JPH0532546A - Peptic ulcer treatment or prevention agent - Google Patents

Abstract

(57) [Summary] (Modified) [Constitution] General formula (I): [Wherein, x is halogen or H, R ¹ is H or C
_{1 to 4} alkyl groups, R ² is a group represented by COOR ⁴ (R ⁴ is H or a C _1-2 alkyl group) or an amide,
R ³ represents a cyano group or an alkylsulfonyl group represented by R ⁵ SO ₂ (R ⁵ is a C _1-2 alkyl group).
R ² and R ³ are bonded to each other to form —CO—NH—CH.
₂ -CH ₂ - or -CO-NH-N (ph) -CO-
(Ph represents a phenyl group). n is 1 to 5 when x is halogen and 1 when x is H. ] A therapeutic or preventive agent for peptic ulcer and a therapeutic or preventive agent for gastric ulcer and / or duodenal ulcer, which comprises a 3-phenylthiomethylstyrene derivative and a salt thereof as an active ingredient. [Effect] In the treatment or prevention of peptic ulcer which is intractable to conventional therapeutic agents, 3 represented by the general formula (I)
A phenylthiostyrene derivative (especially R ¹ = C ₂ H ₅ ;
The therapeutic or prophylactic agent for peptic ulcer of the present invention containing R ² = CONH ₂ ; R ³ = CN) is very effective at a dose at which no toxic effect is observed.

Description

Detailed Description of the Invention

[0001]

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

[0002]

BACKGROUND OF THE INVENTION Conventionally, as a therapeutic or preventive agent for peptic ulcer represented by gastric ulcer and duodenal ulcer,

[0003]

[Outer 1]

A large number of attack factor secretion inhibitors such as muscarinic receptor antagonists and defense factor enhancers such as synthetic amino acids and isoprenoids are known (Yokoyama Fuji,
"Pharmaceutical Assembly, Second Edition, World Pharmaceutical Data Bank"
(Hirokawa Shoten)).

However, all of the drugs have ulcers that are intractable, and there is a need for a drug having a higher therapeutic effect. There is also a need for preventive agents that are effective in preventing recurrence after treating ulcers.

[0006] By the way, various active oxygens produced by the living body are known to sometimes cause serious tissue damage. In recent years, however, active oxygen production is involved in the onset and exacerbation of peptic ulcer. It is becoming clear that substances that eliminate active oxygen and substances that inhibit the production of active oxygen are becoming targets for the development of new therapeutic or preventive agents for peptic ulcer (edited by Kondo, edited by Oyanagi, Yoshikawa, “ Clinic of Free Radicals ", Volume 1, 47, 51 and
P. 119).

[0007]

[Means for Solving the Problems] The inventors of the present invention have repeatedly studied active oxygen and the pathogenic mechanism of peptic ulcer, and as a compound that inhibits the production of active oxygen by neutrophils during the research process. Known α-cyano-3-
It has been found that ethoxy-4-hydroxy-5-phenylthiomethylcinnamic acid amide (ST638) and its derivatives are effective for the treatment or prevention thereof in gastric and duodenal ulcer models. Based on these results, further studies were conducted to complete the present invention.

That is, the present invention has the general formula (I):

[0009]

[Chemical 5]

[Wherein x represents halogen or hydrogen,
R ¹ represents hydrogen or an alkyl group having 1 to 4 carbon atoms, R ^1
2 represents a group or amide represented by COOR ⁴ (R ⁴ represents hydrogen or an alkyl group having 1 to 2 carbon atoms), R ³
Represents an alkylsulfonyl group represented by a cyano group or 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]

[Chemical 6]

Or

[0013]

[Chemical 7]

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

[0015]

[Chemical 8]

[Wherein x and n are the same as described above, and R ¹
Represents hydrogen or an alkyl group having 1 to 2 carbon atoms. ] Of at least α-cyano-4-hydroxycinnamic acid amide derivative and a salt of a salt-forming compound thereof, or α-cyano-3-ethoxy-4-hydroxy-5-phenylthiomethylcinnamic acid amide (ST638) The present invention relates to a therapeutic or prophylactic agent for peptic ulcer and gastric ulcer and / or duodenal ulcer, which contains one kind as an active ingredient.

[0017]

EXAMPLE A derivative represented by the above general formula (I) of the present invention,
For the derivative represented by the general formula (II) and α-cyano-3-ethoxy-4-hydroxy-5-phenylthiomethylcinnamic acid amide (ST638), see JP-A-62-111962,
JP-A-62-29570, JP-A-62-39564 and Chemical Pharmaceutical Bulletin (Che
m. Pharm. Bull.) (Vol. 36, 974-981, 1988)
It is manufactured by the manufacturing method disclosed in each.

The above-mentioned active ingredient of the therapeutic or prophylactic agent for peptic ulcer of the present invention may be administered in any dose as long as it is not toxic to patients (animals and humans) in need of treatment, but it is desirable. , Generally used in several divided doses in the dose range of 10 to 1000 mg / kg. Therefore, 20 ~ per day
It can be administered at a total 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 of skill 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, etc.Examples of liquid preparations for parenteral and oral administration include elixirs, suspensions, emulsions, syrups, Alcohol solution,
An oily solution and the like can be mentioned.

As the pharmaceutical solid carrier, lactose, starch, sucrose, mannite, sorbit, dextrin, cellulose, calcium carbonate and the like can be used, and if necessary, suitable lubricants, binders and other auxiliary agents can be used. The amount usually used can be added. Further, as the liquid carrier for pharmaceuticals, water, ethanol, glycerin, propylene glycol, vegetable oil, a common solvent such as oily ester can be used, and if necessary, a suitable wetting agent, suspending agent, emulsifier, sweetener, flavoring agent. , Auxiliary agents such as preservatives can be added in the amounts usually used.

The therapeutic or prophylactic agent for peptic ulcer of the present invention is
Platelet activating factor (PAF) -induced gastric mucosal injury model (Natur (Natur)
e), No. 319, pp. 54-56, 1986 and the Journal of the Japanese Society of Gastroenterology, No. 86, 858-864, 1989).
It is known 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 is an existing therapeutic agent for peptic ulcer (for example,

[0023]

[Outside 2]

It is also possible to use it in combination with an attack factor inhibitor such as, or a defense factor enhancer such as synthetic amino acids).

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

Example 1 (α-cyano-3-ethoxy-4-hydroxy-5-phenylthiomethylcinnamic acid amide (ST638
Inhibitory effect of platelet activating factor (PAF) -induced gastric mucosal damage by)) 0.2% Tween (7 g / group, 7-8 weeks old) Wistar male rats (7-week-old), which were fasted for 24 hours. Tween) 30-containing α-cyano-3-ethoxy-4-hydroxy-5-phenylthiomethylcinnamic acid amide (ST638) suspended in a 2.5% aqueous solution of gum arabic at 30 mg / k
Oral administration was carried out at g, 100 mg / kg and 200 mg / kg. 2 hours later, 0.25% as a gastric mucosal injury inducing substance
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 excised, and the degree of damage to the gastric mucosa was visually judged and expressed as an index by the score method shown below. As a control group, ST638 was not administered and ST638 and PAF were not administered. As a result, ST638 is
It clearly suppressed the gastric mucosal injury caused by F.
The results are shown in Table 1.

[Score] 0: Normal 1: mild hyperemia 2: Moderate hyperemia and some erosion 3: Severe hyperemia and many erosions

[0028]

[Table 1]

Acute toxicity test ICR female mice (body weight: 23 to 26 g, 1 group: 6 mice) were treated with 0.
The compound of the present invention suspended in a 2.5% aqueous gum arabic solution 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 the administration, the number of dead cases / test cases was calculated, and the 50% lethal dose LD ₅₀ (mg / kg) was estimated. As a result, no death was observed with the compound of the present invention even after administration of 1000 mg / kg, the LD ₅₀ was estimated to be 1000 mg / kg or more, and it was found that the compound had low toxicity (JP-A-62-62).
-111962).

[0030]

INDUSTRIAL APPLICABILITY The 3-phenylthiomethylstyrene derivative of the present invention and its salt-forming salt, especially α-cyano-4-hydroxycinnamic acid amide derivative and its salt-forming salt, and further 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 treating or preventing peptic ulcer which is intractable to conventional therapeutic agents at a dose in which no toxic effect is observed.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical indication location A61K 31/415 7252-4C C07C 323/62 7419-4H 323/64 7419-4H C07D 207/36 7019 -4C 231/36 6701-4C

Claims (6)

[Claims] 1. A compound represented by the 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 is a cyano group or R ⁵ SO ₂ (R ⁵ is 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 [Chemical 3] Represents Further, n represents an integer of 1 to 5 when x is halogen, and 1 when x is hydrogen. ] A therapeutic or preventive agent for peptic ulcer containing as an active ingredient a salt of a 3-phenylthiomethylstyrene derivative represented by the formula and a salt-forming salt thereof. 2. A therapeutic or prophylactic agent for gastric ulcer and / or duodenal ulcer, which comprises, as an active ingredient, a 3-phenylthiomethylstyrene derivative represented by the general formula (I) and a salt of a salt-forming salt thereof. 3. A compound represented by the general formula (II): [In the formula, x and n are the same as defined above, and R ¹ represents hydrogen or an alkyl group having 1 to 2 carbon atoms. ] The therapeutic or prophylactic agent for peptic ulcer according to claim 1, which comprises the salt of an α-cyano-4-hydroxycinnamic acid amide derivative represented by the following formula and a salt-forming salt thereof as an active ingredient. 4. The treatment of gastric ulcer and / or duodenal ulcer according to claim 2, which comprises, as an active ingredient, an α-cyano-4-hydroxycinnamic acid amide derivative represented by the general formula (II) and a salt of a salt-forming salt thereof. Or prophylactic agent. 5. The active ingredient is α-cyano-3-ethoxy-4.
-Hydroxy-5-phenylthiomethylcinnamic acid amide, The therapeutic or prophylactic agent for peptic ulcer according to claim 1. 6. The active ingredient is α-cyano-3-ethoxy-4.
-Hydroxy-5-phenylthiomethylcinnamic acid amide, The therapeutic or prophylactic agent for gastric ulcer and / or duodenal ulcer according to claim 2.