JPH07103089B2 - Phenoxyacetic acid derivative and pharmaceutical preparation containing the same - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel phenoxyacetic acid derivative and a pharmaceutical preparation containing the same.

[Conventional technology]

Thromboxane A ₂ and leukotrienes, allergic inflammation and deep Sekiri such severe ischemic diseases and bronchial asthma, such as cerebral infarction and myocardial infarction has been suggested, thromboxane A ₂ antagonists to date several spider Agents and leukotriene antagonists,
Synthetic enzyme inhibitors are being developed one after another. However, the involvement of multiple chemical mediators has been clarified in actual pathological conditions, and a sufficient existing therapeutic effect cannot be expected with a single existing enzyme inhibitor or receptor antagonist. Based on the above, the present inventors examined the development of a drug having a leukotriene antagonism in addition to a thromboxane A ₂ antagonism. Until now, no one is known to antagonize both receptors of thromboxane A ₂ and leukotrienes at the same time, so this compound is a new type of pharmaceutical preparation.

[Problems to be Solved by the Invention]

The present inventors have synthesized various phenoxyacetic acid derivatives, and as a result of diligent research on their physiological actions, as a result, found that the phenoxyacetic acid derivative according to the present invention has a thromboxane A ₂ antagonistic action and a leukotriene antagonistic action. It was found that the above-mentioned problems with a single synthase inhibitor or receptor antagonist can be solved. Therefore,
The present invention aims to provide a novel phenoxyacetic acid derivative. A further object of the present invention is to provide a pharmaceutical preparation containing a phenoxyacetic acid derivative, which antagonizes thromboxane A ₂ and leukotriene.

[Means for Solving the Problems]

The present invention in accordance with the above object is represented by the formula (I) Is a phenoxyacetic acid derivative.

Further, the present invention is a thromboxane A ₂ antagonist containing the phenoxyacetic acid derivative.

The present invention is also a leukotriene antagonist containing the phenoxyacetic acid derivative. In the present invention, the thromboxane A ₂ antagonist means a preparation that antagonizes thromboxane A _2, and the leukotriene antagonist means a preparation that antagonizes leukotriene.

The phenoxyacetic acid derivative represented by the above formula (I) of the present invention is represented by the following formula (II) Phenoxyacetic acid derivative and p- represented by the following formula (III)
It can be obtained by reacting with chlorobenzenesulfonyl chloride in the presence of a suitable base, followed by hydrolysis.

The phenoxyacetic acid derivative represented by the above formula (II) is 4
-Condensation reaction of acid chloride derivative obtained by treating 4- (4-phenylbutoxy) benzoic acid with thionyl chloride and 4-methoxymethoxy-3-aminophenethyl alcohol, deprotection, and carburization reaction of bromoacetic acid t-butyl ester Obtained by

The phenoxyacetic acid derivative of the present invention is used as a thromboxane A ₂ antagonist and a leukotriene antagonist, and although the dose varies depending on the medical condition, it is generally an adult daily dose of 10 to 2000 mg,
The dose is preferably 20 to 600 mg, and may be administered in 1 to 3 divided doses depending on the condition. The administration method can be 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, alone or mixed with a pharmaceutical carrier or excipient by a conventional method, and then tablets, dragees, powders, capsules, granules, suspensions, emulsions, injections. It can be applied in various forms formulated into liquids and the like. Examples of carriers or excipients include calcium carbonate, calcium phosphate, starch, glucose, lactose, dextrin, alginic acid, mannitol, talc, magnesium stearate and the like.

〔Example〕

Next, the present invention will be described more specifically by showing Examples and Test Examples, but the present invention is not limited to these.

(1) Under an argon stream, to a solution of 4-hydroxy-3-nitrophenylacetic acid (2.00 g) in methylene chloride (40 ml) -N, N-dimethylformamide (5 ml) was added N, N-diisopropylethylamine (8.80 ml) under ice cooling and the mixture was stirred for 10 minutes. Then, 3.84 ml of chloromethyl methyl ether was added, and the mixture was stirred at room temperature for 8 hours. After water was added to the reaction mixture and the mixture was extracted with methylene chloride, the organic layer was washed with diluted hydrochloric acid, saturated saline, saturated aqueous sodium hydrogen carbonate solution and saturated saline, respectively, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, and 2.41 g of methoxymethyl 4-methoxymethoxy-3-nitrophenylacetic acid methoxymethyl ester was obtained from the fraction eluted with hexane-ethyl acetate (4: 1 v / v). (Yield 84%).

(2) Under argon flow, sodium borohydride 235mg
Was suspended in 7 ml of methylene chloride-2 ml of methanol, and a solution of 1.31 g of 4-methoxymethoxy-3-nitrophenylacetic acid methoxymethyl ester in 3 ml of methylene chloride was added dropwise under ice cooling, and the mixture was stirred for 6 hours. After adding water to the reaction mixture and extracting with methylene chloride, the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, and 4-methoxymethoxy-3-nitrophenethyl alcohol was found to be 75% from the elution fraction of hexane-ethyl acetate (2: 1 v / v).
0 mg was obtained (72% yield).

(3) A catalytic amount of 10% palladium carbon was added to a solution of 4-methoxymethoxy-3-nitrophenethyl alcohol (500 mg) in methanol (3 ml), and the mixture was stirred at 1 atm in the presence of hydrogen gas. The reaction mixture was filtered, and the residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography to give 370 mg of 4-methoxymethoxy-3-aminophenethyl alcohol from the hexane-ethyl acetate (1: 1 v / v) elution fraction. (Yield 85%).

(4) 4- (4-phenylbutoxy) under an argon stream
To 5 ml of a chloroform solution of 508 mg of benzoic acid was added 0.20 ml of thionyl chloride under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the yellow oily substance obtained was dried under reduced pressure.
Next, under an argon stream, 0.26 ml of triethylamine was added to 3 ml of a chloroform solution of 370 mg of 4-methoxymethoxy-3-aminophenethyl alcohol under cooling with ice and stirred for 10 minutes, and then a 3 ml solution of the yellow oily substance obtained in the above reaction in chloroform was added. The mixture was added dropwise under ice cooling and stirred at room temperature for 12 hours. After adding water to the reaction mixture and extracting with chloroform, the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, and 4-methoxymethoxy-3- [4- (4-phenylbutoxy) benzoylamino] was obtained from the hexane-ethyl acetate (1: 1 v / v) eluate fraction. 74 phenethyl alcohol
0 mg was obtained (88% yield).

(5) Under a stream of argon, 4-methoxymethoxy-3-
[4- (4-phenylbutoxy) benzoylamino] phenethyl alcohol To a solution of 200 mg of methanol in 3 ml of methanol, 6N hydrochloric acid was added.
0.5 ml was added and the mixture was stirred at 50 ° C for 30 minutes. After adding water to the reaction mixture and extracting with methylene chloride, the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to give 4-hydroxy-3- [4- (4-phenylbutoxy) benzoylamino] phenethyl alcohol.
170 mg was obtained (95% yield).

(6) Under an argon stream, 51 mg of potassium carbonate was added to 6 m of acetone.
suspended in l-hydroxy-3- [4- (4-phenylbutoxy) benzoylamino] phenethyl alcohol 15
A solution of 0 mg dissolved in 2 ml of acetone and a solution of 72 mg of t-butyl bromoacetate dissolved in 2 ml of acetone were added at room temperature and stirred for 10 hours. After adding water to the reaction mixture and extracting 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-) was extracted from the fraction eluted with methylene chloride-methanol (40: 1 v / v).
160 mg of hydroxyethyl) -2- [4- (4-phenylbutoxy) benzoylamino] phenoxyacetic acid t-butyl ester was obtained (yield 83%).

(7) 4- (2-hydroxyethyl) under an argon stream
2- [4- (4-Phenylbutoxy) benzoylamino] phenoxyacetic acid t-butyl ester (160 mg) was added to a solution of methylene chloride in 3 ml of methylene chloride under ice cooling to add pyridine of 0.05 ml.
After stirring for 1 minute, a solution of 65 mg of p-chlorobenzenesulfonyl chloride in 3 ml of methylene chloride was added, and the mixture was stirred at room temperature for 15 hours. After adding water to the reaction mixture and extracting with ethyl acetate, the organic layer was washed with diluted hydrochloric acid and saturated saline, respectively, and dried over anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography, and 4- [2- (2-) was extracted from the fraction eluted with hexane-ethyl acetate (3: 1 v / v).
(4-Chlorobenzenesulfonyloxy) ethyl] -2
-[4- (4-phenylbutoxy) benzoylamino]
110 mg of phenoxyacetic acid t-butyl ester was obtained (yield 51%).

(8) 4- [2- (4-chlorobenzenesulfonyloxy) ethyl] -2- [4- (4-phenylbutoxy) benzoylamino] phenoxyacetic acid t- under an argon stream.
About 1 ml of trifluoroacetic acid was added to a 5 ml solution of methylene chloride in 5 ml of butyl ester under ice cooling, and the mixture was stirred until the raw material disappeared. The reaction solution was concentrated under reduced pressure to remove excess trifluoroacetic acid, and the residue was subjected to silica gel column chromatography. 4- [2- (4- (4- (2- (4- Chlorobenzenesulfonyloxy) ethyl] -2- [4- (4-phenylbutoxy)]
98 ml of benzoylamino] phenoxyacetic acid was obtained (yield 96%). The spectroscopic data of this product is the following formula (I)
Support the structure of.

NMR (CDCl ₃ ) δ: 1.66 to 2.06 (4H, m), 2.53 to 3.23 (4H, m), 3.85 to 4.43 (4H, m), 4.68 (1H, s), 6.76 to 7.06 (4H, m), 7.19 (5H, s), 7.
53 (4H, q, J = 8Hz), 7.93 (2H, d, J = 9Hz), 8.09 (1H, s).

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

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

A trachea section and an ileum section extracted from a Hartley male guinea pig weighing 450 to 550 g were loaded with 0.5 g of a Magnus tank in a Tyrode solution at 37 ° C in which oxygen (95%)-carbon dioxide (5%) was aerated. I hung it over. After stabilizing for about 1 hour, add U-46619 (TXA ₂ analogue) to the tracheal section bath for 10 hours.
^At a concentration of ^-7 M, LTD ₄ was added to the ileum section bath at a concentration of 10 ^-8 M. With respect to the contraction of the trachea and ileum at this time, the contraction of the trachea by U-46619 and the contraction of the ileum by LTD ₄ when the compound of the present invention was added at different concentrations were measured.
IC ₅₀ values were calculated.

[Acute toxicity] An acute toxicity test by oral administration was carried out using male ICR mice (5 years old). LD ₅₀ value of the compound of the present invention is 300 mg / kg
The above was confirmed and higher safety than the effective dose was confirmed.

〔The invention's effect〕

According to the present invention, a novel phenoxyacetic acid and a pharmaceutical preparation containing the same are provided.

The above compound of the present invention is a thromboxane A ₂ antagonist and also a leukotriene antagonist, and therefore an effective preventive agent against allergic diseases such as thrombosis and asthma, which are diseases involving thromboxane A ₂ and leukotrienes. Can be used as

Claims (3)

[Claims] 1. A formula (I) A phenoxyacetic acid derivative represented by. 2. A thromboxane A ₂ antagonist containing the phenoxyacetic acid derivative according to claim 1. 3. A leukotriene antagonist containing the phenoxyacetic acid derivative according to claim 1.