JPS58222019A - Remedy for hepatic disease - Google Patents

Abstract

PURPOSE:The titled remedy, containing a dithiol derivative or a salt thereof as an active constituent, having specific promoting action on the synthesis of proteins, and capable of improving the lipid metabolism without directly affecting the synthesis of cholesterol, and useful for treating hepatitis, etc. CONSTITUTION:A remedy for hepatic diseases containing a dithiol derivative of the formula (R<1> and R<2> are lower alkyl) or a salt thereof as an active constituent. The remedy can be administered by either one of the oral and parenteral routes, but usually is administered by the oral route. Preferably, the daily dose thereof is 12.5-100mg/kg by the oral administration for humans, and 12.5- 50mg/kg by the parenteral administration. In the case of an animal as an object, the daily dose within 12.5-200mg/kg body weight range is effective. A typical compound of the active constituent of the formula is disodium 2,2-bis(isopropoxycarbonyl)ethylene-1,1-dithiolate, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a therapeutic agent for liver diseases containing a dithiol derivative represented by the general formula (1) C (wherein H1 and R2 represent the same or different lower alkyl groups) or a salt thereof.

Acute or chronic liver diseases such as toxic liver damage, hepatitis, or cirrhosis are caused by a variety of causes.

The main feature of these diseases is that histopathological findings suggest accumulation of fat in the liver, proliferation of mesenchymal cells, or necrosis of hepatocytes.

In terms of blood biochemistry, increases in GOT and GPT, decreases in cholinesterase, and decreases in blood proteins and lipids are introduced. In the treatment of these liver diseases, it is considered to be fundamentally important to promote the protein synthesis ability of hepatocytes and normalize liver function. From this point of view, the present inventors have conducted intensive studies to search for a drug that activates hepatocytes and specifically promotes the protein synthesis ability of the liver, and as a result, they have found that the compound of general formula (1) satisfies the purpose.1 The present invention has been carried out. completed.

That is, the compound represented by general formula (I) promotes protein synthesis in the liver without directly affecting cholesterol synthesis in hepatocytes.

In turn, it exhibits the effect of improving lipid recitation.

Therefore, the compound of formula (I) can be used to treat acute illnesses in humans and animals caused by 81 different causes.

It is extremely useful as a fundamentally effective therapeutic agent for chronic liver diseases.

The excellent and specific protein synthesis promoting effect of the compound of formula (1) is due to the ability of protein synthesis in rat hepatocytes.
■ Confirmed by experimental results of cholesterol synthesis ability in cultured rat hepatocytes. Furthermore, the preventive effect on liver damage when carbon tetrachloride was administered to test animals was confirmed through in vivo experiment results.

The drug of the present invention can be administered either orally or parenterally; however, oral administration is usually considered. The dosage varies depending on whether the target is an animal or a human, or other factors (e.g., gender, age, symptoms, etc.).1 Usually, to obtain effective results in animals, oral administration should be performed at a dose of 1 kg body weight. A range of 12.5 to 200,119 per day is valid.

In addition, in order to obtain effective results in humans, oral administration must be taken into account, considering the effective dose, sensitivity, safety, etc. of animals.
For parenteral administration, 12.5 to 1001 n9/9° per day is preferred.

Note that the two compounds targeted by the present invention are known compounds.

Although it is used as a raw material compound for pharmaceuticals, it is not yet known that it has a medicinal effect per se, and its effectiveness as a pharmaceutical was discovered for the first time by the present inventors. or.

The compound of formula (1) has low toxicity to bleeding animals.

The acute oral toxicity L DBo value for male mice of disodium 2,2-bis(isopropoxycarbonyl)ethylene-1,1-dithiolate (1), which is a representative compound of the compound represented by formula (1), is 4100 to 5100. ■／IG9
It is a low-toxic substance with a level of toxicity or less. Moreover, these compounds do not have any adverse effects on test animals within the normal dosage range.

Test Example 1 Effect of promoting protein synthesis in hepatocytes Hepatocytes were prepared according to the method of Nakamura et al. Specifically, rat liver was washed with 0.05% collagenase, centrifuged, and hepatocytes were collected. The obtained liver 1MI+ cells were treated with Dulbecco's Modified Eagle (Dulbecco') containing 2% fetal bovine serum (Fe2) and antibiotics.
s Modified Eagle's ) (DM
E) 5Xi05 cells/- cell suspension 4
ml into a 60tLtIL Falcon dish at 87°C.
Cultured for 8 hours under 5%002-95% air. After removing non-adherent cells, 5% FO8-DME camellia nutrient solution 3- was added, and the cells were further cultured for 18 hours to spread the cells. Next, dissolve the test compound in serum-free DME culture solution and
/-concentration solutions were prepared, and D containing various concentrations of the test compound was prepared.
MIE culture medium, and DME as a control
It was replaced with a culture solution and cultured for 12 hours. Replace the culture medium with the test compound again and add 5 μc of 3H-labeled leucine to 6 dishes.
1 was added and the hepatocytes were further cultured for 24 hours. After collecting the culture solution, the hepatocytes were washed with DME, treated with trypsin, and collected. Trichloroacetic acid (TC-A) was added to a certain amount of the collected culture solution to a final concentration of 10%, and the resulting precipitate was collected by centrifugation.

The remaining hepatocytes were dissolved with N/10 NaOH, TCA was added to the solution, and the precipitate was collected by centrifugation. Protein was measured after neutralization of the remaining hepatocyte lysate. The TCA precipitates of the culture solution and hepatocyte lysate were washed with IO% TCA, then solubilized again with N/10 NaOH, and the radioactivity incorporated into the protein was measured. The protein synthesis promoting effect of the present compound was expressed as a percentage by comparing the total uptake radioactivity of the hepatocytes and the TCA precipitated fraction in the culture medium and the specific radioactivity of the TOA precipitated fraction of the hepatocytes with the control value. The results in Table I represent the average promotion rate of five dishes of hepatocytes. or.

As a test compound, disodium 2,2-bis(impropoxycarbonyl)ethylene-11,1-sithiolate was used as a representative of the compound represented by formula (1) (the same applies to Test Examples 2 and 8).

Table - ■ Protein synthesis promotion rate test example 2 Effect on cholesterol synthesis in hepatocytes Hepatocytes prepared according to the method described above were treated with 5% F (8-DME).
After culturing in the culture solution for 24 hours, serum-free DME culture solution containing 20 pg/- of the test compound and DMR culture solution 8 were added as a control.
- and cultured for 24 hours. Again containing the same test compound;
μC1 was added and cultured for an additional 2 hours. After collecting the culture solution,
Hepatocytes were washed with DME, treated with trypsin, and collected. Hepatocytes were solubilized with N/1ONaOH. Total lipids in the hepatocyte lysate and culture solution were extracted, and the sum of radioactivity incorporated into the free cholesterol and esterified cholesterol fractions was determined by thin layer chromatography.

Restyrol in the NJ fish was measured by an enzymatic method, and the specific radioactivity of one carp was calculated and compared with the control.

The results in the table... show the average promotion rate of the four dishes of hepatocytes,
represent.

Table n Cholesterol Synthesis Promotion Rate Test Example 8 Test method for effect on liver damage caused by single administration of carbon tetrachloride The test compound was dissolved in water, and mice (6 weeks old) were tested.

(1) IY male was administered intravenously at a rate of 12.5.m9/kg, and at the same time carbon tetrachloride was orally administered to Q, 05m/kg at a rate of 9. →Oral administration at a rate of 0.05% and 6 hours later,
It was administered orally at the rate of sa//kg. In either case, the cells were stratified 24 hours after administration of carbon tetrachloride, and CPT, GOT, [, and AP activities in the collected serum were measured. As shown below, the test compound showed a preventive effect on acute liver injury.

Omote Rin Improving effect on liver damage

Claims (1)

[Scope of Claims] A therapeutic agent for liver diseases containing a dithiol derivative or a salt thereof represented by the general formula (in which H1 and R2 represent the same or different lower argyl groups)