WO2016047741A1 - Combination of substituted biaryl compound and other pharmaceutical - Google Patents

Combination of substituted biaryl compound and other pharmaceutical Download PDF

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Publication number
WO2016047741A1
WO2016047741A1 PCT/JP2015/077067 JP2015077067W WO2016047741A1 WO 2016047741 A1 WO2016047741 A1 WO 2016047741A1 JP 2015077067 W JP2015077067 W JP 2015077067W WO 2016047741 A1 WO2016047741 A1 WO 2016047741A1
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Prior art keywords
pyridin
group
aminomethyl
ylamino
ylmethyl
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PCT/JP2015/077067
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French (fr)
Japanese (ja)
Inventor
米田　健治
柴川　信彦
智子 神田
哲嗣 勝部
伊藤　幸治
喜代志 山本
徳明 岩瀬
茂 牛山
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宇部興産株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to a pharmaceutical composition comprising a specific substituted biaryl compound or a pharmacologically acceptable salt thereof, wherein the pharmaceutical composition is administered in combination with another pharmaceutical agent, and a therapeutically effective amount of the pharmaceutical composition.
  • the present invention relates to a method for treating a respiratory disease, which comprises administering a specific substituted biaryl compound or a pharmacologically acceptable salt thereof and a therapeutically effective amount of another pharmaceutical agent to a warm-blooded animal in combination.
  • chronic obstructive pulmonary disease which is an airway obstructive disease, is characterized by chronic bronchitis and irreversible and persistent airway obstruction, resulting in inflamed bronchial inflammation and alveolar destruction caused by smoking. It is a sex disorder.
  • a therapeutic agent for chronic obstructive pulmonary disease a safe and established therapeutic agent has not yet been found.
  • roflumilast which is a phosphodiesterase 4 (hereinafter abbreviated as PDE4) inhibitor
  • PDE4 phosphodiesterase 4
  • Clinical utility is limited due to vomiting and nausea as side effects.
  • interstitial pneumonia and pulmonary fibrosis which are diffuse lung diseases, are also designated as specific diseases in Japan, and the prognosis after onset is poor, and symptomatic treatment with administration of steroids or pirfenidone with strong side effects has been made Yes.
  • asthma which is an allergic lung disease, is a disease that exhibits chronic airway inflammation.
  • Prostaglandin E 2 (hereinafter abbreviated as PGE 2 ) has a wide range of physiological activities as a metabolite in the arachidonic acid cascade, and acts as an agonist for the four receptors EP1, EP2, EP3 and EP4. .
  • PGE 2 is involved in many inflammatory reactions and has inflammatory effects such as vascular permeability enhancing action, release of various inflammatory mediators, induction of inflammatory cells and immune cells, angiogenic action, etc. Have been reported to exhibit an anti-inflammatory action via EP2 and / or EP4 receptors (see Non-Patent Document 1).
  • Non-plastanoid sulfonamide compounds having EP2 agonistic activity have been known (see Patent Documents 1 to 8), and various compounds listed as pharmaceutical uses of the compounds described in Patent Documents 1 to 8 have been known.
  • Diseases include respiratory disease including chronic obstructive pulmonary disease, pulmonary fibrosis and asthma.
  • a combination of a specific compound having an EP2 agonistic action and another pharmaceutical eg, corticosteroid, anticholinergic agent, ⁇ 2-receptor agonist, PDE4 inhibitor, etc.
  • another pharmaceutical eg, corticosteroid, anticholinergic agent, ⁇ 2-receptor agonist, PDE4 inhibitor, etc.
  • a sulfonamide compound having a biaryl group substituted with a specific substituent at a specific site as a partial structure has a strong EP2 agonistic action and anti-inflammatory action, and other Useful for prevention and / or treatment of respiratory diseases such as asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis and pulmonary hypertension in combination with medicine It is neither described nor suggested.
  • the present inventors have provided a pharmaceutical composition comprising a specific substituted biaryl compound or a pharmacologically acceptable salt thereof, wherein the pharmaceutical composition is administered in combination with other pharmaceuticals, and has an anti-inflammatory effect.
  • Treatment of respiratory diseases such as asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis and pulmonary hypertension and / Or it discovered that it had the outstanding effect in prevention, and completed this invention.
  • the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof, wherein the pharmaceutical composition is administered in combination with other pharmaceuticals, And a therapeutically effective amount of a compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof and a therapeutically effective amount of another pharmaceutical agent in combination with a warm-blooded animal:
  • a method of treating a disease is provided.
  • the present invention provides the following from one aspect.
  • a pharmaceutical composition comprising a compound represented by: or a pharmacologically acceptable salt thereof, PDE4 inhibitor, PDE5 inhibitor, corticosteroid, anticholinergic agent, ⁇ 2-receptor agonist, H1-histamine receptor antagonist, leukotriene receptor antagonist, endothelin receptor antagonist, PGI2 receptor agonist, theophylline And a pharmaceutical composition administered in combination with one or more pharmaceuticals selected from the group consisting of pirfenidone.
  • a pharmaceutical composition comprising a compound represented by the general formula (I) or a salt thereof and another pharmaceutical agent are administered as different formulations at the same time or at different times, The pharmaceutical composition according to 1).
  • R 1 represents a carboxy group, an ethoxycarbonyl group, an isopropoxycarbonyl group or a hexyloxycarbonyl group, W represents a nitrogen atom or a group —CH ⁇ ;
  • R 2 represents a 1-propenyl group or a 1-propynyl group, (1) to (3), wherein Z represents a phenyl group, a 3-fluorophenyl group, a pyridin-2-yl group, a pyridin-3-yl group, a thiophen-2-yl group, or a thiophen-3-yl group Pharmaceutical composition in any one.
  • the compound represented by the general formula (I) is (6- ⁇ [3 ′-(1-propenyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl ⁇ pyridin-2-ylamino) ethyl acetate, (6- ⁇ [3 ′-(1-propenyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl ⁇ pyridin-2-ylamino) acetic acid, (6- ⁇ [3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl ⁇ pyridin-2-ylamino) ethyl acetate, (6- ⁇ [3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl ⁇ pyridin-2-ylamin
  • the other drug is one or more drugs selected from the group consisting of a PDE4 inhibitor, a corticosteroid, an anticholinergic drug, a ⁇ 2-receptor agonist, and pirfenidone, (1) to (7) A pharmaceutical composition according to any one of the above.
  • R 1 represents an optionally protected carboxy group, W represents a nitrogen atom or a group —CH ⁇ ; R 2 represents an ethoxy group, a 1-propenyl group or a 1-propynyl group, Z represents a phenyl group, a 3-fluorophenyl group, a pyridin-2-yl group, a pyridin-3-yl group, a thiophen-2-yl group, or a thiophen-3-yl group) Or a pharmacologically acceptable salt thereof, and (Ii) Other medicaments with therapeutically effective amounts (the other medicaments are PDE4 inhibitor, PDE5 inhibitor, corticosteroid, anticholinergic agent, ⁇ 2-receptor agonist, H1-histamine receptor antagonist, leukotriene receptor) One or more drugs selected from the group consisting of a body antagonist, an endothelin receptor antagonist, a PGI2 receptor agonist, theophylline, and pirfenidone.
  • R 1 represents a carboxy group, an ethoxycarbonyl group, an isopropoxycarbonyl group or a hexyloxycarbonyl group, W represents a nitrogen atom or a group —CH ⁇ ;
  • R 2 represents a 1-propenyl group or a 1-propynyl group, (13) to (15), wherein Z represents a phenyl group, a 3-fluorophenyl group, a pyridin-2-yl group, a pyridin-3-yl group, a thiophen-2-yl group, or a thiophen-3-yl group.
  • Z represents a phenyl group, a 3-fluorophenyl group, a pyridin-2-yl group, a pyridin-3-yl group, a thiophen-2-yl group, or a thiophen-3-yl group.
  • the compound represented by the general formula (I) is (6- ⁇ [3 ′-(1-propenyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl ⁇ pyridin-2-ylamino) ethyl acetate, (6- ⁇ [3 ′-(1-propenyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl ⁇ pyridin-2-ylamino) acetic acid, (6- ⁇ [3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl ⁇ pyridin-2-ylamino) ethyl acetate, (6- ⁇ [3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl ⁇ pyridin-2-ylamin
  • the other medicament is one or more medicaments selected from the group consisting of a PDE4 inhibitor, a corticosteroid, an anticholinergic agent, a ⁇ 2-receptor agonist, and pirfenidone, (13) to (19) The method in any one of.
  • the pharmacological effect of the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof is added to the pharmacological effect of another pharmaceutical, and the dosage of the other pharmaceutical is reduced.
  • the pharmaceutical composition is a respiratory disease, preferably asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis or pulmonary hypertension, more preferably asthma .
  • a pharmaceutical composition for the treatment and / or prevention of chronic obstructive pulmonary disease or pulmonary fibrosis and is useful as a pharmaceutical for warm-blooded animals (particularly for humans).
  • the treatment method of the present invention is useful as a treatment method for the above-mentioned diseases, and is also useful as a treatment method for warm-blooded animals (particularly for humans).
  • the optionally protected carboxy group represented by R 1 in the general formula (I) means a carboxy group or a carboxy group protected by a protecting group, and examples of such protecting groups include ester-type protecting groups. be able to.
  • Examples of the partial structure of the ester-type protecting group include methyl group, ethyl group, propyl group, isopropyl group, 1-ethylpropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, 3,3- Dimethylbutyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1-ethylbutyl, 2 A C 1 -C 12 alkyl group such as ethylbutyl, heptyl, octyl, nonyl, dec
  • R 1 is preferably a carboxy group or a C 1 -C 6 alkoxycarbonyl group.
  • R 1 is a carboxy group, an ethoxycarbonyl group, an isopropoxycarbonyl group or a hexyloxycarbonyl group.
  • W is a nitrogen atom or a group —CH ⁇ . That is, in the general formula (I), the aromatic ring containing W is a pyridine ring or a benzene ring. In certain embodiments of general formula (I), W is a group —CH ⁇ . In another particular embodiment of general formula (I), W is a nitrogen atom.
  • R 2 is an ethoxy group, 1-propenyl group or 1-propynyl group. In certain embodiments of general formula (I), R 2 is an ethoxy group. In another particular embodiment of general formula (I), R 2 is a 1-propenyl group or a 1-propynyl group.
  • Z represents a phenyl group, a 3-fluorophenyl group, a pyridin-2-yl group, a pyridin-3-yl group, a thiophen-2-yl group, or a thiophen-3-yl group.
  • Z is a phenyl group, a 3-fluorophenyl group, a pyridin-2-yl group or a pyridin-3-yl group, preferably a phenyl group or a pyridin-2-yl group.
  • Z is a thiophen-2-yl group or a thiophen-3-yl group, preferably a thiophen-2-yl group.
  • the compound represented by the general formula (I) can be converted into a pharmacologically acceptable salt according to a conventional method, if necessary, but can also be separated directly from the reaction mixture as a salt.
  • the compound represented by the general formula (I) is converted into a pharmacologically acceptable acid addition salt by treating with an acid.
  • salts include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or phosphate; or acetate, trifluoroacetate, benzoate Oxalate, malonate, succinate, maleate, fumarate, tartrate, citrate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate, benzenesulfonate, p -Organic acid salts such as toluene sulfonate, glutamate or aspartate.
  • R 1 is a carboxy group
  • the compound represented by the general formula (I) is converted into a pharmacologically acceptable basic salt by treating with a base.
  • salts include metal salts such as sodium salt, potassium salt, calcium salt or magnesium salt; inorganic salts such as ammonium salt; or organic amine salts such as triethylamine salt or guanidine salt.
  • R 1 ′ represents a protecting group for a carboxy group
  • R 3 represents a tert-butoxycarbonyl group or a hydrogen atom
  • X represents A hydroxy group, a chloro group, a bromo group, an iodo group, a methanesulfonyloxy group, a benzenesulfonyloxy group, a p-toluenesulfonyloxy group or a trifluoromethanesulfonyloxy group
  • X ′ represents a chloro group, a bromo group or an iodo group. Show. ]
  • the compound represented by the general formula (I) is obtained by any one of the synthesis routes 1 to 5, wherein R 1 is a carboxy group, and R 3 is a hydrogen atom as the compound (Ia) or R 1 Can be obtained as compound (I ′) in which R 3 is a hydrogen atom.
  • aromatic hydrocarbons such as benzene, toluene or xylene; diethyl ether, tetrahydrofuran , Ethers such as 1,4-dioxane or 1,2-dimethoxyethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide or N-methylpyrrolidone; nitriles such as acetonitrile or propionitrile An ester such as methyl acetate, ethyl acetate or isopropyl acetate; or any mixed solvent thereof, and the like, preferably tetrahydrofuran, N, N-dimethylformamide, acetonitrile or a mixed solvent thereof.
  • Examples of the azo compound-based condensing agent used include diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), N, N, N ′, N′-tetraisopropyl azodicarboxamide (TIPA).
  • DEAD diethyl azodicarboxylate
  • DIAD diisopropyl azodicarboxylate
  • TIPA N, N, N ′, N′-tetraisopropyl azodicarboxamide
  • TMAD 1,1 ′-(azodicarbonyl) dipiperidine
  • DEAD diethyl azodicarboxylate
  • TMAD 1,6-dimethyl-1,5,7-hexahydro-1 , 4,6,7-tetrazocine-2,5-dione
  • TMAD diethyl azodicarboxylate
  • TMAD diethyl azodicarboxylate
  • TMAD diethyl azodicarboxylate
  • TMAD diethyl azodicarboxylate
  • the amount of the azo compound-based condensing agent to be used is generally 0.9 to 10-fold mol amount, preferably 1 to 5-fold mol amount based on 1 mol of Compound (b).
  • Examples of the phosphine reagent to be used include trimethylphosphine, triethylphosphine, tri-n-butylphosphine, triphenylphosphine and the like, and tri-n-butylphosphine or triphenylphosphine is preferable.
  • the amount of the phosphine compound to be used is generally 0.9 to 10-fold mol amount, preferably 1 to 5-fold mol amount based on 1 mol of Compound (b).
  • the amount of compound (a) to be used is generally 0.8 to 2-fold mol amount, preferably 0.9 to 1.5-fold mol amount based on 1 mol of Compound (b).
  • the reaction temperature varies depending on the kind of raw material, solvent, etc., the amount used, etc., but is usually ⁇ 20 ° C. to 100 ° C., preferably ⁇ 5 ° C. to 50 ° C.
  • the reaction time varies depending on the reaction temperature and the like, but is usually 30 minutes to 48 hours, preferably 1 hour to 24 hours.
  • the compound (a) and the compound Compound (I ′) can be obtained by reacting (b) with an inert organic solvent in the presence of a base.
  • the inert solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the raw material to some extent.
  • ethers such as tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane are used.
  • Halogenated aliphatic hydrocarbons such as methylene chloride, chloroform or 1,2-dichloroethane; nitriles such as acetonitrile or propionitrile; esters such as methyl formate, ethyl formate, methyl acetate or ethyl acetate; benzene or toluene
  • Aromatic hydrocarbons such as N; N-dimethylformamide, N, N-dimethylacetamide or amides such as N-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide; or any mixed solvent thereof.
  • tetrahydrofuran , N- dimethylformamide, methylene chloride or 1,2-dichloroethane.
  • the base used include alkali metal hydrides such as sodium hydride or potassium hydride; alkali metal amides such as lithium amide, sodium amide, lithium diisopropylamide or lithium bistrimethylsilylamide; sodium methoxide, sodium ethoxide Alkali metal alkoxides such as sodium tert-butoxide or potassium tert-butoxide; alkali metal carbonates such as sodium carbonate or potassium carbonate; or triethylamine, tributylamine, diisopropylethylamine, pyridine, picoline, 2,6-lutidine or 4- Examples include amines such as dimethylaminopyridine, and preferably sodium hydride, potassium carbonate, triethylamine or diisopropylethyl.
  • the base is preferably triethylamine or diisopropylethylamine.
  • the amount of the base to be used is generally 1 to 5-fold mol amount, preferably 1 to 2.5-fold mol amount based on 1 mol of Compound (b).
  • the amount of compound (a) to be used is generally 0.5 to 3-fold mol amount, preferably 0.5 to 1.5-fold mol amount based on 1 mol of Compound (b).
  • the reaction temperature varies depending on the kind of raw material, solvent, etc., the amount used, etc., but is usually ⁇ 80 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C.
  • the reaction time varies depending on the reaction temperature and the like, but is usually 10 minutes to 48 hours, preferably 1 hour to 24 hours.
  • the compound (c) and the compound Compound (I ′) can be obtained by reacting (d) with an inert organic solvent in the presence of a base.
  • X in the compound (a) is a chloro group in the above [Synthesis route 1] except that the compound (d) is used instead of the compound (a) and the compound (c) is used instead of the compound (b).
  • Synthesis route 3-1 is a step of obtaining compound (f) by reacting compound (c) with compound (e) in the presence of a base in an inert organic solvent.
  • X of compound (a) is a chloro group in the above [Synthesis route 1] except that compound (e) is used instead of compound (a), and compound (c) is used instead of compound (b).
  • Synthetic pathway 3-2 involves the steps of compound (f) and compound (g) obtained in synthetic pathway 3-1 in an inert solvent, in an inert gas atmosphere, in the presence of either a base or fluoride and a palladium catalyst.
  • the inert solvent used is not particularly limited as long as it is a solvent that does not inhibit the reaction and dissolves raw materials, catalysts, and bases (or fluorides) to some extent.
  • an aromatic hydrocarbon such as benzene or toluene.
  • Ethers such as tetrahydrofuran, 1,2-dimethoxyethane or 1,4-dioxane; alcohols such as methanol, ethanol, propanol or isopropanol; esters such as methyl acetate or ethyl acetate; N, N-dimethylformamide; Examples thereof include amides such as N, N-dimethylacetamide or N-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide; nitriles such as acetonitrile; water; or any mixed solvent thereof, preferably toluene, toluene- Ethanol-water mixed solvent or Toluene - is water mixed solvent.
  • Examples of the inert gas used include nitrogen, helium, and argon.
  • Examples of the palladium catalyst to be used include palladium-activated carbon or palladium metal such as palladium black; tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium, 1,1′-bis (diphenylphosphine chloride).
  • Phino) ferrocene palladium or an organic palladium complex such as tris (dibenzylideneacetone) dipalladium; or palladium salts such as palladium chloride or palladium acetate; and tetrakis (triphenylphosphine) palladium or palladium acetate is preferable.
  • the amount of palladium used as the catalyst is usually 0.0001 to 1-fold mol amount, preferably 0.005 to 0.3-fold mol amount based on 1 mol of Compound (f).
  • tris (dibenzylideneacetone) dipalladium, palladium chloride or palladium acetate it is preferable to coexist an organic phosphine compound.
  • organic phosphine compound used examples include tri-n-butylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, butyldi-1-adamantylphosphine, triphenylphosphine, tri (o-tolyl) phosphine, 2- Dicyclohexylphosphino-2 ', 6'-dimethoxybiphenyl, 1,1'-bis (diphenylphosphino) ferrocene or 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino ) Ferrocene and the like, and preferred are tricyclohexylphosphine, butyldi-1-adamantylphosphine, triphenylphosphine or 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl.
  • the amount of the organic phosphine compound used is usually 1 to 5 times the molar amount, preferably 1.5 to 2.5 times the molar amount per 1 mol of palladium.
  • the base or fluoride used include alkali metal acetates such as sodium acetate or potassium acetate; alkali metal carbonates such as sodium carbonate, potassium carbonate or cesium carbonate; trisodium phosphate or tripotassium phosphate Alkali metal phosphates; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide; quaternary ammonium hydroxides such as tetramethylammonium hydroxide, tetraethylammonium hydroxide or tetrabutylammonium hydroxide; Alternatively, fluorides such as cesium fluoride, tetramethylammonium fluoride, tetraethylammonium fluoride, and tetrabutylammonium fluoride can be
  • the amount of the base or fluoride to be used is generally 1 to 10-fold mol amount, preferably 1.5 to 5-fold mol amount based on 1 mol of Compound (f).
  • the amount of compound (g) to be used is generally 1 to 3-fold mol amount, preferably 1 to 2-fold mol amount based on 1 mol of Compound (f).
  • the reaction temperature varies depending on the type of raw material, solvent, etc., the amount used, etc., but is usually 0 ° C. to 200 ° C., preferably 50 ° C. to 150 ° C.
  • the reaction time varies depending on the reaction temperature and the like, but is usually 10 minutes to 120 hours, preferably 1 hour to 48 hours.
  • Compound (I ′) can be obtained by reacting compound (h) with compound (i) in an inert organic solvent in the presence or absence (preferably in the presence) of a base.
  • the inert organic solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the raw material to some extent.
  • aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride, chloroform Or halogenated aliphatic hydrocarbons such as 1,2-dichloroethane; ethers such as 1,4-dioxane, tetrahydrofuran, diethyl ether or 1,2-dimethoxyethane; N, N-dimethylformamide, N, N-dimethyl Amides such as acetamide or N-methylpyrrolidone; Nitriles such as acetonitrile or propionitrile; or any mixed solvent thereof, preferably methylene chloride, 1,2-dichloroethane, N, N-dimethyl Formamide, acetonitrile or a mixture thereof It is a solvent.
  • Examples of the base to be used include organic bases such as triethylamine or diisopropylethylamine; or inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate or potassium carbonate, preferably triethylamine or diisopropylethylamine.
  • the amount of the base to be used is generally 0.9 to 20-fold mol amount, preferably 1 to 10-fold mol amount based on 1 mol of Compound (i).
  • the amount of compound (h) to be used is generally 0.7 to 5-fold mol amount, preferably 0.8 to 1.5-fold mol amount based on 1 mol of Compound (i).
  • the reaction temperature varies depending on the kind of raw material, solvent, etc., the amount used, etc., but is usually ⁇ 20 ° C. to 100 ° C., preferably ⁇ 5 ° C. to 50 ° C.
  • the reaction time varies depending on the reaction temperature and the like, but is usually 1 minute to 36 hours, preferably 1 hour to 18 hours.
  • R 3 is a hydrogen atom
  • R 1 is a carboxy group by subjecting the compound (I ′) to appropriate deprotection by alkali hydrolysis or the like.
  • the compound represented by (I) can be obtained.
  • the substituent R 2 may have a desired substituent introduced from the beginning, and after producing the basic skeleton by the above method, oxidation, reduction, alkylation, esterification, amidation, dehydration reaction, A desired substituent may be introduced using a deprotection reaction, hydrolysis, coupling reaction, cyclization reaction, and / or a commonly used synthetic method combining these reactions.
  • the starting compound of the compound represented by formula (I) is commercially available or can be produced by a production method known to those skilled in the art.
  • the starting compound of the compound represented by the general formula (I) and the production method of the intermediate compound will be described in detail in Reference Examples described later.
  • the target compound produced in each reaction can be obtained from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, then an organic solvent such as ethyl acetate that is immiscible with water is added, and after washing with water, the organic layer containing the target compound is removed.
  • It isolate separates and it obtains by distilling a solvent off after drying with desiccants, such as anhydrous magnesium sulfate or anhydrous sodium sulfate.
  • the obtained target compound can be obtained by a conventional method such as recrystallization; reprecipitation; or a method commonly used for separation and purification of organic compounds (for example, adsorption column chromatography using a carrier such as silica gel or alumina).
  • adsorption column chromatography using a carrier such as silica gel or alumina.
  • the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof can exist as a hydrate or a solvate.
  • a pharmaceutical composition containing a compound represented by the general formula (I) or a pharmacologically acceptable salt thereof is characterized by being administered in combination with other pharmaceuticals.
  • “administered in combination” refers to a pharmaceutical composition containing a compound represented by the general formula (I) or a pharmacologically acceptable salt thereof within a certain period, and other subjects (particularly humans) Means to take the medicine of the body into the body. Therefore, the pharmaceutical composition is (A) A pharmaceutical composition containing a compound represented by the general formula (I) or a pharmacologically acceptable salt thereof and another pharmaceutical agent are administered as different preparations at the same time or at different times.
  • a pharmaceutical composition comprising a pharmaceutical composition comprising a compound represented by general formula (I) or a pharmacologically acceptable salt thereof and another pharmaceutical agent as a single preparation (compound) It can be a composition, and is preferably the pharmaceutical composition of (a) above.
  • the administration time of the preparation containing the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof and the preparation containing another medicine can be administered simultaneously, at different times (separately) or on different days.
  • the order, frequency, route and dose of administration of the above two preparations can be different.
  • the period from administration of one of the above two preparations to administration of the other and a certain period during which one pharmacological effect remains (for example, 1 week, preferably 2 or 3 days, more preferably May be administered within one day, more preferably within 1 to 8 hours).
  • the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof and other medicines do not have to be present in the blood at a certain concentration at the same time, and one of them is administered. Sometimes the other may disappear from the blood.
  • the dosage form of the pharmaceutical composition of the present invention is, for example, as follows.
  • A a preparation containing a compound represented by the general formula (I) or a pharmacologically acceptable salt thereof and a preparation containing other medicaments (two different preparations) are administered simultaneously;
  • B a preparation containing the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof and a preparation containing other medicaments (two different preparations) are administered separately over a period of time;
  • C A single preparation containing both the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof and other pharmaceuticals is administered.
  • medicaments in the pharmaceutical composition of the present invention are not limited as long as they exhibit a desired effect (preferably, an anti-inflammatory effect, an anti-fibrosis, or a bronchodilation effect by suppressing production of inflammatory mediators, etc.).
  • a desired effect preferably, an anti-inflammatory effect, an anti-fibrosis, or a bronchodilation effect by suppressing production of inflammatory mediators, etc.
  • PGI2 receptor agonist PGI2 receptor agonist
  • PGI2 receptor agonist P
  • examples of the PDE4 inhibitor in other pharmaceuticals include silomilast, roflumilast, tetomilast, tofimilast, filaminast, picramylast, and lilimimilast, and are preferably siromilast or roflumilast, and more preferably roflumilast.
  • examples of PDE5 inhibitors in other pharmaceuticals include sildenafil, vardenafil, tadalafil, udenafil, or avanafil.
  • examples of corticosteroids in other medicaments include prednisone, prednisolone, methylprednisolone, cortisone, hydrocortisone, fludrocortisone, dexamethasone, betamethasone, budesonide, fluticasone, beclomethasone, mometasone, triamcinolone or ciclesonide.
  • Budesonide, fluticasone, beclomethasone, mometasone or ciclesonide are preferred, and fluticasone is more preferred.
  • examples of the anticholinergic agent in other pharmaceuticals include glycopyrronium bromide, acridinium bromide, tiotropium bromide, ipratropium bromide, and the like.
  • ⁇ 2-receptor agonists in other pharmaceuticals include, for example, salbutamol, milveterol, indacaterol, carmoterol, salmeterol or formoterol.
  • examples of the H1-histamine receptor antagonist in other pharmaceuticals include azelastine, olopatadine, loratadine, desloratadine, and cetirizine.
  • examples of the leukotriene receptor antagonist in other pharmaceuticals include montelukast, pranlukast, zafirlukast, and the like.
  • endothelin receptor antagonists in other pharmaceuticals include, for example, bosentan, ambrisentan, atrasentan, darsentan, clazosentan, avosentan, and the like.
  • examples of the PGI2 receptor agonist in other pharmaceuticals include beraprost and epoprestenol.
  • compositions (formulation) containing the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof and other pharmaceuticals (formulation) can be administered per se (as is). Or tablets, capsules, powders, syrups, granules, fine granules, pills, suspensions, emulsions manufactured by mixing with appropriate pharmacologically acceptable excipients, diluents, etc.
  • Oral or parenteral in the form of preparations such as transdermal absorption agents, suppositories, ointments, lotions, inhalants or injections , Transrespiratory administration, transpulmonary administration, intradermal administration, subcutaneous administration, etc.
  • the pharmaceutical composition containing the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof and the other medicament may be different formulations, respectively, and the compound represented by the general formula (I) or the
  • the pharmaceutical composition containing a pharmacologically acceptable salt may be a single preparation further containing another pharmaceutical agent.
  • Excipients include, for example, organic excipients or inorganic excipients.
  • organic excipient include sugar derivatives such as lactose, sucrose, glucose, mannitol or sorbitol; starch derivatives such as corn starch, potato starch, ⁇ -starch or dextrin; cellulose derivatives such as crystalline cellulose; gum arabic; Dextran; or pullulan and the like.
  • inorganic excipients include light anhydrous silicic acid; or sulfates such as calcium sulfate.
  • Lubricants include, for example, stearic acid; stearic acid metal salts such as calcium stearate or magnesium stearate; talc; colloidal silica; waxes such as beeswax or gallow; boric acid; adipic acid; sulfate such as sodium sulfate; glycol Fumaric acid; sodium benzoate; D, L-leucine; sodium lauryl sulfate; silicic acids such as anhydrous silicic acid or silicic acid hydrate; or starch derivatives in the above-mentioned excipients.
  • binder examples include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and compounds shown by the above-mentioned excipients.
  • Disintegrants include, for example, cellulose derivatives such as low substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium or internally crosslinked carboxymethylcellulose calcium; crosslinked polyvinylpyrrolidone; or chemically modified starch such as carboxymethyl starch or sodium carboxymethyl starch Or a cellulose derivative etc. are mentioned.
  • the emulsifier is, for example, colloidal clay such as bentonite or bee gum; an anionic surfactant such as sodium lauryl sulfate; a cationic surfactant such as benzalkonium chloride; or polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester Or nonionic surfactants, such as sucrose fatty acid ester, etc. are mentioned.
  • Stabilizers include, for example, parahydroxybenzoates such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; thimerosal; acetic anhydride Or sorbic acid and the like.
  • sweeteners such as saccharin sodium or aspartame
  • acidulants such as citric acid, malic acid or tartaric acid
  • flavors such as menthol, lemon extract or orange extract.
  • Diluents are compounds that are usually used as diluents, such as lactose, mannitol, glucose, sucrose, calcium sulfate, hydroxypropylcellulose, microcrystalline cellulose, water, ethanol, polyethylene glycol, propylene glycol, glycerol, Examples thereof include starch, polyvinyl pyrrolidone, and mixtures thereof.
  • CFCs chlorofluorocarbons
  • trichlorofluoromethane trichlorofluoromethane
  • dichlorotetrafluoroethane Alternatively, carbon dioxide or the like can be used as a propellant.
  • the dose of the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof may vary depending on conditions such as the patient's symptoms, age, weight, etc.
  • the lower limit is 0.001 mg / Kg (preferably 0.01 mg / Kg) and the upper limit is 20 mg / Kg (preferably 10 mg / Kg).
  • a lower limit of 0.0001 mg / Kg (preferably 0.0005 mg / Kg) and an upper limit of 10 mg / Kg (preferably 5 mg / Kg) can be administered to adults 1 to 6 times per day depending on the symptoms.
  • the dosage of other pharmaceuticals may vary depending on other pharmaceutical types, patient symptoms, age, body weight and other conditions.
  • the lower limit is 0.001 mg / Kg (preferably 0.01 mg / Kg) and the upper limit is 500 mg / Kg (preferably 50 mg / Kg). Is 0.0005 mg / Kg), and an upper limit of 50 mg / Kg (preferably 5 mg / Kg) can be administered to adults 1 to 6 times per day depending on the symptoms.
  • Example 12- (6- ⁇ [4- (6-Ethoxypyridin-2-yl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl ⁇ pyridin-2-ylamino) acetic acid in Example 12- (a) The resulting [tert-butoxycarbonyl (6- ⁇ [4- (6-ethoxypyridin-2-yl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl ⁇ pyridin-2-yl) amino] tert-butyl acetate To a solution of 590 mg (0.855 mmol) in methylene chloride (8.6 mL) was added trifluoroacetic acid (8.6 mL, 112 mmol) at room temperature, and the mixture was stirred at room temperature for 6 hours.
  • Example 17 (6- ⁇ [3 ′-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-3-ylsulfonyl) aminomethyl ⁇ pyridin-2-ylamino) ethyl acetate obtained in Reference Example 11- (b) ⁇ 6-[(Thiophen-3-ylsulfonyl) aminomethyl] pyridin-2-ylamino ⁇ ethyl acetate was added to a solution of 284 mg (0.800 mmol) in tetrahydrofuran (4.0 mL) in the same manner as in Reference Example 13 and 3′- 178 mg (0.800 mmol) of (1-propynyl) biphenyl-4-ylmethanol, 395 ⁇ L (1.60 mmol) of tri-n-butylphosphine and 276 mg of N, N, N ′, N′-tetramethylazodicarboxamide (1.
  • Example 18 (6- ⁇ [3 ′-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-3-ylsulfonyl) aminomethyl ⁇ pyridin-2-ylamino) acetic acid obtained in Example 17 (6- ⁇ [3 '-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-3-ylsulfonyl) aminomethyl ⁇ pyridin-2-ylamino) ethyl acetate (426 mg, 0.762 mmol) in ethanol (3.5 mL) Sodium hydroxide aqueous solution 3.5mL (3.5mmol) was added, and it stirred at room temperature for 16 hours.
  • reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate.
  • organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • reaction solution was concentrated under reduced pressure, neutralized with a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate.
  • organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • EXSAS version 7.1.6, manufactured by Arm Systex
  • IC 50 value concentration of test compound required to replace 50% of [ 3 H] prostaglandin E 2 bound to the receptor.
  • the dissociation constant (Kd value) was calculated by Scatchard analysis. The test results are shown in Table 1.
  • the LPS-induced TNF ⁇ production inhibition test was performed by partially modifying the method of Mary et al. (Journal of Pharmacology and Experimental Therapeutics, 284, 420 (1998)).
  • 185 ⁇ L of PBMC suspension prepared to a final concentration of 5 ⁇ 10 5 cells / mL was added to a 96-well plate, and then RPMI1640 medium containing 1 (V / V)% DMSO containing the test compound was added to each well. 10 ⁇ L each was added (DMSO final concentration was 0.05 (V / V)%).
  • RPMI1640 medium containing 1 (V / V)% DMSO was similarly added to wells to which no test compound was added.
  • LPS L2880-500MG, manufactured by SIGMA
  • RPMI 1640 medium 5 ⁇ L of RPMI 1640 medium was added to each well (the final concentration of LPS was 100 ng / mL).
  • RPMI1640 medium 5 ⁇ L was added to wells not stimulated with LPS.
  • the culture supernatant was recovered. The collected culture supernatant was stored at ⁇ 20 ° C. until TNF ⁇ content measurement.
  • a sandwich ELISA kit (Quantikine DTA00c, manufactured by R & D Systems) was used for measuring the TNF ⁇ content.
  • the TNF ⁇ content of each sample was calculated from a standard curve of E. coli-derived human recombinant TNF ⁇ included in the kit.
  • the amount of TNF ⁇ produced by LPS when only DMSO was added was taken as 100%, and the TNF ⁇ production inhibition rate at each concentration of the test compound was calculated. From the relationship between the concentration of the added test compound and the inhibition rate of TNF ⁇ production of the test compound, the concentration of the test compound that inhibits TNF ⁇ production by 50% was calculated as an IC 50 value (nM).
  • the test results are shown in Table 2.
  • RPMI1640 medium containing 1 (V / V)% DMSO was similarly added. After incubation for 30 minutes in a carbon dioxide incubator, 10 ⁇ L of 1 (V / V)% DMSO-containing RPMI1640 medium in which the test compound was dissolved was added to each well (the final DMSO concentration per well was 0.1 (V / V). V)%). RPMI1640 medium containing 1 (V / V)% DMSO was similarly added to wells to which no test compound was added.
  • LPS L2880-500MG, manufactured by SIGMA
  • RPMI 1640 medium 5 ⁇ L of RPMI 1640 medium was added to each well (the final concentration of LPS was 100 ng / mL).
  • RPMI1640 medium 5 ⁇ L was added to wells not stimulated with LPS.
  • the culture supernatant was recovered. The collected culture supernatant was stored at ⁇ 20 ° C. until TNF ⁇ content measurement.
  • a sandwich ELISA kit (Quantikine DTA00c, manufactured by R & D Systems) was used for measuring the TNF ⁇ content.
  • the TNF ⁇ content of each sample was calculated from a standard curve of E. coli-derived human recombinant TNF ⁇ included in the kit.
  • the amount of TNF ⁇ produced by LPS when only DMSO was added was taken as 100%, and the inhibition rate of TNF ⁇ production at each concentration of the test compound and roflumilast was calculated.
  • the TNF ⁇ production inhibition rate at each concentration of the combination of the test compound and roflumilast was calculated, and the effect of the test compound alone and the effect of the combined use with roflumilast were compared.
  • the test results are shown in Tables 3 and 4.
  • the administration solution of roflumilast was prepared by pulverizing roflumilast with agate for 2 to 3 minutes and suspending it in a 0.5% methylcellulose solution (final concentration of roflumilast 0.01 mg / mL).
  • the roflumilast solution thus prepared was orally administered at 10 mL / kg (0.1 mg / Kg) 1 hour before LPS administration.
  • a 0.5% methylcellulose solution was administered to the control group.
  • the test compound administration solution was prepared by dissolving the test compound in a 0.1 mol / L or 1 mol / L sodium hydroxide aqueous solution and neutralizing it by adding a medium (the final concentration of the test compound was 0.1 mg / L). mL).
  • test compound solution thus prepared was intratracheally administered 25 ⁇ L (about 0.01 mg / Kg) in the same manner as LPS administration 10 minutes after administration of roflumilast.
  • the control group received vehicle.
  • 5 rats were used for the test compound administration group and the control group, respectively.
  • bronchoalveolar lavage was performed as follows, and leukocytes in the lung were collected.
  • SD rats were anesthetized by intraperitoneal administration of somnopentyl (1 mL / kg) and then exsanguinated by inferior vena cava incision.
  • an oral sonde for mice (Fujigami Instrument Co., Ltd.) connected to a disposable syringe (5 mL, manufactured by Terumo Corporation)
  • the trachea was ligated and fixed.
  • BALF bronchoalveolar lavage fluid
  • Method 1 The white blood cell count of the BALF cell suspension was measured using a multi-item automatic blood cell counter (KX-21, manufactured by Sysmex Corporation). Next, the white blood cell count was diluted to 10 6 cells / mL, and 100 ⁇ L of this cell suspension was applied to a slide glass to prepare a single-layer smear. Next, after cell staining using a Diff-Quik staining kit (Catalog No. 16920, manufactured by Sysmex), the number of neutrophils in 300 leukocytes was measured under an optical microscope (BH-2, manufactured by Olympus), and leukocytes were measured.
  • KX-21 manufactured by Sysmex Corporation
  • the compound represented by the general formula (I) is used in combination with roflumilast, so that the pharmacological effect of the compound represented by the general formula (I) is added to the pharmacological effect of roflumilast.
  • Infiltration suppression effect was shown.
  • the inhibition rate of lung neutrophil infiltration with the compound of Example 4 and roflumilast alone was 51% and 10%, respectively, but when the compound of Example 4 and roflumilast were used in combination, 64% The inhibition rate of neutrophil infiltration was shown.
  • the pharmacological effect of the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof is added to the pharmacological effect of another pharmaceutical, and the dosage of the other pharmaceutical is reduced.
  • the pharmaceutical composition is a respiratory disease, preferably asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis or pulmonary hypertension, more preferably asthma .
  • a pharmaceutical composition for the treatment and / or prevention of chronic obstructive pulmonary disease or pulmonary fibrosis is useful as a pharmaceutical for warm-blooded animals (particularly for humans).

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Abstract

A pharmaceutical composition is provided which contains a specific substituted biaryl compound or a pharmaceutically acceptable salt thereof and which is characterized by being administered in combination with another pharmaceutical. This pharmaceutical composition is useful as a therapeutic drug and/or a prophylactic drug for respiratory disease such as asthma, chronic obstructive pulmonary disease, bronchitis, pulmonary emphysema, pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis and pulmonary hypertension.

Description

置換ビアリール化合物及び他の医薬の組み合わせSubstituted biaryl compounds and other pharmaceutical combinations
　本発明は、特定の置換ビアリール化合物又はその薬理上許容される塩を含む医薬組成物であって、他の医薬と組み合わせて投与されることを特徴とする医薬組成物、並びに、治療有効量の特定の置換ビアリール化合物又はその薬理上許容される塩及び治療有効量の他の医薬を、組み合わせて温血動物に投与することを特徴とする呼吸器疾患の治療方法に関する。 The present invention relates to a pharmaceutical composition comprising a specific substituted biaryl compound or a pharmacologically acceptable salt thereof, wherein the pharmaceutical composition is administered in combination with another pharmaceutical agent, and a therapeutically effective amount of the pharmaceutical composition. The present invention relates to a method for treating a respiratory disease, which comprises administering a specific substituted biaryl compound or a pharmacologically acceptable salt thereof and a therapeutically effective amount of another pharmaceutical agent to a warm-blooded animal in combination.
　呼吸器疾患は種類が多く、例えば、喘息、慢性閉塞性肺疾患、気管支炎、肺気腫、肺線維症、急性呼吸窮迫症候群、嚢胞性線維症、肺性高血圧症等があり、治療法が確立されている疾患もあれば、慢性化して有効な治療方法がない疾患もある。なかでも、気道閉塞性疾患である慢性閉塞性肺疾患は、慢性気管支炎及び不可逆的で持続的な気道閉塞を特徴とし、喫煙等が原因となって気管支の炎症や肺胞の破壊に至る難治性疾患である。慢性閉塞性肺疾患の治療薬としては、安全で確立された治療薬は未だ見出されていない。例えば、ホスホジエステラーゼ４（以下、ＰＤＥ４と略す）阻害薬であるロフルミラストは、炎症系細胞の機能抑制及び気管支平滑筋弛緩等の優れた薬効により慢性閉塞性肺疾患の治療薬として臨床応用されているものの、副作用としての嘔吐や吐き気のために臨床的有用性が制限されている。また、びまん性肺疾患である間質性肺炎・肺線維症も日本では特定疾患に指定されており、発症後の予後も悪く、副作用が強いステロイド剤やピルフェニドン等の投与による対症療法がなされている。一方、アレルギー性肺疾患である喘息は、慢性の気道炎症を呈する疾患であるが、現在では発作のコントロールが可能な複数の有効な治療薬もあり、治療方法がほぼ確立されている。しかしながら、吸入ステロイド剤の投与でも難治化していく重度の喘息もある。 There are many types of respiratory diseases such as asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis, pulmonary hypertension, etc. Some diseases are chronic, and others are chronic and have no effective treatment. Among them, chronic obstructive pulmonary disease, which is an airway obstructive disease, is characterized by chronic bronchitis and irreversible and persistent airway obstruction, resulting in inflamed bronchial inflammation and alveolar destruction caused by smoking. It is a sex disorder. As a therapeutic agent for chronic obstructive pulmonary disease, a safe and established therapeutic agent has not yet been found. For example, roflumilast, which is a phosphodiesterase 4 (hereinafter abbreviated as PDE4) inhibitor, has been clinically applied as a therapeutic agent for chronic obstructive pulmonary disease due to excellent medicinal effects such as suppression of inflammatory cell function and bronchial smooth muscle relaxation. Clinical utility is limited due to vomiting and nausea as side effects. In addition, interstitial pneumonia and pulmonary fibrosis, which are diffuse lung diseases, are also designated as specific diseases in Japan, and the prognosis after onset is poor, and symptomatic treatment with administration of steroids or pirfenidone with strong side effects has been made Yes. On the other hand, asthma, which is an allergic lung disease, is a disease that exhibits chronic airway inflammation. Currently, there are a plurality of effective therapeutic agents that can control seizures, and treatment methods are almost established. However, there are also severe asthma that becomes intractable even by administration of inhaled steroids.
　プロスタグランジンＥ２（以下、ＰＧＥ２と略す）は、アラキドン酸カスケードの中の代謝産物として幅広い生理活性を有し、ＥＰ１、ＥＰ２、ＥＰ３及びＥＰ４の４つの受容体に対してアゴニストとして作用する。ＰＧＥ２は、多くの炎症反応に関与しており、血管透過性亢進作用、各種の炎症性メディエータ―の放出、炎症性細胞・免疫細胞の誘導、血管新生作用等の起炎的作用を有する一方で、ＥＰ２及び／又はＥＰ４受容体を介して抗炎症作用を示すことが報告されている（非特許文献１を参照）。 Prostaglandin E 2 (hereinafter abbreviated as PGE 2 ) has a wide range of physiological activities as a metabolite in the arachidonic acid cascade, and acts as an agonist for the four receptors EP1, EP2, EP3 and EP4. . PGE 2 is involved in many inflammatory reactions and has inflammatory effects such as vascular permeability enhancing action, release of various inflammatory mediators, induction of inflammatory cells and immune cells, angiogenic action, etc. Have been reported to exhibit an anti-inflammatory action via EP2 and / or EP4 receptors (see Non-Patent Document 1).
　これまで、ＥＰ２アゴニスト作用を有する非プラスタノイド系のスルホンアミド化合物が知られており（特許文献１乃至８を参照）、前記特許文献１乃至８に記載の化合物の医薬用途として列挙された種々の疾患には、慢性閉塞性肺疾患、肺線維症及び喘息を含む呼吸器疾患が含まれている。更に、ＥＰ２アゴニスト作用を有する特定の化合物と他の医薬（例えば、コルチコステロイド、抗コリン薬、β２－受容体作動薬、ＰＤＥ４阻害薬等）との組み合わせが開示されている（例えば、特許文献９）。 So far, non-plastanoid sulfonamide compounds having EP2 agonistic activity have been known (see Patent Documents 1 to 8), and various compounds listed as pharmaceutical uses of the compounds described in Patent Documents 1 to 8 have been known. Diseases include respiratory disease including chronic obstructive pulmonary disease, pulmonary fibrosis and asthma. Furthermore, a combination of a specific compound having an EP2 agonistic action and another pharmaceutical (eg, corticosteroid, anticholinergic agent, β2-receptor agonist, PDE4 inhibitor, etc.) is disclosed (eg, patent document) 9).
国際公開第２００９／１１３６００号パンフレットInternational Publication No. 2009/113600 Pamphlet 国際公開第２０１１／０３０８６４号パンフレットInternational Publication No. 2011/030864 Pamphlet 国際公開第２０１１／０３０８６５号パンフレットInternational Publication No. 2011/030865 Pamphlet 国際公開第２０１１／０３０８６８号パンフレットInternational Publication No. 2011/030868 Pamphlet 国際公開第２０１１／０３０８７１号パンフレットInternational Publication No. 2011/030871 Pamphlet 国際公開第２０１１／０３０８７２号パンフレットInternational Publication No. 2011/030872 Pamphlet 国際公開第２０１１／０３０８７３号パンフレットInternational Publication No. 2011/030873 Pamphlet 国際公開第２０１１／０７８３０３号パンフレットInternational Publication No. 2011/0708303 Pamphlet 国際公開第２０１３／１６４３２６号パンフレットInternational Publication No. 2013/164326 Pamphlet
　しかしながら、上記何れの先行技術文献にも、特定の部位に特定の置換基が置換されたビアリール基を部分構造として有するスルホンアミド化合物が強力なＥＰ２アゴニスト作用及び抗炎症作用を有し、かつ他の医薬との組み合わせによる、喘息、慢性閉塞性肺疾患、気管支炎、肺気腫、肺線維症、急性呼吸窮迫症候群、嚢胞性線維症及び肺性高血圧症等の呼吸器疾患の予防及び／又は治療に有用であることは記載も示唆もされていない。
　本発明者等は、特定の置換ビアリール化合物又はその薬理上許容される塩を含む医薬組成物であって、他の医薬と組み合わせて投与されることを特徴とする医薬組成物が、抗炎症作用、抗線維作用及び気管支拡張作用により、喘息、慢性閉塞性肺疾患、気管支炎、肺気腫、肺線維症、急性呼吸窮迫症候群、嚢胞性線維症及び肺性高血圧症等の呼吸器疾患の治療及び／又は予防において優れた効果を有することを見出し、本発明を完成した。 However, in any of the above prior art documents, a sulfonamide compound having a biaryl group substituted with a specific substituent at a specific site as a partial structure has a strong EP2 agonistic action and anti-inflammatory action, and other Useful for prevention and / or treatment of respiratory diseases such as asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis and pulmonary hypertension in combination with medicine It is neither described nor suggested.
The present inventors have provided a pharmaceutical composition comprising a specific substituted biaryl compound or a pharmacologically acceptable salt thereof, wherein the pharmaceutical composition is administered in combination with other pharmaceuticals, and has an anti-inflammatory effect. Treatment of respiratory diseases such as asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis and pulmonary hypertension and / Or it discovered that it had the outstanding effect in prevention, and completed this invention.
　本発明は、下記一般式（Ｉ）で表される化合物又はその薬理上許容される塩を含む医薬組成物であって、他の医薬と組み合わせて投与されることを特徴とする医薬組成物、並びに、治療有効量の下記一般式（Ｉ）で表される化合物又はその薬理上許容される塩及び治療有効量の他の医薬を、組み合わせて温血動物に投与することを特徴とする呼吸器疾患の治療方法を提供する。
本発明は、一つの側面からは以下を提供する。 The present invention is a pharmaceutical composition comprising a compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof, wherein the pharmaceutical composition is administered in combination with other pharmaceuticals, And a therapeutically effective amount of a compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof and a therapeutically effective amount of another pharmaceutical agent in combination with a warm-blooded animal: A method of treating a disease is provided.
The present invention provides the following from one aspect.
（１）一般式（Ｉ）：
Figure JPOXMLDOC01-appb-C000002
 (1) General formula (I):
Figure JPOXMLDOC01-appb-C000002
（式中、
Ｒ１は、保護されていてもよいカルボキシ基を示し、
Ｗは、窒素原子又は基－ＣＨ＝を示し、
Ｒ２は、エトキシ基、１－プロペニル基又は１－プロピニル基を示し、
Ｚは、フェニル基、３－フルオロフェニル基、ピリジン－２－イル基、ピリジン－３－イル基、チオフェン－２－イル基又はチオフェン－３－イル基を示す）
で表される化合物又はその薬理上許容される塩を含む医薬組成物であって、
ＰＤＥ４阻害薬、ＰＤＥ５阻害薬、コルチコステロイド、抗コリン薬、β２－受容体作動薬、Ｈ１－ヒスタミン受容体拮抗薬、ロイコトリエン受容体拮抗薬、エンドセリン受容体拮抗薬、ＰＧＩ２受容体作動薬、テオフィリン、及び、ピルフェニドンからなる群から選択される一つ以上の医薬
と組み合わせて投与されることを特徴とする、医薬組成物。 (Where
R 1 represents an optionally protected carboxy group,
W represents a nitrogen atom or a group —CH═;
R 2 represents an ethoxy group, a 1-propenyl group or a 1-propynyl group,
Z represents a phenyl group, a 3-fluorophenyl group, a pyridin-2-yl group, a pyridin-3-yl group, a thiophen-2-yl group, or a thiophen-3-yl group)
A pharmaceutical composition comprising a compound represented by: or a pharmacologically acceptable salt thereof,
PDE4 inhibitor, PDE5 inhibitor, corticosteroid, anticholinergic agent, β2-receptor agonist, H1-histamine receptor antagonist, leukotriene receptor antagonist, endothelin receptor antagonist, PGI2 receptor agonist, theophylline And a pharmaceutical composition administered in combination with one or more pharmaceuticals selected from the group consisting of pirfenidone.
（２）一般式（Ｉ）で表される化合物又はその塩を含む医薬組成物と、他の医薬が、それぞれ別異の製剤として、同時に又は異なる時間に投与されることを特徴とする、（１）に記載の医薬組成物。 (2) A pharmaceutical composition comprising a compound represented by the general formula (I) or a salt thereof and another pharmaceutical agent are administered as different formulations at the same time or at different times, The pharmaceutical composition according to 1).
（３）一般式（Ｉ）で表される化合物又はその塩を含む医薬組成物と、他の医薬が、単一の製剤として投与されることを特徴とする、（１）に記載の医薬組成物。 (3) The pharmaceutical composition according to (1), wherein the pharmaceutical composition comprising the compound represented by the general formula (I) or a salt thereof and another pharmaceutical agent are administered as a single preparation. object.
（４）Ｒ１が、カルボキシ基又はＣ１－Ｃ６アルコキシカルボニル基を示す、（１）乃至（３）のいずれかに記載の医薬組成物。 (4) The pharmaceutical composition according to any one of (1) to (3), wherein R 1 represents a carboxy group or a C 1 -C 6 alkoxycarbonyl group.
（５）Ｒ１が、カルボキシ基、エトキシカルボニル基、イソプロポキシカルボニル基又はヘキシルオキシカルボニル基を示す、（１）乃至（３）のいずれかに記載の医薬組成物。 (5) The pharmaceutical composition according to any one of (1) to (3), wherein R 1 represents a carboxy group, an ethoxycarbonyl group, an isopropoxycarbonyl group, or a hexyloxycarbonyl group.
（６）Ｒ１が、カルボキシ基、エトキシカルボニル基、イソプロポキシカルボニル基又はヘキシルオキシカルボニル基を示し、
Ｗが、窒素原子又は基－ＣＨ＝を示し、
Ｒ２が、１－プロペニル基又は１－プロピニル基を示し、
Ｚが、フェニル基、３－フルオロフェニル基、ピリジン－２－イル基、ピリジン－３－イル基、チオフェン－２－イル基又はチオフェン－３－イル基を示す、（１）乃至（３）のいずれかに記載の医薬組成物。 (6) R 1 represents a carboxy group, an ethoxycarbonyl group, an isopropoxycarbonyl group or a hexyloxycarbonyl group,
W represents a nitrogen atom or a group —CH═;
R 2 represents a 1-propenyl group or a 1-propynyl group,
(1) to (3), wherein Z represents a phenyl group, a 3-fluorophenyl group, a pyridin-2-yl group, a pyridin-3-yl group, a thiophen-2-yl group, or a thiophen-3-yl group Pharmaceutical composition in any one.
（７）一般式（Ｉ）で表される化合物が、
（６－｛［３’－（１－プロペニル）ビフェニル－４－イルメチル］（ピリジン－２－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸エチル、
（６－｛［３’－（１－プロペニル）ビフェニル－４－イルメチル］（ピリジン－２－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸、
（６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（ピリジン－２－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸エチル、
（６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（ピリジン－２－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸、
（６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（ピリジン－３－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸エチル、
（６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（ピリジン－３－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸、
｛６－［（３’－エトキシビフェニル－４－イルメチル）（ピリジン－２－イルスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸、
｛６－［（３’－エトキシビフェニル－４－イルメチル）（ピリジン－２－イルスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸ヘキシル、
｛６－［（３’－エトキシビフェニル－４－イルメチル）（ピリジン－３－イルスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸、
｛６－［（ベンゼンスルホニル）（３’－エトキシビフェニル－４－イルメチル）アミノメチル］ピリジン－２－イルアミノ｝酢酸、
｛６－［（３’－エトキシビフェニル－４－イルメチル）（チオフェン－２－イルスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸、
（６－｛［４－（６－エトキシピリジン－２－イル）ベンジル］（ピリジン－２－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸、
（６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（チオフェン－２－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸エチル、
（６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（チオフェン－２－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸、
（６－｛（ベンゼンスルホニル）［３’－（１－プロピニル）ビフェニル－４－イルメチル］アミノメチル｝ピリジン－２－イルアミノ）酢酸エチル、
（６－｛（ベンゼンスルホニル）［３’－（１－プロピニル）ビフェニル－４－イルメチル］アミノメチル｝ピリジン－２－イルアミノ）酢酸、
（６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（チオフェン－３－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸エチル、
（６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（チオフェン－３－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸、
（６－｛（３－フルオロベンゼンスルホニル）［３’－（１－プロピニル）ビフェニル－４－イルメチル］アミノメチル｝ピリジン－２－イルアミノ）酢酸、又は
（６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（ピリジン－２－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸イソプロピル
である（１）乃至（３）のいずれかに記載の医薬組成物。 (7) The compound represented by the general formula (I) is
(6-{[3 ′-(1-propenyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate,
(6-{[3 ′-(1-propenyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
{6-[(3′-ethoxybiphenyl-4-ylmethyl) (pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid,
{6-[(3′-ethoxybiphenyl-4-ylmethyl) (pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetyl hexyl,
{6-[(3′-ethoxybiphenyl-4-ylmethyl) (pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid,
{6-[(benzenesulfonyl) (3′-ethoxybiphenyl-4-ylmethyl) aminomethyl] pyridin-2-ylamino} acetic acid,
{6-[(3′-ethoxybiphenyl-4-ylmethyl) (thiophen-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid,
(6-{[4- (6-Ethoxypyridin-2-yl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
(6-{(benzenesulfonyl) [3 ′-(1-propynyl) biphenyl-4-ylmethyl] aminomethyl} pyridin-2-ylamino) ethyl acetate,
(6-{(benzenesulfonyl) [3 ′-(1-propynyl) biphenyl-4-ylmethyl] aminomethyl} pyridin-2-ylamino) acetic acid,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
(6-{(3-Fluorobenzenesulfonyl) [3 ′-(1-propynyl) biphenyl-4-ylmethyl] aminomethyl} pyridin-2-ylamino) acetic acid or (6-{[3 ′-(1-propynyl) The pharmaceutical composition according to any one of (1) to (3), which is) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) isopropyl acetate.
（８）他の医薬が、ＰＤＥ４阻害薬、コルチコステロイド、抗コリン薬、β２－受容体作動薬及びピルフェニドンからなる群から選択される一つ以上の医薬である、（１）乃至（７）のいずれかに記載の医薬組成物。 (8) The other drug is one or more drugs selected from the group consisting of a PDE4 inhibitor, a corticosteroid, an anticholinergic drug, a β2-receptor agonist, and pirfenidone, (1) to (7) A pharmaceutical composition according to any one of the above.
（９）他の医薬が、ＰＤＥ４阻害薬、コルチコステロイド又はピルフェニドンである、（１）乃至（７）のいずれかに記載の医薬組成物。 (9) The pharmaceutical composition according to any one of (1) to (7), wherein the other medicament is a PDE4 inhibitor, a corticosteroid, or pirfenidone.
（１０）他の医薬が、ロフルミラスト、フルチカゾン又はピルフェニドンである、（１）乃至（７）のいずれかに記載の医薬組成物。 (10) The pharmaceutical composition according to any one of (1) to (7), wherein the other medicament is roflumilast, fluticasone, or pirfenidone.
（１１）喘息、慢性閉塞性肺疾患、気管支炎、肺気腫、肺線維症、急性呼吸窮迫症候群、嚢胞性線維症又は肺性高血圧症の治療もしくは予防のための、（１）乃至（１０）のいずれかに記載の医薬組成物。 (11) (1) to (10) for treating or preventing asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis or pulmonary hypertension A pharmaceutical composition according to any one of the above.
（１２）喘息、慢性閉塞性肺疾患又は肺線維症の治療もしくは予防のための、（１）乃至（１０）のいずれかに記載の医薬組成物。 (12) The pharmaceutical composition according to any one of (1) to (10), for treating or preventing asthma, chronic obstructive pulmonary disease or pulmonary fibrosis.
（１３）（ｉ）治療有効量の一般式（Ｉ）：
Figure JPOXMLDOC01-appb-C000003
 (13) (i) Therapeutically effective amount of general formula (I):
Figure JPOXMLDOC01-appb-C000003
（式中、
Ｒ１は、保護されていてもよいカルボキシ基を示し、
Ｗは、窒素原子又は基－ＣＨ＝を示し、
Ｒ２は、エトキシ基、１－プロペニル基又は１－プロピニル基を示し、
Ｚは、フェニル基、３－フルオロフェニル基、ピリジン－２－イル基、ピリジン－３－イル基、チオフェン－２－イル基又はチオフェン－３－イル基を示す）
で表される化合物又はその薬理上許容される塩、及び、
（ｉｉ）治療有効量の他の医薬（当該他の医薬は、ＰＤＥ４阻害薬、ＰＤＥ５阻害薬、コルチコステロイド、抗コリン薬、β２－受容体作動薬、Ｈ１－ヒスタミン受容体拮抗薬、ロイコトリエン受容体拮抗薬、エンドセリン受容体拮抗薬、ＰＧＩ２受容体作動薬、テオフィリン、及び、ピルフェニドンからなる群から選択される一つ以上の医薬である。）
を組み合わせて温血動物に投与することを特徴とする、疾患の治療方法。 (Where
R 1 represents an optionally protected carboxy group,
W represents a nitrogen atom or a group —CH═;
R 2 represents an ethoxy group, a 1-propenyl group or a 1-propynyl group,
Z represents a phenyl group, a 3-fluorophenyl group, a pyridin-2-yl group, a pyridin-3-yl group, a thiophen-2-yl group, or a thiophen-3-yl group)
Or a pharmacologically acceptable salt thereof, and
(Ii) Other medicaments with therapeutically effective amounts (the other medicaments are PDE4 inhibitor, PDE5 inhibitor, corticosteroid, anticholinergic agent, β2-receptor agonist, H1-histamine receptor antagonist, leukotriene receptor) One or more drugs selected from the group consisting of a body antagonist, an endothelin receptor antagonist, a PGI2 receptor agonist, theophylline, and pirfenidone.)
A method for treating a disease, which comprises administering to a warm-blooded animal in combination.
（１４）一般式（Ｉ）で表される化合物又はその塩及び他の医薬が、それぞれ別異の製剤として、同時に又は異なる時間に投与されることを特徴とする、（１３）に記載の方法。 (14) The method according to (13), wherein the compound represented by the general formula (I) or a salt thereof and another pharmaceutical agent are administered as different formulations at the same time or at different times. .
（１５）一般式（Ｉ）で表される化合物又はその塩及び他の医薬の双方が、単一の製剤として投与されることを特徴とする、（１３）に記載の方法。 (15) The method according to (13), wherein both the compound represented by the general formula (I) or a salt thereof and another pharmaceutical agent are administered as a single preparation.
（１６）Ｒ１が、カルボキシ基又はＣ１－Ｃ６アルコキシカルボニル基を示す、（１３）乃至（１５）のいずれかに記載の方法。 (16) The method according to any one of (13) to (15), wherein R 1 represents a carboxy group or a C 1 -C 6 alkoxycarbonyl group.
（１７）Ｒ１が、カルボキシ基、エトキシカルボニル基、イソプロポキシカルボニル基又はヘキシルオキシカルボニル基を示す、（１３）乃至（１５）のいずれかに記載の方法。 (17) The method according to any one of (13) to (15), wherein R 1 represents a carboxy group, an ethoxycarbonyl group, an isopropoxycarbonyl group, or a hexyloxycarbonyl group.
（１８）Ｒ１が、カルボキシ基、エトキシカルボニル基、イソプロポキシカルボニル基又はヘキシルオキシカルボニル基を示し、
Ｗが、窒素原子又は基－ＣＨ＝を示し、
Ｒ２が、１－プロペニル基又は１－プロピニル基を示し、
Ｚが、フェニル基、３－フルオロフェニル基、ピリジン－２－イル基、ピリジン－３－イル基、チオフェン－２－イル基又はチオフェン－３－イル基を示す、（１３）乃至（１５）のいずれかに記載の方法。 (18) R 1 represents a carboxy group, an ethoxycarbonyl group, an isopropoxycarbonyl group or a hexyloxycarbonyl group,
W represents a nitrogen atom or a group —CH═;
R 2 represents a 1-propenyl group or a 1-propynyl group,
(13) to (15), wherein Z represents a phenyl group, a 3-fluorophenyl group, a pyridin-2-yl group, a pyridin-3-yl group, a thiophen-2-yl group, or a thiophen-3-yl group. The method according to any one.
（１９）一般式（Ｉ）で表される化合物が、
（６－｛［３’－（１－プロペニル）ビフェニル－４－イルメチル］（ピリジン－２－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸エチル、
（６－｛［３’－（１－プロペニル）ビフェニル－４－イルメチル］（ピリジン－２－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸、
（６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（ピリジン－２－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸エチル、
（６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（ピリジン－２－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸、
（６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（ピリジン－３－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸エチル、
（６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（ピリジン－３－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸、
｛６－［（３’－エトキシビフェニル－４－イルメチル）（ピリジン－２－イルスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸、
｛６－［（３’－エトキシビフェニル－４－イルメチル）（ピリジン－２－イルスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸ヘキシル、
｛６－［（３’－エトキシビフェニル－４－イルメチル）（ピリジン－３－イルスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸、
｛６－［（ベンゼンスルホニル）（３’－エトキシビフェニル－４－イルメチル）アミノメチル］ピリジン－２－イルアミノ｝酢酸、
｛６－［（３’－エトキシビフェニル－４－イルメチル）（チオフェン－２－イルスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸、
（６－｛［４－（６－エトキシピリジン－２－イル）ベンジル］（ピリジン－２－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸、
（６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（チオフェン－２－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸エチル、
（６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（チオフェン－２－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸、
（６－｛（ベンゼンスルホニル）［３’－（１－プロピニル）ビフェニル－４－イルメチル］アミノメチル｝ピリジン－２－イルアミノ）酢酸エチル、
（６－｛（ベンゼンスルホニル）［３’－（１－プロピニル）ビフェニル－４－イルメチル］アミノメチル｝ピリジン－２－イルアミノ）酢酸、
（６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（チオフェン－３－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸エチル、
（６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（チオフェン－３－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸、
（６－｛（３－フルオロベンゼンスルホニル）［３’－（１－プロピニル）ビフェニル－４－イルメチル］アミノメチル｝ピリジン－２－イルアミノ）酢酸、又は
（６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（ピリジン－２－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸イソプロピル
である（１３）乃至（１５）のいずれかに記載の方法。 (19) The compound represented by the general formula (I) is
(6-{[3 ′-(1-propenyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate,
(6-{[3 ′-(1-propenyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
{6-[(3′-ethoxybiphenyl-4-ylmethyl) (pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid,
{6-[(3′-ethoxybiphenyl-4-ylmethyl) (pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetyl hexyl,
{6-[(3′-ethoxybiphenyl-4-ylmethyl) (pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid,
{6-[(benzenesulfonyl) (3′-ethoxybiphenyl-4-ylmethyl) aminomethyl] pyridin-2-ylamino} acetic acid,
{6-[(3′-ethoxybiphenyl-4-ylmethyl) (thiophen-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid,
(6-{[4- (6-Ethoxypyridin-2-yl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
(6-{(benzenesulfonyl) [3 ′-(1-propynyl) biphenyl-4-ylmethyl] aminomethyl} pyridin-2-ylamino) ethyl acetate,
(6-{(benzenesulfonyl) [3 ′-(1-propynyl) biphenyl-4-ylmethyl] aminomethyl} pyridin-2-ylamino) acetic acid,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
(6-{(3-Fluorobenzenesulfonyl) [3 ′-(1-propynyl) biphenyl-4-ylmethyl] aminomethyl} pyridin-2-ylamino) acetic acid or (6-{[3 ′-(1-propynyl) ) Biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) isopropyl acetate (13) to (15).
（２０）他の医薬が、ＰＤＥ４阻害薬、コルチコステロイド、抗コリン薬、β２－受容体作動薬及びピルフェニドンからなる群から選択される一つ以上の医薬である、（１３）乃至（１９）のいずれかに記載の方法。 (20) The other medicament is one or more medicaments selected from the group consisting of a PDE4 inhibitor, a corticosteroid, an anticholinergic agent, a β2-receptor agonist, and pirfenidone, (13) to (19) The method in any one of.
（２１）他の医薬が、ＰＤＥ４阻害薬、コルチコステロイド又はピルフェニドンである、（１３）乃至（１９）のいずれかに記載の方法。 (21) The method according to any one of (13) to (19), wherein the other medicament is a PDE4 inhibitor, a corticosteroid, or pirfenidone.
（２２）他の医薬が、ロフルミラスト、フルチカゾン又はピルフェニドンである、（１３）乃至（１９）のいずれかに記載の方法。 (22) The method according to any one of (13) to (19), wherein the other medicament is roflumilast, fluticasone, or pirfenidone.
（２３）疾患が、喘息、慢性閉塞性肺疾患、気管支炎、肺気腫、肺線維症、急性呼吸窮迫症候群、嚢胞性線維症又は肺性高血圧症である、（１３）乃至（２２）のいずれかに記載された方法。 (23) Any of (13) to (22), wherein the disease is asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis or pulmonary hypertension The method described in.
（２３）疾患が、喘息、慢性閉塞性肺疾患又は肺線維症である、（１３）乃至（２２）のいずれかに記載された方法。 (23) The method according to any one of (13) to (22), wherein the disease is asthma, chronic obstructive pulmonary disease or pulmonary fibrosis.
（２５）温血動物が、ヒトである（１３）乃至（２４）のいずれかに記載の方法。 (25) The method according to any one of (13) to (24), wherein the warm-blooded animal is a human.
　本発明の医薬組成物は、他の医薬の薬理効果に、一般式（Ｉ）で表される化合物又はその薬理上許容される塩の薬理効果が上乗せされ、他の医薬の用量を低減化することで他の医薬の副作用を軽減できる点で有用である。上記医薬組成物は、呼吸器疾患、好ましくは、喘息、慢性閉塞性肺疾患、気管支炎、肺気腫、肺線維症、急性呼吸窮迫症候群、嚢胞性線維症又は肺性高血圧症、より好ましくは、喘息、慢性閉塞性肺疾患又は肺線維症の治療及び／又は予防のための医薬組成物であり、温血動物用（特に、ヒト用）の医薬として有用である。
　本発明の治療方法は、上記疾患の治療方法として有用であり、また、温血動物用（特に、ヒト用）の治療方法として有用である。 In the pharmaceutical composition of the present invention, the pharmacological effect of the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof is added to the pharmacological effect of another pharmaceutical, and the dosage of the other pharmaceutical is reduced. This is useful in that the side effects of other drugs can be reduced. The pharmaceutical composition is a respiratory disease, preferably asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis or pulmonary hypertension, more preferably asthma , A pharmaceutical composition for the treatment and / or prevention of chronic obstructive pulmonary disease or pulmonary fibrosis, and is useful as a pharmaceutical for warm-blooded animals (particularly for humans).
The treatment method of the present invention is useful as a treatment method for the above-mentioned diseases, and is also useful as a treatment method for warm-blooded animals (particularly for humans).
　前記一般式（Ｉ）で表される化合物において、各置換基の好ましい形態を以下に示す。 In the compound represented by the general formula (I), preferred forms of each substituent are shown below.
　一般式（Ｉ）のＲ１が示す保護されていてもよいカルボキシ基は、カルボキシ基又は保護基により保護されたカルボキシ基を意味し、そのような保護基としては、エステル型の保護基を挙げることができる。エステル型保護基の部分構造の例としては、メチル基、エチル基、プロピル基、イソプロピル基、１－エチルプロピル基、ブチル基、イソブチル基、ｓｅｃ－ブチル基、ｔｅｒｔ－ブチル基、３，３－ジメチルブチル基、ペンチル基、イソペンチル基、ネオペンチル基、ｔｅｒｔ－ペンチル基、１－メチルブチル基、ヘキシル基、１－メチルペンチル基、２－メチルペンチル基、３－メチルペンチル基、１－エチルブチル基、２－エチルブチル基、ヘプチル基、オクチル基、ノニル基、デシル基、ウンデシル基若しくはドデシル基のようなＣ１－Ｃ１２アルキル基；ベンジル基、フェネチル基、フェニルプロピル基、フェニルブチル基、フェニルペンチル基、フェニルヘキシル基、フェニルヘプチル基、フェニルオクチル基、フェニルノニル基、フェニルデシル基、フェニルウンデシル基若しくはフェニルドデシル基のようなＣ７－Ｃ１８アラルキル基；アセトキシメチル基、１－アセトキシエチル基、１－アセトキシプロピル基、１－アセトキシブチル基、プロパノイルオキシメチル基、１－プロパノイルオキシエチル基、ブタノイルオキシメチル基、１－ブタノイルオキシエチル基、ピバロイルオキシメチル基、１－ピバロイルオキシエチル基、１－ピバロイルオキシプロピル基若しくは１－ピバロイルオキシブチル基のようなＣ２－Ｃ５アルカノイルオキシ基で置換されたＣ１－Ｃ４アルキル基；メトキシカルボニルオキシメチル基、１－メトキシカルボニルオキシエチル基、エトキシカルボニルオキシメチル基、１－エトキシカルボニルオキシエチル基、プロポキシカルボニルオキシメチル基、１－プロポキシカルボニルオキシエチル基、イソプロポキシカルボニルオキシメチル基、１－イソプロポキシカルボニルオキシエチル基、ブトキシカルボニルオキシメチル基、１－ブトキシカルボニルオキシエチル基、ｔｅｒｔ－ブトキシカルボニルオキシメチル基若しくは１－ｔｅｒｔ－ブトキシカルボニルオキシエチル基のような（Ｃ１－Ｃ４アルコキシ）カルボニルオキシ基で置換されたＣ１－Ｃ４アルキル基；Ｎ，Ｎ－ジメチルアミノカルボニルメチル基若しくはＮ，Ｎ－ジエチルアミノカルボニルメチル基のようなＮ，Ｎ－ジアルキルアミノカルボニルアルキル基；２－（Ｎ，Ｎ－ジメチルアミノ）エチル基若しくは２－（Ｎ，Ｎ－ジエチルアミノ）エチル基のような２－（Ｎ，Ｎ－ジアルキルアミノ）エチル基；２－（モルホリン－４－イル）エチル基、２－ピペリジノエチル基若しくは２－（４－メチルピペリジノ）エチル基のようなＮ、Ｏ及びＳから選ばれる１若しくは２個のヘテロ原子を含む５員若しくは６員の複素飽和単環で置換されたＣ１－Ｃ４アルキル基；又は（５－メチル－２－オキソ－１，３－ジオキソレン－４－イル）メチル基若しくは（５－フェニル－２－オキソ－１，３－ジオキソレン－４－イル）メチル基等の生体内で容易に脱保護されてカルボキシ基に変換しうる基が挙げられ、好ましくは、Ｃ１－Ｃ１２アルキル基、Ｃ７－Ｃ１８アラルキル基、Ｃ２－Ｃ５アルカノイルオキシ基で置換されたＣ１－Ｃ２アルキル基、（Ｃ１－Ｃ４アルコキシ）カルボニルオキシ基で置換されたＣ１－Ｃ２アルキル基、Ｎ，Ｎ－ジメチルアミノカルボニルメチル基、２－（モルホリン－４－イル）エチル基、（５－メチル－２－オキソ－１，３－ジオキソレン－４－イル）メチル基又は（５－フェニル－２－オキソ－１，３－ジオキソレン－４－イル）メチル基であり、更に好ましくは、Ｃ１－Ｃ６アルキル基であり、特に好ましくは、エチル基、イソプロピル基又はヘキシル基である。 The optionally protected carboxy group represented by R 1 in the general formula (I) means a carboxy group or a carboxy group protected by a protecting group, and examples of such protecting groups include ester-type protecting groups. be able to. Examples of the partial structure of the ester-type protecting group include methyl group, ethyl group, propyl group, isopropyl group, 1-ethylpropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, 3,3- Dimethylbutyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1-ethylbutyl, 2 A C 1 -C 12 alkyl group such as ethylbutyl, heptyl, octyl, nonyl, decyl, undecyl or dodecyl; benzyl, phenethyl, phenylpropyl, phenylbutyl, phenylpentyl, Phenylhexyl group, phenylheptyl group, phenyloctyl group, phenylnonyl Group, a phenyl decyl group, C 7 -C 18 aralkyl groups such as undecyl group or phenyl dodecyl group; acetoxymethyl group, 1-acetoxyethyl group, 1-acetoxy propyl, 1-acetoxy-butyl group, propanoyloxy Methyl group, 1-propanoyloxyethyl group, butanoyloxymethyl group, 1-butanoyloxyethyl group, pivaloyloxymethyl group, 1-pivaloyloxyethyl group, 1-pivaloyloxypropyl group or A C 1 -C 4 alkyl group substituted by a C 2 -C 5 alkanoyloxy group such as a 1-pivaloyloxybutyl group; a methoxycarbonyloxymethyl group, a 1-methoxycarbonyloxyethyl group, an ethoxycarbonyloxymethyl group 1-ethoxycarbonyloxyethyl group, propoxy Carbonyloxymethyl group, 1-propoxycarbonyloxyethyl group, isopropoxycarbonyloxymethyl group, 1-isopropoxycarbonyloxyethyl group, butoxycarbonyloxymethyl group, 1-butoxycarbonyloxyethyl group, tert-butoxycarbonyloxymethyl group Or a C 1 -C 4 alkyl group substituted with a (C 1 -C 4 alkoxy) carbonyloxy group, such as a 1-tert-butoxycarbonyloxyethyl group; an N, N-dimethylaminocarbonylmethyl group or N, N— N, N-dialkylaminocarbonylalkyl group such as diethylaminocarbonylmethyl group; 2- (N, N, such as 2- (N, N-dimethylamino) ethyl group or 2- (N, N-diethylamino) ethyl group -Dialkyla 1 or 2 heteroatoms selected from N, O and S such as 2- (morpholin-4-yl) ethyl group, 2-piperidinoethyl group or 2- (4-methylpiperidino) ethyl group; A C 1 -C 4 alkyl group substituted with a 5- or 6-membered heterosaturated monocycle containing; or (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl group or (5-phenyl) And a group that can be easily deprotected and converted into a carboxy group in vivo, such as a 2-oxo-1,3-dioxolen-4-yl) methyl group, preferably a C 1 -C 12 alkyl group, C 7 -C 18 aralkyl group, C 2 -C 5 alkanoyloxy C 1 -C 2 alkyl group substituted by a group, (C 1 -C 4 alkoxy) C 1 -C 2 substituted with a carbonyl group Alkyl group, N, N-dimethylaminocarbonylmethyl group, 2- (morpholin-4-yl) ethyl group, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl group or (5- A phenyl-2-oxo-1,3-dioxolen-4-yl) methyl group, more preferably a C 1 -C 6 alkyl group, and particularly preferably an ethyl group, an isopropyl group or a hexyl group.
　したがって、一般式（Ｉ）において、Ｒ１は、好ましくは、カルボキシ基又はＣ１－Ｃ６アルコキシカルボニル基である。一般式（Ｉ）の特定の実施態様において、Ｒ１は、カルボキシ基、エトキシカルボニル基、イソプロポキシカルボニル基又はヘキシルオキシカルボニル基である。 Therefore, in the general formula (I), R 1 is preferably a carboxy group or a C 1 -C 6 alkoxycarbonyl group. In certain embodiments of general formula (I), R 1 is a carboxy group, an ethoxycarbonyl group, an isopropoxycarbonyl group or a hexyloxycarbonyl group.
　一般式（Ｉ）において、Ｗは、窒素原子又は基－ＣＨ＝である。すなわち、一般式（Ｉ）において、Ｗを含む芳香環は、ピリジン環又はベンゼン環である。一般式（Ｉ）の特定の実施態様において、Ｗは、基－ＣＨ＝である。一般式（Ｉ）の他の特定の実施態様において、Ｗは、窒素原子である。 In general formula (I), W is a nitrogen atom or a group —CH═. That is, in the general formula (I), the aromatic ring containing W is a pyridine ring or a benzene ring. In certain embodiments of general formula (I), W is a group —CH═. In another particular embodiment of general formula (I), W is a nitrogen atom.
　一般式（Ｉ）において、Ｒ２は、エトキシ基、１－プロペニル基又は１－プロピニル基である。一般式（Ｉ）の特定の実施態様において、Ｒ２は、エトキシ基である。一般式（Ｉ）の他の特定の実施態様において、Ｒ２は、１－プロペニル基又は１－プロピニル基である。 In the general formula (I), R 2 is an ethoxy group, 1-propenyl group or 1-propynyl group. In certain embodiments of general formula (I), R 2 is an ethoxy group. In another particular embodiment of general formula (I), R 2 is a 1-propenyl group or a 1-propynyl group.
　一般式（Ｉ）において、Ｚは、フェニル基、３－フルオロフェニル基、ピリジン－２－イル基、ピリジン－３－イル基、チオフェン－２－イル基又はチオフェン－３－イル基である。一般式（Ｉ）の特定の実施態様において、Ｚは、フェニル基、３－フルオロフェニル基、ピリジン－２－イル基又はピリジン－３－イル基であり、好ましくは、フェニル基又はピリジン－２－イル基又はピリジン－３－イル基である。一般式（Ｉ）の他の特定の実施態様において、Ｚは、チオフェン－２－イル基又はチオフェン－３－イル基であり、好ましくは、チオフェン－２－イル基である。 In the general formula (I), Z represents a phenyl group, a 3-fluorophenyl group, a pyridin-2-yl group, a pyridin-3-yl group, a thiophen-2-yl group, or a thiophen-3-yl group. In certain embodiments of general formula (I), Z is a phenyl group, a 3-fluorophenyl group, a pyridin-2-yl group or a pyridin-3-yl group, preferably a phenyl group or a pyridin-2-yl group. An yl group or a pyridin-3-yl group. In another particular embodiment of general formula (I), Z is a thiophen-2-yl group or a thiophen-3-yl group, preferably a thiophen-2-yl group.
　一般式（Ｉ）で表される化合物に幾何異性体又は回転異性体が存在する場合、それらの異性体も本発明の範囲に含まれ、また、プロトン互変異性が存在する場合には、それらの互変異性体も本発明に係る一般式（Ｉ）で表される化合物の範囲に含まれる。 When geometric isomers or rotational isomers exist in the compound represented by the general formula (I), these isomers are also included in the scope of the present invention, and when proton tautomerism exists, These tautomers are also included in the scope of the compounds represented by the general formula (I) according to the present invention.
　一般式（Ｉ）で表される化合物は、必要に応じて、常法に従って薬理上許容される塩に変換できるが、反応混合物から直接塩として分離することもできる。 The compound represented by the general formula (I) can be converted into a pharmacologically acceptable salt according to a conventional method, if necessary, but can also be separated directly from the reaction mixture as a salt.
　一般式（Ｉ）で表される化合物は、酸で処理することにより、薬理上許容される酸付加塩に変換される。そのような塩としては、例えば、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、硝酸塩、硫酸塩若しくはリン酸塩等の無機酸塩；又は酢酸塩、トリフルオロ酢酸塩、安息香酸塩、シュウ酸塩、マロン酸塩、コハク酸塩、マレイン酸塩、フマル酸塩、酒石酸塩、クエン酸塩、メタンスルホン酸塩、エタンスルホン酸塩、トリフルオロメタンスルホン酸塩、ベンゼンスルホン酸塩、ｐ－トルエンスルホン酸塩、グルタミン酸塩若しくはアスパラギン酸塩等の有機酸塩等が挙げられる。 The compound represented by the general formula (I) is converted into a pharmacologically acceptable acid addition salt by treating with an acid. Examples of such salts include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or phosphate; or acetate, trifluoroacetate, benzoate Oxalate, malonate, succinate, maleate, fumarate, tartrate, citrate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate, benzenesulfonate, p -Organic acid salts such as toluene sulfonate, glutamate or aspartate.
　一般式（Ｉ）で表される化合物は、Ｒ１がカルボキシ基である場合、塩基で処理することにより、薬理上許容される塩基性塩に変換される。そのような塩としては、例えば、ナトリウム塩、カリウム塩、カルシウム塩若しくはマグネシウム塩等の金属塩；アンモニウム塩等の無機塩；又はトリエチルアミン塩若しくはグアニジン塩等の有機アミン塩等が挙げられる。 When R 1 is a carboxy group, the compound represented by the general formula (I) is converted into a pharmacologically acceptable basic salt by treating with a base. Examples of such salts include metal salts such as sodium salt, potassium salt, calcium salt or magnesium salt; inorganic salts such as ammonium salt; or organic amine salts such as triethylamine salt or guanidine salt.
　一般式（Ｉ）で表される化合物が、Ｒ１が保護基により保護されたカルボキシ基である場合は、生体内に投与した場合（in vivo試験等）、生体内での生化学反応（例えばエステラーゼ等）によって容易に加水分解され、Ｒ１がカルボキシ基である薬理活性体に変換され得る。 Compound represented by the general formula (I), when R 1 is a carboxy group protected by a protecting group, when administered in vivo (in vivo test, etc.), biochemical reactions in vivo (e.g. It can be easily hydrolyzed by esterase etc. and converted to a pharmacologically active form in which R 1 is a carboxy group.
　一般式（Ｉ）で表される化合物の代表的な製造方法を以下に示すが、個々の具体的な製造方法については、後述の実施例で詳細に説明する。 A typical production method of the compound represented by the general formula (I) is shown below, and each specific production method will be described in detail in Examples described later.
Figure JPOXMLDOC01-appb-C000004
〔式中、Ｒ２、Ｗ及びＺは、前記と同意義を示し、Ｒ１’は、カルボキシ基の保護基を示し、Ｒ３は、ｔｅｒｔ－ブトキシカルボニル基又は水素原子を示し、Ｘは、ヒドロキシ基、クロロ基、ブロモ基、ヨード基、メタンスルホニルオキシ基、ベンゼンスルホニルオキシ基、ｐ－トルエンスルホニルオキシ基又はトリフルオロメタンスルホニルオキシ基を示し、Ｘ’は、クロロ基、ブロモ基又はヨード基を示す。〕
Figure JPOXMLDOC01-appb-C000004
[Wherein R 2 , W and Z are as defined above, R 1 ′ represents a protecting group for a carboxy group, R 3 represents a tert-butoxycarbonyl group or a hydrogen atom, and X represents A hydroxy group, a chloro group, a bromo group, an iodo group, a methanesulfonyloxy group, a benzenesulfonyloxy group, a p-toluenesulfonyloxy group or a trifluoromethanesulfonyloxy group, and X ′ represents a chloro group, a bromo group or an iodo group. Show. ]
　一般式（Ｉ）で表される化合物は、合成経路１乃至５のいずれかの方法により、Ｒ１がカルボキシ基であるものは、Ｒ３が水素原子である化合物（Ｉａ）として、またＲ１が保護基により保護されたカルボキシ基であるものは、Ｒ３が水素原子である化合物（Ｉ’）として得ることができる。 The compound represented by the general formula (I) is obtained by any one of the synthesis routes 1 to 5, wherein R 1 is a carboxy group, and R 3 is a hydrogen atom as the compound (Ia) or R 1 Can be obtained as compound (I ′) in which R 3 is a hydrogen atom.
［合成経路１］
　化合物（ａ）において、Ｘがヒドロキシ基である場合は、化合物（ａ）と化合物（ｂ）とを、不活性有機溶媒中、アゾ化合物系の縮合剤とホスフィン試薬の存在下で反応させることにより、化合物（Ｉ’）を得ることができる。
　使用される不活性有機溶媒としては、反応を阻害せず、原料物質をある程度溶解するものであれば特に限定されないが、例えば、ベンゼン、トルエン若しくはキシレン等の芳香族炭化水素類；ジエチルエーテル、テトラヒドロフラン、１，４－ジオキサン若しくは１，２－ジメトキシエタン等のエーテル類；Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド若しくはＮ－メチルピロリドン等のアミド類；アセトニトリル若しくはプロピオニトリル等のニトリル類；酢酸メチル、酢酸エチル若しくは酢酸イソプロピル等のエステル類；又はこれらの任意の混合溶媒等が挙げられ、好ましくは、テトラヒドロフラン、Ｎ，Ｎ－ジメチルホルムアミド、アセトニトリル又はこれらの混合溶媒である。
　使用されるアゾ化合物系の縮合剤としては、例えば、ジエチルアゾジカルボキシレート（ＤＥＡＤ）、ジイソプロピルアゾジカルボキシレート（ＤＩＡＤ）、Ｎ，Ｎ，Ｎ’，Ｎ’－テトライソプロピルアゾジカルボキサミド（ＴＩＰＡ）、１，１’－（アゾジカルボニル）ジピペリジン（ＡＤＤＰ）、Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルアゾジカルボキサミド（ＴＭＡＤ）又は１，６－ジメチル－１，５，７－ヘキサヒドロ－１，４，６，７－テトラゾシン－２，５－ジオン（ＤＨＴＤ）等が挙げられ、好ましくは、ジエチルアゾジカルボキシレート（ＤＥＡＤ）又はＮ，Ｎ，Ｎ’，Ｎ’－テトラメチルアゾジカルボキサミド（ＴＭＡＤ）である。アゾ化合物系の縮合剤の使用量は、化合物（ｂ）１モルに対して、通常、０．９乃至１０倍モル量であり、好ましくは、１乃至５倍モル量である。
　使用されるホスフィン試薬としては、例えば、トリメチルホスフィン、トリエチルホスフィン、トリ－ｎ－ブチルホスフィン又はトリフェニルホスフィン等が挙げられ、好ましくは、トリ－ｎ－ブチルホスフィン又はトリフェニルホスフィンである。ホスフィン化合物の使用量は、化合物（ｂ）１モルに対して、通常、０．９乃至１０倍モル量であり、好ましくは、１乃至５倍モル量である。
　化合物（ａ）の使用量は、化合物（ｂ）１モルに対して、通常、０．８乃至２倍モル量であり、好ましくは、０．９乃至１．５倍モル量である。
　反応温度は、原料、溶媒等の種類、使用量等によって異なるが、通常、－２０℃乃至１００℃であり、好ましくは、－５℃乃至５０℃である。
　反応時間は、反応温度等によって異なるが、通常、３０分間乃至４８時間であり、好ましくは、１時間乃至２４時間である。 [Synthesis route 1]
In the compound (a), when X is a hydroxy group, the compound (a) and the compound (b) are reacted in an inert organic solvent in the presence of an azo compound-based condensing agent and a phosphine reagent. Compound (I ′) can be obtained.
The inert organic solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the raw material to some extent. For example, aromatic hydrocarbons such as benzene, toluene or xylene; diethyl ether, tetrahydrofuran , Ethers such as 1,4-dioxane or 1,2-dimethoxyethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide or N-methylpyrrolidone; nitriles such as acetonitrile or propionitrile An ester such as methyl acetate, ethyl acetate or isopropyl acetate; or any mixed solvent thereof, and the like, preferably tetrahydrofuran, N, N-dimethylformamide, acetonitrile or a mixed solvent thereof.
Examples of the azo compound-based condensing agent used include diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), N, N, N ′, N′-tetraisopropyl azodicarboxamide (TIPA). 1,1 ′-(azodicarbonyl) dipiperidine (ADDP), N, N, N ′, N′-tetramethylazodicarboxamide (TMAD) or 1,6-dimethyl-1,5,7-hexahydro-1 , 4,6,7-tetrazocine-2,5-dione (DHTD), etc., preferably diethyl azodicarboxylate (DEAD) or N, N, N ′, N′-tetramethylazodicarboxamide ( TMAD). The amount of the azo compound-based condensing agent to be used is generally 0.9 to 10-fold mol amount, preferably 1 to 5-fold mol amount based on 1 mol of Compound (b).
Examples of the phosphine reagent to be used include trimethylphosphine, triethylphosphine, tri-n-butylphosphine, triphenylphosphine and the like, and tri-n-butylphosphine or triphenylphosphine is preferable. The amount of the phosphine compound to be used is generally 0.9 to 10-fold mol amount, preferably 1 to 5-fold mol amount based on 1 mol of Compound (b).
The amount of compound (a) to be used is generally 0.8 to 2-fold mol amount, preferably 0.9 to 1.5-fold mol amount based on 1 mol of Compound (b).
The reaction temperature varies depending on the kind of raw material, solvent, etc., the amount used, etc., but is usually −20 ° C. to 100 ° C., preferably −5 ° C. to 50 ° C.
The reaction time varies depending on the reaction temperature and the like, but is usually 30 minutes to 48 hours, preferably 1 hour to 24 hours.
　化合物（ａ）において、Ｘがクロロ基、ブロモ基、ヨード基、メタンスルホニルオキシ基、ベンゼンスルホニルオキシ基、ｐ－トルエンスルホニルオキシ基又はトリフルオロメタンスルホニルオキシ基である場合は、化合物（ａ）と化合物（ｂ）とを、不活性有機溶媒中、塩基の存在下で反応させることにより、化合物（Ｉ’）を得ることができる。
　使用される不活性溶媒としては、反応を阻害せず、原料物質をある程度溶解するものであれば特に限定されないが、例えば、テトラヒドロフラン、１，４－ジオキサン若しくは１，２－ジメトキシエタン等のエーテル類；塩化メチレン、クロロホルム若しくは１，２－ジクロロエタン等のハロゲン化脂肪族炭化水素類；アセトニトリル若しくはプロピオニトリル等のニトリル類；ギ酸メチル、ギ酸エチル、酢酸メチル若しくは酢酸エチル等のエステル類；ベンゼン若しくはトルエン等の芳香族炭化水素類；Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド若しくはＮ－メチルピロリドン等のアミド類；ジメチルスルホキシド等のスルホキシド類；又はこれらの任意の混合溶媒等が挙げられ、好ましくは、テトラヒドロフラン、Ｎ，Ｎ－ジメチルホルムアミド、塩化メチレン又は１，２－ジクロロエタンである。
　使用される塩基としては、例えば、水素化ナトリウム若しくは水素化カリウム等のアルカリ金属水素化物；リチウムアミド、ナトリウムアミド、リチウムジイソプロピルアミド若しくはリチウムビストリメチルシリルアミド等のアルカリ金属アミド；ナトリウムメトキシド、ナトリウムエトキシド、ナトリウムｔｅｒｔ－ブトキシド若しくはカリウムｔｅｒｔ－ブトキシド等のアルカリ金属アルコキシド；炭酸ナトリウム若しく炭酸カリウム等のアルカリ金属炭酸塩；又はトリエチルアミン、トリブチルアミン、ジイソプロピルエチルアミン、ピリジン、ピコリン、２，６－ルチジン若しくは４－ジメチルアミノピリジン等のアミン類等が挙げられ、好ましくは、水素化ナトリウム、炭酸カリウム、トリエチルアミン又はジイソプロピルエチルアミンである。ただし、使用する不活性溶媒が、エステル類、ニトリル類又はハロゲン化脂肪族炭化水素類の場合は、塩基としては、トリエチルアミン又はジイソプロピルエチルアミンが好ましい。
　塩基の使用量は、化合物（ｂ）１モルに対して、通常、１乃至５倍モル量であり、好ましくは、１乃至２．５倍モル量である。
　化合物（ａ）の使用量は、化合物（ｂ）１モルに対して、通常、０．５乃至３倍モル量であり、好ましくは、０．５乃至１．５倍モル量である。
　反応温度は、原料、溶媒等の種類、使用量等によって異なるが、通常、－８０℃乃至１００℃であり、好ましくは、０℃乃至８０℃である。
　反応時間は、反応温度等によって異なるが、通常、１０分間乃至４８時間であり、好ましくは、１時間乃至２４時間である。 In the compound (a), when X is a chloro group, bromo group, iodo group, methanesulfonyloxy group, benzenesulfonyloxy group, p-toluenesulfonyloxy group or trifluoromethanesulfonyloxy group, the compound (a) and the compound Compound (I ′) can be obtained by reacting (b) with an inert organic solvent in the presence of a base.
The inert solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the raw material to some extent. For example, ethers such as tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane are used. Halogenated aliphatic hydrocarbons such as methylene chloride, chloroform or 1,2-dichloroethane; nitriles such as acetonitrile or propionitrile; esters such as methyl formate, ethyl formate, methyl acetate or ethyl acetate; benzene or toluene Aromatic hydrocarbons such as N; N-dimethylformamide, N, N-dimethylacetamide or amides such as N-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide; or any mixed solvent thereof. Preferably, tetrahydrofuran, , N- dimethylformamide, methylene chloride or 1,2-dichloroethane.
Examples of the base used include alkali metal hydrides such as sodium hydride or potassium hydride; alkali metal amides such as lithium amide, sodium amide, lithium diisopropylamide or lithium bistrimethylsilylamide; sodium methoxide, sodium ethoxide Alkali metal alkoxides such as sodium tert-butoxide or potassium tert-butoxide; alkali metal carbonates such as sodium carbonate or potassium carbonate; or triethylamine, tributylamine, diisopropylethylamine, pyridine, picoline, 2,6-lutidine or 4- Examples include amines such as dimethylaminopyridine, and preferably sodium hydride, potassium carbonate, triethylamine or diisopropylethyl. It is an amine. However, when the inert solvent used is an ester, nitrile or halogenated aliphatic hydrocarbon, the base is preferably triethylamine or diisopropylethylamine.
The amount of the base to be used is generally 1 to 5-fold mol amount, preferably 1 to 2.5-fold mol amount based on 1 mol of Compound (b).
The amount of compound (a) to be used is generally 0.5 to 3-fold mol amount, preferably 0.5 to 1.5-fold mol amount based on 1 mol of Compound (b).
The reaction temperature varies depending on the kind of raw material, solvent, etc., the amount used, etc., but is usually −80 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C.
The reaction time varies depending on the reaction temperature and the like, but is usually 10 minutes to 48 hours, preferably 1 hour to 24 hours.
［合成経路２］
　化合物（ｄ）において、Ｘがヒドロキシ基である場合は、化合物（ｃ）と化合物（ｄ）とを、不活性有機溶媒中、アゾ化合物系の縮合剤とホスフィン試薬の存在下で反応させることにより、化合物（Ｉ’）を得ることができる。本工程は、化合物（ａ）の代わりに化合物（ｄ）、化合物（ｂ）の代わりに化合物（ｃ）を使用する以外は、前記の［合成経路１］において化合物（ａ）のＸがヒドロキシ基である場合に準じて行われる。
　化合物（ｄ）において、Ｘがクロロ基、ブロモ基、ヨード基、メタンスルホニルオキシ基、ベンゼンスルホニルオキシ基、ｐ－トルエンスルホニルオキシ基又はトリフルオロメタンスルホニルオキシ基である場合は、化合物（ｃ）と化合物（ｄ）とを、不活性有機溶媒中、塩基の存在下で反応させることにより、化合物（Ｉ’）を得ることができる。本工程は、化合物（ａ）の代わりに化合物（ｄ）、化合物（ｂ）の代わりに化合物（ｃ）を使用する以外は、前記の［合成経路１］において化合物（ａ）のＸがクロロ基、ブロモ基、ヨード基、メタンスルホニルオキシ基、ベンゼンスルホニルオキシ基、ｐ－トルエンスルホニルオキシ基又はトリフルオロメタンスルホニルオキシ基である場合に準じて行われる。 [Synthesis route 2]
In the compound (d), when X is a hydroxy group, the compound (c) and the compound (d) are reacted in an inert organic solvent in the presence of an azo compound-based condensing agent and a phosphine reagent. Compound (I ′) can be obtained. In this step, X in the compound (a) is a hydroxy group in the above [Synthesis route 1] except that the compound (d) is used instead of the compound (a) and the compound (c) is used instead of the compound (b). It is done according to the case.
In the compound (d), when X is a chloro group, bromo group, iodo group, methanesulfonyloxy group, benzenesulfonyloxy group, p-toluenesulfonyloxy group or trifluoromethanesulfonyloxy group, the compound (c) and the compound Compound (I ′) can be obtained by reacting (d) with an inert organic solvent in the presence of a base. In this step, X in the compound (a) is a chloro group in the above [Synthesis route 1] except that the compound (d) is used instead of the compound (a) and the compound (c) is used instead of the compound (b). Bromo group, iodo group, methanesulfonyloxy group, benzenesulfonyloxy group, p-toluenesulfonyloxy group or trifluoromethanesulfonyloxy group.
［合成経路３］
　合成経路３－１は、化合物（ｃ）と化合物（ｅ）とを、不活性有機溶媒中、塩基の存在下で反応させることにより化合物（ｆ）を得る工程である。本工程は、化合物（ａ）の代わりに化合物（ｅ）、化合物（ｂ）の代わりに化合物（ｃ）を使用する以外は、前記の［合成経路１］において化合物（ａ）のＸがクロロ基、ブロモ基、ヨード基、メタンスルホニルオキシ基、ベンゼンスルホニルオキシ基、ｐ－トルエンスルホニルオキシ基又はトリフルオロメタンスルホニルオキシ基である場合に準じて行われる。
　合成経路３－２は、合成経路３－１で得られた化合物（ｆ）と化合物（ｇ）とを、不活性溶媒中、不活性気体雰囲気下、塩基若しくはフッ化物のいずれかとパラジウム触媒存在下で反応させることにより、化合物（Ｉ’）を得ることができる。
　使用される不活性溶媒としては、反応を阻害せず、原料、触媒及び塩基（又はフッ化物）をある程度溶解する溶媒であれば、特に限定されないが、例えば、ベンゼン若しくはトルエン等の芳香族炭化水素類；テトラヒドロフラン、１，２－ジメトキシエタン若しくは１，４－ジオキサン等のエーテル類；メタノール、エタノール、プロパノール若しくはイソプロパノール等のアルコール類；酢酸メチル若しくは酢酸エチル等のエステル類；Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド若しくはＮ－メチルピロリドン等のアミド類；ジメチルスルホキシド等のスルホキシド類；アセトニトリル等のニトリル類；水；又はこれらの任意の混合溶媒等が挙げられ、好ましくは、トルエン、トルエン－エタノール－水混合溶媒又はトルエン－水混合溶媒である。
　使用される不活性気体としては、例えば、窒素、ヘリウム又はアルゴン等が挙げられる。
　使用されるパラジウム触媒としては、例えば、パラジウム－活性炭素若しくはパラジウム黒等の金属パラジウム類；テトラキス（トリフェニルホスフィン）パラジウム、塩化ビス（トリフェニルホスフィン）パラジウム、塩化１，１’－ビス（ジフェニルホスフィノ）フェロセンパラジウム若しくはトリス（ジベンジリデンアセトン）ジパラジウム等の有機パラジウム錯体；又は塩化パラジウム若しくは酢酸パラジウム等のパラジウム塩類等が挙げられ、好ましくは、テトラキス（トリフェニルホスフィン）パラジウム又は酢酸パラジウムである。触媒としてのパラジウムの使用量は、化合物（ｆ）１モルに対して、通常、０．０００１乃至１倍モル量であり、好ましくは、０．００５乃至０．３倍モル量である。
　触媒としてトリス（ジベンジリデンアセトン）ジパラジウム、塩化パラジウム又は酢酸パラジウムを用いる場合は、有機ホスフィン化合物を共存させることが好ましい。使用される有機ホスフィン化合物としては、例えば、トリ－ｎ－ブチルホスフィン、トリ－ｔｅｒｔ－ブチルホスフィン、トリシクロヘキシルホスフィン、ブチルジ－１－アダマンチルホスフィン、トリフェニルホスフィン、トリ（ｏ－トリル）ホスフィン、２－ジシクロヘキシルホスフィノ－２’，６’－ジメトキシビフェニル、１，１’－ビス（ジフェニルホスフィノ）フェロセン又は１，２，３，４，５－ペンタフェニル－１’－（ジ－ｔｅｒｔ－ブチルホスフィノ）フェロセン等が挙げられ、好ましくは、トリシクロヘキシルホスフィン、ブチルジ－１－アダマンチルホスフィン、トリフェニルホスフィン又は２－ジシクロヘキシルホスフィノ－２’，６’－ジメトキシビフェニルである。有機ホスフィン化合物の使用量は、パラジウム１モルに対して、通常、１乃至５倍モル量であり、好ましくは、１．５乃至２．５倍モル量である。
　使用される塩基又はフッ化物としては、例えば、酢酸ナトリウム若しくは酢酸カリウム等のアルカリ金属酢酸塩；炭酸ナトリウム、炭酸カリウム若しくは炭酸セシウム等のアルカリ金属炭酸塩；リン酸三ナトリウム若しくはリン酸三カリウム等のアルカリ金属リン酸塩；水酸化リチウム、水酸化ナトリウム若しくは水酸化カリウム等のアルカリ金属水酸化物；水酸化テトラメチルアンモニウム、水酸化テトラエチルアンモニウム若しくは水酸化テトラブチルアンモニウム等の四級アンモニウム水酸化物；又はフッ化セシウム、フッ化テトラメチルアンモニウム、フッ化テトラエチルアンモニウム若しくはフッ化テトラブチルアンモニウム等のフッ化物等が挙げられ、好ましくは、炭酸ナトリウム又はリン酸三カリウムである。塩基又はフッ化物の使用量は、化合物（ｆ）１モルに対して、通常、１乃至１０倍モル量であり、好ましくは、１．５乃至５倍モル量である。
　化合物（ｇ）の使用量は、化合物（ｆ）１モルに対して、通常、１乃至３倍モル量であり、好ましくは、１乃至２倍モル量である。
　反応温度は、原料、溶媒等の種類、使用量等によって異なるが、通常、０℃乃至２００℃であり、好ましくは、５０℃乃至１５０℃である。
　反応時間は、反応温度等によって異なるが、通常、１０分間乃至１２０時間であり、好ましくは、１時間乃至４８時間である。 [Synthesis route 3]
Synthesis route 3-1 is a step of obtaining compound (f) by reacting compound (c) with compound (e) in the presence of a base in an inert organic solvent. In this step, X of compound (a) is a chloro group in the above [Synthesis route 1] except that compound (e) is used instead of compound (a), and compound (c) is used instead of compound (b). Bromo group, iodo group, methanesulfonyloxy group, benzenesulfonyloxy group, p-toluenesulfonyloxy group or trifluoromethanesulfonyloxy group.
Synthetic pathway 3-2 involves the steps of compound (f) and compound (g) obtained in synthetic pathway 3-1 in an inert solvent, in an inert gas atmosphere, in the presence of either a base or fluoride and a palladium catalyst. To give compound (I ′).
The inert solvent used is not particularly limited as long as it is a solvent that does not inhibit the reaction and dissolves raw materials, catalysts, and bases (or fluorides) to some extent. For example, an aromatic hydrocarbon such as benzene or toluene. Ethers such as tetrahydrofuran, 1,2-dimethoxyethane or 1,4-dioxane; alcohols such as methanol, ethanol, propanol or isopropanol; esters such as methyl acetate or ethyl acetate; N, N-dimethylformamide; Examples thereof include amides such as N, N-dimethylacetamide or N-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide; nitriles such as acetonitrile; water; or any mixed solvent thereof, preferably toluene, toluene- Ethanol-water mixed solvent or Toluene - is water mixed solvent.
Examples of the inert gas used include nitrogen, helium, and argon.
Examples of the palladium catalyst to be used include palladium-activated carbon or palladium metal such as palladium black; tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium, 1,1′-bis (diphenylphosphine chloride). Phino) ferrocene palladium or an organic palladium complex such as tris (dibenzylideneacetone) dipalladium; or palladium salts such as palladium chloride or palladium acetate; and tetrakis (triphenylphosphine) palladium or palladium acetate is preferable. The amount of palladium used as the catalyst is usually 0.0001 to 1-fold mol amount, preferably 0.005 to 0.3-fold mol amount based on 1 mol of Compound (f).
When tris (dibenzylideneacetone) dipalladium, palladium chloride or palladium acetate is used as the catalyst, it is preferable to coexist an organic phosphine compound. Examples of the organic phosphine compound used include tri-n-butylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, butyldi-1-adamantylphosphine, triphenylphosphine, tri (o-tolyl) phosphine, 2- Dicyclohexylphosphino-2 ', 6'-dimethoxybiphenyl, 1,1'-bis (diphenylphosphino) ferrocene or 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino ) Ferrocene and the like, and preferred are tricyclohexylphosphine, butyldi-1-adamantylphosphine, triphenylphosphine or 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl. The amount of the organic phosphine compound used is usually 1 to 5 times the molar amount, preferably 1.5 to 2.5 times the molar amount per 1 mol of palladium.
Examples of the base or fluoride used include alkali metal acetates such as sodium acetate or potassium acetate; alkali metal carbonates such as sodium carbonate, potassium carbonate or cesium carbonate; trisodium phosphate or tripotassium phosphate Alkali metal phosphates; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide; quaternary ammonium hydroxides such as tetramethylammonium hydroxide, tetraethylammonium hydroxide or tetrabutylammonium hydroxide; Alternatively, fluorides such as cesium fluoride, tetramethylammonium fluoride, tetraethylammonium fluoride, and tetrabutylammonium fluoride can be used, and sodium carbonate or tripotassium phosphate is preferable. The amount of the base or fluoride to be used is generally 1 to 10-fold mol amount, preferably 1.5 to 5-fold mol amount based on 1 mol of Compound (f).
The amount of compound (g) to be used is generally 1 to 3-fold mol amount, preferably 1 to 2-fold mol amount based on 1 mol of Compound (f).
The reaction temperature varies depending on the type of raw material, solvent, etc., the amount used, etc., but is usually 0 ° C. to 200 ° C., preferably 50 ° C. to 150 ° C.
The reaction time varies depending on the reaction temperature and the like, but is usually 10 minutes to 120 hours, preferably 1 hour to 48 hours.
［合成経路４］
　化合物（ｈ）と化合物（ｉ）とを、不活性有機溶媒中、塩基の存在下若しくは非存在下（好ましくは存在下）で反応させることにより、化合物（Ｉ’）を得ることができる。
　使用される不活性有機溶媒としては、反応を阻害せず、原料物質をある程度溶解するものであれば特に限定されないが、例えば、ベンゼン、トルエン若しくはキシレン等の芳香族炭化水素類；塩化メチレン、クロロホルム若しくは１，２－ジクロロエタン等のハロゲン化脂肪族炭化水素類；１，４－ジオキサン、テトラヒドロフラン、ジエチルエーテル若しくは１，２－ジメトキシエタン等のエーテル類；Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド若しくはＮ－メチルピロリドン等のアミド類；アセトニトリル若しくはプロピオニトリル等のニトリル類；又はこれらの任意の混合溶媒等が挙げられ、好ましくは、塩化メチレン、１，２－ジクロロエタン、Ｎ，Ｎ－ジメチルホルムアミド、アセトニトリル又はこれらの混合溶媒である。
　使用される塩基としては、例えば、トリエチルアミン若しくはジイソプロピルエチルアミン等の有機塩基；又は炭酸水素ナトリウム、炭酸水素カリウム、炭酸ナトリウム若しくは炭酸カリウム等の無機塩基等が挙げられ、好ましくは、トリエチルアミン又はジイソプロピルエチルアミンである。塩基の使用量は、化合物（ｉ）１モルに対して、通常、０．９乃至２０倍モル量であり、好ましくは、１乃至１０倍モル量である。
　化合物（ｈ）の使用量は、化合物（ｉ）１モルに対して、通常、０．７乃至５倍モル量であり、好ましくは、０．８乃至１．５倍モル量である。
　反応温度は、原料、溶媒等の種類、使用量等によって異なるが、通常、－２０℃乃至１００℃であり、好ましくは、－５℃乃至５０℃である。
　反応時間は、反応温度等によって異なるが、通常、１分間乃至３６時間であり、好ましくは、１時間乃至１８時間である。 [Synthesis route 4]
Compound (I ′) can be obtained by reacting compound (h) with compound (i) in an inert organic solvent in the presence or absence (preferably in the presence) of a base.
The inert organic solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the raw material to some extent. For example, aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride, chloroform Or halogenated aliphatic hydrocarbons such as 1,2-dichloroethane; ethers such as 1,4-dioxane, tetrahydrofuran, diethyl ether or 1,2-dimethoxyethane; N, N-dimethylformamide, N, N-dimethyl Amides such as acetamide or N-methylpyrrolidone; Nitriles such as acetonitrile or propionitrile; or any mixed solvent thereof, preferably methylene chloride, 1,2-dichloroethane, N, N-dimethyl Formamide, acetonitrile or a mixture thereof It is a solvent.
Examples of the base to be used include organic bases such as triethylamine or diisopropylethylamine; or inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate or potassium carbonate, preferably triethylamine or diisopropylethylamine. . The amount of the base to be used is generally 0.9 to 20-fold mol amount, preferably 1 to 10-fold mol amount based on 1 mol of Compound (i).
The amount of compound (h) to be used is generally 0.7 to 5-fold mol amount, preferably 0.8 to 1.5-fold mol amount based on 1 mol of Compound (i).
The reaction temperature varies depending on the kind of raw material, solvent, etc., the amount used, etc., but is usually −20 ° C. to 100 ° C., preferably −5 ° C. to 50 ° C.
The reaction time varies depending on the reaction temperature and the like, but is usually 1 minute to 36 hours, preferably 1 hour to 18 hours.
［合成経路５］
　化合物（Ｉ’）において、Ｒ３がｔｅｒｔ－ブトキシカルボニル基である場合は、化合物（Ｉ’）を酸処理による脱保護に付すことにより、Ｒ１がエステル型の保護基により保護されたカルボキシ基である、一般式（Ｉ）で表される化合物を得ることができる。但し、化合物（Ｉ’）において、Ｒ１’がｔｅｒｔ－ブチル基であり、且つＲ３がｔｅｒｔ－ブトキシカルボニル基である場合は、塩酸、トリフルオロ酢酸等の酸処理による脱保護により、Ｒ１がカルボキシ基である、一般式（Ｉ）で表される化合物を得ることができる。同様に、化合物（Ｉ’）において、Ｒ３が水素原子である場合は、化合物（Ｉ’）をアルカリ加水分解等による適切な脱保護に付すことにより、Ｒ１がカルボキシ基である、一般式（Ｉ）で表される化合物を得ることができる。 [Synthesis route 5]
In the compound (I ′), when R 3 is a tert-butoxycarbonyl group, by subjecting the compound (I ′) to deprotection by acid treatment, R 1 is protected by an ester-type protecting group. A compound represented by the general formula (I) can be obtained. However, 'in, R 1 Compound (I)' is the tert- butyl group, and if R 3 is tert- butoxycarbonyl group, hydrochloric, deprotection by acid treatment, such as trifluoroacetic acid, R 1 A compound represented by the general formula (I) in which is a carboxy group can be obtained. Similarly, in the compound (I ′), when R 3 is a hydrogen atom, R 1 is a carboxy group by subjecting the compound (I ′) to appropriate deprotection by alkali hydrolysis or the like. The compound represented by (I) can be obtained.
　置換基Ｒ２は、当初から所望の置換基を導入しておいてもよく、また、上記の方法により基本骨格を製造した後に、酸化、還元、アルキル化、エステル化、アミド化、脱水反応、脱保護反応、加水分解、カップリング反応、環化反応及び／又はそれらの反応を組み合わせた汎用される合成方法を使用して、所望の置換基を導入してもよい。
　一般式（Ｉ）で表される化合物の出発化合物は、市販されているか、当業者に公知の製造方法により製造することができる。一般式（Ｉ）で表される化合物の出発化合物及び中間体化合物の製造方法については、後述の参考例で詳細に説明する。 The substituent R 2 may have a desired substituent introduced from the beginning, and after producing the basic skeleton by the above method, oxidation, reduction, alkylation, esterification, amidation, dehydration reaction, A desired substituent may be introduced using a deprotection reaction, hydrolysis, coupling reaction, cyclization reaction, and / or a commonly used synthetic method combining these reactions.
The starting compound of the compound represented by formula (I) is commercially available or can be produced by a production method known to those skilled in the art. The starting compound of the compound represented by the general formula (I) and the production method of the intermediate compound will be described in detail in Reference Examples described later.
　各反応において生成した目的化合物は、常法に従って反応混合物から得ることができる。例えば、反応混合物を適宜中和し、また、不溶物が存在する場合には、濾過により除去した後、水と混和しない酢酸エチル等の有機溶媒を加え、水洗後、目的化合物を含む有機層を分離し、無水硫酸マグネシウム又は無水硫酸ナトリウム等の乾燥剤で乾燥後、溶媒を留去することによって得られる。
　得られた目的化合物は、必要ならば、常法、例えば、再結晶；再沈殿；又は通常有機化合物の分離精製に慣用されている方法（例えば、シリカゲル、アルミナ等の担体を使用した吸着カラムクロマトグラフィー法；イオン交換クロマトグラフィー法；又はシリカゲル若しくはアルキル化シリカゲルによる順相・逆相カラムクロマトグラフィー法（好適には、高速液体クロマトグラフィー）である。）を適宜組み合わせ、分離、精製することができる。 The target compound produced in each reaction can be obtained from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, then an organic solvent such as ethyl acetate that is immiscible with water is added, and after washing with water, the organic layer containing the target compound is removed. It isolate | separates and it obtains by distilling a solvent off after drying with desiccants, such as anhydrous magnesium sulfate or anhydrous sodium sulfate.
If necessary, the obtained target compound can be obtained by a conventional method such as recrystallization; reprecipitation; or a method commonly used for separation and purification of organic compounds (for example, adsorption column chromatography using a carrier such as silica gel or alumina). Can be separated and purified by a suitable combination of a chromatography method; an ion exchange chromatography method; or a normal phase / reverse phase column chromatography method (preferably high performance liquid chromatography) using silica gel or alkylated silica gel. .
　一般式（Ｉ）で表わされる化合物又はその薬理上許容される塩は、水和物若しくは溶媒和物として存在することができる。 The compound represented by the general formula (I) or a pharmacologically acceptable salt thereof can exist as a hydrate or a solvate.
　一般式（Ｉ）で表わされる化合物又はその薬理上許容される塩を含む医薬組成物は、他の医薬と組み合わせて投与されることを特徴とする。本発明における「組み合わせて投与される」は、被投与対象（特に、ヒト）が、一定期間内に一般式（Ｉ）で表わされる化合物又はその薬理上許容される塩を含む医薬組成物及び他の医薬をその体内に取り込むことを意味する。したがって上記医薬組成物は、
（ａ）一般式（Ｉ）で表わされる化合物又はその薬理上許容される塩を含む医薬組成物と、他の医薬が、それぞれ別異の製剤として、同時に又は異なる時間に投与されることを特徴とする医薬組成物；又は、
（ｂ）一般式（Ｉ）で表わされる化合物又はその薬理上許容される塩を含む医薬組成物と、他の医薬が、単一の製剤（配合剤）として投与されることを特徴とする医薬組成物
であり得、好ましくは、上記（ａ）の医薬組成物である。 A pharmaceutical composition containing a compound represented by the general formula (I) or a pharmacologically acceptable salt thereof is characterized by being administered in combination with other pharmaceuticals. In the present invention, “administered in combination” refers to a pharmaceutical composition containing a compound represented by the general formula (I) or a pharmacologically acceptable salt thereof within a certain period, and other subjects (particularly humans) Means to take the medicine of the body into the body. Therefore, the pharmaceutical composition is
(A) A pharmaceutical composition containing a compound represented by the general formula (I) or a pharmacologically acceptable salt thereof and another pharmaceutical agent are administered as different preparations at the same time or at different times. Or a pharmaceutical composition; or
(B) A pharmaceutical composition comprising a pharmaceutical composition comprising a compound represented by general formula (I) or a pharmacologically acceptable salt thereof and another pharmaceutical agent as a single preparation (compound) It can be a composition, and is preferably the pharmaceutical composition of (a) above.
　上記（ａ）の医薬組成物において、一般式（Ｉ）で表わされる化合物又はその薬理上許容される塩を含有する製剤及び他の医薬を含有する製剤の投与時期に限定はなく、上記２つの製剤は、同時に、異なる時間に（別々に）又は異なる日に投与され得る。上記２つの製剤の投与の順番、回数、経路及び用量に限定はなく、投与の回数、経路及び用量は異なり得る。また、上記２つの製剤の一方を投与してから他方を投与するまでの期間に限定はなく、一方の薬理効果が残存する一定期間（例えば、１週間、好ましくは、２又は３日間、より好ましくは、１日間、更に好ましくは、１乃至８時間）内に他方が投与されればよい。所望の効果を示す限りにおいては一般式（Ｉ）で表わされる化合物又はその薬理上許容される塩及び他の医薬が同時に一定以上の濃度で血液中に存在する必要はなく、一方が投与される際に他方が血液中から消失していてもよい。 In the pharmaceutical composition of the above (a), there is no limitation on the administration time of the preparation containing the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof and the preparation containing another medicine. The formulations can be administered simultaneously, at different times (separately) or on different days. There is no limitation on the order, frequency, route and dose of administration of the above two preparations, and the frequency, route and dose of administration can be different. Further, there is no limitation on the period from administration of one of the above two preparations to administration of the other, and a certain period during which one pharmacological effect remains (for example, 1 week, preferably 2 or 3 days, more preferably May be administered within one day, more preferably within 1 to 8 hours). As long as the desired effect is exhibited, the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof and other medicines do not have to be present in the blood at a certain concentration at the same time, and one of them is administered. Sometimes the other may disappear from the blood.
　本発明の医薬組成物の投与形態は、例えば、以下の通りである。
（Ａ）一般式（Ｉ）で表わされる化合物又はその薬理上許容される塩を含有する製剤及び他の医薬を含有する製剤（２つの異なる製剤）が同時に投与される；
（Ｂ）一般式（Ｉ）で表わされる化合物又はその薬理上許容される塩を含有する製剤及び他の医薬を含有する製剤（２つの異なる製剤）が一定期間をおいて別々に投与される；
（Ｃ）一般式（Ｉ）で表わされる化合物又はその薬理上許容される塩及び他の医薬の双方を含有する単一の製剤が投与される。 The dosage form of the pharmaceutical composition of the present invention is, for example, as follows.
(A) a preparation containing a compound represented by the general formula (I) or a pharmacologically acceptable salt thereof and a preparation containing other medicaments (two different preparations) are administered simultaneously;
(B) a preparation containing the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof and a preparation containing other medicaments (two different preparations) are administered separately over a period of time;
(C) A single preparation containing both the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof and other pharmaceuticals is administered.
　本発明の医薬組成物における他の医薬は、所望の効果（好ましくは、炎症性メディエータ―の産生抑制等による抗炎症効果、抗線維化、又は気管支拡張効果）を示すものであれば限定はなく、例えば、ＰＤＥ４阻害薬、ＰＤＥ５阻害薬、コルチコステロイド、抗コリン薬、β２－受容体作動薬、Ｈ１－ヒスタミン受容体拮抗薬、ロイコトリエン受容体拮抗薬、エンドセリン受容体拮抗薬、ＰＧＩ２受容体作動薬、テオフィリン及びピルフェニドンからなる群より選択される１以上の医薬であり得、好ましくは、ＰＤＥ４阻害薬、コルチコステロイド、抗コリン薬、β２－受容体作動薬及びピルフェニドンからなる群より選択される１以上の医薬であり、より好ましくは、ＰＤＥ４阻害薬、コルチコステロイド又はピルフェニドンであり、最も好ましくは、ロフルミラスト、フルチカゾン又はピルフェニドンである。 Other medicaments in the pharmaceutical composition of the present invention are not limited as long as they exhibit a desired effect (preferably, an anti-inflammatory effect, an anti-fibrosis, or a bronchodilation effect by suppressing production of inflammatory mediators, etc.). For example, PDE4 inhibitor, PDE5 inhibitor, corticosteroid, anticholinergic agent, β2-receptor agonist, H1-histamine receptor antagonist, leukotriene receptor antagonist, endothelin receptor antagonist, PGI2 receptor agonist One or more medicines selected from the group consisting of drugs, theophylline and pirfenidone, preferably selected from the group consisting of PDE4 inhibitors, corticosteroids, anticholinergics, β2-receptor agonists and pirfenidone One or more medicaments, more preferably a PDE4 inhibitor, a corticosteroid or pirfenidone, most Roflumilast, fluticasone or pirfenidone is preferred.
　本発明において、他の医薬におけるＰＤＥ４阻害薬は、例えば、シロミラスト、ロフルミラスト、テトミラスト、トフィミラスト、フィラミナスト、ピクラミラスト又はリリミラスト等が挙げられ、好ましくは、シロミラスト又はロフルミラストであり、より好ましくは、ロフルミラストである。 In the present invention, examples of the PDE4 inhibitor in other pharmaceuticals include silomilast, roflumilast, tetomilast, tofimilast, filaminast, picramylast, and lilimimilast, and are preferably siromilast or roflumilast, and more preferably roflumilast.
　本発明において、他の医薬におけるＰＤＥ５阻害薬は、例えば、シルデナフィル、バルデナフィル、タダラフィル、ウデナフィル又はアバナフィル等が挙げられる。 In the present invention, examples of PDE5 inhibitors in other pharmaceuticals include sildenafil, vardenafil, tadalafil, udenafil, or avanafil.
　本発明において、他の医薬におけるコルチコステロイドは、例えば、プレドニゾン、プレドニゾロン、メチルプレドニゾロン、コルチゾン、ヒドロコルチゾン、フルドロコルチゾン、デキサメタゾン、ベタメタゾン、ブデソニド、フルチカゾン、ベクロメタゾン、モメタゾン、トリアムシノロン又はシクレソニド等が挙げられ、好ましくは、ブデソニド、フルチカゾン、ベクロメタゾン、モメタゾン又はシクレソニドであり、より好ましくは、フルチカゾンである。 In the present invention, examples of corticosteroids in other medicaments include prednisone, prednisolone, methylprednisolone, cortisone, hydrocortisone, fludrocortisone, dexamethasone, betamethasone, budesonide, fluticasone, beclomethasone, mometasone, triamcinolone or ciclesonide. Budesonide, fluticasone, beclomethasone, mometasone or ciclesonide are preferred, and fluticasone is more preferred.
　本発明において、他の医薬における抗コリン薬は、例えば、グリコピロニウムブロミド、アクリジニウムブロミド、チオトロピウムブロミド又はイプラトロピウムブロミド等が挙げられる。 In the present invention, examples of the anticholinergic agent in other pharmaceuticals include glycopyrronium bromide, acridinium bromide, tiotropium bromide, ipratropium bromide, and the like.
　本発明において、他の医薬におけるβ２－受容体作動薬は、例えば、サルブタモール、ミルベテロール、インダカテロール、カルモテロール、サルメテロール又はフォルモテロール等が挙げられる。 In the present invention, β2-receptor agonists in other pharmaceuticals include, for example, salbutamol, milveterol, indacaterol, carmoterol, salmeterol or formoterol.
　本発明において、他の医薬におけるＨ１－ヒスタミン受容体拮抗薬は、例えば、アゼラスチン、オロパタジン、ロラタジン、デスロラタジン又はセチリジン等が挙げられる。 In the present invention, examples of the H1-histamine receptor antagonist in other pharmaceuticals include azelastine, olopatadine, loratadine, desloratadine, and cetirizine.
　本発明において、他の医薬におけるロイコトリエン受容体拮抗薬は、例えば、モンテルカスト、プランルカスト又はザフィルルカスト等が挙げられる。 In the present invention, examples of the leukotriene receptor antagonist in other pharmaceuticals include montelukast, pranlukast, zafirlukast, and the like.
　本発明において、他の医薬におけるエンドセリン受容体拮抗薬は、例えば、ボセンタン、アンブリセンタン、アトラセンタン、ダルセンタン、クラゾセンタン又はアボセンタン等が挙げられる。 In the present invention, endothelin receptor antagonists in other pharmaceuticals include, for example, bosentan, ambrisentan, atrasentan, darsentan, clazosentan, avosentan, and the like.
　本発明において、他の医薬におけるＰＧＩ２受容体作動薬は、例えば、ベラプロスト又はエポプレステノールが挙げられる。 In the present invention, examples of the PGI2 receptor agonist in other pharmaceuticals include beraprost and epoprestenol.
　これらの他の医薬は、テオフィリン及びピルフェニドンを含め、市販されているか、当業者に公知の製造方法により製造することができる。 These other pharmaceuticals, including theophylline and pirfenidone, are commercially available or can be produced by methods known to those skilled in the art.
　一般式（Ｉ）で表わされる化合物又はその薬理上許容される塩を含む医薬組成物（製剤）及び他の医薬（製剤）は、それ自体で（原末のままで）投与することができ、或いは適宜の薬理学的に許容される賦形剤、希釈剤等と混合して製造される、錠剤、カプセル剤、散剤、シロップ剤、顆粒剤、細粒剤、丸剤、懸濁剤、乳剤、経皮吸収剤、座剤、軟膏剤、ローション、吸入剤又は注射剤等の製剤の形態で、経口又は非経口（静脈内投与、筋肉内投与、腹腔内投与、経皮投与、経鼻投与、経気道投与、経肺投与、皮内投与又は皮下投与等）で投与することができる。一般式（Ｉ）で表わされる化合物又はその薬理上許容される塩を含む医薬組成物及び他の医薬は、それぞれ別異の製剤であってもよく、一般式（Ｉ）で表わされる化合物又はその薬理上許容される塩を含む医薬組成物が、さらに他の医薬を含む、単一の製剤であってもよい。
　これらの製剤は、賦形剤、滑沢剤、結合剤、崩壊剤、乳化剤、安定剤、矯味矯臭剤、希釈剤等の添加剤を使用して、周知の方法で製造される。 The pharmaceutical composition (formulation) containing the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof and other pharmaceuticals (formulation) can be administered per se (as is). Or tablets, capsules, powders, syrups, granules, fine granules, pills, suspensions, emulsions manufactured by mixing with appropriate pharmacologically acceptable excipients, diluents, etc. Oral or parenteral (intravenous administration, intramuscular administration, intraperitoneal administration, transdermal administration, nasal administration) in the form of preparations such as transdermal absorption agents, suppositories, ointments, lotions, inhalants or injections , Transrespiratory administration, transpulmonary administration, intradermal administration, subcutaneous administration, etc.). The pharmaceutical composition containing the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof and the other medicament may be different formulations, respectively, and the compound represented by the general formula (I) or the The pharmaceutical composition containing a pharmacologically acceptable salt may be a single preparation further containing another pharmaceutical agent.
These preparations are produced by well-known methods using additives such as excipients, lubricants, binders, disintegrants, emulsifiers, stabilizers, flavoring agents, and diluents.
　賦形剤は、例えば、有機系賦形剤又は無機系賦形剤が挙げられる。有機系賦形剤は、例えば、乳糖、ショ糖、ブドウ糖、マンニトール若しくはソルビトール等の糖誘導体；トウモロコシデンプン、馬鈴薯デンプン、α－デンプン若しくはデキストリン等のデンプン誘導体；結晶セルロース等のセルロース誘導体；アラビアゴム；デキストラン；又はプルラン等が挙げられる。無機系賦形剤は、例えば、軽質無水珪酸；又は硫酸カルシウム等の硫酸塩等が挙げられる。 Excipients include, for example, organic excipients or inorganic excipients. Examples of the organic excipient include sugar derivatives such as lactose, sucrose, glucose, mannitol or sorbitol; starch derivatives such as corn starch, potato starch, α-starch or dextrin; cellulose derivatives such as crystalline cellulose; gum arabic; Dextran; or pullulan and the like. Examples of inorganic excipients include light anhydrous silicic acid; or sulfates such as calcium sulfate.
　滑沢剤は、例えば、ステアリン酸；ステアリン酸カルシウム若しくはステアリン酸マグネシウム等のステアリン酸金属塩；タルク；コロイドシリカ；ビーズワックス若しくはゲイロウ等のワックス類；硼酸；アジピン酸；硫酸ナトリウム等の硫酸塩；グリコール；フマル酸；安息香酸ナトリウム；Ｄ，Ｌ－ロイシン；ラウリル硫酸ナトリウム；無水珪酸若しくは珪酸水和物等の珪酸類；又は上記の賦形剤におけるデンプン誘導体等が挙げられる。 Lubricants include, for example, stearic acid; stearic acid metal salts such as calcium stearate or magnesium stearate; talc; colloidal silica; waxes such as beeswax or gallow; boric acid; adipic acid; sulfate such as sodium sulfate; glycol Fumaric acid; sodium benzoate; D, L-leucine; sodium lauryl sulfate; silicic acids such as anhydrous silicic acid or silicic acid hydrate; or starch derivatives in the above-mentioned excipients.
　結合剤は、例えば、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、マクロゴール又は上記の賦形剤で示された化合物等が挙げられる。 Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and compounds shown by the above-mentioned excipients.
　崩壊剤は、例えば、低置換度ヒドロキシプロピルセルロース、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム若しくは内部架橋カルボキシメチルセルロースカルシウム等のセルロース誘導体；架橋ポリビニルピロリドン；又はカルボキシメチルスターチ若しくはカルボキシメチルスターチナトリウム等の化学修飾されたデンプン若しくはセルロース誘導体等が挙げられる。 Disintegrants include, for example, cellulose derivatives such as low substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium or internally crosslinked carboxymethylcellulose calcium; crosslinked polyvinylpyrrolidone; or chemically modified starch such as carboxymethyl starch or sodium carboxymethyl starch Or a cellulose derivative etc. are mentioned.
　乳化剤は、例えば、ベントナイト若しくはビーガム等のコロイド性粘土；ラウリル硫酸ナトリウム等の陰イオン界面活性剤；塩化ベンザルコニウム等の陽イオン界面活性剤；又はポリオキシエチレンアルキルエーテル、ポリオキシエチレンソルビタン脂肪酸エステル若しくはショ糖脂肪酸エステル等の非イオン界面活性剤等が挙げられる。 The emulsifier is, for example, colloidal clay such as bentonite or bee gum; an anionic surfactant such as sodium lauryl sulfate; a cationic surfactant such as benzalkonium chloride; or polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester Or nonionic surfactants, such as sucrose fatty acid ester, etc. are mentioned.
　安定剤は、例えば、メチルパラベン若しくはプロピルパラベン等のパラヒドロキシ安息香酸エステル類；クロロブタノール、ベンジルアルコール若しくはフェニルエチルアルコール等のアルコール類；塩化ベンザルコニウム；フェノール若しくはクレゾール等のフェノール類；チメロサール；無水酢酸；又はソルビン酸等が挙げられる。 Stabilizers include, for example, parahydroxybenzoates such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; thimerosal; acetic anhydride Or sorbic acid and the like.
　矯味矯臭剤は、例えば、サッカリンナトリウム若しくはアスパラテーム等の甘味料；クエン酸、リンゴ酸若しくは酒石酸等の酸味料；又はメントール、レモンエキス若しくはオレンジエキス等の香料等が挙げられる。 Examples of the flavoring agent include sweeteners such as saccharin sodium or aspartame; acidulants such as citric acid, malic acid or tartaric acid; or flavors such as menthol, lemon extract or orange extract.
　希釈剤は、通常希釈剤として使用される化合物であり、例えば、乳糖、マンニトール、ブドウ糖、ショ糖、硫酸カルシウム、ヒドロキシプロピルセルロース、微結晶性セルロース、水、エタノール、ポリエチレングリコール、プロピレングリコール、グリセロール、デンプン、ポリビニルピロリドン又はこれらの混合物等が挙げられる。 Diluents are compounds that are usually used as diluents, such as lactose, mannitol, glucose, sucrose, calcium sulfate, hydroxypropylcellulose, microcrystalline cellulose, water, ethanol, polyethylene glycol, propylene glycol, glycerol, Examples thereof include starch, polyvinyl pyrrolidone, and mixtures thereof.
　その他、投与形態に応じて、適切な添加剤を使用することができる。例えば、本発明の医薬組成物の有効成分を、経鼻投与又は経気道投与用にエアロゾル剤とする場合は、例えばジクロロジフルオロメタン、トリクロロフルオロメタン若しくはジクロロテトラフルオロエタン等のクロロフルオロカーボン（ＣＦＣ）類、又は二酸化炭素等を噴射剤として使用することができる。 Other appropriate additives can be used depending on the dosage form. For example, when the active ingredient of the pharmaceutical composition of the present invention is an aerosol for nasal administration or respiratory tract administration, chlorofluorocarbons (CFCs) such as dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane are used. Alternatively, carbon dioxide or the like can be used as a propellant.
　本発明の医薬組成物において、一般式（Ｉ）で表わされる化合物又はその薬理上許容される塩の投与量は、患者の症状、年齢、体重等の条件により変化し得るが、経口投与の場合には、各々、１回当たり下限０．００１ｍｇ／Ｋｇ（好ましくは０．０１ｍｇ／Ｋｇ）、上限２０ｍｇ／Ｋｇ（好ましくは１０ｍｇ／Ｋｇ）を、非経口投与の場合には、各々、１回当たり下限０．０００１ｍｇ／Ｋｇ（好ましくは０．０００５ｍｇ／Ｋｇ）、上限１０ｍｇ／Ｋｇ（好ましくは５ｍｇ／Ｋｇ）を、成人に対して１日当たり１乃至６回、症状に応じて投与することができる。 In the pharmaceutical composition of the present invention, the dose of the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof may vary depending on conditions such as the patient's symptoms, age, weight, etc. In the case of parenteral administration, the lower limit is 0.001 mg / Kg (preferably 0.01 mg / Kg) and the upper limit is 20 mg / Kg (preferably 10 mg / Kg). A lower limit of 0.0001 mg / Kg (preferably 0.0005 mg / Kg) and an upper limit of 10 mg / Kg (preferably 5 mg / Kg) can be administered to adults 1 to 6 times per day depending on the symptoms.
　本発明の医薬組成物において、他の医薬の投与量は、他の医薬の種類、患者の症状、年齢、体重等の条件により変化し得るが、経口投与の場合には、各々、１回当たり下限０．００１ｍｇ／Ｋｇ（好ましくは０．０１ｍｇ／Ｋｇ）、上限５００ｍｇ／Ｋｇ（好ましくは５０ｍｇ／Ｋｇ）を、非経口投与の場合には、各々、１回当たり下限０．０００１ｍｇ／Ｋｇ（好ましくは０．０００５ｍｇ／Ｋｇ）、上限５０ｍｇ／Ｋｇ（好ましくは５ｍｇ／Ｋｇ）を、成人に対して１日当たり１乃至６回、症状に応じて投与することができる。 In the pharmaceutical composition of the present invention, the dosage of other pharmaceuticals may vary depending on other pharmaceutical types, patient symptoms, age, body weight and other conditions. In the case of parenteral administration, the lower limit is 0.001 mg / Kg (preferably 0.01 mg / Kg) and the upper limit is 500 mg / Kg (preferably 50 mg / Kg). Is 0.0005 mg / Kg), and an upper limit of 50 mg / Kg (preferably 5 mg / Kg) can be administered to adults 1 to 6 times per day depending on the symptoms.
　以下に実施例、参考例及び試験例を示して本発明を更に詳細に説明するが、本発明の範囲はこれらに限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples and Test Examples, but the scope of the present invention is not limited thereto.
［実施例１］
（６－｛［３’－（１－プロペニル）ビフェニル－４－イルメチル］（ピリジン－２－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸エチル [Example 1]
(6-{[3 ′-(1-propenyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate
　参考例３－（ｂ）で得られた３’－（１－プロペニル）ビフェニル－４－イルメタノール２０５ｍｇ（０．９１３ｍｍｏｌ）のテトラヒドロフラン９．４ｍＬ溶液に、参考例１－（ｇ）と同様の方法で得られた｛６－［（ピリジン－２－イルスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸エチル３２０ｍｇ（０．９１３ｍｍｏｌ）、トリ－ｎ－ブチルホスフィン５７０μＬ（２．３１ｍｍｏｌ）及びＮ，Ｎ，Ｎ’，Ｎ’－テトラメチルアゾジカルボキサミド２３６ｍｇ（１．３７ｍｍｏｌ）を加え、室温で５時間撹拌した。反応終了後、反応溶液に水を加え、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝２：３（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物５１０ｍｇを微黄色油状物として得た。（定量的）
マススペクトル（ＦＡＢ，ｍ／ｚ）：５５７（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：8.62 (ddd, J = 4.7, 1.8, 1.0 Hz, 1H), 7.83 (ddd, J = 7.8, 1.0, 1.0 Hz, 1H), 7.75 (ddd, J = 7.8, 7.6, 1.8 Hz, 1H), 7.52-7.43 (m, 3H), 7.41-7.30 (m, 6H) , 7.27-7.20 (m, 1H), 6.51 (d, J = 7.3 Hz, 1H) , 6.50-6.42 (m, 1H) , 6.38-6.26 (m, 1H), 6.23 (d, J = 8.3 Hz, 1H), 4.80 (s, 2H), 4.70 (t, J = 5.4 Hz, 0.9H), 4.42 (s, 2H), 4.22 (q, J = 7.1 Hz, 2H), 3.96 (d, J = 5.4 Hz, 2H), 1.91 (dd, J = 6.3, 1.5 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H)。 To a solution of 3 ′-(1-propenyl) biphenyl-4-ylmethanol 205 mg (0.913 mmol) obtained in Reference Example 3- (b) in 9.4 mL of tetrahydrofuran, the same method as in Reference Example 1- (g) {6-[(pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} ethyl acetate 320 mg (0.913 mmol), tri-n-butylphosphine 570 μL (2.31 mmol) and N, N , N ′, N′-Tetramethylazodicarboxamide (236 mg, 1.37 mmol) was added, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 2: 3 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 510 mg of the title compound as a pale yellow oil. Obtained as a thing. (quantitative)
Mass spectrum (FAB, m / z): 557 (M + +1).
1 H-NMR spectrum (CDCl 3 , δ ppm): 8.62 (ddd, J = 4.7, 1.8, 1.0 Hz, 1H), 7.83 (ddd, J = 7.8, 1.0, 1.0 Hz, 1H), 7.75 (ddd, J = 7.8, 7.6, 1.8 Hz, 1H), 7.52-7.43 (m, 3H), 7.41-7.30 (m, 6H), 7.27-7.20 (m, 1H), 6.51 (d, J = 7.3 Hz, 1H), 6.50 -6.42 (m, 1H), 6.38-6.26 (m, 1H), 6.23 (d, J = 8.3 Hz, 1H), 4.80 (s, 2H), 4.70 (t, J = 5.4 Hz, 0.9H), 4.42 (s, 2H), 4.22 (q, J = 7.1 Hz, 2H), 3.96 (d, J = 5.4 Hz, 2H), 1.91 (dd, J = 6.3, 1.5 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H).
［実施例２］
（６－｛［３’－（１－プロペニル）ビフェニル－４－イルメチル］（ピリジン－２－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸 [Example 2]
(6-{[3 ′-(1-propenyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid
　実施例１で得られた（６－｛［３’－（１－プロペニル）ビフェニル－４－イルメチル］（ピリジン－２－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸エチル２２０ｍｇ（０．３９５ｍｍｏｌ）のエタノール２．０ｍＬ溶液に、１ｍｏｌ／Ｌの水酸化ナトリウム水溶液１．９８ｍＬ（１．９８ｍｍｏｌ）を加え、室温で２．５時間撹拌した。反応終了後、反応溶液に水を添加し、次いで１ｍｏｌ／Ｌの塩酸でｐＨ４．５に調整した。析出した固体を濾取した後、減圧乾燥することにより、標記化合物１４６ｍｇを白色固体として得た。（収率７０％）
マススペクトル（ＦＡＢ，ｍ／ｚ）：５２９（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＤＭＳＯ－ｄ６，δppm）：8.64 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 7.95 (ddd, J = 7.7, 7.7, 1.7 Hz, 1H), 7.80 (ddd, J = 7.7, 1.0, 0.9 Hz, 1H), 7.61-7.56 (m, 4H), 7.48-7.44 (m, 1H), 7.39-7.37 (m, 2H), 7.35-7.32 (m, 2H), 7.19 (dd, J = 8.3, 7.2 Hz, 1H), 6.61 (brs, 0.8H), 6.52-6.47 (m, 1H), 6.44-6.37 (m, 1H), 6.33 (d, J = 8.3 Hz, 1H), 6.28 (d, J = 7.2 Hz, 1H), 4.74 (s, 2H), 4.24 (s, 2H), 3.76 (d, J = 4.0 Hz, 2H), 1.87 (dd, J = 6.2, 1.5 Hz, 3H)。 220 mg (0.395 mmol) of ethyl (6-{[3 ′-(1-propenyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) obtained in Example 1 1) 1.98 mL (1.98 mmol) of 1 mol / L sodium hydroxide aqueous solution was added to ethanol 2.0 mL solution, and the mixture was stirred at room temperature for 2.5 hours. After completion of the reaction, water was added to the reaction solution, and then adjusted to pH 4.5 with 1 mol / L hydrochloric acid. The precipitated solid was collected by filtration and dried under reduced pressure to give 146 mg of the title compound as a white solid. (Yield 70%)
Mass spectrum (FAB, m / z): 529 (M + +1).
1 H-NMR spectrum (DMSO-d 6 , δ ppm): 8.64 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 7.95 (ddd, J = 7.7, 7.7, 1.7 Hz, 1H), 7.80 (ddd, J = 7.7, 1.0, 0.9 Hz, 1H), 7.61-7.56 (m, 4H), 7.48-7.44 (m, 1H), 7.39-7.37 (m, 2H), 7.35-7.32 (m, 2H), 7.19 ( dd, J = 8.3, 7.2 Hz, 1H), 6.61 (brs, 0.8H), 6.52-6.47 (m, 1H), 6.44-6.37 (m, 1H), 6.33 (d, J = 8.3 Hz, 1H), 6.28 (d, J = 7.2 Hz, 1H), 4.74 (s, 2H), 4.24 (s, 2H), 3.76 (d, J = 4.0 Hz, 2H), 1.87 (dd, J = 6.2, 1.5 Hz, 3H ).
［実施例３］
（６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（ピリジン－２－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸エチル [Example 3]
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate
　参考例４－（ｂ）で得られた３’－（１－プロピニル）ビフェニル－４－イルメタノール２００ｍｇ（０．９００ｍｍｏｌ）のテトラヒドロフラン４．０ｍＬ溶液に、参考例１－（ｇ）と同様の方法で得られた｛６－［（ピリジン－２－イルスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸エチル３１５ｍｇ（０．９００ｍｍｏｌ）、トリ－ｎ－ブチルホスフィン４５０μＬ（１．８２ｍｍｏｌ）及びＮ，Ｎ，Ｎ’，Ｎ’－テトラメチルアゾジカルボキサミド３１０ｍｇ（１．８０ｍｍｏｌ）を加え、室温で３時間撹拌した。反応終了後、反応溶液に水を加え、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝３：２→２：３（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物４８３ｍｇを白色泡状物として得た。（収率９７％）
マススペクトル（ＦＡＢ，ｍ／ｚ）：５５５（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：8.62 (ddd, J = 4.6, 1.7, 1.0 Hz, 1H), 7.83 (ddd, J = 7.7, 1.3, 1.0 Hz, 1H), 7.75 (ddd, J = 7.7, 7.7, 1.7 Hz, 1H), 7.59-7.58 (m, 1H), 7.47-7.43 (m, 3H), 7.41-7.31 (m, 5H), 7.23 (dd, J = 8.2, 7.1 Hz, 1H), 6.51 (d, J = 7.1 Hz, 1H), 6.23 (d, J = 8.2 Hz, 1H), 4.79 (s, 2H), 4.70 (t, J = 5.4 Hz, 1H), 4.42 (s, 2H), 4.22 (q, J = 7.1 Hz, 2H), 3.96 (d, J = 5.4 Hz, 2H), 2.08 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H)。 To a 4.0 mL tetrahydrofuran solution of 200 mg (0.900 mmol) of 3 ′-(1-propynyl) biphenyl-4-ylmethanol obtained in Reference Example 4- (b), the same method as in Reference Example 1- (g) {6-[(Pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} ethyl acetate 315 mg (0.900 mmol), 450 μL (1.82 mmol) tri-n-butylphosphine and N, N , N ′, N′-Tetramethylazodicarboxamide (310 mg, 1.80 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 3: 2 → 2: 3 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 483 mg of the title compound. Was obtained as a white foam. (Yield 97%)
Mass spectrum (FAB, m / z): 555 (M + +1).
1 H-NMR spectrum (CDCl 3 , δ ppm): 8.62 (ddd, J = 4.6, 1.7, 1.0 Hz, 1H), 7.83 (ddd, J = 7.7, 1.3, 1.0 Hz, 1H), 7.75 (ddd, J = 7.7, 7.7, 1.7 Hz, 1H), 7.59-7.58 (m, 1H), 7.47-7.43 (m, 3H), 7.41-7.31 (m, 5H), 7.23 (dd, J = 8.2, 7.1 Hz, 1H) , 6.51 (d, J = 7.1 Hz, 1H), 6.23 (d, J = 8.2 Hz, 1H), 4.79 (s, 2H), 4.70 (t, J = 5.4 Hz, 1H), 4.42 (s, 2H) , 4.22 (q, J = 7.1 Hz, 2H), 3.96 (d, J = 5.4 Hz, 2H), 2.08 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H).
［実施例４］
（６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（ピリジン－２－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸 [Example 4]
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid
　実施例３で得られた（６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（ピリジン－２－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸エチル４７６ｍｇ（０．８５８ｍｍｏｌ）のエタノール３．０ｍＬ溶液に、１ｍｏｌ／Ｌの水酸化ナトリウム水溶液３．４３ｍＬ（３．４３ｍｍｏｌ）を加え、室温で５時間撹拌した。反応終了後、反応溶液に水を添加し、１ｍｏｌ／Ｌの塩酸でｐＨ４．５に調整した後、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；塩化メチレン：メタノール＝１５：１→１０：１（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物４４４ｍｇを白色泡状物として得た。（収率９８％）
マススペクトル（ＦＡＢ，ｍ／ｚ）：５２７（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＤＭＳＯ－ｄ６，δppm）：12.42 (brs, 0.6H), 8.64 (ddd, J = 4.7, 1.8, 1.0 Hz, 1H), 7.95 (ddd, J = 7.8, 7.7, 1.8 Hz, 1H), 7.80 (ddd, J = 7.8, 1.0, 1.0 Hz, 1H), 7.63-7.56 (m, 5H), 7.43 (dd, J = 7.9, 7.9 Hz, 1H), 7.37 (ddd, J = 7.9, 1.7, 0.9 Hz, 1H), 7.35-7.32 (m, 2H), 7.19 (dd, J = 8.4, 7.0 Hz, 1H), 6.75 (t, J = 5.9 Hz, 1H), 6.34 (d, J = 8.4 Hz, 1H), 6.28 (d, J = 7.0 Hz, 1H), 4.74 (s, 2H), 4.24 (s, 2H), 3.82 (d, J = 5.9 Hz, 2H), 2.07 (s, 3H)。 476 mg (0.858 mmol) of ethyl (6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) obtained in Example 3 ) In ethanol (3.0 mL) was added 1 mol / L aqueous sodium hydroxide solution (3.43 mL, 3.43 mmol), and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, water was added to the reaction solution, adjusted to pH 4.5 with 1 mol / L hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; methylene chloride: methanol = 15: 1 → 10: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 444 mg of the title compound as white. Obtained as a foam. (Yield 98%)
Mass spectrum (FAB, m / z): 527 (M + +1).
1 H-NMR spectrum (DMSO-d 6 , δ ppm): 12.42 (brs, 0.6H), 8.64 (ddd, J = 4.7, 1.8, 1.0 Hz, 1H), 7.95 (ddd, J = 7.8, 7.7, 1.8 Hz) , 1H), 7.80 (ddd, J = 7.8, 1.0, 1.0 Hz, 1H), 7.63-7.56 (m, 5H), 7.43 (dd, J = 7.9, 7.9 Hz, 1H), 7.37 (ddd, J = 7.9 , 1.7, 0.9 Hz, 1H), 7.35-7.32 (m, 2H), 7.19 (dd, J = 8.4, 7.0 Hz, 1H), 6.75 (t, J = 5.9 Hz, 1H), 6.34 (d, J = 8.4 Hz, 1H), 6.28 (d, J = 7.0 Hz, 1H), 4.74 (s, 2H), 4.24 (s, 2H), 3.82 (d, J = 5.9 Hz, 2H), 2.07 (s, 3H) .
［実施例５］
（６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（ピリジン－３－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸エチル [Example 5]
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate
　参考例４－（ｂ）と同様の方法で得られた３’－（１－プロピニル）ビフェニル－４－イルメタノール１７８ｍｇ（０．８００ｍｍｏｌ）のテトラヒドロフラン４．０ｍＬ溶液に、参考例２－（ｂ）と同様の方法で得られた｛６－［（ピリジン－３－イルスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸エチル２８０ｍｇ（０．８００ｍｍｏｌ）、トリ－ｎ－ブチルホスフィン３９５μＬ（１．６０ｍｍｏｌ）及びＮ，Ｎ，Ｎ’，Ｎ’－テトラメチルアゾジカルボキサミド２７６ｍｇ（１．６０ｍｍｏｌ）を加え、室温で３時間撹拌した。反応終了後、反応溶液に水を加え、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝３：７→０：１（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物４００ｍｇを微黄色油状物として得た。（収率９０％）
マススペクトル（ＥＳＩ＋，ｍ／ｚ）：５５５（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：8.97 (dd, J = 2.3, 0.7 Hz, 1H), 8.69 (dd, J = 4.9, 1.7 Hz, 1H), 7.92 (ddd, J = 8.0, 2.3, 1.7 Hz, 1H), 7.61-7.60 (m, 1H), 7.52-7.49 (m, 2H), 7.48-7.46 (m, 1H), 7.38-7.35 (m, 4H), 7.32-7.27 (m, 2H), 6.46 (d, J = 7.0 Hz, 1H), 6.28 (d, J = 8.2 Hz, 1H), 4.74 (t, J = 5.4 Hz, 1H), 4.66 (s, 2H), 4.34 (s, 2H), 4.22 (q, J = 7.2 Hz, 2H), 3.87 (d, J = 5.4 Hz, 2H), 2.08 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H)。 To a 4.0 mL tetrahydrofuran solution of 178 mg (0.800 mmol) of 3 ′-(1-propynyl) biphenyl-4-ylmethanol obtained by the same method as in Reference Example 4- (b), Reference Example 2- (b) 280 mg (0.800 mmol) of ethyl {6-[(pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-ylamino} obtained by the same method as above, 395 μL (1.60 mmol) of tri-n-butylphosphine And 276 mg (1.60 mmol) of N, N, N ′, N′-tetramethylazodicarboxamide were added and stirred at room temperature for 3 hours. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 3: 7 → 0: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 400 mg of the title compound. Was obtained as a slightly yellow oil. (Yield 90%)
Mass spectrum (ESI + , m / z): 555 (M + +1).
1 H-NMR spectrum (CDCl 3 , δ ppm): 8.97 (dd, J = 2.3, 0.7 Hz, 1H), 8.69 (dd, J = 4.9, 1.7 Hz, 1H), 7.92 (ddd, J = 8.0, 2.3, 1.7 Hz, 1H), 7.61-7.60 (m, 1H), 7.52-7.49 (m, 2H), 7.48-7.46 (m, 1H), 7.38-7.35 (m, 4H), 7.32-7.27 (m, 2H) , 6.46 (d, J = 7.0 Hz, 1H), 6.28 (d, J = 8.2 Hz, 1H), 4.74 (t, J = 5.4 Hz, 1H), 4.66 (s, 2H), 4.34 (s, 2H) , 4.22 (q, J = 7.2 Hz, 2H), 3.87 (d, J = 5.4 Hz, 2H), 2.08 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H).
［実施例６］
（６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（ピリジン－３－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸 [Example 6]
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid
　実施例５で得られた（６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（ピリジン－３－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸エチル３９５ｍｇ（０．７１２ｍｍｏｌ）のエタノール３．０ｍＬ溶液に、１ｍｏｌ／Ｌの水酸化ナトリウム水溶液３．０ｍＬ（３．０ｍｍｏｌ）を加え、室温で１６時間撹拌した。反応終了後、反応溶液に水を添加し、１ｍｏｌ／Ｌの塩酸でｐＨ４．５に調整した後、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。残渣にｔｅｒｔ－ブチルメチルエーテル１０ｍＬ及びメタノール０．５ｍＬを添加し、超音波処理により析出した固体を濾取した後に減圧乾燥することにより、標記化合物３４０ｍｇを白色固体として得た。（収率９１％）
マススペクトル（ＥＳＩ＋，ｍ／ｚ）：５２７（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＤＭＳＯ－ｄ６，δppm）：12.42 (brs, 0.6H), 8.83 (dd, J = 2.4, 0.6 Hz, 1H), 8.72 (dd, J = 4.8, 1.6 Hz, 1H), 8.02 (ddd, J = 8.1, 2.4, 1.6 Hz, 1H), 7.65-7.61 (m, 4H), 7.47 (ddd, J = 8.1, 4.8, 0.6 Hz, 1H), 7.44 (dd, J = 7.9, 7.9 Hz, 1H), 7.39-7.36 (m, 3H), 7.24 (dd, J = 8.3, 7.1 Hz, 1H), 6.78 (t, J = 5.9 Hz, 1H), 6.37 (d, J = 8.3 Hz, 1H), 6.33 (d, J = 7.1 Hz, 1H), 4.71 (s, 2H), 4.21 (s, 2H), 3.71 (d, J = 5.9 Hz, 2H), 2.07 (s, 3H)。 395 mg (0.712 mmol) of ethyl (6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) obtained in Example 5 ) In ethanol (3.0 mL) was added 1 mol / L aqueous sodium hydroxide solution (3.0 mL, 3.0 mmol), and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, water was added to the reaction solution, adjusted to pH 4.5 with 1 mol / L hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the residue were added 10 mL of tert-butyl methyl ether and 0.5 mL of methanol, and the solid precipitated by ultrasonication was collected by filtration and dried under reduced pressure to obtain 340 mg of the title compound as a white solid. (Yield 91%)
Mass spectrum (ESI + , m / z): 527 (M + +1).
1 H-NMR spectrum (DMSO-d 6 , δ ppm): 12.42 (brs, 0.6H), 8.83 (dd, J = 2.4, 0.6 Hz, 1H), 8.72 (dd, J = 4.8, 1.6 Hz, 1H), 8.02 (ddd, J = 8.1, 2.4, 1.6 Hz, 1H), 7.65-7.61 (m, 4H), 7.47 (ddd, J = 8.1, 4.8, 0.6 Hz, 1H), 7.44 (dd, J = 7.9, 7.9 Hz, 1H), 7.39-7.36 (m, 3H), 7.24 (dd, J = 8.3, 7.1 Hz, 1H), 6.78 (t, J = 5.9 Hz, 1H), 6.37 (d, J = 8.3 Hz, 1H ), 6.33 (d, J = 7.1 Hz, 1H), 4.71 (s, 2H), 4.21 (s, 2H), 3.71 (d, J = 5.9 Hz, 2H), 2.07 (s, 3H).
［実施例７］
｛６－［（３’－エトキシビフェニル－４－イルメチル）（ピリジン－２－イルスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸 [Example 7]
{6-[(3′-Ethoxybiphenyl-4-ylmethyl) (pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid
７－（ａ）：（ｔｅｒｔ－ブトキシカルボニル｛６－［（３’－エトキシビフェニル－４－イルメチル）（ピリジン－２－イルスルホニル）アミノメチル］ピリジン－２－イル｝アミノ）酢酸ｔｅｒｔ－ブチル
　参考例５で得られた３’－エトキシビフェニル－４－イルメタノール１８３ｍｇ（０．８００ｍｍｏｌ）のテトラヒドロフラン４．０ｍＬ溶液に、参考例１－（ｆ）と同様の方法で得られた（ｔｅｒｔ－ブトキシカルボニル｛６－［（ピリジン－２－イルスルホニル）アミノメチル］ピリジン－２－イル｝アミノ）酢酸ｔｅｒｔ－ブチル４２２ｍｇ（０．８８０ｍｍｏｌ）、トリ－ｎ－ブチルホスフィン３９５μＬ（１．６０ｍｍｏｌ）及びＮ，Ｎ，Ｎ’，Ｎ’－テトラメチルアゾジカルボキサミド２７６ｍｇ（１．６０ｍｍｏｌ）を加え、室温で３時間撹拌した。反応終了後、反応溶液に水を加え、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；トルエン：酢酸エチル＝８：１→６：１（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物５３７ｍｇを白色泡状物として得た。（収率９８％）
マススペクトル（ＦＡＢ，ｍ／ｚ）：６８９（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：8.60 (ddd, J = 4.6, 1.8, 1.0 Hz, 1H), 7.82 (ddd, J = 7.7, 1.0, 1.0 Hz, 1H), 7.77 (ddd, J = 7.7, 7.6, 1.8 Hz, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.48-7.26 (m, 7H), 7.11 (ddd, J = 7.9, 1.7, 0.9 Hz, 1H), 7.07 (dd, J = 2.3, 1.7 Hz, 1H), 6.91 (d, J = 7.3 Hz, 1H), 6.88 (ddd, J = 7.9, 2.3, 0.9 Hz, 1H), 4.74 (s, 2H), 4.51 (s, 2H), 4.46 (s, 2H), 4.10 (q, J = 6.9 Hz, 2H), 1.52 (s, 9H), 1.45 (t, J = 6.9 Hz, 3H), 1.42 (s, 9H)。 7- (a): (tert-Butoxycarbonyl {6-[(3′-ethoxybiphenyl-4-ylmethyl) (pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate Reference To a 4.0 mL tetrahydrofuran solution of 183 mg (0.800 mmol) of 3′-ethoxybiphenyl-4-ylmethanol obtained in Example 5, (tert-butoxycarbonyl) was obtained in the same manner as in Reference Example 1- (f). {6-[(Pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate 422 mg (0.880 mmol), tri-n-butylphosphine 395 μL (1.60 mmol) and N, N , N ′, N′-tetramethylazodicarboxamide 276 mg (1.60 mmol) was added. And stirred at room temperature for 3 hours. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; toluene: ethyl acetate = 8: 1 → 6: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 537 mg of the title compound as white. Obtained as a foam. (Yield 98%)
Mass spectrum (FAB, m / z): 689 (M + +1).
1 H-NMR spectrum (CDCl 3 , δ ppm): 8.60 (ddd, J = 4.6, 1.8, 1.0 Hz, 1H), 7.82 (ddd, J = 7.7, 1.0, 1.0 Hz, 1H), 7.77 (ddd, J = 7.7, 7.6, 1.8 Hz, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.48-7.26 (m, 7H), 7.11 (ddd, J = 7.9, 1.7, 0.9 Hz, 1H), 7.07 (dd , J = 2.3, 1.7 Hz, 1H), 6.91 (d, J = 7.3 Hz, 1H), 6.88 (ddd, J = 7.9, 2.3, 0.9 Hz, 1H), 4.74 (s, 2H), 4.51 (s, 2H), 4.46 (s, 2H), 4.10 (q, J = 6.9 Hz, 2H), 1.52 (s, 9H), 1.45 (t, J = 6.9 Hz, 3H), 1.42 (s, 9H).
７－（ｂ）：｛６－［（３’－エトキシビフェニル－４－イルメチル）（ピリジン－２－イルスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸
　実施例７－（ａ）で得られた（ｔｅｒｔ－ブトキシカルボニル｛６－［（３’－エトキシビフェニル－４－イルメチル）（ピリジン－２－イルスルホニル）アミノメチル］ピリジン－２－イル｝アミノ）酢酸ｔｅｒｔ－ブチル５２５ｍｇ（０．７６２ｍｍｏｌ）の１，４－ジオキサン４．０ｍＬ溶液に、６ｍｏｌ／Ｌの塩酸３．２ｍＬ（１９．２ｍｍｏｌ）及び水０．８ｍＬを加え、７０℃で２時間加熱撹拌した。反応終了後、反応溶液を減圧濃縮し、次いで水を加えて、１ｍｏｌ／Ｌの水酸化ナトリウム水溶液でｐＨ４．４に調整した後、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；塩化メチレン：メタノール＝１５：１→１０：１（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物３６９ｍｇを白色泡状物として得た。（収率９１％）
マススペクトル（ＦＡＢ，ｍ／ｚ）：５３３（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＤＭＳＯ－ｄ６，δppm）：12.41 (brs, 0.4H), 8.64 (ddd, J = 4.6, 1.8, 0.9 Hz, 1H), 7.95 (ddd, J = 7.8, 7.8, 1.8 Hz, 1H), 7.80 (ddd, J = 7.8, 1.0, 0.9 Hz, 1H), 7.59-7.56 (m, 3H), 7.36 (dd, J = 8.1, 8.1 Hz, 1H), 7.33-7.31 (m, 2H), 7.20 (dd, J = 8.2, 7.1 Hz, 1H), 7.18 (ddd, J = 8.1, 1.8, 0.8 Hz, 1H), 7.14 (dd, J = 2.3, 1.8 Hz, 1H), 6.92 (ddd, J = 8.1, 2.3, 0.8 Hz, 1H), 6.75 (t, J = 5.9 Hz, 1H), 6.34 (d, J = 8.2 Hz, 1H), 6.28 (d, J = 7.1 Hz, 1H), 4.74 (s, 2H), 4.24 (s, 2H), 4.10 (q, J = 7.0 Hz, 2H), 3.82 (d, J = 5.9 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H)。 7- (b): {6-[(3′-ethoxybiphenyl-4-ylmethyl) (pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid obtained in Example 7- (a) (Tert-Butoxycarbonyl {6-[(3′-ethoxybiphenyl-4-ylmethyl) (pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate (525 mg, 0.762 mmol) To a 4.0 mL solution of 1,4-dioxane, 3.2 mL (19.2 mmol) of 6 mol / L hydrochloric acid and 0.8 mL of water were added, and the mixture was heated and stirred at 70 ° C. for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, then water was added, the pH was adjusted to 4.4 with a 1 mol / L aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; methylene chloride: methanol = 15: 1 → 10: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 369 mg of the title compound as white. Obtained as a foam. (Yield 91%)
Mass spectrum (FAB, m / z): 533 (M + +1).
1 H-NMR spectrum (DMSO-d 6 , δ ppm): 12.41 (brs, 0.4H), 8.64 (ddd, J = 4.6, 1.8, 0.9 Hz, 1H), 7.95 (ddd, J = 7.8, 7.8, 1.8 Hz) , 1H), 7.80 (ddd, J = 7.8, 1.0, 0.9 Hz, 1H), 7.59-7.56 (m, 3H), 7.36 (dd, J = 8.1, 8.1 Hz, 1H), 7.33-7.31 (m, 2H ), 7.20 (dd, J = 8.2, 7.1 Hz, 1H), 7.18 (ddd, J = 8.1, 1.8, 0.8 Hz, 1H), 7.14 (dd, J = 2.3, 1.8 Hz, 1H), 6.92 (ddd, J = 8.1, 2.3, 0.8 Hz, 1H), 6.75 (t, J = 5.9 Hz, 1H), 6.34 (d, J = 8.2 Hz, 1H), 6.28 (d, J = 7.1 Hz, 1H), 4.74 ( s, 2H), 4.24 (s, 2H), 4.10 (q, J = 7.0 Hz, 2H), 3.82 (d, J = 5.9 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H).
［実施例８］
｛６－［（３’－エトキシビフェニル－４－イルメチル）（ピリジン－２－イルスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸ヘキシル [Example 8]
{6-[(3′-Ethoxybiphenyl-4-ylmethyl) (pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid hexyl
　参考例５で得られた３’－エトキシビフェニル－４－イルメタノール１７１ｍｇ（０．７５０ｍｍｏｌ）のテトラヒドロフラン４．０ｍＬ溶液に、参考例６で得られた｛６－［（ピリジン－２－イルスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸ヘキシル３０５ｍｇ（０．７５０ｍｍｏｌ）、トリ－ｎ－ブチルホスフィン２８０μＬ（１．１４ｍｍｏｌ）及びＮ，Ｎ，Ｎ’，Ｎ’－テトラメチルアゾジカルボキサミド１９６ｍｇ（１．１４ｍｍｏｌ）を加え、室温で１６時間撹拌した。反応終了後、反応溶液に水を加え、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝３：２→２：３（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物４２９ｍｇを無色油状物として得た。（収率９３％）
マススペクトル（ＦＡＢ，ｍ／ｚ）：６１７（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：8.61 (ddd, J = 4.7, 1.7, 1.0 Hz, 1H), 7.82 (ddd, J = 7.7, 1.1, 1.0 Hz, 1H), 7.75 (ddd, J = 7.7, 7.7, 1.7 Hz, 1H), 7.47-7.45 (m, 2H), 7.38 (ddd, J = 7.7, 4.7, 1.1 Hz, 1H), 7.35-7.31 (m, 3H), 7.23 (dd, J = 8.4, 7.3 Hz, 1H), 7.12 (ddd, J = 8.1, 1.8, 1.0 Hz, 1H), 7.08 (dd, J = 2.4, 1.8 Hz, 1H), 6.88 (ddd, J = 8.1, 2.4, 1.0 Hz, 1H), 6.51 (d, J = 7.3 Hz, 1H), 6.23 (d, J = 8.4 Hz, 1H), 4.79 (s, 2H), 4.70 (t, J = 5.3 Hz, 1H), 4.42 (s, 2H), 4.15 (t, J = 6.8 Hz, 2H), 4.10 (q, J = 7.0 Hz, 2H), 3.96 (d, J = 5.3 Hz, 2H), 1.66-1.60 (m, 2H), 1.45 (t, J = 7.0 Hz, 3H), 1.34-1.25 (m, 6H), 0.87 (t, J = 7.0 Hz, 3H)。 To a 4.0 mL tetrahydrofuran solution of 171 mg (0.750 mmol) of 3′-ethoxybiphenyl-4-ylmethanol obtained in Reference Example 5, {6-[(pyridin-2-ylsulfonyl) obtained in Reference Example 6 was added. Aminomethyl] pyridin-2-ylamino} acetyl 305 mg (0.750 mmol), tri-n-butylphosphine 280 μL (1.14 mmol) and N, N, N ′, N′-tetramethylazodicarboxamide 196 mg (1. 14 mmol) and stirred at room temperature for 16 hours. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: n-hexane: ethyl acetate = 3: 2 → 2: 3 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 429 mg of the title compound. Was obtained as a colorless oil. (Yield 93%)
Mass spectrum (FAB, m / z): 617 (M + +1).
1 H-NMR spectrum (CDCl 3 , δ ppm): 8.61 (ddd, J = 4.7, 1.7, 1.0 Hz, 1H), 7.82 (ddd, J = 7.7, 1.1, 1.0 Hz, 1H), 7.75 (ddd, J = 7.7, 7.7, 1.7 Hz, 1H), 7.47-7.45 (m, 2H), 7.38 (ddd, J = 7.7, 4.7, 1.1 Hz, 1H), 7.35-7.31 (m, 3H), 7.23 (dd, J = 8.4, 7.3 Hz, 1H), 7.12 (ddd, J = 8.1, 1.8, 1.0 Hz, 1H), 7.08 (dd, J = 2.4, 1.8 Hz, 1H), 6.88 (ddd, J = 8.1, 2.4, 1.0 Hz , 1H), 6.51 (d, J = 7.3 Hz, 1H), 6.23 (d, J = 8.4 Hz, 1H), 4.79 (s, 2H), 4.70 (t, J = 5.3 Hz, 1H), 4.42 (s , 2H), 4.15 (t, J = 6.8 Hz, 2H), 4.10 (q, J = 7.0 Hz, 2H), 3.96 (d, J = 5.3 Hz, 2H), 1.66-1.60 (m, 2H), 1.45 (t, J = 7.0 Hz, 3H), 1.34-1.25 (m, 6H), 0.87 (t, J = 7.0 Hz, 3H).
［実施例９］
｛６－［（３’－エトキシビフェニル－４－イルメチル）（ピリジン－３－イルスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸 [Example 9]
{6-[(3′-Ethoxybiphenyl-4-ylmethyl) (pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid
９－（ａ）：（ｔｅｒｔ－ブトキシカルボニル｛６－［（３’－エトキシビフェニル－４－イルメチル）（ピリジン－３－イルスルホニル）アミノメチル］ピリジン－２－イル｝アミノ）酢酸ｔｅｒｔ－ブチル
　参考例５で得られた３’－エトキシビフェニル－４－イルメタノール１８３ｍｇ（０．８００ｍｍｏｌ）のテトラヒドロフラン４．０ｍＬ溶液に、参考例２－（ａ）と同様の方法で得られた（ｔｅｒｔ－ブトキシカルボニル｛６－［（ピリジン－３－イルスルホニル）アミノメチル］ピリジン－２－イル｝アミノ）酢酸ｔｅｒｔ－ブチル４２２ｍｇ（０．８８０ｍｍｏｌ）、トリ－ｎ－ブチルホスフィン３９５μＬ（１．６０ｍｍｏｌ）及びＮ，Ｎ，Ｎ’，Ｎ’－テトラメチルアゾジカルボキサミド２７６ｍｇ（１．６０ｍｍｏｌ）を加え、室温で３時間撹拌した。反応終了後、反応溶液に水を加え、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝７：３→１：１（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物５５０ｍｇを白色泡状物として得た。（定量的）
マススペクトル（ＦＡＢ，ｍ／ｚ）：６８９（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：8.96 (dd, J = 2.4, 0.7 Hz, 1H), 8.71 (dd, J = 4.8, 1.6 Hz, 1H), 7.87 (ddd, J = 7.9, 2.4, 1.6 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.54-7.47 (m, 3H), 7.36-7.26 (m, 4H), 7.13 (ddd, J = 7.9, 1.9, 1.0 Hz, 1H), 7.08 (dd, J = 2.3, 1.9 Hz, 1H), 6.89 (ddd, J = 8.3, 2.3, 1.0 Hz, 1H), 6.87 (d, J = 7.3 Hz, 1H), 4.62 (s, 2H), 4.42 (s, 2H), 4.37 (s, 2H), 4.10 (q, J = 7.0 Hz, 2H), 1.52 (s, 9H), 1.45 (t, J = 7.0 Hz, 3H), 1.42 (s, 9H)。 9- (a): (tert-Butoxycarbonyl {6-[(3′-ethoxybiphenyl-4-ylmethyl) (pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate Reference To a 4.0 mL tetrahydrofuran solution of 183 mg (0.800 mmol) of 3′-ethoxybiphenyl-4-ylmethanol obtained in Example 5, (tert-butoxycarbonyl) was obtained in the same manner as in Reference Example 2- (a). {6-[(Pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate 422 mg (0.880 mmol), tri-n-butylphosphine 395 μL (1.60 mmol) and N, N , N ′, N′-tetramethylazodicarboxamide 276 mg (1.60 mmol) was added. And stirred at room temperature for 3 hours. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 7: 3 → 1: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 550 mg of the title compound. Was obtained as a white foam. (quantitative)
Mass spectrum (FAB, m / z): 689 (M + +1).
1 H-NMR spectrum (CDCl 3 , δ ppm): 8.96 (dd, J = 2.4, 0.7 Hz, 1H), 8.71 (dd, J = 4.8, 1.6 Hz, 1H), 7.87 (ddd, J = 7.9, 2.4, 1.6 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.54-7.47 (m, 3H), 7.36-7.26 (m, 4H), 7.13 (ddd, J = 7.9, 1.9, 1.0 Hz, 1H ), 7.08 (dd, J = 2.3, 1.9 Hz, 1H), 6.89 (ddd, J = 8.3, 2.3, 1.0 Hz, 1H), 6.87 (d, J = 7.3 Hz, 1H), 4.62 (s, 2H) , 4.42 (s, 2H), 4.37 (s, 2H), 4.10 (q, J = 7.0 Hz, 2H), 1.52 (s, 9H), 1.45 (t, J = 7.0 Hz, 3H), 1.42 (s, 9H).
９－（ｂ）：｛６－［（３’－エトキシビフェニル－４－イルメチル）（ピリジン－３－イルスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸
　実施例９－（ａ）で得られた（ｔｅｒｔ－ブトキシカルボニル｛６－［（３’－エトキシビフェニル－４－イルメチル）（ピリジン－３－イルスルホニル）アミノメチル］ピリジン－２－イル｝アミノ）酢酸ｔｅｒｔ－ブチル５４０ｍｇ（０．７８４ｍｍｏｌ）の１，４－ジオキサン４．０ｍＬ溶液に、６ｍｏｌ／Ｌの塩酸３．３ｍＬ（２０ｍｍｏｌ）及び水１．０ｍＬを加え、７０℃で２時間加熱撹拌した。反応終了後、反応溶液を減圧濃縮し、次いで水を加えて、１ｍｏｌ／Ｌの水酸化ナトリウム水溶液でｐＨ４．４に調整した後、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；塩化メチレン：メタノール＝１５：１→１０：１（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。濃縮物に酢酸エチル２ｍＬ及びｎ－ヘキサン８ｍＬを添加し、析出した固体を濾取した後に減圧乾燥することにより、標記化合物３８８ｍｇを白色固体として得た。（収率９３％）
マススペクトル（ＦＡＢ，ｍ／ｚ）：５３３（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＤＭＳＯ－ｄ６，δppm）：12.43 (brs, 0.4H), 8.83 (dd, J = 2.4, 0.7 Hz, 1H), 8.72 (dd, J = 4.8, 1.7 Hz, 1H), 8.02 (ddd, J = 8.0, 2.4, 1.7 Hz, 1H), 7.64-7.61 (m, 2H), 7.47 (ddd, J = 8.0, 4.8, 0.7 Hz, 1H), 7.38-7.34 (m, 3H), 7.24 (dd, J = 8.3, 7.2 Hz, 1H), 7.20 (ddd, J = 7.8, 1.7, 0.9 Hz, 1H), 7.16 (dd, J = 2.3, 1.7 Hz, 1H), 6.92 (ddd, J = 8.2, 2.3, 0.9 Hz, 1H), 6.78 (t, J = 5.9 Hz, 1H), 6.37 (d, J = 8.3 Hz, 1H), 6.33 (d, J = 7.2 Hz, 1H), 4.70 (s, 2H), 4.21 (s, 2H), 4.10 (q, J = 7.0 Hz, 2H), 3.71 (d, J = 5.9 Hz, 2H), 1.36 (t, J = 7.0 Hz, 3H)。 9- (b): {6-[(3′-ethoxybiphenyl-4-ylmethyl) (pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid obtained in Example 9- (a) (Tert-Butoxycarbonyl {6-[(3′-ethoxybiphenyl-4-ylmethyl) (pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate 540 mg (0.784 mmol) To a 4.0 mL solution of 1,4-dioxane, 3.3 mL (20 mmol) of 6 mol / L hydrochloric acid and 1.0 mL of water were added, and the mixture was heated and stirred at 70 ° C. for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, then water was added, the pH was adjusted to 4.4 with a 1 mol / L aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; methylene chloride: methanol = 15: 1 → 10: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. 2 mL of ethyl acetate and 8 mL of n-hexane were added to the concentrate, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 388 mg of the title compound as a white solid. (Yield 93%)
Mass spectrum (FAB, m / z): 533 (M + +1).
1 H-NMR spectrum (DMSO-d 6 , δ ppm): 12.43 (brs, 0.4H), 8.83 (dd, J = 2.4, 0.7 Hz, 1H), 8.72 (dd, J = 4.8, 1.7 Hz, 1H), 8.02 (ddd, J = 8.0, 2.4, 1.7 Hz, 1H), 7.64-7.61 (m, 2H), 7.47 (ddd, J = 8.0, 4.8, 0.7 Hz, 1H), 7.38-7.34 (m, 3H), 7.24 (dd, J = 8.3, 7.2 Hz, 1H), 7.20 (ddd, J = 7.8, 1.7, 0.9 Hz, 1H), 7.16 (dd, J = 2.3, 1.7 Hz, 1H), 6.92 (ddd, J = 8.2, 2.3, 0.9 Hz, 1H), 6.78 (t, J = 5.9 Hz, 1H), 6.37 (d, J = 8.3 Hz, 1H), 6.33 (d, J = 7.2 Hz, 1H), 4.70 (s, 2H), 4.21 (s, 2H), 4.10 (q, J = 7.0 Hz, 2H), 3.71 (d, J = 5.9 Hz, 2H), 1.36 (t, J = 7.0 Hz, 3H).
［実施例１０］
｛６－［（ベンゼンスルホニル）（３’－エトキシビフェニル－４－イルメチル）アミノメチル］ピリジン－２－イルアミノ｝酢酸 [Example 10]
{6-[(Benzenesulfonyl) (3′-ethoxybiphenyl-4-ylmethyl) aminomethyl] pyridin-2-ylamino} acetic acid
１０－（ａ）（｛６－［（ベンゼンスルホニル）（３’－エトキシビフェニル－４－イルメチル）アミノメチル］ピリジン－２－イル｝ｔｅｒｔ－ブトキシカルボニルアミノ）酢酸ｔｅｒｔ－ブチル
　参考例７－（ｂ）で得られた（ｔｅｒｔ－ブトキシカルボニル｛６－［（３’－エトキシビフェニル－４－イルメチル）アミノメチル］ピリジン－２－イル｝アミノ）酢酸ｔｅｒｔ－ブチル３５０ｍｇ（０．６３９ｍｍｏｌ）の塩化メチレン１．８ｍＬ溶液に、氷冷下にて、トリエチルアミン１７８μＬ（１．２８ｍｍｏｌ）及びベンゼンスルホニルクロリド９８μＬ（０．７７ｍｍｏｌ）を添加し、室温で１時間撹拌した。反応終了後、反応溶液をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝４：１→７：３（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物３９２ｍｇを白色泡状物として得た。（収率８９％）
マススペクトル（ＣＩ，ｍ／ｚ）：６８８（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：7.77-7.73 (m, 2H), 7.67 (d, J = 8.3 Hz, 1H), 7.56-7.41 (m, 6H), 7.33 (dd, J = 7.9, 7.7 Hz, 1H), 7.24-7.19 (m, 2H), 7.11 (ddd, J = 7.7, 1.7, 0.9 Hz, 1H), 7.07 (dd, J = 2.3, 1.7 Hz, 1H), 6.88 (ddd, J = 7.9, 2.3, 0.9 Hz, 1H), 6.86 (d, J = 7.5 Hz, 1H), 4.54 (s, 2H), 4.39 (s, 2H), 4.35 (s, 2H), 4.09 (q, J = 7.1 Hz, 2H), 1.51 (s, 9H), 1.44 (t, J = 7.1 Hz, 3H), 1.41 (s, 9H)。 10- (a) ({6-[(Benzenesulfonyl) (3′-ethoxybiphenyl-4-ylmethyl) aminomethyl] pyridin-2-yl} tert-butoxycarbonylamino) tert-butyl acetate Reference Example 7- (b ) (Tert-butoxycarbonyl {6-[(3′-ethoxybiphenyl-4-ylmethyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate 350 mg (0.639 mmol) obtained in 1) To the 8 mL solution, 178 μL (1.28 mmol) of triethylamine and 98 μL (0.77 mmol) of benzenesulfonyl chloride were added under ice cooling, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 4: 1 → 7: 3 (V / V)), and the fraction containing the target product is concentrated under reduced pressure. Gave 392 mg of the title compound as a white foam. (Yield 89%)
Mass spectrum (CI, m / z): 688 (M + +1).
1 H-NMR spectrum (CDCl 3 , δ ppm): 7.77-7.73 (m, 2H), 7.67 (d, J = 8.3 Hz, 1H), 7.56-7.41 (m, 6H), 7.33 (dd, J = 7.9, 7.7 Hz, 1H), 7.24-7.19 (m, 2H), 7.11 (ddd, J = 7.7, 1.7, 0.9 Hz, 1H), 7.07 (dd, J = 2.3, 1.7 Hz, 1H), 6.88 (ddd, J = 7.9, 2.3, 0.9 Hz, 1H), 6.86 (d, J = 7.5 Hz, 1H), 4.54 (s, 2H), 4.39 (s, 2H), 4.35 (s, 2H), 4.09 (q, J = 7.1 Hz, 2H), 1.51 (s, 9H), 1.44 (t, J = 7.1 Hz, 3H), 1.41 (s, 9H).
１０－（ｂ）：｛６－［（ベンゼンスルホニル）（３’－エトキシビフェニル－４－イルメチル）アミノメチル］ピリジン－２－イルアミノ｝酢酸
　実施例１０－（ａ）で得られた（｛６－［（ベンゼンスルホニル）（３’－エトキシビフェニル－４－イルメチル）アミノメチル］ピリジン－２－イル｝ｔｅｒｔ－ブトキシカルボニルアミノ）酢酸ｔｅｒｔ－ブチル３８９ｍｇ（０．５６６ｍｍｏｌ）の塩化メチレン５．８ｍＬ溶液に、室温下、トリフルオロ酢酸５．８ｍＬ（７６ｍｍｏｌ）を加え、３．５時間静置した。反応終了後、反応溶液を減圧濃縮し、次いで水を加えて、飽和炭酸水素ナトリウム水溶液及び１ｍｏｌ／Ｌの塩酸でｐＨ４．４に調整した後、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。濃縮物にジイソプロピルエーテル３．９ｍＬを添加し、析出した固体を濾取した後に減圧乾燥することにより、標記化合物２９３ｍｇを白色固体として得た。（収率９７％）
マススペクトル（ＦＡＢ，ｍ／ｚ）：５３２（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＤＭＳＯ－ｄ６，δppm）：12.41 (brs, 0.8H), 7.74-7.72 (m, 2H), 7.61-7.59 (m, 3H), 7.52-7.48 (m, 2H), 7.35 (dd, J = 7.8, 7.8 Hz, 1H), 7.31-7.29 (m, 2H), 7.23 (dd, J = 8.4, 7.2 Hz, 1H), 7.19 (ddd, J = 7.8, 1.7, 0.9 Hz, 1H), 7.14 (dd, J = 2.3, 1.7 Hz, 1H), 6.91 (ddd, J = 7.8, 2.3, 0.9 Hz, 1H), 6.76 (t, J = 5.9 Hz, 1H), 6.37 (d, J = 8.4 Hz, 1H), 6.29 (d, J = 7.2 Hz, 1H), 4.59 (s, 2H), 4.16 (s, 2H), 4.10 (q, J = 7.0 Hz, 2H), 3.77 (d, J = 5.9 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H)。 10- (b): {6-[(Benzenesulfonyl) (3′-ethoxybiphenyl-4-ylmethyl) aminomethyl] pyridin-2-ylamino} acetic acid obtained in Example 10- (a) ({6- To a solution of 389 mg (0.566 mmol) tert-butyl [(benzenesulfonyl) (3′-ethoxybiphenyl-4-ylmethyl) aminomethyl] pyridin-2-yl} tert-butoxycarbonylamino) acetate in 5.8 mL of methylene chloride, At room temperature, 5.8 mL (76 mmol) of trifluoroacetic acid was added and allowed to stand for 3.5 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, then water was added, the pH was adjusted to 4.4 with a saturated aqueous sodium hydrogen carbonate solution and 1 mol / L hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 3.9 mL of diisopropyl ether was added to the concentrate, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 293 mg of the title compound as a white solid. (Yield 97%)
Mass spectrum (FAB, m / z): 532 (M + +1).
1 H-NMR spectrum (DMSO-d 6 , δ ppm): 12.41 (brs, 0.8H), 7.74-7.72 (m, 2H), 7.61-7.59 (m, 3H), 7.52-7.48 (m, 2H), 7.35 (dd, J = 7.8, 7.8 Hz, 1H), 7.31-7.29 (m, 2H), 7.23 (dd, J = 8.4, 7.2 Hz, 1H), 7.19 (ddd, J = 7.8, 1.7, 0.9 Hz, 1H ), 7.14 (dd, J = 2.3, 1.7 Hz, 1H), 6.91 (ddd, J = 7.8, 2.3, 0.9 Hz, 1H), 6.76 (t, J = 5.9 Hz, 1H), 6.37 (d, J = 8.4 Hz, 1H), 6.29 (d, J = 7.2 Hz, 1H), 4.59 (s, 2H), 4.16 (s, 2H), 4.10 (q, J = 7.0 Hz, 2H), 3.77 (d, J = 5.9 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H).
［実施例１１］
｛６－［（３’－エトキシビフェニル－４－イルメチル）（チオフェン－２－イルスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸 [Example 11]
{6-[(3′-Ethoxybiphenyl-4-ylmethyl) (thiophen-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid
１１－（ａ）（ｔｅｒｔ－ブトキシカルボニル｛６－［（３’－エトキシビフェニル－４－イルメチル）（チオフェン－２－イルスルホニル）アミノメチル］ピリジン－２－イル｝アミノ）酢酸ｔｅｒｔ－ブチル
　参考例７－（ｂ）で得られた（ｔｅｒｔ－ブトキシカルボニル｛６－［（３’－エトキシビフェニル－４－イルメチル）アミノメチル］ピリジン－２－イル｝アミノ）酢酸ｔｅｒｔ－ブチル３５０ｍｇ（０．６３９ｍｍｏｌ）の塩化メチレン１．８ｍＬ溶液に、氷冷下にて、トリエチルアミン１７８μＬ（１．２８ｍｍｏｌ）及び２－チオフェンスルホニルクロリド１４１ｍｇ（０．７７２ｍｍｏｌ）の塩化メチレン０．３ｍＬ溶液を添加し、室温で１．５時間撹拌した。反応終了後、反応溶液をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９：１→３：２（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物３７６ｍｇを白色泡状物として得た。（収率８５％）
マススペクトル（ＣＩ，ｍ／ｚ）：６９４（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：7.70 (d, J = 8.5 Hz, 1H), 7.54-7.42 (m, 5H), 7.33 (dd, J = 8.0, 7.8 Hz, 1H), 7.27-7.23 (m, 2H), 7.12 (ddd, J = 7.7, 1.7, 0.9 Hz, 1H), 7.08 (dd, J = 2.4, 1.7 Hz, 1H), 7.02 (dd, J = 5.1, 3.7 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H), 6.88 (ddd, J = 8.0, 2.4, 0.9 Hz, 1H), 4.56 (s, 2H), 4.43 (s, 2H), 4.39 (s, 2H), 4.10 (q, J = 7.0 Hz, 2H), 1.52 (s, 9H), 1.44 (t, J = 7.0 Hz, 3H), 1.42 (s, 9H)。 11- (a) (tert-Butoxycarbonyl {6-[(3′-ethoxybiphenyl-4-ylmethyl) (thiophen-2-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate Reference Example 350 mg (0.639 mmol) of tert-butyl acetate (tert-butoxycarbonyl {6-[(3′-ethoxybiphenyl-4-ylmethyl) aminomethyl] pyridin-2-yl} amino) obtained in 7- (b) To a 1.8 mL solution of methylene chloride was added a solution of triethylamine (178 μL, 1.28 mmol) and 2-thiophenesulfonyl chloride (141 mg, 0.772 mmol) in methylene chloride (0.3 mL) at room temperature. Stir for hours. After completion of the reaction, the reaction solution is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 9: 1 → 3: 2 (V / V)), and the fraction containing the target product is concentrated under reduced pressure. Gave 376 mg of the title compound as a white foam. (Yield 85%)
Mass spectrum (CI, m / z): 694 (M + +1).
1 H-NMR spectrum (CDCl 3 , δ ppm): 7.70 (d, J = 8.5 Hz, 1H), 7.54-7.42 (m, 5H), 7.33 (dd, J = 8.0, 7.8 Hz, 1H), 7.27-7.23 (m, 2H), 7.12 (ddd, J = 7.7, 1.7, 0.9 Hz, 1H), 7.08 (dd, J = 2.4, 1.7 Hz, 1H), 7.02 (dd, J = 5.1, 3.7 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H), 6.88 (ddd, J = 8.0, 2.4, 0.9 Hz, 1H), 4.56 (s, 2H), 4.43 (s, 2H), 4.39 (s, 2H), 4.10 (q, J = 7.0 Hz, 2H), 1.52 (s, 9H), 1.44 (t, J = 7.0 Hz, 3H), 1.42 (s, 9H).
１１－（ｂ）｛６－［（３’－エトキシビフェニル－４－イルメチル）（チオフェン－２－イルスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸
　実施例１１－（ａ）で得られた（ｔｅｒｔ－ブトキシカルボニル｛６－［（３’－エトキシビフェニル－４－イルメチル）（チオフェン－２－イルスルホニル）アミノメチル］ピリジン－２－イル｝アミノ）酢酸ｔｅｒｔ－ブチル３７４ｍｇ（０．５３８ｍｍｏｌ）の塩化メチレン５．６ｍＬ溶液に、室温下、トリフルオロ酢酸５．６ｍＬ（７３ｍｍｏｌ）を加え、３．５時間静置した。反応終了後、反応溶液を減圧濃縮し、次いで水を加えて、飽和炭酸水素ナトリウム水溶液及び１ｍｏｌ／Ｌの塩酸でｐＨ４．４に調整した後、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。濃縮物にｔｅｒｔ－ブチルメチルエーテル３．７ｍＬを添加し、析出した固体を濾取した後に減圧乾燥することにより、標記化合物２７２ｍｇを白色固体として得た。（収率９４％）
マススペクトル（ＦＡＢ，ｍ／ｚ）：５３８（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＤＭＳＯ－ｄ６，δppm）：12.42 (brs, 0.7H), 7.91 (dd, J = 5.1, 1.4 Hz, 1H), 7.61-7.58 (m, 2H), 7.54 (dd, J = 3.7, 1.4 Hz, 1H), 7.35 (dd, J = 7.9, 7.8 Hz, 1H), 7.34-7.31 (m, 2H), 7.27 (dd, J = 8.4, 7.2 Hz, 1H), 7.19 (ddd, J = 7.8, 1.7, 0.9 Hz, 1H), 7.15 (dd, J = 2.3, 1.7 Hz, 1H), 7.13 (dd, J = 5.1, 3.7 Hz, 1H), 6.91 (ddd, J = 7.9, 2.3, 0.9 Hz, 1H), 6.79 (t, J = 5.8 Hz, 1H), 6.41 (d, J = 8.4 Hz, 1H), 6.35 (d, J = 7.2 Hz, 1H), 4.58 (s, 2H), 4.17 (s, 2H), 4.10 (q, J = 7.0 Hz, 2H), 3.83 (d, J = 5.8 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H)。 11- (b) {6-[(3'-ethoxybiphenyl-4-ylmethyl) (thiophen-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid obtained in Example 11- (a) ( tert-Butoxycarbonyl {6-[(3′-ethoxybiphenyl-4-ylmethyl) (thiophen-2-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate 374 mg (0.538 mmol) chloride To a 5.6 mL methylene solution, 5.6 mL (73 mmol) trifluoroacetic acid was added at room temperature, and the mixture was allowed to stand for 3.5 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, then water was added, the pH was adjusted to 4.4 with a saturated aqueous sodium hydrogen carbonate solution and 1 mol / L hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the concentrate was added 3.7 mL of tert-butyl methyl ether, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 272 mg of the title compound as a white solid. (Yield 94%)
Mass spectrum (FAB, m / z): 538 (M + +1).
1 H-NMR spectrum (DMSO-d 6 , δ ppm): 12.42 (brs, 0.7H), 7.91 (dd, J = 5.1, 1.4 Hz, 1H), 7.61-7.58 (m, 2H), 7.54 (dd, J = 3.7, 1.4 Hz, 1H), 7.35 (dd, J = 7.9, 7.8 Hz, 1H), 7.34-7.31 (m, 2H), 7.27 (dd, J = 8.4, 7.2 Hz, 1H), 7.19 (ddd, J = 7.8, 1.7, 0.9 Hz, 1H), 7.15 (dd, J = 2.3, 1.7 Hz, 1H), 7.13 (dd, J = 5.1, 3.7 Hz, 1H), 6.91 (ddd, J = 7.9, 2.3, 0.9 Hz, 1H), 6.79 (t, J = 5.8 Hz, 1H), 6.41 (d, J = 8.4 Hz, 1H), 6.35 (d, J = 7.2 Hz, 1H), 4.58 (s, 2H), 4.17 (s, 2H), 4.10 (q, J = 7.0 Hz, 2H), 3.83 (d, J = 5.8 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H).
［実施例１２］
（６－｛［４－（６－エトキシピリジン－２－イル）ベンジル］（ピリジン－２－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸 [Example 12]
(6-{[4- (6-Ethoxypyridin-2-yl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid
１２－（ａ）：［ｔｅｒｔ－ブトキシカルボニル（６－｛［４－（６－エトキシピリジン－２－イル）ベンジル］（ピリジン－２－イルスルホニル）アミノメチル｝ピリジン－２－イル）アミノ］酢酸ｔｅｒｔ－ブチル
　参考例８で得られた４－（６－エトキシピリジン－２－イル）フェニルメタノール２６７ｍｇ（１．１６ｍｍｏｌ）のテトラヒドロフラン１１ｍＬ溶液に、参考例１－（ｆ）と同様の方法で得られた（ｔｅｒｔ－ブトキシカルボニル｛６－［（ピリジン－２－イルスルホニル）アミノメチル］ピリジン－２－イル｝アミノ）酢酸ｔｅｒｔ－ブチル５６０ｍｇ（１．１７ｍｍｏｌ）、トリ－ｎ－ブチルホスフィン７２４μＬ（２．９０ｍｍｏｌ）及びＮ，Ｎ，Ｎ’，Ｎ’－テトラメチルアゾジカルボキサミド３００ｍｇ（１．７４ｍｍｏｌ）を加え、室温で１．５時間撹拌した。反応終了後、反応溶液に水を加え、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝３：１（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物６０６ｍｇを白色泡状物として得た。（収率７６％）
マススペクトル（ＣＩ，ｍ／ｚ）：６９０（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：8.60 (ddd, J = 4.7, 1.8, 1.1 Hz, 1H), 7.92-7.88 (m, 2H), 7.82 (ddd, J = 7.7, 1.3, 1.1 Hz, 1H), 7.76 (ddd, J = 7.7, 7.5, 1.8 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.61 (dd, J = 8.2, 7.5 Hz, 1H), 7.45 (dd, J = 8.3, 7.5 Hz, 1H), 7.38 (ddd, J = 7.5, 4.7, 1.3 Hz, 1H), 7.34-7.30 (m, 2H), 7.28 (dd, J = 7.5, 0.6 Hz, 1H), 6.90 (d, J = 7.5 Hz, 1H), 6.66 (dd, J = 8.3, 0.6 Hz, 1H), 4.76 (s, 2H), 4.49 (s, 2H), 4.48 (q, J = 7.1 Hz, 2H), 4.46 (s, 2H), 1.52 (s, 9H), 1.44 (t, J = 7.1 Hz, 3H), 1.42 (s, 9H)。 12- (a): [tert-butoxycarbonyl (6-{[4- (6-ethoxypyridin-2-yl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-yl) amino] acetic acid To a solution of 267 mg (1.16 mmol) of 4- (6-ethoxypyridin-2-yl) phenylmethanol obtained in tert-butyl Reference Example 8 in 11 mL of tetrahydrofuran was obtained in the same manner as in Reference Example 1- (f). (Tert-Butoxycarbonyl {6-[(pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate 560 mg (1.17 mmol), tri-n-butylphosphine 724 μL (2. 90 mmol) and 300 mg (1.7) of N, N, N ′, N′-tetramethylazodicarboxamide mmol), and the mixture was stirred for 1.5 hours at room temperature. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 3: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 606 mg of the title compound as a white foam. Obtained as a thing. (Yield 76%)
Mass spectrum (CI, m / z): 690 (M + +1).
1 H-NMR spectrum (CDCl 3 , δ ppm): 8.60 (ddd, J = 4.7, 1.8, 1.1 Hz, 1H), 7.92-7.88 (m, 2H), 7.82 (ddd, J = 7.7, 1.3, 1.1 Hz, 1H), 7.76 (ddd, J = 7.7, 7.5, 1.8 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.61 (dd, J = 8.2, 7.5 Hz, 1H), 7.45 (dd, J = 8.3, 7.5 Hz, 1H), 7.38 (ddd, J = 7.5, 4.7, 1.3 Hz, 1H), 7.34-7.30 (m, 2H), 7.28 (dd, J = 7.5, 0.6 Hz, 1H), 6.90 ( d, J = 7.5 Hz, 1H), 6.66 (dd, J = 8.3, 0.6 Hz, 1H), 4.76 (s, 2H), 4.49 (s, 2H), 4.48 (q, J = 7.1 Hz, 2H), 4.46 (s, 2H), 1.52 (s, 9H), 1.44 (t, J = 7.1 Hz, 3H), 1.42 (s, 9H).
１２－（ｂ）（６－｛［４－（６－エトキシピリジン－２－イル）ベンジル］（ピリジン－２－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸
　実施例１２－（ａ）で得られた［ｔｅｒｔ－ブトキシカルボニル（６－｛［４－（６－エトキシピリジン－２－イル）ベンジル］（ピリジン－２－イルスルホニル）アミノメチル｝ピリジン－２－イル）アミノ］酢酸ｔｅｒｔ－ブチル５９０ｍｇ（０．８５５ｍｍｏｌ）の塩化メチレン８．６ｍＬ溶液に、室温下、トリフルオロ酢酸８．６ｍＬ（１１２ｍｍｏｌ）を加え、室温下、６時間撹拌した。反応終了後、反応溶液を減圧濃縮し、次いで水を加えて、２ｍｏｌ／Ｌの水酸化ナトリウム水溶液及び希塩酸でｐＨ４．５に調整した後、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮することにより、標記化合物３５７ｍｇを白色泡状物として得た。（収率７８％）
マススペクトル（ＦＡＢ，ｍ／ｚ）：５３４（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＤＭＳＯ－ｄ６，δppm）：12.59 (brs, 0.5H), 8.67 (d, J = 4.7 Hz, 1H), 8.01-7.95 (m, 3H), 7.85 (d, J = 7.7 Hz, 1H), 7.76 (dd, J = 8.4, 7.5 Hz, 1H), 7.61 (dd, J = 7.2, 4.7 Hz, 1H), 7.50 (d, J = 7.5 Hz, 1H), 7.36-7.27 (m, 3H), 6.75 (d, J = 8.4 Hz, 1H), 6.44 (s, 1H), 6.37 (s, 1H), 4.72 (s, 2H), 4.42 (q, J = 7.1 Hz, 2H), 4.33 (s, 2H), 3.87 (s, 2H), 1.37 (t, J = 7.1 Hz, 3H)。 12- (b) (6-{[4- (6-Ethoxypyridin-2-yl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid in Example 12- (a) The resulting [tert-butoxycarbonyl (6-{[4- (6-ethoxypyridin-2-yl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-yl) amino] tert-butyl acetate To a solution of 590 mg (0.855 mmol) in methylene chloride (8.6 mL) was added trifluoroacetic acid (8.6 mL, 112 mmol) at room temperature, and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, then water was added, the pH was adjusted to 4.5 with a 2 mol / L aqueous sodium hydroxide solution and dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 357 mg of the title compound as a white foam. (Yield 78%)
Mass spectrum (FAB, m / z): 534 (M + +1).
1 H-NMR spectrum (DMSO-d 6 , δ ppm): 12.59 (brs, 0.5H), 8.67 (d, J = 4.7 Hz, 1H), 8.01-7.95 (m, 3H), 7.85 (d, J = 7.7 Hz, 1H), 7.76 (dd, J = 8.4, 7.5 Hz, 1H), 7.61 (dd, J = 7.2, 4.7 Hz, 1H), 7.50 (d, J = 7.5 Hz, 1H), 7.36-7.27 (m , 3H), 6.75 (d, J = 8.4 Hz, 1H), 6.44 (s, 1H), 6.37 (s, 1H), 4.72 (s, 2H), 4.42 (q, J = 7.1 Hz, 2H), 4.33 (s, 2H), 3.87 (s, 2H), 1.37 (t, J = 7.1 Hz, 3H).
［実施例１３］
（６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（チオフェン－２－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸エチル [Example 13]
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate
　参考例９－（ｂ）で得られた｛６－［（チオフェン－２－イルスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸エチル５３３ｍｇ（１．５０ｍｍｏｌ）のテトラヒドロフラン８．０ｍＬ溶液に、参考例１３と同様の方法で得られた３’－（１－プロピニル）ビフェニル－４－イルメタノール３３３ｍｇ（１．５０ｍｍｏｌ）、トリ－ｎ－ブチルホスフィン７４０μＬ（３．００ｍｍｏｌ）及びＮ，Ｎ，Ｎ’，Ｎ’－テトラメチルアゾジカルボキサミド５１７ｍｇ（３．００ｍｍｏｌ）を加え、室温で７時間撹拌した。反応終了後、反応溶液に水を加え、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１：０→１：１（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物８０６ｍｇを無色油状物として得た。（収率９６％）
マススペクトル（ＣＩ，ｍ／ｚ）：５６０（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：7.60-7.59 (m, 1H), 7.51 (dd, J = 5.0, 1.3 Hz, 1H), 7.48-7.43 (m, 4H), 7.36-7.27 (m, 5H), 7.01 (dd, J = 5.0, 3.8 Hz, 1H), 6.54 (d, J = 6.9 Hz, 1H), 6.29 (d, J = 8.0 Hz, 1H), 4.78 (t, J = 5.4 Hz, 1H), 4.60 (s, 2H), 4.33 (s, 2H), 4.21 (q, J = 7.1 Hz, 2H), 3.99 (d, J = 5.4 Hz, 2H), 2.07 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H)。 To a 8.0 mL solution of 533 mg (1.50 mmol) of ethyl {6-[(thiophen-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetate obtained in Reference Example 9- (b), 3 ′-(1-propynyl) biphenyl-4-ylmethanol 333 mg (1.50 mmol), tri-n-butylphosphine 740 μL (3.00 mmol) and N, N, N ′, 517 mg (3.00 mmol) of N′-tetramethylazodicarboxamide was added, and the mixture was stirred at room temperature for 7 hours. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 1: 0 → 1: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 806 mg of the title compound. Was obtained as a colorless oil. (Yield 96%)
Mass spectrum (CI, m / z): 560 (M + +1).
1 H-NMR spectrum (CDCl 3 , δ ppm): 7.60-7.59 (m, 1H), 7.51 (dd, J = 5.0, 1.3 Hz, 1H), 7.48-7.43 (m, 4H), 7.36-7.27 (m, 5H), 7.01 (dd, J = 5.0, 3.8 Hz, 1H), 6.54 (d, J = 6.9 Hz, 1H), 6.29 (d, J = 8.0 Hz, 1H), 4.78 (t, J = 5.4 Hz, 1H), 4.60 (s, 2H), 4.33 (s, 2H), 4.21 (q, J = 7.1 Hz, 2H), 3.99 (d, J = 5.4 Hz, 2H), 2.07 (s, 3H), 1.27 ( t, J = 7.1 Hz, 3H).
［実施例１４］
（６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（チオフェン－２－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸 [Example 14]
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid
　実施例１３で得られた（６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（チオフェン－２－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸エチル８００ｍｇ（１．４３ｍｍｏｌ）のエタノール６．０ｍＬ溶液に、１ｍｏｌ／Ｌの水酸化ナトリウム水溶液６．０ｍＬ（６．０ｍｍｏｌ）を加え、室温で４時間撹拌した。反応終了後、反応溶液に水を添加し、１ｍｏｌ／Ｌの塩酸でｐＨ４．５に調整した後、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。濃縮物を酢酸エチル１０ｍＬに溶解し、５０℃でｎ－ヘキサン１０ｍＬを添加後、１．５時間かけて室温まで撹拌した。析出した固体を濾取した後に減圧乾燥することにより、標記化合物６２０ｍｇを白色固体として得た。（収率８２％）
マススペクトル（ＥＳＩ＋，ｍ／ｚ）：５３２（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＤＭＳＯ－ｄ６，δppm）：12.39 (brs, 0.9H), 7.91 (dd, J = 5.0, 1.3 Hz, 1H), 7.64-7.59 (m, 4H), 7.54 (dd, J = 3.8, 1.3 Hz, 1H), 7.43 (dd, J = 7.7, 7.7 Hz, 1H), 7.38-7.32 (m, 3H), 7.26 (dd, J = 8.3, 7.2 Hz, 1H), 7.13 (dd, J = 5.0, 3.8 Hz, 1H), 6.80 (t, J = 5.8 Hz, 1H), 6.41 (d, J = 8.3 Hz, 1H), 6.35 (d, J = 7.2 Hz, 1H), 4.59 (s, 2H), 4.18 (s, 2H), 3.84 (d, J = 5.8 Hz, 2H), 2.07 (s, 3H)。 800 mg (1.43 mmol) of ethyl (6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) obtained in Example 13 ) In ethanol (6.0 mL) was added 1 mol / L aqueous sodium hydroxide solution (6.0 mL, 6.0 mmol), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, water was added to the reaction solution, adjusted to pH 4.5 with 1 mol / L hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was dissolved in 10 mL of ethyl acetate, and 10 mL of n-hexane was added at 50 ° C., followed by stirring to room temperature over 1.5 hours. The precipitated solid was collected by filtration and dried under reduced pressure to give 620 mg of the title compound as a white solid. (Yield 82%)
Mass spectrum (ESI + , m / z): 532 (M + +1).
1 H-NMR spectrum (DMSO-d 6 , δ ppm): 12.39 (brs, 0.9H), 7.91 (dd, J = 5.0, 1.3 Hz, 1H), 7.64-7.59 (m, 4H), 7.54 (dd, J = 3.8, 1.3 Hz, 1H), 7.43 (dd, J = 7.7, 7.7 Hz, 1H), 7.38-7.32 (m, 3H), 7.26 (dd, J = 8.3, 7.2 Hz, 1H), 7.13 (dd, J = 5.0, 3.8 Hz, 1H), 6.80 (t, J = 5.8 Hz, 1H), 6.41 (d, J = 8.3 Hz, 1H), 6.35 (d, J = 7.2 Hz, 1H), 4.59 (s, 2H), 4.18 (s, 2H), 3.84 (d, J = 5.8 Hz, 2H), 2.07 (s, 3H).
［実施例１５］
（６－｛（ベンゼンスルホニル）［３’－（１－プロピニル）ビフェニル－４－イルメチル］アミノメチル｝ピリジン－２－イルアミノ）酢酸エチル [Example 15]
(6-{(Benzenesulfonyl) [3 ′-(1-propynyl) biphenyl-4-ylmethyl] aminomethyl} pyridin-2-ylamino) ethyl acetate
　参考例１０－（ｂ）で得られた｛６－［（ベンゼンスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸エチル５２４ｍｇ（１．５０ｍｍｏｌ）のテトラヒドロフラン８．０ｍＬ溶液に、参考例１３と同様の方法で得られた３’－（１－プロピニル）ビフェニル－４－イルメタノール３３３ｍｇ（１．５０ｍｍｏｌ）、トリ－ｎ－ブチルホスフィン７４０μＬ（３．００ｍｍｏｌ）及びＮ，Ｎ，Ｎ’，Ｎ’－テトラメチルアゾジカルボキサミド５１７ｍｇ（３．００ｍｍｏｌ）を加え、室温で２時間撹拌した。反応終了後、反応溶液に水を加え、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝３：１→１：１（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物８０９ｍｇを無色油状物として得た。（収率９７％）
マススペクトル（ＣＩ，ｍ／ｚ）：５５４（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：7.78-7.75 (m, 2H), 7.59-7.58 (m, 1H), 7.53-7.40 (m, 6H), 7.37-7.25 (m, 5H), 6.48 (d, J = 7.0 Hz, 1H), 6.27 (d, J = 8.0 Hz, 1H), 4.74 (t, J = 5.2 Hz, 1H), 4.58 (s, 2H), 4.32 (s, 2H), 4.21 (q, J = 7.2 Hz, 2H), 3.90 (d, J = 5.2 Hz, 2H), 2.07 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H)。 In a solution of 524 mg (1.50 mmol) of ethyl {6-[(benzenesulfonyl) aminomethyl] pyridin-2-ylamino} acetate obtained in Reference Example 10- (b) in 8.0 mL of tetrahydrofuran, the same as in Reference Example 13 333 mg (1.50 mmol) of 3 ′-(1-propynyl) biphenyl-4-ylmethanol obtained by the method, 740 μL (3.00 mmol) of tri-n-butylphosphine and N, N, N ′, N′-tetra 517 mg (3.00 mmol) of methyl azodicarboxamide was added and stirred at room temperature for 2 hours. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 3: 1 → 1: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 809 mg of the title compound. Was obtained as a colorless oil. (Yield 97%)
Mass spectrum (CI, m / z): 554 (M + +1).
1 H-NMR spectrum (CDCl 3 , δ ppm): 7.78-7.75 (m, 2H), 7.59-7.58 (m, 1H), 7.53-7.40 (m, 6H), 7.37-7.25 (m, 5H), 6.48 ( d, J = 7.0 Hz, 1H), 6.27 (d, J = 8.0 Hz, 1H), 4.74 (t, J = 5.2 Hz, 1H), 4.58 (s, 2H), 4.32 (s, 2H), 4.21 ( q, J = 7.2 Hz, 2H), 3.90 (d, J = 5.2 Hz, 2H), 2.07 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H).
［実施例１６］
（６－｛（ベンゼンスルホニル）［３’－（１－プロピニル）ビフェニル－４－イルメチル］アミノメチル｝ピリジン－２－イルアミノ）酢酸 [Example 16]
(6-{(Benzenesulfonyl) [3 ′-(1-propynyl) biphenyl-4-ylmethyl] aminomethyl} pyridin-2-ylamino) acetic acid
　実施例１５で得られた（６－｛（ベンゼンスルホニル）［３’－（１－プロピニル）ビフェニル－４－イルメチル］アミノメチル｝ピリジン－２－イルアミノ）酢酸エチル８０４ｍｇ（１．４５ｍｍｏｌ）のエタノール６．０ｍＬ溶液に、１ｍｏｌ／Ｌの水酸化ナトリウム水溶液６．０ｍＬ（６．０ｍｍｏｌ）を加え、室温で４時間撹拌した。反応終了後、反応溶液に水を添加し、１ｍｏｌ／Ｌの塩酸でｐＨ４．５に調整した後、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。濃縮物を酢酸エチル１０ｍＬに溶解し、５０℃でｎ－ヘキサン１０ｍＬを添加後、２時間かけて室温まで撹拌した。析出した固体を濾取した後に減圧乾燥することにより、標記化合物７２４ｍｇを白色固体として得た。（収率９５％）
マススペクトル（ＥＳＩ＋，ｍ／ｚ）：５２６（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＤＭＳＯ－ｄ６，δppm）：12.40 (brs, 0.6H), 7.75-7.72 (m, 2H), 7.63-7.58 (m, 5H), 7.53-7.48 (m, 2H), 7.43 (dd, J = 7.7, 7.7 Hz, 1H), 7.37 (ddd, J = 7.7, 1.4, 1.4 Hz, 1H), 7.33-7.30 (m, 2H), 7.23 (dd, J = 8.3, 7.2 Hz, 1H), 6.75 (t, J = 5.6 Hz, 1H), 6.37 (d, J = 8.3 Hz, 1H), 6.29 (d, J = 7.2 Hz, 1H), 4.59 (s, 2H), 4.17 (s, 2H), 3.77 (d, J = 5.6 Hz, 2H), 2.07 (s, 3H)。 804 mg (1.45 mmol) of ethyl 6- (6-{(benzenesulfonyl) [3 ′-(1-propynyl) biphenyl-4-ylmethyl] aminomethyl} pyridin-2-ylamino) acetate obtained in Example 15 To the 0.0 mL solution, 6.0 mL (6.0 mmol) of 1 mol / L sodium hydroxide aqueous solution was added, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, water was added to the reaction solution, adjusted to pH 4.5 with 1 mol / L hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was dissolved in 10 mL of ethyl acetate, and 10 mL of n-hexane was added at 50 ° C., followed by stirring to room temperature over 2 hours. The precipitated solid was collected by filtration and dried under reduced pressure to give 724 mg of the title compound as a white solid. (Yield 95%)
Mass spectrum (ESI + , m / z): 526 (M + +1).
1 H-NMR spectrum (DMSO-d 6 , δ ppm): 12.40 (brs, 0.6H), 7.75-7.72 (m, 2H), 7.63-7.58 (m, 5H), 7.53-7.48 (m, 2H), 7.43 (dd, J = 7.7, 7.7 Hz, 1H), 7.37 (ddd, J = 7.7, 1.4, 1.4 Hz, 1H), 7.33-7.30 (m, 2H), 7.23 (dd, J = 8.3, 7.2 Hz, 1H ), 6.75 (t, J = 5.6 Hz, 1H), 6.37 (d, J = 8.3 Hz, 1H), 6.29 (d, J = 7.2 Hz, 1H), 4.59 (s, 2H), 4.17 (s, 2H ), 3.77 (d, J = 5.6 Hz, 2H), 2.07 (s, 3H).
［実施例１７］
（６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（チオフェン－３－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸エチル
　参考例１１－（ｂ）で得られた｛６－［（チオフェン－３－イルスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸エチル２８４ｍｇ（０．８００ｍｍｏｌ）のテトラヒドロフラン４．０ｍＬ溶液に、参考例１３と同様の方法で得られた３’－（１－プロピニル）ビフェニル－４－イルメタノール１７８ｍｇ（０．８００ｍｍｏｌ）、トリ－ｎ－ブチルホスフィン３９５μＬ（１．６０ｍｍｏｌ）及びＮ，Ｎ，Ｎ’，Ｎ’－テトラメチルアゾジカルボキサミド２７６ｍｇ（１．６０ｍｍｏｌ）を加え、室温で３時間撹拌した。反応終了後、反応溶液に水を加え、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝４：１→１：１（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物４３２ｍｇを無色アメ状物として得た。（収率９７％）
マススペクトル（ＣＩ，ｍ／ｚ）：５６０（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：7.80 (dd, J = 3.1, 1.3 Hz, 1H), 7.60-7.59 (m, 1H), 7.50-7.45 (m, 3H), 7.36-7.28 (m, 6H), 7.17 (dd, J = 5.1, 1.3 Hz, 1H), 6.52 (d, J = 7.2 Hz, 1H), 6.31 (d, J = 8.0 Hz, 1H), 4.80 (t, J = 5.4 Hz, 1H), 4.61 (s, 2H), 4.32 (s, 2H), 4.21 (q, J = 7.2 Hz, 2H), 3.99 (d, J = 5.4 Hz, 2H), 2.08 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H)。 [Example 17]
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate obtained in Reference Example 11- (b) { 6-[(Thiophen-3-ylsulfonyl) aminomethyl] pyridin-2-ylamino} ethyl acetate was added to a solution of 284 mg (0.800 mmol) in tetrahydrofuran (4.0 mL) in the same manner as in Reference Example 13 and 3′- 178 mg (0.800 mmol) of (1-propynyl) biphenyl-4-ylmethanol, 395 μL (1.60 mmol) of tri-n-butylphosphine and 276 mg of N, N, N ′, N′-tetramethylazodicarboxamide (1. 60 mmol) was added and stirred at room temperature for 3 hours. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 4: 1 → 1: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 432 mg of the title compound. Was obtained as colorless candy. (Yield 97%)
Mass spectrum (CI, m / z): 560 (M + +1).
1 H-NMR spectrum (CDCl 3 , δ ppm): 7.80 (dd, J = 3.1, 1.3 Hz, 1H), 7.60-7.59 (m, 1H), 7.50-7.45 (m, 3H), 7.36-7.28 (m, 6H), 7.17 (dd, J = 5.1, 1.3 Hz, 1H), 6.52 (d, J = 7.2 Hz, 1H), 6.31 (d, J = 8.0 Hz, 1H), 4.80 (t, J = 5.4 Hz, 1H), 4.61 (s, 2H), 4.32 (s, 2H), 4.21 (q, J = 7.2 Hz, 2H), 3.99 (d, J = 5.4 Hz, 2H), 2.08 (s, 3H), 1.27 ( t, J = 7.2 Hz, 3H).
［実施例１８］
（６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（チオフェン－３－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸
　実施例１７で得られた（６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（チオフェン－３－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸エチル４２６ｍｇ（０．７６２ｍｍｏｌ）のエタノール３．５ｍＬ溶液に、１ｍｏｌ／Ｌの水酸化ナトリウム水溶液３．５ｍＬ（３．５ｍｍｏｌ）を加え、室温で１６時間撹拌した。反応終了後、反応溶液に水を添加し、１ｍｏｌ／Ｌの塩酸でｐＨ４．４に調整した後、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。濃縮物に酢酸エチル５ｍＬ及びｎ－ヘキサン５ｍＬを添加して５０℃に加熱し、その後２時間かけて室温まで撹拌した。析出した固体を濾取した後に減圧乾燥することにより、標記化合物３９０ｍｇを白色固体として得た。（収率９６％）
マススペクトル（ＣＩ，ｍ／ｚ）：５３２（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＤＭＳＯ－ｄ６，δppm）：12.46 (brs, 0.6H), 8.14 (dd, J = 3.0, 1.4 Hz, 1H), 7.66 (dd, J = 5.1, 3.0 Hz, 1H), 7.64-7.59 (m, 4H), 7.45-7.24 (m, 6H), 6.81 (t, J = 5.5 Hz, 1H), 6.40 (d, J = 8.2 Hz, 1H), 6.33 (d, J = 7.0 Hz, 1H), 4.58 (s, 2H), 4.16 (s, 2H), 3.84 (d, J = 5.5 Hz, 2H), 2.07 (s, 3H)。 [Example 18]
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid obtained in Example 17 (6-{[3 '-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate (426 mg, 0.762 mmol) in ethanol (3.5 mL) Sodium hydroxide aqueous solution 3.5mL (3.5mmol) was added, and it stirred at room temperature for 16 hours. After completion of the reaction, water was added to the reaction solution, adjusted to pH 4.4 with 1 mol / L hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the concentrate was added 5 mL of ethyl acetate and 5 mL of n-hexane, heated to 50 ° C., and then stirred to room temperature over 2 hours. The precipitated solid was collected by filtration and dried under reduced pressure to give 390 mg of the title compound as a white solid. (Yield 96%)
Mass spectrum (CI, m / z): 532 (M + +1).
1 H-NMR spectrum (DMSO-d 6 , δ ppm): 12.46 (brs, 0.6H), 8.14 (dd, J = 3.0, 1.4 Hz, 1H), 7.66 (dd, J = 5.1, 3.0 Hz, 1H), 7.64-7.59 (m, 4H), 7.45-7.24 (m, 6H), 6.81 (t, J = 5.5 Hz, 1H), 6.40 (d, J = 8.2 Hz, 1H), 6.33 (d, J = 7.0 Hz , 1H), 4.58 (s, 2H), 4.16 (s, 2H), 3.84 (d, J = 5.5 Hz, 2H), 2.07 (s, 3H).
［実施例１９］
（６－｛（３－フルオロベンゼンスルホニル）［３’－（１－プロピニル）ビフェニル－４－イルメチル］アミノメチル｝ピリジン－２－イルアミノ）酢酸 [Example 19]
(6-{(3-Fluorobenzenesulfonyl) [3 ′-(1-propynyl) biphenyl-4-ylmethyl] aminomethyl} pyridin-2-ylamino) acetic acid
１９－（ａ）［ｔｅｒｔ－ブトキシカルボニル（６－｛（３－フルオロベンゼンスルホニル）［３’－（１－プロピニル）ビフェニル－４－イルメチル］アミノメチル｝ピリジン－２－イル）アミノ］酢酸ｔｅｒｔ－ブチル
　参考例１２－（ｃ）で得られた［ｔｅｒｔ－ブトキシカルボニル（６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］アミノメチル｝ピリジン－２－イル）アミノ］酢酸ｔｅｒｔ－ブチル５４２ｍｇ（１．００ｍｍｏｌ）の塩化メチレン３．５ｍＬ溶液に、氷冷下にて、トリエチルアミン２８０μＬ（２．０１ｍｍｏｌ）及び３－フルオロベンゼンスルホニルクロリド１５０μＬ（１．１３ｍｍｏｌ）を添加し、室温で２時間撹拌した。反応終了後、反応溶液に水を加え、塩化メチレンで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９：１→７：３（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物６７３ｍｇを白色泡状物として得た。（収率９６％）
マススペクトル（ＣＩ，ｍ／ｚ）：７００（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：7.70 (d, J = 8.1 Hz, 1H), 7.59-7.58 (m, 1H), 7.53-7.32 (m, 9H), 7.27-7.19 (m, 3H), 6.87 (d, J = 7.3 Hz, 1H), 4.57 (s, 2H), 4.39 (s, 2H), 4.37 (s, 2H), 2.08 (s, 3H), 1.52 (s, 9H), 1.42 (s, 9H)。 19- (a) [tert-butoxycarbonyl (6-{(3-fluorobenzenesulfonyl) [3 ′-(1-propynyl) biphenyl-4-ylmethyl] aminomethyl} pyridin-2-yl) amino] acetic acid tert- obtained in butyl reference example 12-(c) [tert- butoxycarbonyl (6 - {[3 '- (1-propynyl) biphenyl-4-ylmethyl] aminomethyl} pyridin-2-yl) amino] acetic acid tert- To a solution of 542 mg (1.00 mmol) of butyl in 3.5 mL of methylene chloride, 280 μL (2.01 mmol) of triethylamine and 150 μL (1.13 mmol) of 3-fluorobenzenesulfonyl chloride were added under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Stir. After completion of the reaction, water was added to the reaction solution and extracted with methylene chloride. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 9: 1 → 7: 3 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 673 mg of the title compound. Was obtained as a white foam. (Yield 96%)
Mass spectrum (CI, m / z): 700 (M + +1).
1 H-NMR spectrum (CDCl 3 , δ ppm): 7.70 (d, J = 8.1 Hz, 1H), 7.59-7.58 (m, 1H), 7.53-7.32 (m, 9H), 7.27-7.19 (m, 3H) , 6.87 (d, J = 7.3 Hz, 1H), 4.57 (s, 2H), 4.39 (s, 2H), 4.37 (s, 2H), 2.08 (s, 3H), 1.52 (s, 9H), 1.42 ( s, 9H).
１９－（ｂ）（６－｛（３－フルオロベンゼンスルホニル）［３’－（１－プロピニル）ビフェニル－４－イルメチル］アミノメチル｝ピリジン－２－イルアミノ）酢酸
　実施例１９－（ａ）で得られた［ｔｅｒｔ－ブトキシカルボニル（６－｛（３－フルオロベンゼンスルホニル）［３’－（１－プロピニル）ビフェニル－４－イルメチル］アミノメチル｝ピリジン－２－イル）アミノ］酢酸ｔｅｒｔ－ブチル５９５ｍｇ（０．８５０ｍｍｏｌ）のテトラヒドロフラン５．０ｍＬ溶液に、４ｍｏｌ／Ｌの塩酸５．０ｍＬ（２０ｍｍｏｌ）を加え、７０℃で５時間加熱撹拌した。反応終了後、１ｍｏｌ／Ｌの水酸化ナトリウム水溶液でｐＨ４．５に調整した後、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。濃縮物に酢酸エチル１０ｍＬ及びｎ－ヘキサン５ｍＬを添加して５０℃に加熱し、その後２時間かけて室温まで撹拌した。析出した固体を濾取した後に減圧乾燥することにより、標記化合物４２９ｍｇを白色固体として得た。（収率９３％）
マススペクトル（ＥＳＩ＋，ｍ／ｚ）：５４４（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＤＭＳＯ－ｄ６，δppm）：12.41 (brs, 0.9H), 7.65-7.60 (m, 4H), 7.58-7.50 (m, 2H), 7.46-7.34 (m, 6H), 7.25 (dd, J = 8.3, 7.2 Hz, 1H), 6.79 (t, J = 5.7 Hz, 1H), 6.38 (d, J = 8.3 Hz, 1H), 6.32 (d, J = 7.2 Hz, 1H), 4.67 (s, 2H), 4.19 (s, 2H), 3.74 (d, J = 5.7 Hz, 2H), 2.07 (s, 3H)。 19- (b) (6-{(3-Fluorobenzenesulfonyl) [3 ′-(1-propynyl) biphenyl-4-ylmethyl] aminomethyl} pyridin-2-ylamino) acetic acid obtained in Example 19- (a) [Tert-Butoxycarbonyl (6-{(3-fluorobenzenesulfonyl) [3 ′-(1-propynyl) biphenyl-4-ylmethyl] aminomethyl} pyridin-2-yl) amino] acetic acid tert-butyl 595 mg ( To a 5.0 mL solution of 0.850 mmol) in tetrahydrofuran was added 5.0 mL (20 mmol) of 4 mol / L hydrochloric acid, and the mixture was heated and stirred at 70 ° C. for 5 hours. After completion of the reaction, the pH was adjusted to 4.5 with a 1 mol / L sodium hydroxide aqueous solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the concentrate was added 10 mL of ethyl acetate and 5 mL of n-hexane, heated to 50 ° C., and then stirred to room temperature over 2 hours. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 429 mg of the title compound as a white solid. (Yield 93%)
Mass spectrum (ESI + , m / z): 544 (M + +1).
1 H-NMR spectrum (DMSO-d 6 , δ ppm): 12.41 (brs, 0.9H), 7.65-7.60 (m, 4H), 7.58-7.50 (m, 2H), 7.46-7.34 (m, 6H), 7.25 (dd, J = 8.3, 7.2 Hz, 1H), 6.79 (t, J = 5.7 Hz, 1H), 6.38 (d, J = 8.3 Hz, 1H), 6.32 (d, J = 7.2 Hz, 1H), 4.67 (s, 2H), 4.19 (s, 2H), 3.74 (d, J = 5.7 Hz, 2H), 2.07 (s, 3H).
［実施例２０］
（６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（ピリジン－２－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸イソプロピル [Example 20]
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid isopropyl
　参考例１４で得られた｛６－［（ピリジン－２－イルスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸イソプロピル１．０５ｇ（２．８８ｍｍｏｌ）のテトラヒドロフラン１５．０ｍＬ溶液に、参考例１３と同様の方法で得られた３’－（１－プロピニル）ビフェニル－４－イルメタノール６４０ｍｇ（２．８８ｍｍｏｌ）、トリ－ｎ－ブチルホスフィン１．４２ｍＬ（５．７６ｍｍｏｌ）及びＮ，Ｎ，Ｎ’，Ｎ’－テトラメチルアゾジカルボキサミド９９２ｍｇ（５．７６ｍｍｏｌ）を加え、室温で３時間撹拌した。反応終了後、反応溶液に水を加え、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝３：２→２：３（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物１．５９ｇを無色アメ状物として得た。（収率９７％）
マススペクトル（ＣＩ，ｍ／ｚ）：５６９（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：8.62 (ddd, J = 4.7, 1.7, 1.0 Hz, 1H), 7.83 (ddd, J = 7.7, 1.0, 1.0 Hz, 1H), 7.76 (ddd, J = 7.7, 7.7, 1.7 Hz, 1H), 7.60-7.58 (m, 1H), 7.47-7.43 (m, 3H), 7.38 (ddd, J = 7.7, 4.7, 1.0 Hz, 1H), 7.36-7.32 (m, 4H), 7.23 (dd, J = 8.2, 7.3 Hz, 1H), 6.50 (d, J = 7.3 Hz, 1H), 6.22 (d, J = 8.2 Hz, 1H), 5.09 (sep, J = 6.3 Hz, 1H), 4.79 (s, 2H), 4.70 (t, J = 5.3 Hz, 1H), 4.42 (s, 2H), 3.92 (d, J = 5.3 Hz, 2H), 2.08 (s, 3H), 1.26 (d, J = 6.3 Hz, 6H)。 To a 15.0 mL tetrahydrofuran solution of 1.05-g (2.88 mmol) isopropyl acetate {6-[(pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetate obtained in Reference Example 14, 640 mg (2.88 mmol) of 3 ′-(1-propynyl) biphenyl-4-ylmethanol obtained in the same manner, 1.42 mL (5.76 mmol) of tri-n-butylphosphine and N, N, N ′, 992 mg (5.76 mmol) of N′-tetramethylazodicarboxamide was added and stirred at room temperature for 3 hours. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 3: 2 → 2: 3 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound 1 .59 g was obtained as colorless candy. (Yield 97%)
Mass spectrum (CI, m / z): 569 (M + +1).
1 H-NMR spectrum (CDCl 3 , δ ppm): 8.62 (ddd, J = 4.7, 1.7, 1.0 Hz, 1H), 7.83 (ddd, J = 7.7, 1.0, 1.0 Hz, 1H), 7.76 (ddd, J = 7.7, 7.7, 1.7 Hz, 1H), 7.60-7.58 (m, 1H), 7.47-7.43 (m, 3H), 7.38 (ddd, J = 7.7, 4.7, 1.0 Hz, 1H), 7.36-7.32 (m, 4H), 7.23 (dd, J = 8.2, 7.3 Hz, 1H), 6.50 (d, J = 7.3 Hz, 1H), 6.22 (d, J = 8.2 Hz, 1H), 5.09 (sep, J = 6.3 Hz, 1H), 4.79 (s, 2H), 4.70 (t, J = 5.3 Hz, 1H), 4.42 (s, 2H), 3.92 (d, J = 5.3 Hz, 2H), 2.08 (s, 3H), 1.26 ( d, J = 6.3 Hz, 6H).
　実施例に用いた化合物は以下のようにして合成した。 The compounds used in the examples were synthesized as follows.
［参考例１］
｛６－［（ピリジン－２－イルスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸エチル [Reference Example 1]
{6-[(Pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} ethyl acetate
１－（ａ）：［ｔｅｒｔ－ブトキシカルボニル（６－エトキシカルボニルピリジン－２－イル）アミノ］酢酸ｔｅｒｔ－ブチル
　水素化ナトリウム（鉱物油５５重量％分散物）１５．７ｇ（０．３６０ｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド３６２ｍＬ溶液に、６－ｔｅｒｔ－ブトキシカルボニルアミノピリジン－２－カルボン酸エチル（国際公開第２００６／０７４８８４号パンフレット参照）８１．２ｇ（０．３０５ｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド３００ｍＬ溶液を、アルゴン雰囲気中、氷冷下で２０分間かけて滴下し、室温で１時間撹拌した。次いでブロモ酢酸ｔｅｒｔ－ブチル５４．０ｍＬ（０．３６６ｍｏｌ）を、氷冷下で１０分間かけて滴下し、更に室温で１時間撹拌した。反応終了後、反応溶液に塩化アンモニウム１．７７ｇ（３３．０ｍｍｏｌ）を水３００ｍＬに溶解した水溶液を加え、トルエンで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９：１→４：１（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物１０８ｇを淡黄色油状物として得た。（収率９３％）
マススペクトル（ＣＩ，ｍ／ｚ）：３８１（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：8.04 (d, J = 7.8 Hz, 1H), 7.81 (dd, J = 7.6, 1.5 Hz, 1H), 7.76 (dd, J = 7.8, 7.6 Hz, 1H), 4.67 (s, 2H), 4.40 (q, J = 7.1 Hz, 2H), 1.52 (s, 9H), 1.45 (s, 9H), 1.40 (t, J = 7.1 Hz, 3H)。 1- (a): [tert-Butoxycarbonyl (6-ethoxycarbonylpyridin-2-yl) amino] acetic acid sodium tert-butyl hydride (55 wt% mineral oil dispersion) 15.7 g (0.360 mol) N , N-dimethylformamide in a solution of 362 mL of ethyl 6-tert-butoxycarbonylaminopyridine-2-carboxylate (see WO 2006/074884 pamphlet) 81.2 g (0.305 mol) of N, N-dimethylformamide 300 mL The solution was added dropwise over 20 minutes under ice-cooling in an argon atmosphere and stirred at room temperature for 1 hour. Next, 54.0 mL (0.366 mol) of tert-butyl bromoacetate was added dropwise over 10 minutes under ice cooling, and the mixture was further stirred at room temperature for 1 hour. After completion of the reaction, an aqueous solution in which 1.77 g (33.0 mmol) of ammonium chloride was dissolved in 300 mL of water was added to the reaction solution, and the mixture was extracted with toluene. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 9: 1 → 4: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 108 g of the title compound. Was obtained as a pale yellow oil. (Yield 93%)
Mass spectrum (CI, m / z): 381 (M + +1).
1 H-NMR spectrum (CDCl 3 , δ ppm): 8.04 (d, J = 7.8 Hz, 1H), 7.81 (dd, J = 7.6, 1.5 Hz, 1H), 7.76 (dd, J = 7.8, 7.6 Hz, 1H) ), 4.67 (s, 2H), 4.40 (q, J = 7.1 Hz, 2H), 1.52 (s, 9H), 1.45 (s, 9H), 1.40 (t, J = 7.1 Hz, 3H).
１－（ｂ）：［ｔｅｒｔ－ブトキシカルボニル（６－ヒドロキシメチルピリジン－２－イル）アミノ］酢酸ｔｅｒｔ－ブチル
　参考例１－（ａ）で得られた［ｔｅｒｔ－ブトキシカルボニル（６－エトキシカルボニルピリジン－２－イル）アミノ］酢酸ｔｅｒｔ－ブチル９８．８ｇ（０．２６０ｍｏｌ）のエタノール１９５ｍＬ溶液に、塩化カルシウム３４．６ｇ（０．３１２ｍｏｌ）のエタノール１９５ｍＬ溶液を、氷冷下で２０分間かけて滴下した。滴下終了後、３ｍｏｌ／Ｌの水素化ホウ素ナトリウム／テトラエチレングリコールジメチルエーテル溶液１０５ｍＬ（０．３１５ｍｏｌ）を、３５℃以下で２０分間かけて滴下し、更に室温で１５分間撹拌した。反応終了後、反応溶液を、酢酸１７．８ｍＬ及び水１９５ｍＬの混合溶液に、氷冷下で１０分間かけて滴下し、室温で１時間撹拌した。次いで水３１５ｍＬを加え、トルエンで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、水及び飽和塩化ナトリウム水溶液で順次洗浄し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝４：１→３：２（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物８１．１ｇを淡黄色油状物として得た。（収率９２％）
マススペクトル（ＣＩ，ｍ／ｚ）：３３９（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：7.74 (d, J = 8.2 Hz, 1H), 7.63 (dd, J = 8.2, 7.4 Hz, 1H), 6.93-6.98 (m, 1H), 4.68-4.65 (m, 2H), 4.54 (s, 2H), 3.39 (t, J = 5.3 Hz, 1H), 1.54 (s, 9H), 1.46 (s, 9H)。 1- (b): [tert-Butoxycarbonyl (6-hydroxymethylpyridin-2-yl) amino] [tert-Butoxycarbonyl (6-ethoxycarbonylpyridine) obtained in tert-butyl acetate Reference Example 1- (a) -2-yl) amino] tert-butyl acetate 98.8 g (0.260 mol) in ethanol (195 mL) and calcium chloride (34.6 g, 0.312 mol) in ethanol (195 mL) were added dropwise over 20 minutes under ice cooling. did. After completion of the dropwise addition, 105 mL (0.315 mol) of a 3 mol / L sodium borohydride / tetraethylene glycol dimethyl ether solution was added dropwise at 35 ° C. or lower over 20 minutes, and further stirred at room temperature for 15 minutes. After completion of the reaction, the reaction solution was added dropwise to a mixed solution of 17.8 mL of acetic acid and 195 mL of water over 10 minutes under ice cooling, and stirred at room temperature for 1 hour. Subsequently, 315 mL of water was added and extracted with toluene. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated aqueous sodium chloride solution, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 4: 1 → 3: 2 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound 81 .1 g was obtained as a pale yellow oil. (Yield 92%)
Mass spectrum (CI, m / z): 339 (M + +1).
1 H-NMR spectrum (CDCl 3 , δ ppm): 7.74 (d, J = 8.2 Hz, 1H), 7.63 (dd, J = 8.2, 7.4 Hz, 1H), 6.93-6.98 (m, 1H), 4.68-4.65 (m, 2H), 4.54 (s, 2H), 3.39 (t, J = 5.3 Hz, 1H), 1.54 (s, 9H), 1.46 (s, 9H).
１－（ｃ）：［ｔｅｒｔ－ブトキシカルボニル（６－ホルミルピリジン－２－イル）アミノ］酢酸ｔｅｒｔ－ブチル
　デス－マーチン試薬１２．９ｇ（３０．４ｍｍｏｌ）の塩化メチレン１３０ｍＬ溶液に、参考例１－（ｂ）で得られた［ｔｅｒｔ－ブトキシカルボニル（６－ヒドロキシメチルピリジン－２－イル）アミノ］酢酸ｔｅｒｔ－ブチル１０．０ｇ（２９．６ｍｍｏｌ）の塩化メチレン５０ｍＬ溶液を、アルゴン雰囲気中、氷冷下で２０分間かけて滴下した。滴下終了後、室温で２時間撹拌した。反応終了後、反応溶液に０．１重量％チオ硫酸ナトリウム水溶液３０５ｍＬを加え、塩化メチレンで抽出した。有機層を０．５ｍｏｌ／Ｌの水酸化ナトリウム水溶液及び飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮することにより、標記化合物９．６１ｇを微黄色油状物としてほぼ定量的に得た。
マススペクトル（ＥＩ，ｍ／ｚ）：３３６（Ｍ＋）。
１Ｈ－ＮＭＲスペクトル（ＤＭＳＯ－ｄ６，δppm）：9.82 (s, 1H), 8.11-7.99 (m, 2H), 7.68 (dd, J = 6.6, 1.5 Hz, 1H), 4.58 (s, 2H), 1.48 (s, 9H), 1.42 (s, 9H)。 1- (c): [tert- butoxycarbonyl (6-formyl-2-yl) amino] acetate tert- butyl des - methylene chloride 130mL solution of Martin reagent 12.9 g (30.4 mmol), Reference Example 1 A solution of 10.0 g (29.6 mmol) of [tert-butoxycarbonyl (6-hydroxymethylpyridin-2-yl) amino] acetate obtained in (b) in 50 mL of methylene chloride was ice-cooled in an argon atmosphere. Added dropwise over 20 minutes. After completion of dropping, the mixture was stirred at room temperature for 2 hours. After completion of the reaction, 305 mL of 0.1 wt% aqueous sodium thiosulfate solution was added to the reaction solution, and extracted with methylene chloride. The organic layer was washed successively with 0.5 mol / L aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to almost quantitatively give 9.61 g of the title compound as a pale yellow oil. I got it.
Mass spectrum (EI, m / z): 336 (M + ).
1 H-NMR spectrum (DMSO-d 6 , δ ppm): 9.82 (s, 1H), 8.11-7.99 (m, 2H), 7.68 (dd, J = 6.6, 1.5 Hz, 1H), 4.58 (s, 2H) , 1.48 (s, 9H), 1.42 (s, 9H).
１－（ｄ）：［ｔｅｒｔ－ブトキシカルボニル（６－ヒドロキシイミノメチルピリジン－２－イル）アミノ］酢酸ｔｅｒｔ－ブチル
　参考例１－（ｃ）で得られた［ｔｅｒｔ－ブトキシカルボニル（６－ホルミルピリジン－２－イル）アミノ］酢酸ｔｅｒｔ－ブチル２．８８ｇ（８．５６ｍｍｏｌ）のメタノール２９ｍＬ溶液に、塩化ヒドロキシルアンモニウム０．６５０ｇ（９．３５ｍｍｏｌ）及びピリジン３．５ｍＬ（４３ｍｍｏｌ）を加え、室温で１時間撹拌した。反応終了後、反応溶液を減圧濃縮した。得られた残渣に酢酸エチルを加え、５重量％硫酸水素カリウム水溶液、飽和炭酸水素ナトリウム水溶液及び飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝３：２（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物２．７６ｇを無色油状物として得た。（収率９２％）
マススペクトル（ＥＩ，ｍ／ｚ）：３５１（Ｍ＋）。
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：8.06 (s, 1H), 7.91 (s, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.65 (dd, J = 8.2, 7.6 Hz, 1H), 7.47 (dd, J = 7.6, 0.7 Hz, 1H), 4.59 (s, 2H), 1.53 (s, 9H), 1.45 (s, 9H)。 1- (d): [tert-Butoxycarbonyl (6-hydroxyiminomethylpyridin-2-yl) amino] [tert-butoxycarbonyl (6-formylpyridine) obtained in tert-butyl acetate Reference Example 1- (c) To a solution of -2-yl) amino] tert-butyl acetate (2.88 g, 8.56 mmol) in methanol (29 mL) was added hydroxylammonium chloride (0.650 g, 9.35 mmol) and pyridine (3.5 mL, 43 mmol). Stir for hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, and the mixture was washed successively with 5 wt% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 3: 2 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 2.76 g of the title compound colorless. Obtained as an oil. (Yield 92%)
Mass spectrum (EI, m / z): 351 (M + ).
1 H-NMR spectrum (CDCl 3 , δ ppm): 8.06 (s, 1H), 7.91 (s, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.65 (dd, J = 8.2, 7.6 Hz, 1H ), 7.47 (dd, J = 7.6, 0.7 Hz, 1H), 4.59 (s, 2H), 1.53 (s, 9H), 1.45 (s, 9H).
１－（ｅ）：［（６－アミノメチルピリジン－２－イル）ｔｅｒｔ－ブトキシカルボニルアミノ］酢酸ｔｅｒｔ－ブチル
　参考例１－（ｄ）で得られた［ｔｅｒｔ－ブトキシカルボニル（６－ヒドロキシイミノメチルピリジン－２－イル）アミノ］酢酸ｔｅｒｔ－ブチル２．７５ｇ（７．８３ｍｍｏｌ）のエタノール４９ｍＬ溶液に、１０重量％パラジウム－活性炭素（５０重量％含水）０．９８ｇを加え、１気圧水素雰囲気下、室温で１時間撹拌した。反応終了後、不溶物を濾去し、濾液を減圧濃縮することにより、標記化合物２．４８ｇを無色油状物として得た。（収率９４％）
マススペクトル（ＣＩ，ｍ／ｚ）：３３８（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：7.68 (d, J = 8.3 Hz, 1H), 7.58 (dd, J = 8.3, 7.4 Hz, 1H), 6.91 (d, J = 7.4 Hz, 1H), 4.57 (s, 2H), 3.85 (s, 2H), 1.53 (s, 9H), 1.46 (s, 9H)。 1- (e): [(6-Aminomethylpyridin-2-yl) tert-butoxycarbonylamino] [tert-butoxycarbonyl (6-hydroxyiminomethyl) obtained in tert-butyl acetate Reference Example 1- (d) Pyridin-2-yl) amino] 0.98 g of 10 wt% palladium-activated carbon (containing 50 wt% water) was added to a solution of 2.75 g (7.83 mmol) of tert-butyl acetate in ethanol (49 mL) under a 1 atmosphere hydrogen atmosphere. And stirred at room temperature for 1 hour. After completion of the reaction, the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 2.48 g of the title compound as a colorless oil. (Yield 94%)
Mass spectrum (CI, m / z): 338 (M + +1).
1 H-NMR spectrum (CDCl 3 , δ ppm): 7.68 (d, J = 8.3 Hz, 1H), 7.58 (dd, J = 8.3, 7.4 Hz, 1H), 6.91 (d, J = 7.4 Hz, 1H), 4.57 (s, 2H), 3.85 (s, 2H), 1.53 (s, 9H), 1.46 (s, 9H).
１－（ｆ）：（ｔｅｒｔ－ブトキシカルボニル｛６－［（ピリジン－２－イルスルホニル）アミノメチル］ピリジン－２－イル｝アミノ）酢酸ｔｅｒｔ－ブチル
　２－ピリジルスルホニルクロリド０．６４０ｇ（３．６０ｍｍｏｌ）の塩化メチレン１４ｍＬ溶液に、参考例１－（ｅ）で得られた［（６－アミノメチルピリジン－２－イル）ｔｅｒｔ－ブトキシカルボニルアミノ］酢酸ｔｅｒｔ－ブチル１．２０ｇ（３．５６ｍｍｏｌ）及びトリエチルアミン２．２４ｍＬ（１６．２ｍｍｏｌ）の塩化メチレン１２ｍＬ溶液を加え、室温で０．５時間撹拌した。反応終了後、反応溶液に５重量％硫酸水素カリウム水溶液を加え、塩化メチレンで抽出した。有機層を飽和炭酸水素ナトリウム水溶液及び飽和塩化ナトリウム水溶液で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１：１（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物１．４６ｇを白色固体として得た。（収率８６％）
マススペクトル（ＡＰＣＩ，ｍ／ｚ）：４７９（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：8.56 (ddd, J = 4.7, 1.7, 0.9 Hz, 1H), 7.97 (ddd, J = 7.8, 1.1, 0.9 Hz, 1H), 7.84 (ddd, J = 7.8, 7.7, 1.7 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.52 (dd, J = 8.4, 7.4 Hz, 1H), 7.40 (ddd, J = 7.7, 4.7, 1.1 Hz, 1H), 6.84 (dd, J = 7.4, 0.5 Hz, 1H), 5.86 (t, J = 5.6 Hz, 1H), 4.48 (s, 2H), 4.36 (d, J = 5.6 Hz, 2H), 1.53 (s, 9H), 1.45 (s, 9H)。 1- (f): (tert-Butoxycarbonyl {6-[(pyridin-2- ylsulfonyl ) aminomethyl] pyridin-2-yl} amino) tert-butyl 2-pyridylsulfonyl chloride 0.640 g (3.60 mmol) ) In methylene chloride (14 mL) [(6-aminomethylpyridin-2-yl) tert-butoxycarbonylamino] tert-butyl acetate 1.20 g (3.56 mmol) obtained in Reference Example 1- (e) and A solution of 2.24 mL (16.2 mmol) of triethylamine in 12 mL of methylene chloride was added, and the mixture was stirred at room temperature for 0.5 hour. After completion of the reaction, a 5 wt% aqueous potassium hydrogen sulfate solution was added to the reaction solution, and the mixture was extracted with methylene chloride. The organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 1: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 1.46 g of the title compound in white. Obtained as a solid. (Yield 86%)
Mass spectrum (APCI, m / z): 479 (M + +1).
1 H-NMR spectrum (CDCl 3 , δ ppm): 8.56 (ddd, J = 4.7, 1.7, 0.9 Hz, 1H), 7.97 (ddd, J = 7.8, 1.1, 0.9 Hz, 1H), 7.84 (ddd, J = 7.8, 7.7, 1.7 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.52 (dd, J = 8.4, 7.4 Hz, 1H), 7.40 (ddd, J = 7.7, 4.7, 1.1 Hz, 1H ), 6.84 (dd, J = 7.4, 0.5 Hz, 1H), 5.86 (t, J = 5.6 Hz, 1H), 4.48 (s, 2H), 4.36 (d, J = 5.6 Hz, 2H), 1.53 (s , 9H), 1.45 (s, 9H).
１－（ｇ）：｛６－［（ピリジン－２－イルスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸エチル
　参考例１－（ｆ）と同様の方法で得られた（ｔｅｒｔ－ブトキシカルボニル｛６－［（ピリジン－２－イルスルホニル）アミノメチル］ピリジン－２－イル｝アミノ）酢酸ｔｅｒｔ－ブチル３．５９ｇ（７．５０ｍｍｏｌ）に、２ｍｏｌ／Ｌの塩化水素／エタノール溶液３７．５ｍＬ（７５．０ｍｍｏｌ）を加え、加熱還流下で３時間撹拌した。反応終了後、反応溶液に水を加え、１ｍｏｌ／Ｌの水酸化ナトリウム水溶液で中和した後、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮することにより、標記化合物２．１７ｇを褐色油状物として得た。（収率８３％）
マススペクトル（ＣＩ，ｍ／ｚ）：３５１（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＤＭＳＯ－ｄ６，δppm）： 8.71 (ddd, J = 4.8, 1.8, 0.8 Hz, 1H), 8.18 (brs, 0.1H), 8.05 (ddd, J = 7.8, 7.6, 1.8 Hz, 1H), 7.91 (ddd, J = 7.8, 1.0, 0.8 Hz, 1H), 7.64 (ddd, J = 7.6, 4.6, 1.0 Hz, 1H), 7.33 (dd, J = 8.1, 7.2 Hz, 1H), 6.86 (t, J = 6.1 Hz, 0.2H), 6.52 (d, J = 7.2 Hz, 1H), 6.39 (d, J = 8.1 Hz, 1H), 4.08 (q, J = 7.1 Hz, 2H), 4.01 (s, 2H), 3.95 (s, 2H), 1.16 (t, J = 7.1 Hz, 3H)。 1- (g): {6-[(Pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} ethyl acetate (tert-butoxycarbonyl {) obtained in the same manner as in Reference Example 1- (f) 6-[(Pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate 3.59 g (7.50 mmol) was added to a 2 mol / L hydrogen chloride / ethanol solution 37.5 mL (75 0.0 mmol) was added, and the mixture was stirred for 3 hours under heating to reflux. After completion of the reaction, water was added to the reaction solution, neutralized with a 1 mol / L sodium hydroxide aqueous solution, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 2.17 g of the title compound as a brown oil. (Yield 83%)
Mass spectrum (CI, m / z): 351 (M + +1).
1 H-NMR spectrum (DMSO-d 6 , δ ppm): 8.71 (ddd, J = 4.8, 1.8, 0.8 Hz, 1H), 8.18 (brs, 0.1H), 8.05 (ddd, J = 7.8, 7.6, 1.8 Hz) , 1H), 7.91 (ddd, J = 7.8, 1.0, 0.8 Hz, 1H), 7.64 (ddd, J = 7.6, 4.6, 1.0 Hz, 1H), 7.33 (dd, J = 8.1, 7.2 Hz, 1H), 6.86 (t, J = 6.1 Hz, 0.2H), 6.52 (d, J = 7.2 Hz, 1H), 6.39 (d, J = 8.1 Hz, 1H), 4.08 (q, J = 7.1 Hz, 2H), 4.01 (s, 2H), 3.95 (s, 2H), 1.16 (t, J = 7.1 Hz, 3H).
［参考例２］
｛６－［（ピリジン－３－イルスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸エチル [Reference Example 2]
{6-[(Pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-ylamino} ethyl acetate
２－（ａ）：（ｔｅｒｔ－ブトキシカルボニル｛６－［（ピリジン－３－イルスルホニル）アミノメチル］ピリジン－２－イル｝アミノ）酢酸ｔｅｒｔ－ブチル
　参考例１－（ｅ）と同様の方法で得られた［（６－アミノメチルピリジン－２－イル）ｔｅｒｔ－ブトキシカルボニルアミノ］酢酸ｔｅｒｔ－ブチル１．２０ｇ（３．５６ｍｍｏｌ）を使用し、２－ピリジルスルホニルクロリドの代わりに３－ピリジルスルホニルクロリド６４０ｍｇ（３．６０ｍｍｏｌ）を使用した以外は、参考例１－（ｆ）に準じて反応及び後処理を行い、標記化合物１．４５ｇを無色油状物として得た。（収率８５％）
マススペクトル（ＣＩ，ｍ／ｚ）：４７９（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：9.06 (d, J = 2.2 Hz, 1H), 8.71 (dd, J = 4.6, 1.5 Hz, 1H), 8.13-8.08 (m, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.52 (dd, J = 8.2, 7.4 Hz, 1H), 7.38-7.32 (m, 1H), 6.77 (d, J = 7.4 Hz, 1H), 5.80 (t, J = 5.1 Hz, 1H), 4.40 (s, 2H), 4.24 (d, J = 5.1 Hz, 2H), 1.53 (s, 9H), 1.46 (s, 9H)。 2- (a): (tert-Butoxycarbonyl {6-[(pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate In the same manner as in Reference Example 1- (e) Using 1.20 g (3.56 mmol) of tert-butyl acetate obtained ([6-aminomethylpyridin-2-yl) tert-butoxycarbonylamino] acetate, 3-pyridylsulfonyl chloride instead of 2-pyridylsulfonyl chloride The reaction and post-treatment were performed according to Reference Example 1- (f) except that 640 mg (3.60 mmol) was used, and 1.45 g of the title compound was obtained as a colorless oil. (Yield 85%)
Mass spectrum (CI, m / z): 479 (M + +1).
1 H-NMR spectrum (CDCl 3 , δ ppm): 9.06 (d, J = 2.2 Hz, 1H), 8.71 (dd, J = 4.6, 1.5 Hz, 1H), 8.13-8.08 (m, 1H), 7.68 (d , J = 8.2 Hz, 1H), 7.52 (dd, J = 8.2, 7.4 Hz, 1H), 7.38-7.32 (m, 1H), 6.77 (d, J = 7.4 Hz, 1H), 5.80 (t, J = 5.1 Hz, 1H), 4.40 (s, 2H), 4.24 (d, J = 5.1 Hz, 2H), 1.53 (s, 9H), 1.46 (s, 9H).
２－（ｂ）：｛６－［（ピリジン－３－イルスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸エチル
　（ｔｅｒｔ－ブトキシカルボニル｛６－［（ピリジン－２－イルスルホニル）アミノメチル］ピリジン－２－イル｝アミノ）酢酸ｔｅｒｔ－ブチルの代わりに、参考例２－（ａ）と同様の方法で得られた（ｔｅｒｔ－ブトキシカルボニル｛６－［（ピリジン－３－イルスルホニル）アミノメチル］ピリジン－２－イル｝アミノ）酢酸ｔｅｒｔ－ブチル１．００ｇ（２．０９ｍｍｏｌ）を使用し、２ｍｏｌ／Ｌの塩化水素／エタノール溶液１０．４ｍＬ（２０．８ｍｍｏｌ）を使用した以外は、参考例１－（ｇ）に準じて反応及び後処理を行い、標記化合物６８６ｍｇを褐色油状物として得た。（収率９４％）
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：9.06 (dd, J = 2.3, 0.7 Hz, 1H), 8.71 (dd, J = 4.9, 1.6 Hz, 1H), 8.09 (ddd, J = 8.0, 2.3, 1.6 Hz, 1H), 7.35 (ddd, J = 8.0, 4.9, 0.7 Hz, 1H), 7.28 (dd, J = 8.3, 7.3 Hz, 1H), 6.38 (d, J = 7.3 Hz, 1H), 6.29 (d, J = 8.3 Hz, 1H), 5.95 (t, J = 5.4 Hz, 1H), 4.96 (t, J = 5.4 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 4.14 (d, J = 5.4 Hz, 2H), 4.03 (d, J = 5.4 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H)。 2- (b): {6-[(Pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-ylamino} ethyl acetate (tert-butoxycarbonyl {6-[(pyridin-2-ylsulfonyl) aminomethyl] pyridine (-2-yl} amino) (tert-butoxycarbonyl {6-[(pyridin-3-ylsulfonyl) aminomethyl] obtained in the same manner as in Reference Example 2- (a) instead of tert-butyl acetate Reference Example 1 except that 1.00 g (2.09 mmol) of tert-butyl acetate was used and 10.4 mL (20.8 mmol) of a 2 mol / L hydrogen chloride / ethanol solution was used. The reaction and post-treatment were performed according to-(g) to obtain 686 mg of the title compound as a brown oil. (Yield 94%)
1 H-NMR spectrum (CDCl 3 , δ ppm): 9.06 (dd, J = 2.3, 0.7 Hz, 1H), 8.71 (dd, J = 4.9, 1.6 Hz, 1H), 8.09 (ddd, J = 8.0, 2.3, 1.6 Hz, 1H), 7.35 (ddd, J = 8.0, 4.9, 0.7 Hz, 1H), 7.28 (dd, J = 8.3, 7.3 Hz, 1H), 6.38 (d, J = 7.3 Hz, 1H), 6.29 ( d, J = 8.3 Hz, 1H), 5.95 (t, J = 5.4 Hz, 1H), 4.96 (t, J = 5.4 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 4.14 (d, J = 5.4 Hz, 2H), 4.03 (d, J = 5.4 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H).
［参考例３］
３’－（１－プロペニル）ビフェニル－４－イルメタノール [Reference Example 3]
3 '-(1-propenyl) biphenyl-4-ylmethanol
３－（ａ）：３’－（１－プロペニル）ビフェニル－４－イルカルボアルデヒド
　３’－ブロモビフェニル－４－イルカルボアルデヒド（Journal of Organic Chemistry, 68, 247 (2003)参照）５００ｍｇ（１．９１ｍｍｏｌ）に、トルエン２７．５ｍＬ及び水１．６５ｍＬを加え、次いでリン酸三カリウム１．６３ｇ（７．６８ｍｍｏｌ）及び１－プロペニルボロン酸６５６ｍｇ（７．６４ｍｍｏｌ）を添加後、窒素ガス雰囲気下にした。更に酢酸パラジウム６．２ｍｇ（０．０２８ｍｍｏｌ）及びブチルジ－１－アダマンチルホスフィン２０．２ｍｇ（０．０５６３ｍｍｏｌ）を加え、窒素ガス雰囲気下、１００℃で４．５時間撹拌した。反応終了後、反応溶液に水を加え、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝４：１（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物４２０ｍｇを微黄色油状物として得た。（収率９９％）
マススペクトル（ＣＩ，ｍ／ｚ）：２２３（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：10.06 (s, 1H), 7.98-7.92 (m, 2H), 7.79-7.72 (m, 2H), 7.59-7.55 (m, 1H), 7.49-7.42 (m, 1H), 7.41-7.37 (m, 2H), 6.48 (dd, J = 15.9, 1.5 Hz, 1H), 6.33 (dq, J = 15.9, 6.3 Hz, 1H), 1.92 (dd, J = 6.3, 1.5 Hz, 3H)。 3- (a): 3 ′-(1-propenyl) biphenyl-4-ylcarbaldehyde 3′-bromobiphenyl-4-ylcarbaldehyde (see Journal of Organic Chemistry, 68, 247 (2003)) 500 mg (1. 91 mmol), 27.5 mL of toluene and 1.65 mL of water were added, followed by the addition of 1.63 g (7.68 mmol) of tripotassium phosphate and 656 mg (7.64 mmol) of 1-propenylboronic acid. did. Further, 6.2 mg (0.028 mmol) of palladium acetate and 20.2 mg (0.0563 mmol) of butyldi-1-adamantylphosphine were added, and the mixture was stirred at 100 ° C. for 4.5 hours in a nitrogen gas atmosphere. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 4: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 420 mg of the title compound as a pale yellow oil. Obtained as a thing. (Yield 99%)
Mass spectrum (CI, m / z): 223 (M + +1).
1 H-NMR spectrum (CDCl 3 , δ ppm): 10.06 (s, 1H), 7.98-7.92 (m, 2H), 7.79-7.72 (m, 2H), 7.59-7.55 (m, 1H), 7.49-7.42 ( m, 1H), 7.41-7.37 (m, 2H), 6.48 (dd, J = 15.9, 1.5 Hz, 1H), 6.33 (dq, J = 15.9, 6.3 Hz, 1H), 1.92 (dd, J = 6.3, 1.5 Hz, 3H).
３－（ｂ）：３’－（１－プロペニル）ビフェニル－４－イルメタノール
　参考例３－（ａ）で得られた３’－（１－プロペニル）ビフェニル－４－イルカルボアルデヒド４１７ｍｇ（１．８８ｍｍｏｌ）のエタノール４．６ｍＬ溶液に、室温下で水素化ホウ素ナトリウム３５．６ｍｇ（０．９４１ｍｍｏｌ）を加え、同温度で４５分間撹拌した。反応終了後、反応溶液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝７：３（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物４０１ｍｇを白色固体として得た。（収率９５％）
マススペクトル（ＥＩ，ｍ／ｚ）：２２４（Ｍ＋）。
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：7.63-7.56 (m, 2H), 7.55-7.52 (m, 1H), 7.47-7.29 (m, 5H), 6.47 (dd, J = 15.9, 1.5 Hz, 1H), 6.31 (dq, J = 15.9, 6.6 Hz, 1H), 4.74 (d, J = 5.7 Hz, 2H), 1.91 (dd, J = 6.6, 1.5 Hz, 3H), 1.70 (t, J = 5.7 Hz, 1H)。 3- (b): 3 ′-(1-propenyl) biphenyl-4-ylmethanol Reference Example 3- (a) 3 ′-(1-propenyl) biphenyl-4-ylcarbaldehyde 417 mg (1. 88 mmol) in 4.6 mL of ethanol was added 35.6 mg (0.941 mmol) of sodium borohydride at room temperature, and the mixture was stirred at the same temperature for 45 minutes. After completion of the reaction, a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 7: 3 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 401 mg of the title compound as a white solid. Obtained. (Yield 95%)
Mass spectrum (EI, m / z): 224 (M + ).
1 H-NMR spectrum (CDCl 3 , δ ppm): 7.63-7.56 (m, 2H), 7.55-7.52 (m, 1H), 7.47-7.29 (m, 5H), 6.47 (dd, J = 15.9, 1.5 Hz, 1H), 6.31 (dq, J = 15.9, 6.6 Hz, 1H), 4.74 (d, J = 5.7 Hz, 2H), 1.91 (dd, J = 6.6, 1.5 Hz, 3H), 1.70 (t, J = 5.7 Hz, 1H).
［参考例４］
３’－（１－プロピニル）ビフェニル－４－イルメタノール [Reference Example 4]
3 '-(1-propynyl) biphenyl-4-ylmethanol
４－（ａ）：３’－（１－プロピニル）ビフェニル－４－イルカルボアルデヒド
　３’－ブロモビフェニル－４－イルカルボアルデヒド１．０４ｇ（３．９８ｍｍｏｌ）のトルエン１０ｍＬ溶液を、減圧脱気後、アルゴンガス置換した。次いで、テトラキストリフェニルホスフィンパラジウム２３１ｍｇ（０．２００ｍｍｏｌ）及びトリブチル（１－プロピニル）スズ１．４６ｍＬ（４．８０ｍｍｏｌ）を加え、アルゴンガス雰囲気下、１１０℃で７時間撹拌した。反応終了後、反応溶液に０．８ｍｏｌ／Ｌのフッ化カリウム水溶液６０ｍＬを加え、トルエンで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１：０→４：１（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物６６０ｍｇを淡黄色固体として得た。（収率７５％）
マススペクトル（ＣＩ，ｍ／ｚ）：２２１（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：10.06 (s, 1H), 7.97-7.93 (m, 2H), 7.76-7.72 (m, 2H), 7.68-7.67 (m, 1H), 7.55-7.52 (m, 1H), 7.45-7.37 (m, 2H), 2.08 (s, 3H)。 4- (a): 3 ′-(1-propynyl) biphenyl-4- ylcarbaldehyde 3′-bromobiphenyl-4-ylcarbaldehyde 1.04 g (3.98 mmol) in 10 mL toluene was degassed The gas was replaced with argon gas. Next, 231 mg (0.200 mmol) of tetrakistriphenylphosphine palladium and 1.46 mL (4.80 mmol) of tributyl (1-propynyl) tin were added, and the mixture was stirred at 110 ° C. for 7 hours in an argon gas atmosphere. After completion of the reaction, 60 mL of 0.8 mol / L potassium fluoride aqueous solution was added to the reaction solution and extracted with toluene. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 1: 0 → 4: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 660 mg of the title compound. Was obtained as a pale yellow solid. (Yield 75%)
Mass spectrum (CI, m / z): 221 (M + +1).
1 H-NMR spectrum (CDCl 3 , δ ppm): 10.06 (s, 1H), 7.97-7.93 (m, 2H), 7.76-7.72 (m, 2H), 7.68-7.67 (m, 1H), 7.55-7.52 ( m, 1H), 7.45-7.37 (m, 2H), 2.08 (s, 3H).
４－（ｂ）：３’－（１－プロピニル）ビフェニル－４－イルメタノール
　３’－（１－プロペニル）ビフェニル－４－イルカルボアルデヒドの代わりに、参考例４－（ａ）と同様の方法で得られた３’－（１－プロピニル）ビフェニル－４－イルカルボアルデヒド７２３ｍｇ（３．２８ｍｍｏｌ）を使用し、水素化ホウ素ナトリウム６２．２ｍｇ（１．６４ｍｍｏｌ）を使用した以外は、参考例３－（ｂ）に準じて反応及び後処理を行い、標記化合物５８８ｍｇを微黄白色固体として得た。（収率８１％）
マススペクトル（ＥＩ，ｍ／ｚ）：２２２（Ｍ＋）。
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：7.63-7.62 (m, 1H), 7.60-7.56 (m, 2H), 7.51-7.47 (m, 1H), 7.46-7.42 (m, 2H), 7.38-7.32 (m, 2H), 4.75 (d, J = 6.0 Hz, 2H), 2.07 (s, 3H), 1.68 (t, J = 6.0 Hz, 1H)。 4- (b): 3 ′-(1-propynyl) biphenyl-4-ylmethanol 3 ′-(1-propenyl) biphenyl-4-ylcarbaldehyde instead of Reference Example 4- (a) Reference Example 3 except that 723 mg (3.28 mmol) of 3 ′-(1-propynyl) biphenyl-4-ylcarbaldehyde obtained in 1 was used and 62.2 mg (1.64 mmol) of sodium borohydride was used. The reaction and post-treatment were performed according to-(b) to obtain 588 mg of the title compound as a pale yellowish white solid. (Yield 81%)
Mass spectrum (EI, m / z): 222 (M + ).
1 H-NMR spectrum (CDCl 3 , δ ppm): 7.63-7.62 (m, 1H), 7.60-7.56 (m, 2H), 7.51-7.47 (m, 1H), 7.46-7.42 (m, 2H), 7.38- 7.32 (m, 2H), 4.75 (d, J = 6.0 Hz, 2H), 2.07 (s, 3H), 1.68 (t, J = 6.0 Hz, 1H).
［参考例５］
３’－エトキシビフェニル－４－イルメタノール
　３－ブロモフェネトール１．２１ｇ（６．０２ｍｍｏｌ）にトルエン１５ｍＬ、エタノール１５ｍＬ及び２ｍｏｌ／Ｌの炭酸ナトリウム水溶液４．５ｍｌ（９．０ｍｍｏｌ）を加え、減圧脱気後、アルゴンガス置換した。次いで、４－（ヒドロキシメチル）フェニルボロン酸１．３７ｇ（９．０２ｍｍｏｌ）及びテトラキストリフェニルホスフィンパラジウム３４７ｍｇ（０．３００ｍｍｏｌ）を加え、アルゴンガス雰囲気下、１００℃で４時間撹拌した。反応終了後、反応溶液を減圧濃縮し、残渣に水を加え、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝９：１→７：３（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物１．２３ｇを淡黄色油状物として得た。（収率９０％）
マススペクトル（ＣＩ，ｍ／ｚ）：２２９（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：7.61-7.56 (m, 2H), 7.46-7.41 (m, 2H), 7.34 (dd, J = 8.0, 8.0 Hz, 1H,), 7.18-7.11 (m, 2H), 6.91-6.87 (m, 1H), 4.74 (d, J = 5.9 Hz, 2H), 4.10 (q, J = 7.0 Hz, 2H), 1.67 (t, J = 5.9 Hz, 1H), 1.45 (t, J = 7.0 Hz, 3H)。 [Reference Example 5]
To 1.21 g (6.02 mmol) of 3′- ethoxybiphenyl- 4-ylmethanol 3-bromophenetole, add 15 mL of toluene, 15 mL of ethanol, and 4.5 mL (9.0 mmol) of 2 mol / L sodium carbonate aqueous solution, After the gas was replaced with argon gas. Subsequently, 1.37 g (9.02 mmol) of 4- (hydroxymethyl) phenylboronic acid and 347 mg (0.300 mmol) of tetrakistriphenylphosphine palladium were added, followed by stirring at 100 ° C. for 4 hours in an argon gas atmosphere. After completion of the reaction, the reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 9: 1 → 7: 3 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound 1 .23 g was obtained as a pale yellow oil. (Yield 90%)
Mass spectrum (CI, m / z): 229 (M + +1).
1 H-NMR spectrum (CDCl 3 , δ ppm): 7.61-7.56 (m, 2H), 7.46-7.41 (m, 2H), 7.34 (dd, J = 8.0, 8.0 Hz, 1H,), 7.18-7.11 (m , 2H), 6.91-6.87 (m, 1H), 4.74 (d, J = 5.9 Hz, 2H), 4.10 (q, J = 7.0 Hz, 2H), 1.67 (t, J = 5.9 Hz, 1H), 1.45 (t, J = 7.0 Hz, 3H).
［参考例６］
｛６－［（ピリジン－２－イルスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸ヘキシル
　参考例１－（ｆ）と同様の方法で得られた（ｔｅｒｔ－ブトキシカルボニル｛６－［（ピリジン－２－イルスルホニル）アミノメチル］ピリジン－２－イル｝アミノ）酢酸ｔｅｒｔ－ブチル９５７ｍｇ（２．００ｍｍｏｌ）のｎ－ヘキサノール６．０ｍＬ溶液に、濃硫酸０．５６ｍＬ（１０ｍｍｏｌ）を加え、１００℃で８時間撹拌した。反応終了後、反応溶液を飽和炭酸水素ナトリウム水溶液に注加し、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝１：１→３：７（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物６５８ｍｇを微黄色油状物として得た。（収率８１％）
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：8.62 (ddd, J = 4.6, 1.8, 1.0 Hz, 1H), 7.97 (ddd, J = 7.7, 1.2, 1.0 Hz, 1H), 7.84 (ddd, J = 7.7, 7.7, 1.8 Hz, 1H), 7.41 (ddd, J = 7.7, 4.6, 1.2 Hz, 1H), 7.29 (dd, J = 8.4, 7.4 Hz, 1H), 6.44 (d, J = 7.4 Hz, 1H), 6.28 (d, J = 8.4 Hz, 1H), 6.02 (t, J = 5.3 Hz, 1H), 4.92 (t, J = 5.3 Hz, 1H), 4.25 (d, J = 5.3 Hz, 2H), 4.18 (t, J = 6.7 Hz, 2H), 4.08 (d, J = 5.3 Hz, 2H), 1.71-1.61 (m, 2H), 1.39-1.26 (m, 6H), 0.91-0.87 (m, 3H)。 [Reference Example 6]
{6-[(Pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} hexyl acetate tert-butoxycarbonyl {6-[(pyridine- To a 6.0 mL n-hexanol solution of 957 mg (2.00 mmol) of tert-butyl acetate of 2-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) acetate, 0.56 mL (10 mmol) of concentrated sulfuric acid was added at 100 ° C. Stir for 8 hours. After completion of the reaction, the reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 1: 1 → 3: 7 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 658 mg of the title compound. Was obtained as a slightly yellow oil. (Yield 81%)
1 H-NMR spectrum (CDCl 3 , δ ppm): 8.62 (ddd, J = 4.6, 1.8, 1.0 Hz, 1H), 7.97 (ddd, J = 7.7, 1.2, 1.0 Hz, 1H), 7.84 (ddd, J = 7.7, 7.7, 1.8 Hz, 1H), 7.41 (ddd, J = 7.7, 4.6, 1.2 Hz, 1H), 7.29 (dd, J = 8.4, 7.4 Hz, 1H), 6.44 (d, J = 7.4 Hz, 1H ), 6.28 (d, J = 8.4 Hz, 1H), 6.02 (t, J = 5.3 Hz, 1H), 4.92 (t, J = 5.3 Hz, 1H), 4.25 (d, J = 5.3 Hz, 2H), 4.18 (t, J = 6.7 Hz, 2H), 4.08 (d, J = 5.3 Hz, 2H), 1.71-1.61 (m, 2H), 1.39-1.26 (m, 6H), 0.91-0.87 (m, 3H) .
［参考例７］
（ｔｅｒｔ－ブトキシカルボニル｛６－［（３’－エトキシビフェニル－４－イルメチル）アミノメチル］ピリジン－２－イル｝アミノ）酢酸ｔｅｒｔ－ブチル [Reference Example 7]
(Tert-Butoxycarbonyl {6-[(3′-ethoxybiphenyl-4-ylmethyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate
７－（ａ）：３’－エトキシビフェニル－４－イルカルボアルデヒド
　３－ブロモフェネトールの代わりに４－ブロモベンズアルデヒド４．２０ｇ（２２．７ｍｍｏｌ）、４－（ヒドロキシメチル）フェニルボロン酸の代わりに３－エトキシフェニルボロン酸３．１３ｇ（１８．９ｍｍｏｌ）をそれぞれ使用し、２ｍｏｌ／Ｌの炭酸ナトリウム水溶液２８．４ｍｌ（５６．８ｍｍｏｌ）及びテトラキストリフェニルホスフィンパラジウム２．１８ｇ（１．８９ｍｍｏｌ）を使用した以外は、参考例５に準じて反応及び後処理を行い、標記化合物４．０８ｇを無色油状物として得た。（収率９５％）
マススペクトル（ＣＩ，ｍ／ｚ）：２２７（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：10.06 (s, 1H), 7.97-7.93 (m, 2H), 7.76-7.73 (m, 2H), 7.38 (dd, J = 8.1, 7.9 Hz, 1H), 7.21 (ddd, J = 7.9, 2.0, 0.9 Hz, 1H), 7.16 (dd, J = 2.3, 2.0 Hz, 1H), 6.95 (ddd, J = 8.1, 2.3, 0.9 Hz, 1H), 4.11 (q, J = 6.9 Hz, 2H), 1.46 (t, J = 6.9 Hz, 3H)。 7- (a): 3′ -ethoxybiphenyl-4-ylcarbaldehyde 4.20 g (22.7 mmol) of 4-bromobenzaldehyde instead of 3-bromophenetole, instead of 4- (hydroxymethyl) phenylboronic acid 3.13 g (18.9 mmol) of 3-ethoxyphenylboronic acid was used respectively, 28.4 ml (56.8 mmol) of 2 mol / L sodium carbonate aqueous solution and 2.18 g (1.89 mmol) of tetrakistriphenylphosphine palladium were used. Except for the above, the reaction and post-treatment were carried out according to Reference Example 5 to obtain 4.08 g of the title compound as a colorless oil. (Yield 95%)
Mass spectrum (CI, m / z): 227 (M + +1).
1 H-NMR spectrum (CDCl 3 , δ ppm): 10.06 (s, 1H), 7.97-7.93 (m, 2H), 7.76-7.73 (m, 2H), 7.38 (dd, J = 8.1, 7.9 Hz, 1H) , 7.21 (ddd, J = 7.9, 2.0, 0.9 Hz, 1H), 7.16 (dd, J = 2.3, 2.0 Hz, 1H), 6.95 (ddd, J = 8.1, 2.3, 0.9 Hz, 1H), 4.11 (q , J = 6.9 Hz, 2H), 1.46 (t, J = 6.9 Hz, 3H).
７－（ｂ）：（ｔｅｒｔ－ブトキシカルボニル｛６－［（３’－エトキシビフェニル－４－イルメチル）アミノメチル］ピリジン－２－イル｝アミノ）酢酸ｔｅｒｔ－ブチル
　参考例１－（ｅ）と同様の方法で得られた［（６－アミノメチルピリジン－２－イル）ｔｅｒｔ－ブトキシカルボニルアミノ］酢酸ｔｅｒｔ－ブチル４．０２ｇ（１１．９ｍｍｏｌ）の塩化メチレン１２ｍＬ溶液に、参考例７－（ａ）で得られた３’－エトキシビフェニル－４－イルカルボアルデヒド２．４６ｇ（１０．９ｍｍｏｌ）を加え、室温で３０分間撹拌した。次いで、氷冷下でトリアセトキシ水素化ホウ素ナトリウム３．２５ｇ（１５．３ｍｍｏｌ）を添加し、同温度で３．５時間撹拌した。反応終了後、反応溶液に炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水炭酸カリウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝３：２→０：１（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物３．６８ｇを淡黄色油状物として得た。（収率６２％）
マススペクトル（ＣＩ，ｍ／ｚ）：５４８（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：7.69 (d, J = 8.2 Hz, 1H), 7.59 (dd, J = 8.2, 7.3 Hz, 1H), 7.57-7.53 (m, 2H), 7.43-7.39 (m, 2H), 7.33 (dd, J = 7.9, 7.7 Hz, 1H), 7.16 (ddd, J = 7.7, 1.7, 0.9 Hz, 1H), 7.12 (dd, J = 2.3, 1.7 Hz, 1H), 6.97 (d, J = 7.3 Hz, 1H), 6.87 (ddd, J = 7.9, 2.3, 1.0 Hz, 1H), 4.57 (s, 2H), 4.10 (q, J = 7.1 Hz, 2H), 3.84 (s, 2H), 3.83 (s, 2H), 1.53 (s, 9H), 1.44 (t, J = 7.1 Hz, 3H), 1.42 (s, 9H)。 7- (b): (tert-Butoxycarbonyl {6-[(3′-ethoxybiphenyl-4-ylmethyl) aminomethyl] pyridin-2-yl} amino) Same as tert-butyl acetate reference example 1- (e) Reference Example 7- (a) was added to a solution of [(6-aminomethylpyridin-2-yl) tert-butoxycarbonylamino] tert-butyl acetate 4.02 g (11.9 mmol) obtained by the method of 2.46 g (10.9 mmol) of 3′-ethoxybiphenyl-4-ylcarbaldehyde obtained in 1) was added and stirred at room temperature for 30 minutes. Next, 3.25 g (15.3 mmol) of sodium triacetoxyborohydride was added under ice cooling, and the mixture was stirred at the same temperature for 3.5 hours. After completion of the reaction, an aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous potassium carbonate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 3: 2 → 0: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound 3 Obtained .68 g as a pale yellow oil. (Yield 62%)
Mass spectrum (CI, m / z): 548 (M + +1).
1 H-NMR spectrum (CDCl 3 , δ ppm): 7.69 (d, J = 8.2 Hz, 1H), 7.59 (dd, J = 8.2, 7.3 Hz, 1H), 7.57-7.53 (m, 2H), 7.43-7.39 (m, 2H), 7.33 (dd, J = 7.9, 7.7 Hz, 1H), 7.16 (ddd, J = 7.7, 1.7, 0.9 Hz, 1H), 7.12 (dd, J = 2.3, 1.7 Hz, 1H), 6.97 (d, J = 7.3 Hz, 1H), 6.87 (ddd, J = 7.9, 2.3, 1.0 Hz, 1H), 4.57 (s, 2H), 4.10 (q, J = 7.1 Hz, 2H), 3.84 (s , 2H), 3.83 (s, 2H), 1.53 (s, 9H), 1.44 (t, J = 7.1 Hz, 3H), 1.42 (s, 9H).
［参考例８］
４－（６－エトキシピリジン－２－イル）フェニルメタノール
　３－ブロモフェネトールの代わりに２－ブロモ－６－エトキシピリジン（ＵＳ２００３／１９９４４０号公報参照）０．４９ｇ（２．４ｍｍｏｌ）を使用し、４－（ヒドロキシメチル）フェニルボロン酸０．５９ｇ（３．９ｍｍｏｌ）、２ｍｏｌ／Ｌの炭酸ナトリウム水溶液１．７ｍｌ（３．４ｍｍｏｌ）及びテトラキストリフェニルホスフィンパラジウム１３８ｍｇ（０．１１９ｍｍｏｌ）を使用した以外は、参考例５に準じて反応及び後処理を行い、標記化合物２８４ｍｇを白色固体として得た。（収率５１％）
マススペクトル（ＣＩ，ｍ／ｚ）：２３０（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：8.05-8.01 (m, 2H), 7.62 (dd, J = 8.2, 7.4 Hz, 1H), 7.47-7.43 (m, 2H), 7.32 (dd, J = 7.4, 0.6 Hz, 1H), 6.67 (dd, J = 8.2, 0.6 Hz, 1H), 4.75 (d, J = 6.0 Hz, 2H), 4.49 (q, J = 7.1 Hz, 2H), 1.67 (t, J = 6.0 Hz, 1H), 1.44 (t, J = 7.1 Hz, 3H)。 [Reference Example 8]
4- (6 -Ethoxypyridin-2- yl) phenylmethanol Instead of 3-bromophenetole, 0.49 g (2.4 mmol) of 2-bromo-6-ethoxypyridine (see US2003 / 199440) was used, Except for using 0.59 g (3.9 mmol) of 4- (hydroxymethyl) phenylboronic acid, 1.7 ml (3.4 mmol) of 2 mol / L sodium carbonate aqueous solution and 138 mg (0.119 mmol) of tetrakistriphenylphosphine palladium. The reaction and post-treatment were performed according to Reference Example 5 to obtain 284 mg of the title compound as a white solid. (Yield 51%)
Mass spectrum (CI, m / z): 230 (M + +1).
1 H-NMR spectrum (CDCl 3 , δ ppm): 8.05-8.01 (m, 2H), 7.62 (dd, J = 8.2, 7.4 Hz, 1H), 7.47-7.43 (m, 2H), 7.32 (dd, J = 7.4, 0.6 Hz, 1H), 6.67 (dd, J = 8.2, 0.6 Hz, 1H), 4.75 (d, J = 6.0 Hz, 2H), 4.49 (q, J = 7.1 Hz, 2H), 1.67 (t, J = 6.0 Hz, 1H), 1.44 (t, J = 7.1 Hz, 3H).
［参考例９］
｛６－［（チオフェン－２－イルスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸エチル [Reference Example 9]
{6-[(Thiophen-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} ethyl acetate
９－（ａ）：（ｔｅｒｔ－ブトキシカルボニル｛６－［（チオフェン－２－イルスルホニル）アミノメチル］ピリジン－２－イル｝アミノ）酢酸ｔｅｒｔ－ブチル
　参考例１－（ｅ）と同様の方法で得られた［（６－アミノメチルピリジン－２－イル）ｔｅｒｔ－ブトキシカルボニルアミノ］酢酸ｔｅｒｔ－ブチル１．３５ｇ（４．００ｍｍｏｌ）を使用し、２－ピリジルスルホニルクロリドの代わりに２－チオフェンスルホニルクロリド７３１ｍｇ（４．００ｍｍｏｌ）を使用した以外は、参考例１－（ｆ）に準じて反応及び後処理を行い、標記化合物１．６１ｇを白色固体として得た。（収率８４％）
マススペクトル（ＣＩ，ｍ／ｚ）：４８４（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：7.71 (d, J = 8.4 Hz, 1H), 7.57 (dd, J = 3.8, 1.3 Hz, 1H), 7.56 (dd, J = 8.4, 7.4 Hz, 1H), 7.50 (dd, J = 5.0, 1.3 Hz, 1H), 7.01 (dd, J = 5.0, 3.8 Hz, 1H), 6.83 (d, J = 7.4 Hz, 1H), 5.67 (t, J = 5.3 Hz, 1H), 4.45 (s, 2H), 4.27 (d, J = 5.3 Hz, 2H), 1.53 (s, 9H), 1.47 (s, 9H)。 9- (a): (tert-Butoxycarbonyl {6-[(thiophen-2-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate In the same manner as in Reference Example 1- (e) Using 1.35 g (4.00 mmol) of tert-butyl acetate obtained ([6-aminomethylpyridin-2-yl) tert-butoxycarbonylamino] acetate, 2-thiophenesulfonyl chloride instead of 2-pyridylsulfonyl chloride The reaction and post-treatment were performed according to Reference Example 1- (f) except that 731 mg (4.00 mmol) was used, and 1.61 g of the title compound was obtained as a white solid. (Yield 84%)
Mass spectrum (CI, m / z): 484 (M + +1).
1 H-NMR spectrum (CDCl 3 , δ ppm): 7.71 (d, J = 8.4 Hz, 1H), 7.57 (dd, J = 3.8, 1.3 Hz, 1H), 7.56 (dd, J = 8.4, 7.4 Hz, 1H) ), 7.50 (dd, J = 5.0, 1.3 Hz, 1H), 7.01 (dd, J = 5.0, 3.8 Hz, 1H), 6.83 (d, J = 7.4 Hz, 1H), 5.67 (t, J = 5.3 Hz , 1H), 4.45 (s, 2H), 4.27 (d, J = 5.3 Hz, 2H), 1.53 (s, 9H), 1.47 (s, 9H).
９－（ｂ）：｛６－［（チオフェン－２－イルスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸エチル
　参考例９－（ａ）で得られた（ｔｅｒｔ－ブトキシカルボニル｛６－［（チオフェン－２－イルスルホニル）アミノメチル］ピリジン－２－イル｝アミノ）酢酸ｔｅｒｔ－ブチル１．６０ｇ（３．３１ｍｍｏｌ）に、２ｍｏｌ／Ｌの塩化水素／エタノール溶液２０ｍＬ（４０ｍｍｏｌ）を加え、加熱還流下で３時間撹拌した。反応終了後、反応溶液を減圧濃縮し、飽和炭酸水素ナトリウム水溶液で中和後、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝７：３→１：１（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮することにより、標記化合物１．１０ｇを無色油状物として得た。（収率９３％）
マススペクトル（ＣＩ，ｍ／ｚ）：３５６（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：7.57 (dd, J = 3.8, 1.3 Hz, 1H), 7.51 (dd, J = 5.0, 1.3 Hz, 1H), 7.32 (dd, J = 8.3, 7.3 Hz, 1H), 7.01 (dd, J = 5.0, 3.8 Hz, 1H), 6.44 (dd, J = 7.3, 0.6 Hz, 1H), 6.32 (dd, J = 8.3, 0.6 Hz, 1H), 5.86 (t, J = 4.9 Hz, 1H), 4.96 (t, J = 5.3 Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H), 4.18 (d, J = 4.9 Hz, 2H), 4.06 (d, J = 5.3 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H)。 9- (b): { tert-Butoxycarbonyl {6-[() obtained in {6-[(thiophen-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} ethyl acetate Reference Example 9- (a) Add 20 mL (40 mmol) of a 2 mol / L hydrogen chloride / ethanol solution to 1.60 g (3.31 mmol) of tert-butyl acetate to thiophen-2-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) acetate and heat to reflux Stir for 3 hours under. After completion of the reaction, the reaction solution was concentrated under reduced pressure, neutralized with a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 7: 3 → 1: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound 1 .10 g was obtained as a colorless oil. (Yield 93%)
Mass spectrum (CI, m / z): 356 (M + +1).
1 H-NMR spectrum (CDCl 3 , δ ppm): 7.57 (dd, J = 3.8, 1.3 Hz, 1H), 7.51 (dd, J = 5.0, 1.3 Hz, 1H), 7.32 (dd, J = 8.3, 7.3 Hz) , 1H), 7.01 (dd, J = 5.0, 3.8 Hz, 1H), 6.44 (dd, J = 7.3, 0.6 Hz, 1H), 6.32 (dd, J = 8.3, 0.6 Hz, 1H), 5.86 (t, J = 4.9 Hz, 1H), 4.96 (t, J = 5.3 Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H), 4.18 (d, J = 4.9 Hz, 2H), 4.06 (d, J = 5.3 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H).
［参考例１０］
｛６－［（ベンゼンスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸エチル [Reference Example 10]
{6-[(Benzenesulfonyl) aminomethyl] pyridin-2-ylamino} ethyl acetate
１０－（ａ）：（｛６－［（ベンゼンスルホニル）アミノメチル］ピリジン－２－イル｝ｔｅｒｔ－ブトキシカルボニルアミノ）酢酸ｔｅｒｔ－ブチル
　参考例１－（ｅ）と同様の方法で得られた［（６－アミノメチルピリジン－２－イル）ｔｅｒｔ－ブトキシカルボニルアミノ］酢酸ｔｅｒｔ－ブチル１．３５ｇ（４．００ｍｍｏｌ）を使用し、２－ピリジルスルホニルクロリドの代わりにベンゼンスルホニルクロリド７０７ｍｇ（４．００ｍｍｏｌ）を使用した以外は、参考例１－（ｆ）に準じて反応及び後処理を行い、標記化合物１．７１ｇを微ベージュ色固体として得た。（収率８９％）
マススペクトル（ＣＩ，ｍ／ｚ）：４７８（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：7.86-7.83 (m, 2H), 7.67 (d, J = 8.4 Hz, 1H), 7.53-7.48 (m, 2H), 7.45-7.41 (m, 2H), 6.78 (dd, J = 7.4, 0.6 Hz, 1H), 5.56 (t, J = 5.4 Hz, 1H), 4.41 (s, 2H), 4.19 (d, J = 5.4 Hz, 2H), 1.53 (s, 9H), 1.46 (s, 9H)。 10- (a): ({6-[(Benzenesulfonyl) aminomethyl] pyridin-2-yl} tert-butoxycarbonylamino) tert-butyl acetate Obtained in the same manner as in Reference Example 1- (e) [ (6-Aminomethylpyridin-2-yl) tert-butoxycarbonylamino] 1.35 g (4.00 mmol) of tert-butyl acetate was used and 707 mg (4.00 mmol) of benzenesulfonyl chloride instead of 2-pyridylsulfonyl chloride The reaction and post-treatment were performed according to Reference Example 1- (f) except that was used to obtain 1.71 g of the title compound as a slightly beige solid. (Yield 89%)
Mass spectrum (CI, m / z): 478 (M + +1).
1 H-NMR spectrum (CDCl 3 , δ ppm): 7.86-7.83 (m, 2H), 7.67 (d, J = 8.4 Hz, 1H), 7.53-7.48 (m, 2H), 7.45-7.41 (m, 2H) , 6.78 (dd, J = 7.4, 0.6 Hz, 1H), 5.56 (t, J = 5.4 Hz, 1H), 4.41 (s, 2H), 4.19 (d, J = 5.4 Hz, 2H), 1.53 (s, 9H), 1.46 (s, 9H).
１０－（ｂ）：｛６－［（ベンゼンスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸エチル
　（ｔｅｒｔ－ブトキシカルボニル｛６－［（チオフェン－２－イルスルホニル）アミノメチル］ピリジン－２－イル｝アミノ）酢酸ｔｅｒｔ－ブチルの代わりに、参考例１０－（ａ）で得られた（｛６－［（ベンゼンスルホニル）アミノメチル］ピリジン－２－イル｝ｔｅｒｔ－ブトキシカルボニルアミノ）酢酸ｔｅｒｔ－ブチル１．７０ｇ（３．５６ｍｍｏｌ）を使用し、２ｍｏｌ／Ｌの塩化水素／エタノール溶液２０ｍＬ（４０ｍｍｏｌ）を使用した以外は、参考例９－（ｂ）に準じて反応及び後処理を行い、標記化合物１．１３ｇを白色固体として得た。（収率９１％）
マススペクトル（ＣＩ，ｍ／ｚ）：３５０（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：7.87-7.84 (m, 2H), 7.53-7.42 (m, 3H), 7.28 (dd, J = 8.3, 7.3 Hz, 1H), 6.39 (dd, J = 7.3, 0.6 Hz, 1H), 6.30 (dd, J = 8.3, 0.6 Hz, 1H), 5.73 (t, J = 4.9 Hz, 1H), 4.92 (t, J = 5.2 Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H), 4.09 (d, J = 4.9 Hz, 2H), 4.04 (d, J = 5.2 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H)。 10- (b): {6-[(Benzenesulfonyl) aminomethyl] pyridin-2-ylamino} ethyl acetate (tert-butoxycarbonyl {6-[(thiophen-2-ylsulfonyl) aminomethyl] pyridin-2-yl } Amino) tert-butyl acetate ({6-[(benzenesulfonyl) aminomethyl] pyridin-2-yl} tert-butoxycarbonylamino) obtained in Reference Example 10- (a) instead of tert-butyl acetate The title compound was treated and treated according to Reference Example 9- (b), except that 1.70 g (3.56 mmol) was used and 20 mL (40 mmol) of a 2 mol / L hydrogen chloride / ethanol solution was used. 1.13 g was obtained as a white solid. (Yield 91%)
Mass spectrum (CI, m / z): 350 (M + +1).
1 H-NMR spectrum (CDCl 3 , δ ppm): 7.87-7.84 (m, 2H), 7.53-7.42 (m, 3H), 7.28 (dd, J = 8.3, 7.3 Hz, 1H), 6.39 (dd, J = 7.3, 0.6 Hz, 1H), 6.30 (dd, J = 8.3, 0.6 Hz, 1H), 5.73 (t, J = 4.9 Hz, 1H), 4.92 (t, J = 5.2 Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H), 4.09 (d, J = 4.9 Hz, 2H), 4.04 (d, J = 5.2 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H).
［参考例１１］
｛６－［（チオフェン－３－イルスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸エチル [Reference Example 11]
{6-[(Thiophen-3-ylsulfonyl) aminomethyl] pyridin-2-ylamino} ethyl acetate
１１－（ａ）：（ｔｅｒｔ－ブトキシカルボニル｛６－［（チオフェン－３－イルスルホニル）アミノメチル］ピリジン－２－イル｝アミノ）酢酸ｔｅｒｔ－ブチル
　参考例１－（ｅ）と同様の方法で得られた［（６－アミノメチルピリジン－２－イル）ｔｅｒｔ－ブトキシカルボニルアミノ］酢酸ｔｅｒｔ－ブチル１．３５ｇ（４．００ｍｍｏｌ）を使用し、２－ピリジルスルホニルクロリドの代わりに３－チオフェンスルホニルクロリド７３１ｍｇ（４．００ｍｍｏｌ）を使用した以外は、参考例１－（ｆ）に準じて反応及び後処理を行い、標記化合物１．６４ｇを微黄白色固体として得た。（収率８５％）
マススペクトル（ＣＩ，ｍ／ｚ）：４８４（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：7.93 (dd, J = 2.9, 1.4 Hz, 1H), 7.69 (d, J = 8.3 Hz, 1H), 7.54 (dd, J = 8.3, 7.4 Hz, 1H), 7.30 (dd, J = 5.1, 2.9 Hz, 1H), 7.28 (dd, J = 5.1, 1.4 Hz, 1H), 6.80 (dd, J = 7.4, 0.6 Hz, 1H), 5.59 (t, J = 5.4 Hz, 1H), 4.43 (s, 2H), 4.23 (d, J = 5.4 Hz, 2H), 1.53 (s, 9H), 1.47 (s, 9H)。 11- (a): (tert-Butoxycarbonyl {6-[(thiophen-3-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate In the same manner as in Reference Example 1- (e) Using 1.35 g (4.00 mmol) of tert-butyl acetate obtained ([6-aminomethylpyridin-2-yl) tert-butoxycarbonylamino] acetate, 3-thiophenesulfonyl chloride instead of 2-pyridylsulfonyl chloride The reaction and post-treatment were performed according to Reference Example 1- (f) except that 731 mg (4.00 mmol) was used, and 1.64 g of the title compound was obtained as a slightly yellowish white solid. (Yield 85%)
Mass spectrum (CI, m / z): 484 (M + +1).
1 H-NMR spectrum (CDCl 3 , δ ppm): 7.93 (dd, J = 2.9, 1.4 Hz, 1H), 7.69 (d, J = 8.3 Hz, 1H), 7.54 (dd, J = 8.3, 7.4 Hz, 1H) ), 7.30 (dd, J = 5.1, 2.9 Hz, 1H), 7.28 (dd, J = 5.1, 1.4 Hz, 1H), 6.80 (dd, J = 7.4, 0.6 Hz, 1H), 5.59 (t, J = 5.4 Hz, 1H), 4.43 (s, 2H), 4.23 (d, J = 5.4 Hz, 2H), 1.53 (s, 9H), 1.47 (s, 9H).
１１－（ｂ）：｛６－［（チオフェン－３－イルスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸エチル
　（ｔｅｒｔ－ブトキシカルボニル｛６－［（チオフェン－２－イルスルホニル）アミノメチル］ピリジン－２－イル｝アミノ）酢酸ｔｅｒｔ－ブチルの代わりに、参考例１１－（ａ）で得られた（ｔｅｒｔ－ブトキシカルボニル｛６－［（チオフェン－３－イルスルホニル）アミノメチル］ピリジン－２－イル｝アミノ）酢酸ｔｅｒｔ－ブチル１．６３ｇ（３．３７ｍｍｏｌ）を使用し、２ｍｏｌ／Ｌの塩化水素／エタノール溶液１７．５ｍＬ（３５．０ｍｍｏｌ）を使用した以外は、参考例９－（ｂ）に準じて反応及び後処理を行った。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝７：３→１：１（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた粗体を酢酸エチル５ｍＬで再結晶することにより、標記化合物７３１ｍｇを白色固体として得た。（収率６１％）
マススペクトル（ＣＩ，ｍ／ｚ）：３５６（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：7.93 (dd, J = 3.0, 1.4 Hz, 1H), 7.33-7.28 (m, 3H), 6.40 (dd, J = 7.3, 0.6 Hz, 1H), 6.32 (dd, J = 8.3, 0.6 Hz, 1H), 5.76 (t, J = 5.1 Hz, 1H), 4.95 (t, J = 5.4 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 4.13 (d, J = 5.1 Hz, 2H), 4.06 (d, J = 5.4 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H)。 11- (b): {6-[(thiophen-3-ylsulfonyl) aminomethyl] pyridin-2-ylamino} ethyl acetate (tert-butoxycarbonyl {6-[(thiophen-2-ylsulfonyl) aminomethyl] pyridine -2-yl} amino) Instead of tert-butyl acetate, (tert-butoxycarbonyl {6-[(thiophen-3-ylsulfonyl) aminomethyl] pyridin-2-] obtained in Reference Example 11- (a) Yl} amino) Reference Example 9- (b) except that 1.63 g (3.37 mmol) of tert-butyl acetate was used and 17.5 mL (35.0 mmol) of a 2 mol / L hydrogen chloride / ethanol solution was used. The reaction and post-treatment were performed according to the above. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 7: 3 → 1: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The obtained crude product was recrystallized from 5 mL of ethyl acetate to obtain 731 mg of the title compound as a white solid. (Yield 61%)
Mass spectrum (CI, m / z): 356 (M + +1).
1 H-NMR spectrum (CDCl 3 , δ ppm): 7.93 (dd, J = 3.0, 1.4 Hz, 1H), 7.33-7.28 (m, 3H), 6.40 (dd, J = 7.3, 0.6 Hz, 1H), 6.32 (dd, J = 8.3, 0.6 Hz, 1H), 5.76 (t, J = 5.1 Hz, 1H), 4.95 (t, J = 5.4 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 4.13 (d, J = 5.1 Hz, 2H), 4.06 (d, J = 5.4 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H).
［参考例１２］
［ｔｅｒｔ－ブトキシカルボニル（６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］アミノメチル｝ピリジン－２－イル）アミノ］酢酸ｔｅｒｔ－ブチル [Reference Example 12]
[Tert-Butoxycarbonyl (6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] aminomethyl} pyridin-2-yl) amino] tert-butyl acetate
１２－（ａ）：１－ブロモ－３－（１－プロピニル）ベンゼン
　１－ブロモ－３－ヨードベンゼン７．０７ｇ（２５．０ｍｍｏｌ）のトルエン５０ｍＬ溶液に、ヨウ化銅（Ｉ）１．４３ｇ（７．５１ｍｍｏｌ）及びテトラキストリフェニルホスフィンパラジウム１．４５ｇ（１．２５ｍｍｏｌ）を加え、減圧脱気後、アルゴンガス置換した。次いで、１－トリメチルシリル－１－プロピン２．８１ｇ（２５．０ｍｍｏｌ）、トリエチルアミン１１．５ｍｌ（８２．５ｍｍｏｌ）及び１ｍｏｌ／Ｌのテトラフルオロアンモニウムフロリド／テトラヒドロフラン溶液２５．０ｍＬ（２５．０ｍｍｏｌ）を加え、アルゴンガス雰囲気下、室温で１７時間撹拌した。反応終了後、反応溶液に水及びｔ－ブチルメチルエーテルを添加し、セライト（商品名）濾過により不溶物を濾別した。分液後の有機層を無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン）に付し、目的物を含む画分を減圧濃縮することにより、標記化合物４．２２ｇを無色油状物として得た。（収率８６％）
マススペクトル（ＣＩ，ｍ／ｚ）：１９５，１９７（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：7.53 (dd, J = 1.7, 1.7 Hz, 1H), 7.39 (ddd, J = 8.0, 1.7, 1.0 Hz, 1H), 7.31-7.29 (m, 1H), 7.14 (dd, J = 8.0, 8.0 Hz, 1H), 2.04 (s, 3H)。 12- (a): 1-Bromo-3- (1-propynyl) benzene 1-Bromo-3-iodobenzene 7.07 g (25.0 mmol) in a toluene 50 mL solution with 1.43 g of copper (I) iodide ( 7.51 mmol) and 1.45 g (1.25 mmol) of tetrakistriphenylphosphine palladium were added, degassed under reduced pressure, and then purged with argon gas. Next, 2.81 g (25.0 mmol) of 1-trimethylsilyl-1-propyne, 11.5 ml (82.5 mmol) of triethylamine and 25.0 mL (25.0 mmol) of a 1 mol / L tetrafluoroammonium fluoride / tetrahydrofuran solution were added. The mixture was stirred at room temperature for 17 hours under an argon gas atmosphere. After completion of the reaction, water and t-butyl methyl ether were added to the reaction solution, and insoluble matters were filtered off by Celite (trade name) filtration. The separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane), and the fraction containing the desired product was concentrated under reduced pressure to give 4.22 g of the title compound as a colorless oil. (Yield 86%)
Mass spectrum (CI, m / z): 195, 197 (M + +1).
1 H-NMR spectrum (CDCl 3 , δ ppm): 7.53 (dd, J = 1.7, 1.7 Hz, 1H), 7.39 (ddd, J = 8.0, 1.7, 1.0 Hz, 1H), 7.31-7.29 (m, 1H) , 7.14 (dd, J = 8.0, 8.0 Hz, 1H), 2.04 (s, 3H).
１２－（ｂ）：３’－（１－プロピニル）ビフェニル－４－イルカルボアルデヒド
　３－ブロモフェネトールの代わりに参考例１２－（ａ）と同様の方法で得られた１－ブロモ－３－（１－プロピニル）ベンゼン２．９３ｇ（１５．０ｍｍｏｌ）、４－（ヒドロキシメチル）フェニルボロン酸の代わりに４－ホルミルフェニルボロン酸３．３７ｇ（３７．５ｍｍｏｌ）をそれぞれ使用し、２ｍｏｌ／Ｌの炭酸ナトリウム水溶液１１．３ｍｌ（２２．６ｍｍｏｌ）及びテトラキストリフェニルホスフィンパラジウム８６７ｍｇ（０．７５０ｍｍｏｌ）を使用した以外は、参考例５に準じて反応及び後処理を行い、標記化合物３．３１ｇを淡黄白色固体として得た。（定量的）
　本参考例１２－（ｂ）で得られた化合物のＮＭＲスペクトルは、参考例４－（ａ）で得られた化合物のＮＭＲスペクトルと同一であった。 12- (b): 3 ′-(1-propynyl) biphenyl-4 -ylcarbaldehyde 1-bromo-3-obtained by a method similar to that of Reference Example 12- (a) instead of 3-bromophenetole Using 2.93 g (15.0 mmol) of (1-propynyl) benzene and 3.37 g (37.5 mmol) of 4-formylphenylboronic acid instead of 4- (hydroxymethyl) phenylboronic acid, 2 mol / L Except for using 11.3 ml (22.6 mmol) of an aqueous sodium carbonate solution and 867 mg (0.750 mmol) of tetrakistriphenylphosphine palladium, the reaction and post-treatment were carried out according to Reference Example 5 to obtain 3.31 g of the title compound in a pale yellow color. Obtained as a white solid. (quantitative)
The NMR spectrum of the compound obtained in Reference Example 12- (b) was identical to the NMR spectrum of the compound obtained in Reference Example 4- (a).
１２－（ｃ）：［ｔｅｒｔ－ブトキシカルボニル（６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］アミノメチル｝ピリジン－２－イル）アミノ］酢酸ｔｅｒｔ－ブチル
　参考例１－（ｅ）と同様の方法で得られた［（６－アミノメチルピリジン－２－イル）ｔｅｒｔ－ブトキシカルボニルアミノ］酢酸ｔｅｒｔ－ブチル５．５７ｇ（１６．５ｍｍｏｌ）、及び３’－エトキシビフェニル－４－イルカルボアルデヒドの代わりに、参考例１２－（ｂ）で得られた３’－（１－プロピニル）ビフェニル－４－イルカルボアルデヒド３．３０ｇ（１５．０ｍｍｏｌ）を使用し、トリアセトキシ水素化ホウ素ナトリウム４．４５ｇ（２１．０ｍｍｏｌ）を使用した以外は、参考例７－（ｂ）に準じて反応及び後処理を行い、標記化合物６．４８ｇを淡黄色油状物として得た。（収率８０％）
マススペクトル（ＣＩ，ｍ／ｚ）：５４２（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：7.70 (d, J = 8.2 Hz, 1H), 7.63-7.62 (m, 1H), 7.59 (dd, J = 8.2, 7.4 Hz, 1H), 7.55-7.52 (m, 2H), 7.50-7.47 (m, 1H), 7.43-7.40 (m, 2H), 7.37-7.32 (m, 2H), 6.97 (d, J = 7.4 Hz, 1H), 4.57 (s, 2H), 3.85 (s, 2H), 3.83 (s, 2H), 2.07 (s, 3H), 1.53 (s, 9H), 1.41 (s, 9H)。 12- (c): [tert-Butoxycarbonyl (6-{[3 '-(1-propynyl) biphenyl-4-ylmethyl] aminomethyl} pyridin-2-yl) amino] acetic acid tert-butyl Reference Example 1- ( 5.57 g (16.5 mmol) of tert-butyl [(6-aminomethylpyridin-2-yl) tert-butoxycarbonylamino] acetate obtained in the same manner as in e), and 3′-ethoxybiphenyl-4- Instead of ylcarbaldehyde, 3.30 g (15.0 mmol) of 3 ′-(1-propynyl) biphenyl-4-ylcarbaldehyde obtained in Reference Example 12- (b) was used, and triacetoxyborohydride Except that 4.45 g (21.0 mmol) of sodium was used, the reaction and post-treatment were performed according to Reference Example 7- (b) to give the title compound 6 .48 g was obtained as a pale yellow oil. (Yield 80%)
Mass spectrum (CI, m / z): 542 (M + +1).
1 H-NMR spectrum (CDCl 3 , δ ppm): 7.70 (d, J = 8.2 Hz, 1H), 7.63-7.62 (m, 1H), 7.59 (dd, J = 8.2, 7.4 Hz, 1H), 7.55-7.52 (m, 2H), 7.50-7.47 (m, 1H), 7.43-7.40 (m, 2H), 7.37-7.32 (m, 2H), 6.97 (d, J = 7.4 Hz, 1H), 4.57 (s, 2H ), 3.85 (s, 2H), 3.83 (s, 2H), 2.07 (s, 3H), 1.53 (s, 9H), 1.41 (s, 9H).
［参考例１３］
３’－（１－プロピニル）ビフェニル－４－イルメタノール
　３－ブロモフェネトールの代わりに参考例１２－（ａ）と同様の方法で得られた１－ブロモ－３－（１－プロピニル）ベンゼン３．９０ｇ（２０．０ｍｍｏｌ）を使用し、４－（ヒドロキシメチル）フェニルボロン酸４．５６ｇ（３０．０ｍｍｏｌ）、２ｍｏｌ／Ｌの炭酸ナトリウム水溶液１５ｍｌ（３０ｍｍｏｌ）及びテトラキストリフェニルホスフィンパラジウム１．１６ｇ（１．００ｍｍｏｌ）を使用した以外は、参考例５に準じて反応を行った。反応終了後、反応溶液に水を加え、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル＝４：１→１：１（Ｖ／Ｖ））に付し、目的物を含む画分を減圧濃縮した。得られた粗体を混合溶媒（酢酸エチル：ｎ－ヘキサン＝１：１０（Ｖ／Ｖ））４５ｍＬ中で１時間撹拌し、析出した固体を濾取した後に減圧乾燥することにより、標記化合物３．８５ｇを白色固体として得た。（収率８７％）
　本参考例１３で得られた化合物のＮＭＲスペクトルは、参考例４－（ｂ）で得られた化合物のＮＭＲスペクトルと同一であった。 [Reference Example 13]
3 ′-(1-propynyl) biphenyl-4-ylmethanol 1-bromo-3- (1-propynyl) benzene 3 obtained by the same method as in Reference Example 12- (a) instead of 3-bromophenetole .90 g (20.0 mmol) was used, 4.56 g (30.0 mmol) of 4- (hydroxymethyl) phenylboronic acid, 15 ml (30 mmol) of 2 mol / L sodium carbonate aqueous solution and 1.16 g of tetrakistriphenylphosphine palladium ( The reaction was performed according to Reference Example 5 except that 1.00 mmol) was used. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 4: 1 → 1: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The obtained crude product was stirred in 45 mL of a mixed solvent (ethyl acetate: n-hexane = 1: 10 (V / V)) for 1 hour, and the precipitated solid was collected by filtration and dried under reduced pressure to give the title compound 3 Obtained .85 g as a white solid. (Yield 87%)
The NMR spectrum of the compound obtained in Reference Example 13 was the same as the NMR spectrum of the compound obtained in Reference Example 4- (b).
［参考例１４］
｛６－［（ピリジン－２－イルスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸イソプロピル
　（ｔｅｒｔ－ブトキシカルボニル｛６－［（チオフェン－２－イルスルホニル）アミノメチル］ピリジン－２－イル｝アミノ）酢酸ｔｅｒｔ－ブチルの代わりに、参考例１－（ｆ）と同様の方法で得られた（ｔｅｒｔ－ブトキシカルボニル｛６－［（ピリジン－２－イルスルホニル）アミノメチル］ピリジン－２－イル｝アミノ）酢酸ｔｅｒｔ－ブチル１．４４ｇ（３．０１ｍｍｏｌ）を使用し、２ｍｏｌ／Ｌの塩化水素／エタノール溶液の代わりに２ｍｏｌ／Ｌの塩化水素／イソプロパノール溶液１６．０ｍＬ（３２．０ｍｍｏｌ）を使用した以外は、参考例９－（ｂ）に準じて反応及び後処理を行い、標記化合物１．０５ｇを白色固体として得た。（収率９６％）
マススペクトル（ＣＩ，ｍ／ｚ）：３６５（Ｍ＋＋１）。
１Ｈ－ＮＭＲスペクトル（ＣＤＣｌ３，δppm）：8.63 (ddd, J = 4.7, 1.7, 1.0 Hz, 1H), 7.97 (ddd, J = 7.7, 1.0, 1.0 Hz, 1H), 7.84 (ddd, J = 7.7, 7.7, 1.7 Hz, 1H), 7.41 (ddd, J = 7.7, 4.7, 1.0 Hz, 1H), 7.29 (dd, J = 8.2, 7.3 Hz, 1H), 6.44 (d, J = 7.3 Hz, 1H), 6.28 (d, J = 8.2 Hz, 1H), 6.04 (t, J = 5.4 Hz, 1H), 5.10 (sep, J = 6.3 Hz, 1H), 4.93 (t, J = 5.4 Hz, 1H), 4.25 (d, J = 5.4 Hz, 2H), 4.04 (d, J = 5.4 Hz, 2H), 1.28 (d, J = 6.3 Hz, 6H)。 [Reference Example 14]
{6-[(Pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} isopropyl acetate (tert-butoxycarbonyl) {6-[(thiophen-2-ylsulfonyl) aminomethyl] pyridin-2-yl} amino ) (Tert-Butoxycarbonyl {6-[(pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-yl} obtained in the same manner as in Reference Example 1- (f) instead of tert-butyl acetate Amino) 1.44 g (3.01 mmol) of tert-butyl acetate was used, and 16.0 mL (32.0 mmol) of 2 mol / L hydrogen chloride / isopropanol solution was used instead of 2 mol / L hydrogen chloride / ethanol solution. Except for the above, the reaction and post-treatment were carried out according to Reference Example 9- (b), to give 1.05 g of the title compound as white It was obtained as a body. (Yield 96%)
Mass spectrum (CI, m / z): 365 (M + +1).
1 H-NMR spectrum (CDCl 3 , δ ppm): 8.63 (ddd, J = 4.7, 1.7, 1.0 Hz, 1H), 7.97 (ddd, J = 7.7, 1.0, 1.0 Hz, 1H), 7.84 (ddd, J = 7.7, 7.7, 1.7 Hz, 1H), 7.41 (ddd, J = 7.7, 4.7, 1.0 Hz, 1H), 7.29 (dd, J = 8.2, 7.3 Hz, 1H), 6.44 (d, J = 7.3 Hz, 1H ), 6.28 (d, J = 8.2 Hz, 1H), 6.04 (t, J = 5.4 Hz, 1H), 5.10 (sep, J = 6.3 Hz, 1H), 4.93 (t, J = 5.4 Hz, 1H), 4.25 (d, J = 5.4 Hz, 2H), 4.04 (d, J = 5.4 Hz, 2H), 1.28 (d, J = 6.3 Hz, 6H).
［試験例１］
ＥＰ２受容体結合作用の測定
　ＥＰ２受容体結合作用の測定は、Abramovitzらの方法（Biochimica et Biophysica Acta, 1483, 285 (2000)）に準じて行った。ヒトＥＰ２受容体を発現させたＨＥＫ２９３細胞の膜画分（ＥＳ－５６２－Ｍ、Euroscreen社製）１０μｇを懸濁させた緩衝液（１０ｍＭ　ＭＥＳ－ＫＯＨ（ｐＨ６．０）、１０ｍＭ　ＭｇＣｌ２、１ｍＭ　ＥＤＴＡ）に、ジメチルスルホキシド（終濃度１．０（Ｖ／Ｖ）％）に溶解した被験化合物及び［３Ｈ］プロスタグランジンＥ２（ＮＥＴ－４２８、PerkinElmer社製）（終濃度１０ｎＭ）を加え、３０℃で６０分間インキュベートした。セルハーベスター（Ｍ３０Ｒ、Brandel社製）を使用して、膜画分をガラス繊維濾紙（ＧＦ／Ｂ、Whatman社製）に回収し、緩衝液（１０ｍＭ　ＭＥＳ－ＫＯＨ（ｐＨ６．０）、１０ｍＭ　ＭｇＣｌ２）で洗浄後に、液体シンチレーションアナライザー（２０００ＣＡ、Packard社製）で放射活性を測定した。受容体に結合した［３Ｈ］プロスタグランジンＥ２の５０％を置換するのに必要な被験化合物の濃度（ＩＣ５０値）をＥＸＳＡＳ（バージョン７．１．６、アームシステックス社製）を用いて算出し、以下の式から阻害定数（Ｋｉ値）を求めた。
　　Ｋｉ＝ＩＣ５０／（１＋（［３Ｈ］プロスタグランジンＥ２濃度／Ｋｄ））
　尚、解離定数（Ｋｄ値）はScatchard解析により算出した。
　試験結果を表１に示す。 [Test Example 1]
Measurement of EP2 receptor binding action The EP2 receptor binding action was measured according to the method of Abramovitz et al. (Biochimica et Biophysica Acta, 1483, 285 (2000)). A buffer (10 mM MES-KOH (pH 6.0), 10 mM MgCl 2 , 1 mM EDTA) in which 10 μg of a membrane fraction (ES-562-M, manufactured by Euroscreen) of HEK293 cells expressing human EP2 receptor is suspended. ), A test compound dissolved in dimethyl sulfoxide (final concentration 1.0 (V / V)%) and [ 3 H] prostaglandin E 2 (NET-428, manufactured by PerkinElmer) (final concentration 10 nM) were added, Incubated for 60 minutes at 30 ° C. Using a cell harvester (M30R, manufactured by Brandel), the membrane fraction was collected on a glass fiber filter paper (GF / B, manufactured by Whatman), and a buffer solution (10 mM MES-KOH (pH 6.0), 10 mM MgCl 2. ), And the radioactivity was measured with a liquid scintillation analyzer (2000 CA, manufactured by Packard). EXSAS (version 7.1.6, manufactured by Arm Systex) is the concentration of test compound (IC 50 value) required to replace 50% of [ 3 H] prostaglandin E 2 bound to the receptor. The inhibition constant (Ki value) was determined from the following formula.
Ki = IC 50 / (1 + ([ 3 H] prostaglandin E 2 concentration / Kd))
The dissociation constant (Kd value) was calculated by Scatchard analysis.
The test results are shown in Table 1.
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
　本試験において、一般式（Ｉ）で表わされる化合物は、優れたＥＰ２受容体結合作用を示した。 In this test, the compound represented by the general formula (I) showed an excellent EP2 receptor binding action.
［試験例２］
ヒト末梢血単核球を用いたＬＰＳ誘発ＴＮＦα産生抑制試験
　健常人よりヘパリン存在下で採血した末梢血を２（Ｖ／Ｖ）％ＦＢＳ含有ＰＢＳにて２倍に希釈した。ＳｅｐＭａｔｅＴＭ－５０（STEMCELL社製）に血球分離液（Ｆｉｃｏｌｌ　ＰａｑｕｅＴＭＰＬＵＳ、ＧＥ　ヘルスケアバイオサイエンス社製）を添加し、次いで希釈血液を重層した。２０℃、１２００ｘｇの条件で１０分間遠心することにより末梢血単核球（以下、ＰＢＭＣと略す）層を回収した。得られたＰＢＭＣは更に遠心、洗浄を２回繰り返し、１（Ｖ／Ｖ）％ＦＢＳ含有ＲＰＭＩ１６４０培地に懸濁後、以下の試験に使用した。 [Test Example 2]
LPS-induced TNFα production suppression test using human peripheral blood mononuclear cells Peripheral blood collected from healthy individuals in the presence of heparin was diluted 2-fold with PBS containing 2 (V / V)% FBS. A blood cell separation solution (Ficoll Paque ™ PLUS, manufactured by GE Healthcare Bioscience) was added to SepMate ™ -50 (manufactured by STEMCELL), and then diluted blood was layered. A peripheral blood mononuclear cell (hereinafter abbreviated as PBMC) layer was recovered by centrifugation at 20 ° C. and 1200 × g for 10 minutes. The obtained PBMC were further centrifuged and washed twice, suspended in RPMI 1640 medium containing 1 (V / V)% FBS, and used for the following tests.
　ＬＰＳ誘発ＴＮＦα産生抑制試験は、Maryらの方法（Journal of Pharmacology and Experimental Therapeutics,284,420(1998)）を一部改変して行った。最終濃度が５×１０５ｃｅｌｌｓ／ｍＬになるよう調製したＰＢＭＣ懸濁液１８５μＬを９６ウェルプレートに添加し、次いで被験化合物を溶解した１（Ｖ／Ｖ）％ＤＭＳＯ含有ＲＰＭＩ１６４０培地を、各ウェルに１０μＬずつ添加した（ＤＭＳＯ最終濃度は０．０５（Ｖ／Ｖ）％とした）。被験化合物を添加しないウェルには、１（Ｖ／Ｖ）％ＤＭＳＯ含有ＲＰＭＩ１６４０培地を同様に添加した。炭酸ガスインキュベーター内で１時間インキュベートした後に、ＲＰＭＩ１６４０培地にて調製したＬＰＳ（Ｌ２８８０－５００ＭＧ、SIGMA社製）を各ウェルに５μＬずつ添加した（ＬＰＳの終濃度は１００ｎｇ／ｍＬとした）。ＬＰＳ無刺激のウェルには、ＲＰＭＩ１６４０培地を５μＬ添加した。炭酸ガスインキュベーター内で約１８時間培養した後、培養上清を回収した。回収した培養上清は、ＴＮＦα含量測定まで－２０℃に保存した。 The LPS-induced TNFα production inhibition test was performed by partially modifying the method of Mary et al. (Journal of Pharmacology and Experimental Therapeutics, 284, 420 (1998)). 185 μL of PBMC suspension prepared to a final concentration of 5 × 10 5 cells / mL was added to a 96-well plate, and then RPMI1640 medium containing 1 (V / V)% DMSO containing the test compound was added to each well. 10 μL each was added (DMSO final concentration was 0.05 (V / V)%). RPMI1640 medium containing 1 (V / V)% DMSO was similarly added to wells to which no test compound was added. After incubating in a carbon dioxide incubator for 1 hour, 5 μL of LPS (L2880-500MG, manufactured by SIGMA) prepared in RPMI 1640 medium was added to each well (the final concentration of LPS was 100 ng / mL). To wells not stimulated with LPS, 5 μL of RPMI1640 medium was added. After culturing for about 18 hours in a carbon dioxide incubator, the culture supernatant was recovered. The collected culture supernatant was stored at −20 ° C. until TNFα content measurement.
　ＴＮＦα含量測定にはサンドイッチＥＬＩＳＡキット（Ｑｕａｎｔｉｋｉｎｅ　ＤＴＡ００ｃ、R&D Systems社製）を用いた。各サンプルのＴＮＦα含量は、キット付属の大腸菌由来ヒト組み換えＴＮＦαの標準曲線から算出した。ＤＭＳＯのみ添加の場合のＬＰＳによるＴＮＦα産生量を１００％とし、被験化合物各濃度におけるＴＮＦα産生抑制率を算出した。添加した被験化合物の濃度と被験化合物のＴＮＦα産生抑制率との関係から、ＴＮＦα産生を５０％阻害する被験化合物濃度をＩＣ５０値（ｎＭ）として算出した。
　試験結果を表２に示す。 A sandwich ELISA kit (Quantikine DTA00c, manufactured by R & D Systems) was used for measuring the TNFα content. The TNFα content of each sample was calculated from a standard curve of E. coli-derived human recombinant TNFα included in the kit. The amount of TNFα produced by LPS when only DMSO was added was taken as 100%, and the TNFα production inhibition rate at each concentration of the test compound was calculated. From the relationship between the concentration of the added test compound and the inhibition rate of TNFα production of the test compound, the concentration of the test compound that inhibits TNFα production by 50% was calculated as an IC 50 value (nM).
The test results are shown in Table 2.
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006
　本試験において、一般式（Ｉ）で表わされる化合物は、優れたＴＮＦα産生抑制作用を示した。 In this test, the compound represented by the general formula (I) showed an excellent TNFα production inhibitory action.
［試験例３］
併用効果確認のためのヒト末梢血単核球を用いたＬＰＳ誘発ＴＮＦα産生抑制試験
　本試験は、前記［試験例２］に準じて行った。
　被験化合物及びロフルミラストそれぞれの単独作用、並びに被験化合物とロフルミラストの併用作用を評価するために、最終濃度が５×１０５ｃｅｌｌｓ／ｍＬになるよう調製したＰＢＭＣ懸濁液１７５μＬを９６ウェルプレートに添加し、次いでロフルミラストを溶解した１（Ｖ／Ｖ）％ＤＭＳＯ含有ＲＰＭＩ１６４０培地を、各ウェルに１０μＬずつ添加した。ロフルミラストを添加しないウェルには、１（Ｖ／Ｖ）％ＤＭＳＯ含有ＲＰＭＩ１６４０培地を同様に添加した。炭酸ガスインキュベーター内で３０分間インキュベートした後に、被験化合物を溶解した１（Ｖ／Ｖ）％ＤＭＳＯ含有ＲＰＭＩ１６４０培地を、各ウェルに１０μＬずつ添加した（ウェルあたりのＤＭＳＯ最終濃度は０．１（Ｖ／Ｖ）％とした）。被験化合物を添加しないウェルには、１（Ｖ／Ｖ）％ＤＭＳＯ含有ＲＰＭＩ１６４０培地を同様に添加した。炭酸ガスインキュベーター内で３０分間インキュベートした後に、ＲＰＭＩ１６４０培地にて調製したＬＰＳ（Ｌ２８８０－５００ＭＧ、SIGMA社製）を各ウェルに５μＬずつ添加した（ＬＰＳの終濃度は１００ｎｇ／ｍＬとした）。ＬＰＳ無刺激のウェルには、ＲＰＭＩ１６４０培地を５μＬ添加した。炭酸ガスインキュベーター内で約１６乃至１８時間培養した後、培養上清を回収した。回収した培養上清は、ＴＮＦα含量測定まで－２０℃に保存した。 [Test Example 3]
LPS-induced TNFα production suppression test using human peripheral blood mononuclear cells for confirmation of combined effect This test was performed according to [Test Example 2].
In order to evaluate the single action of each of the test compound and roflumilast, and the combined action of the test compound and roflumilast, 175 μL of a PBMC suspension prepared to a final concentration of 5 × 10 5 cells / mL was added to a 96-well plate. Then, 10 μL of 1 (V / V)% DMSO-containing RPMI1640 medium in which roflumilast was dissolved was added to each well. To wells to which roflumilast was not added, RPMI1640 medium containing 1 (V / V)% DMSO was similarly added. After incubation for 30 minutes in a carbon dioxide incubator, 10 μL of 1 (V / V)% DMSO-containing RPMI1640 medium in which the test compound was dissolved was added to each well (the final DMSO concentration per well was 0.1 (V / V). V)%). RPMI1640 medium containing 1 (V / V)% DMSO was similarly added to wells to which no test compound was added. After incubating for 30 minutes in a carbon dioxide incubator, 5 μL of LPS (L2880-500MG, manufactured by SIGMA) prepared in RPMI 1640 medium was added to each well (the final concentration of LPS was 100 ng / mL). To wells not stimulated with LPS, 5 μL of RPMI1640 medium was added. After culturing for about 16 to 18 hours in a carbon dioxide incubator, the culture supernatant was recovered. The collected culture supernatant was stored at −20 ° C. until TNFα content measurement.
　ＴＮＦα含量測定にはサンドイッチＥＬＩＳＡキット（Ｑｕａｎｔｉｋｉｎｅ　ＤＴＡ００ｃ、R&D Systems社製）を用いた。各サンプルのＴＮＦα含量は、キット付属の大腸菌由来ヒト組み換えＴＮＦαの標準曲線から算出した。ＤＭＳＯのみ添加の場合のＬＰＳによるＴＮＦα産生量を１００％とし、被験化合物及びロフルミラスト各濃度におけるＴＮＦα産生抑制率を算出した。同時に、被験化合物とロフルミラストとの組み合わせ各濃度におけるＴＮＦα産生抑制率を算出し、被験化合物単独での作用と、ロフルミラストとの併用による作用とを比較した。
　試験結果を表３及び表４に示す。 A sandwich ELISA kit (Quantikine DTA00c, manufactured by R & D Systems) was used for measuring the TNFα content. The TNFα content of each sample was calculated from a standard curve of E. coli-derived human recombinant TNFα included in the kit. The amount of TNFα produced by LPS when only DMSO was added was taken as 100%, and the inhibition rate of TNFα production at each concentration of the test compound and roflumilast was calculated. At the same time, the TNFα production inhibition rate at each concentration of the combination of the test compound and roflumilast was calculated, and the effect of the test compound alone and the effect of the combined use with roflumilast were compared.
The test results are shown in Tables 3 and 4.
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000008
　本試験において、一般式（Ｉ）で表わされる化合物は、ロフルミラストと併用することで、ロフルミラストの薬理効果に一般式（Ｉ）で表わされる化合物の薬理効果が上乗せされ、より優れたＴＮＦα産生抑制作用を示した。 In this test, when the compound represented by the general formula (I) is used in combination with roflumilast, the pharmacological effect of the compound represented by the general formula (I) is added to the pharmacological effect of roflumilast, and the TNFα production inhibitory action is more excellent. showed that.
［試験例４］
ラット肺好中球浸潤抑制作用
　約１６時間絶食したＳＤラット（雄、７乃至８週齢、体重２４０ｇ乃至２７０ｇ（平均約２５０ｇ）、日本チャールス・リバー株式会社供給）に、イソフルラン吸入麻酔下、ＬＰＳ（Ｌ２８８０－５００ＭＧ、SIGMA社製）の生理食塩水溶液（濃度０．０４ｍｇ／ｍＬ）を、２５μＬ（約４μｇ／Ｋｇ）気管内投与した。気管内投与にはＭｉｃｒｏＳｐｒａｙｅｒＴＭ（ＩＡ－１Ｃ－Ｍ、PennCentury社製）を用いた。 [Test Example 4]
Inhibition of rat lung neutrophil infiltration About 16 hours SD rats (male, 7-8 weeks old, weight 240g-270g (average: 250g), supplied by Charles River Japan Co., Ltd.) under isoflurane inhalation anesthesia and LPS A physiological saline solution (concentration 0.04 mg / mL) of L2880-500MG (manufactured by SIGMA) was administered into the trachea 25 μL (about 4 μg / Kg). MicroSprayer ™ (IA-1C-M, manufactured by PennCentury) was used for intratracheal administration.
　ロフルミラストの投与溶液は、ロフルミラストをメノウで２乃至３分粉砕後、０．５％のメチルセルロース溶液に懸濁することにより調製した（ロフルミラストの終濃度０．０１ｍｇ／ｍＬ）。このようにして調製したロフルミラスト溶液を、ＬＰＳ投与の１時間前に１０ｍＬ／ｋｇ（０．１ｍｇ／Ｋｇ）経口投与した。コントロール群には０．５％のメチルセルロース溶液を投与した。また被験化合物の投与溶液は、０．１ｍｏｌ／Ｌ若しくは１ｍｏｌ／Ｌの水酸化ナトリウム水溶液に被験化合物を溶解後、媒体を加えて中和することにより調製した（被験化合物の終濃度０．１ｍｇ／ｍＬ）。媒体にはＰＢＳ若しくはリン酸緩衝液（２０ｍＭ、ｐＨ＝７．４）を用いた。このようにして調製した被験化合物溶液を、ロフルミラスト投与の１０分後にＬＰＳ投与と同様の方法で２５μＬ（約０．０１ｍｇ／Ｋｇ）気管内投与した。コントロール群には媒体を投与した。尚、被験化合物投与群及びコントロール群には、それぞれ５匹のラットを用いた。 The administration solution of roflumilast was prepared by pulverizing roflumilast with agate for 2 to 3 minutes and suspending it in a 0.5% methylcellulose solution (final concentration of roflumilast 0.01 mg / mL). The roflumilast solution thus prepared was orally administered at 10 mL / kg (0.1 mg / Kg) 1 hour before LPS administration. A 0.5% methylcellulose solution was administered to the control group. The test compound administration solution was prepared by dissolving the test compound in a 0.1 mol / L or 1 mol / L sodium hydroxide aqueous solution and neutralizing it by adding a medium (the final concentration of the test compound was 0.1 mg / L). mL). PBS or phosphate buffer (20 mM, pH = 7.4) was used as the medium. The test compound solution thus prepared was intratracheally administered 25 μL (about 0.01 mg / Kg) in the same manner as LPS administration 10 minutes after administration of roflumilast. The control group received vehicle. In addition, 5 rats were used for the test compound administration group and the control group, respectively.
　ＬＰＳ投与の４時間後に気管支肺胞洗浄を下記のように実施し、肺中白血球を回収した。ＳＤラットをソムノペンチル（１ｍＬ／ｋｇ）の腹腔内投与で麻酔し、次いで、下大静脈切開により放血致死させた。気管を露出させ、ディスポーザブル注射筒（５ｍＬ、テルモ株式会社製）に接続したマウス用経口ゾンデ(フチガミ器械社製)を挿入した後、気管を結紮固定した。ＢＳＡ（終濃度１％）及びへパリン（終濃度１Ｕ／ｍＬ）を含む生理食塩液４ｍＬを注入し、直ちに回収して気管支肺胞洗浄液（以下、ＢＡＬＦと略す）を得た。この操作を更に２回繰り返して得られたＢＡＬＦを遠心（４２０xｇ、１０分間、４℃）した後、液量が１．５ｍｌになるまで上清を取り除き、沈殿した細胞を懸濁してＢＡＬＦ細胞懸濁液を得た。ＢＡＬＦ細胞懸濁液の白血球数及び好中球数の測定を下記の（方法１）又は（方法２）のいずれかの方法で行った。 4 hours after LPS administration, bronchoalveolar lavage was performed as follows, and leukocytes in the lung were collected. SD rats were anesthetized by intraperitoneal administration of somnopentyl (1 mL / kg) and then exsanguinated by inferior vena cava incision. After exposing the trachea and inserting an oral sonde for mice (Fujigami Instrument Co., Ltd.) connected to a disposable syringe (5 mL, manufactured by Terumo Corporation), the trachea was ligated and fixed. A physiological saline solution (4 mL) containing BSA (final concentration 1%) and heparin (final concentration 1 U / mL) was injected, and immediately recovered to obtain a bronchoalveolar lavage fluid (hereinafter abbreviated as BALF). The BALF obtained by repeating this operation two more times was centrifuged (420 × g, 10 minutes, 4 ° C.), then the supernatant was removed until the liquid volume reached 1.5 ml, the precipitated cells were suspended, and the BALF cell suspension was suspended. A turbid liquid was obtained. The white blood cell count and neutrophil count of the BALF cell suspension were measured by either of the following (Method 1) or (Method 2).
（方法１）
　ＢＡＬＦ細胞懸濁液の白血球数を、多項目自動血球計測装置（ＫＸ－２１、シスメックス社製）を用いて測定した。次に白血球数が１０６ｃｅｌｌｓ／ｍＬになるように希釈し、この細胞懸濁液１００μＬをスライドガラスに塗布し、単層塗抹標本を作製した。次いで、Ｄｉｆｆ－Ｑｕｉｋ染色キット（カタログ番号１６９２０、シスメックス社製）を用いて細胞染色した後、白血球３００個中の好中球数を光学顕微鏡（ＢＨ－２、オリンパス社製）下計測し、白血球中の好中球の割合（ＮＲ＝白血球３００個中の好中球数／３００）を算出した。被験化合物投与における好中球浸潤抑制率を以下の式から算出した。
　　抑制率（％）＝１００－［（ＷＢＣｃ×ＮＲｃ）／（ＷＢＣｖ×ＮＲｖ）］×１００
　　　ＷＢＣｖ：コントロール群のＢＡＬＦ細胞懸濁液中の白血球数
　　　ＷＢＣｃ：被験化合物投与群のＢＡＬＦ細胞懸濁液中の白血球数
　　　ＮＲｖ：コントロール群の白血球中の好中球の割合
　　　ＮＲｃ：被験化合物投与群の白血球中の好中球の割合 (Method 1)
The white blood cell count of the BALF cell suspension was measured using a multi-item automatic blood cell counter (KX-21, manufactured by Sysmex Corporation). Next, the white blood cell count was diluted to 10 6 cells / mL, and 100 μL of this cell suspension was applied to a slide glass to prepare a single-layer smear. Next, after cell staining using a Diff-Quik staining kit (Catalog No. 16920, manufactured by Sysmex), the number of neutrophils in 300 leukocytes was measured under an optical microscope (BH-2, manufactured by Olympus), and leukocytes were measured. The ratio of neutrophils in the middle (NR = number of neutrophils in 300 leukocytes / 300) was calculated. The inhibition rate of neutrophil infiltration in test compound administration was calculated from the following formula.
Inhibition rate (%) = 100 − [(WBCc × NRc) / (WBCv × NRv)] × 100
WBCv: White blood cell count in BALF cell suspension of control group WBCc: White blood cell count in BALF cell suspension of test compound administration group NRv: Proportion of neutrophils in leukocytes of control group NRc: Test compound administration group Proportion of neutrophils in white blood cells
（方法２）
　ＢＡＬＦ細胞懸濁液の好中球数を、多項目自動血球計測装置（ＸＴ－２０００ｉＶ、シスメックス社製）を用いて測定した。被験化合物投与における好中球浸潤抑制率を以下の式から算出した。
　　抑制率（％）＝１００－［（ＮＥＵＴｃ）／（ＮＥＵＴｖ）］×１００
　　　ＮＥＵＴｖ：コントロール群のＢＡＬＦ細胞懸濁液中の好中球数
　　　ＮＥＵＴｃ：被験化合物投与群のＢＡＬＦ細胞懸濁液中の好中球数 (Method 2)
The neutrophil count of the BALF cell suspension was measured using a multi-item automatic blood cell counter (XT-2000iV, manufactured by Sysmex Corporation). The inhibition rate of neutrophil infiltration in test compound administration was calculated from the following formula.
Inhibition rate (%) = 100 − [(NEUTc) / (NEUTv)] × 100
NEUTv: number of neutrophils in BALF cell suspension of control group NEUTc: number of neutrophils in suspension of BALF cell of test compound administration group
　本試験において、一般式（Ｉ）で表わされる化合物は、ロフルミラストと併用することで、ロフルミラストの薬理効果に一般式（Ｉ）で表わされる化合物の薬理効果が上乗せされ、より優れた肺好中球浸潤抑制作用を示した。例えば、実施例４の化合物及びロフルミラスト単独での肺好中球浸潤抑制率は、それぞれ５１％及び１０％であったが、実施例４の化合物とロフルミラストを併用した場合は、６４％の肺好中球浸潤抑制率を示した。 In this test, the compound represented by the general formula (I) is used in combination with roflumilast, so that the pharmacological effect of the compound represented by the general formula (I) is added to the pharmacological effect of roflumilast. Infiltration suppression effect was shown. For example, the inhibition rate of lung neutrophil infiltration with the compound of Example 4 and roflumilast alone was 51% and 10%, respectively, but when the compound of Example 4 and roflumilast were used in combination, 64% The inhibition rate of neutrophil infiltration was shown.
　本発明の医薬組成物は、他の医薬の薬理効果に、一般式（Ｉ）で表される化合物又はその薬理上許容される塩の薬理効果が上乗せされ、他の医薬の用量を低減化することで他の医薬の副作用を軽減できる点で有用である。上記医薬組成物は、呼吸器疾患、好ましくは、喘息、慢性閉塞性肺疾患、気管支炎、肺気腫、肺線維症、急性呼吸窮迫症候群、嚢胞性線維症又は肺性高血圧症、より好ましくは、喘息、慢性閉塞性肺疾患又は肺線維症の治療及び／又は予防のための医薬組成物であり、温血動物用（特に、ヒト用）の医薬として有用である。 In the pharmaceutical composition of the present invention, the pharmacological effect of the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof is added to the pharmacological effect of another pharmaceutical, and the dosage of the other pharmaceutical is reduced. This is useful in that the side effects of other drugs can be reduced. The pharmaceutical composition is a respiratory disease, preferably asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis or pulmonary hypertension, more preferably asthma , A pharmaceutical composition for the treatment and / or prevention of chronic obstructive pulmonary disease or pulmonary fibrosis, and is useful as a pharmaceutical for warm-blooded animals (particularly for humans).

Claims (12)

  1. 　一般式（Ｉ）：
    Figure JPOXMLDOC01-appb-C000001
    （式中、
    Ｒ１は、保護されていてもよいカルボキシ基を示し、
    Ｗは、窒素原子又は基－ＣＨ＝を示し、
    Ｒ２は、エトキシ基、１－プロペニル基又は１－プロピニル基を示し、
    Ｚは、フェニル基、３－フルオロフェニル基、ピリジン－２－イル基、ピリジン－３－イル基、チオフェン－２－イル基又はチオフェン－３－イル基を示す）
    で表される化合物又はその薬理上許容される塩を含む医薬組成物であって、
    ＰＤＥ４阻害薬、ＰＤＥ５阻害薬、コルチコステロイド、抗コリン薬、β２－受容体作動薬、Ｈ１－ヒスタミン受容体拮抗薬、ロイコトリエン受容体拮抗薬、エンドセリン受容体拮抗薬、ＰＧＩ２受容体作動薬、テオフィリン及びピルフェニドンからなる群から選択される一つ以上の医薬と組み合わせて投与されることを特徴とする、医薬組成物。     Formula (I):
    Figure JPOXMLDOC01-appb-C000001
    (Where
    R 1 represents an optionally protected carboxy group,
    W represents a nitrogen atom or a group —CH═;
    R 2 represents an ethoxy group, a 1-propenyl group or a 1-propynyl group,
    Z represents a phenyl group, a 3-fluorophenyl group, a pyridin-2-yl group, a pyridin-3-yl group, a thiophen-2-yl group, or a thiophen-3-yl group)
    A pharmaceutical composition comprising a compound represented by: or a pharmacologically acceptable salt thereof,
    PDE4 inhibitor, PDE5 inhibitor, corticosteroid, anticholinergic agent, β2-receptor agonist, H1-histamine receptor antagonist, leukotriene receptor antagonist, endothelin receptor antagonist, PGI2 receptor agonist, theophylline And a pharmaceutical composition administered in combination with one or more pharmaceuticals selected from the group consisting of pirfenidone and pirfenidone.
  2. 　一般式（Ｉ）で表される化合物又はその塩を含む医薬組成物と、他の医薬が、それぞれ別異の製剤として、同時に又は異なる時間に投与されることを特徴とする、請求項１に記載の医薬組成物。 The pharmaceutical composition comprising the compound represented by the general formula (I) or a salt thereof and the other medicament are administered as different preparations at the same time or at different times, respectively. The pharmaceutical composition as described.
  3. 　一般式（Ｉ）で表される化合物又はその塩を含む医薬組成物と、他の医薬が、単一の製剤として投与されることを特徴とする、請求項１に記載の医薬組成物。 The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprising the compound represented by the general formula (I) or a salt thereof and the other medicament are administered as a single preparation.
  4. 　Ｒ１が、カルボキシ基又はＣ１－Ｃ６アルコキシカルボニル基を示す、請求項１乃至３のいずれかに記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 3, wherein R 1 represents a carboxy group or a C 1 -C 6 alkoxycarbonyl group.
  5. 　Ｒ１が、カルボキシ基、エトキシカルボニル基、イソプロポキシカルボニル基又はヘキシルオキシカルボニル基を示す、請求項１乃至３のいずれかに記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 3, wherein R 1 represents a carboxy group, an ethoxycarbonyl group, an isopropoxycarbonyl group or a hexyloxycarbonyl group.
  6. 　Ｒ１が、カルボキシ基、エトキシカルボニル基、イソプロポキシカルボニル基又はヘキシルオキシカルボニル基を示し、
    Ｗが、窒素原子又は基－ＣＨ＝を示し、
    Ｒ２が、１－プロペニル基又は１－プロピニル基を示し、
    Ｚが、フェニル基、３－フルオロフェニル基、ピリジン－２－イル基、ピリジン－３－イル基、チオフェン－２－イル基又はチオフェン－３－イル基を示す、請求項１乃至３のいずれかに記載の医薬組成物。     R 1 represents a carboxy group, an ethoxycarbonyl group, an isopropoxycarbonyl group or a hexyloxycarbonyl group,
    W represents a nitrogen atom or a group —CH═;
    R 2 represents a 1-propenyl group or a 1-propynyl group,
    Any one of claims 1 to 3, wherein Z represents a phenyl group, a 3-fluorophenyl group, a pyridin-2-yl group, a pyridin-3-yl group, a thiophen-2-yl group, or a thiophen-3-yl group. A pharmaceutical composition according to 1.
  7. 　一般式（Ｉ）で表される化合物が、
    （６－｛［３’－（１－プロペニル）ビフェニル－４－イルメチル］（ピリジン－２－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸エチル、
    （６－｛［３’－（１－プロペニル）ビフェニル－４－イルメチル］（ピリジン－２－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸、
    （６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（ピリジン－２－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸エチル、
    （６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（ピリジン－２－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸、
    （６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（ピリジン－３－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸エチル、
    （６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（ピリジン－３－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸、
    ｛６－［（３’－エトキシビフェニル－４－イルメチル）（ピリジン－２－イルスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸、
    ｛６－［（３’－エトキシビフェニル－４－イルメチル）（ピリジン－２－イルスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸ヘキシル、
    ｛６－［（３’－エトキシビフェニル－４－イルメチル）（ピリジン－３－イルスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸、
    ｛６－［（ベンゼンスルホニル）（３’－エトキシビフェニル－４－イルメチル）アミノメチル］ピリジン－２－イルアミノ｝酢酸、
    ｛６－［（３’－エトキシビフェニル－４－イルメチル）（チオフェン－２－イルスルホニル）アミノメチル］ピリジン－２－イルアミノ｝酢酸、
    （６－｛［４－（６－エトキシピリジン－２－イル）ベンジル］（ピリジン－２－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸、
    （６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（チオフェン－２－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸エチル、
    （６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（チオフェン－２－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸、
    （６－｛（ベンゼンスルホニル）［３’－（１－プロピニル）ビフェニル－４－イルメチル］アミノメチル｝ピリジン－２－イルアミノ）酢酸エチル、
    （６－｛（ベンゼンスルホニル）［３’－（１－プロピニル）ビフェニル－４－イルメチル］アミノメチル｝ピリジン－２－イルアミノ）酢酸、
    （６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（チオフェン－３－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸エチル、
    （６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（チオフェン－３－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸、
    （６－｛（３－フルオロベンゼンスルホニル）［３’－（１－プロピニル）ビフェニル－４－イルメチル］アミノメチル｝ピリジン－２－イルアミノ）酢酸、又は
    （６－｛［３’－（１－プロピニル）ビフェニル－４－イルメチル］（ピリジン－２－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸イソプロピル
    である請求項１乃至３のいずれかに記載の医薬組成物。     The compound represented by the general formula (I) is:
    (6-{[3 ′-(1-propenyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate,
    (6-{[3 ′-(1-propenyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
    (6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate,
    (6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
    (6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate,
    (6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
    {6-[(3′-ethoxybiphenyl-4-ylmethyl) (pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid,
    {6-[(3′-ethoxybiphenyl-4-ylmethyl) (pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetyl hexyl,
    {6-[(3′-ethoxybiphenyl-4-ylmethyl) (pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid,
    {6-[(benzenesulfonyl) (3′-ethoxybiphenyl-4-ylmethyl) aminomethyl] pyridin-2-ylamino} acetic acid,
    {6-[(3′-ethoxybiphenyl-4-ylmethyl) (thiophen-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid,
    (6-{[4- (6-Ethoxypyridin-2-yl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
    (6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate,
    (6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
    (6-{(benzenesulfonyl) [3 ′-(1-propynyl) biphenyl-4-ylmethyl] aminomethyl} pyridin-2-ylamino) ethyl acetate,
    (6-{(benzenesulfonyl) [3 ′-(1-propynyl) biphenyl-4-ylmethyl] aminomethyl} pyridin-2-ylamino) acetic acid,
    (6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate,
    (6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
    (6-{(3-Fluorobenzenesulfonyl) [3 ′-(1-propynyl) biphenyl-4-ylmethyl] aminomethyl} pyridin-2-ylamino) acetic acid or (6-{[3 ′-(1-propynyl) The pharmaceutical composition according to any one of claims 1 to 3, which is) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) isopropyl acetate.
  8. 　他の医薬が、ＰＤＥ４阻害薬、コルチコステロイド、抗コリン薬、β２－受容体作動薬及びピルフェニドンからなる群から選択される一つ以上の医薬である、請求項１乃至７のいずれかに記載の医薬組成物。 The other medicament is one or more medicaments selected from the group consisting of a PDE4 inhibitor, a corticosteroid, an anticholinergic agent, a β2-receptor agonist, and pirfenidone. Pharmaceutical composition.
  9. 　他の医薬が、ＰＤＥ４阻害薬、コルチコステロイド又はピルフェニドンである、請求項１乃至７のいずれかに記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 7, wherein the other medicament is a PDE4 inhibitor, a corticosteroid, or pirfenidone.
  10. 　他の医薬が、ロフルミラスト、フルチカゾン又はピルフェニドンである、請求項１乃至７のいずれかに記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 7, wherein the other medicament is roflumilast, fluticasone or pirfenidone.
  11. 　喘息、慢性閉塞性肺疾患、気管支炎、肺気腫、肺線維症、急性呼吸窮迫症候群、嚢胞性線維症又は肺性高血圧症の治療もしくは予防のための、請求項１乃至１０のいずれかに記載の医薬組成物。 11. The treatment according to any one of claims 1 to 10, for the treatment or prevention of asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis or pulmonary hypertension. Pharmaceutical composition.
  12. 　喘息、慢性閉塞性肺疾患又は肺線維症の治療もしくは予防のための、請求項１乃至１０のいずれかに記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 10, for treating or preventing asthma, chronic obstructive pulmonary disease or pulmonary fibrosis.
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