JPH0558885A - Antiulcer agent - Google Patents

Abstract

PURPOSE:To obtain a protective type antiulcer agent, containing a chalcone derivative as an active ingredient and having powerful antiulcer and gastric membrane protective and further acid secretion inhibitory actions. CONSTITUTION:The objective antiulcer agent is obtained by reacting 2'- hydroxy-4'-(3-methyl-2-butenyloxy)acetophenone with a compound expressed by formula I (R is n-hexyl, n-heptyl, etc.) in the presence of an alkali such as potassium hydroxide in a solvent such as methanol, reacting the resultant compound expressed by formula II with a compound expressed by formula III (R<1> is 1-3C alkyl; X is Cl, Br, etc.) in the presence of a basic reagent such as potassium carbonate and a phase-transfer catalyst such as potassium iodide, further hydrolyzing the prepared compound expressed by formula IV, affording a derivative expressed by formula V, e.g. 2'-carboxymethoxy-4-n-hexyl-4-n- hexyl-4'-(3-methyl-2-butenyloxy)chalcone, adding polyvinylpyrrolidone, urea, etc., and a surfactant to the resultant compound expressed by formula V, dissolving the obtained mixture in an organic solvent, further removing the organic solvent and adding an extending agent, etc., to the prepared composition.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an anti-ulcer agent containing a novel chalcone derivative in which the 4-position of the chalcone skeleton is substituted with an alkyl group, and more specifically, it has an anti-ulcer activity and gastric activity in the treatment of digestive system diseases. The present invention relates to an anti-ulcer agent having a mucosal protective action and an acid secretion suppressing action.

[0002]

2. Description of the Related Art Chalcone derivatives include JP-A-54-32634, which discloses an isoprenyl chalcone compound known by the general name Sofalcone, and US Pat. No. 4,656,305. Are disclosed as compounds having antiulcer activity.

[0003]

At present, in the treatment of gastric ulcer or duodenal ulcer, H ₂ receptor antagonists have become the center of choice for primary treatment due to their high cure rate and early relief of various symptoms. However, drug therapy using H ₂ receptor antagonists still has serious problems to be solved such as side effects such as hypergastrinemia and frequent recurrence after discontinuation of administration.

In order to solve such problems, a strong antiulcer action which can be a primary agent for treating ulcer,
Development of a protective antiulcer agent having a gastric mucosa-protecting action and an acid secretion suppressing action is desired.

[0005]

The present inventors have found that compounds having an alkyl group or an alkenyl group having an appropriate number of carbon atoms at the 4-position of 2'-carboxyalkoxychalcone are superior to known carboxyalkoxychalcone derivatives. The present invention was completed as a result of further detailed investigations, which were found to exhibit antiulcer activity, gastric mucosa protection activity and acid secretion suppression activity.

The present invention has the general formula (I)

[Chemical 2]

(Wherein R represents an n-hexyl group, an n-heptyl group or a t-butyl group) is an anti-ulcer agent containing as an active ingredient a chalcone derivative.

The method for producing the chalcone derivative which is the active ingredient of the present invention is described below, and its outline is shown in the following reaction formula.

[0009]

[Chemical 3]

First, 2'-hydroxy-4 '-(3-methyl-2-butenyloxy) acetophenone and The Journal of Organic Chemistry (J. Or.
g. Chem. ) Volume 49, page 3963 (1984)
General formula (II) which can be produced by the method described in

[0011]

[Chemical 4]

(Wherein R represents an n-hexyl group, an n-heptyl group or a t-butyl group) is condensed with an benzaldehyde derivative in the presence of an alkali to give a compound represented by the general formula (III)

[0013]

[Chemical 5] (In the formula, R has the same meaning as above.) 2 ′
Produce a hydroxychalcone derivative. The alkali used in this condensation reaction includes potassium hydroxide, sodium hydroxide, sodium ethoxide, sodium methoxide, potassium t-butoxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like. As the reaction solvent, methanol, ethanol, n-propanol, isopropanol, t-butanol, or the like can be used alone or by adding water. The reaction temperature can be appropriately selected from 0 ° C. to the boiling point of the solvent used.

Next, the 2'-hydroxychalcone derivative represented by the general formula (III) and the general formula (IV) X-CH ₂ -COOR ¹ (IV) (wherein R ¹ is an alkyl group having 1 to 3 carbon atoms). , X is Cl,
It represents Br, I, a mesyl group or a tosyl group. ) Is reacted with a compound represented by the general formula (V)

[0015]

[Chemical 6]

A compound of the formula (wherein R and R ¹ are as defined above) is obtained. The basic reagent used in this reaction includes potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, potassium hydroxide, sodium hydroxide, sodium hydride, potassium hydride, sodium ethoxide, sodium methoxide, sodium amide. , Potassium amide, n-butyllithium, lithium diisopropylamide, potassium t-butoxide, and the like. As the reaction solvent, methanol, ethanol, n-propanol, isopropanol, acetone, dimethylformamide, dimethylsulfoxide, benzene, toluene, tetrahydrofuran, dioxane, acetonitrile, chloroform, dichloromethane and the like can be used.
Further, a phase transfer catalyst or an iodine compound such as potassium iodide or sodium iodide can be used as a reaction promoter. The reaction temperature can be appropriately selected from -70 ° C to the boiling point of the solvent used.

Then, the compound represented by the general formula (V) is hydrolyzed to produce the compound represented by the general formula (I) which is the active ingredient of the present invention.
This hydrolysis reaction involves potassium carbonate, sodium carbonate,
From 0 ° C to the boiling point of the solvent in an alkaline aqueous solution of sodium hydrogen carbonate, potassium hydrogen carbonate, potassium hydroxide, sodium hydroxide, etc., in an alcohol such as methanol, ethanol, n-propanol, isopropanol or a solvent such as tetrahydrofuran, dioxane, etc. Can be appropriately performed in the temperature range of.

Regarding the toxicity of the compound represented by the general formula (I) which is the active ingredient of the present invention, a single-dose toxicity test using male 5-week-old mice (6 mice in each group) (observation for 7 days) As a result, any of the compounds represented by the general formula (I), which is the active ingredient of the present invention, is highly safe with no death observed even after oral administration of 2000 mg / Kg. The dose of the compound represented by the general formula (I), which is the active ingredient of the present invention, varies depending on the symptoms, but usually, the dose for adults is 10 mg to 300 mg once a day or once a day depending on the symptoms. It is better to administer the above.

The antiulcer agent of the present invention is mainly orally administered. As the dosage form, it can be prepared and used as a solid preparation such as tablets, pills, capsules and granules, or a liquid preparation, emulsion, suppository and the like. To prepare each of the above-mentioned preparations, they are produced according to a conventional preparation technique, but if necessary, commonly used additives such as auxiliary agents, stabilizers, emulsifiers and diluents can be used. For example, solid preparations include excipients such as crystalline cellulose, lactose, corn starch, mannitol, calcium stearate, magnesium stearate, hydrogenated oil, lubricants such as talc, binders such as hydroxypropylmethyl cellulose and hydroxypropyl cellulose. Disintegrators such as carboxymethyl cellulose calcium, low-substituted hydroxypropyl cellulose and the like can be used.

However, the chalcone compound represented by the general formula (I), which is the active ingredient of the present invention, is poorly soluble, and it is preferable to improve the solubility when it is formulated. Solubility can be improved even by using conventional fine powders or soft capsules dissolved in macrogol, but more preferably, the chalcone compound represented by the general formula (I), which is the active ingredient of the present invention, is added to polyvinylpyrrolidone. The solubility of the chalcone compound represented by the general formula (I) can be improved by adding one or more selected from the group consisting of polyethylene glycol, urea, succinic acid, methyl cellulose, hydroxypropyl cellulose and hydroxypropylmethyl cellulose. improves.

The above composition is manufactured as follows. In addition to the chalcone compound represented by the general formula (I), polyvinylpyrrolidone, polyethylene glycol, urea, succinic acid,
A blend with one or more selected from the group consisting of methylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose, or a blend obtained by further adding a surfactant to this blend is dissolved in an organic solvent and then freeze-dried. The organic solvent is removed by a method such as a spray drying method or heating under reduced pressure. A filler and a flavoring agent can be added to the composition thus obtained, if necessary.

The surfactant used may be either a nonionic surfactant or an ionic surfactant. A polyoxyethylene fatty acid ester-based surfactant is preferable. The ratio of the chalcone compound represented by the general formula (I) to the compound is 1: 1 to 10, and the ratio of the surfactant to be added is 1: 0.01 to 1. The organic solvent used is methanol, ethanol, dichloromethane, chloroform, or the like.

[0023]

EFFECTS OF THE INVENTION The antiulcer agent of the present invention has a strong antiulcer action, gastric mucosa protective action, and acid secretion inhibitory action. Therefore, treatment of gastrointestinal inflammatory diseases such as gastritis, gastric ulcer, duodenal ulcer, etc. It is useful for prevention.

[0024]

EXAMPLES The present invention will be described in more detail below with reference to production examples, examples and test examples.

Production Example 1 2'-carboxymethoxy-4-n-hexyl-4'-
Production of (3-methyl-2-butenyloxy) chalcone (1) 4-n-hexyl-2'-hydroxy-4'-
Preparation of (3-methyl-2-butenyloxy) chalcone 2'-hydroxy-4 '-(3-methyl-2-butenyloxy) acetophenone 6.60 g and 4-n-hexylbenzaldehyde 5.70 g were dissolved in 120 ml of isopropyl alcohol. , 6N sodium hydroxide aqueous solution 25
ml was added, and the mixture was reacted at 40 ° C. for 8 hours. After the reaction was completed, it was neutralized with diluted hydrochloric acid. The precipitated solid matter was collected by filtration, washed with water, dried and recrystallized from ethanol. Yellow needle crystals of 4-n-hexyl-2'-hydroxy-4'-
(3-Methyl-2-butenyloxy) chalcone 7.72 g
Got

[0026]

(2) Preparation of 2'-ethoxycarbonylmethoxy-4-n-hexyl-4 '-(3-methyl-2-butenyloxy) chalcone 4-n-hexyl-2'-hydroxy-4'-(3 5.50 g of -methyl-2-butenyloxy) chalcone was dissolved in 55 ml of dry acetone and ground potassium hydroxide was added.
4 g was added. After stirring for 5 minutes, ethyl bromoacetate 2.4
0 g was added, and the mixture was stirred at room temperature for 40 minutes. After the reaction,
While cooling with ice, dilute hydrochloric acid was added dropwise for neutralization, and the precipitated solid matter was collected by filtration. After washing with water and drying, it was recrystallized from ethanol. There were obtained 5.73 g of 2'-ethoxycarbonylmethoxy-4-n-hexyl-4 '-(3-methyl-2-butenyloxy) chalcone as pale yellow needle crystals.

M. p. 56-57 ° C

(3) 2'-carboxymethoxy-4-
Preparation of n-hexyl-4 ′-(3-methyl-2-butenyloxy) chalcone 2′-ethoxycarbonylmethoxy-4-n-hexyl-4 ′-(3-methyl-2-butenyloxy) chalcone
4.30 g was dissolved in 43 ml of ethanol, 6.2 g of potassium carbonate was dissolved in 11 ml of water and added, and the mixture was stirred at 50 ° C. for 5 hours. After the reaction was completed, the reaction mixture was neutralized with dilute hydrochloric acid, and the precipitated solid matter was collected by filtration. After washing with water and drying, it was recrystallized from a mixed solution of ethyl acetate-n-hexane to give 2'-carboxymethoxy-4-n-hexyl-4 '-(3-methyl-2.
3.13 g of -butenyloxy) chalcone were obtained.

[0030] 1.20 to 1.32 (6H, m) 1.51 to 1.70
(2H, m), 1.75 (3H, s), 1.77 (3
H, s), 2.61 (2H, t, J = 7 Hz), 4.6
3 (2H, d, J = 7Hz), 4.92 (2H, s),
5.45 (1H, t, J = 7Hz), 6.65 to 6.7
0 (2H, m), 7.24 (2H, d, J = 8Hz),
7.60 (1H, d, J = 16Hz), 7.68 (1
H, d, J = 9 Hz), 7.69 (2H, d, J = 8H)
z), 7.97 (1H, d, J = 16Hz), 13.2
8 (1H, s).

Production Example 2 2'-carboxymethoxy-4-n-heptyl-4'-
Production of (3-methyl-2-butenyloxy) chalcone (1) 4-n-heptyl-2'-hydroxy-4'-
Preparation of (3-methyl-2-butenyloxy) chalcone 87.7 g of n-heptylbenzene was added to nitroethane 160
ml, and dissolved in 480 ml of dichloroethane, 79.5 g of anhydrous aluminum chloride was added little by little under ice cooling. Next, 54.5 ml of dichloromethyl methyl ether was dissolved in 60 ml of dichloroethane and added dropwise. After completion of dropping, the reaction was further performed at 0 ° C. for 1 hour, and then the reaction mixture was poured into ice water. After extraction with chloroform, washing with water and drying, the solvent was distilled off. The residue was subjected to silica gel chromatography fractionation with a solvent of n-hexane: isopropyl ether (10: 1). A colorless oily substance, 2-heptylbenzaldehyde (17.3 g) was obtained from the fraction that first flowed out. A colorless oily substance, 4-heptylbenzaldehyde (64.8 g) was obtained from the fraction flowing out later.

Then, 8.80 g of 4-heptylbenzaldehyde and 2'-hydroxy-4 '-(3-methyl-
8.26 g of 2-butenyloxy) acetophenone was dissolved in 175 ml of ethanol, 6.8 g of potassium hydroxide was dissolved in 17 ml of water under a nitrogen stream, and the mixture was added at 8 ° C. at 8 ° C.
Stir for hours. The mixture was neutralized with diluted hydrochloric acid under ice cooling and extracted with ethyl acetate. After washing with water and drying, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column fractionation with n-hexane containing 1% ethyl acetate. The obtained target product fraction was recrystallized from ethanol to give yellow needle crystals 4-n-heptyl-
2.96 g of 2'-hydroxy-4 '-(3-methyl-2-butenyloxy) chalcone was obtained. m. p. 83-84
℃

(2) 2'-carboxymethoxy-4-n
-Heptyl-4 '-(3-methyl-2-butenyloxy)
Preparation of chalcone 9.82 g of 4-n-heptyl-2′-hydroxy-4 ′-(3-methyl-2-butenyloxy) chalcone was dissolved in 170 ml of dry acetone, and 2.1 g of ground potassium hydroxide was added. After stirring for 5 minutes, 4.2 g of ethyl bromoacetate was added, and the mixture was stirred at room temperature for 40 minutes. After completion of the reaction, while cooling with ice, dilute hydrochloric acid was added dropwise for neutralization, and the precipitated solid matter was collected by filtration. After washing with water and drying, it was recrystallized from ethanol. 2.15 g of 2'-ethoxycarbonylmethoxy-4-n-heptyl-4 '-(3-methyl-2-butenyloxy) chalcone as pale yellow needle crystals was obtained. m. p. 60 to 63 ° C. This was dissolved in 180 ml of ethanol, 55 ml of 10% potassium carbonate aqueous solution was added, and the mixture was stirred at 60 ° C. for 5 hours. Neutralize with dilute hydrochloric acid under ice cooling, and remove the precipitated solid by ▲ filtration ▼
It was taken and recrystallized from ethanol. 2 ′ of pale yellow needles
-Carboxymethoxy-4-n-heptyl-4 '-(3
7.27 g of -methyl-2-butenyloxy) chalcone was obtained.

[0034] 4.62 (2H, d, J = 7Hz), 4.90 (2H,
s), 5.44 (1H, t, J = 7Hz), 6.64-
6.69 (2H, m), 7.23 (2H, d, J = 8H
z), 7.59 (1H, d, J = 16 Hz), 7.67
(1H, d, J = 9HZ), 7.68 (2H, d, J =
8Hz), 7.96 (1H, d, J = 16Hz), 1
3.27 (1H, s),

Production Example 3 4-t-butyl-2'-carboxymethoxy-4'-
Production of (3-methyl-2-butenyloxy) chalcone (1) 4-t-butyl-2′-hydroxy-4 ′-(3
-Methyl-2-butenyloxy) chalcone production 2'-hydroxy-4 '-(3-methyl-2-butenyloxy) acetophenone 54.4 g and 4-t-butylbenzaldehyde 40.0 g were dissolved in 1000 ml of ethanol and hydroxylated. Add 81.2 g of potassium and add 19 at 40 ° C.
Stir for hours. The mixture was neutralized with diluted hydrochloric acid, and the precipitate was collected by filtration. After washing with water and drying, it was recrystallized from isopropanol to give a yellow powder, 4-t-butyl-2'-hydroxy-4'-.
(3-Methyl-2-butenyloxy) chalcone 47.6 g
Got

(2) Preparation of 4-t-butyl-2'-ethoxycarbonylmethoxy-4 '-(3-methyl-2-butenyloxy) chalcone 4-t-butyl-2'-hydroxy-4'-(3 45.1 g of -methyl-2-butenyloxy) chalcone was dissolved in 500 ml of acetone, 10.6 g of potassium hydroxide was added, and the mixture was stirred for 5 minutes. Further ethyl bromoacetate 21.5
g and stirred for 45 minutes. The mixture was neutralized with dilute hydrochloric acid, and the precipitated crystals were collected by filtration. After washing with water and drying, it was recrystallized from ethanol to give 4-t-butyl-2'-ethoxycarbonylmethoxy-4 '-(3-methyl-2-
47.6 g of butenyloxy) chalcone was obtained. m. p. 78-79 ° C

(3) Preparation of 4-t-butyl-2'-carboxymethoxy-4 '-(3-methyl-2-butenyloxy) chalcone 4-t-butyl-2'-ethoxycarbonylmethoxy-
4 '-(3-methyl-2-butenyloxy) chalcone 4
7.3 g was dissolved in 600 ml of ethanol, 29.0 g of potassium carbonate was dissolved in 100 ml of water and added, and the mixture was reacted at 45 ° C. for 8 hours. It was neutralized with dilute sulfuric acid, and the precipitated crystals were collected by filtration. After washing with water and drying, it was recrystallized from ethyl acetate to give 4-t-butyl-2'- pale yellow needle crystals.
29.9 g of carboxymethoxy-4 '-(3-methyl-2-butenyloxy) chalcone was obtained.

[0038]

Test Examples The strong antiulcer action, gastric mucosal protection action and acid secretion inhibitory action of the compound which is the active ingredient of the present invention will be specifically shown below. As the sample, the compound obtained in the production example having the same sample number as shown in each table was used. Further, the following compounds A to E were used as control compounds. A: 4-carboxy-2'-carboxymethoxy-4 '
-(3-Methyl-2-butenyloxy) chalcone B: 2 ', 4-bis (carboxymethoxy) -4'-
(3-Methyl-2-butenyloxy) chalcone C: 2'-carboxymethoxy-4,4'-bis (3-
Methyl-2-butenyloxy) chalcone D: 2'-carboxymethoxy-4-methyl-4'-
(3-Methyl-2-butenyloxy) chalcone E: 2'-carboxymethoxy-4 '-(3-methyl-
2-butenyloxy) -4-n-propyl chalcone

Test Example 1 Stress ulcer inhibitory action test Takaki (K. Takagi) et al., The Japanese Journal of Pharmacology (Japan JP
armacol. ), Vol. 18, page 9 (1968
Year)) and a stress ulcer inhibitory effect test was conducted. That is, a body weight of 160 to 1 fasted for 18 hours
80 g of Wistar male rats (1 group: 7) were used. 50 mg / kg of each sample is 0.4% C in the sample group.
Those prepared by suspending in MC aqueous solution were orally administered, and only 0.4% CMC aqueous solution was orally administered to the control group. Then, the rat was placed in a wire mesh gauge for stress application and immersed in a thermostat bath at 23 ° C. under the sternum, and after 7 hours, the abdomen was opened and the area of gastric mucosa generated was measured to determine the ulcer index. The inhibition rate was calculated from this ulcer index by the following formula.

(Results) The results are shown in Table 1.

[Table 1]

Test Example 2 Gastric mucosa protective action test A. Robert et al.'S Gastroenterology (Gas
Toenterology) Vol. 77, p. 433-
By the method described on page 443 (1979), 0.6
N-hydrochloric acid-induced gastric disorder inhibitory action (gastric mucosa protective action) was tested. That is, 7 Wistar male rats (body weight: 180 to 210 g) per group were fasted for 24 hours and dehydrated for 18 hours before use. The sample group was orally administered with a sample (50 mg / Kg) prepared by suspending it in 0.4% CMC,
The control group was orally administered with 0.4% CMC aqueous solution alone. After standing at room temperature for 2 hours, 0.6 ml of hydrochloric acid was added to 1 ml.
/ Rat was orally administered. After left at room temperature for 1 hour, the rat was sacrificed and the length of gastric mucosal lesions occurring in the body of the stomach was measured, and the sum of them was used as the lesion coefficient per animal.
The lesion coefficient of the drug administration group was compared with that of the control group, and the inhibition rate was calculated by the following formula.

(Results) The results are shown in Table 2.

[Table 2]

Test Example 3 Gastric Acid Secretion Inhibition Test by Gastric Perfusion Method K. Watanabe et al., The European Journal of Pharmacology (Eur.JP)
Harmology) Vol. 90, pp. 11-17
According to the method described on page (1983), a gastric acid secretion inhibition test was carried out by the intragastric perfusion method. That is, Wistar rats weighing 300 to 350 g (4 animals per group) fasted for 18 hours were treated with urethane (1.25 g / kg, s.c.).
c. ) Under anesthesia, the abdomen was opened, and cannulas for intragastric perfusate were inserted into the stomach from the forestomach and duodenum. As a gastric perfusate, physiological saline was used, and a peristaltic pump was used to flow it into the stomach through the cannula of the forestomach, and the perfusate flowing out of the cannula of the duodenum was sampled at 5-minute intervals, and 0.02N sodium hydroxide was added. Measured at pH start using aqueous solution (end point pH 7.0)
Then, the amount of secreted acid was measured. Stimulation of acid secretion is 2-
Deoxy-D-glucose (200 mg / kg, s.
c. ) And indomethacin (20 mg / kg, s.
c. ), And 80 minutes after the administration, the sample was suspended in a 5% aqueous solution of gum arabic and intraperitoneally administered, and the total amount of gastric acid secretion for 5 hours was compared with that of the control group (only the 5% gum arabic solution was administered). The gastric acid secretion inhibitory rate was calculated from the following formula.

(Results) The results are shown in Table 3.

[Table 3]

Test Example 4 Stress-Indomethacin Ulcer Inhibitory Action Test The test method is Arai et al., The Japanese Journal, Pharmacology Vol. 39, p. 278 (1985).
Year) method. One group of 7 male Wistar rats (body weight: 200 to 250 g) was fasted for 18 hours before use. A sample (100 mg / kg) prepared by suspending in a 5% aqueous solution of gum arabic was orally administered to the sample group, and only a 5% aqueous solution of gum arabic was orally administered to the control group. About 10 minutes later indomethacin 20mg /
Six hours after subcutaneous administration of 4 kg at a low temperature room at 4 ° C., the abdominal cavity was opened and the area of gastric mucosa generated was measured, and this was taken as the ulcer index. The inhibition rate was calculated from this ulcer index by the following formula.

The results are shown in Table 4.

[Table 4]

Test Example 5 Indomethacin ulcer inhibitory activity test The test method is as described by Lee et al., Alkives International Depharmaco Dynamie et Deteraby (A).
rch. Int. Pharmacodyn The
r. ), Vol. 19, pp. 370-377 (1971)
Year) method. One group of 7 Wistar rats (body weight: 200 to 250 g) was fasted for 18 hours before use. A sample (100 mg / kg) prepared by suspending in a 5% aqueous solution of gum arabic was orally administered to the sample group, and only a 5% aqueous solution of gum arabic was orally administered to the control group. About 10 minutes later, 30 mg / kg of indomethacin was subcutaneously administered. After 6 hours, the laparotomy was performed and the area of erosion that developed on the gastric mucosa was measured and used as the ulcer index. The inhibition rate was calculated from this ulcer index by the following formula.

The results are shown in Table 5.

[Table 5]

Test Example 6 Pyloric ligation ulcer inhibitory activity test The test method was carried out according to the method of H. Shay et al., Gastroenterology, Vol. 5, pp. 43-61 (1945). .. 1 group of 7 male Wistar rats (body weight 2
(0-250 g) was used after fasting for 48 hours. The animals were laparotomized under ether anesthesia and pylorus ligation was performed. A sample (100 mg / kg) prepared by suspending in a 5% aqueous solution of gum arabic was intraperitoneally administered to the sample group, and only a 5% aqueous solution of gum arabic was intraperitoneally administered to the control group, and then abdominal closure was performed. .. After 16 hours, the area of the ulcer which was laparotomized and developed in the forestomach was measured and used as the ulcer index. The inhibition rate was calculated from this ulcer index by the following formula.

The results are shown in Table 6.

[Table 6]

Test Example 7 15-OH-PG-DH activity (in vitro) Inhibitory effect test The test method is as follows: Muramatsu et al., Biochemical Pharmacology (Biochem. Pharmacol.) Vol. 33,
It was carried out according to the method of pages 2629 to 2633 (1984). Scrap the porcine gastric mucosa with a scalpel, 150 mM
Sodium phosphate buffer solution (pH 8.0) was added and homogenized. This was centrifuged at 100,000 g for 60 minutes, and the supernatant was used as an enzyme solution. The sample is DMS
It was dissolved in O before use. Sample concentration is 3,10,3
It was set to 0 μM, and DMSO alone was used as a control group. A reaction solution containing a sample, an enzyme solution, a buffer solution and PGE1 was reacted at 37 ° C. for 30 minutes, 2N sodium hydroxide was added to stop the reaction, and the maximum absorbance at 500 nm was measured to calculate the enzyme activity. .. The concentration of the sample that inhibits the enzyme activity of the control group by 50% was determined and used as the IC50 value.

The results are shown in Table 7.

[Table 7]

Test Example 8 15-OH-PG-DH activity (in vivo) inhibitory effect test The test method was carried out according to the method of Muramatsu et al., Life Science Vol. 41, pages 315-322 (1987). .. 1 group of 7 male Wistar rats (body weight 200
~ 250g) was used after fasting for 18 hours. A sample (6.25, 12.5, 25, 50 mg / kg) prepared by suspending in a 5% aqueous solution of gum arabic was orally administered to the sample group, and only a 5% aqueous solution of gum arabic was orally administered to the control group. After administration, the stomach was extracted 2 hours later. The gastric mucosa was scraped off with a scalpel, and 150 mM sodium phosphate buffer (pH 8.0) was added and homogenized. This is 10
The mixture was centrifuged at 10,000 g for 60 minutes, and the supernatant was used as an enzyme solution. Reaction solution containing enzyme solution, buffer solution and PGE ₁ After reacting at 37 ° C. for 30 minutes, 2N sodium hydroxide solution was added to stop the reaction, and the maximum absorbance at 500 nm of the reaction solution was measured to calculate the enzyme activity. However, the minimum dose for which a significant enzyme inhibitory action was observed was defined as the minimum effective dose for the sample.

The results are shown in Table 8.

[Table 8]

Example 1 (Granule) 100 g of the compound of Production Example 1 was crushed with a ball mill, 200 g of sucrose, 200 g of mannitol and 470 g of corn starch were added and mixed, and then 20 g of hydroxypropyl cellulose and 10 g of polysorbate 80,
Was dissolved in 250 g of a mixed solution of purified water and ethanol (1: 2), and mixed with a mixer. This was granulated by an extrusion granulator using a screen having a diameter of 0.5 mm, and then dried by a fluidized bed dryer to obtain a granule containing 10% of the compound.

Example 2 (Fine granules) 100 g of the compound of Production Example 3 was crushed with a jet crusher, and 300 g of lactose, 230 g of glucose and 330 g of corn starch were added and mixed, and then 30 g of hydroxypropyl cellulose and 10 g of polysorbate 80 were added. Using a solution dissolved in 800 g of purified water as a binder, the mixture was granulated with a fluid bed granulator and dried to obtain a fine granule containing 10% of the compound.

Example 3 (tablet) To 100 g of the compound of Production Example 3 was crushed with a jet crusher, 295 g of mannitol, 100 g of potato starch and 25 g of carboxymethyl cellulose calcium were added and mixed, and then 30 g of hydroxypropyl methyl cellulose and 20 g of polysorbate 80 were added. Purified water 8
What was melt | dissolved in 00g was used as a binder, it granulated with the fluid bed granulator, it dried, and after that, it sieved using the No. 22 sieve. To this, add 15 g of calcium stearate and 15 g of talc,
A tablet having a weight of 300 mg was prepared, and the compound
A tablet containing mg was obtained.

Example 4 (Capsule) 100 g of the compound of Production Example 2 was crushed with a ball mill, lactose 100 g, and mannitol 290.
g, low-substituted hydroxypropyl cellulose 30 g and mixed, and then hydroxypropyl methyl cellulose 25
g, polysorbate 80 20 g, dissolved in 800 g of a mixture of purified water and ethanol (1: 2) was added as a binder, granulated with a fluid bed granulator, dried, and sieved using a No. 30 sieve. did. Calcium stearate 15
g and hydrogenated oil 20 g were added, and No. 1 capsule was filled with 300 mg to obtain a capsule containing 50 mg of the above compound.

Front Page Continuation (72) Inventor Shin Muramatsu 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Yoshihiko Isobe 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. In-house (72) Inventor Haruko Kijima 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Susumu Otomo 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. Within

Claims (1)

[Claims] 1. A general formula: (In the formula, R represents an n-hexyl group, an n-heptyl group or a t-butyl group.) An anti-ulcer agent containing a chalcone derivative as an active ingredient.