JPH05194370A - Sulfonamide derivative - Google Patents

Abstract

PURPOSE:To obtain a new compound having a thromboxane A2 antagonism and useful as a platelet agglutination suppressing agent and a preventive and therapeutic agent against an ischemic disease and a therapeutic agent, etc., for cerebrovascular spasm after subarachnoid hemorrhage and asthma. CONSTITUTION:A compound of formula I [R<1> is (halogen-substituted)phenyl; R<2> is H, 1-10C alkyl, phenylsulfonyl, pyridylmethyl, etc.; R<3> is H, 1-4C alkyl or 2-cyanoethyl; n is 0-2; X and Y are H or halogen; A is 1-10C alkylene], e.g. 4-{2-[N-(4-chlorophenylsulfonyl)methylamino)ethylthio}--2,6- difluorophenoxyacetic acid methyl ester. The compound of formula I is obtained by sulfonating a compound of formula II and then halogenating and reducing the resultant compound to give a compound of formula III and reacting the compound of formula III with a compound of formula IV and reacting the product with a compound of the formula Hal-A-CO2R<3> and successively a compound of the formula R<2>-Hal.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel sulfonamide derivative, and more particularly to a novel sulfonamide derivative having a thromboxane A ₂ antagonistic activity.

[0002]

BACKGROUND OF THE INVENTION As a sulfonamide derivative having a thromboxane A ₂ antagonistic effect, a compound described in JP-B-57-35910 is known, but its effect is still insufficient.

[0003]

An object of the present invention is to provide a compound having an excellent thromboxane A ₂ antagonistic activity.

[0004]

Means for Solving the Problems As a result of intensive studies, the present inventors have found a novel sulfonamide derivative useful as a thromboxane A ₂ antagonist and completed the present invention.

The present invention has the following formula [1]:

[0006]

(In the formula, R ¹ represents a phenyl group which may be substituted with a halogen atom, R ² represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or a halogen atom on the benzene ring. Phenylsulfonyl group, pyridylmethyl group, imidazolylmethyl group, benzyl group, or “phenylcarbonylamino group which may have an alkoxycarbonyl group having 2 to 5 carbon atoms, a carboxyl group or a halogen group on a benzene ring” Is substituted with ", is an alkyl group having 1 to 10 carbon atoms, R ³ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or a 2-cyanoethyl group, and n is 0, 1 or 2. X and Y are the same or different and each represents a hydrogen atom or a halogen atom,
Represents an alkylene group having 1 to 10 carbon atoms) and a pharmaceutically acceptable salt thereof.

In the present invention, the alkyl group means a straight chain or branched chain alkyl group such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, pentyl group, isopentyl group and hexyl group. Groups, octyl groups, decyl groups, and the like. The halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. The alkylene group is a straight chain or branched chain alkylene group, and examples thereof include a methylene group, an ethylene group, a propylene group, a trimethylene group, a pentamethylene group, a hexamethylene group and an ethylethylene group.
The alkoxycarbonyl group is an alkoxycarbonyl group having a straight chain or branched chain alkyl group, for example, a methoxycarbonyl group, an ethoxycarbonyl group,
A propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group and the like. The pharmaceutically acceptable salt is a salt that can be formed when R ³ is a hydrogen atom, alkali metals,
It is a salt with alkaline earth metals and ammonium.
They are, for example, sodium salts, potassium salts, calcium salts, ammonium salts, aluminum salts and the like.

The compound of the formula [1] of the present invention can be produced, for example, by the method shown below. (In the reaction formula, X, Y, R ¹ , R ² , R ³ and A have the same meanings as described above, and Hal is any halogen atom.)

[0010]

That is, the compound of formula [2], which is publicly known or obtained by a publicly known method, is sulfonated by a generally known method, and then halogenated to obtain a compound of formula [3]. At this time, as the sulfonating agent, for example, sulfuric acid, fuming sulfuric acid, sulfuric anhydride, chlorosulfonic acid, etc. can be used, and as the halogenating agent,
For example, oxalyl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, chlorosulfonic acid and the like can be used. Further, sodium chloride can be used as a sulfonation reaction accelerator. Examples of the reaction solvent include carbon tetrachloride, methylene chloride, chloroform, 1,1,2,
A solvent inert to the reaction such as 2, -tetrachloroethane can be used.

Then, the compound of the formula [4] is reduced by a commonly used method (for example, a method using tin, zinc, stannous chloride, etc. under acidic conditions). Can be obtained.

Next, the compound of formula [4] and the compound of formula [5] are reacted in the presence of a base to give a compound of formula [6]. Examples of the base at this time include potassium carbonate,
Sodium carbonate, calcium carbonate, sodium hydroxide,
Inorganic bases such as potassium hydroxide, calcium hydroxide, sodium hydride and sodium amide, sodium methylate, alcoholates such as potassium t-butoxide, organic amines such as triethylamine and diisopropylethylamine can be used. As the reaction solvent, a solvent inert to the reaction such as N, N-dimethylformamide, dimethyl sulfoxide, acetone, ethanol, isopropanol, methanol, tetrahydrofuran, acetonitrile and water can be used. Next, the compound of formula [6] and the compound of formula [7] are reacted in the presence of a base to give a compound of formula [8] (R ² = hydrogen,
The compound of the present invention in which n = 0 is obtained. Examples of the base here include inorganic bases such as potassium carbonate, sodium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium hydride and sodium amide, sodium methylate and potassium t-butoxide. Organic amines such as alcoholates, triethylamine and diisopropylethylamine can be used. At this time, a phase transfer catalyst such as trimethylbenzylammonium chloride, sodium iodide, or the like can be used as the reaction accelerator. Examples of the reaction solvent include methylene chloride, chloroform,
A solvent inert to the reaction such as N, N-dimethylformamide, dimethylsulfoxide, acetone, ethanol, isopropanol, methanol, tetrahydrofuran, acetonitrile, water can be used.

Further, the compound of formula [8] is reacted with the compound of formula [9] in the presence of a base to give a compound of formula [10] (R
Other than hydrogen, ² may be a compound of the present invention in which n = 0. Examples of the base here include inorganic bases such as potassium carbonate, sodium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium hydride and sodium amide, sodium methylate and potassium t-butoxide. Organic amines such as alcoholates, triethylamine and diisopropylethylamine can be used. Examples of the reaction solvent include methylene chloride, chloroform, N,
N-dimethylformamide, dimethyl sulfoxide, acetone, ethanol, isopropanol, methanol,
A solvent inert to the reaction such as tetrahydrofuran, acetonitrile, or water can be used.

The compound of the formula [10] can be converted into another compound of the present invention by further hydrolyzing an ester or oxidizing a sulfur atom. Hydrolysis of the ester can be carried out in the same manner as the reaction under general alkaline conditions, and the obtained compound can be re-esterified if necessary. Also, for the oxidation of the sulfur atom, the reaction can be performed in the same manner as the generally performed oxidation condition.

Further, the pharmaceutically acceptable salt can be obtained by reacting with a base such as sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide or aluminum hydroxide.

[0017]

EFFECTS OF THE INVENTION The compound of the formula [1] thus obtained has excellent thromboxane A ₂ antagonism and low toxicity. Therefore, it is a platelet aggregation inhibitor, a preventive and therapeutic agent for ischemic diseases, subarachnoid hemorrhage. It can be used as a preventive and therapeutic agent for subsequent cerebral vascular contraction and cerebral ischemic symptoms associated therewith, a preventive and therapeutic agent for coronary vascular contraction, a therapeutic agent for asthma, and the like.

For this purpose, the compound of the formula [1] is added with conventional fillers, binders, disintegrants, pH adjusters, solubilizers, etc., and tablets, pills, capsules are prepared by conventional formulation techniques. It can be prepared into a drug, a granule, a powder, a liquid, an emulsion, a suspension, an injection and the like. The compound of formula [1] can be orally or parenterally administered to an adult patient at 0.1 to 5000 mg / day in a single dose or in divided doses.
This dose can be appropriately increased or decreased depending on the type of disease, the age, weight and symptoms of the patient.

Hereinafter, the thromboxane A ₂ antagonism of the compound of the formula [1] will be described with reference to test examples.

Test Example [Rabbit In Vitro Test] Citric acid blood sampling from the carotid artery of a New Zealand male rabbit (3.2% sodium citrate solution 1 volume: blood 9 volumes)
The supernatant obtained by centrifuging this blood at 150 g for 15 minutes at room temperature was designated as platelet rich plasma (PRP), and the supernatant obtained by centrifuging at 1500 g for 10 minutes was designated as platelet poor plasma (PPP). .. The platelet count of PRP was adjusted to 50-60 × 10 ⁴ cells / μl by diluting with PPP.

Platelet aggregation is measured by the method of Born [Bor
n, G.N. V. R. , Nature, Vol. 194, Vol. 92
7 (1962)], it has a thromboxane A ₂ agonistic action as an aggregation inducer (15
S) -15-Hydroxy-11,9- (epoxymethano) prostar 5 (Z), 13 (E) -dienoic acid (U-46619; manufactured by Sigma). That is, as a test drug, the compound of the formula [1] was dissolved in dimethylsulfoxide, and 25 μl of a solution prepared to a required concentration with physiological saline was added to 250 μl of PRP, and the mixture was mixed at 37 ° C. for 3 days.
Incubate for 25 minutes, add 25 µl of U-46619 (final concentration 5 µM), and measure for 5 minutes by a platelet aggregometer (Aglycoda TM PA-3210, manufactured by Kyoto Daiichi Kagaku) to suppress maximum aggregation by 50%. The test drug concentration (IC ₅₀ ) was calculated.

As a comparative drug, 4- [2- (phenylsulfonylamino) ethyl] phenoxyacetic acid (Japanese Patent Publication No.
Compounds described in JP-A-7-35910, hereinafter B
(Hereinafter referred to as “M”), a test solution was prepared in the same manner as described above, and the same test as described above was performed for this.

The results are shown in Table 1.

[0024]

[Table 1] a: 2- {4- [2- (4-chlorophenylsulfonylamino) ethylthio] -2,6-difluorophenoxy} sodium propionate

[0025]

The present invention will be described in detail below with reference to examples. Example 1 Chlorosulfonic acid (112.6 g) was added dropwise to 2,6-difluorophenol (25 g) under ice cooling. The reaction solution was stirred at room temperature for 1 hour, poured into ice water (600 ml), and the separated oily substance was extracted with methylene chloride. The methylene chloride layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 4-chlorosulfonyl-2,6-difluorophenol (31.5 g). ¹ H-NMR (CDCl ₃ ) δ: 6.29 (1H,
s), 7.50-7.80 (2H, m) 4-chlorosulfonyl-2,6-difluorophenol (31.5g), tin (87.8g) and methanol (320ml) to a mixture of reaction temperature. Concentrated hydrochloric acid (80 ml) was added dropwise while maintaining the temperature at 40 ° C. The reaction solution was heated under reflux for 3 hours, poured into ice water (600 ml), and the separated oily substance was extracted with methylene chloride. The methylene chloride layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the residue obtained, potassium carbonate (24.2 g) and acetone (200 ml) were added under an argon atmosphere, and to this was added. N- (2-Bromoethyl) -4-chlorophenylsulfonamide (36.2 g) in acetone (100
ml) solution was added dropwise under ice cooling. The reaction solution was stirred at room temperature for 16 hours, poured into 7% hydrochloric acid (1200 ml), and the separated oily substance was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a residue, which was methylene chloride-n-
Crystallization from a hexane mixture gave 4- [2- (4-chlorophenylsulfonylamino) ethylthio] -2,6-difluorophenol (39 g). Melting point 77.5-79 ° C 4- [2- (4-chlorophenylsulfonylamino) ethylthio] -2,6-difluorophenol (1.89)
g), methyl bromoacetate (0.76 g), potassium carbonate (1 g), N, N-dimethylformamide (20 ml)
The mixture was stirred at room temperature for 1 hour and then the reaction mixture was adjusted to 3%.
The mixture was poured into hydrochloric acid water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated, and the obtained residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate: hexane = 1: 3) to give 4-.
Methyl [2- (4-chlorophenylsulfonylamino) ethylthio] -2,6-difluorophenoxyacetate (2.
2 g) was obtained. Melting point 79.5-80.5 ° C Methyl 4- [2- (4-chlorophenylsulfonylamino) ethylthio] -2,6-difluorophenoxyacetate (2.2 g), methyl iodide (1.7 g), potassium carbonate ( 2.75 g), N, N-dimethylformamide (3
The mixture (0 ml) was stirred at room temperature for 1 hour, then the reaction mixture was poured into 3% aqueous hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated, and the obtained residue was subjected to silica gel column chromatography to give 4- {2- [N- (4-chlorophenylsulfonyl) methylamino] ethylthio. } -2,6-Difluorophenoxymethyl acetate (Compound 1) (2.3 g)
Got ¹ H-NMR (CDCl ₃ ) δ: 2.81 (3H,
s), 3.08 (2H, m), 3.20 (2H, m),
3.79 (3H, s), 4.74 (2H, s), 6.9
0 (2H, m), 7.50 (2H, m), 7.68 (2
H, m)

Example 2 Methyl 4- {2- [N- (4-chlorophenylsulfonyl) methylamino] ethylthio} -2,6-difluorophenoxyacetate (1 g), methanol (50 ml), 1
A mixture of 0% sodium hydroxide (4 ml) was added at room temperature to 30
Stir for minutes. The reaction solution was acidified with 3% hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give 4- {2- [N- (4-
Chlorophenylsulfonyl) methylamino] ethylthio} -2,6-difluorophenoxyacetic acid (Compound 2)
Got Melting point 81.5-83 ° C

The following compounds were obtained by performing the same operation as in Example 1 or Example 2. Methyl 2- {4- [2- (4-chlorophenylsulfonylamino) ethylthio] -2,6-difluorophenoxy} propionate (Compound 3) ¹ H-NMR (CDCl ₃ ) δ: 1.62 (3H, d,
J = 7 Hz), 2.99 (2H, t, J = 7 Hz),
3.13 (2H, q, J = 7Hz), 3.78 (3H,
s), 4.80 (1H, q, J = 7Hz), 5.07
(1H, br), 6.80 (2H, m), 7.49 (2
H, m), 7.77 (2H, m) 2- {4- [2- (4-chlorophenylsulfonylamino) ethylthio] -2,6-difluorophenoxy} sodium propionate (Compound 4) Melting point 102-108 ° C. Methyl 2-methyl-2- {4- [2- (4-chlorophenylsulfonylamino) ethylthio] -2,6-difluorophenoxy} propionate (Compound 5) ¹ H-NMR (CDCl ₃ ) δ: 1.54 ( 6H,
s), 3.01 (2H, t, J = 7Hz), 3.15
(2H, m), 3.80 (3H, s), 4.90 (1
H, br), 6.80 (2H, m), 7.50 (2H,
m), 7.78 (2H, m)

2-Methyl-2- {4- [2- (4-chlorophenylsulfonylamino) ethylthio] -2,6-
Sodium difluorophenoxy} propionate (Compound 6) Melting point 136-142 ° C Ethyl 4- {4- [2- (4-chlorophenylsulfonylamino) ethylthio] -2,6-difluorophenoxy} butyrate (Compound 7) ¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t,
J = 7Hz), 2.04 (2H, m), 2.55 (2
H, t, J = 7 Hz), 2.97 (2H, m), 3.1
2 (2H, m), 4.05-4.20 (4H, m),
4.97 (1H, t, J = 6Hz), 6.80 (2H,
m), 7.48 (2H, m), 7.76 (2H, m) 4- {4- [2- (4-chlorophenylsulfonylamino) ethylthio] -2,6-difluorophenoxy} butyric acid (Compound 8) Melting point 71-73 ° C 4- {2- [N- (4-chlorophenylsulfonyl)-
Methyl N- (methoxycarbonylmethyl) amino] ethylthio} -2,6-difluorophenoxyacetate (Compound 9) Melting point 98.5-99.5 ° C 4- {2- [N- (4-chlorophenylsulfonyl)-
N- (carboxymethyl) amino] ethylthio} -2,
6-Difluorophenoxyacetic acid (Compound 10) Melting point 192-1925C 4- {2- [N- (4-chlorophenylsulfonyl) hexylamino] ethylthio} -2,6-difluorophenoxyacetic acid (Compound 11) Melting point 93- 94.5 ° C 4- {2- [N- (4-chlorophenylsulfonyl) benzylamino] ethylthio} -2,6-difluorophenoxyacetic acid (Compound 12) Melting point 99-100 ° C 4- [2- {N- (4 -Chlorophenylsulfonyl)-
Methyl [2- (4-chlorophenylsulfonylamino) ethyl] amino} ethylthio] -2,6-difluorophenoxyacetate (Compound 13) Melting point 126-127 ° C

4- [2- {N- (4-chlorophenylsulfonyl)-[2- (4-chlorophenylsulfonylamino) ethyl] amino} ethylthio] -2,6-difluorophenoxyacetic acid (Compound 14) Melting point 117-119 ° C 4- {2- [N- (4-chlorophenylsulfonyl)-
N- (pyridin-2-ylmethyl) amino] ethylthio} -2,6-difluorophenoxyacetic acid (Compound 1
5) Melting point 119.5-121 ° C 4- {2- [N- (phenylsulfonyl) -N- (imidazol-1-ylmethyl) amino] ethylthio}-
2,6-Difluorophenoxyacetic acid (Compound 16) Melting point 99 to 102 ° C 4- {2- [N, N-bis (4-chlorophenylsulfonyl) amino] ethylthio} -2,6-difluorophenoxyacetate methyl (Compound 17) Melting point 117-118 ° C 4- {2- [N- (phenylsulfonyl) methylamino] ethylsulfonyl} phenoxyacetic acid (Compound 18) Melting point 123-124 ° C 4- [2- (4-chlorophenylsulfonylamino) ethylthio] -2 Methyl -bromo-6-fluorophenoxyacetate (Compound 19) Melting point 79.5-80.5 ° C 4- [2- (4-chlorophenylsulfonylamino) ethylthio] -2-bromo-6-fluorophenoxyacetic acid (Compound 20) Melting point 99.5-100.5 ° C

Example 3 2,6-difluoro-4- [2- (4-chlorophenylsulfonylamino) ethylthio] phenoxyacetic acid (2.
19 g), 2-cyanoethanol (5 ml), N-hydroxybenzotriazole monohydrate (1.53 g), 1
A mixture of-(3-dimethylaminopropyl) -3-ethylcarbodiimide (1.05g) and N, N-dimethylformamide (30ml) was stirred at room temperature for 16 hours. The reaction mixture was poured into 3% aqueous hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate: hexane = 1: 1).
It was attached to 1) to obtain 2,6-difluoro-4- [2- (4-chlorophenylsulfonylamino) ethylthio] phenoxyacetic acid (2-cyanoethyl) ester (Compound 21). Melting point 88-90 ° C

Example 4 2,6-difluoro-4- [2- (4-chlorophenylsulfonylamino) ethylthio] phenoxyacetic acid (2-
A mixture of (cyanoethyl) ester (1.1 g), 4-chlorophenylsulfonyl chloride (0.56 g), potassium carbonate (0.6 g) and acetone (10 ml) was stirred at room temperature for 16 hours. The reaction mixture was poured into 3% aqueous hydrochloric acid and extracted with ethyl acetate. Wash the ethyl acetate layer with saturated saline,
The residue obtained by drying over anhydrous magnesium sulfate and evaporating the solvent was subjected to silica gel column chromatography (elution solvent; ethyl acetate: hexane = 1: 2), and the residue was crystallized from diisopropyl ether-methylene chloride to give 4- {2-
[N, N-bis (4-chlorophenylsulfonyl) amino] ethylthio} -2,6-difluorophenoxyacetic acid (2-cyanoethyl) ester (Compound 22) (1.2
g) was obtained. Melting point 51-55 ° C

Example 5 4- {2- [N, N-bis (4-chlorophenylsulfonyl) amino] ethylthio} -2,6-difluorophenoxyacetic acid (2-cyanoethyl) ester (0.66
2.5% sodium hydroxide solution (1.0 ml) was added dropwise to a mixture of g) and tetrahydrofuran (20 ml) under ice cooling. The reaction solution was stirred at room temperature for 1.5 hours, acidified with 3% hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was crystallized from ethyl acetate-diisopropyl ether to give 4- {2- [N, N-bis (4-chlorophenylsulfonyl) amino] ethylthio} -2,6-difluorophenoxyacetic acid (Compound 23). Melting point 134-135 ° C

Example 6 4- [2- (4-chlorophenylsulfonylamino) ethylthio] -2,6-difluorophenoxyacetic acid (1
Hydrogen chloride gas was introduced into an ethanol (50 ml) solution of g) under ice cooling to be saturated. The reaction solution was left at room temperature for 16 hours, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was crystallized from methylene chloride-hexane to obtain ethyl 4- [2- (4-chlorophenylsulfonylamino) ethylthio] -2,6-difluorophenoxyacetate (Compound 24). Melting point 70 to 71 ° C. The same operation was performed to obtain the following compound. 4- [2- (4
-Chlorophenylsulfonylamino) ethylthio]-
Isopropyl 2,6-difluorophenoxyacetate (Compound 25) Melting point 52-54 ° C

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical indication location A61K 31/215 ABR 8413-4C 31/275 ACB 8413-4C 31/415 AED 7252-4C (72) Inventor Jun Goto 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Yoshiyuki Chiba 559-6 Kitano-cho, Hachioji-shi, Tokyo Inside Central Research Institute of Japan Fisheries Co., Ltd. Mikio 559-6 Kitano-cho, Hachioji-shi, Tokyo Japan Fisheries Co., Ltd. Central Research Laboratory

Claims (1)

[Claims] 1. (In the formula, R ¹ represents a phenyl group which may be substituted with a halogen atom, R ² represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or a phenyl group which may have a halogen atom on the benzene ring. Sulfonyl group, pyridylmethyl group, imidazolylmethyl group, benzyl group, or "having 2 to 5 carbon atoms"
Substituted with a phenylsulfonylamino group which may have a halogen group on the alkoxycarbonyl group, a carboxyl group or a benzene ring "represents an alkyl group having 1 to 10 carbon atoms, and R ³ represents a hydrogen atom or a carbon atom. Number of atoms 1-4
Represents an alkyl group or a 2-cyanoethyl group, n represents 0, 1 or 2, X and Y are the same or different and represent a hydrogen atom or a halogen atom, and A is an alkylene having 1 to 10 carbon atoms. Group) and a pharmaceutically acceptable salt thereof.