JP3086728B2 - Agent for treating or preventing peptic ulcer - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a 3-phenylthiomethylstyrene derivative and a salt of a salt capable of forming a salt thereof, particularly, an α-cyano-4-hydroxycinnamic acid amide derivative and a salt of a salt capable of forming a salt thereof. The present invention relates to a therapeutic or preventive agent for peptic ulcer, comprising α-cyano-3-ethoxy-4-hydroxy-5-phenylthiomethylcinnamic acid amide (hereinafter also referred to as ST638) as an active ingredient.

[0002]

2. Description of the Related Art Conventionally, as a therapeutic or preventive agent for peptic ulcer represented by gastric ulcer and duodenal ulcer,

[0003]

[Outside 1]

[0004] Many aggressive factor secretion inhibitors such as muscarinic receptor antagonists and protective factor enhancers such as synthetic amino acids and isoprenoids are known (Yokoyama Kaji,
"Pharmaceutical Assembly, Second Edition, Global Pharmaceutical Data Bank"
(Hirokawa Shoten)).

[0005] However, each drug has an intractable ulcer, and there is a need for a drug having a higher therapeutic effect. There is also a need for a prophylactic agent that is effective in preventing recurrence after ulcer treatment.

[0006] By the way, various active oxygens produced by living organisms are known to sometimes cause severe tissue damage. In recent years, even in peptic ulcers, active oxygen generation is involved in the onset and exacerbation. Substances that scavenge active oxygen and substances that inhibit the production of active oxygen are becoming targets for the development of new peptic ulcer treatment or prophylactic agents (Kondo, Oyanagi, Yoshikawa, eds. Free Radical Clinical Practice, Vol. 1, 47, 51 and
119).

[0007]

Means for Solving the Problems The inventors of the present invention have repeatedly studied active oxygen and the mechanism of peptic ulcer development. Known α-cyano-3-
Ethoxy-4-hydroxy-5-phenylthiomethylcinnamic acid amide (ST638) and its derivatives have been found to be effective in treating or preventing gastric and duodenal ulcer models. Based on these results, further studies have been made and the present invention has been completed.

That is, the present invention provides a compound represented by the general formula (I):

[0009]

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Wherein x represents halogen or hydrogen;
R ¹ represents hydrogen or an alkyl group having 1 to 4 carbon atoms;
² COOR ⁴ (R ⁴ represents a hydrogen or an alkyl group having 1 to 2 carbon atoms) group or an amide represented by, R ³
Represents a cyano group or an alkylsulfonyl group represented by R ⁵ SO ₂ (R ⁵ represents an alkyl group having 1 to 2 carbon atoms). R ² and R ³ may be bonded to each other.

[0011]

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Or

[0013]

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Represents the following. Further, n represents an integer of 1 to 5 when x is halogen, and represents 1 when x is hydrogen. A salt of a 3-phenylthiomethylstyrene derivative represented by the general formula (II):

[0015]

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Wherein x and n are as defined above, and R ¹
Represents hydrogen or an alkyl group having 1 to 2 carbon atoms. At least one of the α-cyano-4-hydroxycinnamic acid amide derivative represented by the formula [I] and salts thereof, or α-cyano-3-ethoxy-4-hydroxy-5-phenylthiomethylcinnamic acid amide (ST638) The present invention relates to a therapeutic or preventive agent for peptic ulcer and gastric ulcer and / or duodenal ulcer, which contains one as an active ingredient.

[0017]

The derivatives of the present invention represented by the above general formula (I),
The derivative represented by the general formula (II) and α-cyano-3-ethoxy-4-hydroxy-5-phenylthiomethylcinnamic acid amide (ST638) are described in JP-A-62-111962,
JP-A-62-29570, JP-A-62-39564 and Chemical Pharmaceutical Bulletin (Che
m. Pharm. Bull.) (Vol. 36, pp. 974-981, 1988)
Are manufactured by the manufacturing methods disclosed in the above.

The active ingredient of the therapeutic or prophylactic agent for peptic ulcer of the present invention can be administered in any dose as long as it does not show toxicity for patients (animals and humans) in need of treatment. , In the dosage range of 10-1000 mg / kg. Therefore, 20 ~
It can be administered at a daily dose of 4000 mg / kg. However,
This dose can vary depending on the severity of the illness, the weight of the patient and other factors recognized by those skilled in the art.

The therapeutic or prophylactic agent for peptic ulcer of the present invention is prepared as a solid preparation or a liquid preparation and administered orally or parenterally. Examples of solid preparations for oral administration include powders, granules, tablets, pills, capsules and the like. Examples of liquid preparations for parenteral and oral administration include elixirs, suspensions, emulsions, syrups, Alcohol solution,
Oily solutions and the like can be mentioned.

As the solid pharmaceutical carrier, lactose, starch, sucrose, mannite, sorbitol, dextrin, cellulose, calcium carbonate and the like can be used, and if necessary, auxiliary agents such as a suitable lubricant and a binder can be used. Normally used amounts can be added. In addition, as the liquid carrier for medicine, common solvents such as water, ethanol, glycerin, propylene glycol, vegetable oil and oily ester can be used, and if necessary, suitable wetting agents, suspending agents, emulsifiers, sweeteners, flavors and the like. Auxiliaries such as preservatives can be added in the usual amounts.

The therapeutic or prophylactic agent for peptic ulcer of the present invention comprises:
Platelet activating factor (PAF) -induced gastric mucosal injury model (Natur
e), No. 319, pp. 54-56, 1986 and Journal of the Japanese Society of Gastroenterology, No. 86, pp. 858-864, 1989)
It has been found to have a strong inhibitory effect on ulcer formation, and is considered to be extremely useful as a therapeutic or preventive agent for peptic ulcer.

The therapeutic or prophylactic agent for peptic ulcer of the present invention can be used as an existing peptic ulcer therapeutic agent (eg

[0023]

[Outside 2]

These agents can be used in combination with an inhibitory agent such as an aggressive factor or an enhancer of a protective factor such as synthetic amino acids.

Next, the present invention will be described more specifically with reference to the following examples, but the present invention is not limited to only the following examples.

Example 1 (α-cyano-3-ethoxy-4-hydroxy-5-phenylthiomethylcinnamic acid amide (ST638
(2) Inhibition of platelet activating factor (PAF) -induced gastric mucosal injury by a)) Wistar (7- to 8-week-old) Wistar rats (body weight: about 200 g, 7 rats per group) fasted for 24 hours with 0.2% Tween ( Tween) 30 mg / k of α-cyano-3-ethoxy-4-hydroxy-5-phenylthiomethylcinnamic acid amide (ST638) suspended in a 2.5% aqueous gum arabic solution containing 80, respectively.
g, 100 mg / kg and 200 mg / kg were orally administered. Two hours later, 0.25%
Platelet activating factor (PAF) dissolved in albumin-containing physiological saline was intravenously administered at 3 μg / kg at the time of administration. One hour after the administration of PAF, the rats were sacrificed and exsanguinated, the stomach was removed, and the degree of damage to the gastric mucosa was visually evaluated and indexed by the following scoring method. As a control group, a group not receiving ST638 and a group receiving neither ST638 nor PAF were examined. As a result, ST638
It clearly suppressed gastric mucosal injury caused by F.
Table 1 shows the results.

[Score] 0: normal 1: mild hyperemia 2: moderate hyperemia and slight erosion 3: severe hyperemia and many erosions

[0028]

[Table 1]

Acute toxicity test ICR female mice (body weight 23-26 g, 6 mice per group) were treated with 0.
The compound of the present invention suspended in a 2.5% aqueous solution of gum arabic containing 2% Tween 80 was orally administered at a rate of 0.1 ml / 10 g. The general symptoms were observed for 2 weeks after administration, and the number of deaths / tests was determined, and the 50% lethal dose LD ₅₀ (mg / kg) was estimated. As a result, no deaths were observed with the compound of the present invention even after administration of 1000 mg / kg, and it was estimated that the LD ₅₀ was 1000 mg / kg or more, indicating low toxicity.
-111962).

[0030]

EFFECTS OF THE INVENTION The 3-phenylthiomethylstyrene derivative of the present invention and its salt capable of forming a salt, especially the α-cyano-4-hydroxycinnamic acid amide derivative and its salt capable of forming a salt, and furthermore, the salt of α-cyano -3-ethoxy-4-hydroxy-5-phenylthiomethylcinnamic acid amide (ST638
The therapeutic or prophylactic agent for peptic ulcer containing ()) as an active ingredient is very effective for the treatment or prevention of peptic ulcer which is intractable to conventional therapeutic agents at a dose that does not show toxic effects.

Continued on the front page (51) Int.Cl. ⁷ identification code FI A61K 31/415 A61K 31/415 A61P 1/04 A61P 1/04 (58) Investigated field (Int.Cl. ⁷ , DB name) A61K 31 / 275 A61K 31/165 A61K 31/192 A61K 31/215 A61K 31/40 A61K 31/415 A61P 1/04 CA (STN) EMBASE (STN) MEDLINE (STN)

Claims (6)

(57) [Claims] [Claim 1] General formula (I): [In the formula, x represents halogen or hydrogen, R ¹ represents hydrogen or an alkyl group having 1 to 4 carbon atoms, and R ² represents COOR
⁴ (R ⁴ represents hydrogen or an alkyl group having 1 to 2 carbon atoms) or an amide; R ³ represents a cyano group or R ⁵ SO ₂ (R ⁵ represents an alkyl group having 1 to 2 carbon atoms) Represents an alkylsulfonyl group). R ² and R ³ may be bonded to each other. Or Represents Further, n represents an integer of 1 to 5 when x is halogen, and represents 1 when x is hydrogen. Or a salt of a salt capable of forming a salt thereof as an active ingredient, for treating or preventing peptic ulcer. 2. A therapeutic or preventive agent for gastric ulcer and / or duodenal ulcer, comprising as an active ingredient a 3-phenylthiomethylstyrene derivative represented by the general formula (I) and a salt of a salt capable of forming a salt thereof. 3. A compound of the general formula (II): [In the formula, x and n are the same as described above, and R ¹ represents hydrogen or an alkyl group having 1 to 2 carbon atoms. The therapeutic or preventive agent for peptic ulcer according to claim 1, which comprises, as an active ingredient, an α-cyano-4-hydroxycinnamic acid amide derivative represented by the following formula: 4. The treatment for gastric ulcer and / or duodenal ulcer according to claim 2, comprising an α-cyano-4-hydroxycinnamic acid amide derivative represented by the general formula (II) and a salt of a salt capable of forming a salt thereof as an active ingredient. Or prophylactic agents. 5. The method according to claim 1, wherein the active ingredient is α-cyano-3-ethoxy-4.
The therapeutic or preventive agent for peptic ulcer according to claim 1, which is -hydroxy-5-phenylthiomethylcinnamic acid amide. 6. The method according to claim 1, wherein the active ingredient is α-cyano-3-ethoxy-4.
The agent for treating or preventing gastric ulcer and / or duodenal ulcer according to claim 2, which is -hydroxy-5-phenylthiomethylcinnamic acid amide.