JPH02164822A - (H↑++K↑+)-Adenosine triphosphatase inhibitor - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to adenosine triphosphatase inhibitors, more particularly 2',4°4'-1
-dihydroxy-3'-[(E)-3,7-dimethyl2,6-occyenyl]chalcone (hereinafter referred to as xanthoangelol) or 3°-Cy,y-dimethylaryl)-2',4-dihydroxy The present invention relates to a (H"+K")-adenosine triphosphatase inhibitor containing -4'-methoxychalcone (hereinafter referred to as 4-hydroxypridine) as an active ingredient.

Prior Art Xanthoangelol and 4-hydroxypridine are represented by the following structural formula.

Xanthoangelol Hydroxytericinxanthoangelol and 4-hydroxypridine are known compounds.
Ozawa et al. reported in the Pharmaceutical Journal [Vol. 98, No. 2, 210-21
4, 1978].

However, the inhibitory effect of xanthoangelol and 4-hydroxydericine on gastric mucosal (H"+K")-adenosine triphosphatase has not been reported. (
H"+K")-adenosine triphosphatase is present in the parietal cell membrane of the gastric mucosa and plays a role in secreting acid synthesized in the parietal cells into the gastric lumen. Therefore, gastric acid secretion can be suppressed by inhibiting this enzyme.

Problems to be Solved by the Invention As a result of intensive research into the search for (H"10K")-adenosine triphosphatase inhibitors, the present inventors found that xanthoangelol and 4-hydroxychelicin +
)-adenosine triphosphatase was discovered, and the present invention was completed.

Means for Solving the Problems The present invention provides 2',4,4'-1-dihydroxy-3[(
E)-3,7-dimethyl-2,6-octazininylcochalcone or 3'-(7,7-dimethylaryl)-2
'.

It is a (H"10K")-adenosine tonophosphatase inhibitor containing 4-dihydroxy-4'-methoxychalcone as an active ingredient.

The present invention will be explained in detail below.

The xanthoangelol and 4-hydroxypridine are the method of Sawa et al. [Pharmaceutical Journal, Vol. 98, No. 2, 2
10-214, 1978) according to Ashitaba (
Angelica keiskei KOIDZUMI
> can be obtained from

The route of administration of the (H"10K")-adenosine triphosphatase inhibitor of the present invention is oral administration or parenteral administration.

The dosage can be appropriately selected depending on the route of administration, age, and symptoms, but the dose of xanthoangelol for adults is usually 50
~200mg, 4-hydroxypridine is 50~3
Administer 00 mg in 1 to 3 divided doses per day.

The (H"+)-adenosine tonophosphatase inhibitor of the present invention containing xanthoangelol or 4-hydroxypridine as an active ingredient can be formulated into any form such as tablets, capsules, and granules by a conventional method. Depending on the purpose, additives can be added to them as appropriate. For example, in the case of tablets, capsules, granules, etc., crystalline cellulose, starch, lactose, etc. Excipients, binders such as hydroxypropylcellulose and polyvinylpyrrolidone, lubricants such as talc and magnesium stearate, and fluidity improvers such as light silicic anhydride can be used.

The present invention has made it possible to provide a potent (H''+)-adenosine tonophosphatase inhibitor.

Example The present invention will be explained below using test examples and examples.

Test Example 1 [(H''+K'')-adenosine triphosphatase inhibitory activity test] A pig stomach purchased from a slaughterhouse was used, and after removing the mucus adhering to the surface, the anterior bottom mucosa was peeled off with a scalpel. The mucosa was soaked in Tris-HCl buffer (pH 7) containing 0.25M sucrose.
, 4) to prepare a 20% homogenate, 20.
Centrifugation was performed at 100,000 x g for 1 hour, and the supernatant was further centrifuged at 100,000 x g for 1 hour.

The microsomal fraction obtained as a precipitate was resuspended in the above buffer solution, and added with 0.25 sucrose-7% Ficoll 40.
0 (manufactured by Pharmacia) and subjected to a discontinuous density gradient of 7B
After centrifugation at ,000 × g for 1 hour, the interface between the scroll layer and the buoycol layer was collected. The obtained precipitate was lyophilized and then dissolved in a certain amount of water to be used as a H"10K")-adenosine triphosphatase inhibition specimen.

The activity of (H"+K")-adenosine triphosphatase was measured using 40mM Lis-HCl buffer p) 17.4 containing 2mM magnesium chloride and 20mM potassium chloride, and the total volume of the reaction solution was 1ml. Test drug at various concentrations of xanthoangelol or 4-hydrogidideridine dissolved in dimethyl sulfoxide 10. Add u to the reaction solution λ
After that, (H"+)-adenosine lipo-sphatase (4Pg as Kumbaku substance), followed by adenosine tribosphatase-1-(+-lith salt) were added to 2.5mM for reaction. was started and incubated for 20 minutes at 37°C. The reaction solution of the control group contained dimethylsulfoxy F.
10- only was added and the same operation was carried out. The reaction was stopped by adding 1 mQ of chilled 10% trichloroacetic acid, and the amount of phosphorus liberated in the reaction solution was determined and determined as enzyme activity.

Note that phosphorus was quantified by the following method. 10%
Add 1 ml of phosphorus quantitative reagent, which is a mixture of ascorbic acid and ammonium molybdate sulfuric acid solution at a ratio of 1:6, to the reaction solution.
After 1 to 7 minutes of incubation at 45°C,
Absorbance was measured at 70 nm.

The results are shown in Tables 1 and 2. Note that the enzyme activity was expressed as a percentage when the activity of the control group was set as 100%.

Table 1 1.5 1.2 1.0 43.8 66.2 81.5 Each value is the average of 2 cases 5.0X10 1.2 1.0 77.7 86.9 Test Example 2 [Acute toxicity test Eight CoddY mice (body weight 18-22 g) were used as one group, and the progress was observed for 14 days after administration of xanthoangelol and 4-hydroxypridine to determine LDb.

The value was measured. The results are shown in Table 3.

Table 3 Administration route L D s e (mg/kg
) Oral, intraperitoneal, subcutaneous > 3.000 > 2.000 > 2.000 Example 2 Tablets were manufactured by a conventional method according to the following formulation.

50mg 0mg 4-hydroxypridine Low substituted hydroxypropyl cellulose crystalline cellulose lactose Light silicic anhydride 0mg 0mg 0mg Example 1 Tablets were manufactured by a conventional method according to Process 5 below.

00mg 0mg Kisan 1 ~ Angelol Low substituted hydroxypropyl A cellulose crystalline cellulose lactose Light silicic anhydride talc 0mg 0mg 0mg 0mg Example 3 Capsules were manufactured by a conventional method according to the following recipe.

Xanthoangelol 100mg Crystalline Cellulose 100mg Lactose
150mg light silicic anhydride 20
290 mg per tablet (290 mg per tablet) Example 4 Capsules were manufactured in a conventional manner according to the following formulation.

4-hydroxypridine crystalline cellulose lactose Light silicic anhydride Magnesium stearate 50mg 00mg 50mg 0mg 0mg Example 6 Granules were produced in a conventional manner according to the following recipe.

4-hydroxypridine lactose hydroxypropyl cellulose talc 50mg 00mg Su 20mg 0mg Example 5 Granules were produced in a conventional manner according to the following recipe.

xanthoangelol lactose hydroxypropyl cellulose talc 00mg 50mg 0mg 0mg

Claims (1)

[Claims] (1) 2',4,4'-trihydroxy-3'-[(E
)-3,7-dimethyl-2,6-octadienyl]chalcone or 3'-(7,7-dimethylaryl)-2',
(H^++K^+)-adenosine triphosphatase inhibitor containing 4-dihydroxy-4'-methoxychalcone as an active ingredient