JPH04154766A - Phenoxyacetic acid derivative and medicinal preparation containing the same - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (X is H, halogen, lower alkyl, CF3, alkoxy, OH or CN; R1 is H, methyl or ethyl; (n) is 0-2) or salts thereof. EXAMPLE:4-[3-(4-Chlorobenzenesulfonyl)propyl]-2-[4-(2-quinolinemethoxy) benzoylamino] phenoxyacetic acid. USE:Having both thromboxane A2 antagonistic action and leukotriene antagonistic action and useful as a preventive agent for allergic diseases such as throbmosis or asthma. PREPARATION:A sulfonic acid derivative expressed by formula II is made to react with a quinoline derivative expressed by formula III in the presence of a suitable base. Deprotection and carbon increasing action with ethyl bromoacetate are carried out and the produced ester part is then hydrolyzed with an alkali to afford the objective compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a novel phenoxyacetic acid derivative and a pharmaceutical formulation containing the same.

[Conventional technology]

Thromboxane A2 and leukotrienes have been suggested to be closely related to serious ischemic diseases such as cerebral infarction and myocardial infarction, and allergic inflammation such as bronchial asthma. Although antagonistic enzyme inhibitors and leukotriene antagonist two-component enzyme inhibitors have been developed one after another, the involvement of multiple chemical mediators in actual pathological conditions has been revealed, and existing single enzyme inhibitors and Receptor antagonists and the like cannot be expected to have sufficient therapeutic effects.

Based on the above, the present inventors decided to use thromboxane A! We investigated the development of a drug that has leukotriene antagonistic effects in addition to antagonistic effects. Until now, thromboxane A! Since there is no known compound that simultaneously antagonizes both receptors for leukotrienes and leukotrienes, this compound could serve as a new type of pharmaceutical preparation.

[Problem to be solved by the invention]

As a result of synthesizing various phenoxyacetic acid derivatives and intensively studying their physiological effects, the present researchers discovered that the phenoxyacetic acid derivative according to the present invention has leukotriene antagonistic activity as well as thromboxane eight antagonistic activity. It was found that the above-mentioned problems of single synthetic enzyme inhibitors and receptor antagonists can be solved by this method. Therefore, it is an object of the present invention to provide novel phenoxyacetic acid derivatives. A further object of the present invention is to provide a pharmaceutical preparation containing a phenoxyacetic acid derivative, since the phenoxyacetic acid derivative competes with thromboxane A2 and leukotrienes.

[Means for Solving the Problems] The present invention in accordance with the above objects is based on the general formula (1) (wherein X represents hydrogen, a halogen atom, a lower alkyl, trifluoromethyl, alkoxyhydroxyl, or a cyano group, and R1 is hydrogen, methyl.

represents an ethyl group, n represents an integer from O to 2) or a physiologically acceptable salt thereof.

The present invention also provides a thromboxane A2 antagonist containing the phenoxyacetic acid derivative.

The present invention also provides a leukotriene antagonist containing the phenoxyacetic acid derivative. The present invention also provides an antiallergic agent containing the phenoxyacetic acid derivative. In the present invention, a thromboxane At antagonist means a preparation that is a thromboxane A2 antagonist and antagonizes thromboxane At, and a leukotriene antagonist means a preparation that antagonizes leukotrienes at the leukotriene receptor.

The phenoxyacetic acid derivative represented by the formula (1) of the present invention is a sulfone derivative represented by the following formula (II) (in the formula
and n have the same meaning as mentioned above) and the following formula (
It is obtained by reacting the quinoline derivative represented by III) in the presence of an appropriate base, deprotection, and carbonization reaction with ethyl bromoacetate, followed by alkaline hydrolysis of the generated ester moiety. The sulfone derivative represented by (If) above is a 4-methoxymethoxy-3-nitrocinnamic acid methyl ester obtained after the Wittenhorner reaction of 4-methoxymethoxy-3-nitrobenzaldehyde and trimethylphosphonoacetate. After reduction with diisobutylaluminum hydride, chlorination and condensation reaction with various thiophenols yielded 5-[(3-phenylthio)-1.
-propenyl 1-2-methoxymethoxynitrobenzene derivative, oxidized using m-chloroperbenzoic acid if necessary, and then subjected to catalytic reduction.

In addition, the quinoline derivative represented by (III) above is 2
- It is obtained by reacting chloromethylquinoline with hydroxybenzoic acid ester of each isomer in the presence of an appropriate base, followed by hydrolysis and chlorination of the resulting carboxylic acid. These reactions use methylene chloride, tetrahydrofuran, N,N-dimethylformamide, acetone, etc. as solvents, and the reaction temperature is 0°C.
It is desirable to carry out the process in the range of reflux temperature to reflux temperature.

[For production]

The phenoxyacetic acid derivative of the present invention is thromboxane A2
It is used as an antagonist and leukotriene antagonist, and the dosage varies depending on the symptoms, but in general, the daily dose for adults is 10 to 200.
The dosage is preferably 20 to 600 cm, and should be administered in 1 to 3 doses depending on the symptoms. The administration method can take any form suitable for administration, and oral administration is particularly preferred, but intravenous injection is also possible.

The compound of the present invention can be prepared as an active ingredient or one of the active ingredients alone or mixed with a pharmaceutical carrier or excipient in a conventional manner, and can be prepared as a tablet, $! It can be applied in various forms such as coated tablets, capsules, granules, suspensions, emulsions, injections, etc. Examples of carriers or excipients include calcium carbonate, calcium phosphate, starch, glucose, lactose, dextrin, alginic acid, mannitol, talc,
Examples include magnesium stearate.

〔Example〕

EXAMPLES Next, the present invention will be explained in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto.

[Example 1] (1) Under an argon atmosphere, 4.22 g of 2-(chloromethyl)quinoline hydrochloride, 12.84 g of cesium carbonate, and potassium iodide were added to a solution of 3.02 g of 4-hydroxybenzoic acid methyl ester in 80 m of acetone. Add 65■ to each,
The mixture was heated under reflux at 80°C for 11 hours. The reaction mixture was filtered using Celite, washed with acetone, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and hexane-ethyl acetate (4:IV/
V) 4.64 g of 4-(2-quinolinemethoxy)benzoic acid methyl ester was obtained from the elution fraction. (White crystals, yield 80%) (2) 4-(2-quinolinemethoxy) under argon stream
IN sodium hydroxide aqueous solution was added to a solution of 2.32 g of benzoic acid in tetrahydrofuran 12Id, and the mixture was heated under reflux at 90° C. for 14 hours. The reaction mixture was concentrated under reduced pressure, and IN hydrochloric acid was added to the resulting residue to adjust the pH to around 4. The precipitated crystals were filtered and dried under reduced pressure to obtain 1.86 g of 4-(2-quinolinemethoxy)benzoic acid. (White crystals, yield 78%) (3) Under an argon atmosphere, thionyl chloride 2I11 was added to 294 mg of 4-(2-quinolinemethoxy)benzoic acid under water cooling and stirred for 2 and a half hours. The reaction mixture was concentrated under reduced pressure, and the obtained 4-(2-quinolinemethoxy)benzoyl chloride (white crystals) was used in the next reaction without being purified.

Under an argon stream, 0.81 d of triethylamine was added to a solution of 4-(2-quinolinemethoxy)benzoyl chloride in chloroform 3 ynQ under ice cooling, and the mixture was stirred for 10 minutes.
-[3-(4-chlorobenzenesulfonyl)propyl]
-2ml of chloroform solution of 360cm of -2-methoxymethoxyaniline! was added and stirred at room temperature for 16 hours. Water was added to the reaction mixture, extracted with methylene chloride, and 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 hexane-ethyl acetate (1: IV/
V) 5-[3-(4-chlorobenzenesulfonyl)propyl 1-2-methoxymethoxy-N-[
290 μ of 4-(2-quinolinemethoxy)benzoylcoaminophenol were obtained. (White crystals, yield 36%) (4) Under argon atmosphere, 543-(4-chlorobenzenesulfonyl)propyl]-2-methoxymethoxy-N-
[To a solution of 290 μl of 4-(2-quinolinemethoxy)benzoylcoaminophenol in 5Id of 3d-tetrahydrofuran in methanol was added 111 μl of 6N hydrochloric acid, and the mixture was stirred at 50° C. for 2 hours. After diluting the reaction mixture with ethyl acetate, the precipitated crystals were dried under reduced pressure to give 200% of 4-(3-(4-chlorobenzenesulfonyl)propylco-2-[4-(2-quinolinemethoxy)benzoylaminocophenol).
+++g was obtained. (Yellow crystals, yield 74%) (5) Under an argon atmosphere, 4-(3-(4-chlorobenzenesulfonyl)propyl J-2-14-(2-quinolinemethoxy)benzoylamino 1-phenol 200 μg of acetone 15- 47 mg of potassium carbonate was added to the solution under water cooling, and the mixture was stirred for 10 minutes. A 5 m acetone solution of 62 μm of bromoacetic acid ethyl ester was added to the solution, and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture, extracted with ethyl acetate, and the organic layer was saturated. It was washed with brine and dried over anhydrous sodium sulfate.The residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography, and hexane-ethyl acetate (1: IV/V
) From the eluted fraction, 180 μl of 4-[3-(4-chlorobenzenesulfonyl)propyl]-2-14(-2-quinolinemethoxy)benzoylaminocophenoxyacetic acid ethyl ester was obtained. (White crystals, yield 79%) Spectroscopic data of this product support the structure of formula (IV) below.

NMR (CDC13) δ: 1.30 (3H, t, J.
7H2), 1.80-2.28 (2H, m), 2.
67 (2H, t, J・6H2), 2.94-3.21
(2H, m), 4.29 (2H, q, J・8H7),
4.70 (2H, S), 5.48 (28, S),
6.73-8.37 (17H, m).

9.10 (IH, 5) (6) Under an argon atmosphere, 4-[3-(4-chlorobenzenesulfonyl)propyl]-2-(4-(2-quinolinemethoxy)benzoylaminocophenoxyacetic acid ethyl ester 180 μm) To the tetrahydrofuran 2 d solution was added 1 ml of 2N aqueous sodium hydroxide solution under water cooling and stirred for 2 hours.The reaction mixture was concentrated under reduced pressure and IN hydrochloric acid was added to the resulting residue to adjust pl+ to around 4.Precipitation The resulting crystals were collected by filtration, dried under reduced pressure, and then subjected to silica gel column chromatography to obtain ethylene chloride-methanol (to:
IV/V) From the elution fraction, 4-r3-(4-chlorobenzenesulfonyl)propyl]-2-[4-(2-
130 mg of quinoline methoxy)hensylamino 1-phenoxyacetic acid was obtained. (White crystals, yield 75%) Spectroscopic data of this product support the structure of formula (V) below.

NMR (CDCi 3) δ: 1.47-4.66 (8
tl, m), 5.44 (2H, S), 6.70-8
．． 54 (18B, m), 11.95 (1) 1. S) [
Example 2 Under an argon atmosphere, 3-(2-quinolinemethoxy)ammonium, t
4-(3-(4-
chlorobenzenesulfonyl)propyl]-2-13-(
2-4 Norinemethoxy)benzoylaminocophenoxyacetic acid was obtained.

Spectroscopic data of this product support the structure of the following formula (V[).

NMR (CDCl3) δ: 1.85-2.22 (2
H, m).

2.60-2.85 (2H, Akebono), 3.20-3.2
8 (2H, +++).

4.68 (2H, S), 5.50 (2H, S), 6
．． 75-8.40 (17H, m) [Test Example] The compound of the present invention exhibited antagonistic effects against thromboxane A2 and leukotriene D4 in an in vitro system (described later) as shown in Table 1.

TC of antagonism of the compound of the present invention against thromboxane A2 and leukotriene D4 in vitro
s. The values were determined using the following experimental system.

Tracheal sections and ileum sections taken from male Hartley guinea pigs weighing 350-450 g were incubated at 37°C in Tyr.

The samples were suspended in a Magnus tank aerated with a mixed gas of oxygen (95%) and carbon dioxide (5%) in the liquid with a load of 0.3 g and 0.5 g, respectively. After stabilizing for about 1 hour, U-46619 (Lomboxane A, similar substances) (manufactured by Caiman) was added to the bath of the trachea section at a concentration of 10-'M, and the bath of the ileum section was filled with leukotriene D, ( (manufactured by Wako Tsumugi Pharmaceutical Co., Ltd.) 10
- ”M was added at a concentration of 1.3%.For contraction of the trachea and ileum at this time, U
-Tracheal constriction and leukotriene D4 by 46619
Measure the contraction of the ileum due to IC. The value was calculated.

Table 1 [Acute Toxicity] An acute toxicity test was conducted by oral administration using ICR male mice (5 weeks old). LD of the compound of the present invention. value is 3
00■/kg or more, which confirmed high safety compared to the effective dose.

[Effects of the Invention] According to the present invention, a novel phenoxyacetic acid and a pharmaceutical formulation containing the same are provided.

Since the above compound of the present invention is a thromboxane A2 antagonist and a leukotriene antagonist, it can be used as an effective prophylactic agent for thrombosis and allergic diseases such as asthma, which are diseases related to thromboxane A2 and leukotrienes. can do.

Claims (1)

[Claims] (1) Formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) (In the formula, X is hydrogen, halogen atom, lower alkyl, trifluoromethyl, alkoxy, hydroxyl, or cyano. R_1 represents a hydrogen, methyl, or ethyl group, and n represents an integer of 0 to 2) or a physiologically acceptable salt thereof. (2) A thromboxane A_2 inhibitor containing the phenoxyacetic acid derivative according to claim 1. (3) A leukotriene antagonist containing the phenoxyacetic acid derivative according to claim 1. (4) An anti-allergic agent containing the phenoxyacetic acid derivative according to claim 1.