WO2016047741A1 - Association d'un composé biaryle substitué et d'un autre composé pharmaceutique - Google Patents

Association d'un composé biaryle substitué et d'un autre composé pharmaceutique 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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English (en)
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

L'invention concerne une composition pharmaceutique qui contient un composé biaryle substitué spécifique ou un sel pharmaceutiquement acceptable de celui-ci et qui est caractérisée en ce qu'elle est administrée en association avec un autre composé pharmaceutique. Cette composition pharmaceutique est utile comme médicament thérapeutique et/ou comme médicament prophylactique contre une maladie respiratoire telle que l'asthme, la bronchopneumopathie chronique obstructive, la bronchite, l'emphysème pulmonaire, la fibrose pulmonaire, le syndrome de détresse respiratoire aiguë, la fibrose kystique et l'hypertension pulmonaire.
PCT/JP2015/077067 2014-09-26 2015-09-25 Association d'un composé biaryle substitué et d'un autre composé pharmaceutique WO2016047741A1 (fr)

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006043655A1 (fr) * 2004-10-22 2006-04-27 Ono Pharmaceutical Co., Ltd. Préparation thérapeutique pour inhalation
JP2007186424A (ja) * 2004-11-26 2007-07-26 Ono Pharmaceut Co Ltd 気管支拡張剤
WO2009113600A1 (fr) * 2008-03-12 2009-09-17 宇部興産株式会社 Composé d'acide pyridylaminoacétique
JP2009544751A (ja) * 2006-07-28 2009-12-17 ファイザー・プロダクツ・インク Ｅｐ２作動薬
WO2011030873A1 (fr) * 2009-09-11 2011-03-17 宇部興産株式会社 Composés benzyliques
JP2011057633A (ja) * 2009-09-11 2011-03-24 Ube Industries Ltd ピリジルアミノ酢酸化合物を含有する医薬
WO2014157672A1 (fr) * 2013-03-28 2014-10-02 宇部興産株式会社 Composé biaryle substitué
WO2015030250A1 (fr) * 2013-09-02 2015-03-05 宇部興産株式会社 Composition pharmaceutique pour le traitement et/ou la prévention d'une maladie pulmonaire

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006043655A1 (fr) * 2004-10-22 2006-04-27 Ono Pharmaceutical Co., Ltd. Préparation thérapeutique pour inhalation
JP2007186424A (ja) * 2004-11-26 2007-07-26 Ono Pharmaceut Co Ltd 気管支拡張剤
JP2009544751A (ja) * 2006-07-28 2009-12-17 ファイザー・プロダクツ・インク Ｅｐ２作動薬
WO2009113600A1 (fr) * 2008-03-12 2009-09-17 宇部興産株式会社 Composé d'acide pyridylaminoacétique
WO2011030873A1 (fr) * 2009-09-11 2011-03-17 宇部興産株式会社 Composés benzyliques
JP2011057633A (ja) * 2009-09-11 2011-03-24 Ube Industries Ltd ピリジルアミノ酢酸化合物を含有する医薬
WO2014157672A1 (fr) * 2013-03-28 2014-10-02 宇部興産株式会社 Composé biaryle substitué
WO2015030250A1 (fr) * 2013-09-02 2015-03-05 宇部興産株式会社 Composition pharmaceutique pour le traitement et/ou la prévention d'une maladie pulmonaire

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