WO2000056718A1

WO2000056718A1 - Imidazole compounds

Info

Publication number: WO2000056718A1
Application number: PCT/JP2000/001738
Authority: WO
Inventors: Nobuyuki Yasuda; Jun-Ichi Endoh; Masataka Miura; Hideyuki Aizawa; Norio Ohno
Original assignee: Mitsubishi-Tokyo Pharmaceuticals, Inc.
Priority date: 1999-03-24
Filing date: 2000-03-22
Publication date: 2000-09-28
Also published as: AU3324700A; JP2003286266A

Abstract

Compounds represented by general formula (I) or pharmacologically acceptable salts thereof, wherein Y represents hydrogen, cyano or carbamoyl; Z represents CH or nitrogen; -A-B- represents -CH2-CH2- or -CH=CH-; m is 1 or 2; and n is 0 or 1. Because of having an extremely potent and selective antagonism to muscarine M3 receptor, these compounds are useful as preventives or remedies for diseases in which muscarine M3 receptor participates. In addition, these compounds can provide safe drugs scarcely causing thirst which is a side effect of muscarine M3 receptor antagonists.

Description

Description Imidazole Compound Technical Field

The present invention relates to a novel imidazole compound useful as a pharmaceutical, and more specifically, a novel imidazole compound which is a selective musculin receptor antagonist, a pharmacologically acceptable salt thereof, and a novel imidazole compound. The present invention relates to a pharmaceutical composition containing the same and a musculin phosphorus M ₀ receptor antagonist containing the same as an active ingredient. Background art

Mus force phosphate receptor least three sub evening I flop the body Ari, receptors in the brain, Micromax ₂ receptors in the heart, Micromax ₃ receptors is known to be present in smooth muscle and glandular tissue Teshiru Pharmaceuticals having a muscarinic receptor antagonistic action exhibit an analgesic action, an analgesic action, and an antisecretory action, and are therefore used as a therapeutic drug for dysfunction of the intestine or bladder. Atto port pins as a medicament having厶Sukarin receptor antagonism, scopolamine, Okishipuchinin, Nioii匕Purono Nterin, forces that Ipurato port Piu厶等rather, these muscarinic receptors, Micromax Ri and Micromax ₃ receptors relative to It is known that they have almost the same affinity, and because they antagonize acetylcholine in a non-selective manner, side effects cannot be avoided. Therefore, a drug having a highly selective muscarinic receptor antagonistic action, particularly a drug which does not exhibit side effects on the heart involving the が₂ receptor has been desired.

3-substituted pyrrolidine derivatives as compounds that selectively antagonize the muscular force 1 ^ receptor (Japanese Patent Application Laid-Open No. Hei 2-282, Japanese Patent Application Laid-Open No. Hei 4-2505927, Japanese Patent Laid-open No. Hei 7- No. 1 496 40), 3-substituted piperidine derivative (Japanese Patent Application Laid-Open No. 4-5000521 No. 1), carbamate derivative (W095 / 0663) ), diphenyl acetic acid derivative ¾ | but the (JP-8 2 9 1 1 4 1 No.) are known, both isometric against Muscari Micromax ₃ receptor is not sufficient. On the other hand, Japanese Patent Application Laid-Open No. 7-215943 discloses an imidazole derivative having a strong antagonism, having an ill length of 14 ^ higher than that of the muscarinic receptor of the heart and of the muscarinic receptor of flat it®J. Is through an imidazole ring, substituted methyl and an alkylene group having 1 to 6 carbon atoms.

[In the formula, represents a phenyl group or a phenyl group which may have a substituent, and R ₂ represents a cyano group, a hydroxyl group, a carboxyl group, a C〇NR ₇ R ₈ group (wherein, R ₇ , R Are the same or different and each represent a hydrogen atom or a lower alkyl group, or R ₇ and R ₈ may form a ring with an alkylene chain which may contain a heteroatom) or a COORQ group (formula Wherein R ₀ represents a lower alkyl group), R ₃ represents a hydrogen atom or a lower alkyl group, and R, R ₅ and R ₆ are the same or different and have a hydrogen atom and a substituent; T, a carbon atom representing a lower alkynole group or a cycloalkyl group, or a condensed ring with a benzene ring at R ₅ and R ₆ , and m represents an integer of 1 to 6]

Is disclosed. Compound (I) has a pyrrolidine skeleton, a piperidine skeleton, or a cycloalkane skeleton in its structure, and obviously has a different structure. As described later, the compound (III) described in Example 11 of this publication

Shows no significant difference in the interwovenness of muscarin> M ₃ receptor antagonistic activity, whereas the conjugated compound (I) has a low affinity for the muscarinic? ^ ₂ receptor in the heart, and the muscarinic M ₃ It has selective antagonism against the receptor. (See Table 1).

In addition, the present inventors filed a patent application for indolated ^ ¾ (WO 98/54167) and aminocycloalkane compound (WO 99/050 95) having a muscular force 1 ^ ₃ receptor antagonistic action. ing. DISCLOSURE OF THE INVENTION The present invention is to provide a compound having a strong antagonism which is higher in the scale of the musk-phosphorus receptor than that of the heart.

The present inventors have focused on imidazole compounds and conducted intensive studies.

M ₃ receptors Senshaku 1¾ ^ high, imidazo Ichiru compound having Chikaratsu antagonism (I)

Me

Π N ':, N

A, B

m m

Y

(I) or a pharmacologically acceptable salt thereof was found, and the present invention was completed.

In the formula (I), Y is a hydrogen atom, a cyano group or a canolebamoinole group, preferably a rubamoyl group. Z is a CH group or a nitrogen atom, preferably a CH group. One A—B—is one CH. A CH ₂ — group or —CH = CH— group, preferably one CH ₂ —CH. —It is a group. m is 1 or 2, and preferably 1. n is 0 or 1, and is preferably 0.

In the present invention, the “chemically acceptable salts” include inorganic salts such as hydrochloric acid, nitric acid and sulfuric acid, organic acid salts such as acetic acid, citric acid, fumaric acid and alcohol, methanesulfonic acid, p — Sulfonic acids such as toluenesulfonic acid, etc., and aminic acid power such as alanine, leucine, guanolemic acid, and gluminamine.

Since the compound (I) of the present invention has one or more asymmetric carbon atoms in the molecule, optical isomers may be present, and those optical isomers and mixtures thereof may be L-shift.

Further, the compound (I) of the present invention or a pharmaceutically acceptable salt thereof may be isolated as a hydrate or a solvent. These are also included in the present invention.

The present invention of ^ (I) or a pharmacologically acceptable salt thereof, optionally, Chikaratsu strong厶since Sukarin M ₃ having a receptor antagonism, diseases Mus force phosphoric M ₀ receptors are involved In particular, chronic obstruction 'respiratory diseases such as sickness disease, asthma, fibrosis and rhinitis; hypersensitivity' Used as a preventive or therapeutic agent for gastrointestinal diseases such as spastic inflammation and diverticulitis; central illness such as nausea and vomiting, sickness, and menure's disease caused by drug administration; and urinary diseases such as urinary incontinence and pollakisuria be able to.

Further, the compound (I) of the present invention can be produced by the method described below. I DAILY ^! (IV)

-τ ^

? ", M

[Wherein, Y, Z, m and η are the same as described above, and X represents a leaving group. ]

In a solvent such as acetone nitrine, acetone, ethyl methyl ketone, etc.

Me

(V)

[Where, — A— B— is the same as above. ]

The mixture can be obtained as a salt of compound (I) or compound (I) by ordinary operations such as extraction and purification.

Here, any group may be used as long as it functions as a leaving group in a normal chemical reaction. Specifically, a sulfonyloxy group (for example, p-toluenesulfonyloxy group, benzenesulfonyloxy group, methyl sulfonyloxy group, trifluoromethanesulfonyloxy group, etc.) and a halogen atom (for example, chlorine, Bromine, iodine) and the like.

I-Dani (IV)

[Wherein, Y, Z, m and n are the same as above. ] In a solvent such as tetrahydrofuran, ether, chloroform, dichloromethane, or the like, in the presence of a base such as triethylamine, 4-dimethylaminopyridine, sodium carbonate, or carbonated lithium, and p-toluenesulfonyl chloride or medium. The compound can be obtained by reacting with a force for forming a sulfonyl chloride or the like, or by reacting with triphenylphosphine in carbon tetrachloride or carbon tetrabromide.

Compound (VI I) in which Y in Formula (I) is a carbamoyl group

Me

A, _B

m

H ₂ NOC

(VII)

[Wherein, Z, — A— B—, m and n are the same as above. ]

Or a salt thereof, hitherto obtained by a method has been described of ^ ^/ goods (VIII)

[Wherein, Z, —A—B—, m and n are the same as above. ]

Can also be obtained by hydrolysis in a sulfuric acid aqueous solution or a sulfuric acid aqueous solution containing acetic acid at room temperature to 140 ° C, preferably at 70 ° C to 140 ° C.

In addition, the compound (I X) which is a nitrogen atom and a nitrogen atom in the present invention (I)

[Wherein, Y, 一 -Α-, m and η are the same as described above. ]

Or a salt thereof in a solvent such as acetonitrile, tetrahydrofuran, ether, chloroform, dichloromethane, etc.

[Wherein, Y represents the same as above, and X represents de 1. ]

^ J (X I),

Me

'' n N (XI)

H B

m

[Wherein, A-B-, m and n are the same as described above. ]

Furthermore, a base such as triethylamine, 4-dimethinoleaminopyridine, sodium carbonate, carbonic acid lime is added, and the mixture can be stirred under a solution.

Invented ^! The pharmacologically acceptable salts of (I) include, for example, carboxylic acid salts such as hydrochloric acid, nitric acid, and sulfuric acid; organic acid salts such as acetic acid, citric acid, and fumaric acid; methanesulfonic acid; Sulfonic acid ^ X such as tosylic acid can be situated by the action of an amino acid such as alanine, leucine, glutamic acid or glutamine in a conventional manner. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited thereto.

(^ 1) 2— [3- (2-Methyl-1,4,5-dihydroimidazole-1-yl) cyclopentyl] —2,2-diphenylacetonitrile

P-Toluenesulfonic acid 3 — [(1-cyano-1,1-diphenyl) methyl] cyclopentylester (16.7 g: 38.8 mmol) obtained from Production Example 3, 2-methyl-1,4— A solution of dihydroimidazole (16.3 g: 193.8 mmol) in acetonitrile (150 ml) was stirred with heating under reflux for 7 hours. The reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with black hole form, and then washed twice with water. After drying with anhydrous sodium sulfate, the solvent is distilled off under reduced pressure. Graphite [Developing solvent: black-mouthed form / methanol = 3 / 1—black-mouthed formuzumethanol (0.5% triethylamine) = 2/1] to give an oil. Isopropyl ether was added to the oil, and the resulting white crystalline powder was collected by filtration.

47 g (64% yield) was obtained.

Melting point: 109. 0-11 1.0 ° C

^{_{1 H-NMR (CDC 1 3}} ) δ 1. 58 - 2. 02 (6 Η, m), 1. 88 (3 H, s), 3. 04- 3. 22 (1 H, m), 3. 24—3.44 (2H, m), 3.

52 -3. 74 (2H, m), 3.82 -4. 04 (1 H, m), 7.12-7.5.4 (1 OH, m)

(Male Example 2) 2- [3- (2-Methyl-4,5-dihydroimidazole-1-yl) cyclopentyl] —2,2-diphenylacetonitrile (1) Dibenzoyl-L monosalt

2- [3- (2-Methyl-1,4,5-dihydroimidazole obtained from ι

1-yl) cyclopentyl] —2,2-diphenylacetonitrile (6.36 g: 18.5 mmol), (1) dibenzoyl-L—liquor (3.32 g: 18.5 mm 01), Mix of ethanol (40 Om 1) ^! Was dissolved under heat reduction. Thereafter, the mixture was allowed to stand at room temperature, and the resulting white powder was collected by filtration to obtain 3.73 g of an oxide (yield 29%: 75.δ% ee). The powder was dissolved in ethanol (400 ml) under heat reduction. Thereafter, the mixture was allowed to stand at room temperature, and the resulting white powder was collected by filtration to obtain 1.84 g of ^ (yield: 14%: 92.7% ee). Next, in ethanol (180 m 1) and use the repeatedヽsame operation,: 0. 98 ₈ ¾ of ^ as fe crystalline powder (8% yield: 98. 5% ee) was obtained. Optical purity was determined by high performance liquid chromatography under the following conditions. Optical resolution column: CH I RALCE LOD 0.46 cmOx 25 cm

(DA I CEL CHEMI CAL I ND., LTD.)

Eluent: n-hexane: ethanol: getylamine = 100: 10: 1

Flow rate: 1. Om 1 Zmin, detection wavelength: 254 nm, column temperature: 40.0 ° C Melting point: 174.0-175.0 ° C ¹ H-NMR (DMSO-d ₆ ) 5: 1.36-1.64 (2 H, m), 1.66-2.04 (4H, m), 2.15 (3 H, s), 3.36—3.94 (5H, m), 4.12 -4.36 (1H, m), 5.62 (2H, s), 7.14—7.72 (16H, m), 7.76—8.08 (4 H, m)

(Example 3) (+) —2— [3- (2-Methyl-4,5-dihydroimidazoyl-1-yl) cyclopentyl] —2,2-diphenylacetonitrile

2- [3- (2-Methyl-1,4,5-dihydroimidazoyl-11-yl) cyclopentyl] obtained from Example 2—2,2-diphenylacetonitrile (1) dibenzolyl L-tartrate ( To 0.98 g: 1.38 mmo 1), an aqueous sodium hydroxide solution was added to make the mixture basic, and the mixture was extracted with chloroform. The extract was washed with saturated saline, and then sickled with anhydrous sodium sulfate. The solvent was concentrated under 'E to give 0.48 g (quantitative yield) of ¾о 化 ^) as SSfe amorphized ^ /.

^{_{1 H-NMR (CDC 1 3}} ) δ 1. 58- 2. 02 (6Η, m), 1. 88 (3 H, s), 3. 04- 3. 22 (1 H, m), 3. 24 -3.44 (2H, m), 3.52-3.74 (2H, m), 3.82 -4.04 (1Η, m), 7.12-7.54 (10 Η, m)

_{^{^{[] D 27 - 0: +}}} 62. 9 ° (C = 0. 99, CHC 1 3)

(Example 4) 2- [3- (2-Methyl-1,4,5-dihydroimidazole-1-yl) cyclopentyl] —2,2-diphenylacetonitrile (+) — Dibenzoyl —D-sake salt

2- [3- (2-Methyl-4,5-dihydroimidazole-l-yl) cyclopentyl] -l, 2,2-diphenylacetonitrile (1) -Dibenzoyl-L-tartrate (Example 2) The concentrate of the filtrate thus obtained was made basic with an aqueous sodium hydroxide solution. This was extracted with chloroform and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue and (+)-dibenzoyl-D-liquor (3.32 g: 18.8 ammo 1) were dissolved in ethanol (375 ml) under heating and reflux, and the mixture was allowed to stand at room temperature to form. The white powder was collected by filtration, and 2.77 g of the compound (30% yield: 76.7% e e) obtained. After dissolving the powder in ethanol (180 ml) under heating and refluxing, it is left at room temperature, and the resulting white powder is collected by filtration, and 1.66 g of the chloride is obtained (13% yield). : 95.0% ee). The same operation was repeated using ethanol (100 ml) to obtain 1.08 g of a tfe crystalline powder (yield 8%: 99.9% ee). The optics were determined by high performance liquid chromatography under the same conditions as in Example 2.

(麵 Example 5) (—) 1—2— [3 -— (2-Methyl-1,4,5-dihydroimidazo-1-lu-1-inole) cyclopentyl] 1,2,2-diphenylacetonitrile

2- [3- (2-Methyl-4,5-dihydroimidazole-1-11yl) cyclopentyl] -1,2,2-diphenylacetonitrinole obtained from Example 4 (+) — Dibenzoinole D —Salt (1.06 g: 1.δ 1 mm 01) was made basic by adding aqueous sodium hydroxide solution. Then, the extract was extracted with black-mouthed form, washed with a saturated diet ^ ZK, and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to obtain 0.52 g (yield quantitative) of the として compound as a ¾m amorphous compound.

_{^{^{[a] D 27 - 4:}}} - 60. 2 ° (C = 0. 98, CHC 13)

Example 6) (+) —2— [3— (2-methyl-4,5-dihydroimidazolone)

1-yl) cyclopentyl] _2,2-diphenylacetamide

(+) — 2 -— [3 -— (2-Methyl-4,5-dihydroimidazoyl-1-yl) cyclopentyl] -1,2,2-diphenylacetitolinole obtained from Example 3 (0.4 A 70% sulfuric acid solution (11.6 ml) was added to a solution of 8 g: 1.38 mm01) in acetic acid (5 ml), and the mixture was stirred at 140 ° C for 4 hours. ? After the reaction, the reaction solution was made basic by adding an aqueous sodium hydroxide solution, extracted with chloroform, washed with a saturated diet, and then crushed with anhydrous sodium sulfate. 'The solvent was distilled off under E, and the resulting residue was subjected to silica gel column chromatography [Developing solvent: black-mouthed form Z methanol = 3/1-black-mouthed form / methanol (0.5% tritylamine) = 1Z1 — 1Z10] to give 0.43 g (yield 86%) of 麵化 ^ as an achromatic amorphous compound.

¹ H-NMR (CDC) ₃ ) c5: l. 18-1.57 (3 H, m), 1.58- 1.74 (1 H, m), 1.78 -2.04 (2H, m), 1.90 (3H, s), 2. 82-3.04 (2 H, m), 3.30-3.57 (3 H, m), 3.80-4. 00 (1 H, m), o. 45 (2H, brs), . 7. 14-7 48 (1 0 H , m) [a] D 30 - 0: + 9. 72 ° (. C = l 03, CHC 13)

\ 7) (1) 1- 2- [3- (2-Methyl-4,5-dihydroimidazole-11-yl) cyclopentyl] 1,2,2-diphenylacetamide

(1) —2 -— [3- (2-Methyl-1,4,5-dihydroimidazoyl-1-yl) cyclopentyl] obtained from Example 5 —2,2-diphenylacetonitrinole (0. To a solution of 52 g: 1.5 lmmo 1) in acetic acid (lm 1) was added a 70% sulfuric acid swelling solution (11.6 ml), and the mixture was stirred at 140 ° C for 90 minutes. After cooling, the reaction solution was basified by adding aqueous sodium hydroxide solution, extracted with chloroform, washed with a closed port ^ J <, and dried over anhydrous sodium sulfate. The lower solvent was distilled off, and the obtained residue was subjected to gel chromatography. [Developing solvent: black-mouthed form Z methanol = 3Z1-black-mouthed form / methanol (0.5% triethylamine) = Purification by 1-1-1Z10] gave 0.5 g (yield 92%) of the compound as an achromatic amorphous compound.

_{^{^{. [a] D 24 - 4}}} : -9 84 ° (C = 0. 99, CHC 1

(Castle 8) 2- [3- (2-Methyl-4,5-dihydroimidazoyl-1-yl) cyclopentyl] —2,2-diphenylacetamide

According to Example 6, 2- [3- (2-methyl-1,4,5-dihydromidazole-11-yl) cyclopentyl] 1,2,2-diphenylacetonitrile obtained from Example 1 (0. From 26 g: 0.76 mmo 1), 0.07 g (yield: 26%) of an oxide was obtained as amorphous ^.

¹ H-NMR (CDC 1) δ 1.18-1.57 (3H, m), 1.58-1.74 (1 H, m), 1.78-2.04 (2 H, m) , 1.90 (3H, s), 2.82 -3.04 (2H, m), 3.30-3.57 (3 H, m), 3.80-4.00 (1 H, m ), 5.45 (2H, brs), 7.14-7.48 (10H, m) Example 9) 2- [3- (2-Methyl-4,5-dihydroimidazole-1-yl) cyclopentyl ] —2,2-Diphenylacetonitrile According to Example 1, p-toluenesulfonic acid 3-[(1-cyano 1,1-diphenyl) methyl] cyclopentyl ester (0.43 g: lm mo 1) obtained from Example 5 and 2-methynolone By reacting 4,5-dihydroimidazo mono (0.42 g: 5 mmo 1), 0.21 was obtained as pale brown oil (yield 61%).

_{1 H-NMR (CDC 1 3} ) δ: 1. 43 - 2. 24 (6Η, m), 1. 91 (3 H, s), 3. 02 - 3. 45 (3Η, m), 3. 48 -3.76 (2Η, m), 4.02-4.27 (11, m), 7.08-7.59 (10Η, m)

(麵 Example 10) 2- [3- (2-Methyl-1,5-dihydroimidazole-1-yl) cyclopentyl] -1,2,2-diphenylacetamide J £

According to Example 6, 2- [3- (2-methylimidazole-11-yl) -cyclopentyl] -2,2-diphenylacetonitrile obtained from Example 9 (0.21 g: 0.6 mmo 1 ), 0.1 g (46% yield) of the nitride was obtained as {amorphization ^}.

^{_{1 H-NMR (CDC 1 3}} ) 6:. 1. 32- 2. 09 (6H, m), 1. 71 (3 H, s), 3. 16-3 75 (6H, m), 5. 41 (2Η, brs), 7.08 -7.54 (1 OH, m)

(Male Example 11) 1-[(1-diphenylmethyl) pyrrolidine-3-yl] —2-methyl-1H-imidazole

A solution of 2-methylimidazole (0.12 g: l.5 mmol) and sodium heptahydride (36 mg: 1.5 mmol) in N, N-dimethylformamide (5 ml) was added at room temperature to give a solution. After stirring for 1 hour, methanesulfonic acid [(1-diphenylmethyl) pyrrolidine-13-yl] ester (0.41 g: 1.24 mmol) was added, and the mixture was stirred at 80 ° C for 1 hour. Water was added to the reaction solution, extracted with ethyl acetate, and then the organic layer was washed twice with water. After removing the solvent with sodium sulfate anhydride, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography [developing solvent: black-mouthed form]. 27 g (69% yield) was obtained.

_{1 H-NMR (CDC 1 3} ) δ: 1. 82 - 2. 05 (1 Η, m), 2. 23-2. 53 (2H, m), 2.35 (3H, s, 2.55-2.70 (1H, m), 2.71-2.84 (1H, m), 2.86-3.04 (1 H, m), 4.22 (1 H, s), 4.50— 4.70 (1 H, m), 6.9 δ (1 H, s), 7.09-7. Δ 6 (1 1 H, m)

Example 12) 1- [1- (diphenylmethyl) piperidine-14-yl] -12-methyl-1H-imidazole

4- (2-Methylimidazo-1-yl) piperidine hydrochloride (0.48 g: 2 mmo 1), α-bromodiphenylmethane (0.6 g: 2.4 mmol), trieti An acetonitrile (10 ml) solution of luminin (0.84 ml: 6 mmol) was stirred for 6 hours under reflux with heating. 10% hydrochloric acid was added to the solution, and extracted with ethyl acetate. The z layer was adjusted to ρ カリウム 10 with potassium carbonate. The mixture was extracted with ethyl acetate, and the organic layer was washed with an aqueous solution of sodium hydrogen carbonate and water. The residue obtained by distilling off the lower solvent with anhydrous sodium sulfate is purified by silica gel gel column chromatography [developing solvent: chloroform Ζ methanol = 50: 1] to obtain ^ 化 ^ / as white crystals. 0.14 g (yield 22%) was obtained as a functional powder.

Melting point: 138.5-140.5 ° C

^{_{1 H-NMR (CDC 1 3}} ) δ 1. 76-2. 11 (6Η, m), 2. 36 (3 H, s), 2. 93- 3. 16 (2 H, m), 3. 64 -3.95 (1H, m), 4.34 (1H, s), 6.93 (1H, brs), 6.95 (1H, brs), 7.08-7.56 ( 1 OH, m)

Example 13) 1— {[1— (diphenylmethyl) pyrrolidine-3-yl] methyl-12-methyl-1H-imidazole

According to Example 11, methanesulfonic acid [(1-diphenylmethyl) pyrrolidine-13-yl] methyl ester (◦. 33 g: 0.94 mmo 1), 2-methylimidazole (0.1 g: l. 2mmo 1) and sodium hydrogen hydride (29 mg: 1.2 mmo 1) were reacted to obtain 0.16 g of the compound as a pale brown oily compound (yield: 52%). ^{_{1 H-NMR (CDC 1 3}} ) δ:.. 1. 36 - 1. 58 (1 H, m), 1. 84-2 07 (1 H, m), 2. 2 1 -2 74 (5 H , m), 2.36 (3H, s), 3.63—3.95 (2H, m), 4.17 (1H, s), 6.77 (1H, brs), 6 85 (1 H, brs), 7.05—7.56 (10 H, m)

c rn 14) 2— [3— (2-methylimidazoyl i-yl) cyclopentene] -2,2-diphenylacetonitrile

Example 11 According to 1, p-toluenesulfonic acid 3-[(1-cyano 1,1-diphenyl) methyl] cyclopentyl ester (0.65 g: l. 51 mm 01) obtained from Production Example 5, 2 —Methylimidazole (0.19 g: 2.26 mmol) and 7j sodium iodide (0.05 g: 2.26 mmol) react ¾S ^ to a pale brown amorphous 0.35 g (yield 67%) was obtained as the compound ^ /.

^{_{1 H-NMR (CDC 1 3}} ) δ 1. 62-2. 07 (4H, m), 2. 1 1 -2. 47 (2H, m), 2. 37 (3Η, s), 3. 32- 3.55 (1Η, m), 4.57-4.73 (1Η, m), 6.88 (1Η, brs), 6.92 (1Η, brs), 7.14—7. 58 (1 OH, m)

Example 1 5) 2- [3- (2-Methylimidazole-1-11-yl) cyclopentinole] -2,2-diphenylacetamide

According to Example 6, «2— [3- (2-methylimidazo-1-one) -1-pentyl) cyclopentyl] obtained from Example 14—2,2-diphenylacetonitrinole (0.2 g : 0.6 mmo 1): 0.12 g (yield 57%) was obtained as:

^{_{1 H-NMR (CDC 1 3}} ) δ 1. 52 - 2. 14 (6Η, m), 2. 2 1 (3 H, s), 3. 55 - 3. 77 (1 H, m), 3. 83-4.10 (1H, m), 5.44 (2Η, brs), 6.90 (1Η, brs), 6.96 (1Η, brs), 7.1 δ-7. 49 (1 OH, m)

Example 16) 2— [3- (2-Methylimidazole-1-yl) cyclopentinole] —2,2-diphenylacetonitrile According to Example 11, 2- (3-chlorocyclopentyl) -1,2,2-diphenylacetonitrinole obtained from Production Example 4 (0.44 g: l.5mmo 1), 2-methylimidazo (0.19 g: 2.26 mmo 1) and sodium hydride (0.05 g: 2.26 mmo 1) to react with 0.17 g (yield 32 %)Obtained.

¹ H-NMR (CDC 13) δ 1.70-2.73 (6 6, m), 2.35 (3H, s), 3.15-3.36 (1H, m), 4.30 -4.55 (1H, m), 6.91 (1Η, brs), 7.00 (1H, brs), 7.14-7.57 (10H, m)

(Castle 17) 2- [3- (2-Methinoreimidazo-l-l-yl) cyclopentene] —2,2-diphenylacetamide

According to Example 6, 2- [3- (2-methylimidazole-1-yl) cyclopentyl] —2,2-diphenylacetonitrinole obtained from Example 16 (0.17 g: From 0.49 mmo 1), 0.14 g (yield 77%) of an oxide was obtained as »amorphized ^ ¾.

^{_{1 H-NMR (CDC 1 3}} ) δ 1. 32 - 1. 53 (1 Η, m), 1. 55- 1. 82 (2H, m), 1. 89- 2. 14 (2H, m), 2.18-2.40 (1H, m), 2.32 (3H, s), 3.40-3.67 (1H, m), 4.23-4.45 (1H, m) ), 5.44 (2H, brs), 6.45 (1H, brs), 6.77 (1H, brs), 7.14-7.52 (10H, m)

(Difficulty 18) (+)-2- [3- (2-Methylimidazo-1-yl) cyclopentyl] -1,2,2-diphenylacetonitrile

2- [3- (2-Methylimidazole-11-yl) cyclopentyl] -1,2,2-diphenylacetonitrile (4.9 g: 14.4 mmol) of acetonitrile (50 ml) obtained from Example 16 ) solution, L one tartaric acid (2. 1 5 g: 14. 4mmo Asetonitoriru of l) (20 Om 1) after the solution was mixed at 60 ° C and filtered off powder produced in _c stirring was cooled to room temperature under stirring To give 3.07 g of the L-tartrate salt of the title compound (44% yield: 75. 9% ee). Subsequently, the leverage powder was dissolved in acetonitrile (350 ml) under heat reduction, left at room temperature, and the resulting white powder was collected by filtration. 64 g (yield 38%: 98.2% ee) was obtained. Next, an aqueous sodium hydroxide solution was added to this powder (2.5 g: 5.09 mmo 1) to make it basic, followed by extraction with chloroform, washing with saturated maleic water, and anhydrous sodium sulfate. I did. The solvent was concentrated under reduced pressure to obtain 1.69 g (yield 97%) of solidified ^ as amorphous ^. Optical ¾ was determined by high performance liquid chromatography under the same conditions as in Example 2 except that the detection wavelength was 220 nm and the column temperature was 35.0 ° C.

_{1 H-NMR (CDC 1 3} ) 5:.. 1. 70-2 73 (6H, m), 2. 3 δ (3 H, s), 3. 15-3 36 (1 H, m), 4 30-4. 55 (1H, m), 6.91 (1H, brs), 7.00 (1H, brs), 7.14-7.57 (10H, m)

_{^{^{[a] D 30 - 7:}}} + 35. 2 ° (. C = l 04, CHC 1 3)

rn 19) (1) 1 2— [3— (2-Methylimidazo-l-yl) cyclopentyl] 1,2,2-diphenylacetamide

According to Example 6, (+)-2- [3- (2-methylimidazole-11-yl) cyclopentyl] -2,2-diphenylacetitol obtained from Example 18 (1.64) g: 4.8 mmo 1), 1.29 g (yield 75%) of the title compound was obtained as an amorphous compound of fe.

^{_{1 H-NMR (CDC 1 3}} ) δ:.. 1. 32 - 1. 53 (1 Η, m), 1. 55-1 82 (2H, m), 1. 89-2 14 (2Η, m) , 2.18-2.40 (1H, m), 2.32 (3H, s), 3.40-- 3.67 (1H, m), 4.23-4.4.4 δ (1H, m ), 5.44 (2H, brs), 6.45 (1H, brs), 6.77 (1H, brs), 7.14—7.52 (10H, m)

_{^{^{[a] D 30 - 0:}}} - 13. 3. (C = l.10, CHC 13)

(m 20) (—) 1—2— [3— (2-Methylimidazole-i-yl) cyclopentyl] —2,2-diphenylacetitol The concentrate of the filtrate obtained in Example 18 was made basic with an aqueous sodium hydroxide solution, extracted with chloroform, extracted with anhydrous sodium sulfate, and then the lower solvent was distilled off. A mixture of the obtained residue (2.7 g: 7.9 lmmo 1), D-tartaric acid (1.19 g: 7.91 mMol), and acetonitrile (145 ml) was added to 60 ° C with stirring. After warming, it was cooled to room temperature. The powder produced during the stirring was collected by filtration to obtain 3.13 g (yield: 80%: 89.8 ee) of D-alcohol of 化化 ^. Subsequently, this powder was dissolved in acetonitrile (350 m 1) while heating under reflux, and the mixture was allowed to stand at room temperature. The resulting white powder was filtered, and 2.6 g of the title D-alcohol salt ( Yield 70%: 97.2 ee) obtained. The same operation was repeated using acetonitrile (35 Om 1) to obtain 2.13 g (yield 57%: 99.9 ee) of the hydride D-sake salt as an amorphous powder. Then this powder

(2.0 g: 4.07 mmo 1) was made basic by adding aqueous sodium hydroxide solution, extracted with chloroform, washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was concentrated under the following conditions, and 麵化 ^ was obtained as an amorphous compound in an amount of 1.35 g (yield 9

7%). Optical purity was determined by high performance liquid chromatography under the same conditions as in Example 18.

^{_{1 H-NMR (CDC 1 3}} ) 6:. 1. 70-2 73 (6H, m), 2. 35 (3 H, s), 3. 15- 3. 36 (1 H, m), 4. 30 -4. 55 (1Η, m), 6.91 (1Η, brs), 7.00 (1Η, brs), 7.14—7.57 (10Η, m)

_{^{^{[α] D 32 - 0:}}} - 35. 9 ° (. C = l 12, CHC 13)

Example 21) (+) -2-[3--(2-Methylimidazole-1-yl) Cycle mouth -2,2-diphenylacetamide

According to Example 6, (-)-1- [3- (2-methylimidazo-1-yl 1-cyclopentyl) cyclopentyl] _2,2-diphenylacetonitrile obtained from Example 20 (1.3 g: 3 81 mm 0 1), 1.03 g (yield: 75%) of ¾ was converted to fe amorphization!.

^{_{1 H-NMR (CDC 1 3}} ) δ 1. 32 - 1. 53 (1 Η, m), 1. 55- 1. 82 (2H, m), 1.89-2.14 (2H, m), 2.18-2.40 (1H, m), 2.32 (3H, s), 3.40 -3.67 (1 H, m), 4.23-4.4 δ (1 H, m), 5.44 (2 H, brs), 6.45 (1 H, brs), 6.77 (1 H, brs) ), 7.14-7. 52 (10H, m)

_{^{^{[a] D 30 - 7:}}} + 13. 6 ° (.! C = l 06, CHC 3)

(Example 22) 2- [3- (2-Methylimidazoyl-1-yl) pyrrolidine-1-yl]-2,2-diphenylacetonitrile

According to Example 11, 1-[(1-chloro-1,1,1-diphenyl) methyl] pyrrolidine-3-yl methanesulfonate (0.36 g: lmmol), 2-methylimidazole ( 0.17 g: 2mmo 1) and sodium hydride (0.05 g: 2mmo 1) were reacted with 0.17 g (yield 48%) of the fluorinated ^ ⁷ compound as pale yellow oily ^. )Obtained.

^{_{1 H-NMR (CDC 1 3}} ) δ 1. 95-2. 18 (1 Η, m), 2. 38 (3 H, s), 2. 40 -2. 59 (1 H, m), 2. 61-2.76 (1 H, m), 2.77— 3.16 (3 H, m), 4.59 -4.80 (1 H, m), 6.99 (1 H, brs), 7.13—7.46 (7H, m), 7.57-7.78 (4H, m)

(Example 23) 2- [3- (2-Methylimidazo-1-yl) pyrrolidine-1-yl] -2,2-diphenylacetamide

According to Example 12, 2-chloro-2,2-diphenylacetamide (0.62 g: 2.5 mmol), 3- (2-methylimidazoyl-1-yl) pyrrolidine ( 0.43 g: 2.84 mmol) was used to obtain an amorphous compound (of course, 0.03 g (yield 3%)).

^{_{1 H-NMR (CDC 1 3}} ) δ 1. 86 -. 2. 07 (1 Η, m), 2. 14-2 49 (2H, m), 2. 35 (3H, s), 2. 51- 2.69 C 1 H, m), 2.74-2.92 (1 H, m), 2.98-3.18 (1 H, m), 4.33-4.5.5 (1H, m ), 5.36 (1H, brs), 6.78 (1H, brs), 6.96 (1H, brs), 7.03 (1H, brs), 7.17—7.08 ( (10 H, m) (Example l) (Example 8) (Example 15): Example 22

(Example 2) (Example 9 (Example 16) (Example 23)

(Example 4) (Example 11) (Example 18) (Production Example 2)

(Example 6) (Example 13) (Example 20) (Production Example 4)

Example 14) (Example 21) (Production Example 5)

(Example 7) (Implementation

(Production Example 1) 2- (3-oxocyclopentyl) -1,2,2-diphenylacetonitrile

Under argon, diphenylacetonitrile (98.6 g), 2-cyclopentene To a solution of 11-one (41.9 ml) in THF (1 L) was added t-butoxy potassium (0.56 g) at 110 ° C, and the mixture was stirred for 30 minutes. 6ί¾¾HCl (0.83 m 1) was added to the mixture, the lower solvent was distilled off, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. After washing with a vertical mouth, it was dried over anhydrous sodium sulfate. The lower solvent was distilled off, and isopropyl ether (250 ml) was added to the obtained residue. The precipitate was collected by filtration and dried to obtain 121.5 g of 麵化 ^ as a white crystalline powder (yield: 88%). %)Obtained.

Melting point: 96. 7- 97.4 ° C

^{_{1 H-NMR (CDC 1 3}} ) δ 1. 94 -.. 2. 08 (2Η, m), 2. 12-2 56 (4H, m), 3. 21-3 43 (1 Η, m), 7. 16-7. 62 (10 Η, m)

(W 2) 2— (3-Hydroxycyclopentyl) 1,2,2-diphenylacetate nitrile

A suspension of 2- (3-oxocyclopentyl) 1,2,2-diphenylacetonitrinole (22.0 g) in methanol (150 ml) was cooled under ice-cooling with sodium borohydride (3.09). g) was added, and the mixture was stirred for 1.5 hours. The f ^ bath was removed and left at room temperature for one hour. After adding ice and then 6N hydrochloric acid (5 ml), 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 a saturated saline solution, and the solvent was distilled off with anhydrous potassium carbonate under a pressure of m and £ to obtain 22.28 g (quantitative yield) of ¾® 化 ^ / as a crystalline powder. Was.

Melting point: 133.5—134.5 ° C

^{_{1 H-NMR (CDC 1 3}} ) δ 1. 54 -. 1. 89 (5Η, m), 2. 07-2 17 (1 Η, m), 3. 07- 3. 13 (1 Η, m) , 4.27-4.33 (1Η, m), 7.23 -7.46 (10Η, m)

(Mi Example 3) ρ-Toluenesulfonic acid 3-[[(1-cyano-1,1,1-diphenyl) methyl] cyclopentyl ester

Under an argon atmosphere, 2- (3-hydroxycyclopentyl) -1,2,2-diphenylacetonitrile (15.4 g: 55.6 mmol), triphenylphosphine (21. 0 g: 80.1 mmo 1), p-Toluenesulfonic acid methyl ester (12.1 m 1: 80.1 mmo 1) in tetrahydrofuran (240 m 1) solution, azodicarbonate getyl ester (14.5 m 1) l: 92.4 mmol) was added dropwise at −10 ° C., and the mixture was 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 obtained residue was purified by silica gel column chromatography [developing solvent: toluene] to obtain an oil. Isopropyl ether was added to the oil to crystallize it, and 16.7 g (70% yield) of the compound was obtained as white crystalline powder.

Melting point: 1 55. 7—1 58. 4 ° C

^{_{1 H-NMR (CDC 1 3}} ) δ 1. 56-2 14 (6 Η, m), 2. 43 (3 H, s), 3. 28 -. 3. 52 (1 H, m), 4. 88 -5. 06 (1 H, m), 7.10-7.54 (1 2H, m), 7.76 (2H, brd, J = 8.25 Hz)

(4) 2- (3-chlorocyclopentyl) -1,2,2-diphenylacetonitrile

In a solution of 2- (3-hydroxycyclopentyl) -1,2,2-diphenylacetonitrinole (2.10 g: 7.57 mmol) in pyridine (3 Om 1), p-toluenesulfonyl chloride (1 52 g: 7.95 mmo 1) was added under ice-cooling, and the mixture was heated to room temperature and stirred for 3 days. Ice was added to the reaction solution, extracted with ethyl acetate, washed with dilute hydrochloric acid and water, dried over sodium carbonate, and the solvent was distilled off under reduced pressure. The residue obtained was subjected to silica gel column chromatography [developing solvent: hexane Z, ethyl acetate = 10/1]. 02 g (yield 46) was obtained.

Melting point: 98.5—99.8 ° C

¹ H-NMR (CDC) ₃ ) 5: 1.57-1.83 (1 H, m), 1.85-2.50 (δΗ, m), 3.44 -3. 74 (1 H, m ), 4.42-4.67 (1H, m), 7.10-7.66 (10H, m)

(i-Example 5) p-Toluenesulfonic acid 3-[(1-cyano 1,1-diphenyl) methyl] Following the silica gel column chromatography in Production Example 4, the part eluted with [developing solvent: hexane Z ethyl acetate = 3/1] was concentrated under E, and the {S- ^} was converted to a pale yellow crystalline powder. 0.99 g (30% yield).

Melting point: 120.5-121.0 ° C

_{1 H-NMR (CDC 1 3} ) δ 1. 56-2. 14 (6 Η, m), 2. 43 (3 H, s), 2. 84-3. 12 (1 H, m), 4. 81-5.02 (1H, m), 7.10-7.54 (12H, m), 7.77 (2H, brd, J = 7.94Hz)

1. muscarinic M ₃ antagonistic effect on isolated guinea pig trachea

The occipital region of a male Hartley guinea pig was beaten, »slaughtered, and the trachea was removed while removing connective tissue. Thereafter, the esophagus and the remaining connective tissue were excised, cut at intervals of two tracheal cartilages, and used as specimens. The specimen was incubated at 37 ° C and suspended in a 5 m 1 Magnus bath filled with Krepus carbonate buffer containing indomethacin (1 μM) through 95% O ₂ — 5% CO at a static tension of 1 g. Later, a stabilization period of 60 minutes was allowed. Using the cumulative method contractile response by the force Luba calls were measured isometrically than 10- ⁸ M in 1 concentration 7 minute intervals Oyakehi 3. The sample was washed immediately after the measurement, and a 60-minute stabilization period was allowed until the next contraction reaction. The EC _{5 ()} ECA of the carbachol-induced contraction reaction was used as a control when it became stable. The test compound was applied 15 minutes before the application of carbachol. The affinity (p Ao) of the tested ^ / was determined by the Schild method (Arunlakshana, 0. and Schild, H. 0 .: Brit. J. Pharmacol., 1959, J4, 48-58). Table 1 shows the results.

2. muscarinic M ₃ antagonism that in isolated guinea pig bladder

After hitting the back of the male guinea pig guinea pig, exsanguinating and sacrificing, laparotomy was performed, and the tip of the bladder visible in the lower abdomen was lightly picked up with tweezers and cut off at the triangular bladder to remove the nutrient solution. Dipped in. After making a midline incision, a vertical strip of muscle with a length of 10 to 15 mm and a width of 3 to 5 mm was prepared. Thereafter, the visceral tissue was peeled off with ophthalmic scissors and used as a specimen. Incubate the specimen at 37 ° C and 95% O ₂ — 5% CO. The suspension was suspended at a static tension of 1 g in a 10-ml 1-magnus bath filled with Krebs carbonate buffer solution, followed by a 60-minute stabilization period. The contractile response by carbachol was measured isotonic with Oyakehi 3 than use ,, 10 ⁸ M cumulative method. The sample was washed immediately after the measurement, and a 45-minute stabilization period was allowed until the next contraction. The time point at which EC5 ₍₎ of the contractile response by carbachol was strongly stabilized was used as a control. Test ^ / was also applied 15 minutes prior to carbachol application. The affinity (pA ₉ ) of the test substance was determined in the same manner as in the case of the trachea. Table 1 shows the results.

3. Isolated guinea pig times »Muscarinic M ₃ antagonism to the running muscle

The occipital region of a male guinea pig was beaten, exsanguinated and sacrificed, and the ileum was removed while immediately removing the mesentery. After thoroughly washing the contents of the ileum, insert a 57-mm-diameter glass rod into the lumen, cut the longitudinal muscle only along the intestinal membrane attachment with a force razor, and swab the swab with the longitudinal muscle. At the boundary of the muscle, the longitudinal muscle was peeled off while making sure that the paper weave was slightly thin, and used as a specimen. The specimens were incubated at 37 ° C for a 95% 0 ₂ - After suspended in 5% C 0 static ₉ in 10ml organ bath filled with click Repusu carbonate锾衝liquid through il ^ S force 1 g, 6 0 min After a stable period. The contractile response by lightly call was measured isotonic with Oyakehi 3 than use L 10- ⁹ M accumulation method. After the measurement, the sample was washed quickly and quickly, and allowed a 45-minute stabilization period until the next contraction reaction. It was used as a control point when by lightly call was EC ₅ force stable of contraction. The test compound was applied 15 minutes before the application of carbachol, and the affinity (pA ₂ ) of the test compound was determined in the same manner as for the trachea. Table 1 shows the results.

4. Antagonistic effect of muscarinic M ₂ on isolated guinea pig left atrium

The occipital region of the Hartley-type guinea pig was beaten, exsanguinated and sacrificed. Immediately after the cardiopulmonary extirpation, the lungs, combined paper tissue, etc. were excised in the order of the ventricles, cut into the left atrium and the right atrium, and used as a specimen. The specimens were incubated at 32 ° C, to 10 m 1 organ bus meets with Krebs carbonate buffer through 95% 0 _95% C_〇 _2, it was suspended in resting tension 0. 5 g. Thereafter, contraction due to field electric stimulation (4 Hz, 2 ms ec, 1.δx threshold 'EE) was measured. After a stabilization period of 60 minutes, the inhibition by carbachol was measured isometrically at a common ratio of 3 from 10- ° M at intervals of 90 seconds using a cumulative method. The sample was washed immediately after the measurement, and a 45-minute stabilization period was allowed until the next inhibition reaction. The time point at which the EC5 ₍₎ activity of the carbachol inhibition reaction was stabilized was used as a control, and the test compound was treated with carbachol. Applied minutes ago. Affinity of the test of compound (pA ₂₎ are shown in Table 1. _c results obtained in the same manner as in the case of the trachea. Table 1 Muscarinic receptor antagonistic activity (in vitro)

5. Study on guinea pig airway contraction by intravenous administration and inhalation administration

The method of Conzette et al. (Arch. Exp. Path Pharmak., 1940, 195, 71-74) was followed. Male Hartley guinea pigs (320-440 g) were anesthetized with urethane (1.8 g / kg, i.p.), and force trachea was introduced into the trachea. After administration of decatonium bromide (2 mg./kg, i.v.) and immobilization, it was connected to a respiratory system (Lgo Basile) and ventilated. Airway constriction was measured using a bronchospasm transducer (Ugo Basile). A vehicle was administered as a test group or a control group via a drug delivery neuron of the left vein. Five minutes later, Mesacollin (3 g Z '

KG) was administered to induce airway constriction. The change in mm resistance due to the drug is calculated by calculating the contraction rate (%) from the total airway obstruction value (100%) obtained by obstructing the tracheal force neuron. ^ ^ Value. Table 2 shows the results.

6. Rat salivary secretion test

Wistar male rats (230-290 g) were anesthetized with urethane (1.2 g / kg, ip), and the right thigh was incised. did. A solvent was administered as a test compound or a control group through this force adjusting device. Five minutes later, 100 g / kg of oxotremorine was administered intravenously to induce salivation. Salivary secretion was measured using a cotton ball for 10 minutes immediately after the administration of oxotremorine. Calculated percent inhibition on the secretion amount of saliva in the control group, the dose of secreted saliva amount of the control group 5 0% inhibition of the test I spoon compound was ID _{5 0} value. Table 2 shows the results. Table 2 Musculin receptor antagonistic activity (invi vo: intravenous administration of test compound)

Industrial use

Table 1 As shown in Chemical ^ ¾ (I) is in the difference between the sentence Ru p A ₂ values Mus force phosphate 1 ₂ receptor and M ₀ receptor is 1 or more, receiving as compared to the comparative control compound It was clear that the body selectivity was excellent. In addition, compound (I) has an airway contraction inhibitory action equivalent to that of a commercially available atotopin, but has a salivary secretion inhibitory action of about 1 Z2. Table 2 shows the results. Therefore, it is considered that the chemical compound (I) can be sufficiently used clinically, and that it can be used as a safe drug that hardly develops the side effect of muscarinic 1 ^ ₃ receptor antagonist.

As described above, the disease present invention I spoon was involved muscarinic M ₃ receptors, in particular,慢生occlusion City disease, asthma, respiratory diseases such as lung fiber beauty rhinitis; hypersensitivity syndrome, spastic colitis, diverticulitis, etc. It is useful as a preventive or return IJ for central illness such as digestive tract diseases caused by drug administration, nausea and vomiting, vomiting, and Meniere's disease; urinary incontinence and frequent urination such as pollakiuria.

Claims

Scope of request

1. General formula (I)

Me

N

A,

Z B

m

Y

(I)

[In the formula, Y represents a hydrogen atom, a cyano group or a carbamoyl group, and Ζ represents a CH group or a nitrogen atom.

Five

It represents children, - A- Beta one CH ₂ - CH ₂ - group or - represents CH = CH- group, m represents 1 or 2, n represents 0 or 1. ]

Or a pharmacologically acceptable salt thereof.

2. The compound according to claim 1, wherein Y is a carnomoyl group and Z is a CH group, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, wherein m is 1 and n is 0, or a pharmacologically acceptable salt thereof.

4.2- [3- (2-Methyl-4,5-dihydroimidazo-1-yl) cyclopentyl] -12,2-diphenylacetamide or a pharmaceutically acceptable salt thereof.

5. General formula (I)

Me

n: N

Z, ^A , B

m

Y

(I) [wherein, Y represents a hydrogen atom, a cyano group or a carbamoyl group, Ζ represents a CH group or a nitrogen atom, and —Α— Β— represents one CH ₂ —CH. Represents one group or —CH = CH— group, m represents 1 or 2, and n represents 0 or 1. ]

Or a pharmacologically acceptable salt thereof as an active ingredient.

6. muscarinic M ₃ receptor is prophylaxis or jig ^ fij for diseases involving claim 5 Symbol mounting of the pharmaceutical composition.

7. Respiratory diseases, such as chronic obstructive pulmonary disease, asthma, pulmonary fibrosis and rhinitis; nervous frequency, neurogenic bladder, nocturnal enuresis, unstable bladder, bladder) «constriction, chronic cystitis, interstitial Urinary diseases such as urinary incontinence and pollakiuria in irritable cystitis, etc .; Gastrointestinal diseases such as irritable bowel syndrome, spastic colitis, and diverticulitis; Nausea and vomiting due to drug administration, vomiting, Menuel's disease, etc. The pharmaceutical composition according to claim 5 or δ, which is an agent for preventing or treating central diseases.

8. General formula (I)

Me m

Y

(I

[In the formula, Y represents a hydrogen atom, a cyano group or a carbamoyl group, Z represents a CH group or a nitrogen atom, and — A— B— is one CH ₂ —CH. Represents one group or —CH = CH— group, m represents 1 or 2, and n represents 0 or 1. ]

厶Sukarin 1 ^ ₃ receptor antagonist to represented by reduction ^ / or active ingredient a pharmacologically acceptable salt thereof in.