JPS5973515A - Agent for suppressing hepatic disorder - Google Patents

Abstract

PURPOSE:To provide the titled suppressing agent having excellent effect to suppress the hepatic disorder and low toxicity, and useful as a drug, by using aletheine or its derivative as an active component. CONSTITUTION:The objective agent contains aletheine of formula (R<1> is H, acetyl or benzyloxycarbonyl; R<2> is H or acetyl; when R<1> is benzyloxycarbonyl, R<2> is not acetyl) or its derivative as an active component. The compound is e.g. 3-amino-N-(2-mercaptoethyl)propinonamide, 3-(benzyloxycarbonylamino)-N-(2- mercaptoethyl(propionamide, etc. The active component is administered orally in the form of tablet, granule, etc. in combination with a binder such as ethylcellulose, etc., a vehicle such as lactose, etc., a disintegrant such as carboxymethylcellulose calcium salt, etc. Dose: preferably 300-900mg daily for the therapy of adult by oral administration.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a liver damage inhibitor containing aretin represented by formula CII and its derivatives as a main component.

R'-NHCH2CH2CONHCH,, CH25-R
2 [I:1 [In the formula, R1 represents a hydrogen atom, an acetyl group, or a benzyloxycarbonyl group.

R2 represents a hydrogen atom or an acetyl group. Just R”
When representing a capendyloxycarponyl group, R2 does not represent an acetyl group. ] It is known that aretin, which forms the main skeleton of the compound represented by the formula [ITl, contains pantethine and a partial structure of pantethine, which has a lipid metabolism improving effect. However, aretin itself is only known to be used as a synthetic intermediate for pantethine and the like (Japanese Patent Publication No. 19484/1984).

As a result of extensive research into the pharmacological effects of aretin and its derivatives represented by the formula [■], the present inventors have discovered that these compounds have an excellent hepatotoxicity-suppressing effect. Until now, it was completely unknown that aretin and its derivatives had effective pharmacological effects.9 The present inventors have developed a new field of use of aretin and its derivatives.

This makes it possible to use it as a liver damage suppressant. From the pharmacological tests shown below, it is clear that aretin and its derivatives represented by formula 2 [I] have an excellent hepatotoxicity-suppressing effect.

Pharmacological Tests To investigate the inhibitory effect on liver damage, drugs that cause liver damage are administered to animals, and the effect of suppressing experimental liver damage is examined.

Carbon tetrachloride as a drug that causes experimental liver damage.

Thioacetamide, bromobenzene, paracetamol,
D-galactosamine, etc., but especially in carbon tetrachloride liver damage, the chlorine bond to carbon is cleaved by cytochrome P-450, producing a highly toxic free radical (CC13°), and this free radical breaks down the thiol group of hepatocyte membrane protein. CBiochem, Pharmacol, which is thought to cause damage by binding to membranes and promoting lipid peroxidation reactions in membranes.
, 21.49 (1972).

25.2163 (1976)].

In the present invention, in order to search for the inhibitory effect on liver damage, we used carbon tetrachloride as a drug that causes experimental liver damage, and investigated the liver damage inhibitory effect of nine compounds on serum transaminase (S-
GOT and 5-GPT) were investigated as indicators.

Next, the compounds used in the test are shown.

Compound ■: 3-amino-N-(2-mercaptoethyl)
Propionamide [β-aretin J Compound I [: 3- <benzyloxycarbonylamino)-N-(2-mercaptoethyl) Propionamide [N-benzyloxycarbonyl-β-aretin] Compound [11: 3-acetylamino- N-(2-acetylthioethyl)propionamide CN, S-diacetyl-β-aretin] Example Male Wistar rats weighing 170 to 200 y were included in each group of 6 rats and were fasted for 17 hours before being used in the experiment. Oral administration of Compound I ~ 300 kg per kg body weight [7 days]. Carbon tetrachloride was added at 0.25 me/kg of body weight (9 me/kg of body weight as an olive oil solution) 60 minutes after administration of each compound.
5 me per kg) was administered intraperitoneally.

In addition, as a control, only 5 ml of an olive oil solution per 1 kg of body weight was administered intracrotally. and carbon tetrachloride administration 2
Serum transaminases were measured 4 hours later.

As shown in Table 9, compared to the control group, compounds ■～■
Significant inhibition of 5-GOT and 5-GPT was observed.

Each numerical value in the table indicates the standard deviation above the mean. (6 animals per group) Acute toxicity value (LD50) Fi100 of toxicity test compound I ~ In
O! (Experimental animal) Male ddY (SPF) mouse (4 weeks old, body weight 19-21
y) were preliminarily reared for 1 week in a constant temperature and humidity (23±1'C, 55±5℃) breeding room with free access to solid feed (CE-2, made by Nippon Talea) and water, and the condition was stable. Those that showed good growth were used.

(Administration method) The test drug was suspended in 0.5% tragacanth solution.

Administered orally.

As is clear from the above pharmacological tests, the two compounds of the present invention are useful as liver damage suppressants.

The dosage is 10-10-100 ml per day for oral administration when used for the treatment of adults.
The range is 3000 capes, preferably 300 to 900 towns.

The composition of the present invention can be used as tablets or granules for internal use.

Powder and capsule dosage forms are used. For this purpose, binders such as ethylcellulose, polyvinylpyrrolidone, etc.
Excipients such as lactose, crystalline cellulose, disintegrating agents such as carboxymethylcellulose calcium, lubricants such as talc and colloidal silica, and conventional additives may be used as appropriate.

Formulation examples are shown below.

a) Tablet 6- Compound I 100! Ethylcellulose 50 ■Crystalline cellulose
80 ■ Carboxymethyl cellulose calcium 7q total
240 ■ Compound II
100 ethyl cellulose
50■Crystalline cellulose 80
W carboxymethylcellulose calcium
7ki total 240
Misaki compound ill 100! Ethyl cellulose 50 crystalline cellulose 5otI9 carboxymethylcellulose Calcium 7 Magnesium stearate 3q This tablet can be coated with a film as usual, and can also be sugar-coated. 25 town lactose
365■ total
5. . 4゜C) Powder compound 11 200 kg lactose
450q starch
320'ilp meter
1000”Pd) Capsule Compound II 100machi Lactose
32tng crystalline cellulose 5611 total
190 ■ Compound III
1009 glycerin
279.98g1g Applicant: Santen Pharmaceutical Co., Ltd.

Agent Toshio Takigawa 9- 93

Claims (1)

[Scope of Claims] A liver damage suppressant containing a compound represented by formula CI) as a main component. R”-NHCH2CH2CONHCH2CH2S-R2
O) [In the formula, R1 represents a hydrogen atom, an acetyl group, or a benzyloxycarbonyl group. R2 represents a hydrogen atom or an acetyl group. However, R1
When represents a benzyloxycarbonyl group', R2U does not represent an acetyl group. ]