JPH05262736A - Phenoxyacetic acid derivative - Google Patents

Abstract

PURPOSE:To provide the subject phenoxyacetic acid derivative exhibiting a thromboxane A2 antagonism and a leukotriene antagonism and useful as an effective preventive against an allergic disease such as thrombosis or asthma. CONSTITUTION:A compound of formula I (X is H, a halogen, a lower alkyl, CF3, an alkoxy, OH or CN; R1 is carboxyl, an alkoxycarbonyl or tetrazole; A is O, formula II or formula III; m and n are each 0 or 1) or its pharmaceutically permissible salt, e.g. 4-[2-(benzenesulfonamide)ethyl]-2-[3-(2- quinolinemethoxy)benzoylamino]phenoxyacetic acid. The above-mentioned compound is obtained by reacting a sulfonamide derivative of formula IV (R2 is NH2 or OH) with a quinoline derivative of formula V or formula VI (B is NCS or COY; Y is a halogen), as necessary, in the presence of a suitable base in an inert organic solvent at 0 to 100 deg.C.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel phenoxyacetic acid derivative.

[0002]

BACKGROUND ART Thromboxane A ₂ and leukotrienes have been suggested to be closely related to severe ischemic diseases such as cerebral infarction and myocardial infarction, and allergic inflammation such as bronchial asthma. A ₂ antagonists, leukotriene antagonists, and synthase inhibitors are being developed one after another, but the involvement of multiple chemical mediators has been clarified in actual pathological conditions, and existing single enzyme inhibitors and receptors An adequate therapeutic effect has not been obtained with antagonists and the like.

[0003]

Based on the above, the present inventor examined the development of a drug having a leukotriene antagonistic action in addition to a thromboxane A ₂ antagonistic action.

As a result, various phenoxyacetic acid derivatives were synthesized, and as a result of diligent research on their physiological actions, it was found that the phenoxyacetic acid derivatives according to the present invention have a thromboxane A ₂ antagonistic action and a leukotriene antagonistic action. Have found that the above-mentioned problems with a single synthase inhibitor or receptor antagonist can be solved.

Accordingly, the present invention provides a novel phenoxyacetic acid derivative, which is further antagonized by thromboxane A ₂ and leukotriene.
It is an object to provide a pharmaceutical preparation containing the same.

[0006]

The present invention for solving the above-mentioned object is represented by the following general formula 4 (wherein X is a hydrogen, halogen atom, lower alkyl, trifluoromethyl, alkoxy, hydroxy or cyano group). And R ₁ is a carboxyl group or an alkoxycarbonyl group (wherein the alkoxy group has 1 to 4 carbon atoms and is a straight chain or a branched chain)
Or represents a tetrazole group, A is oxygen or the following formula 5
Or a phenoxyacetic acid derivative represented by Chemical Formula 6 and m and n represent an integer of 0 or 1, or a physiologically acceptable salt thereof.

[0007]

[Chemical 4]

[0008]

[Chemical 5]

[0009]

[Chemical 6]

The present invention is also a thromboxane A ₂ antagonist containing the phenoxyacetic acid derivative.

The present invention is also a leukotriene antagonist containing the phenoxyacetic acid derivative.

The present invention is also an antiallergic agent containing the phenoxyacetic acid derivative.

[0013] Note that thromboxane A ₂ by thromboxane A ₂ receptor and the thromboxane A ₂ antagonists in the present invention
And a leukotriene antagonist means a formulation that antagonizes leukotrienes at leukotriene receptors.

The compound represented by the general formula 4 of the present invention may be a physiologically acceptable salt. As such a salt, a salt with an inorganic or organic acid such as hydrochloric acid,
Salts of sulfuric acid, citric acid, succinic acid, methanesulfonic acid, etc. and inorganic or organic bases such as alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, and zinc salt. Examples include heavy metal salts such as ammonium salts, triethylamine salts, organic amine salts such as tromethamine salts, and amino acid salts such as arginine and lysine.

The phenoxyacetic acid derivative represented by the general formula 4 of the present invention is a sulfonamide derivative represented by the following general formula 7 (wherein X is hydrogen, halogen atom, lower alkyl, trifluoromethyl, alkoxy, hydroxy or Represents a cyano group, R ₁ is a carboxyl group or an alkoxycarbonyl group (wherein the alkoxy group has 1 to 1 carbon atoms).
4 is a straight chain or branched chain), represents a tetrazole group, and R ₂ represents an amino or hydroxy group).
And a quinoline derivative represented by the following general formula 8 or 9 (wherein n represents an integer of 0 or 1 and B represents -NCS or-
COY, Y represents a halogen atom), if necessary, in the presence of a suitable base in an inert organic solvent at a temperature between 0 and 100 ° C., and the ester moiety is hydrolyzed if necessary. (Method A).

[0016]

[Chemical 7]

[0017]

[Chemical 8]

[0018]

[Chemical 9]

The sulfonamide derivative represented by the general formula 7 has the following general formula 10 (wherein R ₁ is a carboxyl group, an alkoxycarbonyl group (wherein the alkoxy group has 1 to 4 carbon atoms, and Chain or branched chain) or a tetrazole group, and R ₃ represents a nitro or benzyloxy group) is hydrazine-decomposed to produce a resulting amine derivative and various benzenesulfonyl chlorides. It can be obtained by carrying out catalytic reduction after the condensation reaction.

[0020]

[Chemical 10]

The quinoline derivative represented by the general formula (8) or (9) is a 2-chloromethylquinoline and hydroxybenzyl alcohol or hydroxybenzoic acid alkyl ester of each isomer in the presence of a suitable base in an inert organic solvent. The benzyl alcohol derivative obtained by reacting at a temperature between 0 and 50 ° C. is hydrolyzed in the case of a benzoic acid ester derivative to be converted into a carboxylic acid derivative and then halogenated.

The isothiocyanate derivative can be obtained by reacting the amine derivative obtained by the condensation reaction of 2-chloromethylquinoline with each isomer of nitrophenol and treatment with Raney nickel with thiophosgene.

Further, the general formula 4 is represented by the following general formula 11 (wherein R ₁ is a carboxyl group or an alkoxycarbonyl group (wherein the alkoxy group has 1 to 4 carbon atoms and is a straight chain or a branched chain). ) Or a tetrazole group, A represents oxygen or the formula 5 or 6, and m and n represent an integer of 0 or 1) are hydrazine-decomposed to convert them into amine derivatives. It can also be obtained by carrying out the reaction of with sulfonyl chloride in the presence of a suitable base in an inert organic solvent at a temperature between 0 and 100 ° C (method B).

[0024]

[Chemical 11]

The phthalimide derivative represented by the general formula 11 is inactive in the presence of a quinoline derivative represented by the general formula 8 or 9 and a suitable base after catalytic reduction of the phthalimide derivative represented by the general formula 10. 0 to 5 in organic solvent
Obtained by reacting at a temperature between 0 ° C.

In the phenoxyacetic acid derivative represented by the general formula 4 of the present invention, X is hydrogen or a halogen atom, preferably chlorine or fluorine, lower alkyl is preferably a methyl group, trifluoromethyl, alkoxy is preferably methoxy or ethoxy. R ₁ is a carboxyl group or an alkoxycarbonyl group (wherein the alkoxy group has 1 to 4 carbon atoms and is a straight chain or branched chain, preferably ethyl or t-butyl). Or a tetrazole group, A is oxygen or a compound represented by formula 5 or formula 6, preferably a general formula 5, m and n are 0 or 1, preferably m is 0 and n is an integer of 1. Represent

The base used in the synthesis of the compound of the present invention is preferably triethylamine, potassium carbonate, cesium carbonate or sodium hydride, and the inert organic solvent is, for example, tetrahydrofuran, acetonitrile,
Ether, N, N-dimethylformamide, dimethyl sulfoxide, methylene chloride, methanol, ethanol,
Acetone and dioxane are preferable, but are not particularly limited.

In carrying out the present invention, in each case of Method A and Method B, 1 mol of the sulfonamide derivative represented by the general formula 7 and the amine derivative represented by the general formula 10
1.0 to 1.5 moles of base, if necessary 1.0
In the presence of ˜1.1 mol, the quinoline derivative represented by the general formula 8 or 9 and various sulfonyl chlorides are reacted with 1.0 to 2.0 mol, preferably 1.1 mol.

The reaction temperature is generally 0 to 150 ° C., preferably 0 to 100 ° C., and the reaction time is 30 minutes to 15 hours depending on the temperature.

If necessary, the general formula 4 obtained according to the invention is hydrolyzed in the usual way. Suitable for this hydrolysis include, for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydrogen carbonate,
Trifluoroacetic acid and the like are included.

Typical examples of the phenoxyacetic acid derivative represented by the general formula 4 of the present invention are shown below.

4- [2- (benzenesulfonamido) ethyl] -2- [3- (2-quinolinemethoxy) benzoylamino] phenoxyacetic acid,

4- [2- (4-chlorobenzenesulfonamide) ethyl] -2- [3- (2-quinolinemethoxy) benzoylamino] phenoxyacetic acid,

4- [2- (4-methoxybenzenesulfonamide) ethyl] -2- [3- (2-quinolinemethoxy) benzoylamino] phenoxyacetic acid,

4- [2- (4-hydroxybenzenesulfonamide) ethyl] -2- [3- (2-quinolinemethoxy) benzoylamino] phenoxyacetic acid,

4- [2- (benzenesulfonamido) ethyl] -3- (2-quinolinemethoxy) phenoxyacetic acid,

4- [2- (4-chlorobenzenesulfonamido) ethyl] -3- (2-quinolinemethoxy) phenoxyacetic acid,

4- [2- (4-methoxybenzenesulfonamido) ethyl] -3- (2-quinolinemethoxy) phenoxyacetic acid,

4- [2- (4-hydroxybenzenesulfonamido) ethyl] -3- (2-quinolinemethoxy)
Phenoxyacetic acid,

4- [2- (benzenesulfonamido) ethyl] -3- [3- (2-quinolinemethoxy) benzyloxy] phenoxyacetic acid,

4- [2- (4-chlorobenzenesulfonamido) ethyl] -3- [3- (2-quinolinemethoxy) benzyloxy] phenoxyacetic acid,

4- [2- (4-methoxybenzenesulfonamido) ethyl] -3- [3- (2-quinolinemethoxy) benzyloxy] phenoxyacetic acid,

4- [2- (4-hydroxybenzenesulfonamido) ethyl] -3- [3- (2-quinolinemethoxy) benzyloxy] phenoxyacetic acid,

5-{<4- [2- (4-chlorobenzenesulfonamido) ethyl] -2- [3- (2-quinolinemethoxy) benzoylamino] phenoxy> methyl}-
1H-tetrazole,

5-{<4- [2- (4-chlorobenzenesulfonamido) ethyl] -3- (2-quinolinemethoxy) phenoxy> methyl} -1H-tetrazole,

5-{<4- [2- (4-chlorobenzenesulfonamido) ethyl] -3- [3- (2-quinolinemethoxy) benzyloxy] phenoxy> methyl} -1
H-tetrazole,

4- [2- (benzenesulfonamido) ethyl] -2- {3- [3- (2-quinolinemethoxy) phenyl] thioureido} phenoxyacetic acid,

4- [2- (4-chlorobenzenesulfonamide) ethyl] -2- {3- [3- (2-quinolinemethoxy) phenyl] thioureido} phenoxyacetic acid,

4- [2- (4-methoxybenzenesulfonamido) ethyl] -2- {3- [3- (2-quinolinemethoxy) phenyl] thioureido} phenoxyacetic acid,

4- [2- (4-hydroxybenzenesulfonamide) ethyl] -2- {3- [3- (2-quinolinemethoxy) phenyl] thioureido} phenoxyacetic acid and the like can be mentioned.

The phenoxyacetic acid derivative of the present invention is used as a thromboxane A ₂ antagonist and a leukotriene antagonist, and the dose varies depending on the symptoms but is generally 1
0 to 2000 mg, preferably 20 to 600 mg,
It is advisable to administer in 1 to 3 divided doses as needed depending on the symptoms. The administration method can take any form suitable for administration, and oral administration is particularly preferable, but intravenous injection is also possible.

The compound of the present invention is used as an active ingredient or one of the active ingredients, either alone or mixed with a pharmaceutical carrier or excipient by a conventional method, to obtain tablets, dragees, powders, capsules, granules, suspensions, It can be applied in various forms such as emulsions and injection solutions.

Examples of carriers or excipients include calcium carbonate, calcium phosphate, starch, glucose, lactose, dextrin, alginic acid, mannitol, talc, magnesium stearate and the like.

[0054]

EXAMPLES The present invention will be described more specifically by showing examples and test examples, but the present invention is not limited to these.

Example 1 (1) 3-Nitrotyramine Hydrochloride 6.01 g of water 1
7.58 g of potassium carbonate, N- in 80 ml solution at room temperature
6.02 g of carboethoxyphthalimide was added, and the mixture was stirred for 15 hours. 6N Hydrochloric acid was gradually added to the reaction mixture at 0 ° C to adjust the pH to 1, and the precipitated crystals were filtered,
Recrystallized from methanol to give 4- [2- (phthalimide)
7.79 g of ethyl] -2-nitrophenol was obtained (yield 91%, yellow crystals).

(2) 4- [2- (phthalimido) ethyl] -2-nitrophenol 2.03 under an argon stream
g acetone 40 ml-N, N-dimethylformamide 40 ml solution at room temperature potassium carbonate 973 mg, bromacetic acid t-butyl ester 1.37 g acetone 5 ml
Each solution was added and stirred for 12 hours.

The reaction mixture was diluted with ethyl acetate, poured into ice water and extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure was recrystallized from chloroform-hexane to give 4
2.46 g of-[2- (phthalimido) ethyl] -2-nitrophenoxyacetic acid t-butyl ester was obtained (yield 9
0%, yellow crystals).

(3) 4- [2- (phthalimido) ethyl] -2-nitrophenoxyacetic acid t- under an argon stream.
A solution of butyl ester (4.36 g) in ethanol (35 ml) was added with water hydrazine (1.02 g) in ethanol (5 ml), and the mixture was heated under reflux at 100 ° C. for 2 hours. After cooling, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give 4- (2).
-Aminoethyl) -2-nitrophenoxyacetic acid t-butyl ester (yellow crystals) was used in the next reaction without purification.

Under an argon stream, 1.4 ml of triethylamine was added at 0 ° C. to a 15 ml solution of 4- (2-aminoethyl) -2-nitrophenoxyacetic acid t-butyl ester in N, N-dimethylformamide, and the mixture was stirred for 5 minutes. p-
Chlorobenzenesulfonyl chloride 2.37 g N,
Add 5 ml of N-dimethylformamide solution at room temperature for 1
Stir for 0 hours. The reaction mixture was diluted with ethyl acetate, poured into ice water and extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.

The residue obtained after concentration under reduced pressure was subjected to silica gel column chromatography, and 4- [2- (4-chlorobenzenesulfonamido) ethyl] was extracted from the fraction eluted with hexane-ethyl acetate (2: 1 v / v). 4.20 g of 2-nitrophenoxyacetic acid t-butyl ester was obtained (yield 87%, yellow oily substance).

(4) To a solution of 4- [2- (4-chlorobenzenesulfonamido) ethyl] -2-nitrophenoxyacetic acid t-butyl ester 3.61 g in ethyl acetate 15 ml was added 10% palladium-carbon 360 mg, and hydrogen gas was present. Stirred at 1 atmosphere below. The reaction mixture was filtered and then concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography, and hexane-ethyl acetate (2: 1 v /
v) From the elution fraction, 4- [2- (4-chlorobenzenesulfonamido) ethyl] -2-aminophenoxyacetic acid t-
2.23 g of butyl ester was obtained (yield 66%, yellow oily substance).

(5) Under an argon stream, 2 ml of thionyl chloride was added to 874 mg of 3- (2-quinolinemethoxy) benzoic acid under ice cooling, and the mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure and dried to give 3- (2-quinolinemethoxy).
Benzoyl chloride (white crystals) was used in the next reaction without purification.

Under an argon stream, 2.2 ml of triethylamine was added to a solution of 3- (2-quinolinemethoxy) benzoyl chloride (white crystals) in 5 ml of chloroform under ice cooling, and the mixture was stirred for 10 minutes, and then 4- [2- (4-chlorobenzenesulfone). Amido) ethyl] -2-aminophenoxyacetic acid t
A solution of 1.38 g of butyl ester in 3 ml of chloroform was added, and the mixture was stirred at room temperature for 11 hours. The reaction mixture was diluted with methylene chloride, poured into ice water and extracted with methylene chloride,
The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate.

The residue obtained by concentration under reduced pressure was recrystallized from methylene chloride-hexane to give 4- [2- (4-chlorobenzenesulfonamido) ethyl] -2- [3- (2-quinolinemethoxy) benzoylamino. ] Phenoxyacetic acid t
1.83 g of -butyl ester was obtained (yield 83%, white crystals).

(6) 4- [2- (4
-Chlorobenzenesulfonamido) ethyl] 2- [3-
(2-quinolinemethoxy) benzoylamino] phenoxyacetic acid t-butyl ester 360 mg methylene chloride 5
1.0 ml of trifluoroacetic acid was added to the ml solution under ice cooling, and the mixture was stirred at room temperature for 16 hours.

The residue obtained by concentrating the reaction mixture under reduced pressure was recrystallized from tetrahydrofuran-hexane to give 4-
[2- (4-chlorobenzenesulfonamido) ethyl]
110 mg of 2- [3- (2-quinolinemethoxy) benzoylamino] phenoxyacetic acid was obtained (yield 61%, white crystals).

Spectroscopic data for this supports the structure of Formula 12 below.

NMR (CDCl ₃ -CD ₃ OD) δ:
2.72 (2H, t, J = 7Hz), 2.93-3.7
4 (2H, m), 4.68 (2H, s), 5.53 (2
H, s), 6.80-8.44 (17H, m).

[0069]

[Chemical 12]

Example 2 (1) 4- [2- (phthalimido) ethyl] -2-nitrophenoxyacetic acid t-butyl ester 302 mg was dissolved in a solution of 302 mg of ethyl acetate in 15 ml of ethyl acetate.
Was added, and the mixture was stirred at 1 atm in the presence of hydrogen gas. The reaction mixture was filtered and concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography, and 4- [2- (phthalimido) ethyl]-was extracted from the hexane-ethyl acetate (3: 1 v / v) elution fraction. 240 mg of 2-aminophenoxyacetic acid t-butyl ester was obtained (yield 87%, yellow oily substance).

(2) Under an argon stream, 2 ml of thionyl chloride was added to 170 mg of 3- (2-quinolinemethoxy) benzoic acid under ice cooling, and the mixture was stirred for 2 hours and a half. The reaction mixture was concentrated under reduced pressure and dried to obtain 3- (2-quinolinemethoxy) benzoyl chloride (white crystals), which was used in the next reaction without purification. Under an argon stream, 3- (2-
Quinoline methoxy) benzoyl chloride (white crystals)
0.4 ml of triethylamine was added to a solution of 3 ml of chloroform under ice-cooling and stirred for 10 minutes, and then a solution of 240 mg of 4- [2- (phthalimido) ethyl] -2-aminophenoxyacetic acid t-butyl ester in 2 ml of chloroform was added and the mixture was stirred at room temperature for 10 minutes. Stir for hours.

The reaction mixture was diluted with methylene chloride, poured into ice water and extracted with methylene chloride, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography, and 4- [2- (phthalimido) ethyl] -2- [3] was extracted from the hexane-ethyl acetate (2: 1 v / v) elution fraction.
240 mg of t-butyl ester of-(2-quinolinemethoxy) benzoylamino] phenoxyacetic acid was obtained (yield 6
0%, white crystals).

(3) 4- [2- (phthalimido) ethyl] -2- [3- (2-quinolinemethoxy) benzoylamino] phenoxyacetic acid t-butyl ester (240 mg) in ethanol (5 ml) solution under a stream of argon. 36 ml of ethanol (3 ml) was added, and the mixture was heated under reflux at 100 ° C. for 2 hours.

After cooling, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give 4- (2-aminoethyl) -2.
-[3- (2-quinolinemethoxy) benzoylamino]
Phenoxyacetic acid t-butyl ester (yellow oily substance) was used in the next reaction without purification.

Under an argon stream, a solution of 4- (2-aminoethyl) -2- [3- (2-quinolinemethoxy) benzoylamino] phenoxyacetic acid t-butyl ester (yellow oily substance) in N, N-dimethylformamide (3 ml) was obtained. 0.1 ml of triethylamine was added to the mixture under ice cooling and stirred for 5 minutes,
84 mg of p-chlorobenzenesulfonyl chloride and 2 ml of N, N-dimethylformamide were added, and the mixture was mixed at room temperature for 1 hour.
Stir for 2 hours. The reaction mixture was diluted with ethyl acetate, poured into ice water and extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.

The residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography, and 4- [2- (4-chlorobenzenesulfonamido) ethyl] was extracted from the hexane-ethyl acetate (2: 1 v / v) elution fraction. -2- [3- (2
180 mg of -quinolinemethoxy) benzoylamino] phenoxyacetic acid t-butyl ester were obtained (yield 71%,
White crystals).

Example 3 4- (2-
Aminoethyl) -2-nitrophenoxyacetic acid t-butyl ester and benzenesulfonyl chloride were used according to the same procedure as in Example 1 below, and 4- [2- (benzenesulfonamido) ethyl] -2- [3- (2- Quinolinemethoxy) benzoylamino] phenoxyacetic acid was obtained. The spectroscopic data of this supports the structure of Formula 13 below.

NMR (CDCl ₃ -CD ₃ OD) δ:
2.37-2.90 (2H, m), 3.20 (2H, m)
t, J = 8 Hz), 4.69 (2H, s), 5.52
(2H, s), 6.81-8.44 (18H, m).

[0079]

[Chemical 13]

Example 4 (1) 4- [2- (phthalimide) under an argon stream
Ethyl] -3- (2-quinolinemethoxy) phenoxyacetic acid ethyl ester (340 mg) was added to a solution of ethanol (2 ml) at room temperature in water containing hydrazine (1 ml of ethanol), and the mixture was heated under reflux at 100 ° C. for 2 hours, and the deposited precipitate was filtered off. Then, it was concentrated under reduced pressure and dried.

Under an argon stream, 73 μl of triethylamine was added to a 2 ml solution of N, N-dimethylformamide of the residue under ice cooling, and after stirring for 10 minutes, 111 mg of p-chlorobenzenesulfonyl chloride was added. After stirring at room temperature for 16 hours, ice water was added to the reaction solution and the organic layer extracted with ethyl acetate was washed with saturated brine and dried over anhydrous sodium sulfate.

The residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography, and 4- [2- (4-chlorobenzenesulfonamido) ethyl] was extracted from the hexane-ethyl acetate (1: 1 v / v) elution fraction. -3- (2-quinolinemethoxy) phenoxyacetic acid ethyl ester was added to 130
mg was obtained (yield 35%, yellow oily substance).

(2) 4- [2- (4
-Chlorobenzenesulfonamido) ethyl] -3- (2
-Quinoline methoxy) phenoxyacetic acid ethyl ester 1
2 ml of 30 mg tetrahydrofuran solution at room temperature
After adding 0.2 ml of N sodium hydroxide aqueous solution and stirring for 4 hours, the solvent was distilled off under reduced pressure, and the pH was adjusted to 1 with dilute hydrochloric acid.

The precipitated crystals were collected by filtration, dried under reduced pressure and subjected to silica gel column chromatography to give 10%.
4- [2- (4
-Chlorobenzenesulfonamido) ethyl] -3- (2
80 mg of -quinolinemethoxy) phenoxyacetic acid was obtained (yield 66%, white crystals).

Spectroscopic data for this support the structure of Formula 14 below.

NMR (CDCl ₃ -CD ₃ OD) δ:
2.70 (2H, m), 3.18 (2H, m), 4.3
0 (2H, m), 5.00 (2H, s), 6.23-
8.10 (13H, m).

[0087]

[Chemical 14]

(Example 5) 4- [2-
Using (phthalimido) ethyl] -3- [3- (2-quinolinemethoxy) benzyloxy] phenoxyacetic acid ethyl ester and hydrated hydrazine, 4- [2- (4-chlorobenzenesulfone) was prepared according to the same procedure as in Example 4 below. Amido) ethyl] -3- [3- (2-quinolinemethoxy) benzyloxy] phenoxyacetic acid ethyl ester (shown in Formula 15 below), and further 4- [2- (4-chlorobenzenesulfonamido) ethyl] -3- [3- (2-quinolinemethoxy) benzyloxy] phenoxyacetic acid (shown in formula 16 below) was obtained.

The spectroscopic data of this support the structure of Formula 15 below.

NMR (CDCl ₃ ) δ: 1.31 (3
H, t, J = 7 Hz), 2.70 (2H, m), 3.2
0 (2H, m), 4.28 (2H, q, J = 7Hz),
4.53 (2H, s), 4.90 (2H, s), 5.4
0 (2H, s), 5.45 (1H, brs), 6.20
-8.23 (17H, m).

[0091]

[Chemical 15]

[0092]

[Chemical 16]

Example 6 (1) Thiophosgene (0.26 ml) at room temperature was treated with 3- (2).
-Quinoline methoxy) aminophenol 860 mg solution in methylene chloride 5 ml and anhydrous sodium carbonate 728 m
5 ml of an aqueous solution of g was added dropwise at the same time, and the mixture was stirred for 1 hour. Water was added to the reaction mixture, extracted with chloroform, and dried over anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography, and the fraction eluted with hexane-ethyl acetate (2: 1 v / v) was 3- (2-
Quinoline methoxy) phenyl isothiocyanate 89
0 mg was obtained (white crystals, yield 94%).

(2) 4- [2- (4
-Chlorobenzenesulfonamide) ethyl] -2-aminophenoxyacetic acid t-butyl ester was added to a solution of 570 mg of chloroform in 3 ml of chloroform at room temperature, and 356 mg of 3- (2-quinnolinemethoxy) phenylisothiocyanate was added thereto and stirred for 12 hours. Ice water was added to the reaction mixture and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.

The residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography, and 4- [2- (4-chlorobenzenesulfonamido) ethyl] was collected from the hexane-ethyl acetate (2: 1 v / v) elution fraction. -2- {3- [3
-(2-quinolinemethoxy) phenyl] thioureido}
740 mg of phenoxyacetic acid t-butyl ester was obtained (pale yellow oily substance, yield 80%).

Following the same procedure as in (Example 1), 4
600 mg of-[2- (4-chlorobenzenesulfonamido) ethyl] -2- {3- [3- (2-quinolinemethoxy) phenyl] thioureido} phenoxyacetic acid was obtained (pale yellow crystal, yield 78%).

Spectroscopic data for this supports the structure of general formula 16 below.

NMR (CDCL ₃ -CD ₃ OD) δ:
2.35-2.70 (2H, m), 2.80-3.20
(2H, m), 4.39 (2H, brs), 5.20
(2H, brs), 6.10-9.25 (17H,
m).

[0099]

[Chemical 17]

(Test Example) The compound of the present invention showed an antagonistic action against TXA ₂ and LTD ₄ in the following in vitro system as shown in the following table.

The IC ₅₀ value of the in vitro antagonism of the compounds of the present invention against TXA ₂ and LTD ₄ was determined using the following experimental system.

Tracheal sections removed from Hartley male guinea pigs weighing 300 to 500 g were Tyrod at 37 ° C.
In a liquid e, a Magnus tank in which oxygen (95%)-carbon dioxide (5%) was mixed was aerated, and the Magnus tank was suspended by applying a load of 0.3 g. Stabilize for about 1 hour and then place TXA _{2 in the} Magnus bath.
(Manufactured by Cayman) or LTD
₄ (manufactured by Cayman) respectively 10 ^-7
M, added at a concentration of 10 ^-8 M. The contraction reaction at the time of adding the compound of the present invention to the contraction reaction at this time was measured, and IC ₅₀
The value was calculated. The results are shown in Table 1 below.

[0103]

[Table 1]

As the results are shown in Table 1, the compounds of the present invention showed excellent antagonistic activity against TXA ₂ and LTD ₄ . Although not shown in Table 1, other compounds according to the present invention also showed excellent antagonistic activity against TXA ₂ and LTD ₄ .

[0105]

[Acute toxicity] An acute toxicity test by oral administration was performed using ICR male mice (5 weeks old). L of the compound of the present invention
The D ₅₀ value was 300 mg / kg or more, confirming higher safety than the effective dose.

[0106]

According to the present invention, a novel phenoxyacetic acid derivative is provided.

The above compounds of the present invention are thromboxane A
_Since it is a ₂ antagonist and a leukotriene antagonist, it can be used as an effective preventive agent against allergic diseases such as thrombosis and asthma, which are diseases involving thromboxane A ₂ and leukotriene.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Reference number in the agency FI Technical indication location A61K 31/47 AED (72) Inventor Kenichi Abe 1500 Inokachi, Nakai-cho, Ashigarakami-gun, Kanagawa Terumo Corporation ( 72) Inventor Shinji Ozawa 1500 Inoguchi, Nakai-cho, Ashigaragami-gun, Kanagawa Terumo Corporation

Claims (1)

[Claims] Claims: It is represented by the above general formula 1 (where X is hydrogen, halogen atom, lower alkyl, trifluoromethyl, alkoxy,
Represents a hydroxy or cyano group, R ₁ represents a carboxyl group, an alkoxycarbonyl group (wherein the alkoxy group has 1 to 4 carbon atoms and is a straight chain or branched chain) or a tetrazole group, A Represents oxygen or the following formula 2 or 3, and m and n represent an integer of 0 or 1, or a phenoxyacetic acid derivative or a physiologically acceptable salt thereof. [Chemical 2] [Chemical 3]