JP2003267977A - Quinuclidine derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a medicine which has muscarine M<SB>3</SB>receptor antagonism and is useful as a prophylactic/therapeutic agent for urologic disease, respiratory disease or digestive system disease. <P>SOLUTION: The quinuclidine derivative is represented by general formula (I) (R is a halogen, a lower alkyl which may contain a substituent group or the like; l is 0 or 1; m is an integer of 1-3; R<SP>1</SP>to R<SP>3</SP>are each H, a lower alkyl which may have a substituent group or the like; p is 0, 1 or 2; n is 1 or 2; ring A is an aryl which may contain a substituent group or the like; R<SP>4</SP>is OH, a lower alkyl or a lower alkyl -O- group or the like; L is O or a 2-7C alkylene group which may be interrupted by an NR<SP>5</SP>; R<SP>5</SP>is H, a lower alkyl or a lower alkyl -O-CO- group; X<SP>1</SP>is single bond or a methylene group; X<SP>2</SP>is a single bond or O or S), its salt, its N-oxide or its quaternary ammonium salt. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel compound, particularly a quinuclidine derivative having a muscarinic receptor antagonistic action, a salt thereof, an N-oxide thereof or a quaternary ammonium salt thereof.

[0002]

2. Description of the Related Art Conventionally, studies on muscarinic receptors have been conducted, and compounds having muscarinic receptor antagonistic activity have been found to have bronchodilation, gastrointestinal motility inhibition, acid secretion inhibition, dry mouth, mydriasis, bladder contraction inhibition, and sweating reduction. , And tachycardia are known to occur. It is known that this muscarinic receptor has at least three subtypes. Mainly, the M ₁ receptor is in the brain, the M ₂ receptor is in the heart,
The M ₃ receptor is present in smooth muscle and glandular tissue.

[0003]

There are many conventionally known compounds having the muscarinic receptor antagonistic activity, and atropine is a typical example (Merck Index, 11th Edition, 138).
page). However, since atropine non-selectively antagonizes M ₁ , M ₂ , and M ₃ receptors, it was not easy to aim at the treatment of specific diseases. In recent years, research on muscarinic receptor subtypes has progressed, and compounds that selectively antagonize M ₁ , M ₂ , and M ₃ receptors have been investigated (British Patent Application Publication No. 2,249,093, JP-A-1). -131145 and JP-A-3-133980). Above all, it is desired to create a compound that is selective for the muscarinic M ₃ receptor and has no cardiac side effects caused by the M ₂ receptor.

WO 96/20194 describes compounds having the following general formula, salts thereof, N-oxides thereof or quaternary ammonium salts thereof.

[Chemical 4] (In the formula, ring A is a phenyl group, X is a single bond, l is 0 or 1, m is 0, etc., and n is 1 or 2.) WO 95/21820 has a compound having the following general formula. Is listed.

[Chemical 5] (In the formula, A ring is a benzene ring, B ring is a quinuclidine ring, R ¹ is a phenyl group, X is a single bond, Y is a single bond, etc.) In WO 95/06635, the following general formula is used. Compounds having are described.

[Chemical 6] (In the formula, R is a phenyl group, R ¹ is a phenyl group,
(R ² is H, etc., R ³ is H, etc., A ring is quinuclidine ring, etc., X is O, etc., Y is O, etc., p is 0, etc.) JP-A-8-198751 discloses a compound having the following general formula. Have been described.

[Chemical 7] (In the formula, A is an alkylene group which may be interrupted by O or NR ¹ , R ¹ is H, lower alkyl or lower alkyl-
(O-CO- group, Ph is phenyl group, etc., B ring is quinuclidine ring, etc.) JP-A-10-007675 describes a compound having the following general formula or a salt thereof.

[Chemical 8] (In the formula, R ¹ group is OH, lower alkyl or lower alkyl-O— group, R ² group is phenyl group, and l is 0 or 1, m
Is 0)

[0005]

Means for Solving the Problems As a result of diligent studies on the above-mentioned compound having a muscarinic M ₃ receptor antagonistic action, the present inventors have created a novel quinuclidine derivative having a structure different from that of conventional compounds, and The present invention has been completed by finding that it has an excellent selective muscarinic M ₃ receptor antagonistic action.

That is, the compound of the present invention relates to a quinuclidine derivative represented by the following general formula (I), a salt thereof, an N-oxide thereof or a quaternary ammonium salt thereof.

[Chemical 9] (The symbols in the formulas have the following meanings: R: halogen; lower alkyl optionally having substituents; lower alkenyl optionally having substituents; cyclo optionally having substituents alkyl; optionally substituted aryl; mAY substituted heteroaryl; or 5 may have a substituent 6-membered saturated heterocyclic ring; -O-R ^1; - ^{CO-R 1; -COO-R} 1; -C
^{ON (-R 1) -R 2;} -S (O) p -R 1; -N (-
^{R 1) -R 2; -N (} -R 1) -CO-R 2; -N (-
^{R 1) -COO-R 2;} -N (-R 1) -CO-N (-
^{R 2) -R 3; -N (} -R 1) -S (O) p -R 2; ( when m is 2 or more, R represents may be in different groups in the same group) l: 0 or 1 m : Integers ^{1 to 3 of 1 to 3} : the same or different, H; lower alkyl optionally having substituent (s); lower alkenyl optionally having substituent (s); Optionally aryl; heteroaryl optionally having substituents; or 5- to 6-membered saturated heterocycle optionally having substituents; p: 0, 1 or 2

[Chemical 10] n: 1 or 2 A ring: aryl which may have a substituent; cycloalkyl which may have a substituent; heteroaryl which may have a substituent; or 5 to 7-membered saturated hetero. ring group; R ^4: OH, lower alkyl or lower alkyl -O- group L: O or NR ⁵ C2-7 alkylene group may be interrupted by R ^5: H, lower alkyl or lower alkyl -O-CO-
Group X ¹ : single bond or methylene group X ² : single bond, O or S)

In the compound (I) of the present invention, a particularly preferred compound is a quinuclidine derivative represented by the following general formula (Ia), a salt thereof or a quaternary ammonium salt thereof.

[Chemical 11] (The groups in the formula are as described above.)

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The compound (I) of the present invention is described in detail below. The compound (I) of the present invention is structurally characterized in that it has a substituent at the carbon atom on the quinuclidine ring, unlike the aforementioned known muscarinic M ₃ receptor antagonists.

In the definition of the general formulas herein, the term "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms. Therefore, the “lower alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, and specifically, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl group or These structural isomers, such as an isopropyl group, are preferably an alkyl group having 1 to 4 carbon atoms, and more preferably a methyl or ethyl group. The "lower alkenyl group" is an alkenyl group having 2 to 6 carbon atoms, specifically, a vinyl group, a 1-propenyl group, a 1-butenyl group, a 1-pentenyl group, a 1-hexenyl group or a 1-hexenyl group. These structural isomers such as a methyl-2-propenyl group,
A vinyl or 1-propenyl group is preferred. The "lower alkynyl group" is a linear or branched alkynyl group having 2 to 6 carbon atoms, and specifically, an ethynyl group, a propynyl group, a butynyl group, a methylpropynyl group, a pentynyl group, a methylbutynyl group, These structural isomers such as a hexynyl group and a 1-methylpropynyl group are preferable, and an ethynyl group and a propynyl group are preferable.

The "aryl group" means an aromatic hydrocarbon group, but an aryl group having 6 to 14 carbon atoms is preferable. Specifically, it is a phenyl group, a naphthyl group, an indenyl group, an anthryl group or a phenanthryl group, more preferably a phenyl group. Examples of the “cycloalkyl group” include those having 3 to 8 carbon atoms, and specific examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group and a cyclooctyl group. Of these, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group are preferable, and a cyclohexyl group is more preferable.
"Heteroaryl" means furyl, thienyl, pyrrolyl,
Monocyclic heteroaryl such as imidazolyl, thiazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazyl, triazolyl, tetrazolyl group; indolyl, benzimidazolyl,
Examples include bicyclic heteroaryl such as naphthyridinyl and 1,3-benzodioxyl group. Of these groups, preferably a 5-membered or 6-membered monocyclic heteroaryl group containing 1 to 4 heteroatoms consisting of oxygen atom, nitrogen atom or sulfur atom, more preferably furyl group, thienyl group, It is a pyridyl group. The “5- to 6-membered saturated heterocycle” is specifically, for example, pyrrolidine, piperidine,
Tetrahydrofuran, tetrahydropyran, morpholine, piperazine may be mentioned.

"Halogen atom" means a fluorine atom,
Examples thereof include chlorine atom, bromine atom and iodine atom. "A C2-7 alkylene group which may be interrupted by O or NR ¹ " is an alkylene group in which any position of the alkylene group is interrupted by O, or any position of the alkylene group is interrupted by NR ¹ . An alkylene group or an uninterrupted alkylene group is meant. Also, a C2-7 alkylene group which may be interrupted by O or NR ¹ , that is, 2 at both ends of L.
Since one bond is bonded to the carbon atom to which the phenyl group and the N atom are bonded together, L forms a ring with this carbon atom. Preferred as the ring containing L are cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, tetrahydrofuran, tetrahydropyran, pyrrolidine, hexahydropyridine, N-methylhexahydropyridine, N.
Examples include-(t-butoxycarbonyl) -hexahydropyridine and the like.

"Lower alkyl group", "lower alkenyl"
Group "," cycloalkyl group "," aryl group "," het
"Aryl group" or "5- or 6-membered saturated heterocyclic group"
A substituent is a group usually used as a substituent for these groups.
Any substituent may be used, and each substituent has 1 substituent.
You may have up to three. "Low optionally substituted
Primary alkyl group ”,“ lower alkyl optionally having substituent (s) ”
As a substituent of “kenyl group”, cycloalkyl is preferable.
Group, optionally substituted aryl, optionally substituted
Good 5- or 6-membered saturated heterocyclic group, which may have a substituent
Heteroaryl, -O-aryl, -O-heteroaryl
-NH ₂, -NH-lower alkyl, -N, N-di-
Lower alkyl, -OH, -O-lower alkyl, -S-low
Primary alkyl is mentioned. "May have a substituent
The substituent of “cycloalkyl” is preferably halogen.
Atom, lower alkyl, -OH, -O-lower alkyl,
-NH₂, -NH-lower alkyl, -N, N-di-lower
Alkyl, cyclic amino, -COOH, -COO-lower alkyl
Alkyl, -S-lower alkyl, -SO-lower alkyl,
-SO₂-Lower alkyl, -NH-CO-lower alk
-NH-SO₂-Lower alkyl, -NH-CO-ring
Amino, or -O-lower alkyl-O- group, heteroa
Reel, and the lower alkyl in these groups is
Rogen atom, -OH, NH₂, -NH-lower alkyl,
Or substituted with -N, N-di-lower alkyl group, -COOH
May be formed, or a new ring may be formed with the original ring.
Yes.

"Aryl group which may have a substituent (s)"
Preferred examples of the substituent include a halogen atom, lower alkyl, -OH, -O- lower alkyl, nitro, -NH _2,
-NH-lower alkyl, -N, N-di-lower alkyl,
Cyclic amino, -COOH, -COO-lower alkyl,-
S- lower alkyl, -SO- lower alkyl, -SO ₂ -
Lower alkyl, -NH-CO-lower alkyl, -NH-
SO ₂ - lower alkyl, -NH-CO- cyclic amino, -
O-lower alkyl-O- group, heteroaryl, and lower alkyl in these groups are halogen atom, -O.
It may be substituted with H, NH ₂ , —NH-lower alkyl, —N, N-di-lower alkyl group, or —COOH, and may form a new ring with the original ring. The "heteroaryl which may have a substituent" and the substituent of the "5- to 6-membered saturated heterocycle which may have a substituent" are preferably a halogen atom, a lower alkyl, -COOH,
-Lower alkyl-COOH, -CO-lower alkyl,-
Lower alkyl-aryl, or -lower alkyl-CO-
O-lower alkyl group, -O-lower alkyl, nitro,-
NH _2, -NH- lower alkyl, -N, N-di - lower alkyl, cyclic amino, -COO- lower alkyl, -S-
Lower alkyl, -SO- lower alkyl, -SO ₂ - lower alkyl, -NH-CO- lower alkyl, -NH-SO
₂ -lower alkyl, -NH-CO-cyclic amino, -O-
Lower alkyl-O- group, heteroaryl, and lower alkyl in these groups include a halogen atom, -OH,
It may be substituted with NH ₂ , —NH-lower alkyl, —N, N-di-lower alkyl group, or —COOH, and may form a new ring with the original ring.

The compound (I) of the present invention has a quinuclidine ring, and the nitrogen atom of the quinuclidine ring may be oxidized (l = 1) or may form a quaternary ammonium salt. When forming a quaternary ammonium salt, examples of the group bonded to the nitrogen atom include a lower alkyl group, a lower alkenyl group and a lower alkynyl group. Examples of the anion of the quaternary ammonium salt include an ion of a halogen atom, triflate, tosylate, mesylate, and the like. Particularly, an ion of a halogen atom, that is, a halide ion (for example, chloride ion, bromide ion, iodide). Ions and the like) are preferable, but not limited to these. Other anions include, for example, inorganic anions such as nitrate, sulfate, and phosphate, carbonate, formate (HCOO ⁻ ), acetate (CH ₃ COO ⁻ ), propionate, oxalate, carboxylate such as malonate, glutamic acid. Further examples include anions of amino acids such as Among the halide ions, bromide ion or iodide ion is preferable. The anion can be appropriately converted into a preferable anion by an ordinary ion exchange reaction.

Since the compound (I) of the present invention has an asymmetric carbon atom, optical isomers based on it exist. In addition, the present invention may have stereoisomers such as geometrical isomers, and includes separated isomers such as diastereomers and enantiomers or a mixture thereof. Some of the compound (I) of the present invention can form a salt with an acid. Examples of such salts include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, and maleic acid. , Lactic acid, malic acid, citric acid, tartaric acid,
Examples thereof include acid addition salts with organic acids such as carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid and glutamic acid. Furthermore, the compound (I) of the present invention includes all hydrates, solvates such as ethanol, and polymorphic substances.

(Production Method) The compound (I) of the present invention can be produced by applying various production methods. The typical manufacturing method will be described below. First manufacturing method

[Chemical 12] (In the formula, Q ¹ represents a leaving group advantageous in this reaction, and W, R, l and m have the above-mentioned meanings. The same applies hereinafter.) This reaction is represented by the general formula (II). The reaction is carried out by esterifying the compound and a reaction-corresponding amount of the quinuclidinol derivative represented by the general formula (III) in an inert solvent with stirring under cooling or at room temperature to under heating. Leaving group Q
Examples of ¹ include a halogen atom, a lower alkoxy group, a phenoxy group, an imidazolyl group and the like. Examples of the inert solvent include dimethylformamide (DM
F), dimethylacetamide, tetrahydrofuran (TH
F), dioxane, dimethoxyethane, diethoxyethane, benzene, toluene, xylene and the like, and mixed solvents thereof. In order to accelerate this reaction, it is preferable to add a base (eg, sodium, sodium hydride, sodium methoxide, sodium ethoxide, etc.).

Second manufacturing method

[Chemical 13] (In the formula, W, R, l, m and Q ¹ have the above-mentioned meanings.) In this reaction, the compound represented by the general formula (IV) and the corresponding amount of the general formula (V) are inactivated by the above-mentioned reaction. It is carried out by stirring in a solvent under cooling or at room temperature or under heating. It is preferable to add a base (for example, sodium, sodium hydride, sodium methoxide, sodium ethoxide, triethylamine, pyridine, etc.) in order to accelerate this reaction.

Third method

[Chemical 14] (In the formula, R, l, m, L and X have the above-mentioned meanings.
The same applies below. This reaction is carried out by stirring an isocyanate compound represented by the general formula (VI) and a corresponding amount of the quinuclidinol derivative represented by the general formula (III) in an inert solvent at room temperature or under heating.

(Other Production Method) In the compound of the present invention, the compound in which the nitrogen atom of the quinuclidinyl group is oxidized, or the compound which forms a quaternary ammonium salt is a compound in which the tertiary amine compound of the compound of the present invention is N-oxidized. , N-alkylation reaction. The N-oxidation reaction can be carried out by a conventional oxidation reaction. Specifically, the tertiary amine compound of the compound of the present invention and the corresponding amount or excess amount of the oxidizing agent are added to chloroform, dichloromethane or dichloroethane. It can be carried out by stirring in an inert solvent such as, an alcohol such as methanol and ethanol, water, or a mixed solvent thereof under cooling to room temperature, and optionally under heating. Examples of the oxidizing agent include organic peracids such as m-chloroperbenzoic acid, sodium periodate, hydrogen peroxide and the like. As the N-alkylation reaction,
It can be carried out by a conventional N-alkylation reaction, specifically, the tertiary amine compound of the compound of the present invention,
It can be carried out by stirring in a corresponding amount of an alkylating agent and an inert solvent such as dimethylformamide, chloroform, benzene, 2-butanone, acetone or tetrahydrofuran under cooling to room temperature or optionally under heating. As the alkylating agent, lower alkyl halide, lower alkyl trifluoromethanesulfonate,
Lower alkyl p-toluene sulfonate, lower alkyl methane sulfonate, etc. are mentioned. A lower alkyl halide is preferred. Further, when producing the compound of the present invention, it may be necessary to protect the functional group. In that case, the compound can be produced by introducing a suitable protecting group and deprotecting it by a conventional method. The thus-produced compound of the present invention is isolated or purified as it is in a free state or subjected to a salt-forming treatment by a conventional method. Isolation
Purification is carried out by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization and various chromatographies.

A typical quinuclidinol derivative (III), which is the starting material compound of the present invention, is Chem.
It is a known compound with the following Registry No. in ical abstract.

[Chemical 15] Further, typical examples of the raw material compound (II) are the following compounds described in WO 96/20194.

[0021]

The present invention compounds according to the present invention has affinity and selectivity for muscarinic M ₃ receptors, as M ₃ receptor antagonists, various diseases M ₃ receptor is involved, in particular, neurogenic Pollakiuria, neurogenic bladder, nocturnal enuresis, unstable bladder, bladder spasticity,
Urinary diseases such as urinary incontinence and frequent urination in chronic cystitis,
It is useful as a preventive or therapeutic agent for chronic obstructive pulmonary disease, chronic bronchitis, respiratory diseases such as asthma and rhinitis, and gastrointestinal diseases such as irritable bowel syndrome, spastic colitis and diverticulitis. In particular, the compound of the present invention has high selectivity for M ₃ receptors existing in smooth muscle and glandular tissue as compared with M ₂ receptors existing in heart and the like, and M ₃ receptors having few side effects on heart and the like. It is highly useful as an antagonist, especially as a preventive or therapeutic drug for urinary incontinence and frequent urination, chronic obstructive pulmonary disease, chronic bronchitis, asthma and rhinitis. The affinity and antagonism of the compound of the present invention for the muscarinic receptor were confirmed by the following tests.

Human muscarinic receptor affinity test (in vi
tro) Buckley et al.'s method (Mol. Pharmacol., 35, 469-476, 1989) was improved. a. Preparation of Membrane Specimen Expression vector incorporating human muscarinic receptor gene sequence was applied to Chinese hamster ovary-derived cells (CHO-K1)
Genes were introduced into the strain and each human muscarinic receptor subtype was constitutively expressed. Culturing this stably expressing cell line,
A 25 mM sodium phosphate buffer (pH 7.4, hereinafter abbreviated as binding buffer) containing 5 mM magnesium chloride was added thereto, and the mixture was homogenized in water. This is 14,0
Centrifugation was performed at 00 × g and 4 ° C. for 10 minutes, the precipitate was suspended in binding buffer, and stored at −80 ° C. After that, it was melted at the time of use and tested. b. Muscarinic receptor Each subtype binding test Cell membrane preparation, [ ³ H] -N-methylscopolamine and test compound were added to 1 ml of binding buffer at 25 ° C. for 3 days.
After incubating for an hour, glass filter (Whatma
n GF / B), and the filter was washed 3 times with 5 ml of binding buffer. The radioactivity of [ ³ H] -N-methylscopolamine adsorbed on the filter was measured with a liquid scintillation counter. Non-receptor specific binding was determined by adding 1 μM atropine. The affinity of the compound of the present invention for each muscarinic receptor subtype was determined by Cheng and Prusoff (Biochem.
rmacol., 22, 3099, 1973), the dissociation constant (K) calculated from the concentration (IC ₅₀ ) of the test compound that inhibits the binding of [ ³ H] -N-methylscopolamine, which is a labeled ligand, by 50%.
Determined in i). The compound (I) of the present invention had a high affinity for the M ₃ receptor.

Muscarinic receptor antagonist test (in vivo) a. Test for rat rhythmic bladder contraction Wistar female rats (130-200 g) were anesthetized with urethane (1.O.
g / kg sc) and the ureter was ligated on the kidney side. A urethral catheter was placed in the bladder, and rhythmic bladder contraction was induced by injecting about 1.0 ml of physiological saline into the bladder, and the intravesical pressure was measured by a pressure transducer.
After obtaining a stable rhythmic contraction for 5 minutes or longer, the test compound was cumulatively administered from the external jugular vein, and the bladder pressure was measured 5 to 10 minutes later. The inhibition rate of bladder contraction before administration of the test compound was determined, and the dose of the test compound that inhibits bladder contraction before administration by 30% was defined as ED ₃₀ . As a result of this test, the compound of the present invention showed a good ED ₃₀ value. b. Test for rat salivary secretion Wistar male rats (160-190g) were urethane (0.8g / k)
anesthesia by g ip). Test compound (control group is solvent)
Was administered, and 15 minutes later, 0.8 μmol / kg of oxotremorine was administered. All drugs were administered through the femoral vein. Immediately after the administration of oxotremorine, saliva secreted within 5 minutes was collected and weighed. The inhibitory rate against the amount of secretory saliva in the control group was determined, and the dose of the test compound that suppressed the amount of secretory saliva in the control group by 50% was defined as the ID ₅₀ value. c. Test for rat bradycardia This test method is based on the method of Doods et al. (J. Pharmacol. Exp. Ther., 24
2,257-262,1987). Wistar male rats (250-350g) were treated with sodium pentobarbital (50mg
/ Kg ip) and anesthetized, and after cervical incision, the left and right vagus nerves were cut. After the cannula was inserted into the trachea to secure the airway, a stainless rod was inserted from the orbit to destroy the spinal cord. Under artificial respiration (50 cc / min at 10 cc / kg), rectal temperature 37.5
The heart rate was monitored from the common carotid artery. An indwelling needle was fixed to the femoral vein, and drug administration was performed from this. After spinal cord disruption, the mixture was allowed to stand for 15 minutes to reach an equilibrium state, and then atenolol (10 mg / kg) was administered. After the equilibration for 15 minutes again, the test compound was administered, and 15 minutes later, oxotremorine was cumulatively administered to measure the decrease in heart rate. The dose of the test compound that shifts the dose-response curve of the control group 10 times to the right was DR ₁₀ .

The pharmaceutical composition containing one kind or two or more kinds of the compound of the present invention or a salt thereof is prepared using a usual pharmaceutically acceptable carrier. The pharmaceutical composition of the present invention may be administered orally or parenterally by injection, suppository, transdermal agent, inhalation or intravesical injection. The dose is appropriately determined depending on the individual case, taking into consideration the symptoms, age of the subject, sex, etc., but in the case of oral administration, the adult dose is usually about 0.01 mg / kg to 100 mg / kg per day. And do this once, or 2-4
Administer in divided doses. When administered intravenously due to symptoms, it is usually 0.001 mg / kg to 10 mg per adult
It is administered once or multiple times a day in the range of / kg. Pharmaceutical carriers include non-toxic pharmaceutical substances in solid or liquid form. As the solid composition for oral administration according to the present invention, tablets, pills, capsules, powders, granules and the like are used. In such solid compositions, the one or more active substances are at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, agar. , Pectin, magnesium metasilicate, magnesium aluminate, etc. According to a conventional method, the composition comprises an additive other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrating agent such as calcium fibrin glycolate, a stabilizer such as lactose, glutamic acid or asparagine. It may contain a solubilizing agent such as an acid. If necessary, the tablets or pills may be coated with sugar coating such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate or a film of a gastric or enteric substance.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and generally used inert diluents, For example, it contains purified water and ethanol. This composition may contain, in addition to an inert diluent, auxiliary agents such as a wetting agent and a suspending agent, a sweetening agent, a flavoring agent, an aromatic agent and a preservative.
Injections for parenteral administration according to the present invention include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Examples of the aqueous solution and suspension include distilled water for injection and physiological saline. Examples of the non-aqueous solution and suspension include ethylene glycol, propylene glycol, polyethylene glycol, cocoa butter,
There are vegetable oils such as olive oil and sesame oil, alcohols such as ethanol, gum arabic, and polysorbate 80 (trade name). Such a composition may further contain additives such as isotonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg lactose) and solubilizers (eg glutamic acid, aspartic acid). May be included.
These are for example filtered through a bacteria storage filter,
It is sterilized by blending a germicide or blowing. They can also be used by preparing a sterile solid composition and dissolving it in sterile water or a sterile solvent for injection before use.

The present invention will be described in more detail based on the following examples. The compound of the present invention is not limited to the compounds described in the following examples, and the compounds represented by the general formula (I), salts thereof, hydrates thereof, solvates thereof, geometrical and optical isomers thereof , Including all polymorphs.

Reference Example 1 To a solution of 70.0 g of quinuclidin-3-one hydrochloride in 1050 ml of tetrahydrofuran was added 444 ml of 2M lithium diisopropylamide at 0 ° C., and the mixture was stirred for 30 minutes.
To this solution was added a solution of 20.0 g of acetaldehyde in 100 ml of tetrahydrofuran at -65 ° C or lower, and the mixture was stirred for 2 hours. To this solution, 400 ml of water was added at room temperature, and the mixture was stirred overnight, then separated, and 200 ml of tetrahydrofuran was added to the aqueous layer for extraction. The tetrahydrofuran layers were combined and concentrated under reduced pressure. To the residue were added 500 ml of toluene and 250 ml of 20% potassium carbonate aqueous solution for extraction, and 250 ml of toluene was added to the aqueous layer for extraction. The combined toluene layers were dried over magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 1000: 100: 4) to give 2-ethylidenequinuclidine-. 3-on 43.5g
Got Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.75-1.94 (7H, m), 2.70-3.01 (4H, m), 2.38-2.4
0 (1H, m), 6.23-6.27 (1H, m) Mass spectrum ESI 152 [M + H] ⁺

Reference Example 2 About 7 ml of Raney nickel was added to 600 ml of a solution of 60 g of 2-ethylidenequinuclidin-3-one in 600 ml of methanol, and the mixture was stirred at 90 ° C. for 5 hours under hydrogen pressure (Max 0.98 MPa). After cooling this liquid and filtering off Raney nickel,
The solvent was distilled off under reduced pressure to obtain 59.2 g of 2-ethylquinuclidin-3-ol. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 0.84-0.89 (3H, m), 1.00-1.80 (7H, m), 2.12-2.9
0 (5H, m), 3.11 (0.4H, s), 3.67-3.68 (0.6H, m), 4.3
8 (0.6H, d, J = 4.5Hz), 4.58 (0.4H, s) Mass spectrum ESI 156 [M + H] ⁺

Example 1 2.00 g of 2-ethylquinuclidin-3-ol, 3.68 g of ethyl 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate, 0.18 g of sodium ethoxide. 37 ml of a toluene solution of 1.8 ml of DMF was subjected to reactive distillation for 8 hours at a distillation rate of 3.7 ml / h. To this liquid, 19 ml of toluene, 10 ml of water
Was extracted, and the toluene layer was further extracted with 10 ml of water. 12 ml of 5% hydrochloric acid was added to the toluene layer for extraction, and 20 ml of ethyl acetate and 40% aqueous potassium carbonate solution were added to the aqueous layer 20.
ml was added for extraction. Magnesium sulfate was added to the ethyl acetate layer to dry it, and the solvent was distilled off under reduced pressure to give 2
-Ethylquinuclidin-3-yl 1-phenyl-1,
3.6 g of 2,3,4-tetrahydro-2-isoquinoline carboxylate was obtained. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 0.75-0.85 (3H, m), 1.15-1.65 (6H, m), 1.85-1.
91 (1H, m), 2.44-2.92 (7H, m), 3.38-3.42 (1H, m),
3.80-3.90 (1H, m), 4.31 (0.3H, s), 4,87-4.92 (0.7H,
m), 6.23 (1H, s), 7.10-7.35 (9H, m) mass spectrum ESI 391 [M + H] ⁺

Reference Example 3 2-Methylenequinucudin-3-one hydrochloride 7.5 g,
Triethylamine 4.6g, development Raney nickel about 1m
A mixture of 1, 20 ml of water and 75 ml of methanol was stirred under hydrogen pressure (MAX 0.98 MPa) at 95 ° C. for 8 hours. After Raney nickel was filtered off from this solution, the solvent was distilled off under reduced pressure to give 2-methylquinuclidin-3-ol 6.8.
5 g was obtained. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.28 (3H, d, J = 7.5Hz), 1.56-2.02 (5H, m), 2.97
-3.15 (4H, m), 3.55-3.60 (1H, m), 3.89-3.93 (1H,
m), 5.44 (1H, s) Mass spectrum FAB 142 [M + H] ⁺

Example 2 1.51 g of 2-methylquinuclidin-3-ol, 3.00 g of ethyl 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate, 0.15 g of sodium ethoxide. , 30 ml of a toluene solution of 1.5 ml of DMF was subjected to reactive distillation for 6 hours at a distillation rate of 3.0 ml / h. To this liquid, 15 ml of toluene, 7.5 m of water
l was added for extraction, and the toluene layer was further extracted with 7.5 ml of water. 8.5 ml of 5% hydrochloric acid was added to the toluene layer for extraction, and 15 ml of ethyl acetate and 6 ml of 40% aqueous potassium carbonate solution were added to the aqueous layer for extraction. Magnesium sulfate was added to the ethyl acetate layer to dry it, and the solvent was distilled off under reduced pressure to give 2-methylquinuclidin-3-yl 1-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxy. A rate of 2.9 g was obtained. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 0.89-0.99 (3H, m), 1.08-1.28 (1H, m), 1.35-1.
67 (3H, m), 1.83-1.90 (1H, m), 2.52-2.89 (6H, m),
2.99-3.04 (1H, m), 3.39-3.45 (1H, m), 3.85-3.93 (1
H, m), 4.79-4.84 (1H, m), 6.20-6.25 (1H, m), 7.10-
7.32 (9H, m) Mass spectrum ESI 377 [M + H] ⁺

The following compounds can be produced in the same manner as in the examples by using the above known starting material compounds (II) and (III). Table 1

Table 2

Table 3

Table 4

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 1/04 A61P 1/04 11/00 11/00 11/02 11/02 11/06 11/06 13 / 02 13/02 // A61P 43/00 111 43/00 111 (72) Inventor Naoki Yorimoto 21 Miyukigaoka, Tsukuba, Ibaraki Prefecture Yamanouchi Pharmaceutical Co., Ltd. (72) Ryo Naito Miyuki, Tsukuba, Ibaraki Oka 21 Yamanouchi Pharmaceutical Co., Ltd. (72) Inventor Ken Ikeda Miyukigaoka, Tsukuba City, Ibaraki 21 Yamanouchi Pharmaceutical Co., Ltd. (72) Inventor Toshiki Hatanaka, Miyukigaoka 21, Tsukuba City, Ibaraki 21 F-term ( Reference) 4C064 AA06 CC01 CC02 DD02 EE03 FF01 FF03 FF04 FF06 GG03 GG06 GG07 GG10 GG12 GG16 GG19 4C086 AA01 AA03 CB17 NA05 NA06 NA14 ZA34 ZA59 ZA68 ZA84 ZC42

Claims (2)

[Claims] 1. A quinuclidine derivative represented by the following general formula (I), a salt thereof, an N-oxide thereof or a quaternary ammonium salt thereof. [Chemical 1] (The symbols in the formulas have the following meanings: R: halogen; lower alkyl optionally having substituents; lower alkenyl optionally having substituents; cyclo optionally having substituents alkyl; optionally substituted aryl; mAY substituted heteroaryl; or 5 may have a substituent 6-membered saturated heterocyclic ring; -O-R ^1; - ^{CO-R 1; -COO-R} 1; -CO
^{N (-R 1) -R 2;} -S (O) p -R 1; -N (-R 1)
^{-R 2; -N (-R 1)} -CO-R 2; -N (-R 1) -C
^{OO-R 2; -N (-R} 1) -CO-N (-R 2) -R 3;
^{-N (-R 1) -S (O} ) p -R 2; ( when m is 2 or more,
R may be the same group or different groups) l: 0 or 1 m: integers ^{1 to 3} R ^{1 to} R ³ : same or different, H; lower alkyl optionally having substituents; substituted A lower alkenyl which may have a group; an aryl which may have a substituent; a heteroaryl which may have a substituent; or a 5- to 6-membered saturated which may have a substituent. Heterocycle; p: 0, 1 or 2 n: 1 or 2 A ring: aryl which may have a substituent; cycloalkyl which may have a substituent; heteroaryl which may have a substituent; or 5 to 7-membered saturated hetero. ring group; R ^4: OH, lower alkyl or lower alkyl -O- group L: O or NR ⁵ C2-7 alkylene group may be interrupted by R ^5: H, lower alkyl or lower alkyl -O-CO-
Group X ¹ : single bond or methylene group X ² : single bond, O or S) 2. A compound represented by the following general formula (Ia):
The quinuclidine derivative described, a salt thereof or a quaternary ammonium salt thereof. [Chemical 3] (The groups in the formula are as described above.)