WO2003104198A1

WO2003104198A1 - Chemokine receptor antagonist

Info

Publication number: WO2003104198A1
Application number: PCT/JP2003/007379
Authority: WO
Inventors: 正和佐藤; 広樹梅宮; 結子松永; 哲男高山
Original assignee: 大正製薬株式会社
Priority date: 2002-06-11
Filing date: 2003-06-10
Publication date: 2003-12-18
Also published as: JP2005194193A; JPWO2003104198A1; AU2003242244A1

Abstract

A compound represented by the formula (1) wherein m is 1 or 2; R1 represents linear or branched C_3-8 (un)saturated alkyl, C_5-8 cycloalkyl, C_5-8 cycloalkenyl, C_1-6 alkyl, C_3-8 cycloalkyl, C_5-8 cycloalkyl substituted by phenyl, trifluorobutyl, perhydronaphthyl, -(CH₂)-C(CH₃)=CH-Ph, cinnamyl, or other substituent; and Z represents, e.g., a group represented by the formula (2) (wherein R19 represents C_3-10 cycloalkyl or C_3-10 cycloalkenyl). The compound has a high affinity for chemokine receptors, which play an important role in eosinophilic infiltration, and inhibits the function of chemokine receptors. The compound is hence usable for treatments for or prevention of human and animal diseases in which chemokine receptors participate, such as bronchial asthma and allergic diseases including allergic conjunctivitis.

Description

Specification

Chemokine receptor antagonist compounds

The present invention relates to a compound having an antagonistic effect on a receptor of a chemokine which is a leukocyte chemotactic factor. Background art

Chemokines have been discovered as factors that act primarily on neutrophils and monocytes, and their role in inflammatory diseases has been studied. However, recently discovered new chemokines have been shown to target lymphocyte-dendritic cells as the primary target cells. These chemokines are thought to play a role in the formation of immune system tissues, homeostasis, and immune response. In addition, chemokines have been shown to play important roles not only in cell migration in inflammation and the immune response, but also in various fields such as development, differentiation, viral infection, and cancer.

Eot axin, a type of chemokine, exhibits strong eosinophil chemotaxis and not only acts on the recruitment of eosinophils from the bone marrow to peripheral blood, but also has favorable effects such as eosinophil degranulation and active enzyme production. Promotes activation of acid spheres. In addition, it induces expression of CD1 lb of eosinophil adhesion molecule receptor and expression of adhesion molecules ICAM-1 and VCAM-1 of vascular endothelial cells, and enhances eosinophil adhesion. On the other hand, CCR3 is a G protein-coupled receptor cloned from eosinophils, is expressed on eosinophils, basophils, and Th2 cells, and is a ligand with high affinity for Eotaxin.

Therefore, a substance that specifically inhibits the binding of Eotaxin to CCR3 is considered to be useful as a medicament for treating or preventing allergic diseases such as bronchial asthma and allergic conjunctivitis.

Substances that inhibit the function of chemokine receptors are described in WO98 / 054554 and the like, but the compounds of the present invention are not known.

An object of the present invention is to provide a compound that specifically inhibits the function of a chemokine receptor. You. Disclosure of the invention

The present inventors have conducted various studies to solve the problem 3, and as a result, have found that a certain compound specifically inhibits the function of a chemoforce-in receptor, and completed the present invention.

That is, the present invention

Expression

{Where m represents 1 or 2,

R1

• A linear or branched alkyl group having 3.8 carbon atoms,

-A linear or branched alkenyl group having 3.8 carbon atoms,

A cycloalkyl group having 5'8 carbon atoms,

A cycloalkenyl group having 58 carbon atoms,

An alkyl group having 16 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms or a cycloalkyl group having 5 to 8 carbon atoms substituted with a phenyl group,

• trifluorobutyl group,

Perhydronaphthyl group,

-A group represented by -CH ₂ -C (CH ₃ ) = CH-Ph, a formula

(In the formula, n ₇ represents an integer of 0 to 3, R 2 and R 3 each represent a hydrogen atom or a carbon atom R4 represents a phenyl group, a naphthyl group, a linear or branched alkyl group having 1 to 4 carbon atoms, or a linear or branched alkyl group having 2 to 4 carbon atoms. Represents an alkenyl group of, and represents an oxygen atom, a sulfur atom, a liponyl group or a liponyloxy group. ),

.Formula 1 (CH ₂ ) n factory

(Wherein n ₃ and n ₄ each represent an integer of 0 to 3, R 5 is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, and a straight-chain or branched alkyl group having 1 to 4 carbon atoms. A linear or branched alkenyl group, an alkoxy group having 1 to 6 carbon atoms, a phenyl group, a phenyl group substituted with a halogen atom, or a cycloalkyl group having 3 to 8 carbon atoms; `` Unsubstituted or substituted with 1 to 3 alkyl groups having 1 to 3 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms '', `` cycloalkenyl group having 5 to 8 carbon atoms '', `` unsubstituted or A naphthyl group substituted with an alkoxy group having 1 to 3 carbon atoms "," adamantyl group ",

(Wherein, n ₅ is 1 or 2, methylene groups or - represents a group represented by, A ₂ represents a methylene group, an ethylene group, a vinylene group or a methyl methylene group - C (C) _2.) A group represented by

(R 6 to R 10 are each a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms. An alkoxy group having 1 to 5 carbon atoms., An alkylthio group having 1 to 3 carbon atoms, trifluoromethyl group, trifluoromethyloxy group, benzyl group, phenethyl group, styryl group, phenoxy group, benzyloxy group, It represents a phenyl group or an alkoxyl group having 2 to 4 carbon atoms. ) Or a formula

(Wherein, R11 and R 12 are each a hydrogen atom, an alkyl group or an off Eniru group having 1 to 3 carbon atoms, X ₂ represents a group represented nitrogen atom or = CH- with, X ₃ is an oxygen source Or a sulfur atom or a nitrogen atom.) A group represented by)

• Expression

— A ₃ — X ₄ — (CH ₂ )

[Wherein, n ₆ represents an integer of 1 to 3, X ₄ represents an oxygen atom or a sulfur atom, and R 13 to R 15 are each a hydrogen atom, a halogen atom, an alkoxy group having 1 to 3 carbon atoms or a carbon atom number. 1 shows three of the alkyl group, a ₃ is - (CH ₂₎ n ₇ - group (wherein n ₇ is an integer of 0-5.) represented _{by, -CH 2 - CH = CH-} C - A group or a formula represented by

(In the formula, n ₈ and n ₉ each represent 0 or 1, and R 16 represents an alkyl group having 1 to 3 carbon atoms or a group represented by —C 0 -C¾-Ph.) Is shown. A group represented by

.formula

[Where,. Represents an integer of 0 to 2,

(In the formula, _nu represents 1 or 2, and X ₅ and X ₆ represent a methylene group or an oxygen atom, respectively.)

(In the formula, 11 ₁₂ represents an integer of 1 to 5, R 17 and R 18 each represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and A ₄ represents a methylene group or an oxygen atom. )] Represents a group represented by

Z is Equation 9

Or expression

(Wherein R 19 represents a cycloalkyl group having 3 to 10 carbon atoms or a cycloalkenyl group having 3 to 10 carbon atoms, R20 represents an alkyl group having 1 to 5 carbon atoms, and Y— is Represents an anion.) Represents a group represented by. And a pharmaceutically acceptable salt thereof.

In the present invention, a linear or branched alkyl group is, for example, a methyl group or an ethyl group. , N-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, n -A hydrocarbon group such as a heptyl group and an n-octyl group.

In the present invention, the linear or branched alkenyl group is, for example, a hydrocarbon group such as a vinyl group, an aryl group, an isopropyl group, a butenyl group, an isobutylenyl group, and an isoprenyl group.

In the present invention, the cycloalkyl group is a cyclic saturated hydrocarbon group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.

In the present invention, the cycloalkenyl group is a cyclic unsaturated hydrocarbon group such as a cyclopentenyl group, a cyclohexenyl group, a cyclohexenyl group, a cycloheptenyl group, and a cyclooctenyl group.

In the present invention, the alkoxy group means a methoxy group, an ethoxy group, a propoxy group, a butoxy group, an isopropoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy group, a hexyloxy group, an aryloxy group, or the like. Group.

In the present invention, the anion means a halide ion and the like, and specifically includes a chloride ion, a bromide ion, an iodide ion, a methanesulfonate ion, a monomethylsulfonate ion and the like.

The compound of the present invention can be synthesized, for example, by the following method. That is, the following equation (a)

And a compound represented by the following formula (b):

R 19-C HO (b)

(Wherein, R 19 is as defined above) in a reductive alkylation reaction in the presence of a reducing agent to obtain a compound represented by the following formula (c):

(Wherein R19 is as defined above), and the compound is hydrolyzed by a commonly used method such as treatment with a mineral acid or an organic acid to obtain a compound represented by the following formula (d)

(Wherein R19 is as defined above) or a salt thereof, and then represented by the following formula (e)

(Wherein m is as defined above) or a salt thereof, and condensed by an ordinary method of forming an amide bond,

(Wherein, m and R19 are as defined above), and a compound represented by the following formula (g):

Rl-OH (g)

(Wherein R1 is as defined above) to form an ether bond by a Mitsunobu reaction, thereby obtaining the following formula (h)

(Wherein, m, Rl, and R19 are as defined above) can be synthesized.

Further, the compound of the present invention represented by the above formula (h) is a compound represented by the above formula (f) Or a salt thereof, and the following formula (i)

R l-L (i)

(Wherein, R 1 has the same meaning as described above, and L represents a leaving group. Here, the leaving group is, for example, a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, a methanesulfonyloxy group, p —A sulfonyloxy group such as a toluenesulfonyloxy group, etc.), and reacting in the presence of a base.

Further, the compound represented by the above formula (h) and the following formula (j)

R20-Y (j)

(Wherein R 20 and Y are as defined above) by reacting a compound represented by the following formula (k)

(Wherein, m, R 1, R 19 and R 20 have the same meanings as described above). At this time, cis and trans isomers are generated at the 1- and 4-positions of piperidine. For convenience, a low-polarity compound is named a cis-form and a high-polarity compound is named a trans-form.

The compound of the present invention may have stereoisomers such as optical isomers, diastereoisomers, and geometric isomers depending on the mode of substitution. And mixtures thereof.

When a base is used in the above reaction, examples of the base include sodium carbonate, carbonated carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, gymnyl sodium, sodium hydride, sodium amide, tert-butyl potassium and the like. Alkali metal salts, amines such as triethylamine, diisopropylamine, pyrrolidine, piperidine, etc .; sodium acetate, potassium acetate, etc .; and mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid. , Nitric acid, sulfuric acid, etc., and the organic acid is, for example, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, etc., and the reducing agent is, for example, sodium hydrogen borohydride, cyano hydrogen borohydride. Nato shim, hydrogenation Lithium aluminum, sodium triacetoxyborohydride and the like. Examples of the reaction solvent include water, alcohols such as methanol, ethanol, isopropyl alcohol and tert-butyl alcohol, ethers such as dioxane and tetrahydrofuran, dimethylformamide, dimethylsulfoxide, pyridine, methylene chloride, chloroform and acetone. A solvent inert to the reaction, such as toluene or acetic acid, can be used.

The compound of the present invention may contain a conventional bulking agent, a pH regulator, a solubilizer, etc., and tablets, granules, pills, capsules, powders, solutions, suspensions, injections, It can be adjusted to ophthalmic preparations and administered by oral, injection, ophthalmic routes.

The dose of the compound of the present invention when used as a chemokine receptor action inhibitor varies depending on body weight, age, sex, etc., but is usually 1 to 100 mg / day for an adult patient once per day. It can be administered in several divided doses. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples.

Example 1

Synthesis of Compound 8 1 and Compound 8

(1) A solution of piperidine 4-pyrucalmic acid tert-butyl ester (6.00 g) in tetrahydrofuran (hereinafter abbreviated to THF) (120 ml) was mixed with cyclooct-1-enecarbaldehyde (4.97 g). Acetic acid (1.72 ml) was added, and sodium triacetoxyborohydride (8.25 g) was further added under ice-cooling, followed by stirring at room temperature for 2 hours. After distilling off the solvent, the residue was diluted with ether and washed successively with a 2 mol / l aqueous sodium hydroxide solution and brine. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off. The obtained residue was purified by silica gel flash column chromatography using a mixed solvent of ethyl acetate and hexane, and (1-cyclooct-1-enyl-methyl-piperidine-1-41-yl) rubactic acid tert-butyl ester was used. (3.86 g) was obtained.

(2) (1-Cyclooct-1-enyl-1-methyl-piperidine-14-yl) carboxyacid tert-butyl ester (3.86 g) in methylene chloride (15 ml) solution and trifluoroacetic acid (15 ml) in ice The mixture was added under reduced pressure and stirred at room temperature for 2 hours. After evaporating the solvent, the residue was diluted with chloroform and washed with a 2 mol / l aqueous sodium hydroxide solution. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off to obtain unpurified 1-cyclooct-1-enyl-methyl-piperidine-14-ylamine (2.66 g).

(3) 1-cyclooct-1-enyl-methyl-piperidine-14-ylamine (2.66 g), 2-hydroxyphenylacetic acid (2.18 g) and 1-hydroxybenzotriazole monohydrate (2.75 g) 1) -Ethyl-3- (3-dimethyl) carboimide (3.44 g) was added to a solution of the above) in dimethylformamide (30 ml), and the mixture was stirred at 80 for 3 hours. After the solvent was distilled off, the residue was diluted with ethyl acetate and washed three times with saline. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off. The obtained residue was purified by NH-type silica gel column chromatography using a mixed solvent of methanol and chloroform, to give N- (1-cyclooct_1-enyl-methyl-piperidine-14-yl) 12. — (2-Hydroxyphenyl) acetamide (3.88 g) was obtained.

(4) N- (1-cyclooct-1-ene) was added to a THF (20 ml) solution of phenylethyl alcohol (183 mg), triphenylphosphine (393 mg) and a 40% tert-butyl hexyl azodicarboxylate toluene solution (653 mg). Rumethyl-piperidine-14-yl) -12- (2-hydroxyphenyl) acetamide (357 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 3 hours. Furthermore, a THF (10 ml) solution of phenethyl alcohol (183 mg), triphenylphosphine (393 mg) and a 40% getyl azodicarboxylate toluene solution (653 mg) was added, and the mixture was stirred at room temperature for 2 hours.

After evaporating the solvent, the residue was diluted with ethyl acetate and washed sequentially with a 2 mol / l aqueous sodium hydroxide solution and brine. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off. Obtained The residue was adsorbed on SCX, washed with a mixed solvent of methanol and chloroform, and eluted with a mixed solvent of 7mo1 / 1 ammonia in methanol and chloroform. The solvent was distilled off, and the residue was purified by flash column chromatography using NH-type silica gel with a mixed solvent of ethyl acetate and hexane to give N- (1-cyclooct-1-enylmethyl-piperidine-14-yl). One 2- (2-phenethyloxyphenyl) acetamide (402 mg) was obtained.

(5) N- (1-cyclooct-1-enyl-methyl-piperidine-14-yl) -1-2- (2-phenethyloxyphenyl) acetamide (2.15 g) was added with methyl iodide (2 Oml), Stirred overnight at room temperature. The solvent is distilled off, and the residue is purified by silica gel column chromatography using a mixed solvent of methanol and chloroform. The solvent of the fraction containing a low-polar compound (cis-form) having a high Rf value is distilled off. The title compound (compound 81 in the table) (2.25 g) was obtained. Further, the solvent of a fraction containing a highly polar compound having low Rf value (trans form) was distilled off to obtain the title compound (compound 81 ′ in the table) (0.38 g).

Compound 8 1 Ή NMR (300 MHz, CDC1 3) δ ρπι 1.35-1.72 (m, 8 H), 1.78-1.94 (m, 2 H), 2.11-2.41 On, 6 H), 3.11 (t, J = 6.84 Hz, 2 H), 3.27 (s, 3 H), 3.41-3.67 (m, 4 H), 3.57 (s, 2 H), 4.02 (m, 1 H), 4.05 (s, 2 H), 4.20 (t, J = 6.84 Hz, 2 H), 6.09 (t, J = 8.00 Hz, 1 H), 6.81-7.02 (m, 3 H), 7.14-7.38 (m, 7 H) Compound 8 1 '' _{Η NMR (200 MHz, CDC1 3} ) 5ppm 1.38-1.80 (m, 8 H), 1.80-2.05 (m, 2 H), 2.10-2.42 (m, 6 H), 3.04 (s, 3 H), 3.13 ( t, J = 6.9 Hz, 2 H), 3.35-3.58 (m, 2 H), 3.70 (s, 2 H), 3.92-4.32 (m, 3 H), 4.21 (t, J = 6.9 Hz, 2 H), 4.27 (s, 2 H), 6.15 (t, J = 8.1 Hz, 1 H), 6.80-6.96 (m, 2 H), 7.12-7.41 (m, 8 H)

The same operation as in Example 1 was performed using the corresponding raw materials to obtain the compounds shown in the following table. In the table, the data of cis compounds are shown. Table 11

Replacement form (Rule 26)

t

CO

O / AVεο!

O / AVs /: 2I / uo 6

CO Cs3

O / AVί) i71dfc P

i

1 7 —

Replacement form (Rule 26)

18/1

Replacement form (Rule 26) 1 9

Replacement form (Rule 26) 19/1

Replacement form (Rule 26) 2 0

Replacement form (Rule 26) O

CO

twenty two

Replacement form (Rule 26) / Oto sAV

/ O 6 εζ-οAV

Jutsu S:

CO

/ OfAVΜί

O CM

i7J.pfcd / OsAV: Dimensions

24/1 Table 13-2

Replacement form (Rule 26) twenty five

One one

Replacement form (Rule 26)

1 2

//: 6 minutes CAOsdTI £ / f 0

9

2 1/1

Replacement form (Rule 26) 2 8

Replacement form (Rule 26)

τ-Η

03

0 halla

T ε

6L £ L0 / £ 0dT / 13d 86 οι / εο OAV O / AVεοΜ 6ίΧ1

i:-ε zalla /, C, 0 / C0df / X3d 861 fO OAV ϋ 6

Dimension

CO

/ OsAVM £ i

LO CO

3 6

Table 25

Replacement form (Rule 26)

3 7

Replacement form (Rule 26)

I- ¹

72 Overflow

\ 18 3 / OAVs /: 2 / drIo26

iv: / O / -pfcl £ sa AVsAV

o h- ¹

29

\ 1 ^ 1 Penn

/ Oto sAV

τ

Dimension

/ / O 6 εζ-οsAV

CO

Dimension

4 4

Table 3 3 —

Replacement form (Rule 26) 44/1

Table 33 2

Test example 1. CCR3 receptor binding inhibition test

• Overlaid human peripheral blood on a mono-poly separation solution (Dainippon Pharmaceutical), 1500 rpm, 20 minutes, room replacement paper (Rule 26) 45

Centrifugation was performed at room temperature to obtain a polynuclear cell layer. This polynuclear cell layer was diluted with PBS (-), centrifuged at 1200 卬 m for 5 minutes, and the precipitated cells were suspended in sterile water and lysed. A 1.8% NaCl aqueous solution of the same volume as sterile water was added, centrifuged at 1200 rpm for 5 minutes, and the precipitated cells were washed once with PBS (-). Suspend in ice-cold PBS (-) Z2mM EDTAZO.5% BSA, add CD16 microbeads, incubate at 6 to 12 ° C for 30 minutes, flow onto a MACS column, and collect the passed cell solution. Eosinophils were obtained.

Human peripheral blood eosinophils isolated ^{from, 0. InM [125 I] human} Eotaxin (2000Ci / mmoK Am ersham made Biosciences) and test compounds in _{0. lml 50mM HEPES / 51M MgCl 2} / lmM Ca Cl 2 /0.5% Suspend in BSA (pH 7.2), incubate at 37 ° C for 90 minutes, filter through a glass filter GF / C pre-soaked in 0.5% polyethyleneimine (pH 7.2), and add 1.5 ml of PBS. (—) After washing with Z0.5M NaCl / 0.05% BSA, the radioactivity on the glass filter was measured. Binding affinity for CCR3 was calculated Ru good in various concentrations of compound ^[125 I] 50% binding inhibition concentrations of human Eotaxin (IC _5. Value).

As a result, it was found that the compound of the present invention had an excellent effect. Test Example 2 Rat eosinophil migration test

Lml of poma serum was administered to the abdominal cavity of Brown Norway Rat, and 48 hours later, the abdominal cavity was washed with HBSS to collect the cells. 65% Percoll (manufactured by Amersham Biosciences), 50% Percoll, and the collected cells in the peritoneal cavity were layered in this order and centrifuged at 2500 rpm for 10 minutes to obtain a polynuclear cell layer. This polynuclear cell layer was washed once with HBSS, and suspended in RPMI1640 / 1% FCS to obtain rat eosinophils. Prepare human Eotaxin (10 OnM) and the test compound in 30 μl RPMI1640 / 1% FCS in the lower chamber of a 96-well chemotaxis chamber (Pore Eyes 5μ の η). Rat eosinophils were added. After incubating at 37 ° C for 2 hours, the filter was removed, and the number of cells that moved to the lower chamber was counted. The effect of the test compound on the migration of rat eosinophils was calculated by adding the test compound to human Eotaxin (ΙΟΟηΜ) and calculating the inhibition rate (%) of migration into the lower chamber.

As a result, it was found that the compound of the present invention had an excellent effect. 4 6

Industrial applicability

The compound of the present invention has a high affinity for a chemokine receptor which plays an important role in eosinophil infiltration, and inhibits the action of the chemokine receptor to thereby inhibit the chemokine receptor in humans and animals. It can be used for treating or preventing diseases associated with, for example, allergic diseases such as bronchial asthma and allergic conjunctivitis.

Claims

4 7 Claims

1 set

{Where m represents 1 or 2,

R 1

A linear or branched alkyl group having 38 carbon atoms,

A linear or branched alkenyl group having 38 carbon atoms,

A cycloalkyl group having 58 carbon atoms,

A cycloalkenyl group having 58 carbon atoms,

Trifluorobutyl group,

Perhydronaphthyl group,

-CH ₂ -C (CH ₃ ) = CH-Ph

(In the formula, n ₂ represents an integer of 0 to 3, R 2 and R 3 each represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and R 4 represents a phenyl group, a naphthyl group, or a carbon atom having 1 to 4 carbon atoms. Represents a linear or branched alkyl group or a linear or branched alkenyl group having 2 to 4 carbon atoms, and represents an oxygen atom, a sulfur atom, a carbonyl group or a carboxy group. ),

.formula 4 8

(Wherein n ₃ and n ₄ each represent an integer of 0 to 3, R 5 is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, and a linear chain having 2 to 4 carbon atoms. Or a branched alkenyl group, an alkoxy group having 1 to 6 carbon atoms, a phenyl group, a phenyl group substituted with a halogen atom, or a cycloalkyl group having 3 to 8 carbon atoms. 1 to 3 unsubstituted or substituted with 1 to 3 carbon atoms, an alkyl group having 3 to 8 carbon atoms, cycloalkyl group having 3 to 8 carbon atoms, cycloalkenyl group having 5 to 8 carbon atoms, unsubstituted or carbon A naphthyl group substituted with an alkoxy group having 1 to 3 atoms ", an" adamantyl group ", a" formula

(In the formula, η ₅ represents 1 or 2, represents a methylene group or a group represented by —C (CH ₃ ) ₂ —, and A ₂ represents a methylene group, an ethylene group, a vinylene group or a methylmethylene group. ) Group ”,“ Formula

(R 6 to R 10 are each a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, an alkylthio group having 1 to 3 carbon atoms, a trifluoromethyl group, a trifluoromethyl group. And a group represented by the formula: or a methyloxy group, a benzyl group, a phenethyl group, a styryl group, a phenoxy group, a benzyloxy group, a phenyl group or an alkoxyl group having 2 to 4 carbon atoms. 49

(Wherein, R11 and R12 each represent a hydrogen atom, an alkyl group or an off Eniru group having a carbon number. 1 to 3, X ₂ represents a group represented nitrogen atom or = CH- with, X ₃ is an oxygen atom , A sulfur atom or a nitrogen atom.) A group represented by ")

Expression

— A ₃ — X Factory

[In the formula, n ₆ represents an integer of 1 to 3, X ₄ represents an oxygen atom or a sulfur atom, and R 13 to R 15 are a hydrogen atom, a halogen atom, an alkoxy group having 1 to 3 carbon atoms or a carbon atom number, respectively. shows a 1-3 alkyl group, a ₃ is _ (CH ₂₎ n ₇ - group (. wherein n ₇ is represents an integer of 0 to 5) represented _{by, -CH 2 -CH = CH-CH} 2 A group or a formula represented by

H

— (CH ₂ ) n “C- (CH,) n _g

R16

(Wherein, n _8, n ₉ each represent 0 or 1, R16 is alkyl group or 1 to 3 carbon atoms - a group represented by C -0- CH ₂ -Ph.) Represented by Represents a group. A group represented by

•formula

[Where,. Represents an integer from 0 to 2, 50

(Wherein, _nu represents 1 or 2, X ₅ and X ₆ each represent a methylene group or an oxygen atom.)

(Wherein, n ₁₂ represents an integer of 1 to 5, R17, R18 each represents a hydrogen atom or an alkyl group TansoHara terminal number 1 to 3, A ₄ represents a methylene group or an oxygen atom.)] In Represents the group shown,

Z is the expression

ΊΓ ヽ R, 9 or expression

(Wherein R 19 represents a cycloalkyl group having 3 to 10 carbon atoms or a cycloalkenyl group having 3 to 10 carbon atoms, R20 represents an alkyl group having 1 to 5 carbon atoms, and Y— represents an anion. Represents a group represented by. And a pharmaceutically acceptable salt thereof.