JPH02255616A - Drug for hepatic disease - Google Patents

Abstract

PURPOSE:To provide a drug for hepatic disease, containing sesamol or its derivative, having low side effect and exhibiting excellent preventive effect against hapatocytic disorder. CONSTITUTION:The objective drug is prepared by using a compound of formula (R1 and R2 together form -OCH2O-; R3 is H, OH, NH2, COCH3, CH=CH-CH3 or CH2-CH=CH2) as essential component, properly mixing with conventional drug preparation raw material and forming in the form of drug preparation by conventional process. It can be used as an oral drug such as powder, granule, particle, tablet, troche, capsule or pill or a peritoneal drug such as injection or suppository. The daily dose for adult is 50-5,000mg, preferably 100-500mg of the active component in total.

Description

[Detailed description of the invention] [Industrial application field] TECHNICAL FIELD The present invention relates to a drug for liver diseases.

[Prior Art] Conventionally, as a drug for treating and preventing liver diseases in humans,
Various things have been devised. However, these conventional drugs have strong side effects (in the formula, R+ and Ro
- together represent 10CH20-, and R5 is H, O
H, NHz, CQCHs, CH"represents CH-CH3 or CHz-CH=CJ).

2 in methylene of methylenedioxy group of sesamol
Compounds in which hydrogen atoms have been replaced with alkyl groups, and compounds in which hydroxymethyl groups have been introduced into the aromatic ring of sesamol are known to have antibacterial properties ("Bacterial and Mildew Prevention J Vol. 13, No. 2, 51 ~page 55, issue 11, 495
499, 1985), and sesamol is known to have an antioxidant effect, but it is not yet known that it is useful for liver diseases.

The compound of formula (1) used in the present invention is sesamol (
R3=OH) or a derivative thereof, which is a well-known compound 0. For example, sesamol is prepared by hydrolyzing sesamolin with hydrochloric acid or diazotizing 4-amino-1,2-methylenedioxybenzene, and then It can be obtained by hydrolysis etc.

The drug of the present invention can be administered orally or parenterally. Examples of oral dosage forms include powders, granules, fine granules, tablets, troches, capsules,
Examples include conventionally used dosage forms such as Owari. Examples of parenteral dosage forms include conventionally used dosage forms, such as injections and seated tablets. In manufacturing these dosage forms, conventional methods are used.

For example, in the production of tablets, conventionally used additives are added to the compound of formula (1) and mixed thoroughly.

Examples of additives include excipients such as corn starch, wheat starch, potato starch, lactose, glucose, mannitol, calcium carbonate, calcium sulfate, etc.; binders such as starches, dextrin, gum arabic, gum tragacanth, sodium alginate, gelatin, Methyl cellulose, ethyl cellulose, polyvinyl and lolidone, polyvinyl alcohol, etc.; Disintegrants, such as starches, polyvinyl polypyrrolidone, crystalline cellulose, etc.; Lubricants, such as magnesium stearate, talc, etc.; Coloring agents, fragrances, etc. The resulting mixture is made into tablets by wet or dry granulation, or by using a tablet machine without granulation. The amount of active ingredient in the tablet may be arbitrary.

Also, for example, for parenteral administration, the compound may be suspended or dissolved, depending on the vehicle and concentration, including a compound of formula (1) and a sterile vehicle. Examples of parenteral administration include intraperitoneal and subcutaneous administration.

When administering the drug of the present invention, for adults, the total amount of the active ingredient should be 50-50% per day, once to several times a day, depending on the symptoms.
000■ioo~50omg is preferably used.

The compounds used in the present invention were not found to be toxic at all in the experiments of the following examples.

As can be seen from the experimental results below, the drug of the present invention has a protective effect against liver damage caused by carbon tetrachloride in rats, and is effective against liver diseases.

[Example code] Next, examples will be shown.

Example 1 Q
Arc Works and Active Ingredients
50 carboxymethylcellulose sodium,
140 liters
Five tablets each of the 40 active ingredients and additives were weighed out and mixed uniformly. One tablet was weighed out from the mixture and directly compressed using a tablet press at a pressure of 200 kg/cd to obtain a tablet.Tablet 0 contained 50 mg of the active ingredient per tablet.

[Effect Co. 1 shows the protective effect of the drug of the present invention on liver disease.

Experimental animal Wistar male rat (7 weeks old, weight 180~
200 g, Saitama Experimental Animal Supply Center) were used, with 3 to 4 animals per group. Feed (manufactured by Oriental Yeast) was given ad libitum, but 4 hours in total, 24 hours before CCl4 administration and 24 hours before blood collection.
The animals were fasted for 8 hours and had free access to drinking water until blood sampling.

Creation of CCl4 liver-damaged rats The dose of CCL (Wako Pure Chemical, special grade) was 0.3 d/kg.
It was prepared by intraperitoneally administering it as a 20% olive oil (Japanese Pharmacopoeia) solution to rats that had been fasted for 24 hours.

Sample administration method Samples were suspended in 5% Tween 80 and 0.4NN
Add aOH to correct the pH to 7, and adjust the volume of the administered solution to 014~1t.
xl/200g and administered before CC1 treatment.

Blood Sampling and Measurement Method CC1. Twenty-four hours after administration, the rats were laparotomyd under ether anesthesia, and blood was collected from the abdominal descending vena cava. The obtained blood was centrifuged (3000 rpm, 10 minutes) to separate serum. For measurement of serum components, GOT and GPT are
Men method, LDH is Wacker method, LAP is Na
By gel method, T-BIL and D-OIL are Jendra
Using the ssik method, each measurement reagent (Denka Seiken)
It was measured using an automatic biochemical analyzer (TBA-380, Toshiba Medical).

Display of liver damage protection efficacy The liver damage protection efficacy was calculated by substituting the average of the measured values of serum components of the untreated normal group, the CCl4 administration group, and the drug+CCt and CCl4 administration groups into the following formula.

The significance of the efficacy of each measured value was determined by CCl4 administration moromi-correction 5 student's t-test. +: p<0.05. ++:p
<0.01 Experiment 1 C
C1, (0.3 g/kg, i, p,) was administered intraperitoneally 30 minutes before treatment.

The results are shown in Table 1.
ol/kg, slightly better at dosages of 0.5 and 0,
25 n+mol/kg with good tearing.

Table 1 0.5 0.25 a, 12 0.06 95.8 + medium 91.5” 91.4” 82.4” 0.7 92.2” 88.7” 87.9” 55.1” 17.9 97.1"95.5"81.5" 47.4 -48.1 102.2 + Medium 80.4"60J" 30.4 = 4.3 100.9"96.4" 87.4 " 58.6 ÷ 18.4 87.3"80.3" 71, P"58.5" 32.1 Experiment 2 Rats (n = 4 or 3) with different doses of sesamol
CC1a (0,3+d/kg%i,p,) was administered intraperitoneally at the time shown in the table before treatment.

The results are shown in Table 2. The liver condition was determined by intraperitoneal administration.
Slightly good after 30 minutes at dose 0.250o1/kg, slightly good after 30 minutes before subcutaneous administration at doses 1 and 0,5*mol/kg, and slightly good after 30 minutes before oral administration at doses 0, 5
It was slightly better at mmol/kg before 60 minutes.

Experiment 3 The compounds shown in the table were subcutaneously administered to rats (n: 4) at different doses 30 minutes before treatment with CCl4 (0.3 rods/kg, i, p). The results are shown in Table 3.

Todoroki 2nd table 0.25 b, 4hr b, no r b, 30Isin b, 301Lin b, 30ILin b, 30ILin b, 60odn b260 company n -13,4 21,0 84,2"89.5" 11.9 35.2"118.7"73.4" 0.9 9.6 69, O"84.8" 0.7 19.2 80.3" 70.0 " -n, 2 1.2 611. 0"97.4" -n, 9 16.8 95.8"78.1" -5,7 0,0 34,3 out of 83.3 out of 10 -2,9 22,9 go, o" 45. 7+" -16,7 18,3 41,7 69,6" 5.0 18.3 88.7"713.7" 2°C113H Cl1=C11-COO1! 0.5 In the items in each table, A indicates the dose, B indicates the administration method, C indicates the time before administration, and D indicates the liver condition.

As can be seen from Table 3, the compounds of the present invention (i.e. No.
Good or somewhat good results can be obtained with 1.5.8, 13.14 and ll, but satisfactory results cannot be obtained with other compounds whose structures are extremely similar to these compounds. Therefore, it can be easily understood that the drug of the present invention is superior.

Claims (1)

[Claims] Formula (1) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(1) (In the formula, R_1 and R_2 together represent -OCH_
2O-, R_3 is H, OH, NH_2, COCH
_3, CH=CH-CH_3 or CH_2-CH=CH
_2) A drug for liver diseases.