WO2012115177A1 - Dérivé de n-[(biaryloxy)alkylcarbonyle]sulfonamide - Google Patents

Dérivé de n-[(biaryloxy)alkylcarbonyle]sulfonamide Download PDF

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WO2012115177A1
WO2012115177A1 PCT/JP2012/054350 JP2012054350W WO2012115177A1 WO 2012115177 A1 WO2012115177 A1 WO 2012115177A1 JP 2012054350 W JP2012054350 W JP 2012054350W WO 2012115177 A1 WO2012115177 A1 WO 2012115177A1
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group
compound
acceptable salt
atom
pharmacologically acceptable
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Japanese (ja)
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達矢 西
健 有田
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第一三共株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • 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
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to an N-[(biaryloxy) alkylcarbonyl] sulfonamide derivative or a pharmacologically acceptable salt thereof useful as a pharmaceutical product. More specifically, the present invention relates to an N-[(biaryloxy) alkylcarbonyl] sulfonamide derivative having a platelet aggregation inhibitory action or a pharmacologically acceptable salt thereof.
  • thrombotic diseases such as cerebral infarction, myocardial infarction and peripheral circulatory disorder not only have a high mortality rate, but patients are forced to bear a lot of personal and social burdens such as poor prognosis and restrictions on life.
  • vascular stenosis caused by thrombus caused by platelet activation adheresion to vascular injury site, release of physiologically active substance, formation of aggregates, etc.
  • ischemia accompanying stenosis It has been known.
  • Drugs that inhibit platelet aggregation which suppress platelet activation, play an important role in the prevention, recurrence prevention or treatment of these diseases, and will become increasingly important as thrombotic diseases increase in the future It is thought that the nature increases.
  • ADP adenosine 5′-diphosphate
  • TXA 2 thromboxane A 2
  • collagen serotonin (5-hydroxytryptamine, 5-HT), etc.
  • antithrombotic agents include ticlopidine and clopidogrel, and these compounds are commonly known to have a thienopyridine structure.
  • drugs with higher safety and superior medicinal effects.
  • ADP derivatives (see Patent Literatures 1 and 2), nicotinic acid ester derivatives (see Patent Literature 3), thienopyrimidine derivatives (see Patent Literatures 4 and 5).
  • Sulfonylurea derivatives see Patent Literature 6
  • piperazine derivatives see Patent Literatures 7 and 8
  • quinoline derivatives Patent Literature 9
  • quinolone derivatives see Patent Literatures 10 and 11
  • quinazolinedione derivatives see Patent Literature 12 Etc.
  • the present inventors searched for a compound having higher safety and an excellent platelet aggregation inhibitory effect.
  • the compound having the general formula (I) of the present invention, or a compound thereof The present inventors have found that a pharmacologically acceptable salt has an excellent platelet aggregation inhibitory action and completed the present invention.
  • R 1 represents a halogen atom, a cyano group, an amino group, a C 1-4 alkyl group, a halogenated C 1-4 alkyl group or a C 1-4 alkoxy group
  • R 2 represents a hydrogen atom, a halogen atom, a cyano group, or a C 1-4 alkyl group
  • R 3 and R 4 each independently represent a hydrogen atom, a C 1-4 alkyl group, a halogenated C 1-4 alkyl group or a C 1-4 alkoxy C 1-4 alkyl group, or R 3 and R 4 Represents a group which together with the carbon atom to which they are attached forms a C 3-5 cycloalkyl
  • R 5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a C 1-4 alkyl group, or an amino group
  • R 6 represents a hydrogen atom, a halogen atom, or
  • an effective amount of the compound according to any one of the above [1] to [25] or a pharmacologically acceptable salt thereof is orally or parenterally administered to a mammal (preferably a human).
  • a mammal preferably a human.
  • Ischemic cerebrovascular disorder, acute coronary syndrome, coronary artery bypass surgery (CABG) or percutaneous coronary angioplasty (PCI) is applied, restenosis or reocclusion of acute coronary syndrome, vascular surgery and This is a method for preventing and / or treating thromboembolism or chronic arterial occlusion associated with extracorporeal blood circulation.
  • the “halogen atom” in the definitions of R 1 , R 2 , R 5 to R 8 and Ra represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • C 1-4 alkyl group in the definition of R 1 to R 11 and Ra represents a linear or branched alkyl group having 1 to 4 carbon atoms.
  • a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group and the like can be mentioned.
  • Specific examples include (spiro) cyclopropyl group, (spiro) cyclobutyl group, and (spiro) cyclopentyl group.
  • the “halogenated C 1-4 alkyl group” in the definition of R 1 , R 3 , and R 4 is one or more of the above “C 1-4 alkyl group” Represents a group in which the hydrogen atom is substituted with the above-mentioned “halogen atom”. Examples thereof include a fluoromethyl group, a chloromethyl group, a bromomethyl group, a difluoromethyl group, a dichloromethyl group, a dibromomethyl group, a trifluoromethyl group, a trichloromethyl group, and a 2,2,2-trifluoroethyl group.
  • the “C 1-4 alkoxy group” in the definition of R 1 represents a group in which an oxygen atom is bonded to the above “C 1-4 alkyl group”. Examples thereof include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a sec-butoxy group, and a tert-butoxy group.
  • the “C 1-4 alkoxy C 1-4 alkyl group” in the definition of R 3 and R 4 means that the above “C 1-4 alkoxy group” is the above “C 1-4 alkyl group”.
  • bonded with "group” is shown. Examples thereof include a methoxymethyl group, a methoxyethyl group, a methoxypropyl group, a methoxybutyl group, an ethoxymethyl group, and an ethoxyethyl group.
  • R 1 in the compound (I) of the present invention preferably represents a fluorine atom, a chlorine atom, a cyano group, a methyl group, an ethyl group, or a trifluoromethyl group, and more preferably, R 1 represents a chlorine atom, or Represents a cyano group, and even more preferably, R 1 represents a chlorine atom.
  • R 2 in the compound (I) of the present invention preferably represents a hydrogen atom, a chlorine atom or a methyl group, and more preferably R 2 represents a hydrogen atom.
  • R 3 and R 4 in the compound of the present invention preferably each independently represent a hydrogen atom or a methyl group, or R 3 and R 4 together with the carbon atom to which they are bonded form cyclopropyl. More preferably, R 3 and R 4 each independently represent a hydrogen atom or a methyl group, and more preferably R 3 represents a methyl group, and R 4 represents a hydrogen atom or a methyl group. Indicates.
  • R 3 represents a methyl group
  • R 4 represents a hydrogen atom
  • the carbon atom to which R 3 and R 4 are bonded is an asymmetric carbon, but R 3 and R 4
  • the three-dimensional arrangement is preferably the following arrangement (S arrangement).
  • R 5 in the compound (I) of the present invention preferably represents a hydrogen atom, a chlorine atom, a fluorine atom, a hydroxyl group, a nitro group, a methyl group, or an amino group, and more preferably R 5 represents a fluorine atom, a methyl group, or a methyl group. A group or an amino group, and even more preferably, R 5 represents a fluorine atom.
  • R 6 in the compound (I) of the present invention preferably represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, and more preferably R 6 represents a hydrogen atom or a fluorine atom.
  • R 6 is preferably substituted at the following position.
  • R 7 and R 8 in the compound (I) of the present invention preferably each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, or a methyl group, and more preferably R 7 and R 8 are each independently Represents a hydrogen atom or a fluorine atom. R 7 and R 8 are preferably substituted at the following positions.
  • R 9 and R 10 in the compound (I) of the present invention preferably each independently represent a hydrogen atom, a methyl group, an ethyl group, or an n-propyl group, and more preferably R 9 represents a hydrogen atom.
  • R 10 represents a hydrogen atom, a methyl group, or an ethyl group, and even more preferably, R 9 represents a hydrogen atom, and R 10 represents a methyl group or an ethyl group.
  • R 9 represents a hydrogen atom and R 10 represents a methyl group or an ethyl group
  • the carbon atom to which R 9 and R 10 are bonded is an asymmetric carbon.
  • n is 1,
  • the steric configuration of R 9 and R 10 preferably takes the following configuration (R configuration).
  • R 11 in the compound (I) of the present invention preferably represents a methyl group, an ethyl group, or a phenyl group, more preferably a methyl group or a phenyl group.
  • X in the compound (I) of the present invention preferably represents an oxygen atom or a group represented by —CH 2 —.
  • Y in the compound (I) of the present invention preferably represents a nitrogen atom or a group represented by ⁇ C (Ra) —
  • Ra represents a hydrogen atom, more preferably, or ⁇ C (Ra) —.
  • Ra represents a hydrogen atom.
  • R 1 represents a fluorine atom, a chlorine atom, a cyano group, a methyl group, an ethyl group, or a trifluoromethyl group
  • R 2 represents a hydrogen atom, a chlorine atom, or R represents a methyl group
  • R 3 and R 4 each independently represent a hydrogen atom or a methyl group, or R 3 and R 4 together with the carbon atom to which they are bonded form a group that forms cyclopropyl.
  • R 5 represents a hydrogen atom, chlorine atom, fluorine atom, hydroxyl group, nitro group, methyl group, or amino group
  • R 6 represents a hydrogen atom, fluorine atom, chlorine atom, or methyl group
  • R 7 And R 8 each independently represents a hydrogen atom, a fluorine atom, a chlorine atom, or a methyl group
  • R 9 and R 10 each independently represent a hydrogen atom, a methyl group, an ethyl group, or an n-propyl group.
  • R 11 is A methyl group, an ethyl group or a phenyl group
  • X represents an oxygen atom
  • Y represents a nitrogen atom or a group represented by ⁇ C (Ra) —
  • Ra represents a hydrogen atom
  • Z represents R 1 represents a fluorine atom, a chlorine atom, a cyano group, a methyl group, an ethyl group, or a trifluoromethyl group
  • R 2 represents a hydrogen atom, a chlorine atom, or a methyl group
  • R 3 and R 4 each independently represent a hydrogen atom or a methyl group, or R 3 and R 4 together with the carbon atom to which they are attached represent a group that forms cyclopropyl
  • R 5 is Represents a hydrogen atom, a chlorine atom, a fluorine atom, a hydroxyl group, a nitro group, a methyl group, or an amino group
  • R 6 represents a hydrogen atom,
  • X represents an oxygen atom
  • Y represents a nitrogen atom or a group represented by ⁇ C (Ra) —
  • Ra represents a hydrogen atom
  • Z represents a group represented by ⁇ CH—.
  • R 1 represents a fluorine atom, a chlorine atom, a cyano group, a methyl group, an ethyl group, or a trifluoromethyl group
  • R 2 represents a hydrogen atom, a chlorine atom, or a methyl group
  • R 3 and R 4 represent Each independently represents a hydrogen atom or a methyl group, or R 3 and R 4 together with the carbon atom to which they are bonded form a cyclopropyl group
  • R 5 represents a hydrogen atom or a chlorine atom.
  • R 6 represents a hydrogen atom, a fluorine atom, a chlorine atom, or a methyl group
  • R 7 and R 8 each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, or a methyl group
  • R 9 and R 10 each independently represent a hydrogen atom, a methyl group, an ethyl group, or an n-propyl group
  • R 11 represents a methyl group, an ethyl group, or a phenyl group
  • X represents —CH 2 -Represents a group represented by-
  • Ra represents a hydrogen atom
  • Z represents a nitrogen atom
  • R 1 represents , A fluorine atom, a chlorine atom, a cyano group, a methyl group, an ethyl group, or a triflu
  • R 2 represents a hydrogen atom
  • R 3 is a methyl group shows
  • R 4 is a hydrogen atom, or a methyl group
  • R 5 is a fluorine atom, a methyl group, or an amino group
  • R 6 is a hydrogen atom, or a fluorine atom
  • R 7 and R 8 are each Independently, it represents a hydrogen atom or a fluorine atom
  • R 9 represents a hydrogen atom
  • R 10 represents a hydrogen atom, a methyl group, or an ethyl group
  • R 11 represents a methyl group or an ethyl group
  • X represents an oxygen atom
  • Y represents a nitrogen atom or a group represented by ⁇ C (Ra) —
  • Ra represents a hydrogen atom
  • Z represents a nitrogen atom
  • R 1 represents a chlorine atom
  • R 2 represents a hydrogen atom
  • R 3 represents a methyl group
  • R 4 represents a hydrogen atom or a
  • Y represents a nitrogen atom or a group represented by ⁇ C (Ra) —
  • Ra represents a hydrogen atom
  • Z represents a nitrogen atom
  • R 1 represents a chlorine atom
  • R 2 represents a hydrogen atom
  • R 3 represents a methyl group
  • R 4 represents a hydrogen atom or a methyl group
  • R 5 represents a fluorine atom, a methyl group or an amino group
  • R 6 Represents a hydrogen atom or a fluorine atom
  • R 7 and R 8 each independently represent a hydrogen atom or a fluorine atom
  • R 9 represents a hydrogen atom
  • R 10 represents a hydrogen atom, a methyl group, Or an ethyl group
  • R 11 represents a methyl group or an ethyl group
  • X represents a group represented by —CH 2 —
  • Y represents a nitrogen atom or ⁇ C (Ra) —
  • Ra represents a hydrogen atom
  • Z represents
  • the pharmacologically acceptable salt thereof means that when the compound (I) of the present invention has a basic group such as an amino group, it is reacted with an acid or a carboxyl group. When it has such an acidic group, it can be converted into a salt by reacting with a base, so that salt is shown.
  • Salts based on basic groups include, for example, hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide; nitrates, perchlorates, sulfates, Inorganic acid salts such as phosphates; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate, aryl sulfonates such as benzene sulfonate and p-toluene sulfonate , Acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate and other organic acid salts; and glycine salt, lysine salt, arginine salt, An amino acid salt such as ornithine salt, glutamate, and aspartate can be exemplified, and methanesulfonate is preferable.
  • examples of the salt based on the acidic group include alkali metal salts such as sodium salt, potassium salt and lithium salt, alkaline earth metal salts such as calcium salt and magnesium salt, metal salts such as aluminum salt and iron salt.
  • Inorganic salt such as ammonium salt; tert-octylamine salt, dibenzyl salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexane Hexylamine salt, N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, tris (hydroxymethyl) aminomethane salt Amine salts such as organic salts; and glycine salts
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof may absorb water and become a hydrate when left in the atmosphere, and such a hydrate is also included in the present invention. Is done.
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof may become a solvate when left in a solvent, and such a solvate is also encompassed in the present invention. .
  • the compound (I) of the present invention may have an optical isomer based on an asymmetric center in the molecule.
  • these isomers and mixtures of these isomers are all represented by a single formula, that is, the general formula (I). Accordingly, the present invention includes all of these isomers and mixtures of these isomers.
  • the atropisomer derived from axial asymmetry caused by the rotation of the bond connecting the two benzene rings of the biphenyl group being restricted by steric hindrance May exist.
  • the invention also includes these isomers and mixtures of these isomers.
  • the compound (I) of the present invention may also contain an unnatural proportion of atomic isotopes at one or more of the atoms constituting the compound.
  • atomic isotopes include deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), carbon-14 ( 14 C), and the like.
  • the compound may be radiolabeled with a radioisotope such as tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C).
  • Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.
  • typical compounds include, for example, the following compounds, but the present invention is not limited to these compounds.
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent platelet aggregation inhibitory action, and thus is useful as an active ingredient of a pharmaceutical, particularly an antiplatelet agent, and is a thrombus embolus. It is useful as an active ingredient of a preventive and / or therapeutic agent for sexual diseases.
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is an ischemic cerebrovascular disorder (transient ischemic attack (TIA), atherothrombotic cerebral infarction).
  • Lacunar infarction) prevention and / or treatment agent acute coronary syndrome (unstable angina, acute myocardial infarction) prevention and / or treatment agent, coronary artery bypass surgery (CABG) or percutaneous coronary angioplasty (PCI) Is useful as an active ingredient of a preventive agent for restenosis or reocclusion of acute coronary syndrome.
  • CABG coronary artery bypass surgery
  • PCI percutaneous coronary angioplasty
  • treatment of thrombosis and embolism associated with vascular surgery and extracorporeal blood circulation improvement of blood flow disorder, improvement of ulcers associated with chronic arterial occlusion, improvement of ischemic symptoms such as pain and coldness, It can also be used to improve blood flow disorders associated with cerebral vasospasm.
  • the compound of the present invention or a pharmacologically acceptable salt thereof can be produced by applying various known synthesis methods utilizing characteristics based on the basic skeleton or the type of substituent.
  • an appropriate protecting group a group that can be easily converted into the functional group
  • functional groups include, for example, amino groups, hydroxyl groups, carboxyl groups, and the like
  • the protecting groups thereof include, for example, Green and Wuts, “Protective Groups in Organic Synthesis (3rd edition, 1999)”. Or the like, and may be appropriately selected and used depending on the reaction conditions.
  • a desired compound can be obtained by introducing the protecting group and carrying out the reaction, and then removing the protecting group as necessary.
  • Production method 1 is a method for producing compound (I) of the present invention from compound (1) and compound (2) obtained by the production method described later.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , X, Y and Z are as defined above. Show.
  • Step 1-1 In this step, the tert-butyloxycarbonyl group in compound (1) is removed with an acid, and then reacted with compound (2) in the presence of a condensing agent and a base in a solvent inert to the reaction to give compound (2).
  • 3) is a process of manufacturing.
  • the acid used for removing the tert-butyloxycarbonyl group in the compound (1) is described in Green and Wuts, “Protective Groups in Organic Synthesis (3rd edition, 1999)”, etc.
  • the acid is preferably a trifluoroacetic acid or hydrochloric acid solution in 1,4-dioxane.
  • Solvents include aromatic hydrocarbons such as benzene, toluene, or xylene; aliphatic hydrocarbons such as pentane, hexane, or cyclohexane; dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, Or halogenated hydrocarbons such as dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, or diethyl carbonate; diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, Or ethers such as tert-butyl methyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-but
  • the reaction temperature is ⁇ 50 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C.
  • the reaction time is 15 minutes to 48 hours, preferably 30 minutes to 24 hours.
  • Solvents used for the reaction with the compound (2) include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran Ethers such as 1,4-dioxane, dimethoxyethane, or tert-butyl methyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol , 2-methoxyethanol, diethylene glycol, or alcohols such as glycerin; N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl Amides such as -2-pyrrolidinone or
  • halogenated hydrocarbons Preferred are halogenated hydrocarbons, amides, or a mixed solvent thereof, and more Preferred is dichloromethane, N, N-dimethylformamide, or a mixed solvent thereof.
  • the condensing agent include 1,1′-carbonyldiimidazole, N, N′-diisopropylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 2- (1H-benzotriazol-1-yl ) -1,1,3,3-tetramethyluronium hexafluorophosphate, (1H-benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate, or 4- (4,6-dimethoxy-1,3 5-triazin-2-yl) -4-methylmorpholinium chloride and the like, and 1-ethyl-3- (3-dimethylaminopropyl
  • the base examples include organic bases such as triethylamine, diisopropylethylamine, N-methylmorpholine, or pyridine; or inorganic bases such as potassium carbonate, cesium carbonate, or sodium hydrogen carbonate, preferably organic bases, and more preferably. Is diisopropylethylamine.
  • organic bases such as triethylamine, diisopropylethylamine, N-methylmorpholine, or pyridine
  • inorganic bases such as potassium carbonate, cesium carbonate, or sodium hydrogen carbonate, preferably organic bases, and more preferably. Is diisopropylethylamine.
  • 4- (N, N-dimethylamino) pyridine may be used as an additive.
  • the reaction temperature is 0 ° C. to 100 ° C., preferably 20 ° C. to 50 ° C.
  • the reaction time is 2 to 48 hours, preferably 4 to 24 hours.
  • Manufacturing method 2 is a method for producing compound (1a) in which X is an oxygen atom in compound (1).
  • LG 1 represents a leaving group and is a chlorine atom or a bromine atom.
  • This step is a step of producing compound (5) by reacting compound (3) with compound (4) in the presence of a base in a solvent inert to the reaction.
  • Compound (4) is a commercially available compound or a known method such as “Protective Groups in Organic Synthesis (3rd edition, 1999)” by Green and Wuts, or C.I. P. It can be produced according to the method described in “Journal of Organic Chemistry, 1995, 60, 4782-4785” by Decicco et al.
  • Solvents include aromatic hydrocarbons such as benzene, toluene, or xylene; hydrocarbons such as pentane, hexane, or cyclohexane; dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, or di- Halogenated hydrocarbons such as chlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl methyl ether; N, N-dimethylformamide, N, N-dimethylacetamide, N Amides such as methyl-2-pyrrolidinone or hexamethylphosphorotriamide; sulfoxides such as dimethyl sulfoxide or sulfolane; nitriles such as acetonitrile; These mixed solvents and the like, preferably
  • the base examples include sodium hydride, potassium hydride, calcium hydride, sodium tert-butoxide, potassium tert-butoxide and the like, preferably sodium hydride.
  • the reaction temperature is ⁇ 50 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C.
  • the reaction time is 30 minutes to 24 hours, preferably 1 hour to 12 hours.
  • Step 2-2 This step is a step of producing compound (6) by reacting compound (5) in the presence of a metal catalyst in a solvent inert to the reaction.
  • Solvents include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or glycerin; diethyl ether , Diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or ethers such as tert-butyl methyl ether; water; acetic acid; or a mixed solvent thereof, preferably alcohols, water, acetic acid, or a mixture thereof Solvent, more preferably acetic acid or ethanol-water mixed solvent.
  • alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol
  • the metal catalyst examples include iron, zinc, aluminum, tin, indium, Raney nickel, and the like, preferably iron.
  • the reaction temperature is 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C.
  • the reaction time is 30 minutes to 24 hours, preferably 1 hour to 12 hours.
  • Step 2-3 This step is a step of producing compound (8) by reacting compound (6) with compound (7) in the presence of a reducing agent and an acid in a solvent inert to the reaction.
  • Solvents include aromatic hydrocarbons such as benzene, toluene, or xylene; aliphatic hydrocarbons such as pentane, hexane, or cyclohexane; dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, Or halogenated hydrocarbons such as dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl methyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol , Isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or glycerin
  • Examples of the reducing agent include sodium triacetoxyborohydride, sodium cyanoborohydride, or sodium borohydride, and sodium triacetoxyborohydride is preferable.
  • Examples of the acid include trifluoroacetic acid, acetic acid, hydrochloric acid, or phosphoric acid, and trifluoroacetic acid or acetic acid is preferable.
  • the reaction temperature is ⁇ 50 ° C. to heating under reflux, preferably room temperature to 80 ° C.
  • the reaction time is 30 minutes to 48 hours, preferably 1 hour to 24 hours.
  • Step 2-4 This step is a step of producing compound (1a) by reacting compound (8) in the presence of a base in a solvent inert to the reaction.
  • Solvents include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl methyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, Alcohols such as isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or glycerin; N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, or hexamethylphosphorotri Amides such as amides; or a mixed solvent thereof, and the like.
  • ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dime
  • amides Preferred are amides, and more preferred is N, N-dimethylform. It is an amide.
  • the base include sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, potassium methoxide, sodium carbonate, potassium carbonate, cesium carbonate, and the like, and preferably cesium carbonate.
  • the reaction temperature is 20 ° C. to 200 ° C., preferably 40 ° C. to 150 ° C.
  • the reaction time is 2 to 48 hours, preferably 4 to 24 hours.
  • Production method 3 is a method for producing compound (1b) in which X is an oxygen atom and Z is a nitrogen atom in compound (1).
  • LG 2 represents a leaving group such as a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, or a p-toluenesulfonyloxy group, or a hydroxyl group.
  • Step 3-1 This step is a step of producing the compound (11) from the compound (9) and the compound (10), and includes (Step 3-1a) or (Step 3-1b).
  • Compound (10) is a commercially available compound or a known method such as “Protective Groups in Organic Synthesis (3rd edition, 1999)” by Green and Wuts or C.I. P. It can be produced according to the method described in “Journal of Organic Chemistry, 1995, 60, 4782-4785” by Decicco et al.
  • Step 3-1a This step can be used when LG 2 of compound (10) is a leaving group, and reacting compound (9) with compound (10) in the presence of a base in a solvent inert to the reaction. To produce compound (11).
  • Solvents include aromatic hydrocarbons such as benzene, toluene or xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl-methyl ether; methanol, ethanol, n Alcohols such as propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or glycerine; N, N-dimethylformamide, N, N- Amides such as dimethylacetamide, N-methyl-2-pyrrolidinone, or hexamethylphosphorotriamide; dimethyl sulfoxide or sulfo Sulfoxides such as acetone; ketones such as acetone; n
  • Bases include inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, sodium tert-butoxide, or potassium tert-butoxide; or triethylamine, diisopropylethylamine, N-methylmorpholine , Pyridine, or 2,6-lutidine, and the like, preferably an inorganic base, and more preferably cesium carbonate or potassium carbonate.
  • the reaction temperature is 0 ° C. to 150 ° C., preferably 50 ° C. to 100 ° C.
  • the reaction time is 30 minutes to 100 hours, preferably 1 hour to 48 hours.
  • Step 3-1b This step can be used when LG 2 of compound (10) is a hydroxyl group, and compound (9) is converted to compound (10) in the presence of a reagent used for Mitsunobu reaction in a solvent inert to the reaction. In this step, compound (11) is produced by reacting with.
  • Solvents include aromatic hydrocarbons such as benzene, toluene, or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, or dichlorobenzene; diethyl ether, Examples include ethers such as diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl-methyl ether; or a mixed solvent thereof. Ethers are preferable, and tetrahydrofuran is more preferable.
  • Examples of the reagent used in the Mitsunobu reaction include diethyl azodicarboxylate, di-tert-butyl azodicarboxylate, or azodicarboxylic acid derivatives such as azodicarboxylic acid dipiperidine amide, triphenylphosphine, tri (2-tolyl) phosphine, Alternatively, a combination of phosphine compounds such as tri-n-butylphosphine can be used, and a combination of di-tert-butyl azodicarboxylate and triphenylphosphine is preferable.
  • the reaction temperature is 0 ° C. to 100 ° C., preferably 20 ° C. to 70 ° C.
  • the reaction time is 30 minutes to 48 hours, preferably 1 hour to 24 hours.
  • Step 3-2 This step is a step for producing compound (12) by removing the tert-butyl group in compound (11) in the presence of an acid in a solvent inert to the reaction.
  • Solvents include aromatic hydrocarbons such as benzene, toluene, or xylene; hydrocarbons such as pentane, hexane, or cyclohexane; dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, or di- Halogenated hydrocarbons such as chlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, or diethyl carbonate; diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, or tert -Ethers such as butyl methyl ether; water; or a mixed solvent thereof, and the like.
  • aromatic hydrocarbons such as benzene, toluene, or xylene
  • hydrocarbons such as pen
  • Halogenated hydrocarbons are preferable, and dichloromethane is more preferable.
  • the acid include those described in Green and Wuts, “Protective Groups in Organic Synthesis (3rd edition, 1999)”, and preferably trifluoroacetic acid.
  • the reaction temperature is ⁇ 50 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C.
  • the reaction time is 15 minutes to 48 hours, preferably 30 minutes to 24 hours.
  • Step 3-3 This step is a step for producing compound (14) by reacting compound (12) with compound (13) in the presence of a condensing agent and a base in a solvent inert to the reaction.
  • solvent examples include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butylmethyl.
  • halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, or dichlorobenzene
  • diethyl ether diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butylmethyl.
  • Ethers such as ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or glycerin N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, or hexamethi Amides such as triamide; water; or a mixed solvent thereof and the like can be mentioned, preferably, dichloromethane, tetrahydrofuran, methanol, N, N- dimethylformamide, or a mixed solvent.
  • condensing agent examples include 1,1-carbonyldiimidazole, N, N′-diisopropylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate, (1H-benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate, or 4- (4,6-dimethoxy-1,3,5) -Triazin-2-yl) -4-methylmorpholinium chloride and the like, preferably 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 2- (1H-benzotriazole-1- Yl) -1,1,3,3-tetramethyluronium hexafluo Phosphates, or 4- (4,6-
  • 1-hydroxybenzotriazole can be used simultaneously.
  • the base include organic bases such as triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, or 4- (N, N-dimethylamino) pyridine; or inorganic bases such as potassium carbonate, cesium carbonate, or sodium bicarbonate.
  • organic bases Preferably an organic base, more preferably diisopropylethylamine or N-methylmorpholine.
  • the reaction temperature is 0 ° C. to 100 ° C., preferably 20 ° C. to 50 ° C.
  • the reaction time is 2 to 48 hours, preferably 4 to 24 hours.
  • Step 3-4 This step is a step for producing compound (16) by reacting compound (13) with compound (15) in the same manner as in step 3-3.
  • Step 3-5 This step is a step for producing compound (17) by reacting compound (16) in a hydrogen atmosphere in the presence of a transition metal catalyst in a solvent inert to the reaction.
  • Solvents include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl methyl ether; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, or diethyl carbonate; Alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or glycerin; N, N-dimethylformamide Amides such as N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, or hexamethylphosphorotriamide; acetic acid; water Or the like and mixed
  • transition metal catalyst examples include platinum oxide, platinum carbon, platinum black, palladium carbon, palladium black, palladium hydroxide carbon, or Raney nickel, and preferably palladium carbon or palladium hydroxide carbon.
  • the reaction temperature is 0 ° C. to 80 ° C., preferably 20 ° C. to 60 ° C.
  • the reaction pressure is normal pressure to increased pressure under a hydrogen atmosphere, and preferably normal pressure.
  • the reaction time is 1 hour to 48 hours, preferably 3 hours to 24 hours.
  • Step 3-6 This step is a step for producing compound (14) by reacting compound (17) with compound (9) in the same manner as in step 3-1b.
  • Step 3--7 This step is a step for producing compound (1b) by reacting compound (14) in the presence of a base in a solvent inert to the reaction.
  • the solvent examples include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl methyl ether; N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone Or amides such as hexamethylphosphorotriamide; nitriles such as acetonitrile; or a mixed solvent thereof, and the like, preferably ethers or amides, more preferably tetrahydrofuran or N, N -Dimethylformamide.
  • ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl methyl ether
  • N, N-dimethylformamide N, N-dimethylacetamide, N-methyl-2-pyrrol
  • the base examples include inorganic bases such as sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, cesium carbonate, or sodium hydrogen carbonate, preferably sodium hydride or cesium carbonate.
  • the reaction temperature is 0 ° C. to 150 ° C., preferably 10 ° C. to 100 ° C.
  • the reaction time is 30 minutes to 24 hours, preferably 1 hour to 12 hours.
  • Manufacturing method 4 is a method for producing compound (1c) in which compound X is an oxygen atom and Z is a group represented by ⁇ CH—.
  • R 1 , R 2 , R 3 , and R 4 have the same meaning as described above.
  • LG 3 is a chlorine atom or a bromine atom.
  • LG 4 is a methoxy group, an ethoxy group, or a tert-butoxy group.
  • Step 4-1 This step is a step for producing compound (19) from compound (18) in the same manner as in step 2-2.
  • Step 4-2 This step is a step for producing compound (20) by reacting compound (19) with compound (7) in the same manner as in step 2-3.
  • Step 4-3 This step is a step of producing compound (1c) by reacting compound (20) with compound (21) in the presence of a base in a solvent inert to the reaction.
  • Solvents include aromatic hydrocarbons such as benzene, toluene, or xylene; aliphatic hydrocarbons such as pentane, hexane, or cyclohexane; dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, Or halogenated hydrocarbons such as dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl methyl ether; N, N-dimethylformamide, N, N-dimethylacetamide Amides such as N-methyl-2-pyrrolidinone, or hexamethylphosphorotriamide; Sulfoxides such as dimethyl sulfoxide or sulfolane; Nitto such as acetonitrile Le like; or a mixed solvent thereof and
  • the base examples include an inorganic base such as sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, or potassium tert-butoxide, or an organic such as triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, or 2,6-lutidine.
  • a base is mentioned, Preferably it is an inorganic base, More preferably, it is cesium carbonate.
  • the reaction temperature is 20 ° C. to 200 ° C., preferably 60 ° C. to 160 ° C.
  • the reaction time is 30 minutes to 48 hours, preferably 1 hour to 24 hours.
  • Production method 5 is a method for producing compound (1d) in which X is a sulfur atom and Z is a nitrogen atom in compound (1).
  • R 1 , R 2 , R 3 , R 4 , LG 1 , LG 3 , and LG 4 have the same meaning as described above.
  • Step 5-1 This step is a step of producing compound (24) by reacting compound (22) with thiourea (23) in a solvent inert to the reaction and then reacting with a base.
  • Solvents used in the reaction with thiourea (23) include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, Examples include alcohols such as diethylene glycol or glycerin, and methanol or ethanol is preferable.
  • the reaction temperature is 20 ° C to 100 ° C, preferably 40 ° C to 80 ° C.
  • the reaction time is 1 to 24 hours, preferably 3 to 12 hours.
  • Solvents that act as bases include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or glycerin.
  • Water; or a mixed solvent thereof, and the like preferably an alcohols-water mixed solvent, more preferably a methanol-water mixed solvent, or an ethanol-water mixed solvent.
  • the base include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, or potassium hydroxide, and potassium hydroxide or sodium hydroxide is preferable.
  • the reaction temperature is 0 ° C. to 80 ° C., preferably 0 ° C. to 40 ° C.
  • the reaction time is 10 minutes to 12 hours, preferably 30 minutes to 6 hours.
  • Step 5-2 This step is a step for producing compound (25) by reacting compound (24) with compound (21) in the presence of a base in a solvent inert to the reaction.
  • Solvents include aromatic hydrocarbons such as benzene, toluene, or xylene; aliphatic hydrocarbons such as pentane, hexane, or cyclohexane; dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, Or halogenated hydrocarbons such as dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl methyl ether; N, N-dimethylformamide, N, N-dimethylacetamide Amides such as N-methyl-2-pyrrolidinone, or hexamethylphosphorotriamide; Sulfoxides such as dimethyl sulfoxide or sulfolane; Nitto such as acetonitrile Le like; or a mixed solvent thereof and
  • the base examples include inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, or potassium tert-butoxide; or organics such as triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, or 2,6-lutidine.
  • a base is mentioned, Preferably it is an inorganic base, More preferably, it is potassium carbonate.
  • the reaction temperature is 0 ° C. to 100 ° C., preferably 20 ° C. to 80 ° C.
  • the reaction time is 30 minutes to 48 hours, preferably 1 hour to 24 hours.
  • Step 5-3 This step is a step for producing compound (26) from compound (25) in the same manner as in step 2-2.
  • Step 5-4 This step is a step for producing compound (27) by reacting compound (26) with compound (7) in the same manner as in step 2-3.
  • Step 5-5 This step is a step of producing compound (1d) by reacting compound (27) in the presence of a base in a solvent inert to the reaction.
  • Solvents include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl methyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, Alcohols such as isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or glycerin; N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, or hexamethylphosphorotri Amides such as amides; or a mixed solvent thereof, and the like.
  • ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dime
  • amides Preferred are amides, and more preferred is N, N-dimethylform. It is an amide.
  • the base include sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, potassium methoxide, sodium carbonate, potassium carbonate, cesium carbonate, and the like, and preferably cesium carbonate.
  • the reaction temperature is 20 ° C. to 200 ° C., preferably 40 ° C. to 150 ° C.
  • the reaction time is 2 to 48 hours, preferably 4 to 24 hours.
  • Production method 6 is a method for producing compound (1e) in which X is a group represented by —CH 2 — in compound (1).
  • R 1 , R 2 , R 3 , R 4 , Z, and LG 1 have the same meaning as described above.
  • Step 6-1 This step is a step for producing compound (30) by reacting compound (28) with compound (29) in the presence of a palladium catalyst and a base in a solvent inert to the reaction.
  • Solvents include aromatic hydrocarbons such as benzene, toluene or xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl methyl ether; N, N-dimethylformamide Amides such as N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, or hexamethylphosphorotriamide; water; or a mixed solvent thereof, preferably amides, more preferably Is N, N-dimethylformamide, N, N-dimethylacetamide, or N-methyl-2-pyrrolidinone.
  • the palladium catalyst examples include bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium, bis (triphenylphosphine) dichloropalladium, palladium acetate, palladium trifluoroacetate, or palladium carbon. Palladium acetate.
  • the base examples include inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, or tripotassium phosphate; or triethylamine, diisopropylethylamine, tri-n-butylamine, or 1,4-diazabicyclo [2,
  • An organic base such as 2,2] octane may be mentioned, and an organic base is preferable, and diisopropylethylamine or triethylamine is more preferable.
  • Addition of 1,4-bis (diphenylphosphino) butane and tetra-n-butylammonium bromide as additives is useful for allowing the reaction to proceed smoothly.
  • the reaction temperature is 60 ° C to 200 ° C, preferably 100 ° C to 140 ° C.
  • the reaction time is 12 hours to 48 hours, preferably 20 hours to 30 hours.
  • Step 6-2 This step is a step for producing compound (31) by reacting compound (30) with compound (7) in the same manner as in step 2-3.
  • Step 6-3 This step is a step for producing a compound (32) by reacting the compound (31) in a solvent inert to the reaction in the presence of a transition metal catalyst in a hydrogen atmosphere.
  • solvent examples include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butylmethyl.
  • halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, or dichlorobenzene
  • diethyl ether diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butylmethyl.
  • Ethers such as ether; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, or diethyl carbonate; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl Alcohols such as alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or glycerine; or a mixed solution thereof Etc., and preferably, alcohols, more preferably methanol or ethanol.
  • transition metal catalyst examples include platinum oxide, platinum carbon, platinum black, palladium carbon, palladium black, palladium hydroxide carbon, palladium fibroin, and Raney nickel, and preferably palladium fibroin.
  • the reaction temperature is 0 ° C. to 80 ° C., preferably 20 ° C. to 50 ° C.
  • the reaction pressure is normal pressure to increased pressure under a hydrogen atmosphere, and preferably normal pressure.
  • the reaction time is 3 to 100 hours, preferably 18 to 48 hours.
  • Step 6-4 This step is a step for producing compound (33) by reacting compound (32) in the presence of a base in a solvent inert to the reaction.
  • Solvents include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl methyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, Alcohols such as isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or glycerin; N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, or hexamethylphosphorotri Amides such as amides; or a mixed solvent thereof, and the like, preferably ethers, more preferably tetrahydrofuran A.
  • ethers such as diethyl ether, diisopropyl
  • the base examples include sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, potassium methoxide, sodium carbonate, potassium carbonate, cesium carbonate and the like, and potassium tert-butoxide is preferable.
  • the reaction temperature is ⁇ 50 ° C. to 100 ° C., preferably ⁇ 20 ° C. to 30 ° C.
  • the reaction time is 1 minute to 12 hours, preferably 10 minutes to 6 hours.
  • Step 6-5 This step is a step for producing compound (1e) by reacting compound (33) with an electrophile in the presence of a base in a solvent inert to the reaction.
  • R 3 and R 4 of the compound (33) are both hydrogen atoms, this step is not performed.
  • Solvents include aromatic hydrocarbons such as benzene, toluene or xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl methyl ether; N, N-dimethylformamide Amides such as N, N-dimethylacetamide, N-methyl-2-pyrrolidinone or hexamethylphosphorotriamide; or a mixed solvent thereof, preferably ethers, more preferably Tetrahydrofuran.
  • aromatic hydrocarbons such as benzene, toluene or xylene
  • ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl methyl ether
  • N, N-dimethylformamide Amides such as N, N-di
  • Examples of the base include lithium hexamethyldisilazide, sodium hexamethyldisilazide, lithium diisopropylamide, sodium hydride, sodium tert-butoxide, or potassium tert-butoxide, preferably lithium hexamethyldisilazide.
  • Examples of the electrophile include alkyl halides, methylsulfonic acid alkyl esters, p-toluenesulfonic acid alkyl esters, and the like (the alkyl group may be substituted with a halogen atom, an alkoxy group, or a protected hydroxyl group. Can be deprotected if necessary).
  • the reaction temperature is ⁇ 100 ° C. to 80 ° C., preferably ⁇ 78 ° C. to 50 ° C.
  • the reaction time is 5 minutes to 24 hours, preferably 10 minutes to 12 hours.
  • Production Method 7 is a method for producing compound (2) in Production Method 1.
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and Y have the same meaning as described above.
  • PG 1 represents a protecting group for carboxylic acid, and examples thereof include a protecting group described in Green and Wuts, “Protective Groups in Organic Synthesis (3rd edition, 1999)”.
  • M 1 represents a chlorine atom, a bromine atom, an iodine atom, or a trifluoromethanesulfonyloxy group, and M 2 represents a boronic acid or a boronic acid ester.
  • LG 2 represents a leaving group such as a chlorine atom, a bromine atom, or an iodine atom, or a hydroxyl group.
  • Step 7-1 This step is a step for producing compound (35) by reacting compound (34) with an alkylating agent in the presence of a base in a solvent inert to the reaction.
  • Solvents include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or glycerin; N, Examples include amides such as N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, or hexamethylphosphorotriamide; nitriles such as acetonitrile; or ketones such as acetone.
  • alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene
  • amides, nitriles, or ketones Preferably N, N-dimethylformamide, acetonitrile, or acetone.
  • the base include an inorganic base such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium tert-butoxide, or potassium tert-butoxide; or triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, or Examples include organic bases such as 2,6-lutidine, preferably inorganic bases, and more preferably potassium carbonate, cesium carbonate, sodium bicarbonate, or potassium bicarbonate.
  • the alkylating agent methyl iodide, ethyl iodide, or benzyl bromide is used.
  • the reaction temperature is 0 ° C. to 100 ° C., preferably 20 ° C. to 80 ° C.
  • the reaction time is 1 to 24 hours, preferably 2 to 12 hours.
  • Step 7-2 This step is a step for producing compound (37) by reacting compound (35) with compound (36) in the presence of a palladium catalyst and a base in a solvent inert to the reaction.
  • Solvents include aromatic hydrocarbons such as benzene, toluene or xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl methyl ether; N, N-dimethylformamide Amides such as N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, or hexamethylphosphorotriamide; water; or a mixed solvent thereof, preferably amides, ethers, water Or a mixed solvent thereof, more preferably an N, N-dimethylformamide, 1,4-dioxane, or a dimethoxyethane-water mixed solvent.
  • aromatic hydrocarbons such as benzene, toluene or xylene
  • ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, diox
  • the palladium catalyst examples include tetrakis (triphenylphosphine) palladium, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium, bis (triphenylphosphine) dichloropalladium, and [1,1′-bis (diphenylphosphino).
  • Tetrakis (triphenylphosphine) palladium or [1,1′-bis (diphenylphosphino) ferrocene is preferable. It is dichloropalladium.
  • the base examples include sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, tripotassium phosphate, sodium tert-butoxide, or potassium tert-butoxide, and preferably sodium carbonate, potassium carbonate, or tripotassium phosphate.
  • the reaction temperature is 20 ° C. to 150 ° C., preferably 80 ° C. to 100 ° C.
  • the reaction time is 30 minutes to 24 hours, preferably 1 hour to 12 hours.
  • Step 7-3) This step is a step for producing compound (39) by reacting compound (37) with compound (38) in the same manner as in step 3-1a or step 3-1b.
  • Compound (38) is a commercially available compound or a known method such as “Protective Groups in Organic Synthesis (3rd edition, 1999)” by Green and Wuts, or C.I. P. It can be produced according to the method described in “Journal of Organic Chemistry, 1995, 60, 4782-4785” by Decicco et al.
  • Step 7-4 This step is a step for producing compound (40) by removing the tert-butyl group in compound (39) in the presence of an acid in a solvent inert to the reaction.
  • Solvents include aromatic hydrocarbons such as benzene, toluene, or xylene; aliphatic hydrocarbons such as pentane, hexane, or cyclohexane; dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, Or halogenated hydrocarbons such as dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, or diethyl carbonate; diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, Or ethers such as tert-butyl methyl ether; water; or a mixed solvent thereof, and the like, preferably halogenated hydrocarbons or ethers, more preferably dichloromethane or 1,4-di-
  • the acid examples include acids described in Greene and Wuts, “Protective Groups in Organic Synthesis (3rd edition, 1999)”, preferably trifluoroacetic acid or hydrochloric acid. 1,4-dioxane solution.
  • the reaction temperature is ⁇ 50 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C.
  • the reaction time is 15 minutes to 100 hours, preferably 30 minutes to 72 hours.
  • Step 7-5 This step is a step for producing compound (42) by reacting compound (40) with compound (41) in the presence of a condensing agent and a base in a solvent inert to the reaction.
  • solvent examples include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, or dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butylmethyl.
  • halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, or dichlorobenzene
  • diethyl ether diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butylmethyl.
  • Ethers such as ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or glycerin N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, or hexamethi Amides such as phosphorotriamide; water; or a mixed solvent thereof, and the like, preferably halogenated hydrocarbons, ethers, amides, or a mixed solvent thereof, more preferably dichloromethane, Tetrahydrofuran, N, N-dimethylformamide, or a mixed solvent thereof.
  • condensing agent examples include 1,1-carbonyldiimidazole, N, N′-diisopropylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate or (1H-benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate, etc., preferably 1-ethyl-3- ( 3-dimethylaminopropyl) carbodiimide hydrochloride.
  • the base examples include organic bases such as triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, or 4- (N, N-dimethylamino) pyridine; or inorganic bases such as potassium carbonate, cesium carbonate, or sodium bicarbonate.
  • organic bases such as triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, or 4- (N, N-dimethylamino) pyridine
  • inorganic bases such as potassium carbonate, cesium carbonate, or sodium bicarbonate.
  • it is an organic base, More preferably, it is diisopropylethylamine.
  • the reaction temperature is 0 ° C. to 100 ° C., preferably 20 ° C. to 50 ° C.
  • the reaction time is 2 to 48 hours, preferably 4 to 24 hours.
  • Step 7-6 This step is a step for producing compound (2) by reacting compound (42) in the presence of a base in a solvent inert to the reaction.
  • Solvents include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, or tert-butyl methyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, Examples include alcohols such as tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or glycerin; water; or a mixed solvent thereof, preferably tetrahydrofuran, ethanol, methanol, water, Or these mixed solvents.
  • ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, or tert-butyl methyl
  • the base examples include those described in Green and Wuts, “Protective Groups in Organic Synthesis (3rd edition, 1999)”, preferably lithium hydroxide, hydroxide Sodium or potassium trimethylsilanolate.
  • the reaction temperature is 0 ° C. to 100 ° C., preferably 20 ° C. to 60 ° C.
  • the reaction time is 30 minutes to 24 hours, preferably 1 hour to 12 hours.
  • compound (2) can also be produced by reacting compound (42) with hydrogen in a solvent inert to the reaction in the presence of a transition metal catalyst.
  • Solvents include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, or tert-butyl methyl ether; such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, or diethyl carbonate Esters such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or glycerol; N, Amides such as N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, or hexamethylphosphorotriamide; Acid; water; or a mixed solvent
  • the transition metal catalyst examples include platinum oxide, platinum carbon, platinum black, palladium carbon, palladium black, palladium hydroxide carbon, or Raney nickel, and preferably palladium carbon or palladium hydroxide carbon.
  • the reaction temperature is 10 ° C to 60 ° C, preferably 20 ° C to 35 ° C.
  • the reaction pressure is normal pressure to increased pressure under a hydrogen atmosphere, and preferably normal pressure.
  • the reaction time is 1 hour to 48 hours, preferably 3 hours to 24 hours.
  • Manufacturing method 8 is another method for producing compound (37) in production method 7.
  • R 5 , R 6 , R 7 , R 8 , Y, PG 1 , M 1 , and M 2 have the same meaning as described above.
  • Step 8-1 This step is a step for producing compound (44) by reacting compound (43) with compound (36) in the same manner as in step 7-2.
  • Step 8-2 This step is a step for producing compound (45) by reacting compound (44) with an acid or a base in water.
  • the acid examples include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, and phosphoric acid; or acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid Or an organic acid such as trifluoromethanesulfonic acid, or the base includes an inorganic base such as sodium hydroxide, potassium hydroxide, or lithium hydroxide.
  • An inorganic acid is preferable, and sulfuric acid or hydrochloric acid is more preferable.
  • the reaction temperature is 20 ° C. to 150 ° C., preferably 80 ° C. to 100 ° C.
  • the reaction time is 1 to 24 hours, preferably 4 to 12 hours.
  • Step 8-3 This step is a step for producing compound (37) by reacting compound (41) with an alkylating agent in the same manner as in step 7-1.
  • Manufacturing method 9 Production Method 9 is another method for producing compound (40) in Production Method 7.
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , Y, and PG 1 have the same meaning as described above.
  • PG 2 represents a protective group for a hydroxyl group, and examples thereof include a protective group described in Green and Wuts, “Protective Groups in Organic Synthesis (3rd edition, 1999)”, preferably tert -Butyldimethylsilyl group or tert-butyldiphenylsilyl group, or tetrahydropyranyl group.
  • Step 9-1 This step is a step for producing compound (47) by reacting compound (37) with compound (46) in the same manner as in step 3-1b.
  • Compound (46) is a commercially available compound or a known method from a known compound, for example, the method described in Green and Wuts, “Protective Groups in Organic Synthesis (3rd edition, 1999)” and the like. According to this, it can be manufactured.
  • Step 9-2 This step can be used when PG 2 of the compound (47) is a silyl group such as a tert-butyldimethylsilyl group or a tert-butyldiphenylsilyl group.
  • the compound (47) Is a step of producing compound (48) by reacting with a base.
  • Solvents include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl methyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, Alcohols such as isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or glycerin; N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, or hexamethylphosphorotri Amides such as amides; nitriles such as acetonitrile; water; or a mixed solvent thereof.
  • ethers such as diethyl ether, diisopropyl ether, tetrahydr
  • ethers More preferably tetrahydrofuran.
  • the base include those described in Green and Wuts, “Protective Groups in Organic Synthesis (3rd edition, 1999)”, and preferably tetra-n-fluoride. Butylammonium.
  • acetic acid it may be useful to use as an additive.
  • the reaction temperature is 0 ° C. to 80 ° C., preferably 20 ° C. to 40 ° C.
  • the reaction time is 30 minutes to 48 hours, preferably 3 hours to 24 hours.
  • compound (48) can be produced by reacting compound (47) with an acid in a solvent inert to the reaction. it can.
  • Solvents include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl methyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, Examples include alcohols such as isoamyl alcohol, octanol, cyclohexanol, 2-methoxyethanol, diethylene glycol, or glycerin; water; or a mixed solvent thereof, preferably alcohols, more preferably methanol or ethanol. It is.
  • ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl methyl ether
  • methanol ethanol, n-propano
  • the acid examples include acids described in Green and Wuts, “Protective Groups in Organic Synthesis (3rd edition, 1999)”, and preferably p-toluenesulfonic acid. is there.
  • the reaction temperature is 0 ° C. to 70 ° C., preferably 20 ° C. to 40 ° C.
  • the reaction time is 30 minutes to 12 hours, preferably 1 to 6 hours.
  • Step 9-3 This step is a step for producing compound (40) by reacting compound (48) with an oxidizing agent in a solvent inert to the reaction.
  • Solvents include aromatic hydrocarbons such as benzene, toluene, or xylene; aliphatic hydrocarbons such as pentane, hexane, or cyclohexane; dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, Or halogenated hydrocarbons such as dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, or diethyl carbonate; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or tert-butyl Preferred examples include ethers such as methyl ether; alcohols such as tert-butanol; nitriles such as acetonitrile; ketones such as acetone; water; or a mixed solvent
  • Ku is the esters, nitriles, water, or a mixed solvent thereof, more preferably, acetonitrile or ethyl acetate - is water mixed solvent.
  • Oxidizing agents include chromium (VI) / sulfuric acid combinations, ruthenium (III) chloride / orthoperiodic acid combinations, or 2,2,6,6-tetramethyl-1-piperidyloxy radical / hypochlorous acid.
  • a combination of sodium / sodium chlorite is exemplified, and a combination of 2,2,6,6-tetramethyl-1-piperidyloxy radical / sodium hypochlorite / sodium chlorite is preferable.
  • reaction temperature is 0 ° C. to 80 ° C., preferably 20 ° C. to 60 ° C.
  • the reaction time is 1 to 48 hours, preferably 4 to 24 hours.
  • Manufacturing method 10 Production Method 10 is a compound (43) in which R 5 is a nitro group and Y is a nitrogen atom, and R 3 is a fluorine atom and Y is a nitrogen atom. (50).
  • R 6 and M 1 are as defined above.
  • Step 10-1 This step is a step of producing compound (50) from compound (49) according to the method described in Organic Letters, 2005, 7 (4), 577-579.
  • the bromine atom of R 1 can be converted to a cyano group, an ethyl group, or a methoxy group.
  • the method described in Tetrahedron Letters, 2000, 41 (18), 3271-3273 can be used for the conversion to a cyano group.
  • a compound in which R 1 is a cyano group can be produced by allowing tris (dibenzylideneacetone) dipalladium and zinc cyanide to act on a compound in which R 1 is a bromine atom in N, N-dimethylformamide. .
  • Use of 1,1′-bis (diphenylphosphino) ferrocene and zinc as additives is useful for allowing the reaction to proceed smoothly.
  • the reaction temperature is 100 ° C. to 150 ° C., preferably 120 ° C. to 140 ° C.
  • the reaction time is 15 minutes to 12 hours, preferably 45 minutes to 6 hours.
  • a compound in which R 1 is an ethyl group is obtained by allowing [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium and diethylzinc to act on a compound in which R 1 is a bromine atom in 1,4-dioxane.
  • the reaction temperature is 0 ° C. to 100 ° C., preferably 20 ° C. to 80 ° C.
  • the reaction time is 1 hour to 48 hours, preferably 3 hours to 24 hours.
  • a compound in which R 1 is a methoxy group can be produced by allowing a catalyst and a base to act on a compound in which R 1 is a bromine atom and methanol in toluene.
  • the catalyst copper iodide can be used.
  • the base cesium carbonate can be used.
  • Addition of 3,4,7,8-tetramethyl-1,10-phenanthroline as an additive is useful for allowing the reaction to proceed smoothly.
  • the reaction temperature is 60 ° C to 110 ° C.
  • the reaction time is 15 to 30 hours.
  • a compound in which R 5 is an amino group can be produced from a compound in which R 5 is a nitro group in the same manner as in Step 2-2.
  • the product of each of the above steps is a free compound or a salt thereof, after completion of the reaction, if necessary, a conventional method, for example, (1) a method of concentrating the reaction solution as it is, or (2) filtering insoluble matter such as a catalyst. (3) A method in which water and a solvent immiscible with water (for example, dichloroethane, diethyl ether, ethyl acetate, toluene, etc.) are added to the reaction solution, and the product is extracted (4) )
  • the crystallized or precipitated product can be isolated from the reaction mixture, such as by filtration.
  • the isolated product can be purified by a conventional method such as recrystallization, reprecipitation, various chromatographies and the like, if necessary.
  • the product of each step can be used in the next step without isolation or purification.
  • the compound (I) of the present invention is isolated and purified as a free compound, a pharmacologically acceptable salt, hydrate or solvate thereof.
  • the pharmacologically acceptable salt of the compound (I) of the present invention can be produced by subjecting it to a conventional salt formation reaction. Isolation and purification are carried out by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, or various chromatography.
  • Various isomers can be separated by utilizing differences in physicochemical properties between isomers. For example, a racemic mixture can be converted to an optically pure isomer by fractional crystallization leading to a diastereomeric salt with an optically active base or acid, or chromatography using a chiral column. Further, the diastereo mixture can be separated by fractional crystallization or various chromatographies. An optically active compound can also be produced by using an appropriate optically active raw material.
  • Examples of the administration form of the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof include oral administration by tablet, granule, powder, capsule or syrup, or injection or suppository. Parenteral administration, and the like, and can be administered systemically or locally.
  • Examples of the oral pharmaceutical form of the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof include tablets, pills, granules, powders, capsules, solutions, suspensions, emulsions, Examples include syrups and elixirs.
  • Examples of pharmaceutical forms for parenteral use include injections, ointments, gels, creams, patches, sprays, inhalants, sprays, eye drops, suppositories and the like. These forms of pharmaceuticals are pharmaceutically acceptable such as excipients, binders, diluents, stabilizers, preservatives, colorants, solubilizers, suspending agents, buffers, wetting agents, etc.
  • the additives can be prepared according to a conventional method using additives appropriately selected as necessary.
  • the dosage of the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is as follows: symptoms, body weight, age, administration method of the administered person (warm-blooded animal, eg, human) Varies depending on etc.
  • the lower limit is 0.001 mg / kg body weight (preferably 0.01 mg / kg body weight) and the upper limit is 500 mg / kg body weight (preferably 50 mg / kg body weight). It is desirable to administer one to several times a day depending on the symptoms.
  • the lower limit is 0.0005 mg / kg body weight (preferably 0.05 mg / kg body weight) and the upper limit is 50 mg / kg body weight (preferably 5 mg / kg body weight). Is preferably administered one to several times per day depending on the symptoms.
  • Example 1-1 To a solution of 4-bromo-2-fluorobenzoic acid (50.3 g) in N, N-dimethylformamide (400 ml) was added potassium carbonate (63.5 g) and benzyl bromide (27.3 ml) at room temperature. For 3 hours. The precipitate was removed by filtration, and the filtrate was concentrated to 100 ml and diluted with ethyl acetate. This was washed successively with saturated aqueous ammonium chloride solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give benzyl 4-bromo-2-fluorobenzoate (70.5 g).
  • Example 1-2 1,2-Dimethoxyethane (750 ml) of 2-benzyl-2-fluorobenzoate (67.0 g) and 2-hydroxyphenylboronic acid (31.3 g) obtained in Example 1-1 and water (250 ml) )
  • 2-benzyl-2-fluorobenzoate (67.0 g) and 2-hydroxyphenylboronic acid (31.3 g) obtained in Example 1-1 and water (250 ml)
  • sodium carbonate 68.7 g
  • tetrakis (triphenylphosphine) palladium (12.5 g)
  • the reaction solution was returned to room temperature, poured into ice water, and extracted with ethyl acetate.
  • the organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Example 1-3 Benzyl 3-fluoro-2′-hydroxybiphenyl-4-carboxylate (1.43 g) obtained in Example 1-2, tert-butyl (2S) -2-hydroxybutanoate (746 mg) and triphenylphosphine ( To a tetrahydrofuran solution (10 ml) of 1.22 g) was added di-tert-butyl azodicarboxylate (1.07 g) in an ice bath. The reaction solution was stirred at room temperature for 2 hours and then concentrated under reduced pressure.
  • Example 1-4 At room temperature, 2 ′- ⁇ [(1R) -1- (tert-butoxycarbonyl) propyl] oxy ⁇ -3-fluorobiphenyl-4-carboxylate (607 mg) obtained in Example 1-3 was mixed with hydrochloric acid. 1,4-Dioxane solution (4M, 5 ml) was added and stirred for 63 hours. The reaction mixture was concentrated under reduced pressure, toluene was added, and the mixture was concentrated again under reduced pressure. Hexane was added to the resulting residue.
  • Example 1-6 Ethanol solution of benzyl 3-fluoro-2 ′-( ⁇ (1R) -1-[(methylsulfonyl) carbamoyl] propyl ⁇ oxy) biphenyl-4-carboxylate (1.48 g) obtained in Example 1-5 (30 ml) was added with 10% palladium carbon (300 mg), and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. The reaction solution is filtered through celite, and the filtrate is concentrated under reduced pressure to give 3-fluoro-2 ′-( ⁇ (1R) -1-[(methylsulfonyl) carbamoyl] propyl ⁇ oxy) biphenyl-4-carboxylic acid.
  • Example 1--7 At room temperature, 2-amino-4-chlorophenol (5.00 g) in dichloromethane (100 ml) was added to trifluoroacetic acid (2.69 ml), tert-butyl 4-oxopiperidine-1-carboxylate (8.50 g). And sodium triacetoxyborohydride (11.7 g) was added and heated to reflux for 1 hour. After returning to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Example 1-8 To a solution of tert-butyl 4-[(5-chloro-2-hydroxyphenyl) amino] piperidine-1-carboxylate (1.15 g) obtained in Example 1-7 in N, N-dimethylformamide solution (23 ml). Then, cesium carbonate (5.73 g) and methyl 2-bromo-2-methylpropanoate (1.27 g) were added at room temperature, and the mixture was stirred at 140 ° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Example 1-9 4- (6-Chloro-2,2-dimethyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl) piperidine- obtained in Example 1-8 at room temperature
  • tert-butyl 1-carboxylate 198 mg
  • a 1,4-dioxane solution of hydrochloric acid 4M, 1.25 ml
  • the reaction solution was stirred for 1 hour and then concentrated under reduced pressure.
  • To the dichloromethane solution (4 ml) of the obtained residue was added 3-fluoro-2 ′-( ⁇ (1R) -1-[(methylsulfonyl) carbamoyl] propyl ⁇ oxy) biphenyl-4 obtained in Example 1-6.
  • Carboxylic acid (198 mg), diisopropylethylamine (0.35 ml), 4- (N, N-dimethylamino) pyridine (67.2 mg) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (106 mg ) was added at room temperature. The reaction was stirred for 18 hours and then diluted with ethyl acetate. This diluted solution was washed successively with 1N hydrochloric acid, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Example 2-1 A solution of 2,5-dichloropyridin-3-ol (20.0 g) (Synthesis, 1990, 6, 499-501) and tert-butyl 2-bromo-2-methylpropionate (54.4 g) in acetonitrile (400 ml) To the solution, potassium carbonate (30.3 g) was added at room temperature, and the mixture was stirred for 12 hours while heating under reflux. The insoluble material was removed by filtration and washed with ethyl acetate.
  • Example 2-2 To a dichloromethane solution (157 ml) of tert-butyl 2-[(2,5-dichloropyridin-3-yl) oxy] -2-methylpropionate (79.1 g) obtained in Example 2-1 at 0 ° C. Trifluoroacetic acid (157 ml) was added. The reaction solution was returned to room temperature and stirred overnight, and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Example 2-3 2-[(2,5-dichloropyridin-3-yl) oxy] -2-methylpropionic acid (81.1 g) obtained in Example 2-2 and tert-butyl 4-aminopiperidine-1-carboxylate
  • a dichloromethane solution (1500 ml) of (67.3 g) diisopropylethylamine (161 ml) and 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluoro were added under ice cooling. Phosphate (127 g) was added.
  • Example 2-4 4-( ⁇ 2-[(2,5-dichloropyridin-3-yl) oxy] -2-methylpropanoyl ⁇ amino) piperidine-1-carboxylic acid tert--obtained in Example 2-3 at room temperature
  • Cesium carbonate (146 g) was added to a solution of butyl (97.1 g) in N, N-dimethylformamide (1000 ml), and the mixture was stirred at 100 ° C. for 4 hours.
  • the reaction mixture was poured into water and extracted with ethyl acetate.
  • the organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Example 2-5 According to the method of Example 1-9, the compound of Example 2-4 was used instead of the compound of Example 1-8, and (2R) -2-[(4 ′- ⁇ [4- (7-chloro- 3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrido [2,3-b] [1,4] oxazin-1-yl) piperidin-1-yl] carbonyl ⁇ -3′-fluoro Biphenyl-2-yl) oxy] -N- (methylsulfonyl) butanamide was obtained.
  • Example 3-1 According to the methods of Examples 1-7 and 1-8, 4- (2,2,6-trimethyl-3-oxo was used instead of 2-amino-4-chlorophenol, using 2-amino-4-methylphenol.
  • 2-amino-4-methylphenol Tert-Butyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl) piperidine-1-carboxylate was obtained.
  • Example 3-2 According to the method of Example 1-9, the compound of Example 3-1 was used instead of the compound of Example 1-8, and (2R) -2-[(3′-fluoro-4 ′- ⁇ [4- (2,2,6-trimethyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl) piperidin-1-yl] carbonyl ⁇ biphenyl-2-yl) oxy] -N -(Methylsulfonyl) butanamide was obtained.
  • Example 4-1 According to the method of Example 1, 4-bromo-2-methylbenzoic acid was used instead of 4-bromo-2-fluorobenzoic acid and (2R) -2-[(4 ′- ⁇ [4- (6- Chloro-2,2-dimethyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl) piperidin-1-yl] carbonyl ⁇ -3'-methylbiphenyl-2-yl) Oxy] -N- (methylsulfonyl) butanamide was obtained.
  • Example 5-1 According to the method of Example 1, 4-bromo-2-methylbenzoic acid was used instead of 4-bromo-2-fluorobenzoic acid, and the compound of Example 2-4 was used instead of the compound of Example 1-8.
  • Example 6-1 2,5-dichloropyridin-3-amine (81.2 g), palladium acetate (11.2 g), 1,4-bis (diphenylphosphino) butane (42.5 g), ethyl acrylate (109 ml), diisopropylethylamine (174 ml) and a suspension of tetrabutylammonium bromide (161 g) in N, N-dimethylformamide (406 ml) were stirred at 140 ° C. for 30 hours. After returning the reaction solution to room temperature, ethyl acetate and water were added for liquid separation, and the aqueous layer was extracted with ethyl acetate.
  • Example 6-2 Ethyl (2E) -3- (3-amino-5-chloropyridin-2-yl) acrylate (37.7 g) and trifluoroacetic acid (12.7 ml) obtained in Example 6-1 in dichloromethane (377 ml) ) To the solution was added tert-butyl 4-oxopiperidine-1-carboxylate (49.7 g). After stirring at room temperature for 15 minutes, sodium triacetoxyborohydride (70.5 g) was added and stirred at 40 ° C. for 1.5 hours.
  • the reaction solution was returned to room temperature, dichloromethane and a saturated aqueous sodium hydrogen carbonate solution were added to separate the solution, and the aqueous layer was extracted with dichloromethane.
  • the collected organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the obtained residue was dissolved in methanol (2 ml), 1.7% palladium-fibroin (10 g) was added, and the mixture was stirred at room temperature for 18 hours in a hydrogen atmosphere.
  • the reaction solution was filtered, and the filtrate was concentrated under reduced pressure.
  • Example 6-3 Under ice cooling, tert-butyl 4- ⁇ [5-chloro-2- (3-ethoxy-3-oxopropyl) pyridin-3-yl] amino ⁇ piperidine-1-carboxylate obtained in Example 6-2
  • a tetrahydrofuran solution (1M, 159 ml) of potassium tert-butoxide was added dropwise to a tetrahydrofuran solution (500 ml) of (54.7 g) over 15 minutes. After stirring at the same temperature for 15 minutes, water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Example 6-4 4- (7-Chloro-2-oxo-3,4-dihydro-1,5-naphthyridin-1 (2H) -yl) piperidine-1-carboxylate tert-butyl (13) obtained in Example 6-3 0.0 g) in tetrahydrofuran (195 ml) was added dropwise a solution of lithium hexamethyldisilazide in tetrahydrofuran (1M, 39.1 ml) at ⁇ 78 ° C. After stirring for 30 minutes at the same temperature, a tetrahydrofuran solution (65 ml) of methyl iodide (2.65 ml) was added dropwise.
  • Example 6-5 4- (7-Chloro-3-methyl-2-oxo-3,4-dihydro-1,5-naphthyridin-1 (2H) -yl) piperidine-1-carboxylic acid tert obtained in Example 6-4
  • a tetrahydrofuran solution (161 ml) of -butyl (10.7 g) lithium hexamethyldisilazide (1.0 M tetrahydrofuran solution, 31.0 ml) was added dropwise at -78 ° C.
  • Example 6-6 According to the method of Example 1, 4-bromo-2-methylbenzoic acid was used instead of 4-bromo-2-fluorobenzoic acid, and the compound of Example 6-5 was used instead of the compound of Example 1-8.
  • Example 7-1 (2E) -3- (2-Amino-4-chlorophenyl) ethyl acrylate instead of the compound of Example 6-1 according to the methods of Examples 6-2, 6-3, 6-4 and 6-5 (Journal of Organic Chemistry, 2003, 68 (10), 4104-4107) and 4- (7-chloro-3,3-dimethyl-2-oxo-3,4-dihydroquinolin-1 (2H) -yl ) Tert-butyl piperidine-1-carboxylate was obtained.
  • Example 7-2 According to the method of Example 1-9, the compound of Example 7-1 was used instead of the compound of Example 1-8, and (2R) -2-[(4 ′- ⁇ [4- (7-chloro- 3,3-dimethyl-2-oxo-3,4-dihydroquinolin-1 (2H) -yl) piperidin-1-yl] carbonyl ⁇ -3′-fluorobiphenyl-2-yl) oxy] -N- (methyl Sulfonyl) butanamide was obtained.
  • Powder A powder can be obtained by mixing the compound 5g of this invention, 895g of lactose, and 100g of corn starch with a blender.
  • Test Example 1 Method for Measuring Human Platelet Aggregation Inhibitory Activity Blood was collected from the radial vein of a healthy person using a syringe for blood collection containing 1/10 volume of a 3.8% sodium citrate solution. The collected blood was centrifuged at 180 ⁇ g for 10 minutes at room temperature to separate the supernatant (platelet rich plasma; PRP). After the PRP was collected, the remaining blood was centrifuged at 1,600 ⁇ g for 10 minutes to collect the upper platelet poor plasma (PPP). PRP was allowed to stand at 16 ° C. for 30 minutes and then used for measurement.
  • PRP platelet rich plasma
  • Dispense 200 ⁇ L of the collected PRP into an agglutination test cuvette add 1 ⁇ L of a test compound solution diluted with dimethyl sulfoxide (control) or dimethyl sulfoxide, incubate at 37 ° C. for 2 minutes, and then add 2 ⁇ L of 2 mM ADP (final concentration) 20 ⁇ M) to induce platelet aggregation.
  • Platelet aggregation was measured for 8 minutes using a platelet aggregometer (MCM HEMA TRACER 313M; MC Medical). The light transmittance of PPP was taken as the 100% aggregation value, the maximum aggregation rate at each concentration of the test compound was determined, and the IC 50 value was calculated.
  • Example 1 (Table 1) ⁇ Test compound IC 50 ⁇ Example 1 8 Example 2 7.3 Example 3 17.1 Example 4 20.4 Example 5 7.4 Example 6 8 Example 7 7.2 Example 8 11.6 Example 9 11.7 Example 10 4.4 Example 11 6.7 ⁇ .
  • Test Example 2 Method for Measuring Platelet Aggregation Inhibitory Activity During Oral Administration of Rats To male rats (Slc: Wistar, 8-9 weeks old) fasted overnight with 3 mg / 10 mL / kg or 1 mg / 10 mL / kg test compound. It was administered orally using a sonde. Four hours after administration, blood was collected from anesthetized rat abdominal aorta using a syringe containing 1/10 volume of 3.13% sodium citrate solution. From the collected blood, platelet rich plasma (PRP) and platelet poor plasma (PPP) were prepared in the same manner as described in the method for measuring human platelet aggregation inhibitory activity. PRP was allowed to stand at 16 ° C. for 30 minutes and then used for measurement.
  • PRP platelet rich plasma
  • PPP platelet poor plasma
  • the dispensed PRP was dispensed in 200 ⁇ L into an agglutination test cuvette, incubated at 37 ° C. for 2 minutes, and then added with 2 ⁇ L of 0.3 mM ADP (final concentration 3 ⁇ M) to induce platelet aggregation.
  • Platelet aggregation was measured for 8 minutes using a platelet aggregometer (MCM HEMA TRACER 313M; MC Medical). The light transmittance of PPP was taken as a 100% aggregation value, the maximum aggregation rate of PRP was determined, and the inhibition rate was calculated in comparison with the maximum aggregation rate of control PRP (rat administered with solvent alone).
  • Example 2 (Table 2) ⁇ Test compound inhibition rate (%) 3mg 1mg ⁇ Example 1 82 62 Example 2 86 Example 3 73 Example 4 57 Example 5 57 Example 6 58 Example 7 80 64 Example 8 83 Example 9 68 Example 10 45 Example 11 71 ⁇
  • Compound (I) or a pharmacologically acceptable salt thereof of the present invention has an excellent platelet aggregation inhibitory action. Therefore, the present invention is useful because it can provide a novel preventive and / or therapeutic agent for thromboembolic diseases such as ischemic cerebrovascular disorders and acute coronary syndromes.

Abstract

La présente invention concerne un composé qui possède un excellent effet anti-agrégation plaquettaire et qui est utile dans la prophylaxie et/ou le traitement de maladies thromboemboliques. Ledit composé est représenté par la formule générale (I) ou son sel pharmacologiquement acceptable. (Dans ladite formule générale (I), n représente 1 ou 2 ; R1 représente un atome d'halogène, un groupe cyano, un groupe amine, un groupe alkyle en C1-4, un groupe alkyle en C1-4 halogéné ou un groupe alkoxy en C1-4 ; R2 représente un atome d'hydrogène, un atome d'halogène, un groupe cyano ou un groupe alkyle en C1-4 ; R3 et R4 représentent chacun un atome d'hydrogène, un groupe alkyle en C1-4, un groupe alkyle en C1-4 halogéné, un groupe alkoxy en C1-4 alkyle en C1-4 ou un groupe qui forme un groupe cycloalkyle en C3-5 ; R5 représente un atome d'hydrogène, un atome d'halogène, un groupe hydroxyle, un groupe nitro, un groupe alkyle en C1-4 ou un groupe amine ; R6 représente un atome d'hydrogène, un atome d'halogène ou un groupe alkyle en C1-4 ; R7 et R8 représentent chacun un atome d'hydrogène, un atome d'halogène ou un groupe alkyle en C1-4 ; R9 et R10 représentent chacun un atome d'hydrogène ou un groupe alkyle en C1-4 ; R11 représente un groupe alkyle en C1-4 ou un groupe phényle ; X représente un atome d'oxygène, un atome de soufre ou -CH2- ; Y représente un atome d'azote ou =C(Ra)- ; Ra représente un atome d'hydrogène, un atome d'halogène ou un groupe alkyle en C1-4 ; et Z représente un atome d'azote ou =CH-.)
PCT/JP2012/054350 2011-02-25 2012-02-23 Dérivé de n-[(biaryloxy)alkylcarbonyle]sulfonamide WO2012115177A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03173870A (ja) * 1989-02-10 1991-07-29 Otsuka Pharmaceut Co Ltd カルボスチリル誘導体
JPH04334351A (ja) * 1991-01-24 1992-11-20 Dr Karl Thomae Gmbh ビフェニル誘導体、これらの化合物を含む製薬組成物及びそれらの調製法
US5356904A (en) * 1992-10-07 1994-10-18 Merck & Co., Inc. Carbostyril oxytocin receptor antagonists
JPH09500134A (ja) * 1993-07-16 1997-01-07 メルク エンド カンパニー インコーポレーテッド ベンゾオキサジノンおよびベンゾピリミジノンピペリジニル早産防止オキシトシン受容体拮抗剤
WO2003022214A2 (fr) * 2001-09-06 2003-03-20 Millennium Pharmaceuticals, Inc. Composes a base de piperazine et d'homopiperazine
WO2011024933A1 (fr) * 2009-08-28 2011-03-03 第一三共株式会社 Dérivé d'acide 3-(biaryloxy)propionique

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03173870A (ja) * 1989-02-10 1991-07-29 Otsuka Pharmaceut Co Ltd カルボスチリル誘導体
JPH04334351A (ja) * 1991-01-24 1992-11-20 Dr Karl Thomae Gmbh ビフェニル誘導体、これらの化合物を含む製薬組成物及びそれらの調製法
US5356904A (en) * 1992-10-07 1994-10-18 Merck & Co., Inc. Carbostyril oxytocin receptor antagonists
JPH09500134A (ja) * 1993-07-16 1997-01-07 メルク エンド カンパニー インコーポレーテッド ベンゾオキサジノンおよびベンゾピリミジノンピペリジニル早産防止オキシトシン受容体拮抗剤
WO2003022214A2 (fr) * 2001-09-06 2003-03-20 Millennium Pharmaceuticals, Inc. Composes a base de piperazine et d'homopiperazine
WO2011024933A1 (fr) * 2009-08-28 2011-03-03 第一三共株式会社 Dérivé d'acide 3-(biaryloxy)propionique

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