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WO2010113952A1 - Antagoniste de récepteurs muscariniques - Google Patents

Antagoniste de récepteurs muscariniques Download PDF

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Publication number
WO2010113952A1
WO2010113952A1 PCT/JP2010/055710 JP2010055710W WO2010113952A1 WO 2010113952 A1 WO2010113952 A1 WO 2010113952A1 JP 2010055710 W JP2010055710 W JP 2010055710W WO 2010113952 A1 WO2010113952 A1 WO 2010113952A1
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Prior art keywords
group
carbamoyl
diphenylpropyl
methylimidazolium bromide
carbon atoms
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PCT/JP2010/055710
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English (en)
Japanese (ja)
Inventor
一典 福地
哲也 岸
徳太郎 安江
智彦 永楽
靖志 河野
昌弘 野村
弘幸 宮地
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杏林製薬株式会社
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Priority to JP2011507218A priority Critical patent/JPWO2010113952A1/ja
Publication of WO2010113952A1 publication Critical patent/WO2010113952A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/61—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to an imidazolium derivative useful as a selective muscarinic receptor antagonist.
  • muscarinic receptors There are at least five subtypes of muscarinic receptors, M1 receptor with high affinity for pirenzepine, M2 receptor with high affinity for AFDX-116, and M3 with high affinity for pF-hexahydrosiladifenidol.
  • the receptors were classified into three subtypes by pharmacological methods. Among these, it is known that the M1 receptor is present in the brain, the M2 receptor is present in the heart, and the M3 receptor is present in smooth muscle and glandular tissues.
  • m1-m5 were identified by cloning of cDNA. m1-m3 corresponds to the M1-M3 receptor subtype, respectively (Non-patent Document 1).
  • Drugs with muscarinic receptor antagonism have antispasmodic and antisecretory effects and are therefore used as therapeutic agents for respiratory, urinary or gastrointestinal dysfunction. Etc. are used clinically.
  • side effects due to non-selective antagonism with acetylcholine cannot be avoided because they show almost the same affinity for the M1, M2 and M3 receptors of muscarinic receptors.
  • Antimuscarinic agents suitable for pulmonary administration include ambutonium, benzylonium, dibutrin, diphemanyl, emepromonium, glycopyrrolate, isopropamide, ratchecin, mepenzolate, methanthelin, oxyphenonium, oxitropium bromide, penthienato, fenthimentonium, pipenzolate, Polgin, thiemonium, tiotropium, tricyclamol, tridihexetyl and the like are known (Patent Document 1).
  • Non-patent Document 2 tachycardia, supraventricular tachycardia and palpitations, which are side effects on the circulatory organ, have been reported even with antimuscarinic agents suitable for pulmonary administration (Non-patent Document 2), and are highly selective for the M3 receptor
  • pharmaceuticals having muscarinic receptor antagonism in particular, pharmaceuticals that do not exhibit side effects on the heart involving the M2 receptor.
  • Patent Document 2 an imidazolium derivative having a muscarinic M3 receptor antagonistic action and a novel nitrogen-containing heterocyclic compound (Patent Document 3) are disclosed.
  • Patent Document 2 an imidazolium derivative having a muscarinic M3 receptor antagonistic action and a novel nitrogen-containing heterocyclic compound
  • R 1 represents phenyl or the like which may have a substituent
  • R 2 represents carbamoyl or the like
  • R 3 represents hydrogen, lower alkyl or the like
  • R 4 , R 5 and R 6 is the same or different and represents a hydrogen atom, lower alkyl or the like
  • R 10 represents a lower alkyl group or an araalkyl group which may have a substituent
  • m represents an integer of 1 to 6
  • Z represents a halogen atom.
  • the compound represented by the formula does not contain an alkenyl group which may have a substituent in R 10 , and has a structure different from that of the present application compound. Further, the following general formula described in Patent Document 3,
  • R 1 represents an aryl group or the like which may have a substituent
  • R 2 represents an aryl group or the like which may have a substituent
  • R 3 represents a carbamoyl group or the like
  • R 4 represents an alkyl group or the like which may have a substituent
  • R 5 represents a hydrogen atom, a lower alkyl group, or the like
  • R 6 and R 7 are each independently absent, a hydrogen atom or It represents a lower alkyl group
  • the sum of m and n is an integer from 1 to 6
  • Z - represents an anion.
  • the nitrogen-containing heterocycle and the carbon bonded to R 3 are connected by a cycloalkane, and the structure is different from that of the compound of the present application.
  • An object of the present invention is to provide a compound having a chemical structure different from that of a known compound, having a selective muscarinic M3 receptor antagonism, and excellent in efficacy, durability and safety.
  • the inventors of the present invention have demonstrated that the novel imidazolium derivative having an allyl group at the 3-position can selectively and continuously antagonize muscarinic M3 receptors.
  • the present invention has been completed by finding that it has excellent effects in vivo and has few side effects and is safe.
  • R 1 represents an aryl group which may have a substituent, a heteroaryl group which may have a substituent, or a cycloalkyl group having 3 to 9 carbon atoms
  • R 2 represents an aryl group which may have a substituent, or a heteroaryl group which may have a substituent
  • R 3 represents hydrogen or a lower alkyl group having 1 to 6 carbon atoms
  • R 4 represents an aryl group which may have a substituent, a heteroaryl group which may have a substituent, or a cycloalkyl group having 3 to 9 carbon atoms
  • Y ⁇ represents an anion
  • A is an alkylene chain having 1 to 4 carbon atoms, or
  • R 1 represents a phenyl group, a thienyl group, or a cycloalkyl group having 5 to 9 carbon atoms
  • R 2 represents a phenyl group or a thienyl group
  • R 3 represents hydrogen or a lower alkyl group having 1 to 4 carbon atoms
  • R 4 represents an optionally substituted phenyl group, thienyl group, thiazolyl group, or a cycloalkyl group having 3 to 7 carbon atoms
  • Y ⁇ represents a halogen ion
  • A represents an imidazolium derivative according to 1) above, which represents an alkylene chain having 1 to 4 carbon atoms, an oxyethylene chain, or an oxypropylene chain
  • R 1 represents a phenyl group, a 2-thienyl group, or a cyclooct
  • the present invention it has become possible to provide a compound having a selective and long-lasting antagonistic action on the muscarinic M3 receptor, a weak antagonistic action on the muscarinic M2 receptor, and a short action time. .
  • it is useful as a therapeutic agent for respiratory diseases involving the effective and safe muscarinic M3 receptor.
  • various diseases associated with airflow obstruction such as chronic bronchial asthma and chronic obstructive pulmonary disease (COPD) It is useful as a preventive or therapeutic agent for asthma, chronic airway obstruction, pulmonary fibrosis, emphysema, diffuse panbronchiolitis, bronchiectasis, idiopathic interstitial pneumonia, rhinitis and the like.
  • COPD chronic obstructive pulmonary disease
  • An aryl group means an aromatic hydrocarbon group having 6 to 14 carbon atoms, and specific examples include a phenyl group and a naphthyl group.
  • the heteroaryl group means a 5-membered or 6-membered aromatic ring group containing a hetero atom and a condensed ring group thereof.
  • Examples of the optionally substituted substituent for the aryl group or heteroaryl group include a halogen atom, a hydroxyl group, an optionally substituted amino group, a cyano group, a nitro group, and a lower alkyl group having 1 to 6 carbon atoms.
  • Preferred examples include a group, a lower alkoxy group having 1 to 6 carbon atoms, a lower haloalkyl group having 1 to 6 carbon atoms, a lower haloalkoxy group having 1 to 6 carbon atoms, and a cycloalkyl group. These substituents may be used alone or in combination of 2 to 3 substituents.
  • the lower alkyl group having 1 to 6 carbon atoms is a linear or branched alkyl group having 1 to 6 carbon atoms, preferably an alkyl group having 1 to 4 carbon atoms. Examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, and a t-butyl group.
  • the lower haloalkyl group having 1 to 6 carbon atoms is a group in which one or more hydrogen atoms of the alkyl group are substituted with halogen atoms, and specifically includes a trifluoromethyl group, a difluoromethyl group, a penta A fluoroethyl group, a difluoroethoxy group, etc. are mentioned.
  • the lower alkoxy group having 1 to 6 carbon atoms is a linear or branched alkoxy group having 1 to 6 carbon atoms, preferably an alkoxy group having 1 to 4 carbon atoms.
  • methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, t-butoxy group and the like can be mentioned.
  • the cycloalkyl group having 3 to 9 carbon atoms means an alicyclic hydrocarbon having 3 to 9 carbon atoms, and specifically includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopeptyl, cyclooctyl, cyclononyl and the like. Can be mentioned.
  • Examples of the substituent in the amino group which may have a substituent include an alkanoyl group having 2 to 6 carbon atoms, a lower alkylsulfonyl group having 1 to 6 carbon atoms, a lower haloalkylsulfonyl group having 1 to 6 carbon atoms, and a carbon number
  • Preferable examples include 1 to 6 lower alkyl groups.
  • the alkanoyl group having 2 to 6 carbon atoms is an alkanoyl group having 2 to 6 carbon atoms having a straight chain or branched chain, and examples thereof include an acetyl group and a propanoyl group.
  • the lower alkylsulfonyl group having 1 to 6 carbon atoms is a linear or branched alkylsulfonyl group, and examples thereof include a methanesulfonyl group and an ethanesulfonyl group.
  • the lower haloalkylsulfonyl group having 1 to 6 carbon atoms is one in which one or more hydrogen atoms of the alkylsulfonyl group are substituted with halogen atoms, and examples thereof include a trifluoromethanesulfonyl group. These substituents may be one or two identical or different substituents.
  • a halogen atom is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • a lower haloalkyl group having 1 to 6 carbon atoms is a group in which one or more hydrogen atoms of an alkyl group are substituted with a halogen. Specifically, a trifluoromethyl group, a difluoromethyl group, a fluoromethyl group, or the like. Group, pentafluoroethyl group, difluoroethyl group, trichloromethyl group, chloromethyl group, chloroethyl group and the like.
  • a lower haloalkoxy group having 1 to 6 carbon atoms is a group in which one or more hydrogen atoms of an alkoxy group are substituted with a halogen. Specifically, a trifluoromethoxy group, a difluoromethoxy group, a penta A fluoroethoxy group, a difluoroethoxy group, etc. are mentioned.
  • the anion means an anion formed from a halogen atom, an inorganic acid, an organic sulfonic acid, a carboxylic acid, and the like, specifically, a chlorine ion, a bromine ion, an iodine ion, a tosylate ion, a mesylate ion. Etc.
  • the compound represented by the general formula (1) in the present invention includes optical isomers based on asymmetric carbon, geometric isomers, stereoisomers, tautomers, and the like. All such mixtures are included within the scope of this invention.
  • the compound represented by the general formula (1) can be produced, for example, by the route shown below. ⁇ Synthesis route A>
  • examples of the leaving group represented by Y include a halogen atom, a lower alkylsulfonyloxy group having 1 to 6 carbon atoms, a lower haloalkylsulfonyloxy group having 1 to 6 carbon atoms, and an optionally substituted arylsulfonyloxy group.
  • examples of the lower alkylsulfonyloxy group having 1 to 6 carbon atoms include a methanesulfonyloxy group and an ethanesulfonyloxy group.
  • examples of the lower haloalkylsulfonyloxy group having 1 to 6 carbon atoms include a trifluoromethanesulfonyloxy group.
  • arylsulfonyloxy group which may be substituted include a phenylsulfonyloxy group and a p-tolylsulfonyloxy group.
  • Conversion from the general formula (2) and the general formula (4) to the general formula (1) (step A-1) can be carried out without solvent or in a suitable solvent such as tetrahydrofuran (THF), 1,4-dioxane, acetonitrile, The reaction can be carried out in ethanol, methanol, acetone, or a mixed solution thereof at 0 ° C. to 100 ° C. for 1 to 100 hours.
  • THF tetrahydrofuran
  • 1,4-dioxane 1,4-dioxane
  • acetonitrile acetonitrile
  • the reaction can be carried out in ethanol, methanol, acetone, or a mixed solution thereof at 0 ° C. to 100 ° C. for 1 to 100 hours.
  • step A-2 The conversion from the general formula (3) and the general formula (5) to the general formula (1) (step A-2) can be performed by the same method as in step A-1.
  • the synthetic route A among the compounds represented by the general formula (2), the compound of the general formula (2a) in which A is an alkylene chain can be produced, for example, by the route shown below. ⁇ Synthetic route B>
  • R 5 represents a lower alkyl group, an araalkyl group which may have a substituent
  • M represents lithium or MgX (X is as described above)
  • R 1 , R 2 , R 3 and n are as described above.
  • step B-1 Conversion of the compound represented by the general formula (6) and the compound represented by the general formula (7) to the compound represented by the general formula (8) (step B-1) can be carried out by using an appropriate solvent such as dimethylformamide (DMF ), Diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, cyclopentyl methyl ether or a mixture thereof, sodium hydride, sodium amide, lithium diisopropylamide (LDA), lithium hexamethyldisilazane (LHMDS),
  • the reaction can be carried out in the presence of a base such as sodium hexamethyldisilazane (NaHMDS) or potassium hexamethyldisilazane (KHMDS) at ⁇ 80 ° C. to room temperature for 0.1 to 24 hours.
  • a base such as sodium hexamethyldisilazane (NaHMDS) or potassium hexamethyldisilazane (K
  • step B-2 Conversion from the compound represented by the general formula (8) and the compound represented by the general formula (9) to the compound represented by the general formula (10) (step B-2) can be carried out without a solvent or an appropriate solvent such as dimethyl Base such as triethylamine, diisopropylethylamine, pyridine, sodium hydride, potassium hydride, potassium carbonate, sodium carbonate in sulfoxide (DMSO), N, N-dimethylformamide (DMF), acetonitrile or a mixture thereof And the reaction is carried out at room temperature to 150 ° C. for 1 to 100 hours.
  • a solvent or an appropriate solvent such as dimethyl Base such as triethylamine, diisopropylethylamine, pyridine, sodium hydride, potassium hydride, potassium carbonate, sodium carbonate in sulfoxide (DMSO), N, N-dimethylformamide (DMF), acetonitrile or a mixture thereof
  • DMSO sulfoxide
  • step B-3 Conversion from the compound represented by the general formula (10) to the compound represented by the general formula (2a) (step B-3) is performed without a solvent or an appropriate solvent such as DMSO, 1,4-dioxane, THF, ethanol. , Methanol, water or a mixture of these, using an acid such as hydrochloric acid, sulfuric acid or nitric acid, or a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, at 0 ° C. to 150 ° C. For 1 to 100 hours. When a base is used, hydrogen peroxide solution can be added as necessary.
  • an appropriate solvent such as DMSO, 1,4-dioxane, THF, ethanol. , Methanol, water or a mixture of these, using an acid such as hydrochloric acid, sulfuric acid or nitric acid, or a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, at
  • step B-4 Conversion from the compound represented by the general formula (9) and the compound represented by the general formula (7) to the compound represented by the general formula (11) (step B-4) should be performed in the same manner as in step B-2. I can do it. Conversion from the compound represented by the general formula (11) and the compound represented by the general formula (6) to the compound represented by the general formula (10) (step B-5) should be performed in the same manner as in step B-1. I can do it.
  • Step B-6 Conversion of the compound represented by the general formula (12) and the compound represented by the general formula (13) to the compound represented by the general formula (14) (Step B-6) can be carried out by using an appropriate solvent such as THF, 1,
  • the reaction can be carried out by reacting in 4-dioxane, diethyl ether, cyclopentyl methyl ether or a mixture thereof at ⁇ 80 ° C. to 100 ° C. for 0.1 to 48 hours.
  • Conversion of the compound represented by the general formula (14) and the compound represented by the general formula (15) into the compound represented by the general formula (16) is performed by the same method as in step B-6. be able to.
  • Conversion from the compound represented by the general formula (16) to the compound represented by the general formula (10) is carried out by using a suitable solvent such as dichloromethane, chloroform, 1,2-dichloroethane, benzene, chlorobenzene, dichlorobenzene.
  • Trichlorobenzene, nitromethane, or a mixture thereof in the presence of a Lewis acid such as aluminum chloride or tetrafluoroborane diethyl ether complex, can be carried out by reacting trimethylsilylcyanide at room temperature to 150 ° C. for 1 to 100 hours.
  • a Lewis acid such as aluminum chloride or tetrafluoroborane diethyl ether complex
  • Step C-1 Conversion of the compound represented by the general formula (17) and the compound represented by the general formula (18) into the compound represented by the general formula (19) (Step C-1) can be carried out by using an appropriate solvent such as dichloromethane, chloroform, In 1,2-dichloroethane, benzene N-methylpyrrolidone, or a mixture of these, silver salt such as silver trifluoromethanesulfonate is used as necessary, pyridine, 4- (N, N-dimethyl) pyridine, collected ethylamine In the presence of a base such as 2,6-di-tert-butylpyridine, the reaction can be performed, for example, at 0 ° C.
  • an appropriate solvent such as dichloromethane, chloroform, In 1,2-dichloroethane, benzene N-methylpyrrolidone, or a mixture of these, silver salt such as silver trifluoromethanesulfonate is used as necessary, pyridine, 4- (
  • Conversion from the compound represented by the general formula (19) to the compound represented by the general formula (20) (step C-2) can be carried out without a solvent or an appropriate solvent such as DMSO, 1,4-dioxane, THF , Ethanol, methanol, water, mixed liquids thereof, etc., using hydrochloric acid, sulfuric acid, nitric acid and other acids, or bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, for example
  • the hydrolysis can be performed at 0 ° C. to 150 ° C., for example, for 1 to 100 hours.
  • Step C-3 Conversion from the compound represented by the general formula (20) to the compound represented by the general formula (2b) (Step C-3) is carried out by using an appropriate solvent such as dichloromethane, chloroform, THF, diethyl ether, DMF, or a mixture thereof.
  • an appropriate solvent such as dichloromethane, chloroform, THF, diethyl ether, DMF, or a mixture thereof.
  • bases such as pyridine, triethylamine, N-methylmorpholine, N-hydroxybenzotriazole, N-hydroxysuccinimide, 3,4-dihydro-3-hydroxy-4-oxo-1,2,3 as necessary -In the presence of reaction aids such as benzotriazine and 4- (dimethylamino) pyridine, using a condensing agent such as dicyclohexylcarbodiimide, diethyl cyanophosphate, diphenylphosphate azide, and carbonyldiimidazole, ammonia (ammonia gas, containing ammonia) 1,4-Geo containing water and ammonia And Sun, etc.), for example, in the -15 ⁇ 80 ° C., for example, can be carried out by reacting 0.1 to 100 hours.
  • a condensing agent such as dicyclohexylcarbodiimide, diethyl cyanophosphate, diphenylphosphate azide, and carbon
  • the compound represented by the general formula (26) is used in the presence of a base such as pyridine or triethylamine in a solvent-free or appropriate solvent, for example, toluene, THF, dichloromethane, DMF or a mixture thereof, if necessary.
  • a base such as pyridine or triethylamine
  • a solvent-free or appropriate solvent for example, toluene, THF, dichloromethane, DMF or a mixture thereof, if necessary.
  • thionyl chloride, thionyl bromide, acetic anhydride, ethyl chlorocarbonate and the like are reacted at, for example, ⁇ 15 to 50 ° C., for example, for 5 minutes to 3 hours to convert the carboxyl group to acid chloride, acid bromide, acid anhydride.
  • a suitable solvent such as toluene, THF, dichloromethane, DMF, a mixed solution thereof, ammonia gas or ammonia-containing water, or 1,4-dioxane, ether, THF, and the like.
  • the reaction can be performed at ⁇ 15 to 80 ° C., for example, for 0.1 to 100 hours.
  • 2-methylimidazole (1.31 g, 16.0 mmol) was added to a solution of sodium hydride (640 mg, 16.0 mmol) in DMF (145 mL) under ice-cooling and stirring for 0.5 hours.
  • the compound of Reference Example 1 (4.54 g, 14.5 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours.
  • a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate (80 mL). The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate.
  • 1,1-carbonyldiimidazole (716 mg, 4.41 mmol) was added to a solution of the compound of Reference Example 15 (1.24 g, 3.68 mmol) in dichloromethane (12.4 mL), stirred at room temperature for 30 minutes, and then 25% aqueous ammonia solution ( 3.76 mL, 55.2 mmol) was added and stirred for 2.5 hours.
  • the solvent was distilled off under reduced pressure, followed by extraction with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate.
  • Cinnamyl bromide (43.2 g, 0.219 mol) was added to a solution of 4- (2-methyl-1H-imidazol-1-yl) -2,2-diphenylbutanamide (35.0 g, 0.110 mol) in THF (700 mL). And heated to reflux for 5 hours. The precipitated crystals were collected by filtration, and the obtained solid was recrystallized (methanol-water) to give the title compound (52.4 g) as a white solid.
  • Example 1 using 4- (2-methyl-1H-imidazol-1-yl) -2,2-diphenylbutanamide (377 mg, 1.18 mmol) and 2-methoxycinnamyl bromide (804 mg, 3.54 mmol) The title compound as a colorless solid was obtained as a white solid.
  • Example 1 with 4- (2-methyl-1H-imidazol-1-yl) -2,2-diphenylbutanamide (319 mg, 1.00 mmol) and 3-methoxycinnamyl bromide (1.14 g, 5.00 mmol) The same treatment was performed to obtain 486 mg of the title compound as a white solid as a colorless powder.
  • Example 1 using 4- (2-methyl-1H-imidazol-1-yl) -2,2-diphenylbutanamide (247 mg, 0.773 mmol) and 4-methoxycinnamyl bromide (526 mg, 2.32 mmol) The title compound as a colorless powder was obtained as a white solid.
  • Example 1 using 4- (2-methyl-1H-imidazol-1-yl) -2,2-diphenylbutanamide (400 mg, 1.25 mmol) and 2-chlorocinnamyl bromide (2.03 g, 8.75 mmol) The title compound as a colorless powder was obtained as a white solid.
  • Example 1 using 4- (2-methyl-1H-imidazol-1-yl) -2,2-diphenylbutanamide (379 mg, 1.19 mmol) and 3-chlorocinnamyl bromide (2.75 g, 11.9 mmol) The title compound as a colorless powder was obtained as a white solid.
  • Example 1 using 4- (2-methyl-1H-imidazol-1-yl) -2,2-diphenylbutanamide (400 mg, 1.25 mmol) and 4-chlorocinnamyl bromide (2.39 g, 10.3 mmol) The title compound as a colorless powder was obtained as a white solid.
  • Example 1 using 4- (2-methyl-1H-imidazol-1-yl) -2,2-diphenylbutanamide (200 mg, 0.626 mmol) and 2-nitrocinnamyl bromide (1.52 g, 6.26 mmol) The title compound as a colorless powder was obtained as a white solid.
  • Example 1 using 4- (2-methyl-1H-imidazol-1-yl) -2,2-diphenylbutanamide (200 mg, 0.626 mmol) and 3-nitrocinnamyl bromide (960 mg, 3.97 mmmol) The title compound as a colorless powder was obtained as a white solid.
  • Example 6 The same treatment as in Example 1 was carried out using Reference Example 6 (180 mg, 0.543 mmol) and cinnamyl bromide (1.07 g, 5.43 mmol), and recrystallization with water gave 205 mg of the title compound as a white solid. .
  • Cinnamyl bromide (1.17 mL, 5.96 mmol) was added to a solution of the compound of Reference Example 16 (200 mg, 0.596 mmol) in tetrahydrofuran (5.96 mL), and the mixture was stirred at room temperature for 20 hours, and then the precipitated crystals were collected by filtration. The obtained solid was dissolved in water, washed with ethyl acetate, and the aqueous layer was lyophilized to give 95 mg of the title compound as a colorless amorphous product.
  • ⁇ Test Example 1 Human muscarinic M3 to the binding affinity test tube to the receptor, 1 Unit of human muscarinic M3 receptor expressing membrane preparation (GE Healthcare Sciences Inc.) and 0.5 nM [3 H] -scopolamine ( N-methyl) ( Perkin Elma)), the test substance was added to make 0.5 ml with phosphate buffered saline, and incubated at 25 ° C. for 4 hours. For the measurement of the amount of nonspecific binding radioactivity, 5 ⁇ M atropine sulfate (manufactured by Tokyo Chemical Industry Co., Ltd.) was added.
  • a membrane sample of human muscarinic M3 receptor was collected on a Whatman GF / B filter using a cell harvester, and washed 5 times with 5 ml each of ice-cooled 50 mM Tris-HCl aqueous solution (4 ° C.).
  • a filter and 5 ml of liquid scintillator ACSII were added to the vial, and the radioactivity remaining on the filter was measured with a liquid scintillation analyzer.
  • the IC 50 value of the test substance was determined and converted to a Ki value using the Cheng-Prosoff equation. The results are shown in Table 1 below.
  • the imidazolium derivatives of the present invention are a novel compound group exhibiting excellent affinity for the muscarinic M3 receptor.
  • ⁇ Test Example 2 1 unit of human muscarinic M2 or M3 receptor-expressing membrane preparation (manufactured by GE Healthcare Science) and 0.5 nM [ 3 H] -scopolamine (N-methyl) ) (Manufactured by Perkin Elma), the test substance was added to make 0.5 ml with phosphate buffered saline, and incubated at 25 ° C. for 4 hours. For the measurement of the amount of non-specific binding radioactivity, 5 ⁇ M atropine sulfate (manufactured by Tokyo Chemical Industry Co., Ltd.) was added.
  • the imidazolium derivatives of the present invention are a novel compound group showing excellent selectivity for the muscarinic M3 receptor.
  • a filter and 5 mL of liquid scintillator ACSII were added to the vial, and the radioactivity remaining on the filter was measured with a liquid scintillation analyzer.
  • the value was defined as the inhibition rate of the effect of the test substance, with the value when 5 ⁇ M atropine sulfate was added as 100% inhibition.
  • the results are shown in FIG. From the above results, it was confirmed that the imidazolium derivative of the present invention exhibits excellent binding persistence for the muscarinic M3 receptor.
  • Example 4 Effect of Example Compound 24 hours on acetylcholine-induced airway contraction in guinea pigs Guinea pigs (450-600 g, Std: Hartley, clean, SLC Japan) were anesthetized with pentobarbital (30 mg / kg, ip), and the airways were A semicircular incision is made, and the tip of the administration device is inserted into the incision site.
  • An example compound solution 200 ⁇ L / kg
  • Otsuka sugar solution together with compressed air is jetted and administered intratracheally.
  • the control group received 5% Otsuka sugar solution (200 ⁇ L / kg).
  • the incised trachea and skin were sutured.
  • Guinea pigs were anesthetized with pentobarbital (30 mg / kg, ip) 24 hours after administration. An incision is made in the skin and a cannula is inserted into the left external jugular vein, which serves as a route for administration of gallamine solution and acetylcholine (ACh) solution. A tracheal cannula was inserted into the respiratory tract, connected to a ventilator (60 times / min, 10 mL / kg / stroke), and spontaneous respiration was stopped by administering a galamine solution (10 mg / kg) via a vein.
  • a galamine solution (10 mg / kg
  • Air overflowing from the side branch of the tracheal cannula was measured using a bronchospasm transducer and output to a computer via Power Lab.
  • ACh 10, 20, 30, and 40 ⁇ g / kg were administered every 3 minutes from 6 minutes after the start of measurement.
  • each symbol has the following meaning.
  • a 0 Maximum value of airway contraction when ACh 40 ⁇ g / kg was administered in the control group
  • B: Baseline value before ACh administration in the test substance administration group B 0 Baseline value before ACh administration in the control group
  • the imidazolium derivative of the present invention exhibits excellent affinity for the muscarinic M3 receptor. Therefore, the compound of the present invention is used in the pharmaceutical field for chronic bronchial asthma, chronic obstructive pulmonary disease (COPD), asthma, chronic airway obstruction, pulmonary fibrosis, emphysema, diffuse panbronchiolitis, bronchiectasis, idiopathic It is effective as a preventive or therapeutic agent for interstitial pneumonia, rhinitis and the like.
  • COPD chronic obstructive pulmonary disease

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Abstract

L'invention porte sur un composé représenté par la formule (1). Le composé est un nouveau dérivé d'imidazolium ayant une excellente activité antagoniste sur un récepteur muscarinique M3 et ayant une excellente efficacité, une efficacité à long terme et une excellente sécurité. Le composé est un agent prophylactique ou thérapeutique pour diverses maladies associées à une obstruction des voies aériennes, telles que l'asthme bronchique chronique, la bronchopneumopatie chronique obstructive (COPD), l'asthme, une obstruction des voies aériennes chronique, le poumon fibreux, un emphysème pulmonaire, la panbrochiolite diffuse, la bronchiectasie, la pneumonie interstitielle idiopathique et la rhinite.
PCT/JP2010/055710 2009-03-31 2010-03-30 Antagoniste de récepteurs muscariniques WO2010113952A1 (fr)

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JP2011507218A JPWO2010113952A1 (ja) 2009-03-31 2010-03-30 ムスカリン受容体拮抗薬

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995015951A1 (fr) * 1993-12-10 1995-06-15 Kyorin Pharmaceutical Co. Ltd. Nouveau derive de l'imidazole et sa methode d'obtention
WO2007013421A1 (fr) * 2005-07-25 2007-02-01 Mitsubishi Tanabe Pharma Corporation Nouveau composé hétérocyclique azoté

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995015951A1 (fr) * 1993-12-10 1995-06-15 Kyorin Pharmaceutical Co. Ltd. Nouveau derive de l'imidazole et sa methode d'obtention
WO2007013421A1 (fr) * 2005-07-25 2007-02-01 Mitsubishi Tanabe Pharma Corporation Nouveau composé hétérocyclique azoté

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