WO2010113952A1 - Muscarinic receptor antagonist - Google Patents

Abstract

Disclosed is a compound represented by formula (1). The compound is a novel imidazolium derivative having an excellent antagonistic activity on a muscarinic M3 receptor and having excellent effectiveness, long-lasting efficacy and safety. The compound is a prophylactic or therapeutic agent for various diseases associated with airflow obstruction, such as chronic bronchial asthma, chronic obstructive pulmonary disease (COPD), asthma, chronic airway obstruction, fibroid lung, pulmonary emphysema, diffuse panbronchiolitis, bronchiectasis, idiopathic interstitial pneumonia and rhinitis.

Description

Muscarinic receptor antagonist

The present invention relates to an imidazolium derivative useful as a selective muscarinic receptor antagonist.

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. On the other hand, five kinds of muscarinic receptor subtypes 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. However, it is known that 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).

However, 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 There has been a demand for pharmaceuticals having muscarinic receptor antagonism, in particular, pharmaceuticals that do not exhibit side effects on the heart involving the M2 receptor.
On the other hand, an imidazolium derivative (Patent Document 2) having a muscarinic M3 receptor antagonistic action and a novel nitrogen-containing heterocyclic compound (Patent Document 3) are disclosed. However, the following general formula described in Patent Document 2,

[Wherein 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,

[Wherein 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, and R ⁶ and R ⁷ are each independently absent, a hydrogen atom or It represents a lower alkyl group, -A-B- represents -C = C-like, the sum of m and n is an integer from 1 to 6, Z ^- represents an anion. ]
In the compound represented by the formula, 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.

International Publication No. 2001/76575 Pamphlet International Publication No. 1995/15951 Pamphlet International Publication No. 2007/013421 Pamphlet

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.

As a result of intensive studies to solve the above problems, 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.

That is, the present invention relates to the following 1) to 13).
1) General formula (1),

[Where:
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

(Wherein n represents an integer of 1 to 4). ]
An imidazolium derivative represented by:
2) In the general formula (1),
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,
3) In the general formula (1),
R ¹ represents a phenyl group, a 2-thienyl group, or a cyclooctyl group,
R ² represents a phenyl group or a 2-thienyl group,
R ³ represents a methyl group,
R ⁴ represents an optionally substituted phenyl group, 2-thienyl group, thiazol-2-yl group, or a cycloalkyl group having 3 to 6 carbon atoms;
Y ⁻ represents a bromine ion,
A represents an imidazolium derivative according to 1) above, which represents an alkylene chain having 2 to 3 carbon atoms, an oxyethylene chain, or an oxypropylene chain,
4) In the general formula (1),
R ⁴ represents a chlorine atom, a methoxy group, a phenyl group optionally substituted with a nitro group, a 2-thienyl group, a thiazol-2-yl group, or a cyclohexyl group;
A represents an imidazolium derivative according to 3) above, which represents an ethylene chain,
5) In the general formula (1),
R ⁴ is a phenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 3-nitrophenyl group, 4-nitrophenyl group, 2-thienyl group , An imidazolium derivative according to the above 4), which represents a thiazol-2-yl group or a cyclohexyl group,
6) The compound is
(E) -1- (3-carbamoyl-3,3-diphenylpropyl) -3-cinnamyl-2-methylimidazolium bromide,
(E) -1- (3-carbamoyl-3,3-diphenylpropyl) -3- (2-methoxycinnamyl) -2-methylimidazolium bromide,
(E) -1- (3-carbamoyl-3,3-diphenylpropyl) -3- (3-methoxycinnamyl) -2-methylimidazolium bromide,
(E) -1- (3-carbamoyl-3,3-diphenylpropyl) -3- (4-methoxycinnamyl) -2-methylimidazolium bromide,
(E) -1- (3-carbamoyl-3,3-diphenylpropyl) -3- (2-chlorocinnamyl) -2-methylimidazolium bromide,
(E) -1- (3-carbamoyl-3,3-diphenylpropyl) -3- (3-chlorocinnamyl) -2-methylimidazolium bromide,
(E) -1- (3-carbamoyl-3,3-diphenylpropyl) -3- (4-chlorocinnamyl) -2-methylimidazolium bromide,
(E) -1- (3-carbamoyl-3,3-diphenylpropyl) -3- (2-nitrocinnamyl) -2-methylimidazolium bromide,
(E) -1- (3-carbamoyl-3,3-diphenylpropyl) -3- (3-nitrocinnamyl) -2-methylimidazolium bromide,
(E) -1- (3-carbamoyl-3,3-diphenylpropyl) -3- (4-nitrocinnamyl) -2-methylimidazolium bromide,
(E) -1- [3-carbamoyl-3,3-di (thiophen-2-yl) propyl] -3-cinnamyl-2-methylimidazolium bromide,
(E) -1- (3-carbamoyl-3,3-diphenylpropyl) -3- (3-cyclohexylallyl) -2-methylimidazolium bromide,
(E) -1- (3-carbamoyl-3,3-diphenylpropyl) -3- (3-cyclopropylallyl) -2-methylimidazolium bromide,
(E) -1- (3-carbamoyl-3,3-diphenylpropyl) -2-methyl-3- [3- (thiophen-2-yl) allyl] imidazolium bromide,
(E) -1- (3-carbamoyl-3,3-diphenylpropyl) -2-methyl-3- [3- (thiazol-2-yl) allyl] imidazolium bromide,
(E) -1- (4-carbamoyl-4,4-diphenylbutyl) -3-cinnamyl-2-methylimidazolium bromide,
(E) -1- (3-cyclooctyl-3-carbamoyl-3-phenylpropyl) -3-cinnamyl-2-methylimidazolium bromide, or (E) -1- [2- (α-carbamoylbenzhydryl) Oxy) ethyl] -3-cinnamyl-2-methylimidazolium bromide,
The imidazolium derivative according to any one of 1) to 3) above,
7) A muscarinic M3 receptor antagonist comprising the imidazolium derivative according to any one of 1) to 6) as an active ingredient,
8) From the group consisting of chronic bronchial asthma, chronic obstructive pulmonary disease (COPD), asthma, chronic airway obstruction, pulmonary fibrosis, emphysema, diffuse panbronchiolitis, bronchiectasis, idiopathic interstitial pneumonia and rhinitis A preventive or therapeutic agent for a selected disease, comprising the imidazolium derivative according to any one of 1) to 6) as an active ingredient,
9) From the group consisting of chronic bronchial asthma, chronic obstructive pulmonary disease (COPD), asthma, chronic airway obstruction, pulmonary fibrosis, emphysema, diffuse panbronchiolitis, bronchiectasis, idiopathic interstitial pneumonia and rhinitis A method for the treatment or prevention of a selected disease, which comprises administering the imidazolium derivative according to any one of 1) to 6) above,
10) From the group consisting of chronic bronchial asthma, chronic obstructive pulmonary disease (COPD), asthma, chronic airway obstruction, pulmonary fibrosis, emphysema, diffuse panbronchiolitis, bronchiectasis, idiopathic interstitial pneumonia and rhinitis Use of the imidazolium derivative according to any one of the above 1) to 6) for producing a medicament for treatment or prevention of a selected disease,
11) A pharmaceutical composition comprising the imidazolium derivative according to any one of 1) to 6) as an active ingredient,
12) A pharmaceutical composition comprising the imidazolium derivative according to any one of 1) to 6) above and a pharmaceutically acceptable carrier, and 13) chronic bronchial asthma, chronic obstructive pulmonary disease (COPD), 1-6 for the treatment or prevention of a disease selected from the group consisting of asthma, chronic airway obstruction, pulmonary fibrosis, emphysema, diffuse panbronchiolitis, bronchiectasis, idiopathic interstitial pneumonia and rhinitis The imidazolium derivative according to any one of
It is about.

According to 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. . As a result, it is useful as a therapeutic agent for respiratory diseases involving the effective and safe muscarinic M3 receptor. In particular, 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.

The graph which shows the result of the affinity test 20 hours after in a human muscarinic (M3) receptor. The graph which shows the effect 24 hours after administration with respect to acetylcholine induction airway contraction in a guinea pig.

The meanings of terms used in the present specification are described below, and the present invention is described in more detail.
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. Specifically, a 2-furyl group, a 3-furyl group, a 2-thienyl group, 3-thienyl group, 3-pyrazolyl group, 4-pyrazolyl group, 2-imidazolyl group, 4-imidazolyl group, 2-oxazolyl group, 4-oxazolyl group, 5-oxazolyl group, 2-thiazolyl group, 4-thiazolyl group, 5-thiazolyl group, 3-isoxazolyl group, 4-isoxazolyl group, 5-isoxazolyl group, 3-isothiazolyl group, 4-isothiazolyl group, 5-isothiazolyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-pyrimidinyl group, 4-pyrimidinyl group, 5-pyrimidinyl group, 3-pyridazinyl group, 4-pyridazinyl group, 2-pyrazinyl group, 2-I Drill group, 3-indolyl group, 2-benzoxazolyl group, 2-benzothiazolyl group, 2-benzofuranyl group, 3-benzofuranyl group, 2-benzo [b] thienyl group, 3-benzo [b] thienyl group, 2 -Benzimidazolyl group, 2-quinolyl group, 3-quinolyl group, 4-quinolyl group, 1-isoquinolyl group, 3-isoquinolyl group, 4-isoquinolyl group, 2-quinazolinyl group, 3-quinazolinyl group, 2-quinoxalinyl group, Examples include imidazopyridyl group, pyrazolopyridyl group, imidazopyrimidinyl group and the like.
Here, as a hetero atom, elements, such as oxygen, sulfur, and nitrogen, can be mentioned suitably, for example.

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. For example, 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. Here, 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.
In addition, 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.

According to the present invention, the compound represented by the general formula (1) can be produced, for example, by the route shown below.
<Synthesis route A>

[Where
Y represents a leaving group, and R ¹ , R ² , R ³ , R ⁴ , A and Y ⁻ are as described above. ]

Here, 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. Groups and the like. Here, 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. In addition, preferable examples of the 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.
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.
In 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>

[Where
X ¹ and X ² represent a leaving group,
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), and R ¹ , R ² , R ³ and n are as described above. ]

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.

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.
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.

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.
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) (step B-7) 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) (Step B-8) 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.
Among the compounds represented by the general formula (2), A is

[Wherein n is as described above. ]
The compound represented by the general formula (2b) can be produced by the following route, for example.
<Synthesis route D>

[Where
X represents a halogen atom, and R ¹ , R ² , R ³ , R ⁵ , and n are as described above. ]
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. to 100 ° C., for example, for 0.1 to 100 hours.
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.

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. Among them, 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.

In addition, 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. For example, 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. And 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. For example, the reaction can be performed at −15 to 80 ° C., for example, for 0.1 to 100 hours.

The present invention will be described in more detail with reference examples and examples below, but the scope of the present invention is not limited to these reference examples and examples.
<Reference Example 1>
5-Bromo-2,2-diphenylpentanenitrile

Under an argon atmosphere, a DMF (20 mL) solution of diphenylacetonitrile (5.00 g, 25.9 mmol) was added to a DMF (30 mL) solution of sodium hydride (1.09 g, 27.2 mmol) under ice-cooling and stirring. After stirring for 2 hours, 1,3-dibromopropane (7.96 mL, 77.7 mmol) was added and stirred for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate, and the extract was washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give 5.79 g of the title compound as a white solid.
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.97-2.02 (2H, m), 2.54-2.59 (2H, m), 3.442H, t, J = 6.1 Hz), 7.28-7.33 (2H, m), 7.34-27.41 (8H, m).

<Reference Example 2>
5- (2-Methyl-1H-imidazol-1-yl) -2,2-diphenylpentanenitrile

Under an argon atmosphere, 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. After evaporating the solvent of the extract under reduced pressure, the residue was washed with ethyl acetate-hexane to give 4.16 g of the title compound as a white solid.
¹ H NMR (CDCl ₃ , 400 MHz): δ1.85-1.92 (2H, m), 2.30 (3H, s), 2.32-2.36 (2H, m), 3.89 (2H, t, J = 6.7 Hz), 6.75 (1H, d, J = 1.2 Hz), 6.92 (1H, d, J = 1.2 Hz), 7.28-7.38 (10H, m).

<Reference Example 3>
5- (2-Methyl-1H-imidazol-1-yl) -2,2-diphenylpentanamide

A mixture of the compound of Reference Example 2 (500 mg, 1.59 mmol) and 70% sulfuric acid (20 mL) was heated at 110 ° C. and stirred for 2 hours. Ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent of the extract under reduced pressure, the residue was washed with ethyl acetate to obtain 511 mg of the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 400 MHz): δ1.27-1.35 (2H, m), 2.10 (3H, s), 2.23-2.27 (2H, m), 3.76 (2H, t, J = 7.3 Hz) , 6.65 (1H, d, J = 1.2 Hz), 6.86 (1H, d, J = 1.2 Hz), 7.15 (1H, br s), 7.19-7.24 (6H, m), 7.27-7.31 (4H, m) .

<Reference Example 4>
3- (2-Methyl-1H-imidazol-1-yl) -1,1-di (thiophen-2-yl) propanol

1 mol / L 2-thienyllithium-THF solution (45 mL, 45.0 mmol) in methyl 3- (2-methylimidazol-1-yl) propionate (2.52 g, 15.0 mmol) at -50 ° C under argon atmosphere A THF (40 mL) solution was added dropwise. The mixture was stirred at -50 ° C for 2 hours. Water (40 mL) and hexane (40 mL) were added to the reaction mixture, and the precipitated crystals were collected by filtration and purified by recrystallization (chloroform-hexane) to give 2.30 g of the title compound as a pale yellow solid.
¹ H-NMR (400Mz, CDCl ₃ ): δ2.28 (3H, s), 2.65-2.74 (2H, m), 3.90-3.98 (2H, m), 6.77 (1H, s), 6.86 (1H, s ), 7.05-6.95 (4H, m), 7.29 (2H, dd, J = 4.9, 1.2 Hz).
EIMS (+): 304 [M +] ⁺

<Reference Example 5>
4- (2-Methyl-1H-imidazol-1-yl) -2,2-di (thiophen-2-yl) butanenitrile

Aluminum chloride (4.16 g, 31.2 mmol) was added to a solution of the compound of Reference Example 4 (1.90 g, 6.24 mmol) in dichloroethane (100 mL), and the mixture was stirred at room temperature for 10 minutes. Trimethylsilylcyanide (3.91 mL, 31.5 mmol) was added and heated to reflux for 8 hours. The reaction mixture was allowed to cool and then added to a saturated aqueous potassium carbonate solution, insolubles were filtered through celite, and the filtrate was extracted with ethyl acetate (300 mL). The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent of the extract under reduced pressure, the residue was purified by chromatolex NH silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 3: 1 → 1: 1 → 1: 3) to give the title compound 813. mg was obtained as a brown solid.
¹ H-NMR (400Mz, CDCl ₃ ): δ2.33 (3H, s), 2.76-2.85 (2H, m), 3.96-4.05 (2H, m), 6.80 (1H, d, J = 1.2 Hz), 6.92 (1H, d, J = 1.2 Hz), 7.02 (2H, dd, J = 4.9, 3.7 Hz), 7.23 (2H, d, J = 3.7 Hz), 7.37 (2H, dd, J = 4.9, 1.2 Hz) ).
EIMS (+): 313 [M +] ⁺

<Reference Example 6>
4- (2-Methyl-1H-imidazol-1-yl) -2,2-di (thiophen-2-yl) butanamide

To a solution of the compound of Reference Example 5 (400 mg, 1.28 mmol) in t-butanol (15 mL) was added potassium hydroxide (71.6 mg, 1.28 mmol), and the mixture was heated to reflux for 3 hours. The solvent of the reaction solution was evaporated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate (100 mL). The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent of the extract under reduced pressure, the residue was purified by chromatolex NH silica gel column chromatography (hexane: ethyl acetate = 1: 1 → 2: 3 → 1: 2) to give 436 mg of the title compound as a white color. Obtained as a solid.
¹ H-NMR (400Mz, CDCl ₃ ): δ 2.28 (3H, s), 2.70-2.78 (2H, m), 3.87-3.96 (2H, m), 5.55 (1H, br s), 5.73 (1H, br s), 6.77 (1H, s), 6.87 (1H, s), 7.03 (2H, dd, J = 4.9, 3.7 Hz), 7.12 (2H, d, J = 3.7 Hz), 7.36 (2H, d, J = 4.9 Hz).
ESIMS (+): 332 [M + H] ⁺

<Reference Example 7>
(E) -Ethyl 3-cyclopropyl acrylate

Under argon gas atmosphere, a solution of sodium hydride (3.14 g, 78.5 mmol) in tetrahydrofuran (72 mL) and a solution of ethyl diethylphosphonoacetate (15.6 mL, 78.5 mmol) in tetrahydrofuran (12 mL) under ice-cooling And stirred at the same temperature for 40 minutes. After raising the temperature to room temperature, a solution of cyclopropanecarboxaldehyde (5.00 g, 71.3 mmol) in tetrahydrofuran (6.00 mL) was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent of the extract was distilled off under reduced pressure, and the resulting residue was distilled (b. P. 89-90 ° C./15 mmHg) to give 6.21 g of the title compound as a colorless oil.
¹ H NMR (CDCl _3, 400 MHz): δ 0.64 (2H, dt, J = 8.4, 3.4 Hz), 0.94 (2H, dt, J = 8.6, 3.4 Hz), 1.28 (3H, t, J = 7.3 Hz), 1.53-1.61 (1H, m), 4.17 (2H, q, J = 7.3 Hz), 5.89 (1H, d, J = 15.3 Hz), 6.42 (1H, dt, J = 15.3, 10.1 Hz).

<Reference Example 8>
(E) -3-Cyclopropyl-2-propenol

Dissolve the compound of Reference Example 7 (5.34 g, 27.2 mmol) in methylene chloride (68.1 mL) and add 1.02 mol / L lithium diisobutylaluminum hydride-hexane solution (58.8 mL, 60.0 mmol) at -78 ° C. It was. After stirring at the same temperature for 3 hours, a saturated aqueous Rochelle salt solution was added, the temperature was raised to room temperature, and extraction was performed with methylene chloride. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent of the extract was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 4.67 g of the title compound as a colorless oil.
¹ H NMR (CDCl _3, 400 MHz): δ0.64 (2H, dt, J = 6.7, 4.3 Hz), 0.94 (2H, dt, J = 8.0, 4.3 Hz), 1.24-1.27 (1H, m), 1.36-1.45 (1H, m), 4.07 (2H, d, J = 6.1 Hz), 5.22 (1H, dd, J = 15.3, 6.7 Hz), 5.72 (1H, dt, J = 15.3, 6.1 Hz).

<Reference Example 9>
(E) -3- (thiazol-2-yl) -2-propenol

(E) -Ethyl 3- (thiazol-2-yl) acrylate (1.24 g, 6.77 mmol) was used and 483 mg of the title compound was obtained in the same manner as in Reference Example 8.
¹ H NMR (CDCl ₃ , 400 MHz): δ 2.29 (1H, br s), 4.37 (2H, q, J = 2.0 Hz), 6.70 (1H, dt, J = 5.3, 4.8 Hz), 6.89-6.94 ( 1H, m), 7.23 (1H, d, J = 3.0 Hz), 7.75 (1H, d, J = 3.0 Hz).

<Reference Example 10>
2-cyclooctyl-2-phenylacetonitrile

A mixture of phenylacetonitrile (1.00 g, 8.54 mmol), cyclooctyl bromide (2.45 g, 12.8 mmol) and n-tetrabutylammonium bromide (27.5 mg, 0.0854 mmol) in 60% aqueous potassium hydroxide solution (7.99 mL, 85.4 mmol) Was added dropwise (at 50 ° C. or lower) and stirred at 70 ° C. for 12 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (200 mL). The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent of the extract under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 1 → 80: 1 → 50: 1) to give 620 mg of the title compound as a pale yellow oil. Obtained.
¹ H-NMR (400Mz, CDCl ₃ ): δ1.28-1.86 (21H, m), 2.00-2.12 (1H, m), 3.68 (1H, d, J = 6.7 Hz), 7.28-7.34 (3H, m ), 7.42-7.34 (2H, m).

<Reference Example 11>
4-Bromo-2-cyclooctyl-2-phenylbutanenitrile

To a THF (5 mL) solution of the compound of Reference Example 11 (120 mg, 0.528 mmol), 1 mol / L LIHMDS (792 μL, 0.792 mmol) was added dropwise at −78 ° C. in an argon atmosphere. After stirring at 0 ° C. for 10 minutes, a solution of dibromoethane (298 mg, 1.58 mmol) in THF (1.5 mL) was added dropwise at −78 ° C. After stirring at −78 ° C. for 30 minutes and at 0 ° C. for 2 hours, a saturated aqueous ammonium chloride solution was added. The reaction solution was extracted with ethyl acetate (50 mL). The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent of the extract under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 1 → 80: 1 → 50: 1) to give 156 mg of the title compound as a colorless oil. It was.
¹ H-NMR (400Mz, CDCl ₃ ): δ1.00-1.16 (1H, m), 1.17-1.73 (15H, m), 1.75-1.88 (1H, m), 1.88-1.99 (1H, m), 2.06 -2.15 (1H, m), 2.30-2.41 (1H, m), 2.70-2.83 (2H, m), 3.26-3.36 (1H, m), 7.48-7.28 (5H, m).

<Reference Example 12>
2-Cyclooctyl-4- (2-methyl-1H-imidazol-1-yl) -2-phenylbutanenitrile

To a solution of the compound of Reference Example 11 (730 mg, 2.18 mmol) in DMSO (30 mL) was added 2-methylimidazole (1.79 g, 21.8 mmol), and the mixture was heated with stirring at 100 ° C. for 8 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL). The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent of the extract under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 → ethyl acetate) to obtain 531 mg of the title compound as a colorless solid.
¹ H-NMR (400Mz, CDCl ₃ ): δ1.01-1.15 (1H, m), 1.18-1.75 (13H, m), 1.75-1.96 (2H, m), 2.06-2.19 (2H, m), 2.19 (3H, s), 2.54 (1H, ddd, J = 13.4, 12.2, 4.9 Hz), 3.33 (1H, ddd, J = 14.1, 12.2, 4.9 Hz), 3.86 (1H, ddd, J = 14.1, 12.2, 4.3 Hz), 6.69 (1H, d, J = 1.2 Hz), 6.87 (1H, d, J = 1.2 Hz), 7.35-7.42 (1H, m), 7.50-7.43 (4H, m).
ESIMS (+): 336 [M + H] ⁺

<Reference Example 13>
2-Cyclooctyl-4- (2-methyl-1H-imidazol-1-yl) -2-phenylbutanamide

70% sulfuric acid (10 mL) of the compound of Reference Example 12 (380 mg, 1.13 mmol) was stirred at 130 ° C. for 6 hours. The reaction solution was poured into ice and neutralized with sodium hydroxide and saturated aqueous sodium hydrogen carbonate solution. The reaction solution was extracted with ethyl acetate (150 mL). The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent of the extract under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give 354 mg of the title compound as a colorless amorphous product.
¹ H-NMR (400Mz, CDCl ₃ ): δ1.15-2.01 (21H, m), 2.20 (3H, s), 2.29-2.39 (1H, m), 2.62 (1H, td, J = 12.2, 4.9 Hz ), 3.23-3.37 (1H, m), 3.92 (1H, td, J = 12.2, 4.9 Hz), 5.45 (1H, br s), 5.55 (1H, br s), 6.69 (1H, s), 6.84 ( 1H, s), 7.29-7.38 (3H, m), 7.45-7.37 (2H, m).
ESIMS (+): 354 [M + H] ⁺

<Reference Example 14>
Methyl 2- [2- (2-methyl-1H-imidazol-1-yl) ethoxy] -2,2-diphenylacetate

Under an argon atmosphere, 2- (2-methyl-1H-imidazol-1-yl) ethanol (916 mg, 7.26 mmol) in dichloromethane (13 mL) was added to silver trifluoromethanesulfonate (2.24 g, 8.71 mmol), 2, 6-Di-tert-butylpyridine (2.39 mL, 10.9 mmol) was added under ice-cooling, and then methyl 2-chloro-2,2-diphenylacetate (2.08 g, 7.99 mmol) in dichloromethane (3 mL) was added. The mixture was stirred at room temperature for 16 hours. The reaction solution was filtered through celite, saturated aqueous sodium hydrogen carbonate solution was added to the filtrate, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to obtain 1.75 g of the title compound as a colorless amorphous.
¹ H NMR (CDCl ₃ , 400 MHz): δ 2.30 (3H, s), 3.53 (2H, t, J = 6.0 Hz), 3.72 (3H, s), 4.00 (2H, t, J = 6.0 Hz), 6.81 (1H, d, J = 1.2 Hz), 6.87 (1H, d, J = 1.2 Hz), 7.26-7.32 (10H, m).
ESIMS (+): 351 [M + H] ⁺ .

<Reference Example 15>
2- [2- (2-Methyl-1H-imidazol-1-yl) ethoxy] -2,2-diphenylacetic acid

To a solution of the compound of Reference Example 14 (1.47 g, 4.20 mmol) in ethanol (29.4 mL) was added 2 mol / L aqueous potassium hydroxide (472 mg, 8.41 mmol), and the mixture was heated and stirred at 80 ° C. for 4.5 hours. After cooling, the pH was adjusted to 5 with dilute hydrochloric acid, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.24 g of the title compound.
¹ H NMR (CDCl ₃ , 400 MHz): δ2.66 (3H, s), 3.52 (2H, t, J = 4.9 Hz), 4.27 (2H, t, J = 4.9 Hz), 7.22-7.23 (4H, m), 7.32-7.33 (6H, m), 7.44 (1H, m), 7.52 (1H, m), 13.8 (1H, brs).

<Reference Example 16>
2- [2- (2-Methyl-1H-imidazol-1-yl) ethoxy] -2,2-diphenylacetamide

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. After the solvent was distilled off under reduced pressure, the residue was purified by NH silica gel column chromatography (ethyl acetate: methanol = 5: 1) to obtain 718 mg of the title compound as a colorless amorphous.
¹ H NMR (CDCl ₃ , 400 MHz): δ 2.37 (3H, s), 3.36 (2H, t, J = 5.2 Hz), 3.99 (2H, t, J = 5.2 Hz), 5.21 (1H, s) , 6.20 (1H, s), 6.91 (1H, d, J = 1.2 Hz), 6.96 (1H, d, J = 1.2 Hz), 7.32-7.39 (10H, m).
ESIMS (+): 336 [M + H] ⁺ .

<Example 1>
(E) -1- (3-carbamoyl-3,3-diphenylpropyl) -3-cinnamyl-2-methylimidazolium bromide

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.
¹ H NMR (DMSO-d ₆ , 400 MHz): δ2.44 (3H, s), 2.72-2.82 (2H, m), 3.76-3.87 (2H, m), 4.90 (2H, d, J = 6.7 Hz) , 6.37 (1H, dt, J = 15.9, 6.7 Hz), 6.62 (1H, d, J = 15.9 Hz), 6.78 (1H, br s), 7.41-7.25 (13H, m), 7.44 (3H, d, J = 7.3 Hz), 7.62 (2H, t, J = 6.7 Hz).
ESI (+) MS: 436 [M-Br] ⁺ .

<Example 2>
(E) -1- (3-carbamoyl-3,3-diphenylpropyl) -3- (2-methoxycinnamyl) -2-methylimidazolium bromide

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.
¹ H NMR (DMSO-d ₆ , 400 MHz): δ2.44 (3H, s), 2.74-2.78 (2H, m), 3.79 (3H, s), 3.80-3.84 (2H, m), 4.90 (2H, d, J = 6.7 Hz), 6.33 (1H, dt, J = 15.9, 6.7 Hz), 6.78 (1H, s), 6.88-6.94 (2H, m), 7.02 (1H, d, J = 7.9 Hz), 7.26-7.39 (1H, m), 7.45 (1H, s), 7.47 (1H, dd, J = 7.9, 1.5 Hz), 7.59 (1H, d, J = 2.4 Hz), 7.63 (1H, d, J = 2.4 Hz).
ESIMS (+): 466 [M-Br] ⁺ .

<Example 3>
(E) -1- (3-carbamoyl-3,3-diphenylpropyl) -3- (3-methoxycinnamyl) -2-methylimidazolium bromide

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.
¹ H NMR (DMSO-d ₆ , 400 MHz): δ2.44 (3H, s), 2.75-2.79 (2H, m), 3.74 (3H, s), 3.77-3.84 (2H, m), 4.89 (2H, d, J = 5.5 Hz), 6.39 (1H, dt, J = 15.9, 6.1 Hz), 6.58 (1H, d, J = 15.9 Hz), 6.78 (1H, s), 6.84-6.87 (1H, m), 7.01 (2H, t, J = 4.3 Hz), 7.24-7.39 (11H, m), 7.45 (1H, s), 7.62 (2H, dd, J = 11.0, 1.8 Hz).
ESIMS (+) 466 [M-Br] ⁺ .

<Example 4>
(E) -1- (3-carbamoyl-3,3-diphenylpropyl) -3- (4-methoxycinnamyl) -2-methylimidazolium bromide

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.
¹ H NMR (DMSO-d ₆ , 400 MHz): δ2.44 (3H, s), 2.75-2.79 (2H, m), 3.74 (3H, s), 3.79-3.83 (2H, m), 4.85 (2H, d, J = 6.1 Hz), 6.21 (1H, dt, J = 15.9, 6.1 Hz), 6.59 (1H, d, J = 15.9 Hz), 6.77 (1H, s), 6.91 (2H, dt, J = 9.2 , 2.4 Hz), 7.27-7.40 (12H, m), 7.45 (1H, s), 7.59 (1H, d, J = 2.4 Hz), 7.62 (1H, d, J = 2.4 Hz).
ESIMS (+) 466 [M-Br] ⁺ .

<Example 5>
(E) -1- (3-carbamoyl-3,3-diphenylpropyl) -3- (2-chlorocinnamyl) -2-methylimidazolium bromide

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.
¹ H NMR (DMSO-d ₆ , 400 MHz): δ2.46 (3H, s), 2.76-2.77 (2H, m), 3.81-3.84 (2H, m), 4.98 (2H, d, J = 5.5 Hz) , 6.43 (1H, dt, J = 15.9, 5.5 Hz), 6.79 (1H, s), 6.91 (2H, d, J = 15.9 Hz), 7.28-7.39 (13H, m), 7.45-7.48 (2H, m ), 7.61 (1H, d, J = 2.4 Hz), 7.66 (1H, d, J = 2.4 Hz), 7.68-7.70 (1H, m).
ESIMS (+): 470 [M-Br] ⁺ .

<Example 6>
(E) -1- (3-carbamoyl-3,3-diphenylpropyl) -3- (3-chlorocinnamyl) -2-methylimidazolium bromide

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.
¹ H NMR (DMSO-d ₆ , 400 MHz): δ2.44 (3H, s), 2.75-2.79 (2H, m), 3.79-3.83 (2H, m), 4.91 (2H, d, J = 4.9 Hz) , 6.48 (1H, dt, J = 15.9, 4.9 Hz), 6.56 (1H, d, J = 15.9 Hz), 6.78 (1H, s), 7.31-7.39 (13H, m), 7.45 (1H, s), 7.55 (1H, s), 7.62 (1H, d, J = 1.8 Hz), 7.64 (1H, d, J = 1.8 Hz).
HRESIMS (+): 470.2000 (calculated as C ₂₉ H ₂₉ ClN ₃ O 470.1999).

<Example 7>
(E) -1- (3-carbamoyl-3,3-diphenylpropyl) -3- (4-chlorocinnamyl) -2-methylimidazolium bromide

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.
¹ H NMR (DMSO-d ₆ , 400 MHz): δ2.44 (3H, s), 2.75-2.79 (2H, m), 3.79-3.83 (2H, m), 4.90 (2H, d, J = 6.1 Hz) , 6.41 (1H, dt, J = 15.9, 6.1 Hz), 6.60 (2H, d, J = 15.9), 6.78 (1H, s), 7.28-7.49 (14H, m), 7.61 (1H, d, J = 1.8 Hz), 7.64 (1H, d, J = 1.8 Hz).
HRESIMS (+): 470.1997 (calculated as C ₂₉ H ₂₉ ClN ₃ O 470.1999).

<Example 8>
(E) -1- (3-carbamoyl-3,3-diphenylpropyl) -3- (2-nitrocinnamyl) -2-methylimidazolium bromide

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.
¹ H NMR (DMSO-d ₆ , 400 MHz): δ 2.45 (3H, s), 2.72-2.82 (2H, m), 3.77-3.88 (2H, m), 4.99 (2H, d, J = 5.5 Hz) , 6.42 (1H, dt, J = 15.9, 6.1 Hz), 6.78 (1H, s), 6.82 (1H, d, J = 15.9 Hz), 7.27-7.42 (10H, m), 7.45 (1H, s), 7.53-7.59 (1H, m), 7.63 (2H, dd, J = 9.8, 2.4 Hz), 7.79-7.69 (2H, m), 7.99 (1H, d, J = 7.9 Hz).
ESIMS (+): 481 [M-Br] ⁺

<Example 9>
(E) -1- (3-carbamoyl-3,3-diphenylpropyl) -3- (3-nitrocinnamyl) -2-methylimidazolium bromide

Example 1 and 4- (2-methyl-1H-imidazol-1-yl) -2,2-diphenylbutanamide (127 mg, 0.397) and 3-nitrocinnamyl bromide (960 mg, 3.97 mmmol) The same treatment was performed to obtain 191 mg of the title compound as a white solid as a colorless powder.
¹ H NMR (DMSO-d ₆ , 400 MHz): δ2.44 (3H, s), 2.73-2.83 (2H, m), 3.76-3.88 (2H, m), 4.95 (2H, d, J = 4.3 Hz) , 6.59-6.73 (2H, m), 6.78 (1H, s), 7.26-7.41 (10H, m), 7.46 (1H, s), 7.69-7.60 (3H, m), 7.92 (1H, d, J = 7.9 Hz), 8.13 (1H, dd, J = 7.9, 1.2 Hz), 8.28 (1H, s).
ESIMS (+): 481 [M-Br] ⁺

<Example 10>
(E) -1- (3-carbamoyl-3,3-diphenylpropyl) -3- (4-nitrocinnamyl) -2-methylimidazolium bromide

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.
¹ H NMR (DMSO-d ₆ , 400 MHz): δ2.44 (3H, s), 2.73-2.83 (2H, m), 3.77-3.87 (2H, m), 4.97 (2H, d, J = 3.7 Hz) , 6.62-6.73 (2H, m), 6.78 (1H, br s), 7.26-7.41 (10H, m), 7.46 (1H, br s), 7.64 (2H, dd, J = 9.2, 1.8 Hz), 7.72 (2H, d, J = 8.6 Hz), 8.21 (2H, d, J = 8.6 Hz).
ESIMS (+): 481 [M-Br] ⁺

<Example 11>
(E) -1- [3-carbamoyl-3,3-di (thiophen-2-yl) propyl] -3-cinnamyl-2-methylimidazolium bromide

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. .
¹ H-NMR (400Mz, DMSO-d ₆ ): δ 2.49 (3H, s), 2.81-2.90 (2H, m), 3.92-4.01 (2H, m), 4.91 (2H, d, J = 6.1 Hz ), 6.38 (1H, dt, J = 15.9, 6.1 Hz), 6.64 (1H, d, J = 15.9 Hz), 7.01 (2H, dd, J = 5.5, 3.7 Hz), 7.13 (2H, d, J = 3.7 Hz), 7.23 (1H, br s), 7.25-7.31 (1H, m), 7.35 (2H, t, J = 7.3 Hz), 7.45 (2H, d, J = 7.3 Hz), 7.49 (2H, d , J = 5.5 Hz), 7.68-7.59 (3H, m).
ESIMS (+): 448 [M-Br] ⁺

<Example 12>
(E) -1- (3-carbamoyl-3,3-diphenylpropyl) -3- (3-cyclohexylallyl) -2-methylimidazolium bromide

4- (2-Methyl-1H-imidazol-1-yl) -2,2-diphenylbutanamide (400 mg, 1.25 mmol) and (E) -3-bromo-1-propenylcyclohexane (2.54 g, 12.5 mmol) Was used in the same manner as in Example 1 to obtain 584 mg of the title compound as a white solid as a colorless powder.
¹ H NMR (DMSO-d ₆ , 400 MHz): δ0.92-1.21 (5H, m), 1.60 (4H, d, J = 11.0 Hz), 1.90-1.92 (1H, m), 2.32 (3H, s) , 2.70-2.71 (2H, m), 3.71-3.75 (2H, m), 4.59 (2H, d, J = 6.1 Hz), 5.42 (1H, ddt, J = 16.4, 7.8, 3.3 Hz), 5.64 (1H , dd, J = 16.0, 6.7 Hz), 6.72 (1H, br s), 7.23-7.34 (10H, m), 7.39 (1H, br s), 7.43 (1H, d, J = 2.0 Hz), 7.50 ( (1H, d, J = 2.0 Hz).
ESIMS (+): 442 [M-Br] ⁺ .

<Example 13>
(E) -1- (3-carbamoyl-3,3-diphenylpropyl) -3- (3-cyclopropylallyl) -2-methylimidazolium bromide

The compound of Reference Example 8 (2.00 g, 11.9 mmol) and carbon tetrabromide (5.90 g, 17.8 mmol) were dissolved in methylene chloride (60.0 mL), and triphenylphosphine (3.11 g, 14.8 mmol) was cooled with ice. Was added. After stirring at the same temperature for 1 hour, the solvent was distilled off under reduced pressure. Crude (E) -3-cyclopropyl-2-propenyl bromide (2.23 g, 9.50 mmol) and 4- (2-methyl-1H-imidazol-1-yl) obtained by washing the residue with hexane -2,2-Diphenylbutanamide (424 mg, 1.33 mmol) was treated in the same manner as in Example 1, and recrystallized from acetonitrile to obtain 320 mg of the title compound as a white solid.
¹ H NMR (DMSO-d _6, 400 MHz): δ0.01 (2H, dt, J = 5.5, 4.3 Hz), 0.34 (2H, dt, J = 12.2, 4.3 Hz), 1.04-1.07 (1H, m ), 2.01 (3H, s), 2.36-2.40 (2H, m), 3.40-3.44 (2H, m), 4.246 (2H, d, J = 6.7 Hz), 4.94 (1H, dd, J = 15.3, 9.2 Hz), 5.22 (1H, dt, J = 15.3, 6.7 Hz), 6.41 (1H, s), 6.94-7.00 (10H, m), 7.08 (1H, s), 7.17 (1H, d, J = 2.4 Hz ), 7.19 (1H, d, J = 2.4 Hz).
HRESIMS (+): 400.2394 (calculated as C ₂₆ H ₃₀ N ₃ O 400.2389).

<Example 14>
(E) -1- (3-carbamoyl-3,3-diphenylpropyl) -2-methyl-3- [3- (thiophen-2-yl) allyl] imidazolium bromide

(E) -3- (Thiophen-2-yl) -2-propenol (442 mg, 3.15 mmol) and carbon tetrabromide (5.90 g, 17.8 mmol) were dissolved in methylene chloride (60 mL), and cooled with ice. Triphenylphosphine (3.11 g, 14.8 mmol) was added. After stirring at the same temperature for 1 hour, the solvent was distilled off under reduced pressure. The obtained residue was washed with hexane to obtain crude (E) -3-cyclopropyl-2-propenyl bromide (2.23 g, 9.50 mmol).
Crude (E) -3-cyclopropyl-2-propenyl bromide (2.23 g, 9.50 mmol) and 4- (2-methyl-1H-imidazol-1-yl) -2,2-diphenylbutanamide (424 mg, 1.33 mmol) was used in the same manner as in Example 1, and recrystallization from ethanol gave 82.2 mg of the title compound as a white solid.
¹ H NMR (DMSO-d _6, 400 MHz): δ2.43 (3H, s), 2.77-2.78 (2H, m), 3.79-3.82 (2H, m), 4.85 (2H, d, J = 5.5 Hz ), 6.08 (1H, dt, J = 15.9, 5.5 Hz), 6.77 (1H, s), 6.84 (1H, d, J = 15.9 Hz), 7.03 (1H, dd, J = 4.9, 3.1 Hz), 7.13 (1H, d, J = 3.1 Hz), 7.28-7.39 (10H, m), 7.44 (1H, s), 7.47 (1H, d, J = 4.9 Hz), 7.60 (1H, d, J = 1.8 Hz) , 7.62 (1H, d, J = 1.8 Hz).
HRESIMS (+): 442.1959 (calculated as C ₂₇ H ₂₈ N ₃ OS 442.1951).

<Example 15>
(E) -1- (3-carbamoyl-3,3-diphenylpropyl) -2-methyl-3- [3- (thiazol-2-yl) allyl] imidazolium bromide

(E) -3- (Thiazol-2-yl) -2-propenol (439 mg, 3.11 mmol) Carbon tetrabromide (1.29 g, 3.89 mmol) was dissolved in methylene chloride (15.6 mL) and the mixture was cooled with ice. Triphenylphosphine (1.02 g, 3.89 mmol) was added. After stirring at the same temperature for 1 hour, the solvent was distilled off under reduced pressure. Crude (E) -3- (thiazol-2-yl) -2-propenyl bromide (490 mg, 2.40 mmol) and 4- (2-methyl-1H-imidazole) obtained by washing the residue with hexane The title compound (281 mg) was obtained as a white solid by treating in the same manner as in Example 1 using -1-yl) -2,2-diphenylbutanamide (767 mg, 2.40 mmol).
¹ H NMR (DMSO-d _6, 400 MHz): δ2.43 (3H, s), 2.76-2.80 (2H, m), 3.79-3.83 (2H, m), 4.96 (2H, d, J = 5.5 Hz ), 6.64 (1H, dt, J = 15.9, 5.5 Hz), 6.78 (1H, s), 6.83 (1H, d, J = 15.9 Hz), 7.28-7.39 (10H, m), 7.45 (1H, br s ), 7.62 (1H, d, J = 1.8 Hz), 7.65 (1H, d, J = 1.8 Hz), 7.71 (1H, d, J = 3.1 Hz), 7.83 (1H, d, J = 3.1 Hz).
ESIMS (+): 443 [M-Br] ⁺ .

<Example 16>
(E) -1- (4-Carbamoyl-4,4-diphenylbutyl) -3-cinnamyl-2-methylimidazolium bromide

The title compound (143 mg) was obtained as a colorless powder by treating in the same manner as in Example 1 using the compound of Reference Example 3 (200 mg, 0.600 mmol) and cinnamyl bromide (236 mg, 1.20 mmol).
¹ H NMR (DMSO-d ₆ , 400 MHz): δ1.41-1.48 (2H, m), 2.27-2.32 (2H, m), 2.51 (3H, s), 4.08 (2H, t, J = 7.0 Hz) , 4.91 (2H, d, J = 6.1 Hz), 6.40 (1H, dt, J = 15.9, 6.1 Hz), 6.60 (1H, d, J = 15.9 Hz), 6.85 (1H, s), 7.20-7.36 ( 14H, m), 7.42 (1H, s), 7.44 (1H, d, J = 1.8 Hz), 7.62 (1H, d, J = 1.8 Hz), 7.65 (1H, d, J = 1.8 Hz).
ESIMS (+): 450 [M-Br] ⁺

<Example 17>
(E) -1- (3-Cyclooctyl-3-carbamoyl-3-phenylpropyl) -3-cinnamyl-2-methylimidazolium bromide

The title compound (132 mg) was obtained as a white solid by treating in the same manner as in Example 1 using the compound of Reference Example 13 (100 mg, 0.283 mmol) and cinnamyl bromide (279 mg, 1.41 mmol).
¹ H-NMR (400Mz, DMSO-d ₆ ): δ1.07-1.26 (2H, m), 1.28-1.80 (13H, m), 2.17-2.30 (1H, m), 2.29-2.40 (1H, m) , 3.29 (3H, s), 3.60-3.74 (1H, m), 3.95-4.08 (1H, m), 4.92 (2H, d, J = 6.1 Hz), 6.39 (1H, dt, J = 15.9, 6.1 Hz ), 6.64 (1H, d, J = 15.9 Hz), 6.86 (1H, br s), 7.22-7.32 (3H, m), 7.32-7.40 (6H, m), 7.45 (2H, d, J = 7.9 Hz ), 7.65 (2H, dd, J = 7.9, 1.8 Hz).
ESIMS (+): 470 [M-Br] ⁺

<Example 18>
(E) -1- [2- (α-carbamoylbenzhydryloxy) ethyl] -3-cinnamyl-2-methylimidazolium bromide

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.
¹ H NMR (DMSO-d ₆ , 400 MHz): δ2.53 (3H, s), 3.28 (2H, s), 3.31 (2H, s), 3.36 (2H, t, J = 4.3 Hz), 4.35 ( 2H, t, J = 4.3 Hz), 4.96 (2H, d, J = 6.7 Hz) 6.40 (1H, dt, J = 15.9, 6.7 Hz), 6.65 (1H, d, J = 15.9 Hz), 7.17-7.20 (4H, m), 7.25-7.36 (9H, m), 7.39-7.42 (2H, m), 7.53 (1H, s), 7.64 (1H, s), 7.68-7.70 (2H, m).
ESIMS (+): 452 [M-Br] ⁺ .

<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 μM atropine sulfate (manufactured by Tokyo Chemical Industry Co., Ltd.) was added. Thereafter, 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 (manufactured by GE Healthcare Science) 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.

From the above results, it was confirmed that 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 μM atropine sulfate (manufactured by Tokyo Chemical Industry Co., Ltd.) was added. Then, collect membrane samples of human muscarinic M2 or M3 receptor on Whatman GF / B filters using a cell harvester and wash 5 times with ice-cold 50 mM Tris-HCl aqueous solution (4 ° C) 5 times. did. A filter and 5 mL of liquid scintillator ACSII (GE Healthcare Science) 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 2. In addition, it shows that it has the outstanding binding affinity, so that the value of Ki value is small.

Comparative compound 1: International Publication No. 2007/013421 Example 43
Comparative Compound 2: International Publication No. 1995/15951 Example 24

From the above results, it was confirmed that the imidazolium derivatives of the present invention are a novel compound group showing excellent selectivity for the muscarinic M3 receptor.

<Test Example 3>
Human muscarinic (M3) receptor 20-hour affinity test 1 μL of test substance dissolved in DMSO (final concentration is IC90 value obtained from binding affinity test) and 2 units of human muscarinic M3 receptor 1 mL of a phosphate buffer containing an expression membrane preparation (GE Healthcare Science) was added and incubated at 25 ° C. for 4 hours.
(Membrane cleaning)
After centrifugation at 13,000 x g, 0.95 mL of the supernatant was discarded, and 0.95 mL of phosphate buffer was added. After centrifugation at 13,000 x g again, the supernatant was discarded, and 0.95 mL of phosphate buffer was added to remove the test substance not bound to the membrane preparation. This washing operation was repeated three times. Phosphate buffer was added to make 1 mL and incubated at 25 ° C. for 16 hours.
(Control)
Incubation was carried out at 25 ° C. for 16 hours without centrifugation.
(Measurement of inhibition rate)

Tracer 0.5 nM [ ³ H] -scopolamine (N-methyl) (Perkin Elma) was added and incubated for 4 hours. For measuring the amount of nonspecific binding radioactivity, 5 μM atropine sulfate (manufactured by Tokyo Chemical Industry Co., Ltd.) was added. Thereafter, 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 (GE Healthcare Science) 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 μM 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.

<Test 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 μL / kg) dissolved in 5% Otsuka sugar solution together with compressed air is jetted and administered intratracheally. The control group received 5% Otsuka sugar solution (200 μL / 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. Air overflowing from the side branch of the tracheal cannula (air flow) was measured using a bronchospasm transducer and output to a computer via Power Lab. ACh 10, 20, 30, and 40 μg / kg were administered every 3 minutes from 6 minutes after the start of measurement.

Data processing method:
Data processing method for evaluation 24 hours after administration of test substance:
% Control = (A-B) / (A ₀ -B ₀ ) x 100

In the above formula, each symbol has the following meaning.
A: Maximum airway contraction when ACh 10, 20, 30 or 40 μg / kg was administered in the test substance administration group
A ₀ : Maximum value of airway contraction when ACh 40 μg / 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

2 that the compound of Example 1 is an M3 inhibitor.

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.

Claims (13)

1. Formula (1),
   

   

   [Where:
   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 the following formula:
   

   

   (Wherein n represents an integer of 1 to 4)]
   An imidazolium derivative represented by:
2. In the general formula (1),
   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 alkylene chain having 1 to 4 carbon atoms, an oxyethylene chain, or an oxypropylene chain.
   The imidazolium derivative according to claim 1.
3. In the general formula (1),
   R ¹ represents a phenyl group, a 2-thienyl group, or a cyclooctyl group,
   R ² represents a phenyl group or a 2-thienyl group,
   R ³ represents a methyl group,
   R ⁴ represents an optionally substituted phenyl group, 2-thienyl group, thiazol-2-yl group, or a cycloalkyl group having 3 to 6 carbon atoms;
   Y ⁻ represents a bromine ion,
   A represents an alkylene chain having 2 to 3 carbon atoms, an oxyethylene chain, or an oxypropylene chain.
   The imidazolium derivative according to claim 1.
4. In the general formula (1),
   R ⁴ represents a chlorine atom, a methoxy group, a phenyl group optionally substituted with a nitro group, a 2-thienyl group, a thiazol-2-yl group, or a cyclohexyl group;
   A represents an ethylene chain,
   The imidazolium derivative according to claim 3.
5. In the general formula (1),
   R ⁴ is a phenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 3-nitrophenyl group, 4-nitrophenyl group, 2-thienyl group Represents a thiazol-2-yl group or a cyclohexyl group,
   The imidazolium derivative according to claim 4.
6. The compound is
   (1) (E) -1- (3-carbamoyl-3,3-diphenylpropyl) -3-cinnamyl-2-methylimidazolium bromide,
   (2) (E) -1- (3-carbamoyl-3,3-diphenylpropyl) -3- (2-methoxycinnamyl) -2-methylimidazolium bromide,
   (3) (E) -1- (3-carbamoyl-3,3-diphenylpropyl) -3- (3-methoxycinnamyl) -2-methylimidazolium bromide,
   (4) (E) -1- (3-carbamoyl-3,3-diphenylpropyl) -3- (4-methoxycinnamyl) -2-methylimidazolium bromide,
   (5) (E) -1- (3-carbamoyl-3,3-diphenylpropyl) -3- (2-chlorocinnamyl) -2-methylimidazolium bromide,
   (6) (E) -1- (3-carbamoyl-3,3-diphenylpropyl) -3- (3-chlorocinnamyl) -2-methylimidazolium bromide,
   (7) (E) -1- (3-carbamoyl-3,3-diphenylpropyl) -3- (4-chlorocinnamyl) -2-methylimidazolium bromide,
   (8) (E) -1- (3-carbamoyl-3,3-diphenylpropyl) -3- (2-nitrocinnamyl) -2-methylimidazolium bromide,
   (9) (E) -1- (3-carbamoyl-3,3-diphenylpropyl) -3- (3-nitrocinnamyl) -2-methylimidazolium bromide,
   (10) (E) -1- (3-carbamoyl-3,3-diphenylpropyl) -3- (4-nitrocinnamyl) -2-methylimidazolium bromide,
   (11) (E) -1- [3-carbamoyl-3,3-di (thiophen-2-yl) propyl] -3-cinnamyl-2-methylimidazolium bromide,
   (12) (E) -1- (3-carbamoyl-3,3-diphenylpropyl) -3- (3-cyclohexylallyl) -2-methylimidazolium bromide,
   (13) (E) -1- (3-carbamoyl-3,3-diphenylpropyl) -3- (3-cyclopropylallyl) -2-methylimidazolium bromide,
   (14) (E) -1- (3-carbamoyl-3,3-diphenylpropyl) -2-methyl-3- [3- (thiophen-2-yl) allyl] imidazolium bromide,
   (15) (E) -1- (3-carbamoyl-3,3-diphenylpropyl) -2-methyl-3- [3- (thiazol-2-yl) allyl] imidazolium bromide,
   (16) (E) -1- (4-carbamoyl-4,4-diphenylbutyl) -3-cinnamyl-2-methylimidazolium bromide,
   (17) (E) -1- (3-cyclooctyl-3-carbamoyl-3-phenylpropyl) -3-cinnamyl-2-methylimidazolium bromide, or (18) (E) -1- [2- ( α-carbamoylbenzhydryloxy) ethyl] -3-cinnamyl-2-methylimidazolium bromide,
   The imidazolium derivative according to any one of claims 1 to 3, wherein
7. A muscarinic M3 receptor antagonist comprising the imidazolium derivative according to any one of claims 1 to 6 as an active ingredient.
8. Selected from the group consisting of chronic bronchial asthma, chronic obstructive pulmonary disease (COPD), asthma, chronic airway obstruction, pulmonary fibrosis, emphysema, diffuse panbronchiolitis, bronchiectasis, idiopathic interstitial pneumonia and rhinitis A preventive or therapeutic agent for a disease, comprising the imidazolium derivative according to any one of claims 1 to 6 as an active ingredient.
9. Selected from the group consisting of chronic bronchial asthma, chronic obstructive pulmonary disease (COPD), asthma, chronic airway obstruction, pulmonary fibrosis, emphysema, diffuse panbronchiolitis, bronchiectasis, idiopathic interstitial pneumonia and rhinitis A method for treating or preventing a disease, comprising administering the imidazolium derivative according to any one of claims 1 to 6.
10. Selected from the group consisting of chronic bronchial asthma, chronic obstructive pulmonary disease (COPD), asthma, chronic airway obstruction, pulmonary fibrosis, emphysema, diffuse panbronchiolitis, bronchiectasis, idiopathic interstitial pneumonia and rhinitis Use of the imidazolium derivative according to any one of claims 1 to 6 for the manufacture of a medicament for the treatment or prevention of certain diseases.
11. A pharmaceutical composition comprising the imidazolium derivative according to any one of claims 1 to 6 as an active ingredient.
12. A pharmaceutical composition comprising the imidazolium derivative according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier.
13. Selected from the group consisting of chronic bronchial asthma, chronic obstructive pulmonary disease (COPD), asthma, chronic airway obstruction, pulmonary fibrosis, emphysema, diffuse panbronchiolitis, bronchiectasis, idiopathic interstitial pneumonia and rhinitis The imidazolium derivative according to any one of claims 1 to 6, for the treatment or prevention of a disease.

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