JPH0832688B2 - 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, heretofore several shoes also thromboxane A ₂ antagonistic Agents, 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 receptor antagonists have been revealed. In such cases, a sufficient therapeutic effect cannot be expected. 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. To date, no one is known to antagonize both thromboxane A ₂ and leukotrienes receptors at the same time, so this compound could be a new type of pharmaceutical formulation.

[Problems to be Solved by the Invention]

The present researchers have synthesized various phenoxyacetic acid derivatives,
As a result of diligent research on their physiological actions, it was found that the phenoxyacetic acid derivative according to the present invention has a leukotriene antagonistic action together with a thromboxane A ₂ antagonistic action, and as a result, the above-mentioned single synthase inhibitor or receptor antagonist It was found that the problems of the agent can be solved. Therefore, the object of the present invention is 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 by antagonizing thromboxane A ₂ and leukotriene.

[Means for solving the problem]

The present invention in accordance with the above object is represented by the general formula (I) (Wherein X represents a hydrogen, halogen atom, lower alkyl, trifluoromethyl, alkoxyhydroxyl, or cyano group, R ₁ represents a hydrogen, methyl or ethyl group,
and n represents an integer of 0 to 2) or a phenoxyacetic acid derivative or a physiologically acceptable salt thereof.

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

Further, the present invention is a leukotriene antagonist containing the phenoxyacetic acid derivative. The present invention is also an antiallergic agent containing the phenoxyacetic acid derivative. In the present invention, the thromboxane A ₂ antagonist means a preparation that antagonizes thromboxane A ₂ at the thromboxane A ₂ receptor, and the leukotriene antagonist means a preparation that antagonizes leukotriene at the leukotriene receptor.

The phenoxyacetic acid derivative represented by the above formula (I) of the present invention is a sulfone derivative represented by the following formula (II) (wherein X is
And n have the same meaning as described above) and quinoline derivative represented by the following formula (III) Reaction in the presence of a suitable base, followed by deprotection and carburization reaction with ethyl bromoacetate, and then the ester formed Obtained by alkaline hydrolysis of a portion. The sulfone derivative represented by the above (II) is 4-methoxymethoxy-3-nitrocinnamic acid methyl ester obtained after the Witthorner reaction of 4-methoxymethoxy-3-nitrobenzaldehyde and trimethylphosphonoacetate. After reduction with diisobutylaluminum hydride, chlorination and condensation reaction with various thiophenols,
5-[(3-phenylthio) -1-propenyl] -2-
It can be obtained by converting it to a methoxymethoxynitrobenzene derivative, oxidizing it with m-chloroperbenzoic acid if necessary, and then performing catalytic reduction.

Further, the quinoline derivative represented by the above (III) is 2
-Chloromethylquinoline is reacted with the hydroxybenzoic acid ester of each isomer in the presence of a suitable base, followed by hydrolysis to obtain the resulting carboxylic acid by chlorination. These reactions are preferably carried out using methylene chloride, tetrahydrofuran, N, N-dimethylformamide, acetone or the like as a solvent at a reaction temperature of 0 ° C. to a reflux temperature.

[Action]

The phenoxyacetic acid derivative of the present invention is a thromboxane A ₂
It is used as an antagonist and a leukotriene antagonist, and the dose varies depending on the symptoms, but in general, the daily dose for adults is 10 to 2000 mg, preferably 20 to 600 mg.
It is recommended to administer in 3 divided doses. 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 an excipient by a conventional method to give tablets, dragees, powders, capsules, granules,
It can be applied in various forms formulated into suspensions, emulsions, injections and the like. Examples of carriers or excipients are calcium carbonate, calcium phosphate, starch, glucose, lactose,
Examples include dextrin, alginic acid, mannitol, talc and magnesium stearate.

〔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.

[Example 1] (1) Under an argon stream, 4.22 g of 2- (chloromethyl) quinoline hydrochloride, 12.84 g of cesium carbonate and 65 mg of potassium iodide were added to a solution of 3.02 g of 4-hydroxybenzoic acid methyl ester in 80 ml of acetone. The mixture was heated under reflux at 80 ° C for 11 hours. The reaction mixture was filtered through Celite, washed with acetone, the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography. From the hexane-ethyl acetate (4: 1 V / V) elution fraction 4.64 g of 4- (2-quinolinemethoxy) benzoic acid methyl ester was obtained.
(White crystals, yield 80%) (2) 4- (2-quinolinemethoxy) under argon flow
To a solution of 2.32 g of benzoic acid in 12 ml of tetrahydrofuran was added 1N aqueous sodium hydroxide solution, and the mixture was heated under reflux at 90 ° C. for 14 hours. The reaction mixture was concentrated under reduced pressure, and 1N 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 give 4- (2-quinolinemethoxy) benzoic acid.
1.86 g was obtained. (White crystals, yield 78%) (3) 4- (2-quinolinemethoxy) under argon flow
2 ml of thionyl chloride was added to 294 mg of benzoic acid under ice cooling, and the mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure and dried to obtain 4- (2-quinolinemethoxy) benzoyl chloride (white crystals), which was used in the next reaction without purification.

Under an argon stream, 0.81 ml of triethylamine was added to a 3 ml solution of 4- (2-quinolinemethoxy) benzoyl chloride in chloroform under ice cooling, and the mixture was stirred for 10 minutes, and then 5- [3-
2 ml of a chloroform solution of 360 mg of (4-chlorobenzenesulfonyl) propyl] -2-methoxymethoxyaniline was added, and the mixture was stirred at room temperature for 16 hours. 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 5- [3-] was extracted from the hexane-ethyl acetate (1: 1 V / V) elution fraction.
(4-Chlorobenzenesulfonyl) propyl] -2-methoxymethoxy-N- [4- (2-quinolinemethoxy)
290 mg of benzoyl] aminophenol were obtained. (White crystals, yield 36%) (4) Under an argon stream, 5- [3- (4-chlorobenzenesulfonyl) propyl] -2-methoxymethoxy-N.
-[4- (2-quinolinemethoxy) benzoyl] aminophenol 290 mg methanol 3 ml-tetrahydrofuran
To a 5 ml solution, 1 ml of 6N hydrochloric acid was added, and the mixture was stirred at 50 ° C for 2 hours.
The reaction mixture was diluted with ethyl acetate and the precipitated crystals were dried under reduced pressure to give 4- [3- (4-chlorobenzenesulfonyl).
200 mg of propyl] -2- [4- (2-quinolinemethoxy) benzoylamino] phenol was obtained. (Yellow crystal, yield 74%) (5) Under argon stream, 4- [3- (4-chlorobenzenesulfonyl) propyl] -2- [4- (2-quinolinemethoxy) benzoylamino] phenol 200 mg in acetone 15 ml solution Under ice cooling, 47 mg of potassium carbonate was added, and the mixture was stirred for 10 minutes.
The solution was added and stirred at room temperature for 12 hours. Water was added to the reaction mixture and extracted with ethyl acetate, the organic layer was washed with saturated saline,
It was dried over anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography,
Hexane-ethyl acetate (1: 1 V / V) elution fraction 4- [3
-(4-chlorobenzenesulfonyl) propyl] -2-
180 mg of [4 (2-quinolinemethoxy) benzoylamino] phenoxyacetic acid ethyl ester was obtained. (White crystals, 79% yield) Spectroscopic data for this support the structure of formula (IV) below.

NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7HZ), 1.80 to 2.28 (2
H, m), 2.67 (2H, t, J = 6HZ), 2.94 to 3.21 (2H, m), 4.29
(2H, q, J = 8HZ), 4.70 (2H, S), 5.48 (2H, S), 6.73 ~ 8.
37 (17H, m), 9.10 (1H, S) (6) Under an argon stream, a solution of 4- [3- (4-chlorobenzenesulfonyl) propyl] -2- [4- (2-quinolinemethoxy) benzoylamino] phenoxyacetic acid ethyl ester (180 mg) in tetrahydrofuran (2 ml) was cooled with ice,
1 ml of 2N sodium hydroxide aqueous solution was added and stirred for 2 hours.
The reaction mixture was concentrated under reduced pressure, and 1N hydrochloric acid was added to the resulting residue to adjust the pH to around 4. The precipitated crystals were collected by filtration, dried under reduced pressure, and subjected to silica gel column chromatography to obtain 4 from the fraction eluted with ethylene chloride-methanol (10: 1 V / V).
-[3- (4-chlorobenzenesulfonyl) propyl]
130 mg of 2- [4- (2-quinolinemethoxy) benzoylamino] phenoxyacetic acid was obtained. (White crystals, yield 75%) The spectroscopic data of this support the structure of formula (V):

NMR (CDCl ₃ ) δ: 1.47 to 4.66 (8H, m), 5.44 (2H, S),
6.70 ~ 8.54 (18H, m), 11.95 (1H, S) [Example 2] 3- (2-quinolinemethoxy) benzoic acid and 5- [3- (4-chlorobenzenesulfonyl) under an argon stream.
Using [propyl] -2-methoxymethoxyaniline and following the same procedure as in [Example 1], 4- [3- (4-chlorobenzenesulfonyl) propyl] -2- [3- (2
-Quinolinemethoxy) benzoylamino] phenoxyacetic acid was obtained.

Its spectroscopic data supports the structure of formula (VI) below.

NMR (CDCl ₃ ) δ: 1.85 to 2.22 (2H, m), 2.60 to 2.85 (2
H, m), 3.20 to 3.28 (2H, m), 4.68 (2H, S), 5.50 (2H,
S), 6.75 ~ 8.40 (17H, m) [Test Example] The compound of the present invention is thromboxane A ₂ and leukotriene.
An in vitro system (described later) showed an antagonistic action against D ₄ as shown in Table 1.

The in vitro IC ₅₀ of the antagonism of the compound of the present invention against thromboxane A ₂ and leukotriene D ₄ was determined using the following experimental system.

Trachea and ileum sections extracted from male Hartley guinea pigs weighing 350 to 450 g were placed in a Tyrode solution at 37 ° C in a Magnus tank with a mixed gas of oxygen (95%)-carbon dioxide (5%) aerated to 0.3 g and 0.5, respectively. Suspended with a load of g. After stabilizing for about 1 hour, U-46619 (thromboxane A ₂ analog) (manufactured by Cayman) was added to the tracheal section bath at a concentration of 10 ^-7 M, and leukotriene D ₄ (Wako Pure was used in the ileal section bath. Yakusha) was added 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 leukotriene D ₄ when the concentration of the compound of the present invention was changed and added, and the IC ₅₀ value was calculated from this. did.

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

〔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

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Shinji Ozawa 1500 Inoguchi, Nakai-cho, Ashigarakami-gun, Kanagawa Prefecture Terumo Corporation Examiner Norihiro Sano

Claims (4)

[Claims] 1. A formula (I) (Wherein X represents a hydrogen, halogen atom, lower alkyl, trifluoromethyl, alkoxy, hydroxyl or cyano group, 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 antagonist 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.