JP2000226385A - Quinoline compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new quinoline compound having excellent selectivity to muscarine M3 receptor, especially selectivity to muscarine M3 receptor of ileum, further having excellent selectivity to muscarine M3 receptor compared with muscarine M2 receptor and useful as a muscarine M3 receptor antagonistic agent. SOLUTION: The objective compound is expressed by formula I (R is A-W-B or a 5-10C alkenyl; A is a lower alkylene; W is none or O; B is a lower cycloalkyl, phenyl which may contain one or more substituents on the ring or the like), e.g. (+)-3-[(S)-1-phenethylpyrrolidin-3-yl]-3-phenyl-3,4-dihydro-1H- quinolin-2-one. The compound of formula I can be produced e.g. by reacting a compound of formula III synthesizable from a compound of formula II with a compound of the formula R-Y (Y is an eliminable group) (e.g. phenethyl tosylate) in an organic solvent such as acetonitrile in the presence of a base such as potassium carbonate.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION The present invention relates to quinoline compounds, specifically pharmaceutical and selective muscarinic M ₃ quinoline compound showing a receptor antagonism or a pharmacologically acceptable salt thereof and it active ingredient composition About things.

[0002]

There are at least three subtypes of the Related Art Muscarinic receptor, M ₁ receptors in the brain, M ₂ receptors in the heart, M ₃ receptors to be present in smooth muscle and glandular tissue Are known.

[0003] Pharmaceuticals having a muscarinic receptor antagonistic action exhibit an antispasmodic action, an analgesic action and an antisecretory action, and are therefore used as a therapeutic drug for dysfunction such as intestine or bladder. Atropine as a medicament having a muscarinic receptor antagonist activity, scopolamine, oxybutynin, there are propantheline bromide, etc., they have a substantially equal affinity for M _1, M ₂ and M ₃ receptors of muscarinic receptors are doing.
Therefore, it is known that side effects cannot be avoided because each receptor non-selectively antagonizes acetylcholine.
Therefore, a drug having a highly selective muscarinic receptor antagonistic action, particularly a drug not showing a side effect on the heart associated with the M ₂ receptor has been desired.

As a compound which selectively antagonizes the muscarinic M ₃ receptor, a 3-substituted pyrrolidine derivative (Japanese Patent Application Laid-Open No.
No. 82360, Japanese Patent Application Laid-Open No. 4-505927, Japanese Patent Application Laid-Open No.
149640), 3-substituted piperidine derivatives (Japanese Patent Application Laid-Open No. 4-500521), carbamate derivatives (WO95 / 06635), imidazole derivatives (Japanese Patent Application Laid-Open No. 7-215943), and diphenylacetic acid derivatives (Japanese Patent Application Laid-Open No. 7-215943). No. 8-291141 JP) and the like are known, both selectivity for muscarinic M ₃ receptor is not sufficient.

On the other hand, JP-A-3-197462 discloses 3-phenyl-1,2,3,4-tetrahydro-2-.
It is described that oxo-3-quinoline carboxylate has a muscarinic antagonistic action, but the structure is greatly different from that of the compound of the present invention.

[0006]

Selectivity object of the present invention is to provide a relative muscarinic M ₃ receptors, especially selectivity for muscarinic M ₃ receptors ileum, more against muscarinic M ₃ receptor over the muscarinic M ₂ receptor An object of the present invention is to provide a novel compound having excellent selectivity, a pharmacologically acceptable salt thereof, and a pharmaceutical composition containing the same as an active ingredient.

[0007]

Means for Solving the Problems The present inventors have conducted intensive studies on compounds having a muscarinic M ₃ receptor antagonistic activity and found that the compound represented by the general formula (I):

[0008]

Embedded image

[Wherein, R represents a -AWB group (A represents a lower alkylene group which may be branched, W represents absent or represents an oxygen atom, and B represents a lower cycloalkyl group or a cycloalkyl group) Represents a phenyl group, a pyridyl group, or a furyl group which may have one or more substituents) or an alkenyl group having 5 to 10 carbon atoms which may be branched. ] Represented by 3-Ari - Rukinorin compound or a pharmacologically acceptable salt thereof, muscarinic M ₃ receptors, in particular high selectivity to muscarinic M ₃ receptors ileum, and has a strong antagonism This led to the completion of the present invention.

In the present invention, the "lower alkylene group which may be branched" is an alkylene group having 1 to 6 carbon atoms, specifically, a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, a pentamethylene group. Groups, a hexamethylene group, a methylethylene group, an ethylethylene group, a propylene group, a dimethylethylene group, a dimethylpropylene group and the like, and a methylene group, an ethylene group or a trimethylene group is preferable.

The "lower cycloalkyl group" is a cycloalkyl group having 3 to 6 carbon atoms, specifically, cyclopropyl group, cyclobutyl group, 1-methylcyclopropyl group, 2-methylcyclopropyl group, cyclopentyl. Group,
1-methylcyclobutyl group, 2-methylcyclobutyl group, 3-methylcyclobutyl group, 1,2-dimethylcyclopropyl group, 2,2-dimethylcyclopropyl group,
2,3-dimethylcyclopropyl group, cyclohexyl group, 1-methylcyclopentyl group, 2-methylcyclopentyl group, 3-methylcyclopentyl group, 1,2-dimethylcyclobutyl group, 1,3-dimethylcyclobutyl group, 2,2-dimethylcyclobutyl group, 2,3-dimethylcyclobutyl group, 2,4-dimethylcyclobutyl group,
Examples include a 3,3-dimethylcyclopentyl group, a 1,2,2-trimethylcyclopropyl group, a 1,2,3-trimethylcyclopropyl group, and a 2,2,3-trimethylcyclopropyl group, and a cyclopropyl group is preferable.

The "substituent which B may have" is a monovalent substituent such as a halogen atom, an amino group, a nitro group, a lower alkyl group, a lower alkoxy group, a methylenedioxy group, a trimethylene group, A divalent group such as an ethyleneoxy group, preferably an amino group, a nitro group, a lower alkyl group, a lower alkoxy group or an ethyleneoxy group, more preferably an amino group, a nitro group, a methyl group, a methoxy group or a dihydro group; An ethyleneoxy group that forms a benzofuran ring.

The "lower alkyl group" is an alkyl group having 1 to 6 carbon atoms, specifically, a methyl group, an 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, and methyl group, ethyl group, propyl group Group, isopropyl group, butyl group, isobutyl group, s-butyl group, t
-A butyl group is preferred, and a methyl group is particularly preferred.

"Lower alkoxy group" refers to a group having 1 to 6 carbon atoms.
And specifically, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, an s-butoxy group, a t-butoxy group,
A pentyloxy group, an isopentyloxy group, a neopentyloxy group, a t-pentyloxy group, a hexyloxy group, and the like, and a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group,
An s-butoxy group and a t-butoxy group are preferred, and a methoxy group is particularly preferred.

The "optionally branched alkenyl group having 5 to 10 carbon atoms" includes a 4-methylpent-3-ynyl group, a 3-methylbut-3-ynyl group and a 3-methylbut-2-yl group.
-Nyl group, 4-methylpent-4-ynyl group, 8-methylnone-7-nyl group, 8-methylnone-8-nyl group, 5-
Methylhex-4-ynyl group, 5-methylhex-5-nyl group, 6-methylhept-5-nyl group, 6-methylhept-6-nyl group, 7-methyloct-6-nyl group, 7-
Examples include a methyloct-7-nyl group, a 3-cyclohexylidenepropyl group, and a 2-cyclohexylideneethyl group, and a 4-methylpent-3-ynyl group is preferable.

"Pharmacologically acceptable salts" include inorganic acid salts such as hydrochloric acid, nitric acid and sulfuric acid, organic acid salts such as acetic acid, citric acid, fumaric acid and tartaric acid, methanesulfonic acid and p-toluenesulfone. Sulfonates such as acids and amino acid salts such as alanine, leucine, glutamic acid and glutamine are exemplified.

The compound (I) of the present invention has 1
Since it has the above asymmetric carbon, it has optical isomers. All of these optical isomers and mixtures thereof are included in the present invention.

The compound (I) of the present invention or a pharmaceutically acceptable salt thereof may be isolated as a hydrate, a solvate or a polymorphic substance. Is included.

[0019] Salts present invention as compound (I) or a pharmaceutically acceptable, selective, and because they have a strong muscarinic M ₃ receptor antagonism, diseases involving muscarinic M ₃ receptors, in particular Irritable bowel syndrome, which is a digestive disorder,
Functional dyspepsia, spastic colitis and diverticulitis; nausea, vomiting, sickness and menule disease due to drug administration, a central illness; urinary incontinence and frequent urination, urinary illness; chronic obstruction, a respiratory illness It can be used as a prophylactic or therapeutic agent for inflammatory lung disease, chronic bronchitis, asthma, pulmonary fibrosis and rhinitis.

The compound (I) of the present invention can be produced by the method described below.

[0021]

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Wherein X and Y each represent a leaving group, and Z represents a protecting group.

(First step) Hydrocarbostyril compound (II) (for example, Organic synthesis Collective Volume)
e) Starting from a compound synthesized by the method described in Vol. 4, page 730, Gazetta Chemia Italiana, Vol. 20, 40
And the compound (III).
And condensing the compound to obtain the compound (IV).

The hydrocarbostyril compound (II) is treated with -7 in an organic solvent such as dry tetrahydrofuran, ether, dioxane, diethylene glycol and dimethyl ether.
Strongly basic compounds such as methyllithium, n-butyllithium, s-butyllithium, t-butyllithium, phenyllithium, sodium amide, lithium diisopropylamide and the like in 2 equivalents at 8 ° C to room temperature, preferably at -20 ° C to 4 ° C. The metal reagent is added, and the mixture is stirred at the same temperature to the boiling point of the solvent, preferably at -20 ° C to 4 ° C, for 5 minutes to 2 hours, preferably 10 minutes to 1 hour. Next, the compound (III) is added, and the mixture is reacted under stirring at -20 ° C to the boiling point of the solvent, preferably at room temperature to the boiling point of the solvent, to obtain the compound (IV).

The compound (IV) obtained here is a mixture of diastereomers, but can also be separated by ordinary silica gel column chromatography.

X may be any group which functions as a leaving group in a normal chemical reaction, and includes a sulfonyloxy group such as a p-toluenesulfonyloxy group, a benzenesulfonyloxy group, a methanesulfonyloxy group, and a trifluoromethanesulfonyloxy group. , Chlorine, bromine and iodine are preferred.

Z may be any group which functions as a protecting group for the amino group of the secondary amine in a normal chemical reaction.
-A sulfonyl group such as a toluenesulfonyl group (hereinafter referred to as "tosyl group") and a benzenesulfonyl group is preferable.

Compound (III) is disclosed in JP-A-2-28.
It can be produced according to the method described in JP-A-2360, JP-T4-500521 or the like.

(Second step) Z of compound (IV) is removed,
This is a step of obtaining a compound (V).

Compound (V) can be obtained by treating compound (IV) with hydrobromic acid or hydrobromic acid-acetic acid in the presence of phenol or anisole.

The compound (V) obtained here can be crystallized with an appropriate solvent, for example, in ethyl acetate to selectively obtain one diastereomer.

(Step 3) Compound (V) is converted to compound (VI)
Alternatively, this is a step of condensing with compound (VII) to obtain compound (I).

As for A), compound (V) can be prepared by adding sodium carbonate, potassium carbonate, sodium hydrogencarbonate or potassium hydrogencarbonate in an organic solvent such as acetonitrile, methanol, ethanol, isopropyl alcohol or acetone. Compound (I) is reacted with Compound (VI) by adding an inorganic catalyst such as sodium iodide or potassium iodide, if necessary, in the presence of an inorganic base such as triethylamine or pyridine. Obtainable. Here, Y may be any group that functions as a leaving group in a normal chemical reaction, and includes a tosyloxy group,
Examples include a sulfonyloxy group such as a benzenesulfonyloxy group, a methanesulfonyloxy group, and a trifluoromethanesulfonyloxy group, and a halogen atom such as chlorine, bromine, and iodine.

As for B), the compound (V) and the compound (VI)
Compound (I) can be obtained by reductive amination reaction of I) with sodium triacetoxyborohydride in an organic solvent such as tetrahydrofuran or 1,2-dichloroethane in the presence of acetic acid.

The pharmacologically acceptable salts of the compound (I) of the present invention include compounds (I) such as inorganic acid salts such as hydrochloric acid, nitric acid and sulfuric acid, and organic acid salts such as acetic acid, citric acid, fumaric acid and tartaric acid. ,
It can be produced by allowing a sulfonate such as methanesulfonic acid and tosylic acid or an amino acid such as alanine, leucine, glutamic acid and glutamine to act in a conventional manner.

The optically active form of the compound (I) of the present invention can be obtained by reacting the compound (I) with an acidic optical resolving agent to form a crystalline diastereomer salt, which can be optically resolved by a recrystallization method or the like. In addition, compound (I) or a modified compound thereof can be prepared by high performance liquid chromatography using a chiral stationary phase.
Optical resolution can also be carried out using the enantiomer-separation technique described in (1).

Further, the optically active compound (I) can also be obtained by using an optically active intermediate in the above production method.

The compound of the present invention may be administered in the form of tablets,
Oral administration by capsule, granule, powder, inhalant or syrup or parenteral administration by injection or suppository can be mentioned.

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

[0040]

DETAILED DESCRIPTION OF THE INVENTION

[0041]

【Example】

Example 1 (+)-3-[(S) -1-
Phenethylpyrrolidin-3-yl] -3-phenyl-
3,4-dihydro-1H-quinolin-2-one

(+)-3-phenyl-3-[(S) -pyrrolidin-3-yl] -3,4-dihydro-1H-quinolin-2-one (0.20 g: 0.68 mmol, Reference Example 1) ), Phenethyl sylate (0.21 g: 0.75)
mmol) and anhydrous potassium carbonate (0.28 g: 2.0
(4 mmol) was stirred in acetonitrile (10 ml) under reflux for 4 hours. After cooling, the reaction solution was poured into water, extracted with chloroform, and dried over anhydrous sodium carbonate. The residue obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography (eluent: chloroform / methanol = 50/1) to obtain 0.13 g (yield) of the title compound as a pale yellow amorphous substance. 47%).

[Α] _D ^28.1 : + 28.7 ° (C = 0.6
4, CHCl ₃ ) ¹ H-NMR (CDCl ₃ ) δ: 1.78-1.90 (1
H, m), 2.10-2.23 (1H, m), 2.35
-2.38 (2H, m), 2.52-2.79 (6H,
m), 3.25-3.38 (3H, m), 6.55 (1
H, d, J = 7.32 Hz), 6.92-6.94.
(1H, m), 7.02-7.10 (1H, m), 7.
12-7.35 (11H, m), 7.87 (1H, s) MS m / z: 397 (C 27 H 28 N 2 O + H)

Example 2 (+)-3-[(S) -1-
[2- (2,3-dihydrobenzofuran-5-yl) d
Tyl] pyrrolidin-3-yl] -3-phenyl-3,4
-Dihydro-1H-quinolin-2-one

(+)-3-phenyl-3-[(S) -pyrrolidin-3-yl] -3,4-dihydro-1H-quinolin-2-one (0.21 g: 0.7 mmol), 2-
(2,3-Dihydrobenzofuran-5-yl) ethyl tosylate (0.23 g: 0.7 mmol) and anhydrous potassium carbonate (0.15 g: 1.1 mmol) were added to acetonitrile (10 ml) under reflux for 1.5 hours. Stirred for hours. After cooling, the reaction solution was poured into ice water, and chloroform (50 ml, 20 ml) was added.
ml) and dried over anhydrous potassium carbonate. The residue obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography (eluent: chloroform / methanol =
100 / 1-30 / 1) to give 0.27 g (87% yield) of the title compound as a pale yellow amorphous substance.

[Α] _D ^27.9 : + 34.9 ° (C = 0.9
5, CHCl ₃ ) ¹ H-NMR (CDCl ₃ ) δ: 1.80-1.92 (1
H, m), 2.09-2.23 (1H, m), 2.38
-2.70 (8H, m), 3.13-3.20 (2H,
m), 3.25-3.38 (3H, m), 6.54 (1
H, d, J = 7.33 Hz), 6.70 (1H, d, J)
= 7.93 Hz), 6.90-7.35 (10H,
m), 7.76 (1H, s ) MS m / z: 439 (C 29 H 30 N 2 O 2 + H)

Example 3 (+)-3-phenyl-3-
[(S) -1- (3-phenylpropyl) pyrrolidine-
3-yl] -3,4-dihydro-1H-quinolin-2-
on

(+)-3-Phenyl-3-[(S) -pyrrolidin-3-yl] -3,4-dihydro-1H-quinolin-2-one (0.30 g: 1.0 mmol),
Phenylpropyl bromide (0.20 g: 1.0 mmol
l), anhydrous potassium carbonate (0.42 g: 3.0 mmol)
l) in acetonitrile (20 ml) under reflux at 1.5
Stirred for hours. After cooling, the reaction solution was poured into ice water, extracted with ethyl acetate, washed with water and saturated saline, and then dried over anhydrous potassium carbonate. The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (eluent: hexane / ethyl acetate = 1 / 3-1 / 5) to obtain 0.27 g of the title compound as a white amorphous substance (67% yield).

[Α] _D ^27.3 : + 14.8 ° (C = 0.9
1, CHCl ₃ ) ¹ H-NMR (CDCl ₃ ) δ: 1.73-1.90 (3
H, m), 2.07-2.21 (1H, m), 2.28
-2.65 (8H, m), 3.21-3.45 (3H,
m), 6.57 (1H, d, J = 7.32 Hz), 6.
94 (1H, t, J = 7.32 Hz), 7.04 (1
H, t, J = 7.32 Hz), 7.08-7.39 (1
1H, m), 8.06 (1H , s) MS m / z: 411 (C 28 H 30 N 2 O + H)

Example 4 (+)-3-[(S) -1-
(2-phenoxyethyl) pyrrolidin-3-yl] -3
-Phenyl-3,4-dihydro-1H-quinoline-2-
on

According to Example 3, (+)-3-phenyl-3-[(S) -pyrrolidin-3-yl] -3,4-dihydro-1H-quinolin-2-one (0.30 g: 1m
mol) and 2-phenoxyethyl bromide (0.21
g: 1 mmol) to obtain 0.11 g (yield 27%) of the title compound as a pale yellow amorphous substance.

[Α] _D ^27.7 : + 21.4 ° (C = 0.5
8, CHCl ₃ ) ¹ H-NMR (CDCl ₃ ) δ: 1.79-1.92 (1
H, m), 2.08-2.22 (1H, m), 2.37
-2.94 (6H, m), 3.22-3.45 (3H,
m), 4.04-4.08 (2H, m), 6.55 (1
H, d, J = 7.93 Hz), 6.86-7.34 (1
3H, m), 7.90 (1H , s) MS m / z: 413 (C 27 H 28 N 2 O 2 + H)

Example 5 3-[(S) -1- [3-
(2,3-dihydrobenzofuran-5-yl) propyl
[Pyrrolidin-3-yl] -3-phenyl-3,4-
Dihydro-1H-quinolin-2-one

According to Example 2, (+)-3-phenyl-3-[(S) -pyrrolidin-3-yl] -3,4-dihydro-1H-quinolin-2-one (0.09 g: 0.
3 mmol) and 3- (2,3-dihydrobenzofuran-
5-yl) propyl tosylate (0.11 g: 0.33
mmol) to give 0.11 g (yield 81%) of the title compound as a syrup-like compound.

¹ H-NMR (CDCl ₃ ) δ: 1.69-
1.91 (3H, m), 2.10-2.20 (1H,
m), 2.30-2.67 (8H, m), 3.16 (2
H, t, J = 8.55 Hz), 3.23-3.44 (3
H, m), 4.53 (2H, t, J = 8.55 Hz),
6.56 (1H, d, J = 7.32 Hz), 6.68
(1H, d, J = 7.93 Hz), 6.87-7.39
(10H, m), 8.00 ( 1H, s) MS m / z: 453 (C 30 H 32 N 2 O 2 + H)

Example 6 3-[(S)-(4-methyl)
Pent-3-yn) pyrrolidin-3-yl] -3-fe
Nyl-3,4-dihydro-1H-quinolin-2-one

According to Example 3, (+)-3-phenyl-3-[(S) -pyrrolidin-3-yl] -3,4-dihydro-1H-quinolin-2-one (0.26 g: 0.
9 mmol) and 5-bromo-2-methyl-2-pentene (0.15 g: 0.9 mmol) to give 0.05 g (yield 25%) of the title compound as a syrup-like compound.

¹ H-NMR (CDCl ₃ ) δ: 1.59
(3H, s), 1.69 (3H, s), 1.77-1.
89 (1H, m), 2.12-2.70 (9H, m),
3.22-3.45 (3H, m), 5.07-5.13
(1H, m), 6.59 (1H, d, J = 7.32H
z), 6.92-6.97 (1H, m), 7.02-
7.36 (7H, m), 8.39 (1H, s) MS m / z: 375 (C 25 H 30 N 2 O + H)

Example 7 3-Phenyl-3-[(S)
-1- (cyclopropylmethyl) pyrrolidine-3-i
)]-3,4-dihydro-1H-quinolin-2-one

According to Example 3, (+)-3-phenyl-3-[(S) -pyrrolidin-3-yl] -3,4-dihydro-1H-quinolin-2-one (0.21 g: 0.
7 mmol) and bromomethylcyclopropane (0.11
g: 0.8 mmol) to obtain 0.05 g (yield 21%) of the title compound as a syrup-like compound.

¹ H-NMR (CDCl ₃ ) δ: 0.39
(2H, t, J = 5.49 Hz), 0.69-0.74
(2H, m), 1.21-1.25 (1H, m), 2.
13-2.18 (2H, m), 2.83 (2H, d, J
= 7.33 Hz), 3.06-3.50 (7H, m),
6.66 (1H, d, J = 7.94 Hz), 6.92
(1H, t, J = 7.32 Hz), 7.02-7.08
(1H, m), 7.16-7.29 (6H, m) 8.1
3 (1H, s) MS m / z: 347 (C 23 H 26 N 2 O + H)

Example 8 3-Phenyl-3-[(S)
-1- (2-cyclopropylethyl) pyrrolidine-3-
Yl] -3,4-dihydro-1H-quinolin-2-one

According to Example 2, (+)-3-phenyl-3-[(S) -pyrrolidin-3-yl] -3,4-dihydro-1H-quinolin-2-one (0.14 g: 0.
5 mmol) and 2-cyclopropylethyl tosylate (0.13 g: 0.6 mmol) to give 0.14 g (yield 81%) of the title compound as a syrup-like compound.

¹ H-NMR (CDCl ₃ ) δ: 0.02-
0.04 (2H, m), 0.39-0.43 (2H,
m), 0.60-0.69 (1H, m), 1.35 (2
H, q, J = 7.32 Hz), 1.77-1.89 (1
H, m), 2.02-2.71 (7H, m), 3.21
-3.39 (3H, m), 6.57 (1H, d, J =
7.32 Hz), 6.92-6.97 (1H, m),
7.05 (1H, t, J = 7.32 Hz), 7.11-
7.40 (6H, m), 8.03 (1H, H, s) MS m / z: 361 (C 24 H 28 N 2 O + H)

Example 9 (+)-3-phenyl-3-
[(S) -1- (3-methylbenzyl) pyrrolidine-3
-Yl] -3,4-dihydro-1H-quinolin-2-o
In

(+)-3-Phenyl-3-[(S) -pyrrolidin-3-yl] -3,4-dihydro-1H-quinolin-2-one (0.2 g: 0.4 mmol) and m- Tolualdehyde (0.05 g: 0.4 mmol), sodium borohydride triacetate (0.17 g: 0.8 mmol)
l) and acetic acid (0.02 g) in tetrahydrofuran (10
ml) at room temperature for 1.5 hours. The reaction solution was poured into ice water, made basic with an aqueous sodium hydroxide solution, extracted with chloroform, washed with water, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (eluent: chloroform / methanol = 100/1 to 10/1) to obtain 0.09 g of the title compound as an amorphous compound ( (Yield 58%).

[Α] _D ^27.5 : + 28.9 ° (C = 1.8
5, CHCl ₃ ) ¹ H-NMR (CDCl ₃ ) δ: 1.78-1.91 (1
H, m), 2.06-2.20 (1H, m), 2.29
-2.44 (2H, m), 2.33 (3H, s), 2.
49-2.65 (2H, m), 3.20-3.60 (5
H, m), 6.58 (1H, d, J = 7.33 Hz),
6.92-6.97 (1H, m), 7.02-7.39
(11H, m), 8.23 ( 1H, s) MS m / z: 397 (C 27 H 28 N 2 O + H)

Example 10 (+)-3-phenyl-3
-[(S) -1- (4-methoxy-3-methylbenzyl)
Ru) pyrrolidin-3-yl] -3,4-dihydro-1H
-Quinolin-2-one

According to Example 9, (+)-3-phenyl-3-[(S) -pyrrolidin-3-yl] -3,4-dihydro-1H-quinolin-2-one (0.12 g: 0.
4 mmol) and 3-methyl-p-anisaldehyde (0.06 g: 0.4 mmol) to obtain 0.11 g (yield 64%) of the title compound as an amorphous compound.

[Α] _D ^26.5 : + 28.2 ° (C = 2.1
8, CHCl ₃ ) ¹ H-NMR (CDCl ₃ ) δ: 1.80-1.88 (1
H, m), 2.08-2.60 (5H, m), 2.20
(3H, s), 3.22-3.55 (5H, m), 3.
81 (3H, s), 6.54 (1H, d, J = 7.32)
Hz), 6.74 (1H, d, J = 8.45 Hz),
6.91-7.33 (10H, m), 7.66 (1H,
s) MS m / z: 427 (C 28 H 30 N 2 O 2 + H)

Example 11 (+)-3-phenyl-3
-[(S) -1- (3-methoxybenzyl) pyrrolidine
-3-yl] -3,4-dihydro-1H-quinoline-2
-ON

According to Example 9, (+)-3-phenyl-3-[(S) -pyrrolidin-3-yl] -3,4-dihydro-1H-quinolin-2-one (0.12 g: 0.
4 mmol) and m-anisaldehyde (0.06 g:
0.41 mmol) to give 0.11 g (yield 64%) of the title compound as an amorphous compound.

[Α] _D ^27.5 : + 37.5 ° (C = 2.8
4, CHCl ₃ ) ¹ H-NMR (CDCl ₃ ) δ: 1.78-1.90 (1
H, m), 2.08-2.21 (1H, m), 2.29
-2.41 (2H, m), 2.55-2.59 (2H,
m), 3.21-3.60 (5H, m), 3.80 (3
H, s), 6.54 (1H, d, J = 6.71 Hz),
6.76-6.80 (1H, m), 6.88-7.34
(11H, m), 7.70 ( 1H, s) MS m / z: 413 (C 27 H 28 N 2 O 2 + H)

Example 12 (+)-3-phenyl-3
-[[(S) -1- (5-methylfuran-2-yl) me
Tyl] pyrrolidin-3-yl] -3,4-dihydro-1
H-quinolin-2-one

According to Example 9, (+)-3-phenyl-3-[(S) -pyrrolidin-3-yl] -3,4-dihydro-1H-quinolin-2-one (0.12 g: 0.4
mmol) and 5-methylfurfural (0.04 g:
0.4 mmol) to give the title compound as an oil (0.08, yield 51%).

[Α] _D ^27.8 : + 15.5 ° (C = 0.7
9, CHCl ₃ ) ¹ H-NMR (CDCl ₃ ) δ: 1.70-1.95 (1
H, m), 2.00-2.36 (2H, m), 2.25
(3H, s), 2.37-2.58 (2H, m), 2.
60-2.78 (1H, m), 3.12-3.72 (5
H, m), 5.86 (1H, brs), 6.00 (1
H, d, J = 3.05 Hz), 6.56 (1H, d, J)
= 7.32 Hz), 6.84-7.40 (8H, m),
7.74-8.10 (1H, brs) MS m / z: 387 (C 25 H 26 N 2 O 2 + H)

Example 13 (+)-3-phenyl-3
-[(S) -1- (3-nitrobenzyl) pyrrolidine-
3-yl] -3,4-dihydro-1H-quinolin-2-
on

According to Example 9, (+)-3-phenyl-3-[(S) -pyrrolidin-3-yl] -3,4-dihydro-1H-quinolin-2-one (0.15 g: 0.5
mmol) and 3-nitrobenzaldehyde (0.08
g: 0.5 mmol) to give 0.12 g (yield 54%) of the title compound as an oil.

[Α] _D ^28.2 : + 23.1 ° (C = 1.1
6, CHCl ₃ ) ¹ H-NMR (CDCl ₃ ) δ: 1.74-1.96 (1
H, m), 2.04-2.44 (3H, m), 2.45
-2.78 (2H, m), 3.10-3.79 (5H,
m), 6.56 (1H, d, J = 7.94 Hz), 6.
84-7.52 (9H, m), 7.60 (1H, d, J
= 7.32 Hz), 7.76-8.03 (1H, br
7.s), 8.09 (1H, d, J = 7.94 Hz),
16-8.30 (1H, m) MS m / z: 428 (C 26 H 25 N 3 O 3 + H)

Example 14 (+)-3-phenyl-3
-[(S) -1- (3-aminobenzyl) pyrrolidine-
3-yl] -3,4-dihydro-1H-quinolin-2-
on

(+)-3-[(S) -1-
(3-Nitrobenzyl) pyrrolidin-3-yl] -3-
A mixture of phenyl-3,4-dihydro-1H-quinolin-2-one (0.08 g: 0.17 mmol), 10% palladium on carbon, 1N hydrochloric acid (0.17 ml) and ethanol (10 ml) was placed under a stream of hydrogen. Stir for 1.5 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure.
A 5% aqueous sodium hydroxide solution was added, and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the mixture is concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography (eluent: chloroform / methanol = 100/1 to 20: 1).
/ 1) to give the title compound as an amorphous compound in 0.0
5 g (79% yield) was obtained.

[Α] _D ^30.8 : + 28.3 ° (C = 0.1
6, CHCl ₃ ) ¹ H-NMR (CDCl ₃ ) δ: 1.68-1.92 (1
H, m), 1.98-2.02 (1H, m), 2.04
-2.72 (4H, m), 3.10-3.78 (7H,
m), 6.48-6.62 (2H, m), 6.63-
6.76 (2H, m), 6.88-7.46 (9H,
m), 7.72 (1H, s ) MS m / z: 398 (C 26 H 27 N 3 O + H)

Example 15 (+)-3-phenyl-3
-[(S) -1- (2-pyridylmethyl) pyrrolidine-
3-yl] -3,4-dihydro-1H-quinolin-2-
on

According to Example 9, (+)-3-phenyl-3-[(S) -pyrrolidin-3-yl] -3,4-dihydro-1H-quinolin-2-one (0.12 g: 0.4
mmol) and pyridine 2-aldehyde (0.05 g:
0.51 mmol) to give 0.11 g (yield 71%) of the title compound as a yellow syrup-like compound.

[Α] _D ^29.3 : + 18.1 ° (C = 2.0
5, CHCl ₃ ) ¹ H-NMR (CDCl ₃ ) δ: 1.74-1.92 (1
H, m), 2.11-2.24 (1H, m), 2.33
-2.48 (2H, m), 2.54-2.74 (2H,
m), 3.24-3.49 (3H, m), 3.66-
3.78 (2H, m), 6.54 (1H, d, J = 7.
32 Hz), 6.92-7.37 (10H, m), 7.
60-7.69 (2H, m), 8.52 (1H, d, J
= 4.27Hz) MS m / z: 384 (C 25 H 25 N 3 O + H)

Example 16 (+)-3-phenyl-3
-[(S) -1- (3-pyridylmethyl) pyrrolidine-
3-yl] -3,4-dihydro-1H-quinolin-2-
on

According to Example 9, (+)-3-phenyl-3-[(S) -pyrrolidin-3-yl] -3,4-dihydro-1H-quinolin-2-one (0.12 g: 0.4
mmol) and pyridine-3-aldehyde (0.04 g:
From 0.4 mmol), 0.08 g (yield 54%) of the title compound was obtained as an amorphous compound.

[Α] _D ^28.9 : + 27.4 ° (C = 0.4
9, CHCl ₃ ) ¹ H-NMR (CDCl ₃ ) δ: 1.63-1.98 (1
H, m), 2.02-2.21 (1H, m), 2.25
-2.43 (2H, m), 2.56 (2H, t, J =
6.71 Hz), 3.10-3.69 (5H, m),
6.56 (1H, d, J = 7.94 Hz), 6.83-
7.43 (9H, m), 7.47 (1H, d, J = 7.
32 Hz), 7.81-8.11 (1H, brs),
8.36-8.59 (2H, m) MS m / z: 384 (C 25 H 25 N 3 O + H)

Example 17 (+)-3-phenyl-3
-[(S) -1- (4-pyridylmethyl) pyrrolidine-
3-yl] -3,4-dihydro-1H-quinolin-2-
on

According to Example 9, (+)-3-phenyl-3-[(S) -pyrrolidin-3-yl] -3,4-dihydro-1H-quinolin-2-one (0.12 g: 0.4
mmol) and pyridine-4-aldehyde (0.04 g:
0.41 mmol) to give 0.11 g (yield 69%) of the title compound as an amorphous compound.

[Α] _D ^29.1 : + 22.6 ° (C = 0.7
7, CHCl ₃ ) ¹ H-NMR (CDCl ₃ ) δ: 1.59-1.96 (1
H, m), 2.05-2.24 (1H, m), 2.36
(2H, d, J = 7.32 Hz), 2.57 (2H,
t, J = 6.71 Hz), 3.11-3.69 (5H,
m), 6.56 (1H, d, J = 6.71 Hz), 6.
83-7.43 (10H, m), 7.93 (1H,
s), 8.39-8.59 (2H, m ) MS m / z: 384 (C 25 H 25 N 3 O + H)

Example 18 (+)-3-[(S) -1
-[2- (2,3-dihydrobenzofuran-5-yl)
Methyl] pyrrolidin-3-yl] -3-phenyl-3,
4-dihydro-1H-quinolin-2-one

According to Example 9, (+)-3-phenyl-3-[(S) -pyrrolidin-3-yl] -3,4-dihydro-1H-quinolin-2-one (0.12 g: 0.4
mmol) and 2,3-dihydrobenzofuran-5-aldehyde (0.06 g: 0.4 mmol) to obtain 0.05 g (yield 30%) of the title compound as an amorphous compound.

[Α] _D ^29.3 : + 23.6 ° (C = 0.5
1, CHCl ₃ ) ¹ H-NMR (CDCl ₃ ) δ: 1.70-1.96 (1
H, m), 1.98-2.20 (1H, m), 2.22
-2.80 (4H, m), 3.02-3.58 (7H,
m), 4.54 (2H, t, J = 8.55 Hz), 6.
56 (1H, d, J = 7.32 Hz), 6.62-6.
76 (2H, m), 6.82-7.42 (9H, m),
7.78-8.06 (1H, brs) MS m / z: 425 (C 28 H 28 N 2 O 2 + H)

[0096]

Embedded image

Reference Example 1 (+)-3-phenyl-3-
[(S) -Pyrrolidin-3-yl] -3,4-dihydro
-1H-quinolin-2-one

Under a stream of argon, 3-phenyl-3,4-
Dihydro-1H-quinolin-2-one (3.66 g: 1
6.4 mmol) of tetrahydrofuran (120 ml)
The n-butyllithium-hexane solution (20.1 ml: 32.8 mmol; 1.63 M solution) was added to the solution under an ice bath.
Was added dropwise over 5 minutes and stirred for 10 minutes. (S) -N-Tosyl-3-pyrrolidinyl tosylate (6.48 g: 16.4 mmol) was added to the reaction mixture (JP-A-2-282).
360) and the mixture was stirred under reflux for 1 hour. After cooling, ice water and then a saturated aqueous ammonium chloride solution were added to the reaction solution, and chloroform (100 ml, 50 ml) was added.
Extracted in 1) and dried over anhydrous potassium carbonate. The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1 to 3/2) to give 3-phenyl-3-[(S)-( 1
-Tosyl) pyrrolidin-3-yl] -3,4-dihydro-1H-quinolin-2-one as a colorless amorphous 5.4.
1 g (74% yield) was obtained. This compound was a mixture of two diastereomers, and the ratio was 14/86 based on ¹ H-NMR.

Subsequently, 3-phenyl-3-[(S)-
(1-Tosyl) pyrrolidin-3-yl] -3,4-dihydro-1H-quinolin-2-one (5.25 g: 16.
4 mmol), a mixture of phenol (5.30 g) and 47% hydrobromic acid (50 ml) was stirred under reflux for 1.5 hours. After cooling, the mixture was washed with isopropyl ether (100
Then, the aqueous layer was adjusted to pH 12 with 8N aqueous sodium hydroxide solution, and chloroform (1 ml) was extracted.
00 ml, 50 ml) and dried over anhydrous potassium carbonate. Ethyl acetate was added to the residue obtained by evaporating the solvent under reduced pressure, and the precipitated crystalline compound was collected by filtration, washed with ethyl acetate, dried, and 1.86 g of the title compound as a white crystalline powder ( (54% yield).

Melting point: 175.0-175.5 ° C. [α] _D ^29.1 : + 46.8 ° (C = 1.04, CHC
l ₃ ) ¹ H-NMR (CDCl ₃ ) δ: 1.76-1.95 (2
H, m), 2.69-3.03 (5H, m), 3.27.
-3.41 (2H, m), 6.60 (1H, d, J =
7.32 Hz), 6.90-6.95 (1H, m),
7.01-7.33 (7H, m), 7.75-8.50
(1H, br)

Reference Example 2 2- (2,3-dihydroben )
Zofran-5-yl) ethyl tosylate

2- (2,3-dihydrobenzofuran-5)
-Yl) ethanol (33.5 g: 0.204 mol)
(See JP-A-2-282360), triethylamine (31 ml) in tetrahydrofuran (400 ml)
Tosyl chloride (38.9 g: 1.1 equivalents) was added to the solution under ice cooling, and the mixture was stirred at room temperature. Water-ether was added to the reaction solution, and the organic layer was washed with saturated saline and dried over anhydrous sodium carbonate. The residue obtained by evaporating the organic layer under reduced pressure was subjected to silica gel column chromatography (eluent:
Hexane / ethyl acetate = 6/1 to 3/1) to give 49.18 g (76% yield) of the title compound.

¹ H-NMR (CDCl ₃ ) δ: 2.44
(3H, s), 2.87 (2H, t, J = 7.32H
z), 3.14 (2H, t, J = 8.55 Hz), 4.
15 (2H, t, J = 7.32 Hz), 4.54 (2
H, td, J = 8.55, 3.05 Hz), 6.65
(1H, d, J = 7.93 Hz), 6.82 (1H, d
d, J = 7.93, 1.83 Hz), 6.94 (1H,
s), 7.28 (2H, d, J = 8.55 Hz), 7.
69 (2H, d, J = 8.55 Hz)

Reference Example 3 2,3-dihydro-5-phor
Milbenzofuran

2,3-dihydrobenzofuran (10.6
Phosphorous oxychloride (15.5 g: 5 g: 0.089 mol) in N, N-dimethylformamide (70 ml) solution.
0.101 mol) and 100 ml of Vilsmeier reagent prepared from N, N-dimethylformamide (45 ml).
To 105 ° C. over 2 hours, followed by stirring at the same temperature for 8 hours. After cooling, the reaction solution was poured into ice water, made alkaline with an 8N aqueous sodium hydroxide solution, and extracted with a mixed solvent of ethyl acetate-ether. The organic layer was washed three times with water, further washed with saturated saline, and dried over potassium carbonate. The residue obtained by evaporating the organic layer under reduced pressure was subjected to silica gel column chromatography (eluent: hexane / ethyl acetate = 5/1) to obtain the title compound as a pale yellow oily compound.

¹ H-NMR (CDCl ₃ ) δ: 3.27
(2H, t, J = 8.55 Hz), 4.69 (2H, t, J = 8.55 Hz)
t, J = 8.55 Hz), 6.88 (1H, d, J =
8.55 Hz), 7.67 (1H, d, J = 7.94H)
z), 7.75 (1H, d, J = 1.22 Hz), 9.
83 (1H, s)

Reference Example 4 3- (2,3-dihydroben )
Zofran-5-yl) ethyl acrylate

A solution of ethyl phosphonoacetic acid ethyl ester (1.58 g: 7.05 mmol) in tetrahydrofuran (10 ml) was suspended at room temperature in 60% oily sodium hydride (0.27 g: 6.73 mmol) in tetrahydrofuran (25 ml). The mixture was added to the liquid, and then stirred under reflux of tetrahydrofuran for 10 minutes. After cooling, 2,3-dihydro-5-formylbenzofuran (0.95 g: 6.4
(1 mmol) in tetrahydrofuran (25 ml) and stirred under reflux for 2 hours. After cooling, ice was added to the reaction solution, which was extracted with ether. The ether layer was washed successively with water and saturated saline and dried over anhydrous potassium carbonate. The solvent was distilled off under reduced pressure to obtain 1.38 g (yield 98%) of the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.33
(3H, t, J = 7.33 Hz), 3.22 (2H,
t, J = 8.55 Hz), 4.25 (2H, q, J =
7.33H), 4.62 (2H, t, J = 8.55H)
z), 6.27 (1H, d, J = 15.87 Hz),
6.78 (1H, d, J = 8.54 Hz), 7.27-
7.32 (1H, m), 7.40 (1H, s), 7.6
3 (1H, d, J = 15.87 Hz)

Reference Example 5 3- (2,3-dihydrofura )
N-5-yl) ethyl propionate

3- (2,3-dihydrobenzofuran-5
-Yl) acrylic acid ethyl ester (1.38 g: 6.
To a solution of 4 mmol) in ethanol (30 ml) was added 10% palladium on carbon (0.20 g), and the mixture was stirred under a hydrogen stream. After consumption of the calculated amount of hydrogen, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 1.36 g of the title compound as a colorless oil (yield: 96).
%).

¹ H-NMR (CDCl ₃ ) δ: 1.24
(3H, t, J = 7.33 Hz), 2.57 (2H,
t, J = 8.55 Hz), 2.87 (2H, t, J =
7.94 Hz), 3.17 (2H, t, J = 8.55H)
z), 4.12 (2H, q, J = 7.33 Hz);
54 (2H, t, J = 8.55 Hz), 6.69 (1
H, d, J = 8.55 Hz), 6.92 (1H, d, J)
= 7.93 Hz), 7.04 (1H, s)

Reference Example 6 3- (2,3-dihydroben )
Zofran-5-yl) propanol

Ethyl 3- (2,3-dihydrofuran-5-yl) propionate was added to a suspension of lithium aluminum hydride (0.28 g: 7.35 mmol) in tetrahydrofuran (20 ml) under ice-cooling under an argon stream. A solution of the ester (1.35 g: 6.13 mmol) in tetrahydrofuran (10 ml) was added dropwise over 5 minutes, and the mixture was stirred at the same temperature for 4.5 hours. Water (0.5 ml) and then an 8 N aqueous sodium hydroxide solution (5 ml) were carefully added to the reaction solution, and insolubles were removed with celite. The filtrate was washed sequentially with water and saturated saline, and dried over anhydrous potassium carbonate. The solvent was distilled off under reduced pressure to obtain 0.98 g (yield 90%) of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.51
(1H, s), 1.86 (2H, q), 2.64 (2
H, t), 3.17 (2H, t), 3.66 (2H,
t), 4.54 (2H, t), 6.70 (1H, d),
6.93 (1H, d), 7.03 (1H, s)

Reference Example 7 3- (2,3-dihydroben )
Zofran-5-yl) propyl tosylate

3- (2,3-dihydrobenzofuran-5
-Yl) propanol (0.97 g: 5.44 mmol)
l), triethylamine (1.1 ml: 7.1 mmol)
To a solution of 1) in tetrahydrofuran (20 ml), tosyl chloride (1.35 g: 7.1 mmol) was added in several portions under ice-cooling, followed by stirring at room temperature. The reaction solution was poured into ice water and extracted with ether. The ether layer was washed successively with water and saturated saline, and then dried over anhydrous sodium carbonate. The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (eluent: hexane / ethyl acetate = 5/1).
To give 1.42 g (79% yield) of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.85-
1.96 (2H, m), 2.46 (3H, s), 2.5
7 (2H, t), 3.14 (2H, t), 4.02
(2H, t), 4.52 (2H, t), 6.64 (1
H, d), 6.79 (1H, d), 6.90 (1H,
s), 7.34 (2H, d), 7.78 (2H, d)

[0119]

Embedded image

[0120]

Advantages of the Invention Muscarinic M ₃ antagonism of isolated guinea pig ileum longitudinal muscles The occipital region of the Hartley-type guinea pig was beaten, exsanguinated and sacrificed, and the ileum was immediately removed while removing the mesentery. After thoroughly washing the contents of the ileum, the lumen is 5 to 7 m in diameter.
Insert a glass rod of length m, cut only the longitudinal muscle along the intestinal membrane attachment with a razor, apply a cotton swab to the boundary between the longitudinal muscle and the circular muscle, and remove the longitudinal muscle while taking care not to dry the tissue A sample was prepared. Incubate this specimen at 37 ° C, 95%
After suspension at a static tension of 1 g in a 10 ml organ bath filled with Krebs carbonate buffer through O ₂ -5% CO ₂ , 6
There was a 0 minute stabilization period. The contraction reaction by carbachol was measured isotonicity from 10 ⁻⁹ M at a common ratio of 3 using a cumulative method. The sample was washed immediately after the measurement, and a stabilization period of 45 minutes was allowed until the next contraction reaction. The time when the EC ₅₀ of the contraction reaction by carbachol became stable was used as a control. The test compound was applied 15 minutes before the application of carbacol, and the affinity (pA ₂ ) of the test compound was determined by the Schild method (Arunl method).
akshana, O. and Schild, HO: Brit. J. Pharmaco
l., 14, 48-58 (1959)). Table 1 shows the results.

2. Muscarinic M ₃ antagonism on the isolated guinea pig bladder The occipital region of a male Hartley guinea pig was beaten, exsanguinated and sacrificed. After laparotomy, the bladder tip visible in the lower abdomen was lightly picked up with forceps and cut at the bladder triangle. It was excised and immersed in a nutrient solution. After making a midline incision, length 10-
The strip was 15 mm in length and 3 to 5 mm in width. afterwards,
Mucosal tissue was peeled off with ophthalmic scissors and used as a specimen.
The sample was suspended at 37 ° C. in a 10 ml Magnus bath filled with Krebs' carbonate buffer buffered with 95% O ₂ -5% CO ₂ at a static tension of 1 g, followed by a 60 minute stabilization period. The contraction reaction due to carbachol was determined using the cumulative method.
^It was measured isotonic at a common ratio of 3 from ^-8 M. The sample was washed immediately after the measurement, and a stabilization period of 45 minutes was allowed until the next contraction reaction. The time when the EC ₅₀ of the contraction reaction by carbachol became stable was used as a control. The test compound was applied 15 minutes before the application of carbachol. The affinity (pA ₂ ) of the test compound was determined in the same manner as in the case of the ileum. Table 1 shows the results.

3. Muscarinic M ₃ antagonism on isolated guinea pig trachea The occipital region of a male Hartley guinea pig was beaten, exsanguinated and sacrificed, and the cervical trachea was isolated while removing connective tissue and the like. Thereafter, the esophagus and the remaining connective tissue were cut off, and resected at intervals of two tracheal cartilages to prepare specimens. The specimen was incubated at 37 ° C. and filled with 5 ml of Krebs' carbonate buffer containing indomethacin (1 μM) through 95% O ₂ -5% CO _2.
The suspension was suspended in the Magnus bath at a static tension of 1 g, and then a stabilization period of 60 minutes was allowed. The contraction reaction due to carbachol was measured isometrically at a common ratio of 3 from 10 ^-8 M at intervals of 7 minutes using a cumulative method. Promptly samples were washed after measurement, placing the stabilization period of 60 minutes until the next contraction reaction, EC ₅₀ of contractile response by carbachol was used as a control stability time points. The test compound was applied 15 minutes before the application of carbachol. The affinity (pA ₂ ) of the test compound was determined in the same manner as in the case of the ileum. Table 1 shows the results.

4. Muscarinic M ₂ antagonism of the isolated guinea pig left atrium Beat the occipital region of the Hartley-type guinea pig, exsanguine and sacrificed, immediately remove the cardiopulmonary lungs, resect the lungs, connective tissue, etc. in the ventricle in order, and cut into the left and right atrium A sample was prepared. The specimen was incubated at 32 ° C. and placed in a 10 ml organ bath filled with Krebs carbonate buffer through 95% O ₂ -5% CO ₂ .
It was suspended at a static tension of 0.5 g. Thereafter, contraction due to field electrical stimulation (4 Hz, 2 msec, 1.5 × threshold voltage) was measured. After a stabilization period of 60 minutes, the inhibitory reaction with carbazole was measured at 10-second intervals at a concentration of 90 seconds using a cumulative method.
Measured isometrically at a common ratio of 3 from ^-8 M. The sample was washed immediately after the measurement, and a stabilization period of 45 minutes was allowed until the next inhibition reaction. Note EC ₅₀ for inhibition reaction by carbachol and controls a stable point, the test compound Karubako -
30 minutes before application. Test compound affinity (p
A ₂ ) was determined in the same manner as for the ileum. Table 1 shows the results
Shown in

[0124] The compounds of the present invention, the as shown in Table 1 as compared to the muscarinic M ₂ receptor muscarinic M ₃ receptors, was among others showed very selective antagonistic activity muscarinic M ₃ receptors ileum.

[0125]

[Table 1]

As described above, the compound of the present invention is useful for diseases involving muscarinic M ₃ receptors, particularly, irritable bowel syndrome,
Gastrointestinal diseases such as functional dyspepsia, spastic colitis, diverticulitis, etc .; central illnesses such as nausea and vomiting, sickness, and menule disease caused by drug administration; urinary diseases such as urinary incontinence and pollakisuria; chronic obstruction sex pulmonary disease, chronic bronchitis, asthma, useful as prophylactic or therapeutic agents against respiratory diseases such as pulmonary fibrosis and rhinitis, prevention of inter alia gastrointestinal disorders muscarinic M ₃ receptors ileum are disease involving or It is particularly useful as a therapeutic.

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (Reference) A61P 13/10 A61P 13/10 25/04 25/04 C07D 401/14 C07D 401/14 405/14 405/14 F-term (Reference) 4C063 CC76 DD03 EE01 4C086 AA01 AA02 AA03 GA06 MA01 NA14 ZA28 ZA66 ZA81

Claims (6)

[Claims] 1. A compound of the general formula [Wherein, R represents a -AWB group (A represents a lower alkylene group which may be branched, W represents absent or represents an oxygen atom, B represents a lower cycloalkyl group or 1 or Represents a phenyl group, a pyridyl group or a furyl group which may have two or more substituents) or an alkenyl group having 5 to 10 carbon atoms which may be branched. Or a pharmacologically acceptable salt thereof. 2. The compound according to claim 1, wherein A is an ethylene group, a trimethylene group, or a tetramethylene group, or a pharmaceutically acceptable salt thereof. (3) B is a phenyl group, a 2,3-dihydrobenzofuran-5-yl group, a cyclopropyl group, a 3-methylphenyl group, a 4-methoxy-3-methylphenyl group,
A methoxyphenyl group, a 5-methylfuran-2-yl group,
The compound according to claim 1 or 2, which is a 3-nitrophenyl group, a 3-aminophenyl group, or a pyridyl group, or a pharmacologically acceptable salt thereof. 4. A compound of the general formula [Wherein, R represents a -AWB group (A represents a lower alkylene group which may be branched, W represents absent or represents an oxygen atom, B represents a lower cycloalkyl group or 1 or Represents a phenyl group, a pyridyl group or a furyl group which may have two or more substituents) or an alkenyl group having 5 to 10 carbon atoms which may be branched. Or a pharmacologically acceptable salt thereof as an active ingredient. 5. The muscarinic M ₃ 4. The pharmaceutical composition according receptor is a preventive or therapeutic agent for diseases involved. 6. A compound of the general formula [Wherein, R represents a -AWB group (A represents a lower alkylene group which may be branched, W represents absent or represents an oxygen atom, B represents a lower cycloalkyl group or 1 or Represents a phenyl group, a pyridyl group or a furyl group which may have two or more substituents) or an alkenyl group having 5 to 10 carbon atoms which may be branched. Quinoline compound or muscarinic M ₃ receptor antagonist to a pharmaceutically acceptable salt thereof effective ingredient represented by.