JP2559814B2 - Catechol derivative and pharmaceutical preparation containing the same - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel catechol derivative, a 5-lipoxygenase action inhibitor and an antiulcer agent containing the same.

[Problems to be Solved by Conventional Techniques and Inventions]

Leukotriene C ₄ (LT
Leukotrienes such as C ₄ ) and leukotriene D ₄ (LTD ₄ ) are biosynthesized in vivo from arachidonic acid by the action of 5-lipoxygenase.

Recently, leukotrienes have caused not only allergies but also nephritis,
It has been clarified that it is involved in the development of pathological conditions such as hepatitis, rheumatism, and gastric ulcer.

Therefore, it has been a subject to suppress the biosynthesis of leukotrienes and to find a substance effective for treating these diseases. Further, finding a substance having an anti-ulcer activity that suppresses gastric ulcer and the like has also been an issue.

The present inventors have synthesized various catechol derivatives, and as a result of diligent examination of their 5-lipoxygenase action-inhibiting activity and anti-ulcer activity. As a result, the catechol derivative of the present invention has a strong 5-lipoxygenase action-inhibiting activity and anti-ulcer. They found that they have activity and completed the present invention. The catechol derivative of the present invention having an activity of inhibiting the action of 5-lipoxygenase suppresses the biosynthesis of leukotrienes and is useful for the treatment of allergic diseases such as asthma and rhinitis, nephritis, hepatitis, rheumatism and gastric ulcer.

The catechol derivative of the present invention having anti-ulcer activity is also useful for treating ulcer such as gastric ulcer.

Therefore, an object of the present invention is to provide a novel catechol derivative, a 5-lipoxygenase action inhibitor containing the same, and an antiulcer agent.

[Means for solving the problem]

The present invention in accordance with the above object is represented by the general formula (In the formula, X represents a group selected from —CH ₂ —CH ₂ — or —CH═CH—, and n is an integer of 4 to 8.).

The present invention also provides a 5-lipoxygenase action inhibitor and an anti-ulcer agent containing the catechol derivative represented by the above formula (I).

In the present invention, the 5-lipoxygenase action inhibitor means a preparation having an action of suppressing the action of 5-lipoxygenase. Further, in the present invention, the anti-ulcer agent means a preparation having an action of suppressing ulcer such as gastric ulcer.

The method for producing the catechol derivative represented by the above formula (I) of the present invention is shown below. First, a benzylideneacetone derivative represented by the following formula (II) (In the formula, (R) ¹ represents a 3,4-dimethoxymethyloxy group or a 3,4-dihydroxy group) and the corresponding alkanoic acid imidazole amide are subjected to Claisen reaction to obtain an adduct. Further, the compound according to the present invention can be obtained by subjecting this adduct to a deprotecting group reaction.
Further, the compound thus obtained is further subjected to catalytic reduction to obtain another compound according to the present invention.

The catechol derivative of the present invention can be used as a 5-lipoxygenase action inhibitor and an anti-ulcer agent, and although the dose varies depending on the symptoms, it is generally 10 to 500 mg per day for adults.
The preferred dose is 20 to 100 mg, and it may be administered in 1 to 3 divided doses depending on the symptoms. 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 include calcium carbonate, calcium phosphate, starch, glucose, lactose,
Examples include dextrin, alginic acid, mannitol, talc and magnesium stearate.

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 1.17 g of diisopropylamine was dissolved in 30 ml of dry tetrahydrofuran under an argon atmosphere, and after cooling to -15 ° C,
7.50 ml of a 1.6M n-butyllithium hexane solution is added dropwise. 4- (3,4) dissolved in 10 ml of dry tetrahydrofuran
-Dimethoxymethyloxyphenyl) -3-butene-2
After adding 2.67 g of -ON at -15 ° C, stir at the same temperature for 20 minutes. After cooling to −78 ° C., 1.95 g of caprylic acid imidazole amide dissolved in 50 ml of dry tetrahydrofuran was added dropwise,
The mixture is stirred at the same temperature for 3 hours and at room temperature for 12 hours. Saturated saline is added to the reaction solution to separate the organic layer, and the aqueous layer is extracted with ethyl acetate. The organic layer is washed with 2N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and from the fraction eluted with methylene chloride-hexane (3: 1 V / V), 1- (3,4-dimethoxymethyloxyphenyl) -1-dodecene-3,5-dione 2.0
Get 7g.

1.15 g of this Claisen reaction adduct was dissolved in 20 ml of methanol-tetrahydrofuran (1: 1V / V), and 6N hydrochloric acid was added to 2.
Add 0 ml and stir at 60 ° C. for 20 minutes. The solvent was distilled off under reduced pressure, and the precipitated crystals were collected by filtration and washed with water to give 1- (3,4
0.81 g of -dihydroxyphenyl) -1-dodecene-3,5-dione (III) is obtained. Its spectroscopic data supports the structure of formula (III) below. ¹ HNMR (CDCl ₃ ) δ; 0.85 (3H, t, J = 4.5Hz) 1.0 to 1.8 (10H, m) 2.34 (2H, t, J = 6.5Hz) 5.58 (1H, s) 6.23 (1H, d, J = 15.5Hz) 6.5 to 7.3 (3H, m) 7.44 (1H, d, J = 15.5Hz) Example 2 300 mg of 1- (3,4-dihydroxyphenyl) -1-dodecene-3,5-dione was dissolved in 6 mg of methanol, 0.10 g of 5% palladium carbon was added, and the mixture was reacted for 20 hours under a hydrogen gas atmosphere. Then the reaction mixture is filtered and the solvent is evaporated under reduced pressure. The residue is subjected to silica gel column chromatography, and 1- (3,4-dihydroxyphenyl) -3,5-dodecanedione (IV) (157 mg) is obtained from the methylene chloride elution fraction. The spectroscopic data of this support the structure of formula (IV): ¹ HNMR (CDCl ₃ ) δ; 0.86 (3H, t, J = 4.5Hz) 1.03 to 1.95 (10H, m) 2.77 to 2.92 (6H, m) 5.43 (1H, s) 6.47 to 6.97 (3H, m) Example 3 1- (3,4-dihydroxyphenyl) was reacted using caproic acid imidazole amide in the same manner as in Example 1.
-1-decene-3,5-dione (V) is obtained (2 step yield;
38%). Its spectroscopic data supports the structure of formula (V): ¹ HNMR (CDCl ₃ -Methanol d ₄ ; 9: 1) δ; 0.89 (3H, t, J = 4.5Hz) 1.05 to 1.83 (6H, m)) 2.39 (2H, t, J = 6.5Hz) 6.23 (1H , d, J = 16Hz) 6.50 to 7.15 (3H, m) 7.42 (1H, d, J = 16Hz) Example 4 1- (3,4-dihydroxyphenyl) -1-decene-
Reaction was carried out in the same manner as in Example 2 using 3,5-dione, and 1
-(3,4-Dihydroxyphenyl) -3,5-decanedione (VI) is obtained (yield: 54%). Its spectroscopic data supports the structure of formula (VI) below. ¹ HNMR (CDCl ₃ ) δ: 0.87 (3H, t, J = 4.5Hz) 1.0 to 1.93 (6H, m) 2.0 to 3.0 (6H, m) 5.38 (1H, s) 6.23-6.79 (3H, m) Example 5 Reaction was carried out in the same manner as in Example 1 using n-butyric acid imidazole amide to give 1 (-3,4-dihydroxyphenyl).
-1-Octene-3,5-dione (VII) is obtained (2 step yield: 43%). The spectroscopic data of this product is given by the following formula (VI
Support the structure of I). ¹ HNMR (DMSOd ₆ ) δ: 0.91 (3H, t, J = 7Hz) 1.59 (2H, sex, J = 7Hz) 2.34 (2H, t, J = 7Hz) 5.81 (1H, s) 6.40 (1H, d, J = 15.5Hz) 6.60-7.14 (3H, m) 7.39 (1H, d, J = 15.5Hz) Example 6 Using 1- (3,4-dihydroxyphenyl) -1-octene-3,5-dione, a reaction was carried out in the same manner as in Example 2,
1- (3,4-dihydroxyphenyl) -3,5-octadione (VIII) is obtained (yield: 62%). Its spectroscopic data supports the structure of formula (VIII): ¹ HNMR (CDCl ₃ ) δ: 0.92 (3H, t, J = 6Hz) 1.14−3.0 (8H, m) 5.46 (1H, s) 6.34−6.90 (3H, m) [Test Example] (1) 5-lipoxygenase action-inhibitory activity Rat-derived basophilic leukemia cell line RBL-1 was used as a basic medium of Eagle [Gibco Laboratories (GibcoLa
boratories)) in a culture solution containing 10% FCS,
After culturing at 37 ° C in a 5% CO ₂ incubator, the culture solution is centrifuged at 4 ° C to collect cells. The cells were adjusted to pH 7.
Resuspend in 4 phosphate buffer and cell density 1.0-3.0 × 10 ⁷ cells / m
Let l. The suspended cells are treated with an ultrasonic cell disruptor and then centrifuged for 30 minutes at 15,000 rpm at 4 ° C., and the supernatant is used as a 5-lipoxygenase enzyme solution. Arachidonic acid (50 μg) and the catechol derivative according to the present invention to be tested were placed in respective test tubes, and a phosphate buffer solution (0.10 ml) and the above enzyme solution (0.40 m) were added to the test tubes.
l, add 5μ of 100mM CaCl ₂ (calcium chloride) solution,
Incubate at 37 ℃ for 15 minutes. After ice cooling 1N-HCl (hydrochloric acid) 1 drop
Is added and extracted with 2 ml of ethyl acetate. After the extract was concentrated to dryness, 100 μm of methanol was added to prepare a sample.

The sample was injected into octadecylsilane (ODS) -based reverse phase high performance liquid chromatography (HPLC) and eluted with a solvent of methanol: acetonitrile: acetic acid = 15: 45: 35: 0.01, which was detected in about 25 minutes. -The lipoxygenase product 5-HETE (5- (s) -hydroxy-6,8,1
1,14-Eicosatetraenoic acid) peak height is measured. The action-inhibiting activity of 5-lipoxygenase is confirmed by the decrease in the peak height of the 5-lipoxygenase product. As a result of the test, a prominent 5-lipoxygenase action inhibitory activity was found as shown in Table I below. Also, Table I
It was confirmed that the catechol derivative according to the present invention, which is not shown in the above, also has the similar 5-lipoxygenase action inhibitory activity.

The 50% inhibitory concentration in the table means that when the production amount of 5-HETE when the catechol derivative according to the present invention is not introduced is 100%, the production amount of the 5-lipoxygenase product is obtained by the introduction of the catechol derivative. It means the concentration of catechol derivative required to suppress to 50%.

(2) Anti-ulcer action After wistar male rats (body weight: 150 to 200 g) were fasted for 24 hours, the catechol derivative according to the present invention was orally administered, and 1 hour later, ethanol-hydrochloric acid (60% ethanol containing 150 mM hydrochloric acid) was added. It was orally administered in a volume of 0.5 ml / 100 g body weight.

One hour later, lethal with ether, and the stomach was removed and treated with formalin, and the length of damage (mm) generated in the glandular stomach was measured.
The total damage per animal was taken as the Ulcer Index.

Results of the test As shown in Table II, a prominent antiulcer effect was found. It was also confirmed that the catechol derivatives according to the present invention, which are not shown in Table II, also have similar antiulcer action.

The ulceration inhibition rate (%) in the table is the value obtained by dividing the value obtained by dividing the ulcer index of the rat to which the catechol derivative according to the present invention was orally administered by the ulcer index of the rat not to be orally administered, from 1 and multiplying by 100. Is.

[Acute toxicity]

An acute toxicity test by oral administration was performed using ICR male mice (5 weeks old). The LD ₅₀ value of each of the compounds of the present invention was 2000 mg / kg or more, confirming higher safety than the effective dose.

〔The invention's effect〕

According to the present invention, a novel catechol derivative, a 5-lipoxygenase action inhibitor and an antiulcer agent containing the same are provided.

The above compounds of the present invention have potent 5-lipoxygenase action inhibitory activity and anti-ulcer activity. That is, the above-mentioned compound inhibits the action of 5-lipoxygenase to produce LT produced by the action of 5-lipoxygenase.
Suppresses the production of leukotrienes such as C ₄ and LTD ₄ .
Therefore, the catechol derivative according to the present invention can be effectively used as a 5-lipoxygenase action inhibitor against asthma and rhinitis, which are allergic diseases, as well as against gastritis, hepatitis, rheumatism, gastric ulcer and the like.

Further, since the compound of the present invention has an effect of suppressing ulcer, it can be effectively used as a therapeutic agent for gastric ulcer and the like.

Continuation of the front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical display location A61K 31/12 ACL A61K 31/12 ACL ACS ACS AED AED C07C 49/248 C07C 49/248 C12N 9/99 C12N 9 / 99 (72) Hideto Ushijima 2-44-1, Hatagaya, Shibuya-ku, Tokyo Zenmo Wakimura Examiner, Terumo Corporation

Claims (3)

(57) [Claims] 1. A general formula (In the formula, X represents a group selected from —CH ₂ —CH ₂ — or —CH═CH—, and n is an integer from 4 to 8.). 2. A 5-lipoxygenase action inhibitor containing the catechol derivative according to claim 1. 3. An anti-ulcer agent containing the catechol derivative according to claim 1.