WO2000039096A1

WO2000039096A1 - 2-methylimidazoline compounds

Info

Publication number: WO2000039096A1
Application number: PCT/JP1999/007327
Authority: WO
Inventors: Norio Ohno; Jun-Ichi Endoh; Masataka Miura; Hideyuki Aizawa
Original assignee: Mitsubishi-Tokyo Pharmaceuticals, Inc.
Priority date: 1998-12-25
Filing date: 1999-12-27
Publication date: 2000-07-06
Also published as: AU1801800A; JP2003089688A

Abstract

Imidazoline compounds represented by general formula (I) or pharmacologically acceptable salts thereof: (I) [wherein R1 is optionally substituted phenyl; R2 is phenyl or lower cycloalkyl; and m is 2 or 3]. These compounds exhibit extremely potent and selective antagonism against muscarinic M3 receptor, and thus are not only useful as preventive or therapeutic agents for diseases in which muscarinic M3 receptor participates, but also capable of providing safe drugs which are lowered in the adverse effects on the heart in which muscarinic M3 receptor participates.

Description

Specification

2 —Methylimidazoline compounds Technical field

The present invention relates to imidazol emission compounds, more particularly selective muscarinic M ₃ receptor Imidazori emission compound showing an antagonistic action and pharmaceutical compositions you it as an active ingredient. Background art

At least the muscarinic receptor 3 subtypes is Ari, M i receptors in the brain, M ₂ receptors in the heart, M ₃ receptors are known to be present in smooth muscle and glandular tissue ing.

Pharmaceuticals having a muscarinic receptor antagonistic action show antispasmodic action, analgesic action and antisecretory action, and are therefore used as therapeutic drugs for dysfunctions such as intestines or bladder. Pharmaceuticals that have musculin receptor antagonism include atotopine, scopolamine, oxiptinin, propanterine bromide, iprat pitum, flute pitum, and oxitropium. i, has substantially the same affinity for M ₂ and M ₃ receptors, it is known that unavoidable side effects to antagonize non-selectively Asechirukori down in these. Therefore medicament having high Mus force Li emissions receptor antagonism selective had medicament that does not exhibit side-effects is desired to cardiac particularly involving M ₂ receptor.

As compounds that selectively antagonize the muscarinic 1 ^ ₃ receptor, 3-substituted pyrrolidine derivatives (Japanese Patent Application Laid-Open Nos. 282,360 / 1990, 509,927 / 1991, and -1 496 40 publication), 3-Substituted piperidine derivatives 4-5,052,1 1), carbamate derivatives (W95 / 066,355), imidazole derivatives (JP-A 7-215,943), diphenyl acetic acid derivatives (JP-8 - 2 9 1 1 4 1 JP) but the like are known, both selectivity for Mus force phosphate 1 \ 4 ₃ receptor is not sufficient. Disclosure of the invention

An object of the present invention, the muscarinic M ₃ selective for the receptor, especially beam Sukari down 1 ^ ₂ receptor high selectivity for muscarinic M ₃ receptor over the body, and novel Imidazorin compounds have potent antagonistic activity and it An object of the present invention is to provide a pharmaceutical composition containing as an active ingredient.

The present inventors have, per compounds having muscarinic M ₃ receptor antagonism, of extensive studies, the general formula (I)

ΓΛ

J, I '

2 Me

(I)

[Wherein, R represents a phenyl group which may have a substituent, R ₂ represents a phenyl group or a lower cycloalkyl group, and m represents 2 or 3.] emissions compound or a pharmacologically acceptable salt thereof, Mus force re down ^ 1 ₃ high selectivity to the receptor, and found that you have a strong antagonism, and have completed the present invention.

In the present invention, the “substituent which the phenyl group optionally has” includes a lower alkyl group, a halogen atom, a lower alkyl group or a lower alkoxy group substituted with a halogen atom. The number of substituents is not limited, but is preferably 1 or 2, and more preferably 1. The substitution site is o-position, m-position, p-position, 2,3-position, 2,4-position, 2,5-position, 2,6-position, 3,4 first or 3,5 position. -Position, etc., but o-position, m-position or-position is preferred. And the o-position is more preferred.

A “lower alkyl group substituted with a halogen atom” is an alkyl group having 1 to 3 carbon atoms in which all hydrogen atoms have been substituted with halogen atoms, and specifically, a trifluoromethyl group, a trichloromethyl group, Bromomethyl group, pentafluoroethyl group, pentachloroethyl group, pentabromoethyl group, heptafluoropropyl group, heptachloropropyl propyl group, heptafluoromethyl group, heptafluoroisopropyl group, Examples include a heptachloroisopropyl group and a heptabromobromoisopropyl group, preferably a trifluoromethyl group, a trichloromethyl group, a pentafluoroethyl group, and a pentachloroethyl group, and more preferably a trifluoromethyl group.

“Halogen atom” includes fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine, more preferably chlorine.

The “lower alkyl group” is an alkyl group having 1 to 6 carbon atoms, specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group, tributyl group, Examples include a pentyl group, an isopentyl group, a neopentyl group, a t-pentyl group, and a hexyl group, and a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, an s-butyl group and an tributyl group. Preferably, a methyl group and an isopropyl group are more preferable.

The “lower alkoxy group” is an 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, an s-butoxy group, Butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, topopentyloxy group, hexyloxy group, etc., methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group. Groups, s-butoxy groups and t-butoxy groups are preferred, and methoxy groups are more preferred. The “lower cycloalkyl group” is a cycloalkyl group having 3 to 6 carbon atoms, and specific examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group, and a cyclobutyl group is preferred.

“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, p-toluenesulfonic acid and the like. Sulfonates and amino acid salts such as alanine, oral glycine, glutamic acid, glutamine and the like can be mentioned.

The compound (I) of the present invention has one or more asymmetric carbon atoms in the molecule, and thus 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 or a solvate, and these are also included in the present invention.

Salts present invention as compound (I) or a pharmaceutically acceptable, selective, One or because they have antagonistic activity stronger muscarinic M ₃ receptors, diseases involving muscarinic M ₃ receptors, in particular, Respiratory diseases such as chronic obstructive pulmonary disease, asthma, pulmonary fibrosis and rhinitis; Urinary diseases such as urinary incontinence and pollakiuria; Digestive diseases such as irritable bowel syndrome, spastic colitis and diverticulitis; It can be used as a prophylactic or therapeutic drug against nausea, vomiting, sickness, and Meniere's disease caused by the administration of a drug that is a sexual disease.

Compound (I) of the present invention, methods described in the literature (Olga Nick Synthesis, Collective Volume vol. 4, 7 2 pages, 1 9 6 3 years) compounds made if in accordance with (II) j ^y m

R ² (H) [Wherein R i R ₂ and m are the same as above, and X represents a halogen atom. ]

It is obtained by the reaction of 2-methyl-2-imidazoline with water. More specifically, the compound (II) and an equivalent amount or an excess amount of 2-methyl-2-imidazoline can be used without solvent or with acetonitrile, acetone, tetrahydrofuran, dioxane, diethylene glycol, dimethyl ether, ethanol, or methanol. , 2-methyl-2-propanol, NN-dimethylformamide, etc. in a solvent without catalyst or alkali carbonate such as sodium carbonate and potassium carbonate, alkali bicarbonate such as sodium bicarbonate and potassium bicarbonate, water By stirring at room temperature to the boiling point of the solvent, preferably at the boiling point of the solvent in the presence of an inorganic base such as caustic alkali such as sodium oxide and potassium hydroxide or an organic base such as triethylamine, pyridine and 4-dimethylaminopyridine, the compound ( I) or a salt thereof can be obtained.

Compound (I) can also be obtained as follows. First, the compound OH OH

R ₂ ('««)

[Wherein R i R ₂ and m are the same as described above. ]

And compound (IV)

I m

2 (IV)

[Wherein R ₂ and m are the same as described above, and R ₃ represents an aryl group or a lower alkyl group. ]

(Journal of Organic Chemistry, Vol. 13, pp. 830 or 832, 1948). Then, the resulting compound (IV) is reacted with 2-methyl-2-imidazoline.

That is, compound (III) and a haloalkyl ester are reacted with benzene, toluene, xylene, tetrahydrofuran, dioxane, dimethyloxetane, diglyme or benzene in the presence of a base such as sodium, potassium, sodium hydride, potassium hydride or alkyllithium. Compound (V) is obtained by stirring in a solvent such as -methyl-2-propanol at room temperature to the boiling point of the solvent.

[Wherein R ₂ and m are the same as described above, and R ₄ represents a lower alkyl group. ].

Then, in a solvent such as tetrahydrofuran, dioxane, ether, dimethoxetane, benzene or toluene, this compound (V) or the hydrolyzed carboxylic acid compound is hydrogenated with lithium aluminum hydride, lithium borohydride or diborane. Reduction using a compound to give an alcohol compound (VI)

J no m

R ² (VI)

[Wherein R ₁ R ₂ and m are the same as described above. ]

Get.

The obtained compound (VI) is treated with dichloromethane, chloroform, and the like in the presence of an inorganic base such as an organic base such as triethylamine, pyridine or 4-dimethylaminopyridine, an alkali carbonate, an alkali bicarbonate or a caustic alkali salt. Methanesulfonic acid in a solvent such as benzotrifluoride, tetrahydrofuran, ether, dioxane, dimethoxetane or diglyme Compound (IV) is obtained by reacting with sulfonic acid chloride such as chloride, tosylic acid chloride, benzenesulfonic acid chloride or trifluoromethanesulfonic acid chloride or sulfonic acid anhydride such as trifluoromethanesulfonic acid anhydride. be able to.

Also, under neutral conditions, the compound (VI) is reacted with a phosphorus compound such as triphenylphosphine in carbon tetrachloride or carbon tetrabromide (Organic Synthesis, Vol. 54, p. 63, p. 1974). Year) and compound (II).

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, organic acid salts such as acetic acid, citric acid, fumaric acid and tartaric acid; It can be produced by allowing a sulfonate such as sulfonic acid or tosylic acid or an amino acid such as alanine, leucine, glutamic acid or glutamine to act in a conventional manner.

When the compound of the present invention or a pharmacologically acceptable salt thereof is clinically used, excipients such as a stabilizer, a buffer, a diluent, an isotonic agent, and a preservative may be added. Dosage forms include oral administration of tablets, capsules, granules, powders, syrups, etc., parenteral administration of injections, suppositories, liquids, etc., and topical administration of ointments, creams, patches, etc. Can be. BEST MODE FOR CARRYING OUT THE INVENTION

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

(Example 1) 1 [2— (benzhydryloxy) ethyl] 1—2-methyl 2-imidazoline

1 Benzhydryloxy-2-bromoene (1.46 g: 5 mmol), 2-methyl-2-imidazoline (2.52 g: 30 mmo1) And acetonitrile (30 ml) were stirred under reflux for 3 hours. Ice water was added, and the mixture was extracted with black hole form, washed three times with water, and dried over anhydrous potassium carbonate. The solvent was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (eluent: chloroform / methanol = 5Z1 followed by methanol) to give the title compound as a colorless oil. 30 g (yield 21%) was obtained.

_{^ - NMR (CDC 1 3)} (5 ppm: 1. 9 8 (3 H, s), 3. 2 7 - 3. 3 9 (4 H, m), 3. 5 4 (2 H, t, J = 5.49 Hz), 3.67 (2H, t, J = 9.77Hz), 5.35 (1H, s), 7.25-7.33 ( 10 0 H, m).

(Example 2) 2-Methyl-1 [3-(phenyl o-trimethoxy) propyl]-2-imidazoline

In the same manner as in Example 1, 1-promo-3- (phenyl o-tolylmethoxy) propane (0.44 g: l.4 mmo1) and 2-methyl-2-imidazoline (0.58 g) : 6.9 mmo 1) to give 0.440 g (yield 90%) of the title compound as a pale yellow oily substance.

^{_{1 H - NMR (CDC 1 3}} ) δρ pm: 1. 5 6- 2. 1 2 (5 H, m),

2.24 (3H, s), 3.04-3.36 (4H, m), 3.36 —

3.80 (4H, m), 5-48 (1H, s), 7.02-7.50 (9H, m).

(Example 3) 2-Methyl-1- (2- (phenyl o-tolylmethoxy) ethyl) —2-imidazoline

1—Promo 2— (phenyl o-trimethoxy) (0.92 g: 3 mm 01), 2—Methyl-2—imidazoline (1.5 1 g: 18 mm o 1) and acetonitrile (20 ml) was stirred under reflux for 2.5 hours. The solvent was concentrated under reduced pressure, and the residue was extracted with chloroform. It was washed with water once and dried over anhydrous potassium carbonate. The residue obtained by evaporating the chromate form under reduced pressure was subjected to silica gel column chromatography (eluent: chloroform / methanol = 1 Z, followed by chloroform Z methanol containing 1% triethylamine = 1 Z 1). This gave 0.75 g (yield 81%) of the title compound as a pale yellow oil.

1 H-NMR (CDC 13) δ ppm: 1.96 (3H, s), 2.25 (3H, s), 3.29 (2H, t, J = 9.1) 6 H z), 3.35 (2 H, t, J = 5.49 H z), 3.54 (2 H, t, J = 5.49 H z), 3.66 ( 2H, t, J = 9.16 Hz), 5.51 (1H, s), 7.11-7.32 (8H, m), 7.41-7.4 5 (1H, m).

(Example 4) 1- [2-((2-chlorophenyl) phenylmethoxy) ethyl] -1-methyl-2-imidazoline

In the same manner as in Example 1, 1-bromo-2-((2-chlorophenyl) phenylmethoxy) phenyl (0.89 g: 2.7 mmol) and 2-methyl-2-imidazoline (0.89 g: 2.7 mmol) From 1.15 g: 13.7 mmo 1), 0.88 g (yield 98%) of the title compound was obtained as a pale yellow oily substance.

_{^ - NMR (CDC 1 3)} 6p pm: 1. 9 5 (3 H, s), 3. 1 2 - 3. 4 3 (4 H, m), 3. 4 3 - 3. 8 0 (4 H , M), 5.82 (1H, s), 7.15-7.60 (9H, m).

(Example 5) 2-Methyl-11- [2- (phenyl (2-trifluoromethylphenyl) methoxy) ethyl] -12-imidazoline

In the same manner as in Example 1, 1-bromo-2- (phenyl (2-trifluoromethylphenyl) methoxy) benzene (0.46 g: 1.3 mm 01) and 2 —Methyl-2-imidazoline (0.54 g: 6.4 mmo 1) afforded 0.28 g (60% yield) of the title compound as a pale yellow oil. Was.

_{^ - NMR (CDC 1 3)} 0p pm: 2. 0 1 (3 H, s), 3. 1 2 - 3. 8 8 (8 H, m), 5. 8 3 (1 H, s), 7 1 0—7.80 (9 H, m).

(Example 6) 1- [2-((2-methoxyphenyl) phenylmethoxy) ethyl] 1-2-methyl-2-imidazoline

In the same manner as in Example 1, methanesulfonic acid 2-((2-methoxyphenyl) phenylmethoxy) ethyl ester (0.27 g: 0.8 mm 01) and 2-methyl-2-imidazoline ( From 0.34 g: 4 mm 01), 0.128 (yield: 44%) of the title compound was obtained as a pale yellow oily substance.

^-NMR (CD CI 3) 6p pm: 2.08 (3 H, s), 3.30 — 3.48 (4 H, m), 3.57 (2 H, dd, J = 5.49, 4.88 Hz), 3.60-3.85 (2H, m), 3.81 (3H, s), 5.80 (1H, s) , 6.85-7.42 (9H, m).

(Example 7) 1- [2- (cyclobutylphenylmethoxy) ethyl] 1-2-methyl-2-imidazoline

In the same manner as in Example 1, methanesulfonic acid 2- (cyclobutylphenylmethoxy) ethyl ester (0.20 g: 0.7 mmol) and 2-methyl-2-imidazoline (0.30 g: 3) .5 mmol) gave the title compound as a pale yellow oil (0.09 g, yield 44%). ^-NMR (CDCI 3) 6p pm: 1.58-2.21 (9H, m), 2.42-2.70 (lH, m), 3.08-3.5 0 (6 H, m), 3.65 (2 H, t, J = 9.77 Hz), 4.09 (1 H, d, J = 7.94 Hz), 7- 10-7.44 (5H, m).

(Example 8) 1- [2- (cyclobutyl o-toluylmethoxy) ethyl] — 2 — Methyl-2 — imidazoline

In the same manner as in Example 1, methanesulfonic acid 2- (cyclobutyl o-tolylmethoxy) ethyl ester (0.14 g: 0.46 mmo1) and 2-methyl-2-imidazoline (0.1%) were used. From 19 g: 2.3 mmo 1), 0.06 g (yield 48%) of the title compound was obtained as a pale yellow oily substance.

^{_{1 H - NMR (CDC 1 3}} ) δρ pm: 1. 6 0 - 2. 2 0 (9 H, m),

2.3.4 (3H, s), 2.44-2.80 (lH, m), 3.10-

3.50 (6H, s), 3.55-3.78 (2H, m), 4.44 (1H, d, J = 6.71Hz), 7.1 0 — 7.29 (4H, m).

Real

1. Mus force Li emissions M ₃ antagonistic activity against isolated guinea pig trachea

The occipital region of a male Hartley guinea pig was beaten, exsanguinated and sacrificed, and the abdominal trachea was removed while removing connective tissue and the like. Thereafter, the esophagus and the remaining connective tissue were excised, cut at intervals of two tracheal cartilages, and used as specimens. This specimen The 3 7 ° and kept at C 9 5% O ₂ - to 5 m 1 Magnus tank filled with Krebs bicarbonate buffer containing 5% C 0 ₂ a through the Lee Ndome evening Shin a (1 M), suspended in resting tension lg After a 60 minute stabilization period. The contractile response to carbachol was measured isometrically at a common ratio of 3 from 10 to ⁸ M at intervals of 7 minutes using a cumulative method. Promptly samples were washed after measurement until the next contraction reaction every stable period for 60 minutes, EC ₅ of contractile response by carbachol. The time when was stabilized was used as control. The test compound was applied 15 minutes before the application of carbachol. Incidentally affinity of the test compound (p A ₂₎ is to shield method (Arunl akshana, 0. and Schi Id , H. 0.:.. Brit J. Pharmacol, 1959, 14, 48-58) was determined by. Table 1 shows the results.

2. Antagonism of Muscle Lin M: excised guinea pig bladder

After hitting the occipital region of a male Hartley guinea pig, exsanguinating and sacrificing blood, laparotomy was performed, and the tip of the bladder, which is visible in the lower abdomen, was lightly picked up with tweezers and cut off at the triangular bladder to remove it and put it in nutrient solution. Soaked. After making a midline incision, a longitudinal strip of 10 to 15 mm in length and 3 to 5 mm in width was obtained. Thereafter, the mucosal tissue was peeled off with ophthalmic scissors and used as a specimen. The specimens were incubated at 37 to 95% 〇 ₂ - After suspended in 5% C_〇 1 was filled ₂ using the clock Rebusu carbonate buffer through 0 m 1 Magnus tank resting tension 1 g, 6 0 min stable The period was set. The contractile response by carbachol using the cumulative method, was measured in isotonic with 1 0- ⁸ M by Rioyakehi 3. Samples were washed immediately after the measurement, and a 45-minute stabilization period was allowed until the next contraction reaction. EC _{5 for the} contractile response to carbachol. The point at which was stabilized was taken as control. The test compound was applied 15 minutes prior to the application of KYRUBACOL. The affinity (p A ₂ ) of the test compound was determined in the same manner as in the case of the trachea. Table 1 shows the results. 3. Mus force Li M ₃ antagonistic effect on isolated guinea pig ileum longitudinal muscle

The back of the head of a male Hartley guinea pig was beaten, exsanguinated and killed, immediately The ileum was removed while removing the mesentery. After thoroughly washing the contents of the ileum, insert a glass rod 5 to 7 mm in diameter into the lumen, cut only the longitudinal muscle along the intestinal membrane attachment with a razor, and swab the swab with the longitudinal muscle and the circular muscle The longitudinal muscle was peeled off while taking care not to dry the tissue. The sample was incubated at 3 7 ° C, 9 5% 0 2 - 5% C 0 2 to 1 0 ml organ bath filled with click Repusu carbonate buffer through was suspended in resting tension 1 g, 6 0 min Has a stable period. The contractile response by carbachol using the cumulative method, was measured in isotonic than 1 0- ⁸ M in Oyakehi 3. The sample was washed immediately after the measurement, and a stabilization period of 45 minutes was allowed until the next contraction reaction. EC ₅ of the contractile response by the force Luba call. The point at which was stabilized was taken as control. The test compounds were applied to 1 5 minutes before carbachol application, the affinity of the test compound (p A ₂₎ was obtained in the same manner as in the trachea. Table 1 shows the results.

4. Antagonism of Muscarinic Phosphorus in Isolated Left Guinea Pig Atrium

The occipital region of the guinea pig was beaten, exsanguinated and sacrificed. Immediately after cardiopulmonary extirpation, the lungs, connective tissue, etc., were resected in the ventricle in that order, and cut into the left and right atrium to prepare a specimen. The specimens were incubated at 3 2 ° C and 95% 〇 ₂ - to 1 0 ml organ bath filled with Krebs carbonate buffer through the 5% CO _2, it was suspended in resting tension 0. 5 g. Then, contraction by field electrical stimulation (4 Hz, 2 msec, 1.5 X threshold voltage) was measured. After a 6 0 minutes between stable period was measured inhibition reaction by carbachol isometrically than 1 0- ⁸ M in Oyakehi 3 in 1 concentration 9 0 second intervals using the cumulative method. The sample was washed immediately after the measurement, and a stabilization period of 45 minutes was allowed until the next inhibition reaction. The EC ₅ of the inhibition reaction due to calvacol. The test compound was applied 30 minutes before the application of carbachol. The affinity of the test compound (p Aj was determined in the same manner as for the trachea. The results are shown in Table 1. Muscarinic receptor antagonistic activity (in vitro)

5. Study on guinea pig airway contraction by inhalation

The method of Konzet et al. (Arch. Exp. Path Pharmak., 1940, 195, 71-74) was used. Male Hartley guinea pigs (350-504 g) were fixed in the dorsal position under urea (1.8 g Z kg, ip) anesthesia. More trachea in the neck midline incision to expose the left common carotid artery and left total s vein, to stop tracheal force Nyure, a _t spontaneous breathing inserted respectively blood pressure measurement force Nyure and drug administration force Nyure, Dekame Toniumu (2 magZ kg, i.v.), stop the spontaneous breathing, perform artificial respiration, and use the Konzet Rossler method under a constant pressure load (10 cmH ₂ O) to ventilate the ventilation. Low (ventilationoutflow) volume was measured via a bronchospasm transducer as an indicator of airway resistance. The test compound or physiological saline as a control group was inhaled for 1 minute using an ultrasonic inhaler (0MR0N), and 10 minutes later, mesacolin (3 / xg / kg) to induce airway constriction. The change in the airway stake caused by the drug is the total airway obstruction value (1 Calculate the contraction rate (%) from (0 0%) and determine the dose of the test compound that suppresses airway contraction by 50% (ID ₅₎ . Value. Table 2 shows the results. Table 2 Muscarinic receptor antagonistic activity (in vivo: Inhalation of test compound)

As apparent from Table 1, when compared with comparative control compound, Compound (I) has a strong antagonistic effect on muscarinic! ^ 1 ₃ receptor. Furthermore, since the antagonistic effect of compound (I) on the muscarinic acid ₂ receptor was weaker than that of the control compound, it was evident that the compound had superior receptor selectivity. In addition, the animal model shown in Table 2 also has five times the activity of pipum at the mouth of the rat, and is therefore considered to be sufficiently clinically usable. As described above, since the present invention compounds have a potent拮anti action on Mus force Li down Micromax ₃ receptors, disease muscarinic Micromax ₃ receptor is involved, in particular, chronic obstructive pulmonary disease, chronic bronchial Respiratory diseases such as inflammation, asthma, pulmonary fibrosis and rhinitis; gastrointestinal diseases such as irritable bowel syndrome, spastic colitis, diverticulitis; nausea and vomiting, sickness, and Meniere's disease caused by drug administration Central disease; useful as a preventive or therapeutic agent for urinary diseases such as urinary incontinence and pollakiuria. The present invention compounds found is from a selectively antagonize child to muscarinic 1 ₃ receptors, less is not prophylactic or therapeutic agent for side effects is provided to the heart by Mus force Li> Micromax ₂ receptor antagonism .

Claims

7 Claims General formula (I)

[Wherein, R represents a phenyl group which may have a substituent, R ₂ represents a phenyl group or a lower cycloalkyl group, and m represents 2 or 3.] The imidazoline compound represented by the formula: Or a pharmacologically acceptable salt thereof.

2. The compound according to claim 1, wherein R is a phenyl group or a substituent bonded to the phenyl group of R is a methyl group, a chlorine atom, a trifluoromethyl group or a methoxy group, or a pharmacologically active compound thereof. Acceptable salt.

3. The compound according to claim 1 or 2, wherein R i is a phenyl group having a substituent at the o-position, or a pharmacologically acceptable salt thereof.

4. The compound according to claim 14, wherein R ₂ is a phenyl group, or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 15, wherein m is 2, or a pharmacologically acceptable salt thereof.

6.2—Methyl-1— [2— (phenyl o-tolylmethoxy) ethyl] —2—imidazoline or a pharmaceutically acceptable salt thereof.

7. General formula (I)

[Wherein, R represents a phenyl group which may have a substituent, R ₂ represents a phenyl group or a lower cycloalkyl group, and m represents 2 or 3] A pharmaceutical composition comprising, as an active ingredient, an imidazoline compound represented by the formula: or a pharmacologically acceptable salt thereof.

8. Muscarinic M ₃ prophylaxis against diseases receptor is involved or therapeutic agent der Ru claim 7 pharmaceutical composition according

9. The pharmaceutical composition according to claim 7, which is an agent for preventing or treating digestive diseases, respiratory diseases, urological diseases, and central diseases.

10. The pharmaceutical composition according to claims 7 to 9, wherein the digestive tract disease is irritable bowel syndrome, spastic colitis, or diverticulitis.

1 1. Claims where the respiratory disease is chronic obstructive pulmonary disease, asthma, pulmonary fibrosis, rhinitis? 10. The pharmaceutical composition according to any one of claims 9 to 9.

12. The pharmaceutical composition according to claims 7 to 9, wherein the urological disease is urinary incontinence or frequent urination.

13. The pharmaceutical composition according to any one of claims 7 to 9, wherein the central disease is nausea or vomiting, motion sickness, or menure's disease caused by drug administration.

1 4. General formula (I)

[Wherein, R represents a phenyl group which may have a substituent, R ₂ represents a phenyl group or a lower cycloalkyl group, and m represents 2 or 3.] A muscarinic receptor antagonist comprising a compound or a pharmacologically acceptable salt thereof as an active ingredient.