JP2007031325A - New nitrogen-containing heterocyclic compounds - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound having selective muscarine M<SB>3</SB>receptor antagonism, rapid in metabolic rate, quickly vanishing in blood plasma and transformable to a metabolite having weak muscarine M<SB>3</SB>antagonistic activity, thereby, hardly causing thirst and side effects to the heart, and useful as a preventive or therapeutic agent for respiratory diseases, urologic diseases, gastrointestinal diseases or central diseases. <P>SOLUTION: The muscarine M<SB>3</SB>receptor antagonist comprises a nitrogen-containing heterocyclic derivative represented by general formula (I) (wherein, each symbol has specified meaning), or a hydrate or solvate thereof. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

The present invention relates to a novel nitrogen-containing heterocyclic compound useful as a pharmaceutical product. More specifically, a novel nitrogen-containing heterocyclic compound which is a selective muscarinic receptor antagonist or a pharmacologically acceptable salt thereof, a production method thereof, a pharmaceutical composition containing the same, and an active ingredient thereof it relates muscarinic M ₃ receptor antagonists.

There are at least three subtypes of muscarinic receptors. It is known that the M ₁ receptor is present in the brain, the M ₂ receptor is present in the heart, and the M ₃ receptor is present in smooth muscle and glandular tissues.

Drugs having muscarinic receptor antagonistic action have antispasmodic action and antisecretory action, so they are used as therapeutic drugs for functional disorders such as respiratory, urological or digestive organs, and atropine, butyl scopolamine, ipratropium, tiotropium, oxybutynin, Compounds such as propantheline are used clinically. However, since they have almost the same affinity for the M ₁ , M ₂ and M ₃ receptors of muscarinic receptors, it is known that side effects due to non-selective antagonism with acetylcholine cannot be avoided. Therefore, a drug having a highly selective muscarinic receptor antagonistic action, particularly a drug showing no side effects on the heart involving the M ₂ receptor has been desired. In addition, since thirst based on muscarinic M ₃ receptor antagonism is regarded as a clinical problem, a drug having a weak thirst suppression action has been desired.

The present inventors have an aminocycloalkane compound having a selective muscarinic M ₃ receptor antagonistic activity (Patent Document 1; International Publication No. WO99 / 05095) and an imidazole compound (Patent Document 2; International Publication No. WO00 / 56718). Has applied for a patent. As a compound structurally similar to the compound of the present invention, a compound described in WO00 / 56718

[Wherein Y represents a hydrogen atom, a cyano group or a carbamoyl group, preferably a carbamoyl group. Z is a CH group or a nitrogen atom, preferably a CH group. -A-B- is -CH ₂ -CH ₂ - group or a -CH = CH- group, preferably -CH ₂ -CH ₂ - is a group. m is 1 or 2, and preferably 1. n is 0 or 1, preferably 0. ]
Although it has been disclosed that it has a higher selectivity for the smooth muscle muscarinic receptor than the cardiac muscarinic receptor and has a strong antagonism, there is no specific disclosure about the effect of inhalation administration. There is no suggestion. Further, there is no specific disclosure or suggestion about the compound of the present invention.
International Publication No. WO99 / 05095 International Publication WO00 / 56718

  The inventors of the present invention focused on nitrogen-containing heterocyclic compounds and, as a result of intensive research, have found that the compounds of the general formula (I)

[Wherein, R ¹ is an aryl group which may have a substituent on the ring, R ² is an aryl group which may have a substituent on the ring, a lower alkyl group which may have a substituent, or Represents a cycloalkyl group which may have a substituent, R ³ represents a nitrile group or CONHR ⁸ (R ⁸ represents a hydrogen atom or a lower alkyl group), and R ⁴ represents a lower group which may have a substituent. An alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group or Represents an aralkyl group which may have a substituent, R ⁵ represents a hydrogen atom or a lower alkyl group, R ⁶ and R ⁷ represent a hydrogen atom or a lower alkyl group, and —A—B— represents —CH—CH. -, -C = C-, -C = N- or -N = C-, m ¹ and m ² Is an integer of 1 to 6, n is an integer of 1 to 10, and Z ⁻ represents an anion], or a hydrate or solvate thereof. Since this compound has a selective antagonism at the muscarinic M ₃ receptor, it is safe with few side effects in the heart, and since the metabolic rate in plasma is fast, the thirst action is weak. Various diseases involving ₃ receptors, such as chronic obstructive pulmonary disease, chronic bronchitis, asthma, chronic airway obstruction, pulmonary fibrosis, emphysema, diffuse panbronchiolitis, bronchiectasis, idiopathic interstitial pneumonia The present invention has been found to be extremely useful for the treatment of respiratory diseases such as rhinitis and the like, preferably respiratory diseases associated with airflow obstruction.

  The meanings of terms used in the present specification are described below, and the present invention is described in more detail.

  In the present invention, the “substituent” which the aryl group, lower alkyl group, cycloalkyl group, lower alkenyl group, lower alkynyl group and aralkyl group may have is a halogen atom, a lower alkyl group, an aryl group, a lower alkenyl group. Group, lower alkynyl group, lower alkoxy group, hydroxyl group and the like.

  “Aryl group” means an aryl group having 6 to 11 carbon atoms, and specific examples include a phenyl group and a naphthyl group.

  The “lower alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s -Butyl group, t-butyl group, pentyl group, isopentyl group, neopentyl group, t-pentyl group, hexyl group and the like.

  The “cycloalkyl group” means an alicyclic hydrocarbon having 3 to 8 carbon atoms, and specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cyclohexyl group, and a cyclooctyl group.

  The “lower alkenyl group” means a straight or branched alkenyl group having 2 to 6 carbon atoms, specifically, vinyl group, 1-propenyl group, 2-propenyl group, isopropenyl group, 1- Butenyl group, 2-butenyl group, 3-butenyl group, 1-methyl-1-propenyl group, 1-methyl-2-propenyl group, 1-ethyl-1-ethenyl group, 2-methyl-1-propenyl group, 2 -Methyl-2-propenyl group, 3-methyl-2-butenyl group, 4-pentenyl group and the like can be mentioned.

  The “lower alkynyl group” means an alkynyl group having 2 to 6 carbon atoms, and specifically includes an acetylenyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3- Examples include butynyl group, pentynyl group, hexynyl group and the like.

  The “aralkyl group” is a group in which a linear or branched alkylene group having 1 to 6 carbon atoms is bonded to a phenyl group which may be substituted with a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or the like. Specifically, benzyl group, phenylethyl group, phenylpropyl group and the like can be mentioned.

  “Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

  The “lower alkoxy group” is a linear or branched alkoxy group having 1 to 6 carbon atoms, specifically, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, s -Butoxy group, t-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, t-pentyloxy group, hexyloxy group and the like.

  “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. Is mentioned.

  The compound of the present invention includes hydrates and solvates. These can be obtained by known methods. The compound of the present invention may have stereoisomers or tautomers such as optical isomers, diastereoisomers, geometric isomers, etc. depending on the mode of the substituents. These optical isomers, tautomers and mixtures thereof are also encompassed in the present invention.

The compound (I) of the present invention can be produced, for example, by the following production method or the method shown in the examples. However, the production method of the compound (I) of the present invention is not limited to these reaction examples.
Manufacturing method 1
Formula (II)

[Wherein R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁷ , -A-B-, m ¹ or m ² have the above-mentioned meanings] or a salt thereof; General formula (III)

[Wherein X ¹ represents a leaving group, and R ⁴ or n has the above-mentioned meaning] to react with a compound represented by the general formula (I)

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , -A-B-, m ¹ , m ² , n or Z have the aforementioned meanings] Can be produced.

  The “salt” of the compound represented by the general formula (II) means an acid addition salt at a basic nitrogen atom, for example, an inorganic acid salt such as hydrochloride, sulfate, nitrate, phosphate, acetate, Examples thereof include organic acid salts such as citrate, fumarate and tartrate, and sulfonates such as methanesulfonate and tosylate.

The leaving group X ¹ represented by the general formula (III), chlorine atom, bromine atom, a halogen atom such as iodine atom, p- toluenesulfonyloxy group, benzenesulfonyloxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy Examples thereof include sulfonyloxy groups such as a group, and chlorine atom, bromine atom, iodine atom, p-toluenesulfonyloxy group, and methanesulfonyloxy group are particularly preferable.

  The reaction of the compound represented by the general formula (II) or a salt thereof and the compound represented by the general formula (III) is usually performed in an inert solvent that does not affect the reaction. Examples of the inert solvent include ethers such as tetrahydrofuran, diethyl ether and dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, halogen solvents such as chloroform and dichloromethane, acetone, acetonitrile, dimethyl sulfoxide, N, N-dimethyl. Examples include aprotic polar solvents such as formamide, or mixed solvents thereof, and tetrahydrofuran, dioxane, acetone, and acetonitrile are particularly preferable.

  The compound represented by the general formula (III) is usually used in an amount of 1 mol to excess mol, preferably 1 to 10 mol, relative to 1 mol of the compound (II).

  The reaction temperature is usually from room temperature to the boiling point of the solvent, and the reaction time is from 10 minutes to 48 hours, but more or less conditions can be used if necessary.

  In order to facilitate the reaction, the reaction can be performed in the presence of a base.

  Examples of the base include inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate and potassium carbonate, triethylamine, N-methylmorpholine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0]. And organic bases such as undeca-7ene (DBU).

  The base is usually used in an amount of 1 mol to excess mol, preferably 1 to 10 mol, per 1 mol of compound (II).

After completion of the reaction, normal treatment can be carried out to obtain the compound represented by the general formula (I).
Manufacturing method 2
Formula (IV)

[Wherein X ² represents a leaving group, and R ¹ , R ² , R ³ , m ¹ or m ² have the above-mentioned meanings] and a general formula (V)

[Wherein R ⁴ , R ⁵ , R ⁶ , R ⁷ , —A—B— or n has the above-mentioned meanings] or a salt thereof is reacted with the compound represented by the general formula (I)

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , -A-B-, m ¹ , m ² , n or Z have the aforementioned meanings] Can be produced.

  The “salt” of the compound represented by the general formula (V) means an acid addition salt at a basic nitrogen atom, for example, an inorganic acid salt such as hydrochloride, sulfate, nitrate, phosphate, acetate, Examples thereof include organic acid salts such as citrate, fumarate and tartrate, and sulfonates such as methanesulfonate and tosylate.

The leaving group X ² represented by the general formula (IV) is a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, p-toluenesulfonyloxy group, benzenesulfonyloxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy. Examples thereof include sulfonyloxy groups such as a group, and chlorine atom, bromine atom, iodine atom, p-toluenesulfonyloxy group, and methanesulfonyloxy group are particularly preferable.

  The reaction of the compound represented by the general formula (IV) with the compound represented by the general formula (V) or a salt thereof is usually performed in an inert solvent that does not affect the reaction. Examples of the inert solvent include ethers such as tetrahydrofuran, diethyl ether and dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, halogen solvents such as chloroform and dichloromethane, acetone, acetonitrile, dimethyl sulfoxide, N, N-dimethyl. Examples include aprotic polar solvents such as formamide, or mixed solvents thereof, and tetrahydrofuran, dioxane, acetone, and acetonitrile are particularly preferable.

  The compound represented by the general formula (V) is usually used in an amount of 1 mol to excess mol, preferably 1 mol to 10 mol, relative to 1 mol of the compound (IV).

  The reaction temperature is usually from room temperature to the boiling point of the solvent, and the reaction time is from 10 minutes to 48 hours, but more or less conditions can be used if necessary.

  In order to facilitate the reaction, the reaction can be performed in the presence of a base.

  Examples of the base include inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate and potassium carbonate, or triethylamine, N-methylmorpholine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0]. ] Organic bases such as undeca-7ene (DBU).

  The base is usually used in an amount of 1 mol to excess mol, preferably 1 to 10 mol, per 1 mol of compound (II).

  After completion of the reaction, normal treatment can be carried out to obtain the compound represented by the general formula (I).

  Isolation / purification of the compound represented by the general formula (I) or a salt thereof obtained by the above method is, for example, column chromatography using silica gel, adsorption resin, etc., liquid chromatography, solvent extraction or recrystallization. This is achieved by carrying out conventional separation means such as reprecipitation alone or in combination.

The anion represented by Z < ^- > of the compound represented by the general formula (I) can be converted into another kind of anion by conventional means.

  As a method for converting the above anions, for example, a compound represented by the general formula (I) having a certain kind of anions is adsorbed on a column packed with an appropriate carrier, and an excess of the desired anions is removed. Examples include a method of eluting a compound having a desired anion after treatment with an acid salt that can be supplied.

  As the compound represented by the general formula (II), (III), (IV) or (V), for example, a commercially available product is used, or a known method, a method described in the literature (International Publication WO00 / 56718) or It can be produced by a method according to these methods, or the following method or the methods described in Examples and Reference Examples.

  Formula (II)

[Wherein R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁷ , -AB-, m ¹ or m ² have the above-mentioned meanings], the compound represented by the method described below Can be manufactured.
Manufacturing method A
Formula (IV)

[Wherein R ¹ , R ² , R ³ , m ¹ , m ² or X ² has the above-mentioned meanings] and a general formula (VI)

[Wherein R ⁵ , R ⁶ , R ⁷ or —A—B— has the aforementioned meanings] or a salt thereof is reacted with a compound represented by the general formula (II). Can be manufactured.

  The “salt” of the compound represented by the general formula (VI) means an acid addition salt at a basic nitrogen atom, for example, an inorganic acid salt such as hydrochloride, sulfate, nitrate, phosphate, acetate, Examples thereof include organic acid salts such as citrate, fumarate and tartrate, and sulfonates such as methanesulfonate and tosylate.

  The reaction between the compound represented by the general formula (IV) and the compound represented by the general formula (VI) or a salt thereof is usually performed in an inert solvent that does not affect the reaction. Examples of the inert solvent include ethers such as tetrahydrofuran, diethyl ether and dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, halogen solvents such as chloroform and dichloromethane, acetone, acetonitrile, dimethyl sulfoxide, N, N-dimethyl. Examples include aprotic polar solvents such as formamide, or mixed solvents thereof, and tetrahydrofuran, dioxane, toluene, acetone, acetonitrile, dimethyl sulfoxide, and N, N-dimethylformamide are particularly preferable.

  The compound represented by the general formula (VI) is usually used in an amount of 1 mol to excess mol, preferably 1 mol to 10 mol, relative to 1 mol of the compound (IV).

  The reaction temperature is usually from room temperature to the boiling point of the solvent, and the reaction time is from 10 minutes to 48 hours, but more or less conditions can be used if necessary.

  In order to facilitate the reaction, the reaction can be performed in the presence of a base.

  Examples of the base include inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate and sodium hydride, triethylamine, N-methylmorpholine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5]. 4.0] organic bases such as undeca-7ene (DBU), pyridine, 4-dimethylaminopyridine, and the like.

  The base is usually used in an amount of 1 mol to excess mol, preferably 1 to 10 mol, per 1 mol of compound (VI).

After completion of the reaction, normal treatment can be performed to obtain the compound represented by the general formula (II).
Manufacturing method B
Formula (VII)

[Wherein R ¹ , R ² or R ³ has the above-mentioned meanings] and a general formula (VIII)

[Wherein X ³ represents a leaving group, and R ⁵ , R ⁶ , R ⁷ , -AB-, m ¹ or m ² are the same as described above] or a salt thereof and the presence of a base The compound represented by the general formula (II) can be produced by performing the reaction below.

The leaving group X ³ represented by the general formula (VIII), a chlorine atom, a bromine atom, a halogen atom such as iodine atom, p- toluenesulfonyloxy group, benzenesulfonyloxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy Examples thereof include sulfonyloxy groups such as a group, and chlorine atom, bromine atom, iodine atom, p-toluenesulfonyloxy group, and methanesulfonyloxy group are particularly preferable.

  The “salt” of the compound represented by the general formula (VIII) means an acid addition salt at a basic nitrogen atom, for example, an inorganic acid salt such as hydrochloride, sulfate, nitrate, phosphate, acetate, Examples thereof include organic acid salts such as citrate, fumarate and tartrate, and sulfonates such as methanesulfonate and tosylate.

  Examples of the base include sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydroxide, sodium hydroxide, potassium hydroxide and other inorganic bases, triethylamine, N-methylmorpholine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7ene (DBU), pyridine, 4-dimethylaminopyridine, methyllithium, n-butyllithium, s-butyllithium, t-butyllithium And organic bases such as phenyl lithium, sodium amide, lithium diisopropylamide, and the like.

  The base is generally used in an amount of 0.001 mol to excess mol, preferably 0.1 mol to 10 mol, per 1 mol of compound (VII).

  The reaction of the compound represented by the general formula (VII) with the compound represented by the general formula (VIII) or a salt thereof is usually performed in an inert solvent that does not affect the reaction. Examples of the inert solvent include ethers such as tetrahydrofuran, diethyl ether and dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, halogen solvents such as chloroform and dichloromethane, acetone, acetonitrile, dimethyl sulfoxide, N, N-dimethyl. Examples include aprotic polar solvents such as formamide, or mixed solvents thereof, and tetrahydrofuran, dioxane, toluene, acetone, acetonitrile, dimethyl sulfoxide, and N, N-dimethylformamide are particularly preferable.

  The compound represented by the general formula (VII) is usually used in an amount of 1 mol to excess mol, preferably 1 mol, relative to 1 mol of the compound (VIII).

  The reaction temperature is usually from room temperature to the boiling point of the solvent, and the reaction time is from 10 minutes to 48 hours, but more or less conditions can be used if necessary.

After completion of the reaction, normal treatment can be performed to obtain the compound represented by the general formula (II).
Manufacturing method C
Formula (II)

In the compound represented by the formula: wherein R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁷ , -A-B-, m ¹ or m ² have the aforementioned meanings, When B- is —CH ₂ —CH ₂ —, the general formula (IX)

[In the formula, R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁷ , m ¹ or m ² have the above-mentioned meaning] formula (II) [wherein, -A-B- is _-CH 2 -CH ₂ - ^{represents, R 1, R 2, R} 3, R 5, R 6, R 7, m 1 or ^{m 2} is the above-mentioned Can be produced.

  Examples of the halogenating agent include chlorinating agents such as phosphorus oxychloride, phosphorus trichloride, sulfonyl chloride, oxalyl chloride, carbon tetrachloride / triphenylphosphine, and brominating agents such as phosphorus oxybromide and tetrabromoline. Can be mentioned.

  The reaction of the compound represented by the general formula (IX) and the halogenating agent is carried out in the absence of solvent or in an inert solvent that does not affect the reaction. Examples of the inert solvent include ethers such as tetrahydrofuran, diethyl ether and dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, halogen solvents such as chloroform and dichloromethane, aprotic polar solvents such as acetonitrile, or a mixture thereof. A solvent etc. are mentioned.

  The halogenating agent is generally used in an amount of 1 mol to excess mol, preferably 1 mol to 10 mol, per 1 mol of compound (IX).

  The reaction temperature is usually from room temperature to the boiling point of the solvent, and the reaction time is from 10 minutes to 48 hours, but more or less conditions can be used if necessary.

  After completion of the reaction, normal treatment can be performed to obtain the compound represented by the general formula (II).

  Isolation / purification of the compound represented by the general formula (II) obtained by the above method or a salt thereof is, for example, column chromatography using silica gel, adsorption resin, etc., liquid chromatography, solvent extraction or recrystallization. This is achieved by carrying out conventional separation means such as reprecipitation alone or in combination.

  When the compound of the present invention is used as a pharmaceutical, a pharmaceutical composition or formulation (eg, tablet, liquid, etc.) obtained by mixing the compound of the present invention with a pharmaceutically acceptable carrier (excipient, binder, disintegrant, etc.) Can be administered orally or parenterally. The pharmaceutical composition can be formulated according to a usual method.

  Dosage depends on age, weight, general health, sex, diet, time of administration, method of administration, excretion rate, combination of drugs, patient's condition being treated at that time, or other factors Determined in consideration of The compound of the present invention can be used safely with low toxicity, and the daily dose varies depending on the patient's condition and body weight, the type of compound, the route of administration, etc., for example, 0.01 -1000 mg / kg body weight / day, administered once to several times a day, or parenterally, about 0.01-100 mg / kg body weight / day, administered one to several times a day It is preferable to do this.

  This compound is useful as a preventive or therapeutic agent for respiratory diseases, urological diseases, digestive organ diseases or central diseases.

  The present invention will be further described with reference to examples, but the present invention is not limited to these examples.

Reference example 1
((3-Oxo) cyclopentyl) diphenylacetonitrile In a stream of argon, diphenylacetonitrile (98.6 g) and 2-cyclopenten-1-one (41.9 ml) in THF (1 l) at −10 ° C. at t-butoxypotassium ( 0.56 g) was added and stirred for 30 minutes. 6N hydrochloric acid (0.83 ml) was added to the reaction mixture, the solvent was distilled off under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, isopropyl ether (250 ml) was added to the obtained residue, and the precipitate was collected by filtration and dried to give 122 g (yield 88%) of the title compound as a white crystalline powder.

¹ H-NMR (CDCl ₃ , δPPM): 2.00 (2H, m), 2.49-2.16 (4H, m), 3.36 (1H, m), 7.51-7.29 ( 10H, m).

Reference example 2
Boron hydride was added to a suspension of ((3-oxo) cyclopentyl) diphenylacetonitrile (22.0 g) obtained from (cis- (3-hydroxy) cyclopentyl) diphenylacetonitrile Reference Example 1 in methanol (150 ml) under ice-cooling. Sodium (3.09 g) was added, and after stirring for 1.5 hours, the ice bath was removed and the mixture was allowed to stand overnight at room temperature. Ice and then 6N hydrochloric acid (5 ml) were added, the solvent was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine and dried over anhydrous potassium carbonate, and the solvent was evaporated under reduced pressure to obtain 22.3 g (quantitative yield) of the title compound as a colorless crystalline powder.

¹ H-NMR (CDCl ₃ , δPPM): 1.54-1.89 (5H, m), 2.07-2.17 (1H, m), 3.07-3.13 (1H, m), 4.27-4.33 (1H, m), 7.23-7.37 (6H, m), 7.43-7.46 (4H, m).

Reference example 3
Para-toluenesulfonic acid (trans-3- (cyano (diphenyl) methyl) cyclopentyl) ester (cis- (3-hydroxy) cyclopentyl) diphenylacetonitrile (15.4 g: 55. 5) obtained from Reference Example 2 under an argon atmosphere. 6 mmol), triphenylphosphine (21.0 g: 80.1 mmol), para-toluenesulfonic acid methyl ester (12.1 ml: 80.1 mmol) in tetrahydrofuran (240 ml) solution in azodicarboxylic acid diethyl ester (14.5 ml: 92.4 mmol) was added dropwise at −10 ° C., stirred at 0 ° C. or lower for 2 hours, and then stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: toluene) to obtain an oil. The oil was crystallized by adding isopropyl ether to obtain 16.7 g (yield 70%) of the title compound as a white crystalline powder.

¹ H-NMR (CDCl ₃ , δPPM): 1.56-2.14 (6H, m), 2.43 (3H, s), 3.28-3.52 (1H, m), 4.88- 5.06 (1H, m), 7.10-7.54 (12H, m), 7.76 (2H, brd, J = 8.25 Hz).

Reference example 4
Para-toluenesulfonic acid (trans-3- (cyano (diphenyl) methyl) cyclopentyl) ester (66.0 g) obtained from (cis-3- (2-methylimidazol-1-yl) cyclopentyl) diphenylacetonitrile Reference Example 3 : 0.15 mol), 2-methylimidazole (25.5 g: 0.31 mol), and a suspension of potassium carbonate (23.2 g: 0.17 mol) in acetonitrile (300 ml) were stirred with heating under reflux for 16 hours. The reaction mixture was concentrated under reduced pressure, water was added, extraction was performed with ethyl acetate, and the organic layer was washed twice with water. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: chloroform / methanol = 20 / 1-10 / 1), and the title compound was pale brown 36.3 g (69% yield) was obtained as an oil.

¹ H-NMR (CDCl ₃ , δPPM): 1.62-2.07 (4H, m), 2.11-2.47 (5H, m), 3.32-3.55 (1H, m), 4.57-4.73 (1H, m), 6.88 (1H, brs), 6.92 (1H, brs), 7.14-7.58 (10H, m)
MS (ESI) m / z: 342 (MH) ^<+> .

Reference Example 5
(Cis-3- (2-methylimidazol- 1-yl) cyclopentyl) diphenylacetonitrile (36.3 g: obtained from (cis-3- (2-methylimidazol-1-yl) cyclopentyl) diphenylacetamide Reference Example 4) 0.11 mol) was added 70% sulfuric acid aqueous solution (57 ml) and stirred at 140 ° C. for 4 hours. After cooling, the reaction mixture was made basic by adding an aqueous sodium hydroxide solution, extracted with chloroform, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and acetone (75 ml) was added to the resulting concentrate, followed by stirring while heating under reflux. The mixture was allowed to cool to room temperature, and the resulting precipitate was filtered to obtain 18.5 g (48%) of the title compound as a white crystalline compound.

¹ H-NMR (CDCl ₃ , δPPM): 1.52-2.14 (6H, m), 2.21 (3H, s), 3.55-3.77 (1H, m), 3.83- 4.10 (1H, m), 5.44 (2H, brs), 6.90 (1H, brs), 6.96 (1H, brs), 7.15-7.49 (10H, m)
MS (ESI) m / z: 360 (MH) ^<+> .

Reference Example 6
3- (cis-3- (carbamoyl (diphenyl) methyl) cyclopentyl) -1-carboxymethyl-2-methyl-3H-imidazol-1-ium bromide obtained from Reference Example 5 (cis-3- (2-methyl The title compound was prepared in the same manner as in Example 10 using imidazol-1-yl) cyclopentyl) diphenylacetamide (0.36 g: 1.00 mmol) and p-nitrophenyl bromoacetate (2.60 g: 0.01 mol). As a white crystalline compound, 0.07 g (yield 13%) was obtained.

¹ H-NMR (DMSO-d6, δPPM): 1.30-1.49 (3H, m), 1.99-2.06 (2H, m), 2.41-2.46 (1H, m) , 2.54 (3H, s), 3.59-3.66 (1H, m), 4.80-4.84 (1H, m), 5.04 (2H, s), 6.75 (1H) , Brs), 6.95 (1H, d, J = 1.9 Hz), 7.19 (1H, brs), 7.28-7.51 (10H, m), 7.54 (1H, d, J = 1.9 Hz), 13.70 (1H, brs)
MS (ESI) m / z: 418 [M] ^<+> .

Example 1
1-benzyloxycarbonylmethyl-3- (cis-3- (carbamoyl (diphenyl) methyl) cyclopentyl) -2-methyl-3H-imidazol-1-ium bromide obtained from Reference Example 5 (cis-3- (2 A solution of -methylimidazol-1-yl) cyclopentyl) diphenylacetamide (0.30 g: 0.83 mmol) and benzyl bromoacetate (0.20 ml) in acetone (3 ml) was stirred with heating under reflux for 16 hours. After cooling to room temperature, the precipitate was collected by filtration to obtain 0.48 g (yield 98%) of the title compound as a white crystalline compound.

¹ H-NMR (DMSO-d6, δPPM): 1.21-1.55 (3H, m), 1.91-2.12 (2H, m), 2.36-2.46 (1H, m) , 2.56 (3H, s), 3.60-3.73 (1H, m), 4.77-4.89 (1H, m), 5.20 (2H, brs), 5.25 (2H , Brs), 6.75 (1H, brs), 6.98 (1H, brs), 7.20 (1H, brs), 7.25-7.45 (15H, m), 7.56 (1H, brs)
MS (ESI) m / z: 508 [M] ^<+> .

Example 2
3- (cis-3- (carbamoyl (diphenyl) methyl) cyclopentyl) -1-ethoxycarbonylmethyl-2-methyl-3H-imidazol-1-ium bromide obtained from Reference Example 5 (cis-3- (2- Methylimidazol-1-yl) cyclopentyl) diphenylacetamide (0.30 g: 0.83 mmol) and ethyl bromoacetate (0.20 ml) were used in the same manner as in Example 1 to give the title compound as a white crystalline compound. .28 g (64% yield) was obtained.

¹ H-NMR (DMSO-d6, δPPM): 1.22 (3H, t, J = 7.0 Hz), 1.25-1.55 (3H, m), 1.93-2.13 (2H, m), 2.35-2.47 (1H, m), 2.56 (3H, s), 3.59-3.70 (1H, m), 4.14-4.24 (2H, m) 4.76-4.89 (1H, m), 5.16 (2H, brs), 6.75 (1H, brs), 6.98 (1H, brs), 7.19 (1H, brs), 7.23-7.39 (10H, m), 7.55 (1H, d, J = 1.6 Hz)
MS (ESI) m / z: 446 [M] ^<+> .

Example 3
3- (cis-3- (carbamoyl (diphenyl) methyl) cyclopentyl) -2-methyl-1-propoxycarbonylmethyl-3H-imidazol-1-ium bromide obtained from Reference Example 5 (cis-3- (2- Methylimidazol-1-yl) cyclopentyl) diphenylacetamide (0.30 g: 0.83 mmol) and propyl bromoacetate (0.20 ml) were used as a white crystalline compound in the same manner as in Example 1 to obtain the title compound as a white crystalline compound. .31 g (68% yield) was obtained.

¹ H-NMR (DMSO-d6, δPPM): 0.83-0.93 (3H, m), 1.23-1.54 (3H, m), 1.55-1.66 (2H, m) 1.92-2.15 (2H, m), 2.36-2.46 (1H, m), 2.56 (3H, s), 3.58-3.73 (1H, m), 4 .09 (2H, t, J = 6.4 Hz), 4.75-4.89 (1H, m), 5.19 (2H, brs), 6.75 (1H, brs), 6.98 (1H , D, J = 2.0 Hz), 7.20 (1H, brs), 7.23-7.39 (10H, m), 7.56 (1H, brs)
MS (ESI) m / z: 460 [M] ^<+> .

Example 4
1-t-Butoxycarbonylmethyl-3- (cis-3- (carbamoyl (diphenyl) methyl) cyclopentyl) -2-methyl-3H-imidazol-1-ium bromide obtained from Reference Example 5 (cis-3- ( 2-Methylimidazol-1-yl) cyclopentyl) diphenylacetamide (0.30 g: 0.83 mmol) and t-butyl bromoacetate (0.20 ml) were used to give the title compound as white crystals in the same manner as in Example 1. As a functional compound, 0.18 g (yield 40%) was obtained.

¹ H-NMR (DMSO-d6, δPPM): 1.23-1.55 (3H, m), 1.43 (9H, s), 1.93-2.13 (2H, m), 2.36 -2.47 (1H, m), 2.54 (3H, s), 3.58-3.70 (1H, m), 4.77-4.87 (1H, m), 5.07 (2H) , Brs), 6.75 (1H, brs), 6.97 (1H, brs), 7.20 (1H, brs), 7.23-7.38 (10H, m), 7.56 (1H, brs)
MS (ESI) m / z: 474 [M] ^<+> .

Example 5
3- (cis-3- (carbamoyl (diphenyl) methyl) cyclopentyl) -1- (5-ethoxycarbonylpentyl) -2-methyl-3H-imidazol-1-ium bromide obtained from Reference Example 5 (cis-3 -(2-Methylimidazol-1-yl) cyclopentyl) diphenylacetamide (0.30 g: 0.83 mmol) and ethyl 6-bromohexanoate (0.20 ml) were used in the same manner as in Example 1 to obtain the title compound. Was obtained as a white crystalline compound (yield 52%).

¹ H-NMR (DMSO-d6, δPPM): 1.10-1.19 (3H, m), 1.20-1.59 (7H, m), 1.61-1.73 (2H, m) , 1.90-2.10 (2H, m), 2.22-2.32 (2H, t, J = 7.3 Hz), 2.34-2.46 (1H, m), 2.57 ( 3H, s), 3.58-3.73 (1H, m), 3.95-4.10 (4H, m), 4.71-4.83 (1H, m), 6.75 (1H, brs), 6.92 (1H, brs), 7.18 (1H, brs), 7.23-7.38 (10H, m), 7.58 (1H, d, J = 2.0 Hz)
MS (ESI) m / z: 502 [M] ^<+> .

Example 6
3- (cis-3- (carbamoyl (diphenyl) methyl) cyclopentyl) -1- (4-ethoxycarbonylbutyl) -2-methyl-3H-imidazol-1-ium bromide obtained from Reference Example 5 (cis-3 -(2-Methylimidazol-1-yl) cyclopentyl) diphenylacetamide (0.30 g: 0.83 mmol), ethyl 5-bromovalerate (0.20 ml) and the title compound in the same manner as in Example 1. Was obtained as a white crystalline compound (yield 29%).

¹ H-NMR (DMSO-d6, δPPM): 1.13 to 1.20 (3H, m), 1.24 to 1.56 (5H, m), 1.64 to 1.75 (2H, m) 1.91.9-2.10 (2H, m), 2.32 (2H, t, J = 7.3 Hz), 2.36-2.46 (1H, m), 2.57 (3H, s) 3.60-3.72 (1H, m), 3.99-4.11 (4H, m), 4.70-4.83 (1H, m), 6.75 (1H, brs), 6 .92 (1H, d, J = 1.8 Hz), 7.18 (1H, brs), 7.23-7.39 (10H, m), 7.58 (1H, brs)
MS (ESI) m / z: 488 [M] ^<+> .

Example 7
3- (cis-3- (carbamoyl (diphenyl) methyl) cyclopentyl) -1-isopropoxycarbonylmethyl-2-methyl-3H-imidazol-1-ium bromide obtained from Reference Example 5 (cis-3- (2 -The title compound was converted into a white crystalline compound in the same manner as in Example 1, using -methylimidazol-1-yl) cyclopentyl) diphenylacetamide (0.30 g: 0.83 mmol) and isopropyl bromoacetate (0.20 ml). 0.26 g (yield 58%) was obtained.

¹ H-NMR (DMSO-d6, δPPM): 1.22 (6H, d, J = 6.2 Hz), 1.25-1.56 (3H, m), 1.92-2.14 (2H, m), 2.36-2.46 (1H, m), 2.55 (3H, s), 3.60-3.73 (1H, m), 4.76-4.88 (1H, m) , 4.92-5.04 (1H, m), 5.14 (2H, brs), 6.75 (1H, brs), 6.98 (1H, d, J = 2.1 Hz), 7.20. (1H, brs), 7.24-7.38 (10H, m), 7.55 (1H, d, J = 2.1 Hz)
MS (ESI) m / z: 460 [M] ^<+> .

Example 8
3- (cis-3- (carbamoyl (diphenyl) methyl) cyclopentyl) -1- (3-ethoxycarbonylpropyl) -2-methyl-3H-imidazol-1-ium bromide obtained from Reference Example 5 (cis-3 -(2-Methylimidazol-1-yl) cyclopentyl) diphenylacetamide (0.30 g: 0.83 mmol) and ethyl 4-bromobutyrate (0.20 ml) were used in the same manner as in Example 1 to obtain the title compound. As a white crystalline compound, 0.04 g (yield 8.5%) was obtained.

¹ H-NMR (DMSO-d6, δPPM): 1.12-1.20 (3H, m), 1.24-1.50 (3H, m), 1.87-2.10 (4H, m) 2.30-2.46 (3H, m), 2.57 (3H, s), 3.58-3.70 (1H, m), 3.95-4.10 (4H, m), 4 .69-4.80 (1H, m), 6.75 (1H, brs), 6.91 (1H, brs), 7.19 (1H, brs), 7.22-7.42 (10H, m ), 7.57 (1H, d, J = 1.8 Hz)
MS (ESI) m / z: 474 [M] ^<+> .

Example 9
3- (cis-3- (carbamoyl (diphenyl) methyl) cyclopentyl) -1- (10-methoxycarbonyldecyl) -2-methyl-3H-imidazol-1-ium bromide obtained from Reference Example 5 (cis-3 -(2-Methylimidazol-1-yl) cyclopentyl) diphenylacetamide (0.30 g: 0.83 mmol) and methyl 10-bromodecanoate (0.20 ml) were used in the same manner as in Example 1 to obtain the title compound. As a white crystalline compound, 0.15 g (yield 28%) was obtained.

¹ H-NMR (DMSO-d6, δPPM): 1.14 to 1.55 (17H, m), 1.56-1.72 (2H, m), 1.90-2.11 (2H, m) 2.28 (2H, t, J = 7.3 Hz), 2.34-2.46 (1H, m), 2.57 (3H, s), 3.57 (3H, s), 3.60. -3.72 (1H, m), 4.02 (2H, t, J = 7.3 Hz), 4.70-4.83 (1H, m), 6.75 (1H, brs), 6.92 (1H, brs), 7.18 (1H, brs), 7.22-7.40 (10H, m), 7.58 (1H, brs)
MS (ESI) m / z: 558 [M] ^<+> .

Example 10
3- (cis-3- (carbamoyl (diphenyl) methyl) cyclopentyl) -1-methoxycarbonylmethyl-2-methyl-3H-imidazol-1-ium bromide obtained from Reference Example 5 (cis-3- (2- A solution of methylimidazol-1-yl) cyclopentyl) diphenylacetamide (0.36 g: 1 mmol) and methyl bromoacetate (1.5 g: 10 mmol) in tetrahydrofuran (4 ml) was stirred with heating under reflux for 16 hours. After cooling to room temperature, the precipitate was collected by filtration to obtain 0.17 g (yield 34%) of the title compound as a white crystalline compound.

¹ H-NMR (DMSO-d6, δPPM): 1.32-1.51 (3H, m), 1.95-2.00 (1H, m), 2.05-2.09 (1H, m) 2.39-2.46 (1H, m), 2.56 (3H, s), 3.66-3.73 (1H, m), 3.74 (3H, s), 4.81-4 .85 (1H, m), 5.16 (2H, s), 6.75 (1H, brs), 6.98 (1H, d, J = 2.1 Hz), 7.20 (1H, brs), 7.27-7.35 (10H, m), 7.54 (1H, d, J = 2.1 Hz)
MS (ESI) m / z: 432 [M] ^<+> .

Example 11
3- (cis-3- (carbamoyl (diphenyl) methyl) cyclopentyl) -1- (4-methoxycarbonylbutyl) -2-methyl-3H-imidazol-1-ium bromide obtained from Reference Example 5 (cis-3 -(2-Methylimidazol-1-yl) cyclopentyl) diphenylacetamide (0.36 g: 1 mmol), methyl 5-bromovalerate (1.9 g: 10 mmol) and the title compound in the same manner as in Example 10. Was obtained as a white crystalline compound (yield 18%).

¹ H-NMR (DMSO-d6, δPPM): 1.29-1.53 (5H, m), 1.65-1.70 (2H, m), 1.94-2.06 (2H, m) , 2.32-2.44 (3H, m), 2.57 (3H, s), 3.58 (3H, s), 3.63-3.68 (1H, m), 4.02-4 .06 (2H, m), 4.74-4.78 (1H, m), 6.75 (1H, brs), 6.92 (1H, d, J = 2.1 Hz), 7.18 (1H , Brs), 7.26-7.35 (10H, m), 7.58 (1H, d, J = 2.1 Hz)
MS (ESI) m / z: 474 [M] ^<+> .

Example 12
3- (cis-3- (carbamoyl (diphenyl) methyl) cyclopentyl) -2-methyl-1-phenoxycarbonylmethyl-3H-imidazol-1-ium bromide obtained from Reference Example 5 (cis-3- (2- Methylimidazol-1-yl) cyclopentyl) diphenylacetamide (0.36 g: 1 mmol) and phenyl bromoacetate (2.2 g: 10 mmol) were used as a white crystalline compound in the same manner as in Example 10. 0.07 g (yield 12%) was obtained.

¹ H-NMR (DMSO-d6, δPPM): 1.30-1.49 (3H, m), 1.96-2.09 (2H, m), 2.42-2.45 (1H, m) , 2.65 (3H, s), 3.64-3.68 (1H, m), 4.82-4.87 (1H, m), 5.45 (2H, s), 6.75 (1H , Brs), 7.02 (1H, d, J = 2.2 Hz), 7.20-7.35 (14H, m), 7.44-7.48 (2H, m), 7.64 (1H) , D, J = 2.2 Hz)
MS (ESI) m / z: 494 [M] ⁺
The compounds obtained in Reference Examples and Examples are shown below.

Test Example 1 Muscarinic M ₃ antagonistic activity Hartley male guinea for isolated guinea pig trachea (350~600g) were excised trachea after bled lethal, was sampled by cutting with tracheal two intervals. This sample was kept at 37 ° C., suspended in a 5 mL Magnus tank filled with Krebs carbonate buffer containing indomethacin (1 μM) through 95% O ₂ -5% CO ₂ at a static tension of 1 g, and a stable period of 60 minutes was obtained. Oita. The contraction reaction by carbachol was measured using the cumulative method, and was measured isometrically at a common ratio of 3 from 10 ⁻⁸ M at intervals of 7 minutes per concentration. After the measurement, the specimen was immediately washed, a stable period of 60 minutes was allowed until the next contraction reaction, and the time when EC ₅₀ of the contraction reaction by carbachol was stabilized was used as a control. The test compound was applied 15 minutes before the addition of carbazole. In addition, the affinity (pA ₂ ) of the test compound was determined by the Schild method (Arunlakshana, O. and SchIld, H.O .: BrIt.J. phrmalcol., 1959, 14 , 48-58). The results are shown in Table 1. In addition, ipratropium and atropine in the table are reagents manufactured by SIGMA, and tests were performed using purchased reagents.

Test Example 2 Muscarin M ₂ antagonistic action on isolated guinea pig left atrium After Hartley guinea pig (350-600 g) was lethal to death, the left atrium was extracted and used as a specimen. The specimen was kept at 37 ° C. and suspended at a static tension of 0.5 g in a 10 mL Magnus tank filled with Krebs carbonate buffer through 95% O ₂ -5% CO ₂ . Thereafter, contraction due to field electrical stimulation (4 Hz, 2 msec, 1.5 × threshold voltage) was measured. After a stable period of 60 minutes, the shrinkage inhibition reaction by carbazole was measured isometrically at a common ratio of 3 from 10 ⁻⁸ M at intervals of 90 seconds using a cumulative method. After the measurement, the specimen was immediately washed, and a stable period of 45 minutes was allowed until the next suppression reaction. Incidentally, EC ₅₀ shrinkage control reaction by carbachol and controls a stable point, the test compound Karubako - were applied 30 min prior to Le added. The affinity (pA ₂ ) of the test compound was determined in the same manner as in the trachea.

  The results are shown in Table 1. In addition, ipratropium and atropine in the table are reagents manufactured by SIGMA, and tests were performed using purchased reagents.

Test Example 3 Metabolic stability test using guinea pig liver microsomes After adding guinea pig liver microsomes (Nippon Agricultural Industries), NADPH production reagent (oriental yeast) and test compound (2 μM) to 100 mM potassium phosphate buffer (pH 7.4), 37 Incubation was performed at 0 ° C. for 10 minutes. The remaining amount of unchanged product in this sample was measured by LC / MS / MS, and the residual rate (%) was calculated.
The results are shown in Table 2.

Test Example 4 Pharmacokinetic analysis in guinea pigs Test compounds (100 μg / kg) were intravenously administered from the penile vein of Hartley male guinea pigs (350-600 g), and blood was temporally measured by cardiac puncture using a heparin-treated syringe. Were collected. The collected blood was centrifuged at 15,000 rpm for 10 minutes at 4 ° C., and the plasma fraction was collected. After removing the protein component from this sample, the test compound concentration was measured by LC / MS / MS, and T _1/2 (biological half-life) was calculated.
The results are shown in Table 3.

Test Example 5. Test Conzet et al. Method (Arch. Exp. Path Pharmak., 1940, 195 , 71-74) for guinea pig airway contraction by inhalation administration . A Hartley male guinea pig (350-600 g) was anesthetized with urethane (1.8 g / kg, ip), and a cannula for drug administration was inserted into the left jugular vein. After immobilization with decamethonium (2 mg / kg, iv), a tracheal cannula was inserted, and controlled respiration was performed with a ventilator (Harvard). Airway contraction was measured as a change in airway pressure via a differential pressure transducer (Nihon Kohden). The test compound was administered from a dissected trachea using a liquid intratracheal administration device for guinea pigs (Penn Century). Thereafter, acetylcholine (4 μg / kg, iv) was administered to induce airway contraction, and the rate of airway contraction (%) was observed over time until 3 hours, and airway contraction was completely suppressed even after 3 hours. The dose of test compound to be determined was determined. The results are shown in Table 4.

Test Example 6. Test on guinea pig salivary secretion by inhalation administration A Hartley male guinea pig (350-600 g) was anesthetized with urethane (1.8 g / kg, ip), and a cannula for drug administration was inserted into the left jugular vein. The test compound was administered from the incised trachea using a liquid intratracheal administration device for guinea pigs. Thereafter, mesacholine (4 μg / kg, iv) was administered to induce salivation. The amount of saliva secretion was measured using a cotton ball for 5 minutes immediately after the administration of mesacholine. The inhibition rate for the secretory saliva amount of the control group was determined, and the dose of the test compound that suppressed the secretory saliva amount of the control group by 50% was defined as the ID ₅₀ value. The results are shown in Table 4.

Examples 2 and 3 are rapidly metabolized as shown in Tables 2 and 3, and as shown in Table 4, while maintaining strong activity in the airway contraction evaluated by intratracheal administration, to saliva secretion In Reference Example 6 in which Examples 2 and 3 were presumed to be hydrolyzed in blood because of the low effects of the test, IC of “muscarinic M ₃ antagonistic action on isolated guinea pig trachea” according to the method of Test Example 1 As a result of calculating ₅₀ values, Examples 2, 3 and Reference Example 6 were 16 nM, 16 nM and 794 nM, respectively.

From this fact, it was shown that when the compound shown in the example undergoes metabolism and is hydrolyzed, the muscarinic M ₃ antagonistic activity is reduced to about 1/50.

Compound (I) represented by Examples 2 and 3 shown in Table 1 has muscarinic M ₃ antagonistic activity equivalent to that of Reference Example 5, and has pA ₂ against muscarinic M ₂ receptor and M ₃ receptor. Receptor selectivity with a value difference of 1 or more is maintained. Further, from the results of the in vitro test shown in Table 2, it was shown that the compound (I) had a higher metabolic rate than the compound group shown in the reference example. When it was confirmed whether the activity reflected the metabolic rate in the plasma of the animal individual, as shown in Table 3, it was confirmed in the in vivo pharmacokinetic parameter analysis that the disappearance from the plasma was early. . Furthermore, from Test Example 6 using an animal model, it became clear that the thirst action of Compound (I) was weak. That is, it is considered that compound (I) is metabolized in the systemic bloodstream and muscarinic M ₃ antagonistic activity is attenuated. This compound (I), (e.g., Example 2, is hydrolyzed in such plasma has a structure of Example 6, the M ₃ antagonist activity as lost as large as about one fiftieth) Blood quickly hydrolyzed unchanged drug disappeared at medium shows that can attenuate the side effects of systemic based on M ₃ antagonistic activity by being converted to weak structures M ₃ antagonistic activity.

Thus, Compound (I) is a safe difficult to express more side effects in the heart, and are believed to be providing less dry mouth muscarinic M ₃ receptor antagonists.

As described above, the diseases present invention compounds involved muscarinic M ₃ receptors, in particular, chronic obstructive pulmonary disease, chronic bronchitis, asthma, chronic airway obstruction, pulmonary fibrosis, emphysema, diffuse panbronchiolitis, It is useful as a preventive or therapeutic agent for respiratory diseases such as bronchiectasis, idiopathic interstitial pneumonia and rhinitis, and preferably respiratory diseases associated with airflow obstruction. Further, by analogy from the pharmacological activity of the compound of the present invention, urinary incontinence and / or urinary frequency in neurogenic pollakiuria, neurogenic bladder, nocturnal urine, unstable bladder, bladder spasticity, chronic cystitis, interstitial cystitis Urinary diseases such as irritable bowel syndrome, spastic colitis, diverticulitis, functional diarrhea, gastroesophageal spasm, biliary convulsions, etc .; nausea and vomiting caused by drug administration, motion sickness, It may be useful as a preventive or therapeutic agent for central diseases such as Menuel disease.

Claims (16)

Formula (I)


[Wherein, R ¹ is an aryl group which may have a substituent on the ring, R ² is an aryl group which may have a substituent on the ring, a lower alkyl group which may have a substituent, or Represents a cycloalkyl group which may have a substituent, R ³ represents a nitrile group or CONHR ⁸ (R ⁸ represents a hydrogen atom or a lower alkyl group), and R ⁴ represents a lower group which may have a substituent. An alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group or Represents an aralkyl group which may have a substituent, R ⁵ represents a hydrogen atom or a lower alkyl group, R ⁶ and R ⁷ represent a hydrogen atom or a lower alkyl group, and —A—B— represents —CH—CH. -, -C = C-, -C = N- or -N = C-, m ¹ and m ² Is an integer of 1 to 6, n is an integer of 1 to 10, and Z ⁻ represents an anion], or a hydrate or solvate thereof. R ¹ and R ² are phenyl groups, R ³ is a nitrile group or CONH ₂ group, R ⁵ is a hydrogen atom or a lower alkyl group, R ⁶ and R ⁷ are hydrogen atoms or a lower alkyl group, The nitrogen-containing heterocyclic derivative or the hydrate or solvate thereof according to claim 1, wherein m ¹ is 1 or 2, and m ² is an integer of 2 or 3. R ¹ and R ² are phenyl groups, R ³ is a nitrile group or CONH ₂ group, R ⁵ is a hydrogen atom or a lower alkyl group, R ⁶ and R ⁷ are hydrogen atoms or a lower alkyl group, The nitrogen-containing heterocyclic derivative or hydrate or solvate thereof according to claim 1, wherein m ¹ is an integer of 1 and m ² is an integer of 2. R ⁴ may have a lower alkyl group which may have a substituent, a lower alkoxy group which may have a substituent, an aryl group which may have a substituent, or a substituent. The nitrogen-containing heterocyclic derivative according to claim 2 or 3, which is an aralkyl group, or a hydrate or solvate thereof. The general formula is 1-benzyloxycarbonylmethyl-3- (cis-3- (carbamoyl (diphenyl) methyl) cyclopentyl) -2-methyl-3H-imidazol-1-ium bromide, 3- (cis-3- (carbamoyl) (Diphenyl) methyl) cyclopentyl) -1-ethoxycarbonylmethyl-2-methyl-3H-imidazol-1-ium bromide, 3- (cis-3- (carbamoyl (diphenyl) methyl) cyclopentyl) -2-methyl-1- Propoxycarbonylmethyl-3H-imidazol-1-ium bromide, 1-t-butoxycarbonylmethyl-3- (cis-3- (carbamoyl (diphenyl) methyl) cyclopentyl) -2-methyl-3H-imidazol-1-ium bromide , 3- (cis-3- (Cal Moyl (diphenyl) methyl) cyclopentyl) -1- (5-ethoxycarbonylpentyl) -2-methyl-3H-imidazol-1-ium bromide, 3- (cis-3- (carbamoyl (diphenyl) methyl) cyclopentyl) -1 -(4-Ethoxycarbonylbutyl) -2-methyl-3H-imidazol-1-ium bromide, 3- (cis-3- (carbamoyl (diphenyl) methyl) cyclopentyl) -1-isopropoxycarbonylmethyl-2-methyl- 3H-imidazol-1-ium bromide, 3- (cis-3- (carbamoyl (diphenyl) methyl) cyclopentyl) -1- (3-ethoxycarbonylpropyl) -2-methyl-3H-imidazol-1-ium bromide, 3 -(Cis-3- (carbamoyl (di Enyl) methyl) cyclopentyl) -1- (10-methoxycarbonyldecyl) -2-methyl-3H-imidazol-1-ium bromide, 3- (cis-3- (carbamoyl (diphenyl) methyl) cyclopentyl) -1-methoxy Carbonylmethyl-2-methyl-3H-imidazol-1-ium bromide, 3- (cis-3- (carbamoyl (diphenyl) methyl) cyclopentyl) -1- (4-methoxycarbonylbutyl) -2-methyl-3H-imidazole -1-ium bromide, 3- (cis-3- (carbamoyl (diphenyl) methyl) cyclopentyl) -2-methyl-1-phenoxycarbonylmethyl-3H-imidazol-1-ium bromide or 3- (cis-3- ( Carbamoyl (diphenyl) methyl) cyclo Pentyl) -1- (3-methoxycarbonylpropyl) -2-methyl-3H-imidazol-1-ium bromide, The nitrogen-containing heterocyclic derivative or hydrate or solvate thereof according to claim 1. Formula (I)


[Wherein, R ¹ is an aryl group which may have a substituent on the ring, R ² is an aryl group which may have a substituent on the ring, a lower alkyl group which may have a substituent, or Represents a cycloalkyl group which may have a substituent, R ³ represents a nitrile group or CONHR ⁸ (R ⁸ represents a hydrogen atom or a lower alkyl group), and R ⁴ represents a lower group which may have a substituent. An alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group or Represents an aralkyl group which may have a substituent, R ⁵ represents a hydrogen atom or a lower alkyl group, R ⁶ and R ⁷ represent a hydrogen atom or a lower alkyl group, and —A—B— represents —CH—CH. -, -C = C-, -C = N- or -N = C-, m ¹ and m ² Is an integer of 1 to 6, n is an integer of 1 to 10, and Z ⁻ represents an anion] or a hydrate or solvate thereof and a drug A pharmaceutical composition comprising a top acceptable carrier. R ¹ and R ² are phenyl groups, R ³ is a nitrile group or CONH ₂ group, R ⁵ is a hydrogen atom or a lower alkyl group, R ⁶ and R ⁷ are hydrogen atoms or a lower alkyl group, The pharmaceutical composition according to claim 6, wherein m ¹ is 1 or 2, and m ² is an integer of 2 or 3. R ¹ and R ² are phenyl groups, R ³ is a nitrile group or CONH ₂ group, R ⁵ is a hydrogen atom or a lower alkyl group, R ⁶ and R ⁷ are hydrogen atoms or a lower alkyl group, m ¹ is 1, ^{m 2} is the pharmaceutical composition of claim 6 wherein the second integer. R ⁴ may have a lower alkyl group which may have a substituent, a lower alkoxy group which may have a substituent, an aryl group which may have a substituent, or a substituent. The pharmaceutical composition according to any one of claims 6 to 8, which is an aralkyl group. Muscarinic M ₃ receptor is a preventive or therapeutic agent for diseases involving claims 6 to 9 pharmaceutical composition. 10. The pharmaceutical composition according to claim 6, which is a preventive or therapeutic agent for respiratory diseases, urological diseases, digestive organ diseases or central diseases. 12. The respiratory disease is chronic obstructive pulmonary disease, chronic bronchitis, asthma, chronic airway obstruction, pulmonary fibrosis, emphysema, diffuse panbronchiolitis, bronchiectasis, idiopathic interstitial pneumonia or rhinitis The pharmaceutical composition as described. The pharmaceutical composition according to claim 11, wherein the urinary disease is urinary incontinence and / or frequent urination in neurogenic pollakiuria, neurogenic bladder, enuresis, unstable bladder, bladder spasticity, chronic cystitis, interstitial cystitis. 12. The pharmaceutical composition according to claim 11, wherein the digestive system disease is irritable bowel syndrome, spastic colitis, diverticulitis, functional diarrhea, anesophageal anorexia, cardia spasm or biliary spasm. 12. The pharmaceutical composition according to claim 11, wherein the central disease is nausea or vomiting, motion sickness or Menuel disease caused by drug administration. Formula (I)


[Wherein, R ¹ is an aryl group which may have a substituent on the ring, R ² is an aryl group which may have a substituent on the ring, a lower alkyl group which may have a substituent, or Represents a cycloalkyl group which may have a substituent, R ³ represents a nitrile group or CONHR ⁸ (R ⁸ represents a hydrogen atom or a lower alkyl group), and R ⁴ represents a lower group which may have a substituent. An alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group or Represents an aralkyl group which may have a substituent, R ⁵ represents a hydrogen atom or a lower alkyl group, R ⁶ and R ⁷ represent a hydrogen atom or a lower alkyl group, and —A—B— represents —CH—CH. -, -C = C-, -C = N- or -N = C-, m ¹ and m ² Is an integer of 1 to 6, n is an integer of 1 to 10, and Z ⁻ represents an anion]] or a hydrate or solvate thereof. muscarinic M ₃ receptor antagonist to components.