JPS6344728B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the following general formula () [In the formula, R represents a lower alkyl group, and n represents an integer of 2 to 9. ] The present invention relates to a therapeutic agent for liver diseases containing a lower alkyl polyprenylcarboxylate represented by the following. The liver is often considered to be a delicate chemical factory because of its various functions. In this way, various chemical reactions take place in the liver, such as detoxification, sugar metabolism, protein metabolism, lipid metabolism, bile production and secretion, hormone regulation, blood coagulation prothrombin formation, hepatocyte regeneration, and various essential biological components (fat and fat metabolism). , carbohydrates, proteins, and vitamins) storage, etc. However, despite its delicate and well-balanced functions, the liver can sometimes be damaged acutely or chronically by various factors such as alcohol, nutritional deficiencies, viral infections, chemicals, and toxins. Diseases such as liver necrosis, fatty liver, bile secretion disorder, and liver cirrhosis will occur. Glycyrrhizin can be mentioned as a drug currently widely used for the treatment and prevention of these diseases. Glycyrrhizin can cause liver damage, cirrhosis,
It is said to be effective in treating hepatitis and protecting the liver after surgery, but its medicinal effects are not very strong.
The development of even better drugs is expected. As a result of extensive research, the present inventors discovered that the compound represented by the general formula () activates hepatocytes and has effects on glucose metabolism, detoxification, and bile production. It was discovered that the drug exerts a healing effect and reduces damage to the liver, achieving its intended purpose as a treatment for liver diseases. That is, the results of pharmacological tests supporting the excellent therapeutic effects of the compounds of the present invention are as described below. <Pharmacological test> Test compound The following compounds were selected from the compounds of the present invention () as test compounds. Ethylgeranylgeranoate (hereinafter referred to as the present compound A) toethoxycarbonyl 2,6,10,14,18,
22,26,30,34,38-decamethyl-nonatriacontadecaene 1,5,9,13,17,21,25,29,
33, 37 (hereinafter referred to as the compound B of the present invention) Glycyrrhizin was selected as the standard drug. Experimental method 1 Protective effect against experimental acute liver injury induced by D-galactosamine The protective effect of the test compound against acute liver injury experimentally induced by D-galactosamine was investigated. As a laboratory animal, S weighs around 250g.
Using D-type rats, D-galactosamine (hydrochloride 250 mg/Kg each time) and the test compound (50 mg/Kg each time) were administered.
Kg) was administered intraperitoneally on the following schedule, and blood was collected from the experimental animals after drug administration, and the GOT value,
GPT value, alkaline phosphatase value and total cholesterol amount were measured. The test compound was administered after being suspended in a 5% aqueous gum arabic solution, and D-galactosamine hydrochloride was dissolved in distilled water and the pH was adjusted to 7 with an aqueous potassium hydroxide solution before administration. In parallel with setting up the test animal group to which the test compound was administered (test compound group, 8 animals per group),
A test animal group to which a 5% gum arabic aqueous solution was administered instead of the test compound (control group, 8 animals per group);
An untreated test animal group (normal group, 8 animals per group) was established. Experimental results The GOT value, GPT value, alkaline phosphatase value, total cholesterol amount of the test compound group, and those of the control group and normal group are listed below.

[Table] As is clear from this table, compounds A and B of the present invention
inhibited the increase in GOT value, GPT value, alkaline phosphatase value, and total cholesterol level, and its inhibitory effect was superior to that of glycyrrhizin. 2. Acute Toxicity (LD ₅₀ ) Test for Acute Toxicity Using normal Wistar rats as test animals, the compounds A and B of the present invention were suspended in a 5% aqueous gum arabic solution and orally administered. LD ₅₀ >4000 mg/Kg Based on the above, the compound () of the present invention can be used as a low toxicity therapeutic agent for liver diseases for the treatment and prevention of the above-mentioned diseases. The administration method and dosage of the compound of the present invention () can be appropriately selected and adjusted depending on the disease to be treated and its symptoms, but the oral dosage for adults is 10 to 1000 mg, preferably 50 to 200 mg per day. The compounds of the invention () can be prepared for administration using conventional formulation techniques. Therefore, the present invention also includes a pharmaceutical composition containing at least one compound represented by the general formula () or a pharmaceutically acceptable salt, which is suitable as a human medicine. Such compositions are provided for use in a conventional manner with any required pharmaceutical carriers or excipients. Desirably, the composition is provided in a form suitable for absorption from the gastrointestinal tract. Tablets and capsules for oral administration are in unit dosage form and contain binders such as syrup, acacia, gelatin, sorbit, tragacanth, or polyvinylpyrrolidone, excipients such as lactose, sugar, corn starch, calcium phosphate, sorbitate, or It may contain conventional excipients such as glycine, lubricants such as magnesium stearate, talc, polyethylene glycol or silica, disintegrants such as potato starch, or acceptable wetting agents such as sodium lauryl sulfate. The tablets may be coated by methods well known in the art. Oral liquid preparations may be aqueous or oily suspensions, solutions, syrups, elixirs, etc., or they may be dry products for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain commonly used additives such as suspending agents such as sorbitol syrup, methylcellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats, Emulsifiers such as lecithin, sorbitan monooleate or gum arabic, non-aqueous vehicles such as almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol, preservatives such as methyl p-hydroxybenzoate, propyl p-hydroxybenzoate or sorbin. It may contain an acid. Compositions for injection may be presented in unit-dose ampoules or in multi-dose containers with an added preservative. The compositions may be in the form of suspensions, solutions, emulsions in oily or aqueous vehicles, suspending agents,
Formulation agents such as stabilizing and/or dispersing agents may also be included. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, eg sterile pyrogen-free water, before use. Prescriptions using the compound ethylgeranylgeranoate (hereinafter abbreviated as the main drug) of the present invention will be described as examples. Example 1 Capsule main drug 5g Microcrystalline cellulose 80g Corn starch 20g Lactose 22g Polyvinylpyrrolidone 3g Total amount 130g The above ingredients were granulated by a conventional method and then filled into 1000 hard gelatin capsules. Each capsule contains 5mg of the active ingredient. Example 2 Powder main drug 50g Microcrystalline cellulose 400g Corn starch 550g Total amount 1000g The main drug was dissolved in acetone, then adsorbed on microcrystalline cellulose, and then dried. This was mixed with corn starch and a 20-fold powder of the main drug was prepared as a powder using a conventional method. Example 3 Tablet main drug 5g Corn starch 10g Refined white sugar 20g Carboxymethylcellulose calcium 10g Microcrystalline cellulose 40g Polyvinylpyrrolidone 5g Talc 10g Total amount 100g The main drug was dissolved in acetone, then adsorbed on microcrystalline cellulose, and then dried. did. Corn starch, refined sucrose, and carboxymethyl cellulose calcium were mixed with this, and then an aqueous solution of polyvinylpyrrolidone was added as a binder, and the mixture was granulated by a conventional method. Talc was added as a lubricant to this, mixed, and then tableted into 100 mg tablets. Each tablet contains 5mg of the active ingredient. Example 4 Injection active ingredient 10g Nikkol HCO-60 37g Sesame oil 2g Sodium chloride 9g Propylene glycol 40g Phosphate buffer (0.1M, PH6.0) 100ml distilled water Total volume 1000ml Active ingredient Nikkol HCO-60, sesame oil and half of propylene glycol were mixed and dissolved by heating at about 80°C, and to this was added a phosphate buffer solution and distilled water in which sodium chloride and propylene glycol had been dissolved in advance at about 80°C to make an aqueous solution with a total volume of 1000 ml. This aqueous solution was dispensed into 2 ml ampoules, which were sealed and sterilized by heating. Each tube contains 20mg of the main drug.

Claims (1)

[Claims] 1. General formula [In the formula, R represents a lower alkyl group, and n represents an integer of 2 to 9. ] A liver disease therapeutic agent containing a carboxylic acid lower alkyl ester represented by: 2. The liver disease therapeutic agent according to claim 1 _, wherein n=2 and R= _C2H5 . 3. The liver disease therapeutic agent according to claim 1 _, wherein n=3 and R= _C2H5 . 4. The liver disease therapeutic agent according to claim 1, wherein n= ₉ and R= _C2H5 .