JPH0753375A - Therapeutic agent for hepatopathy - Google Patents

Abstract

PURPOSE:To provide a therapeutic agent for hepatopathy having suppressive activity against decline in hepatic function and improving effect for hepatic function, effective against the rise of the serum GPT, GOT and LDH of experimental rats with hepatopathy, containing, as the active ingredient, a specific cycloheptenopyridine derivative or a salt thereof. CONSTITUTION:The objective therapeutic agent containing, as the active ingredient, a cycloheptenopyridine derivative of the formula ( R<1> is H or methyl; R<2> is H or methoxy; n is 0 or 1) or a salt thereof [e.g. 9-(benzimidazole-2-yl) sulfinyl-4-methoxy-2, 3-cycloheptenopyridine sodium salt]. This agent can be obtained by mixing the active ingredient with a carrier as solid or liquid vehicle followed by, where appropriate, incorporation of disintegrant, lubricant, analgesic agent etc., and then pharmaceutical manufacturing into the form of a solid such as tablets, capsules, granules, powder or fine granules, or a liquid such as injection.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a preventive and therapeutic agent for liver diseases, and more particularly to a therapeutic agent for liver diseases containing a cycloheptenopyridine derivative or a salt thereof as an active ingredient.

[0002]

2. Description of the Related Art The liver contains viruses, drugs, alcohol,
It is damaged by various factors such as malnutrition and hepatic circulatory system disorder, and causes liver diseases such as acute hepatitis, chronic hepatitis, fatty liver, jaundice, and cirrhosis. Only a few other malotilates are clinically used as therapeutic agents for these liver diseases. Even antiviral agents such as interferon have not been able to eliminate the hepatitis virus steadily, and no clear effective therapeutic agents have been found, including rest, fluid therapy, steroids, drug therapy with immunostimulants, etc. It is not.

[0003]

As described above, at present, no satisfactory therapeutic agent has been found for liver diseases, especially chronic diseases. In particular, drug therapy with antiviral agents, steroids, and immunostimulants has a problem of serious side effects.

[0004]

Means for Solving the Problems As a result of intensive studies for the purpose of developing a more effective therapeutic agent for liver diseases, the present inventors have found that the cycloheptenopyridine derivative represented by the general formula (I) is remarkable. The present invention was completed by discovering that it has a clear inhibitory effect on liver function or an improvement effect. The present invention has the general formula (I)

[Chemical 2] (Wherein R ¹ is a hydrogen atom or a methyl group, R ² is a hydrogen atom or a methoxy group, and n is 0 or 1), and a liver disease treatment containing a cycloheptenopyridine derivative or a salt thereof as an active ingredient It is an agent.

The salt of the compound (I) is a salt with a pharmacologically acceptable acid or base, for example, a salt with an inorganic acid such as hydrochloride, sulfate or nitrate, oxalate or succinate. And an addition salt with a suitable alkali metal ion such as sodium salt, potassium salt, magnesium salt and the like. The above compound (I) is disclosed in JP-A-3-2
It can be produced by the method described in Japanese Patent No. 18372.

To use the compound (I) of the present invention as a prophylactic and therapeutic agent for liver diseases, for example, the compound (I) of the present invention is mixed with a carrier of a solid or liquid excipient, and the compound is orally or non-orally administered. It can be prepared and used in a form suitable for oral administration (for example, intramuscular injection, intravenous injection, subcutaneous administration, rectal administration, transdermal administration, etc.). The solid preparation can be prepared into tablets, capsules, granules, powders and fine granules, and an enteric coating agent may be prepared by a coating method. The liquid preparation can be prepared by forming the alkali salt and the physiologically acceptable salt of the compound (I) of the present invention, and then dissolving the salt in water.

In order to prepare the above-mentioned preparation, it can be manufactured by mixing a medically acceptable additive and according to a conventional method for manufacturing a preparation. In the case of orally-administered preparations as additives, excipients (eg lactose, corn starch, crystalline cellulose, mannitol, maltitol etc.), disintegrants (eg partially pregelatinized starch, croscarmellose sodium, carboxymethyl starch sodium) , Low-substituted hydroxypropyl cellulose, etc.), lubricants (eg, magnesium stearate, talc, etc.) and the like. In the case of an injectable preparation for injection, an excipient (eg, sodium dihydrogen phosphate, sodium hydrogen phosphate), a soothing agent (eg, chlorobutanol, xylocaine hydrochloride, etc.) and the like can be mentioned.

The dose varies depending on the age of the patient, the type of disease, the degree, etc., but in general, for adults, the daily dose is 20 to 1000 mg, preferably 50 to 500 m by oral administration.
When administered parenterally, it varies depending on the patient's age, type of disease, degree, etc.
The dose is 2 to 100 mg, preferably 5 to 50 mg, and may be administered in 1 to 3 divided doses depending on the symptoms.

[0009]

EXAMPLES The test results showing the pharmacological effects of the compound (I) of the present invention are shown below. [Hepatopathy inhibitory effect] Test compound A [Compound (A)]: 9
-(Benzimidazol-2-yl) sulfinyl-4
- methoxy-2,3 cycloheptenylidenephenyl Tenofovir pyridine sodium salt ^{(R 1 = Na, R 2} = OCH 3, n = 1) Test Compound B [compound (B)]: 9- (benzimidazol-2-yl) thio methoxy-2,3 cycloheptenylidenephenyl Tenofovir pyridine ^{(R 1 = H, R 2} = OCH 3, n =
0) Test Example 1 [Action on D-galactosamine-induced liver injury] (Sample) Compound (A) Compound (B) Malotilate (control drug): isopropyl 1,3-dithiol-2-ylidene malonate (test animal) Male SD rat (8-10 weeks old, weight 25
A group of 9 to 10 animals was used for the test.

(Test method) A sample was prepared by suspending it in 0.5% CMC sodium solution (adjusted to pH 10.5) and
Oral administration was performed once daily for 2 days. A control group was prepared by administering only 0.5% CMC sodium solution (adjusted to pH 10.5%). Rats were orally administered with the sample solution and 0.5% sodium CMC solution per 5 ml / kg body weight, respectively. One hour after the final administration on the second day, D-galactosamine (400 mg / kg) was dissolved in distilled water, and 4 ml / kg was intraperitoneally injected. Twenty-four hours after the administration of D-galactosamine, blood was collected from the abdominal aorta of the rat under ether anesthesia, and the plasma GPT, GOT and LDH values were measured after centrifugation. As a non-treatment group, 5 male SD rats were collected as a group under ether anesthesia and centrifuged, and plasma GPT, GOT and LDH values were measured and set as normal values. The test results are shown by the plasma enzyme activity (GPT, GOT and LDH) increase suppression rate (%) calculated by the following formula. Inhibition rate of increase in plasma enzyme activity (%) = X / Y × 100 X = plasma enzyme activity of control group-plasma enzyme activity of various sample groups Y = plasma enzyme activity of control group-normal plasma enzyme activity

(Results) The results are shown in Table 1.

[Table 1]

Test Example 2 [Action on carbon tetrachloride-induced liver injury] (Sample) Compound (A) Compound (B) (Test animal) Male SD rat (8-10 weeks old, body weight 25)
A group of 4 to 10 animals was used for the test. (Test Method) A sample was prepared by suspending it in a 0.5% CMC sodium solution (pH adjusted to 10.5 with a carbonate buffer) and orally administered once a day for 2 days. A control group was prepared by administering only a 0.5% CMC sodium solution (adjusted to pH 10.5 with carbonate buffer). Sample solution and 0.
Rats were orally dosed with 5% CMC sodium solution per 5 ml / kg body weight, respectively. One hour after the final administration on the second day, 1 ml / kg of 2.5% carbon tetrachloride (V / V, olive oil) was intraperitoneally injected. Twenty-four hours after the administration of carbon tetrachloride, blood was collected from the abdominal aorta of the rat under ether anesthesia,
After centrifugation, plasma GPT, GOT and LDH values were measured. In addition, as a non-treatment group, 5 male SD rats were treated as one group, blood was collected under ether anesthesia, centrifuged, and plasma GP was added.
The T, GOT and LDH values were measured and regarded as normal values. The test results are the plasma enzyme activity (GP
T, GOT, and LDH) increase inhibition rate (%).

(Results) The results are shown in Table 2.

[Table 2] [Acute toxicity] These compounds have extremely low toxicity to humans and mammals. For example, the acute toxicity of compound (A) L
D ₅₀ value (oral) is 711 mg / k in rats (male)
g, 2000 mg / kg or more in mouse (male),
It is a highly safe compound.

Formulation Example 1 The present invention will be specifically described below with reference to test examples and formulation examples of compound (I). The present invention is not limited to these examples. Tablet Compound (A) 100 mg Maltitol 135.5 mg Partially pregelatinized starch 60 mg Magnesium stearate 3 mg Talc 1.5 mg ──────────────────────── ── Total amount 300 mg One tablet 300 mg was prepared by a conventional method. One tablet contains 100 mg of compound (A). Formulation Example 2 Powder, capsule Compound (A) 100 mg Corn starch 197 mg Talc 3 mg The above powders were mixed to give a powder. Further, this powder was filled in a No. 1 hard gelatin capsule to prepare a capsule. One capsule contains 100 mg of the compound (A).

[0015]

INDUSTRIAL APPLICABILITY The compound (I) of the present invention markedly suppresses the elevation of serum GPT, GOT and LDH in D-galactosamine- or carbon tetrachloride-induced experimental liver injury rats and prevents liver diseases. Alternatively, it is a therapeutically effective drug.

Claims (1)

[Claims] 1. A compound represented by the general formula (I): (Wherein R ¹ is a hydrogen atom or a methyl group, R ² is a hydrogen atom or a methoxy group, and n is 0 or 1), and a liver disease treatment containing a cycloheptenopyridine derivative or a salt thereof as an active ingredient Agent.