JP2000086663A - Aryltetrahydropyridine derivative - Google Patents

Abstract

(57) [Problem] To provide a compound effective for a disease in which CRF is considered to be involved. SOLUTION: The formula: [Wherein, Ar represents a phenyl group, a substituted phenyl group, a thienyl group or a furyl group, and Z represents a group represented by the formula: (Wherein, R ¹ , R ² and R ³ are the same or different and represent a hydrogen atom or a lower alkyl group, and X ¹ , X ² and X ³ are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group,
It represents a lower alkoxy group, a lower alkylthio group or a lower alkylamino group. ). Or a pharmaceutically acceptable salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to depression, anxiety,
Corticotropin Releasing Factor (CRF) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorders, hypertension, gastrointestinal disorders, drug dependence, cerebral infarction, cerebral ischemia, cerebral edema, head trauma, inflammation, and immune-related diseases The present invention relates to a therapeutic agent for a disease in which is considered to be involved.

[0002]

2. Description of the Related Art CRF is a hormone consisting of 41 amino acids (Science, 213, 1394-1397, 1981; J. Neuro
sci., 7, 88-100, 1987), suggesting that it plays a central role in biological responses to stress (Ce
ll. Mol. Neurobiol., 14, 579-588, 1994; Endocrino
l., 132, 723-728, 1994; Neuroendocrinol. 61, 445-45
2,1995). CRF acts on the peripheral immune system and sympathetic nervous system via the hypothalamus-pituitary-adrenal system, and is thought to function as a neurotransmitter in the central nervous system (in Corticotropin Releasing Factor: Basic and Clin).
ical Studies of aNeuropeptide, pp 29-52, 1990),
For example, when CRF is intracerebroventricularly administered to hypophysectomized rats and normal rats, anxiety-like symptoms (Pharmacol.
v., 43, 425-473, 1991; Brain Res. Rev., 15,71-100,
1990).

The disease associated with CRF was described in 1991 by Owens
And Nemeroff's review (Pharmacol. Rev., 43, 425-47).
4, 1991). That is, CRF is involved in depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorders, hypertension, gastrointestinal diseases, drug dependence, inflammation, immune-related diseases, and the like.
Recently, it has been reported that CRF is also involved in epilepsy, cerebral infarction, cerebral ischemia, cerebral edema and head injury (Brain
Res. 545, 339-342, 1991; Ann. Neurol. 31, 48-498,
1992; Dev. Brain Res. 91, 245-251, 1996; Brain Re
s. 744, 166-170, 1997). Therefore, CRF receptor antagonists are useful as therapeutic or prophylactic agents for these diseases.

[0004]

The object of the present invention is to provide depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorders, hypertension, digestive disorders, drug dependence, epilepsy, cerebral infarction, An object of the present invention is to provide a CRF antagonist which is effective as a therapeutic or preventive agent for diseases in which CRF is involved, such as cerebral ischemia, cerebral edema, head trauma, inflammation, and immune-related diseases.

[0005]

The present inventors have made intensive studies on aryltetrahydropyridine derivatives,
An aryltetrahydropyridine derivative showing high affinity for the CRF receptor has been found, and the present invention has been completed.

The present invention provides the following formula [1]

Embedded image [Wherein, Ar represents a phenyl group, a substituted phenyl group, a thienyl group or a furyl group, and Z represents the following formula [2]-[11]

Embedded image (Wherein, R ¹ , R ² and R ³ are the same or different and represent a hydrogen atom or a lower alkyl group, and X ¹ , X ² and X ³ are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group,
It represents a lower alkoxy group, a lower alkylthio group or a lower alkylamino group. ). And a pharmaceutically acceptable salt thereof.

In the present invention, the substitution position of Ar is at the 4- or 5-position. The substituted phenyl group is a halogen atom, an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms,
And a phenyl group having 1 to 3 substituents selected from a trifluoromethyl group, for example, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl Group, 4-chlorophenyl group, 2-bromophenyl group,
3-bromophenyl group, 4-bromophenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 3, 4-difluorophenyl group, 3,5-difluorophenyl group, 2,4-difluorophenyl group, 3,4-dichlorophenyl group, 3,
Examples thereof include a 5-dichlorophenyl group and a 3-trifluoromethylphenyl group. The lower alkyl group refers to a linear or branched alkyl group having 1 to 5 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group, and a pentyl group. And an isopentyl group. The lower alkylamino group means one or two of a linear or branched alkyl group having 1 to 5 carbon atoms.
Represents an alkylamino group substituted with, for example, a methylamino group, a dimethylamino group, an ethylamino group, a diethylamino group, a propylamino group, a dipropylamino group,
And an isopropylamino group. A halogen atom is
It represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. The lower alkoxy group means a linear or branched alkoxy group having 1 to 5 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, isopentyl. And an oxy group. A lower alkylthio group refers to a linear or branched alkylthio group having 1 to 5 carbon atoms, such as a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, an isobutylthio group,
A pentylthio group and an isopentylthio group. The pharmaceutically acceptable salts in the present invention include, for example, salts with physiologically usable mineral acids such as sulfuric acid, hydrochloric acid, and phosphoric acid, acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, citric acid, and the like. And salts with organic acids such as acid, benzenesulfonic acid and methanesulfonic acid.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The compound of the formula [1] can be produced, for example, by the method shown in the following reaction formulas 1-3 (where Ar, Z, R ¹ , R ² , R ³ ,
X ¹ , X ² and X ³ are the same as described above, and R ⁴ and R ⁵ are the same or different and represent an alkyl group having 1 to 5 carbon atoms, or 1,2-ethylenedioxy together with an adjacent oxygen atom Or a 1,3-propylenedioxy group, R ⁴ O and R ⁵ O
Are bonded to the same carbon at the 4- or 5-position, and X ⁴
Represents a chlorine atom, a bromine atom or an iodine atom, and X ⁵ represents a hydrogen atom, a chlorine atom, a bromine atom or an iodine atom. )

That is, as shown in the following reaction formula 1, the derivative (3) of the present invention is obtained by converting a 4- or 5-aryl-1,2,3,6-tetrahydropyridine derivative (1) to a halogenated heterocyclic ring. It can be synthesized by Step A in which the derivative (2) is reacted in the presence or absence of a base in an inert solvent.

Embedded image

Here, the term "base" means, for example, amines such as triethylamine, diisopropylethylamine and pyridine; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide and sodium hydride; and sodium methoxide. Alkoxides such as sodium ethoxide and potassium tert-butoxide; metal amides such as sodium amide and lithium diisopropylamide; and Grignard reagents such as methyl magnesium bromide. Examples of the inert solvent include alcohols such as methanol, ethanol, isopropyl alcohol, and ethylene glycol, diethyl ether, tetrahydrofuran, dioxane, and 1,2.
Ethers such as -dimethoxyethane, hydrocarbons such as benzene and toluene, amides such as N, N-dimethylformamide, acetonitrile, water, and mixed solvents selected from these solvents.

The derivative (3) of the present invention can also be synthesized by the following reaction formula 2.

Embedded image

That is, first, a ketal derivative (5) is synthesized in the same manner as in the step A using the halogenated heterocyclic derivative (2) and the piperidine derivative (4) as raw materials. Next, the ketone derivative (6) is obtained by the step B of treating the ketal derivative (5) with an acid in an inert solvent. Here, the inert solvent is, for example, alcohols such as methanol, ethanol, isopropyl alcohol, and ethylene glycol, for example, ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane;
For example, hydrocarbons such as benzene, toluene, xylene,
Examples thereof include ketones such as acetone and methyl ethyl ketone, amides such as N, N-dimethylformamide, water, and a mixed solvent selected from these solvents. What is an acid?
For example, inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid, for example, p-
Organic acids such as toluenesulfonic acid, methanesulfonic acid and trifluoroacetic acid, and salts of amines with acids such as pyridinium p-toluenesulfonate.

Next, in step C, the ketone derivative (6) is reacted with an aryl metal reagent obtained from the aryl derivative (7) and the metal reagent in an inert solvent to obtain an alcohol compound (8). Here, the metal reagent is a metal such as magnesium and lithium, and an organic lithium compound such as n-butyllithium, tert-butyllithium, phenyllithium and lithium diisopropylamide. Examples of the inert solvent include ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane, and hydrocarbons such as hexane, benzene, toluene, and xylene.

Finally, in the step D, the compound (3) of the present invention can be obtained by dehydrating the alcohol derivative (8) under acidic conditions or by converting the alcohol to an active form and then reacting under basic conditions. it can. Here, dehydration under acidic conditions refers to, as an inert solvent, alcohols such as methanol, ethanol, isopropyl alcohol, and ethylene glycol, for example, ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane, for example, Using ketones such as acetone and methyl ethyl ketone, water, or a mixed solvent thereof, as an acid, an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or the like; a hydrogen halide such as hydrogen chloride or hydrogen bromide; −
Organic acids such as toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, and formic acid are used.

The active form refers to a sulfonylated derivative or an acylated derivative of the hydroxyl group of the alcohol derivative (8), or a halogen-substituted derivative in which the hydroxyl group of the alcohol derivative (8) is substituted with a halogen atom. These active substances are used as inert solvents, for example, ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, and hydrocarbons such as benzene, toluene and xylene, such as chloroform and dichloromethane. Using a halide, for example, an amide such as N, N-dimethylformamide or the like, and using, as a base, for example, triethylamine, diisopropylethylamine,
Amines such as pyridine and 4-dimethylaminopyridine,
For example, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, inorganic bases such as sodium hydride, for example, sodium amide, using metal amides such as lithium diisopropylamide,
For example, sulfonyl chlorides such as methanesulfonyl chloride and p-toluenesulfonyl chloride; organic carbonyl chlorides such as acetyl chloride; organic carboxylic acid anhydrides such as acetic anhydride and trifluoroacetic anhydride; halogens such as sulfonyl chloride and phosphoryl chloride; It can be obtained by reacting an agent or the like.

The reaction under basic conditions refers to an inert solvent such as ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, and hydrocarbons such as benzene, toluene and xylene. For example, a halide such as chloroform, dichloromethane or the like, an amide such as N, N-dimethylformamide or the like is used, and as a base, for example, triethylamine, diisopropylethylamine, pyridine, 1,8-
Amines such as diazabicyclo [5.4.0] -7-undecene; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, sodium hydride; sodium amide;
This indicates that metal amides such as lithium diisopropylamide are allowed to act.

Instead of the step A in which the halogenated heterocyclic derivative (2) is reacted with the piperidine derivative (4), the hydrogen atom on the nitrogen atom of the piperidine derivative (4) is replaced by a suitable protecting group. You may. In this case, after the steps B, C and D, the compound of the present invention can be synthesized by substituting the protective group with a hydrogen atom and reacting with the halogenated heterocyclic derivative (2).

The compound (13) of the present invention can be synthesized by the following reaction scheme 3.

Embedded image

First, in step E, 4- or 5-aryl-1,2,3,6-tetrahydropyridine derivative (1)
Is reacted with a 2,4-dichloropyrimidine derivative (9) in an inert solvent in the presence of a base to obtain a compound (10). Here, the base refers to, for example, amines such as triethylamine, diisopropylethylamine, and pyridine; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, and sodium hydride; sodium methoxide; and sodium ethoxide. And alkoxides such as potassium tert-butoxide and metal amides such as sodium amide and lithium diisopropylamide. The inert solvent is, for example, methanol, ethanol, isopropyl alcohol,
Alcohols such as ethylene glycol; ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane; hydrocarbons such as benzene and toluene; and amides such as N, N-dimethylformamide.

Next, in step F, compound (10) and aniline derivative (11) are added in the presence or absence of a base,
The reaction is performed in an inert solvent to obtain compound (12). Here, the base refers to, for example, amines such as triethylamine, diisopropylethylamine, and pyridine; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, and sodium hydride; sodium methoxide; and sodium ethoxide. And alkoxides such as potassium tert-butoxide and metal amides such as sodium amide and lithium diisopropylamide. The inert solvent, for example, methanol, ethanol, isopropyl alcohol, alcohols such as ethylene glycol, diethyl ether,
Ethers such as tetrahydrofuran, dioxane, and 1,2-dimethoxyethane; hydrocarbons such as benzene, toluene and xylene; and amides such as N, N-dimethylformamide.

Finally, in step G, compound (12)
Is reacted with phosgene or a phosgene homolog such as phosgene trimer and then reacted with an amine represented by HNR ² R ³ or phosgene or a phosgene homolog such as phosgene trimer and HN
ClCONR ² obtained from amines represented by R ² R ³
The compound of the present invention represented by the formula (13) can be obtained by reacting R ³ with the compound (12) or reacting potassium cyanate with a mixed solvent of acetic acid and water. Here, the reaction using the phosgene homologue is, for example, diethyl ether, tetrahydrofuran, dioxane,
Ethers such as 1,2-dimethoxyethane, benzene,
Hydrocarbons such as toluene and xylene, for example, amides such as N, N-dimethylformamide, for example, in an inert solvent such as a halogen-based solvent such as dichloromethane and chloroform, etc., if necessary, for example, amines such as triethylamine, diisopropylethylamine and pyridine , Sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like; and bases such as sodium amide and metal amides such as lithium diisopropylamide.

[0022]

The present invention will be specifically described below with reference to examples and test examples. Example 1: 6- [4- (4-chlorophenyl) -1,2,3,
6-tetrahydropyridin-1-yl] -2-methyl-
Synthesis of 9- (2-methylthio-4-isopropylphenyl) purine 6-chloro-2-methyl-9- (2-methylthio-4-
Isopropylphenyl) purine (204 mg) and 4- (4-chlorophenyl) -1,2,3,6-tetrahydropyridine hydrochloride (212 mg) in diisopropylethylamine (4.2 m)
and stirred for 1 hour while heating under reflux. The reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate, extracted with chloroform, and the extract was dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate = 8: 1-6: 1), and recrystallized from ethyl acetate. , 6- [4- (4-chlorophenyl) -1,2,3,6
-Tetrahydropyridin-1-yl] -2-methyl-9
235 mg of-(2-methylthio-4-isopropylphenyl) purine were obtained.

Table 1 shows the structures and physical properties of the above compounds and the compounds obtained by variously changing the substituents of tetrahydropyridine hydrochloride and purine. Further, the structure and physical property data of the compound of the present invention obtained by reacting a compound having a structure corresponding to Formulas [2] to [10] with 4-substituted tetrahydropyridine hydrochloride in the same manner as described above, instead of purine, are shown. The results are shown in Table 2 to Table 9.

Example 2 2-methyl-6- [5- (2-methylphenyl) -1,2,3,6-tetrahydropyridine-
Synthesis of 1-yl] -9- (2-methylthio-4-isopropylphenyl) purine (1) A solution of 17.50 g of Nt-butoxycarbonyl-3-oxopiperidine in 90 ml of tetrahydrofuran was treated with 18 ml of o-bromotoluene. 03g and magnesium 2.
A solution of a Grignard reagent prepared from 35 g in 90 ml of tetrahydrofuran was added dropwise under ice cooling. After stirring at room temperature for 1 hour, 100 ml of a saturated aqueous ammonium chloride solution was added dropwise to the ice-cooled reaction mixture. The reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate, and the extract was washed with brine and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate = 5: 1) to give Nt-butoxycarbonyl-3-hydroxy-3. 9.68 g of-(2-methylphenyl) piperidine were obtained. (2) Nt-butoxycarbonyl-3-hydroxy-
590 mg of 3- (2-methylphenyl) piperidine was added to 1,
Dissolve in 0.84 ml of 4-dioxane and 8.4 ml of concentrated hydrochloric acid
Was added dropwise, and the mixture was stirred at room temperature overnight, heated under reflux for further 3 hours, and then concentrated under reduced pressure. (3) 6-chloro-2-methyl-9- (2-
Methylthio-4-isopropylphenyl) purine 200
mg and diisopropylethylamine 5.0 ml,
The mixture was stirred for 1 hour while heating under reflux. The reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate, extracted with chloroform, and the extract was dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate is concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography (developing solvent: hexane-ethyl acetate = 8: 1).
And recrystallized from ethyl acetate-hexane.
-Methyl-6- [5- (2-methylphenyl) -1,2,3,
243 mg of 6-tetrahydropyridin-1-yl] -9- (2-methylthio-4-isopropylphenyl) purine
I got

Table 1 shows the structure and physical properties of the above compounds and the compounds obtained by variously changing the substituents of the Grignard reagent and purine. The structure and physical property data of the compound of the present invention obtained by reacting compounds having structures corresponding to formulas [2] to [5] and [7] to [10] in the same manner as described above, instead of purine, are shown. The results are shown in Table 2 to Table 9.

Example 3 1- (4- (4- (3-Fluorophenyl) -1,2,3,6-tetrahydropyridin-1-yl) -6-methylpyrimidin-2-yl) -1
-(4-isopropyl-2-methylthio) phenyl-3
-Methylurea Synthesis Triphosgene 114mg in methylene chloride solution 3ml 4
-(4- (3-fluorophenyl) -1,2,3,6-
432 mg of tetrahydropyridin-1-yl) -2- (4-isopropyl-2-methylthio) phenylamino-6-methylpyrimidine and 0.20 of diisopropylamine
5 ml of methylene chloride solution was added dropwise, and after stirring for 10 minutes, 1.0 ml of a 40% aqueous solution of methylamine was added dropwise, and the mixture was further stirred for 1 hour. After concentration of the reaction solution under reduced pressure, ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate were poured, and after liquid separation,
The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (developing solvent:
Purification with hexane-ethyl acetate = 4: 1, crystallization with diisopropyl ether, and 1- (4- (4- (3
-Fluorophenyl) -1,2,3,6-tetrahydropyridin-1-yl) -6-methylpyrimidin-2-yl) -1- (4-isopropyl-2-methylthio) phenyl-3-methylurea (240 mg) was obtained. Was. Table 10 shows the structure and physical property data of the compound obtained in the same manner as described above except that the kinds of the present compound and the amine to be reacted were changed.

[0027]

[Table 1]

[0028]

[Table 2]

[0029]

[Table 3]

[0030]

[Table 4]

[0031]

[Table 5]

[0032]

[Table 6]

[0033]

[Table 7]

[0034]

[Table 8]

[0035]

[Table 9]

[0036]

[Table 10]

Next, several compounds including the present invention were tested for CRF receptor antagonism. Test Example [CRF receptor binding experiments: using rat frontal cortical membranes as a receptor preparation, ¹²⁵ I as ¹²⁵ I-labeled ligand
-CRF was used. Binding reactions using ¹²⁵ I-labeled ligands are described in The Journal of Neuroscience, 7, 88 (1987).
Year)).

Preparation of receptor membrane preparation: 1 rat frontal cortex
Homogenize with 50 mM Tris-HCl buffer (pH 7.0) containing 0 mM MgCl ₂ and 2 mM EDTA.
Centrifuge at 000 xg, and precipitate the precipitate with Tris-HCl buffer.
Washed once. The precipitate was washed with 10 mM MgCl ₂ , 2 mM EDT.
A, A suspension was prepared in a 50 mM Tris-HCl buffer (pH 7.0) containing 0.1% bovine serum albumin and 100 kallikrein units / ml aprotinin to prepare a membrane preparation. CRF receptor binding experiment: membrane preparation (0.3 mg protein / ml), ¹²⁵ I-CRF (0.2 nM) and test drug
The reaction was performed at 25 ° C. for 2 hours. After the reaction was completed, a glass filter (GF / GF) treated with 0.3% polyethyleneimine was used.
C) The mixture was filtered by suction and the glass filter was filtered with 0.01% Tr.
3 with phosphate buffered saline containing itonX-100
Washed once. After washing, the radioactivity of the filter paper was measured with a gamma counter. The amount of binding when the reaction was performed in the presence of 1 μM CRF was defined as nonspecific binding of ¹²⁵ I-CRF, and the difference between total binding and nonspecific binding was defined as specific binding. An inhibition curve was obtained by reacting a constant concentration (0.2 nM) of ¹²⁵ I-CRF with a test drug having a different concentration under the above conditions, and from the inhibition curve, a test drug which inhibited the ¹²⁵ I-CRF binding by 50% was obtained. The concentration (IC ₅₀ ) was determined. As a result, 1-10 can be mentioned as a typical compound, and its IC ₅₀ value is 2
It was 0.19 nM.

[0039]

According to the present invention, there is provided a compound having a high affinity for the CRF receptor. These compounds are CRF
Diseases that may be involved, such as depression, anxiety,
Effective for Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorders, hypertension, gastrointestinal disorders, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head trauma, inflammation, immune-related diseases, etc. .

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/505 AAK A61K 31/505 AAK AAM AAM ABA ABA ABE ABE ABN ABN ABU ABU ABU ACJ ACJ ADR AED ADR AED / 52 31/52 C07D 401/04 239 C07D 401/04 239 405/14 211 405/14 211 409/14 211 409/14 211 471/04 104 471/04 104Z 111 111 111 473/00 473/00 475/00 475/00 495/04 105 495/04 105Z (72) Inventor Taketoshi Okubo 3-24-1 Takada, Toshima-ku, Tokyo Inside Taisho Pharmaceutical Co., Ltd. (72) Inventor Hiromi Kataoka 3-24-, Takada, Toshima-ku, Tokyo 1. Inside Taisho Pharmaceutical Co., Ltd. (72) Inventor Kazuki Tomizawa 3-24-1, Takada, Toshima-ku, Tokyo F-term within Taisho Pharmaceutical Co., Ltd. (reference) 4C050 AA01 BB04 BB05 BB06 BB08 CC07 CC08 EE02 EE03 EE04 EE05 FF01 FF02 FF05 GG04 HH02 HH03 HH04 4C063 AA01 AA03 BB01 CC29 CC75 CC92 DD11 EE01 BB01 CC03 LL01 PP12 4C071 AA01 BB01 CC02 CC21 EE12 FF05 FF10 GG01 GG02 GG04 HH16 JJ08 4C086 CB05 CB07 CB08 CB09 GA03 GA07 GA10 GA12 MA01 NA14 ZA05 ZA12 ZA16 ZA36 ZA42 ZA66 ZA11 ZB09 Z

Claims (1)

[Claims] (1) Formula (1) [Wherein, Ar represents a phenyl group, a substituted phenyl group, a thienyl group, or a furyl group, and Z represents a group represented by the formula: (Wherein, R ¹ , R ² and R ³ are the same or different and represent a hydrogen atom or a lower alkyl group, and X ¹ , X ² and X ³ are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group,
It represents a lower alkoxy group, a lower alkylthio group or a lower alkylamino group. ). Or a pharmaceutically acceptable salt thereof.