups (e.g., Protective Groups in Organic Synthesis, 3 rd ed., Greene, TW, Wuts, PGM, John Wiley & Sons, Inc., The protecting group for each functional group selected from New York, 1999, etc.).
  • Pro 5 is not particularly limited as long as it is stably present during the reaction and does not inhibit the reaction, and is preferably a methyl group.
  • the compound having the general formula (2) is prepared by a known method [for example, (i) a substituted ethane imidamide (10) synthesized according to a known method and a 2-alkyloxy-3-oxosuccinic acid diester (11) Subcondensation method: Dreher, S. D., Ikemoto, N., Gresham, V., Liu, J., Dormer, P. G., Balsells, J., Mathre, D., Novak. T. III, J.
  • the reaction product obtained in each of the above steps is isolated and purified as various solvates such as a non-solvate, a salt thereof or a hydrate.
  • the salt can be produced by a conventional method. Isolation or purification is performed by applying ordinary methods such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography.
  • optical isomers can be isolated by a conventional method using the difference in physicochemical properties between isomers.
  • optical isomers can be separated by a general optical resolution method (for example, fractional crystallization or chromatography).
  • Optical isomers can also be produced from appropriate optically active raw material compounds.
  • Preparations containing the compound of the present invention as an active ingredient are prepared using additives such as carriers and excipients used in ordinary preparations.
  • the compound of the present invention can be administered orally in the form of tablets, pills, capsules, granules, powders, liquids, etc., or injections (eg, intravenous injection, intramuscular injection, etc.), suppositories, transdermal agents , Parenteral administration in the form of nasal agents, inhalants and the like.
  • the dose and frequency of administration of the compound of the present invention are appropriately determined according to individual cases in consideration of symptoms, age or sex of the administration target.
  • the dose is usually 0.001 mg / kg to 100 mg / kg per adult, and in the case of intravenous administration, it is usually 0.0001 mg / kg to 10 mg / kg per adult.
  • the administration frequency is usually once to six times a day or once to seven days once a day.
  • Administration to a patient undergoing dialysis is preferably performed once before and after each dialysis received by the patient (preferably before dialysis).
  • the solid preparation for oral administration according to the present invention may be a tablet, powder, granule or the like.
  • Such formulations are prepared according to conventional methods by mixing one or more active substances with inert excipients, lubricants, disintegrants, solubilizers or the like.
  • the excipient can be, for example, lactose, mannitol, glucose.
  • the lubricant can be, for example, magnesium stearate.
  • the disintegrant can be, for example, sodium carboxymethyl starch. If necessary, tablets or pills may be coated with sugar coating or gastric or enteric coating agent.
  • Liquid preparations for oral administration can be pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, and the like.
  • Such formulations contain commonly used inert solvents (eg purified water, ethanol), and further solubilizers, wetting agents, suspending agents, sweeteners, flavoring agents, fragrances, or preservatives.
  • An agent may be contained.
  • the injection for parenteral administration can be a sterile aqueous or non-aqueous solution, suspension, or emulsion.
  • An aqueous solvent for injections can be, for example, distilled water or physiological saline.
  • Non-aqueous solvents for injections can be, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, or polysorbate 80 (Pharmacopeia).
  • Such formulations may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubilizers.
  • compositions obtained by dissolving or suspending a sterile solid composition in sterile water or an injectable solvent before use can also be used as these preparations.
  • Diisopropylamine (30 mL, 210 mmol) is dissolved in tetrahydrofuran (100 mL), n-butyllithium hexane solution (2.77 M, 77 mL, 210 mmol) is added dropwise at 3 ° C, and then at -78 ° C for 30 minutes.
  • a tetrahydrofuran solution of lithium diisopropylamide (LDA) was prepared by stirring.
  • reaction solution was concentrated under reduced pressure, diluted with dichloromethane, and washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution.
  • the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate) to give the title compound (0.11 g, 0.19 mmol). Obtained as a pale yellow solid (98% yield).
  • Example 1- (8) 1,4-dibromobenzene was used in place of [(4′-bromobiphenyl-4-yl) methoxy] (tert-butyl) dimethylsilane, and the title compound (yield 18 %) As an orange oil.
  • Example 1- (10) 5- (benzyloxy) -2-( ⁇ 1- [4 ′-(hydroxymethyl) biphenyl-4-yl] piperidin-4-yl ⁇ methyl) -6-methyl 5- (benzyloxy) -2- ⁇ [1- (4-bromophenyl) piperidin-4-yl] methyl ⁇ -6-methylpyrimidine-4-carboxylic acid tert instead of tert-butyl pyrimidine-4-carboxylate Using -butyl, the title compound (94% yield) was obtained as an oil.
  • Example 4- [( ⁇ 2-[(1- ⁇ 4- [6- (Aminomethyl) pyridin-3-yl] phenyl ⁇ piperidin-4-yl) methyl] -5- () obtained in Example 4- (1) (Benzyloxy) -6-methylpyrimidin-4-yl ⁇ carbonyl) amino] acetic acid hydrochloride Hydrochloride (0.079 g) was suspended in tetrahydrofuran (3 mL), and ethyl isocyanate (0.046 mL, 0.58 mmol) and triethylamine (0.08 mL) were suspended at room temperature. 0.064 mL, 0.46 mmol) was added, and the mixture was stirred at room temperature for 5 hours.
  • Example 3- According to (1), 5-bromo-2- ⁇ [(triisopropylsilyl) oxy] methyl ⁇ pyridine instead of tert-butyl [(5-bromopyridin-2-yl) methyl] carbamate To give the title compound (quantitative yield) as an oil.
  • Example 3- According to Example 3- (4), 1- (10), 1- (14), ( ⁇ [5- (benzyloxy) -2- ⁇ [1- (4-bromophenyl) piperidin-4-yl ] Methyl ⁇ -6-methylpyrimidin-4-yl] carbonyl ⁇ amino) 5- (benzyloxy) -2- ⁇ [1- (4-bromo) obtained in Example 3- (2) instead of ethyl acetate Phenyl) piperidin-4-yl] methyl ⁇ -6-methylpyrimidine-4-carboxylate, and ⁇ [5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2) -Yl) pyridin-2-yl] methyl ⁇ carbamate instead of tert-butyl 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2- ⁇ [ (Triisopropylsilyl) oxy] methyl Using ⁇ pyridine to give
  • a tetrahydrofuran solution (2 ⁇ ⁇ ⁇ M, 1.0 mL, 2.0 mmol) of n-butylmagnesium chloride is diluted in tetrahydrofuran (2 mL), and a hexane solution of n-butyllithium (2.6 M, 1.5 mL, 4.0) at 0 ° C under a nitrogen atmosphere. mmol) was added, followed by stirring at the same temperature for 20 minutes to prepare a tetrahydrofuran solution of tri-n-butylmagnesium lithium.
  • 4,4′-Dibromodiphenylmethane (1.6 g, 4.9 mmol) was dissolved in tetrahydrofuran (10 mL), and a tetrahydrofuran solution of tri-n-butylmagnesium lithium was added at 0 ° C. under a nitrogen atmosphere.
  • 2-Ethyloxirane (0.47 mL, 5.4 mmol) was added to the reaction solution, and then the mixture was warmed to room temperature and further stirred for 15 hours.
  • a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Chromium oxide (0.040 g, 0.40 mmol) and orthoperiodic acid (9.1 g, 40 mmol) are dissolved in a mixed solvent of acetonitrile (91 ml) and water (0.70 ml) and stirred at room temperature for 2 hours under nitrogen atmosphere.
  • acetonitrile 9.1 g, 40 mmol
  • Oxalyl chloride (0.046 g, 0.37 mmol) was dissolved in dichloromethane (5 mL), dimethyl sulfoxide (0.057 g, 0.73 mmol) was added dropwise at ⁇ 78 ° C., and the mixture was stirred at the same temperature for 10 min.
  • Example 3- (1) 1- (3-bromophenyl) acetone was used instead of tert-butyl [(5-bromopyridin-2-yl) methyl] carbamate, and the title compound (yield 99 %) As a white solid.
  • 1 H-NMR (400 MHz, CDCl 3 ) ⁇ : 7.72 (1H, d, J 7 Hz), 7.64 (1H, s), 7.41-7.27 (2H, m), 3.70 (2H, s), 2.15 ( 3H, s), 1.34 (12H, s).
  • Example 1- (8) (4-bromophenoxy) (tert-butyl) diphenylsilane was used instead of [(4′-bromobiphenyl-4-yl) methoxy] (tert-butyl) dimethylsilane
  • the title compound (74% yield) was obtained as an orange oil.
  • the reaction solution was diluted with ethyl acetate and washed with a saturated aqueous sodium chloride solution, and then the organic layer was dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.8 g, 3.7 mmol) as a white solid (yield 97%). ).
  • Example 1- (5) 5- (benzyloxy) -2- ⁇ [1- (tert-butoxycarbonyl) piperidin-4-yl] methyl ⁇ -6-hydroxypyrimidine-4-carboxylic acid tert- Using tert-butyl 5- (benzyloxy) -2- ⁇ [1- (4-hydroxyphenyl) piperidin-4-yl] methyl ⁇ -6-methylpyrimidine-4-carboxylate instead of butyl, the title compound ( (88% yield) was obtained as an orange oil.
  • Example 3- ( ⁇ [5- (benzyloxy) -2- ⁇ [1- (4-bromophenyl) piperidin-4-yl] methyl ⁇ -6-methylpyrimidin-4-yl ] Carbonyl ⁇ amino) 1-bromo-4- (bromomethyl) benzene instead of ethyl acetate, and ⁇ [5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Tert-Butyl (dimethyl) ⁇ 1-methyl-2- [4- (4,4,5,5-tetramethyl-1,3,2-) instead of tert-butylpyridin-2-yl] methyl ⁇ carbamate Using dioxaborolan-2-yl) phenyl] ethoxy ⁇ silane, the title compound (56% yield) was obtained as a colorless oil.
  • Example 1- 5- (benzyloxy) -2-( ⁇ 1- [4 ′-(hydroxymethyl) biphenyl-4-yl] piperidin-4-yl ⁇ methyl) -6-methyl 5- (Benzyloxy) -2- ⁇ [1- (4-bromophenyl) piperidin-4-yl] methyl ⁇ obtained in Example 3- (2) instead of tert-butyl pyrimidine-4-carboxylate ⁇ Using tert-butyl -6-methylpyrimidine-4-carboxylate and glycine ethyl ester hydrochloride instead of glycine tert-butyl ester hydrochloride gave the title compound (quantitative yield) as an orange oil.
  • Example 9- (1) 16- (4), ⁇ [(5-hydroxy-6-methyl-2- ⁇ [1- (4- ⁇ 6-[(1E) -3-oxobut-1 —En-1-yl] pyridin-3-yl ⁇ phenyl) piperidin-4-yl] methyl ⁇ pyrimidin-4-yl) carbonyl] amino ⁇ obtained in Example 16- (3) instead of ethyl acetate [ ( ⁇ 5- (Benzyloxy) -6-methyl-2-[(1- ⁇ 4 '-[(1E) -3-oxobut-1-en-1-yl] biphenyl-4-yl ⁇ piperidine-4- Yl) methyl] pyrimidin-4-yl ⁇ carbonyl) amino] tert-butyl acetate was used to obtain the title compound (yield 51%) as a pale yellowish white solid.
  • Example 1- (10) 5- (benzyloxy) -2-( ⁇ 1- [4 ′-(hydroxymethyl) biphenyl-4-yl] piperidin-4-yl ⁇ methyl) -6-methyl 5- (benzyloxy) -2- ⁇ [1- (5-bromopyridin-2-yl) piperidin-4-yl] methyl ⁇ -6-methylpyrimidine-4 instead of tert-butyl pyrimidine-4-carboxylate Using tert-butyl carboxylate, the title compound (yield 95%) was obtained as a yellow oil.
  • Example 3- (1) instead of tert-butyl [(5-bromopyridin-2-yl) methyl] carbamate ( ⁇ [5- (benzyloxy) -2- ⁇ [1- (5 -Bromopyridin-2-yl) piperidin-4-yl] methyl ⁇ -6-methylpyrimidin-4-yl] carbonyl ⁇ amino) ethyl acetate was used to give the title compound (quantitative yield) as a black oil. . MS m / z: 630 (M + H) + .
  • Example 18- (4) 4- (1), (4-bromobenzyl) imidodicarbonate di-tert-butyl was used instead of 1- (4-bromophenyl) acetone, and the title compound (yield 43%) was obtained as a white solid.
  • Example 5- 1- (14), 1- (15), [( ⁇ 2-[(1- ⁇ 4- [6- (aminomethyl) pyridin-3-yl] phenyl ⁇ Piperidin-4-yl) methyl] -5- (benzyloxy) -6-methylpyrimidin-4-yl ⁇ carbonyl) amino] acetic acid ethyl instead of the hydrochloride obtained in Example 20- (1) [( ⁇ 2-[(1- ⁇ 5- [4- (Aminomethyl) phenyl] pyridin-2-yl ⁇ piperidin-4-yl) methyl] -5- (benzyloxy) -6-methylpyrimidin-4-yl ⁇ carbonyl ) Amino] ethyl acetate
  • the hydrochloride was used to give the title compound (yield 9.8%) as a pale yellow solid.
  • Example 18- (4) 7- (1), 2- (2), 11- (3), (4-iodophenyl) methanol was used instead of 1- (4-bromophenyl) acetone The title compound (12% yield) was obtained as a white solid.
  • Formulation Example 2 (hard capsule) 100 mg of the powdered Example Compound, 128.7 mg of lactose, 70 mg of cellulose and 1.3 mg of magnesium stearate were mixed, passed through a 60 mesh sieve, and the resulting powder was mixed with 250 mg of No. 3 gelatin. Put into capsules to make capsules.
  • Formulation Example 3 100 mg of the powdered Example Compound, 124 mg of lactose, 25 mg of cellulose and 1 mg of magnesium stearate are mixed, and tableted by a tableting machine to make one tablet of 250 mg. This tablet can be sugar-coated if necessary.
  • EPO erythropoietin
  • the EPO concentration when each Example compound was used as the test compound was expressed as a multiple of the EPO concentration in Control.
  • the results are shown in Table 1.
  • the EPO concentration when each Example compound was used was remarkably increased as compared with the EPO concentration of the solvent control (Control). That is, the compound of the present invention exhibits excellent EPO production enhancing activity and is useful as a medicament (particularly, a medicament for the prevention or treatment of anemia).
  • the compound of the present invention or a pharmacologically acceptable salt thereof has an excellent EPO production enhancing activity, and is useful for diseases caused by a decrease in EPO.
  • the compound of the present invention or a pharmacologically acceptable salt thereof is anemia, preferably renal anemia, premature infant anemia, anemia associated with chronic disease, anemia associated with cancer chemotherapy, or cancerous anemia. It is useful as a medicament for the prevention and / or treatment of inflammation-related anemia or anemia associated with congestive heart failure, and more preferably anemia associated with chronic kidney disease. It can also be used as a medicament for treatment.

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Abstract

La présente invention concerne un composé qui améliore la production d'érythropoïétine. La présente invention concerne un composé exprimé par la formule (1). Dans la formule (1), R1 représente la formule (1A), R2 représente un alkyle ou méthylsulfanyle et R3 représente H ou méthyle. Dans la formule (1A), le noyau Q1 représente un groupe cyclique hétérocyclique monocyclique; le noyau Q2 représente un groupe cyclique hydrocarboné monocyclique ou un groupe cyclique hétérocyclique monocyclique; le noyau Q3 représente un groupe cyclique hydrocarboné monocyclique ou un groupe cyclique hétérocyclique monocyclique; X représente une simple liaison, méthylène, éthylène.
PCT/JP2013/059655 2012-03-30 2013-03-29 Dérivé de 5-hydroxypyrimidine-4-carboxamide WO2013147214A1 (fr)

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WO2017104725A1 (fr) * 2015-12-16 2017-06-22 第一三共株式会社 Agent de traitement des plaies
WO2017175859A1 (fr) 2016-04-08 2017-10-12 学校法人 慶應義塾 Médicament pour prévenir ou traiter l'acidose lactique
JP2018504392A (ja) * 2015-01-09 2018-02-15 ザ ボード オブ トラスティーズ オブ ザ ユニヴァーシティ オブ イリノイＴｈｅ Ｂｏａｒｄ Ｏｆ Ｔｒｕｓｔｅｅｓ Ｏｆ Ｔｈｅ Ｕｎｉｖｅｒｓｉｔｙ Ｏｆ Ｉｌｌｉｎｏｉｓ 小分子を用いた鉄欠乏生物における生理機能の回復
WO2019160130A1 (fr) 2018-02-19 2019-08-22 第一三共株式会社 Agent thérapeutique pour maladie inflammatoire de l'intestin

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JP2011088840A (ja) * 2009-10-21 2011-05-06 Daiichi Sankyo Co Ltd ５−ヒドロキシピリミジン−４−カルボキサミド化合物を含有する医薬組成物
JP2011105708A (ja) * 2009-10-21 2011-06-02 Daiichi Sankyo Co Ltd ５−ヒドロキシピリミジン−４−カルボキサミド化合物を含有する医薬組成物
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WO2009131127A1 (fr) * 2008-04-22 2009-10-29 第一三共株式会社 Composé 5-hydroxypyrimidine-4-carboxamide
WO2011049127A1 (fr) * 2009-10-21 2011-04-28 第一三共株式会社 Dérivé de 5-hydroxypyrimidine-4-carboxamide comportant un groupe hydrocarboné cyclique
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JP2011088840A (ja) * 2009-10-21 2011-05-06 Daiichi Sankyo Co Ltd ５−ヒドロキシピリミジン−４−カルボキサミド化合物を含有する医薬組成物
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JP2018504392A (ja) * 2015-01-09 2018-02-15 ザ ボード オブ トラスティーズ オブ ザ ユニヴァーシティ オブ イリノイＴｈｅ Ｂｏａｒｄ Ｏｆ Ｔｒｕｓｔｅｅｓ Ｏｆ Ｔｈｅ Ｕｎｉｖｅｒｓｉｔｙ Ｏｆ Ｉｌｌｉｎｏｉｓ 小分子を用いた鉄欠乏生物における生理機能の回復
US11517540B2 (en) 2015-01-09 2022-12-06 The Board Of Trustees Of The University Of Illinois Restoring physiology in iron-deficient organisms using small molecules
WO2017104725A1 (fr) * 2015-12-16 2017-06-22 第一三共株式会社 Agent de traitement des plaies
CN108367007A (zh) * 2015-12-16 2018-08-03 第三共株式会社 用于伤口的治疗剂
KR20180093932A (ko) 2015-12-16 2018-08-22 다이이찌 산쿄 가부시키가이샤 창상 치료제
WO2017175859A1 (fr) 2016-04-08 2017-10-12 学校法人 慶應義塾 Médicament pour prévenir ou traiter l'acidose lactique
EP3441070A4 (fr) * 2016-04-08 2019-12-11 Keio University Médicament pour prévenir ou traiter l'acidose lactique
WO2019160130A1 (fr) 2018-02-19 2019-08-22 第一三共株式会社 Agent thérapeutique pour maladie inflammatoire de l'intestin
KR20200121784A (ko) 2018-02-19 2020-10-26 다이이찌 산쿄 가부시키가이샤 염증성 장 질환 치료제
CN112074272A (zh) * 2018-02-19 2020-12-11 第一三共株式会社 炎症性肠疾病的治疗剂
EP3756671A4 (fr) * 2018-02-19 2021-10-27 Daiichi Sankyo Company, Limited Agent thérapeutique pour maladie inflammatoire de l'intestin

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