JP2002104968A - Antitonic agent for ciliary muscle - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new medicine selectively having antitonic actions on ciliary muscles. SOLUTION: This antitonic agent for the ciliary muscles comprises a quinuclidine derivative represented by the general formula (I) (wherein, symbols have the following meanings: ring A is an aryl group, a cycloalkyl group, a cycloalkenyl group or the like; X is a single bond or methylene group; R1 is a halogen atom, hydroxy group, a lower alkoxy group, carboxy group, a lower alkoxycarbonyl group, a lower acyl group, mercapto group or the like; R2 is hydrogen, hydroxy group, a lower alkoxy group or a lower alkyl group; (l) is 0 or 1; (m) is 0 or an integer of 1-3; and (n) is 1 or 1), a salt or a quaternary ammonium salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an agent for relaxing ciliary muscle tone containing a quinuclidine derivative, a salt thereof or a quaternary ammonium salt thereof.

[0002]

2. Description of the Related Art There are iris sphincter, dilator muscle and ciliary muscle as smooth muscles in the eye. Ciliary muscle is the muscle responsible for regulation, but also plays an important role in aqueous outflow. Therefore, relieving the hypertonia of the ciliary muscle is considered to be effective in preventing and treating myopia, eye strain and glaucoma as described below. Myopia refers to a state in which parallel rays of light entering the eye form an image in front of the retina, and a distant image appears blurred. With respect to the occurrence of myopia, a refraction theory mainly due to an increase in the refractive power of the lens and an ocular length theory mainly due to elongation of the axial axis have been advocated, but it is considered that both are actually related. Normally, at the time of near work, a ciliary muscle contracts due to an adjustment reaction (autofocus function). As a result, the ciliary folds advance, the circumference formed by the folds becomes smaller, the front surface of the lens advances,
Increasing the curvature increases the lens power. However,
When excessive near work is continued, the state where the contraction of the ciliary muscle is continued even if the near work is stopped causes myopia. The increase in the refractive power of the lens is caused not only by an increase in the contraction or relaxation of the ciliary muscle, but also by an increase in the refractive index of the lens. In weak myopia, it is considered that the eye axis is prolonged in relation to the contraction of the ciliary muscle. That is, if the hypertonia of the ciliary muscle continues, it gradually becomes disuse atrophy, and the accommodation power weakens.
At the same time, the choroids atrophy, and as they progress further, the sclera and retina also atrophy. It is considered that the decrease in the resistance of the ophthalmic membrane causes the extension of the posterior pole of the eye which is not protected by the eye muscle, and causes the extension of the axial axis.

[0003] Eye strain is caused by various symptoms such as tired eyes, painful eyes, difficulty in seeing, dizziness, and headache after long hours of close work. Does not resolve. Factors that cause eye strain include physical conditions such as anastomosis and strabismus, work environment such as excessive VDT (Video Display Terminal) work, and mental stress. The objective symptom that is experienced is abnormalities in regulatory function. Glaucoma is a disease in which intraocular pressure is abnormally increased, impairs visual function, and may cause blindness. Intraocular pressure is kept constant by the circulation of aqueous humor, and contraction and relaxation of ciliary muscles play an important role in such aqueous circulation.
Relieving ciliary muscle hypertonia may promote increased aqueous humor outflow through the uveosclera, thus reducing elevated intraocular pressure.

[0004] Such myopia, eye strain or glaucoma
For hypertension of ciliary muscle
Relaxing is considered significant. Muscari
Choline inhibitors have a ciliary muscle tone-relieving effect,
Atropine, homatropine, tropicamide, etc.
Department has been applied. Up to now, 5 types (m1 to m5)
The muscarinic receptor gene has been cloned and
In theory, M₁, M_TwoAnd M_ThreeClassified as a receptor
(Gregor W., et al. Eye 1999; 13: 285-300). Human
Reported presence of all subtypes in ciliary muscle
(Gil.DW., et.al.Invest.Ophthalmol.Vis.S.
ci. 1997; 38: 1434-1442), involved in ciliary muscle contraction
Mainly do M_ThreeReceptor (Pang IH. Et al. J. Ocul.
Pharmacol. 1994; 10: 125-136)._ThreeReceptor selection
Inhibitors inhibit contraction of bovine ciliary muscle by electrical stimulation
(Masuda H. et al. Gen. Phar
macol. 1998; 30: 579-584). However, M _ThreeAcceptance
In the human eye, the body is not only ciliary muscle, but also ciliary epithelial cells,
Also present in the iris, trabecular meshwork, corneal epithelium and lens epithelium
(Gupta N. et al. Ophthalmic Res. 1994; 26: 207-213)
Therefore, suppression of aqueous humor outflow and ciliary protrusion due to ciliary muscle contraction
Effects on intraocular pressure due to increased aqueous humor production
Miosis associated with iris sphincter contraction and (GilDW, et al.
Above), promotion of tear secretion from lacrimal glands (Nakamura M. et al. Cur
r. Eye Res. 1997; 16: 614-619), Muscarin M_Three Acceptance
Various functions through the body are assumed. Atropine above
Conventional muscarinic receptor inhibitors such as
Poor selectivity for body subtypes and relaxation of the iris sphincter
Although it is used as a mydriatic because of its slowing action,
Cure certain diseases such as myopia, eye strain or glaucoma
Has not been put into practical use for medical treatment
It is.

On the other hand, as compounds having a muscarinic M ₃ receptor inhibitory activity, quinuclidine derivatives are described in WO 96/20194 and JP-A-10-7675. However, these compounds
It is only shown to be useful as a preventive or therapeutic agent for urinary diseases, respiratory diseases or gastrointestinal diseases, but nothing is described about the relaxing action of ciliary muscle.

[0006]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel drug having a selective action of relaxing ciliary muscle tone.

[0007]

Means for Solving the Problems In view of the above-mentioned prior art, the present inventors have conducted intensive studies on a drug having an action of relaxing ciliary muscle tone. The present inventors have found that a ciliary tension relaxing agent can be obtained and completed the present invention. That is, the present invention provides a compound represented by the general formula (I):

[0008]

Embedded image (The symbols in the formula have the following meanings: Ring A: an aryl group; a cycloalkyl group; a cycloalkenyl group; a heteroaryl group containing 1 to 4 heteroatoms consisting of an oxygen atom, a nitrogen atom or a sulfur atom; A 5- to 7-membered saturated heterocyclic group; these rings may be substituted with any substituent; X: a single bond or a methylene group; R ₁ : a halogen atom; a hydroxyl group; a lower alkoxy group; A lower alkoxycarbonyl group; a lower acyl group, a mercapto group, a lower alkylthio group, a sulfonyl group, a lower alkylsulfonyl group, a sulfinyl group, a lower alkylsulfinyl group, a sulfonamide group, a lower alkane sulfonamide group, a carbamoyl group, and a thiocarbamoyl group; A mono- or di-lower alkylcarbamoyl group; a nitro group; a cyano group; A amino group; a mono- or di-lower alkylamino group; a methylenedioxy group; an ethylenedioxy group; or a substituted with a halogen atom, a hydroxyl group, a lower alkoxy group, an amino group, or a mono- or di-lower alkylamino group. R ₂ : hydrogen; a hydroxyl group; a lower alkoxy group or a lower alkyl group; 1: 0 or 1; m: 0 or an integer of 1 to 3; n: 1 or 2). It is intended to provide a ciliary muscle tone relaxing agent containing a derivative, a salt thereof or a quaternary ammonium salt thereof.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The compound of the formula (I) which is an active ingredient of the ciliary muscle tone relaxing agent of the present invention will be described below.
It is as follows. Unless otherwise specified in the definition of the general formula in the present specification, the term “lower” means a straight or branched carbon chain having 1 to 6 carbon atoms.

Accordingly, the lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms. Specifically, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec
-Butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1
-Methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1 2,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, , 1,2-trimethylpropyl group, 1,2,2
-Trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group and the like. Among these groups, methyl, ethyl, propyl, isopropyl, butyl and the like have 1 to 4 carbon atoms.
Is preferred, a methyl group and an ethyl group are more preferred, and a methyl group is even more preferred.

The "lower alkoxy group" includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, te
rt-butoxy group, pentyloxy (amyloxy)
Group, isopentyloxy group, tert-pentyloxy group, neopentyloxy group, 2-methylbutoxy group,
Examples thereof include a 1,2-dimethylpropoxy group, a 1-ethylpropoxy group, and a hexyloxy group, and a methoxy group is preferable.

[0012] The "aryl group" includes 6 to 14 carbon atoms.
Aryl groups are preferred, specifically, a phenyl group,
Tolyl group, xylyl group, biphenyl group, naphthyl group, indenyl group, anthryl group, phenanthryl group,
More preferably, it is a phenyl group or a naphthyl group, particularly preferably a phenyl group. "Cycloalkyl group"
Examples thereof include those having 3 to 8 carbon atoms, and specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group. Examples of the “cycloalkenyl group” include those having 3 to 8 carbon atoms.
-Cyclopropenyl group, 2-cyclopropenyl group, 1-
Cyclobutenyl group, 2-cyclobutenyl group, 1-cyclopentenyl group, 2-cyclopentenyl group, 3-cyclopentenyl group, 1-cyclohexenyl group, 2-cyclohexenyl group, 3-cyclohexenyl group, 1-cycloheptenyl group, 2 -Cycloheptenyl group, 3-cycloheptenyl group, 4-cycloheptenyl group, 1-cyclooctenyl group, 2-cyclooctenyl group, 3-cyclooctenyl group, 4-cyclooctenyl group, 2,4-cyclopentadienyl group, 2,5-cyclohexadi Enyl group, 2,4-
And a cycloheptadienyl group and a 2,6-cycloheptadienyl group.

Specific examples of the "heteroaryl group containing 1 to 4 oxygen atoms, sulfur atoms or nitrogen atoms" include furyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, pyrazolyl, pyrazolyl, isothiazolyl,
Examples include isoxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazolyl, and tetrazolyl groups. Of these groups, a furyl group,
Thienyl group, pyrrolyl group, imidazolyl group, thiazolyl group, isothiazolyl group, pyridyl group, pyrimidinyl group,
A pyrazinyl group and the like are preferable, and a furyl group, a thienyl group and a pyridyl group are particularly preferable. Specific examples of the "5- to 7-membered saturated heterocyclic group" include a pyrrolidinyl group, an imidazolidinyl group, a pyrazolidinyl group, a piperidinyl group, a piperazinyl group, and a morpholinyl group.

"Halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. As the "lower alkoxycarbonyl group", a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group, a sec-butoxycarbonyl group, a tert-butoxycarbonyl group, a pentyloxy ( Amyloxy) carbonyl group, isopentyloxycarbonyl group, tert-pentyloxycarbonyl group, neopentyloxycarbonyl group, 2-methylbutoxycarbonyl group, 1,2-dimethylpropoxycarbonyl group, 1-ethylpropoxycarbonyl group, hexyloxycarbonyl And the like.

As the "lower acyl group", a formyl group,
Examples include an acetyl group, a propionyl group, a butyryl group, a valeryl group, and a pivaloyl group. "Lower alkylthio group" means a group in which a hydrogen atom in a mercapto group has been substituted with the above lower alkyl group, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, pentylthio, hexylthio, and the like. Is mentioned.

As the "lower alkylsulfonyl group",
Examples include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, an isopropylsulfonyl group, a butylsulfonyl group, a pentylsulfonyl group, and a hexylsulfonyl group. As the "lower alkylsulfinyl group", a methylsulfinyl group, an ethylsulfinyl group,
Propylsulfinyl group, isopropylsulfinyl group, butylsulfinyl group, pentylsulfinyl group,
And a hexylsulfinyl group. Examples of the “lower alkane sulfonamide group” include a methane sulfonamide group, an ethane sulfonamide group, a propane sulfonamide group, an isopropane sulfonamide group, a butane sulfonamide group, a pentane sulfonamide group, and a hexane sulfonamide group.

The "mono- or di-lower alkylcarbamoyl group" includes hydrogen atom 1 to carbamoyl group.
A carbamoyl group in which two are substituted with the above lower alkyl group means a methylcarbamoyl group, an ethylcarbamoyl group, a propylcarbamoyl group, a dimethylcarbamoyl group, and the like. The “mono- or di-lower alkylamino group” means an amino group in which one or two hydrogen atoms in an amino group are substituted with the above “lower alkyl group”,
Methylamino group, ethylamino group, propylamino group,
Examples include a dimethylamino group, a diethylamino group, a dipropylamino group and the like.

An "aryl group", a "cycloalkyl group", a "cycloalkenyl group", a "heteroaryl group containing 1 to 4 heteroatoms consisting of oxygen, nitrogen or sulfur" on ring A, or Each ring of the “5- to 7-membered saturated heterocyclic group” may be substituted with an arbitrary substituent, and the number of substituents is not limited to one, and may be plural. Here, the optional substituent may be any group as long as it is a group that can be substituted on these rings, but is preferably a halogen atom, a hydroxyl group, a lower alkoxy group, a carboxyl group,
Lower alkoxycarbonyl group, lower acyl group, mercapto group, lower alkylthio group, sulfonyl group, lower alkylsulfonyl group, sulfinyl group, lower alkylsulfinyl group, sulfonamide group, lower alkanesulfonamide group, carbamoyl group, thiocarbamoyl group, mono −
Or a di-lower alkylcarbamoyl group, a nitro group,
Cyano group, amino group, mono- or di-lower alkylamino group, methylenedioxy group, ethylenedioxy group,
Or a halogen atom, a hydroxyl group, a lower alkoxy group, an amino group, or a lower alkyl group which may be substituted with a mono- or di-lower alkylamino group, preferably a halogen atom, a lower alkyl group, a hydroxyl group. A lower alkoxy group, a nitro group, a cyano group, an amino group, a mono- or di-lower alkylamino group,
More preferred are a halogen atom, a lower alkyl group, a hydroxyl group and a lower alkoxy group, particularly a halogen atom and a lower alkyl group.

When n is 2, the compound represented by the formula (I), which is an active ingredient of the present invention, has an R ₂ group of 1,2,3,4-
Compounds substituted at the 4-position of the tetrahydro-2-isoquinoline ring are preferred. Further, in the formula (I), a phenyl group, a pyridyl group, a thienyl group, a furyl group or a cyclohexyl group in which the ring A may be substituted with a halogen atom or a lower alkyl group, X is a single bond or a methylene group, and l is 0 ,
Compounds in which m is 0 and n is 1 or 2 are preferred, and in formula (I), compounds in which ring A is a phenyl group, X is a single bond, and n is 2 are particularly preferred. For example, 3-quinuclidinyl 1-phenyl-1,2,3,4-tetrahydro-2-
Isoquinoline carboxylate, 3-quinuclidinyl
1- (4-pyridyl) -1,2,3,4-tetrahydro-2-isoquinolinecarboxylate, 3-quinuclidinyl 1,2,3,4-tetrahydro-1- (2-thienyl) -2-isoquinolinecarboxylate , 3-quinuclidinyl 1,2,3,4-tetrahydro-1- (3
-Thienyl) -2-isoquinolinecarboxylate, 3
-Quinuclidinyl 1- (2-furyl) -1,2,3,
4-tetrahydro-2-isoquinolinecarboxylate, 3-quinuclidinyl 1- (4-chlorophenyl)
-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate, 3-quinuclidinyl 1- (4-fluorophenyl) -1,2,3,4-tetrahydro-2-
Isoquinoline carboxylate, 3-quinuclidinyl
1- (4-tolyl) -1,2,3,4-tetrahydro-
2-isoquinolinecarboxylate, 3-quinuclidinyl 1-cyclohexyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate, 3-quinuclidinyl 1- (3-furyl) -1,2,3,4-tetrahydro- 2-isoquinoline carboxylate, 3-quinuclidinyl 4-hydroxy-1-phenyl-1,2,2
3,4-Tetrahydro-2-isoquinoline carboxylate, geometric isomers thereof, and compounds consisting of these optical isomers are exemplified. Among them, 3-quinuclidinyl 1-phenyl-1,2,3,4-tetrahydro-2
-Isoquinoline carboxylate is more preferred, (1
S, 3'R) -3'-Quinuclidinyl 1-phenyl-
1,2,3,4-tetrahydro-2-isoquinolinecarboxylate is most preferred.

The compound represented by the formula (I) of the present invention has a quinuclidinyl group. The nitrogen atom of the quinuclidinyl group may be oxidized (l = 1) or form a quaternary ammonium salt. You may. When a quaternary ammonium salt is formed, specific examples of the group bonded to the nitrogen atom include a lower alkyl group, a lower alkenyl group, and a lower alkynyl group. The “lower alkenyl group” is a linear or branched alkenyl group having 2 to 6 carbon atoms, specifically, a vinyl group, a propenyl group, a butenyl group, a methylpropenyl group, a dimethylvinyl group, a pentenyl group, Methylbutenyl group, dimethylpropenyl group, ethylpropenyl group, hexenyl group, dimethylbutenyl group,
And a methylpentenyl group. Of these groups, a probenyl group is preferred. "Lower alkynyl group"
Is a straight or branched alkynyl group having 2 to 6 carbon atoms, and specific examples thereof include an ethynyl group, a propynyl group, a butynyl group, a methylpropynyl group, a pentynyl group, a methylbutynyl group, and a hexynyl group. Can be Among these groups, an alkynyl group having 2 to 3 carbon atoms such as an ethynyl group and a propynyl group is preferable. Examples of the quaternary ammonium salt anion include a halogen atom ion, triflate, tosylate, mesylate and the like. In particular, a halogen atom ion, that is, a halide ion (for example, chloride ion, bromide ion, iodide) Ions, triiodide ions, etc.) are preferred, but not limited thereto. Other anions include, for example, inorganic anions such as nitrate ion, sulfate ion, phosphate ion and carbonate ion, formate (HCOO-), acetate (CH ₃ COO).
-), Carboxylate such as propionate, oxalate and malonate, and anion of amino acid such as glutamic acid. Among the halide ions, bromide ions or iodide ions are preferred. The anion can be appropriately converted to a preferable anion by a usual ion exchange reaction.

Since the compound represented by the formula (I) of the present invention has an asymmetric carbon atom, there are optical isomers based on this. In addition, the present invention includes those in which structural isomers and tautomers exist, and includes separated or mixtures of these isomers such as diastereomers and enantiomers. Some of the compounds represented by the formula (I) of the present invention can form a salt with an acid other than the quaternary ammonium salt of the quinuclidinyl group. Such salts include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, Acid addition salts with organic acids such as lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid and glutamic acid can be mentioned. Of these, succinate is particularly preferred. Further, the compound represented by the formula (I) of the present invention also contains all hydrates, solvates such as ethanol, and polymorphic substances.

The compound of the present invention represented by the formula (I) can be produced by applying various production methods known in the art, and particularly, WO 96/201.
No. 94 and JP-A-10-7675.

The quinuclidine derivative of the present invention represented by the formula (I), a salt thereof or a quaternary ammonium salt thereof has a muscarinic M ₃ receptor inhibitory action, and comprises a ciliary body containing this compound as an active ingredient. Muscle relaxation agents are myopia,
It can be used as a prophylactic and / or therapeutic agent for eyestrain or glaucoma. The prophylactic and / or therapeutic agent of the present invention can be combined with a pharmaceutically acceptable carrier or excipient, if desired, and mixed into a known dosage form according to a known formulation technique for mixing and dissolving the desired components. Can be prepared. Prevention of diseases based on the relaxing action of ciliary muscle in the present invention,
The therapeutic effect is useful by local administration to the eye, but the effect can be expected by systemic administration such as oral administration and injection.

For topical administration to the eye, aqueous ophthalmic solutions such as aqueous suspension ophthalmic solution, viscous ophthalmic solution, gel, aqueous solution and emulsion can be used. Further, it may be in the form of a powder, granule, tablet or the like, which is used by suspending or dissolving in purified water or the like before use. Furthermore, non-aqueous eye drops such as oily eye drops and eye ointments, and sustained or sustained release eye drops can also be prepared. Eye drops are usually pH 3-8,
Preferably pH 4-7, osmotic pressure 230-450 mOs
m, preferably about 260 to 320 mOsm.

If desired, parabens (eg, methylparaben, propylparaben), inverted soaps (eg, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, cetylpyridinium chloride), alcohol derivatives (chlorobutanol, phenethyl alcohol, benzyl alcohol) ), Organic acids and their salts (such as sodium dehydroacetate, sorbic acid or its salts), phenols (parachloromethoxyphenol,
Preservatives such as parachlorometacresol), organic mercury agents (such as thimerosal, phenylmercuric acetate, and nitromesol); isotonic agents such as sodium chloride, sorbitol, mannitol, and glycerin; hydrochloric acid, acetic acid, sodium hydroxide, and phosphoric acid PH adjusting agents such as phosphates (disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate), boric acid and its salts (borax, etc.), citrate And buffering agents such as acetates (sodium acetate, ammonium acetate, etc.), amino acid salts (glutamic acid, etc.); stable, such as chelating agents (sodium edetate, citric acid and its salts), antioxidants (sulfurous acid, its salts, etc.) Agents: polyhydric alcohols (glycerin, macrogol, etc.), sugars (sorbitol, mannitol, Thickeners such as sucrose), celluloses (methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, etc.) and synthetic high molecular compounds (polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, etc.); Additives such as suspending agents such as activators may be added. Examples of surfactants include nonionic surfactants such as polysorbate and polyoxyethylene hydrogenated castor oil, cationic surfactants such as quaternary ammonium salts, anionic surfactants such as alkyl sulfates, and amphoteric surfactants such as lecithin. Surfactants. In addition, as a base of eye ointment, vaseline, lanolin,
Plastibase can be used.

The prophylactic or therapeutic agent of the present invention may optionally contain, in addition to the compound represented by formula (I), one or more other pharmaceutically active agents or a combination thereof. Although not particularly limited, the formula (I) is usually used for adults.
Of 0.001 to 10 w / v%, preferably 0.0
A desired effect can be obtained by instilling 1 drop, preferably 1 to 3 drops, about 1 to 8 times a day as an eye drop having a concentration of 5 to 5 w / v%. Hereinafter, the present invention will be described in detail with reference to Examples and Test Examples, but these are merely examples, and the present invention is not limited thereto.

[0027]

The following are quinuclidine derivatives (1S,
3′R) -3′-Quinuclidinyl 1-phenyl-1,2,2
A formulation example using 3,4-tetrahydro-2-isoquinolinecarboxylate succinate (hereinafter, referred to as compound A) is shown.

Example 1 Ophthalmic solution Compound A 3.0 g Sodium monohydrogen phosphate decahydrate 0.1 g Sodium chloride 0.9 g Hydrochloric acid Appropriate amount (pH 7.0) Benzalkonium chloride 0.005 g Purified water Total 100 mL Compound A and sodium chloride were added and dissolved in about 80 mL of purified water, and pH was adjusted to 7.0 by adding benzalkonium chloride, sodium monohydrogen phosphate decahydrate and hydrochloric acid. Purified water was added to make a total volume of 100 mL to prepare eye drops.

Example 2 Eye Drops Compound A 0.1 g Sodium monohydrogen phosphate dodecahydrate 0.1 g Concentrated glycerin 2.6 g Hydrochloric acid Appropriate amount (pH 5.0) Methyl paraben 0.014 g Propyl paraben 0.026 g Purified water Compound A and concentrated glycerin were added to and dissolved in about 80 mL of purified water, and sodium monohydrogen phosphate dodecahydrate, methylparaben and propylparaben were added. Then, hydrochloric acid was added to adjust the pH to 5.0. Add purified water and add a total of 10
The volume was adjusted to 0 mL to prepare eye drops.

Example 3 Eye Drops Compound A 3.0 g Sodium acetate 0.05 g Hydrochloric acid Appropriate amount (pH 5.0) Hydroxypropyl methylcellulose 0.1 g Sodium chloride 0.9 g Benzalkonium chloride 0.005 g Purified water Total 100 mL Purified water After about 80 mL of hydroxypropyl methylcellulose was heated and dispersed, it was cooled to room temperature and dissolved. Compound A, sodium chloride, sodium acetate and benzalkonium chloride were added to this solution to dissolve it, and hydrochloric acid was added to adjust the pH to 5.0. Add purified water and add 1
The volume was adjusted to 00 mL to prepare eye drops.

Test Example 1 Effect of rabbit ciliary muscle on carbachol contraction Test Method Animal used A male white rabbit weighing about 2 kg was used. 2. Test Drugs Compound A (lot no. K9059905) and carbachol (carbamylcholine chloride, Sigma), a non-selective muscarinic receptor agonist, were used. Compound A
And carbachol was prepared by dissolving a concentrated solution in distilled water and used in experiments. 3. Test Procedure An excess amount of Nembutal was injected into a white rabbit through the ear vein and euthanized.
A ciliary muscle specimen of 3 mm and a length of 4-5 mm was prepared. Specimen was passed through a gas mixture of 95% O ₂ -5% CO ₂
bs-Henseleit solution (118 mM NaCl,
4.7 mM KCl, 1.2 mM CaCl ₂ , 1.2
mM KH ₂ PO ₄ , 1.2 mM MgSO ₄ , 25 mM
NaHCO ₃ , 11.5 mM glucose, 37 ° C.
Suspended in a Magnus tube filled with pH 7.4)
Equilibrated under a static tension of 80 mg. The change in tension was recorded isometrically on the recorder via transducer and amplifier. Carbachol is used as a constrictor, and the initial contraction (phasic) that occurs rapidly due to carbachol is used.
The effect of (shrinkage) on the dose response and on the tonic contraction (tonic shrinkage) following the initial contraction were studied. The effect of the drug on the initial contraction was determined by repeatedly adding a carbachol (10 ⁻⁷ M to 3 × 10 ⁻⁴ M) cumulatively from a low concentration and repeatedly producing a concentration-dependent contraction reaction. min prior to compound a (10 ^{- 8}
M to ^{- 4} M) was added cumulatively from a low concentration, 3 × 10
It was evaluated by calculating the ratio of the maximum shrinkage of ^-4 M carbachol as 100%. Moreover, persistence elicit contraction by 10 ^-4 M carbachol for contraction, the contraction height at which tension is stabilized is 100% Compound A (10 ^{- 8} M
To 10 ^{- 4} M) was evaluated by obtaining the ratio of contraction height when applied cumulatively than lower concentrations.

Test Results The effect of Compound A on the initial contraction of carbachol in rabbit ciliary muscle was investigated, and the results are shown in FIG. The vertical axis is 3
100% reduction in shrinkage caused by × 10 ^-4 M carbachol
The abscissa shows the concentration of added carbachol when the shrinkage ratio was set as follows. Each value is expressed as mean ± standard error (n = 5). Rabbit ciliary muscle 10 ^{- 7} m3 × concentration-dependent contraction by 10 ^-4 M carbachol, Compound A 10 ^{- 6} significantly inhibited the contraction at a concentration of at least M (both sides with respect to control group p
aired-t-test, *; p <0.05, **;
p <0.01). Compound A 10 ^{- 4} almost completely suppressed M In carbachol contraction, this effect after washing was also sustained. Compound A did not affect the static tension. FIG. 2 shows the results of examining the effect of Compound A on the continuous contraction of carbachol in rabbit ciliary muscle. The vertical axis shows the contraction height caused by 10 ^-4 M carbachol as 100%.
The abscissa indicates the concentration of compound A added. Each value is expressed as mean ± standard error (n = 5). Compound A 10 ^{- 5} significantly inhibited the sustained contraction due to carbachol at a concentration of at least M (both sides Student's t-t
est, ** p <0.01). From the above results, it was clarified that Compound A suppresses ciliary muscle contraction caused by carbachol, and it was considered that Compound A may alleviate the tension of ciliary muscle due to parasympathetic nerve stimulation.

Test Example 2 Effect on Rabbit Pupil Diameter Test Method Animal used A male white rabbit weighing about 2 kg was used. 2. Test Drug Compound A solution was prepared to be 0.03 and 0.1% using the bases shown below and used for the test. (Base formulation) Sodium dihydrogen phosphate dihydrate 0.1 g Sodium chloride 0.9 g Hydrochloric acid Appropriate amount (pH 7) Purified water Total 100 mL Midrin P (Santen Pharmaceutical registered trademark,
0.5% tropicamide and 0.5% phenylephrine hydrochloride) were used. 3. Test procedure 1) Ophthalmic administration: 0.1 or 0.03% compound A solution was applied to one eye of each animal once using a micropipette.
Instillation was performed three times at 1-hour intervals in 0 μL increments. In addition, 50 μL of midulin P was instilled once in one eye of another animal. 2) Pupillary diameter measurement: before the start of instillation and at the first time in the compound A solution instillation group at 30, 60 and 150 minutes, and in the midulin P instillation group at 5, 15, 25, 40, 55 and 7 after the instillation.
Pupil diameters were measured at 0, 85, 115 and 145 minutes using digital calipers.

Test Results The effect of 0.03 and 0.1% compound A solutions on the pupil diameter of eye drops is shown in FIG. The vertical axis indicates the pupil diameter, and the horizontal axis indicates the lapse of time from the start of instillation. Each value is expressed as mean ± standard error (n = 3). The initial pupil diameters of the 0.03% and 0.1% Compound A ophthalmic group and the Midulin P ophthalmic group before the start of instillation were 5.26, 5.19, and 6.08 mm, respectively. 30, 6 after the first instillation of the 0.1% Compound A instillation group
Pupil diameters at 0 and 150 minutes are 5.69 and 5.8, respectively.
6 and 5.99 mm. The pupil diameters of the 0.03% Compound A instillation group at 30, 60 and 150 minutes after the first instillation were 5.84, 5.72 and 6.26 mm, respectively, and both groups had slight pupil dilation. . On the other hand, 5, 15, 25, 40, 55,
Pupil diameters at 70, 85, 115 and 145 minutes are 7.58, 8.17, 8.45, 8.84, 8.92, respectively.
8.93, 9.00, 9.08, and 8.85 mm. Compared with the Compound A instillation group, the Midrin P instillation group showed a marked mydriasis with a single instillation, and the mydriasis was 145 minutes after instillation. Lasted until The above results indicate that Compound A has a small mydriatic action and selectively relaxes ciliary muscle.

[0035]

According to the present invention, the use of the quinuclidine derivative represented by the formula (I) as an active ingredient, a ciliary muscle tone relaxing agent which selectively has a ciliary muscle tone relaxing action. Is obtained.

[Brief description of the drawings]

FIG. 1 shows the effect of Compound A on the initial contraction of carbachol in rabbit ciliary muscle in Test Example 1.

FIG. 2 shows the effect of Compound A on continuous contraction of carbachol in rabbit ciliary muscle in Test Example 1.

FIG. 3 shows the effect of Compound A on rabbit pupil diameter in Test Example 2.

 ──────────────────────────────────────────────────続 き Continued on the front page F term (reference) 4C064 AA06 DD01 EE03 FF01 GG13 4C086 AA01 AA02 BC30 CB17 MA01 MA04 MA58 NA14 ZA33 ZA94

Claims (8)

[Claims] 1. An active ingredient represented by the following general formula (I): (The symbols in the formula have the following meanings: Ring A: an aryl group; a cycloalkyl group; a cycloalkenyl group; a heteroaryl group containing 1 to 4 heteroatoms consisting of an oxygen atom, a nitrogen atom or a sulfur atom; A 5- to 7-membered saturated heterocyclic group; these rings may be substituted with any substituent; X: a single bond or a methylene group; R ₁ : a halogen atom; a hydroxyl group; a lower alkoxy group; A lower alkoxycarbonyl group; a lower acyl group, a mercapto group, a lower alkylthio group, a sulfonyl group, a lower alkylsulfonyl group, a sulfinyl group, a lower alkylsulfinyl group, a sulfonamide group, a lower alkane sulfonamide group, a carbamoyl group, and a thiocarbamoyl group; A mono- or di-lower alkylcarbamoyl group; a nitro group; a cyano group; A amino group; a mono- or di-lower alkylamino group; a methylenedioxy group; an ethylenedioxy group; or a substituted with a halogen atom, a hydroxyl group, a lower alkoxy group, an amino group, or a mono- or di-lower alkylamino group. R ₂ : hydrogen; a hydroxyl group; a lower alkoxy group or a lower alkyl group; 1: 0 or 1; m: 0 or an integer of 1 to 3; n: 1 or 2). An agent for relaxing ciliary muscle tone containing a derivative, a salt thereof or a quaternary ammonium salt thereof. 2. In the formula (I), a phenyl group in which the ring A may be substituted with a halogen atom or a lower alkyl group,
A pyridyl group, a thienyl group, a furyl group or a cyclohexyl group, X is a single bond or a methylene group, l is 0, m is 0,
The agent for relaxing ciliary muscle tone according to claim 1, wherein n is 1 or 2. 3. The agent for relaxing ciliary muscle tone according to claim 2, wherein in formula (I), ring A is a phenyl group, X is a single bond and n is 2. 4. The method according to claim 1, wherein the active ingredient is (1S, 3′R) -3′-quinuclidinyl 1-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate or an acid salt thereof. An agent that relaxes ciliary muscle. 5. The agent for relaxing ciliary muscle tone according to claim 4, wherein the active ingredient is succinate. 6. The agent for relaxing ciliary muscle tone according to any one of claims 1 to 5, which is a prophylactic and / or therapeutic agent for myopia. 7. The agent for relaxing ciliary muscle tone according to any one of claims 1 to 5, which is an agent for preventing and / or treating eye strain. 8. The agent for relaxing ciliary muscle tone according to any one of claims 1 to 5, which is an agent for preventing and / or treating glaucoma.