JPH05301816A - Anti-aids agent - Google Patents

Abstract

PURPOSE:To obtain an anti-AIDS agent, comprising gomisin J having hypotensive action, etc., and gomisin A having improving action, etc., on hepatopathy as an active ingredient and capable of preventing infection of a normal cell with AIDS virus, on the other hand, with hardly any side effects. CONSTITUTION:The objective anti-AIDS agent comprises a compound expressed by the formula (R2 and R4 are OH and R3 is H when R1 is methoxyl; i.e. gomisin J or R3 is OH and R4 is methoxyl when R1 and R2 denote a cyclic form by methylendioxy, i.e. gomisin A) as an active ingredient. The gomisins J and A have the anti-HIV activity in vitro with hardly any side effects in vivo. The gomisins J and A can directly or, together with a usually used pharmaceutical carrier, be administered to animals and humans. The administration form is an oral agent such as a tablet, a capsule, a granule, a fine granule or powder, a parenteral agent such as a parenteral injection or a suppository, etc., The dose of the oral agent is usually preferably 30mg to 0.5g expressed in terms of the weight of the gomisin J or A for an adult.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an anti-AIDS agent effective against diseases (AIDS) caused by human immunodeficiency syndrome virus (HIV).

[0002]

2. Description of the Related Art Conventionally, extensive research has been conducted to develop a therapeutic agent for AIDS (acquired immunodeficiency syndrome), and various drugs such as antiviral agents have been developed.

On the other hand, the following equation (1) Of the compounds represented by, R ₁ is a methoxyl group, R ₂ and R ₄
The compound in which is a hydroxyl group and R ₃ is a hydrogen atom is gomisin J, and it has been conventionally known to have a pharmacological effect such as an antihypertensive action (Patent Publication No. 42421 of 1988). Also,
Among the compounds represented by the formula (1), a compound in which R ₁ and R ₂ are cyclic with a methylenedioxy group, R ₃ is a hydroxyl group, and R ₄ is a methoxyl group is conventionally known as a liver damage-improving effect, etc. It is known to have the pharmacological effect of
No. 82315).

[0004]

The drugs that have been conventionally studied as effective in treating AIDS have problems such as strong side effects and the emergence of drug-resistant virus strains relatively early.

[0005] As an example, the antiviral agents of nucleic acid derivatives that have been studied so far have a mechanism of action that inhibits DNA synthesis in the replication process of HIV and suppresses the proliferation of HIV. At the same time, DNA synthesis in normal cells is also suppressed,
There was a problem of causing serious side effects.

Therefore, it has been desired to develop a drug which has a high pharmacological effect in the living body and has few side effects.

[0007]

[Means for Solving the Problems] As a result of intensive studies to solve the above problems, the present inventors have found that gomisin J and gomisin A have anti-HIV activity in vitro and also have side effects in vivo. They found that there were few and completed the present invention.

That is, while conventional drugs inhibit DNA synthesis in the process of HIV replication and suppress HIV growth, Gomisin J and Gomisin A prevent infection of normal cells with AIDS virus. It is excellent in that it has few side effects.

A method for producing the garbage Shin J is disclosed in Japanese Patent Application Laid-Open No. 64-42421.
No.

[0010] The method for producing Gomisin A is described by Taguchi et al.
m. Pharm. Bull. (Tokyo), 23, 3296 (1975) and Taguchi et al., Chem. Pharm. Bull. (Tokyo), 25, 3
Page 64 (1977), and an improved manufacturing method thereof is described in JP-A-2-48592.

Next, it will be explained that gomisin J and gomisin A are useful as anti-AIDS agents by way of experimental examples.

Experimental Example 1 [Experimental Method] SupT ₁ cells (1.0 × 10 ⁶ cells) were infected with AIDS virus [HIV-1 (◆ B); about 20 TCID ₅₀ (50% of Tissue Culture I
Inhibition Dose)] at 37 ° C. under 5% carbon dioxide for 1 hour, and then inoculate the infected cells (0.4 × 10 ⁵ (Cells / well), 4 at 37 ° C, 5% CO2
Cultured for a day.

In the above experiment, the experimental result without using the test drug was used as a control.

The suppression of cell damage due to infection is determined by culturing multi-nucleated giant cells (GIANT CELL;
The number of cells was calculated and determined by comparing with the control. The results are shown in Table 1. Table 1

Experimental Example 2 [Experimental Method] AIDS virus [HIV-1 (◆ B); about 20 TCID ₅₀ (50% of Tiss) on MT-4 cells (T cell line system) 1.0 × 10 ⁶ cells
ue Culture Inhibition Dose)] at 37 ° C under 5% carbon dioxide for 1 hour, and then infected cells (0.
4 × 10 ⁵ cells / well) were seeded and cultured at 37 ° C. under 5% carbon dioxide for 5 days.

In the above experiment, the result of experiment without Gomisin J was used as a control.

The determination of suppression of cell damage due to infection was determined by measuring living cells after culturing for 5 days by the MTT method.
The results are shown in Table 2. Table 2

Experimental Example 3 [Experimental Method] Clone H9 cells 1.0 × 10 ⁶ cells with AIDS virus
[HIV-1 (◆ B); about 20 TCID ₅₀ (50% of Tissue Culture Inh
ibition Dose)] at 37 ° C and 5% carbon dioxide for 1 hour, and then prepare CloneH9 cells to a final concentration of 1 × 10 ⁵ cells / ml, then at 37 ° C and 5% carbon dioxide. Cultured for 5 days. After culturing for 5 days, the culture supernatant is collected by centrifugation,
P24 antigen in the collected culture supernatant (p24 antigen; g
ag protein) to the p24 detection kit (p24 detecti
on kit; manufactured by COULTER) and measured by the ELISA method. A calibration curve was prepared using the antigen reagent included in the kit as a positive control. Each measured data was converted into grams from the calibration curve, and the p24 amount of the drug-untreated group was set to 100, and the p24 amount of the drug-treated group (Gomisin J and Gomisin A) was converted. Furthermore, the inhibition rate was defined as the decrease in p24. The results are shown in Table 3. Table 3

From the above experimental results, it was confirmed that gomisin J and gomisin A have high pharmacological effects as anti-AIDS agents.

Next, the acute toxicity by intraperitoneal administration in mice was 750 mg / kg for Gomisin J and 390 mg / kg for Gomisin A.
Since it was kg, no acute toxicity was observed at the effective dose, confirming low toxicity.

Next, doses of Gomisin J and Gomisin A and formulation examples will be described.

Gomisin J and Gomisin A can be administered to animals and humans as they are or together with conventional pharmaceutical carriers. The dosage form is not particularly limited and may be appropriately selected and used as needed, and examples thereof include oral preparations such as tablets, capsules, granules, fine granules and powders, parenteral preparations such as injections and suppositories. Be done.

In order to exert a desired effect as an oral preparation, it varies depending on the age, body weight and degree of disease of the patient, but usually, in adults, the weight of gomisin J or gomisin A is 30 mg or more.
It seems appropriate to take 0.5g in several divided doses a day.

Oral preparations include, for example, starch, lactose, sucrose,
Mannitol, carboxymethyl cellulose, corn starch, inorganic salts and the like are used according to a conventional method.

In addition to the above-mentioned excipients, a binder, a disintegrating agent, a surfactant, a lubricant, a fluidity promoter, a flavoring agent, a coloring agent, a flavoring agent, etc., may be appropriately used in this type of formulation. You can
Specific examples of each are as follows.

[Binder] Starch, dextrin, gum arabic powder, gelatin, hydroxypropyl starch, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose,
Ethyl cellulose, polyvinylpyrrolidone, macrogol.

[Disintegrant] Starch, hydroxypropyl starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, low-substituted hydroxypropyl cellulose.

[Surfactant] sodium lauryl sulfate, soybean lecithin, sucrose fatty acid ester, polysorbate 8
0.

[Lubricant] Talc, waxes, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol.

[Flowability Accelerator] Light anhydrous silicic acid, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate.

Gomisin J and Gomisin A can also be administered as suspensions, emulsions, syrups and elixirs, and these various dosage forms contain a flavoring agent and a coloring agent. Good.

In order to exert the desired effect as a parenteral agent, it depends on the age, weight and degree of disease of the patient.
5 as a weight of Gomisin J and Gomisin A in normal adults per day
Intravenous injection, intravenous infusion, subcutaneous injection, and intramuscular injection of mg to 50 mg seem appropriate.

This parenteral preparation is manufactured by a conventional method, and is generally used as a diluent in distilled water for injection, physiological saline, glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol. Etc. can be used. Further, if necessary, a bactericidal agent, a preservative, and a stabilizer may be added. Further, from the viewpoint of stability, this parenteral preparation can be frozen after filling in a vial or the like, water is removed by a usual freeze-drying technique, and a liquid preparation can be re-prepared from the freeze-dried product immediately before use. Further, if necessary, a tonicity agent, a stabilizer, a preservative, a soothing agent and the like may be added appropriately.

Other parenteral agents include external preparations, coating agents such as ointments, and suppositories for rectal administration.
It is manufactured according to a conventional method.

Next, examples of the preparation of the present invention will be described. [Example 1] According to the above prescription, the ingredients (1) to (2) were uniformly mixed and compression-molded with a tableting machine to give 200 mg tablets. 20 mg of Gomisin A is contained in each tablet, and 3 to 10 tablets for adults are to be taken in divided doses.

[Example 2] Crystalline cellulose 84.5 g Magnesium stearate 0.5 g Carboxymethyl cellulose calcium 5 g Gomisin J 10 g Total 100 g According to the above formulation, a part of and was uniformly mixed, compression-molded, and then pulverized, The remaining amounts of and were added and mixed, and compression molding was carried out using a tableting machine to obtain tablets of 200 mg each. This tablet contains 20 mg of Gomisin J, and 3 to 10 tablets for adults are to be taken in divided doses.

Example 3 Crystalline Cellulose 79.5 g 10% Hydroxypropyl Cellulose Ethanol Solution 50 g Carboxymethyl Cellulose Calcium 5 g Magnesium Stearate 0.5 g Gomisin A 10 g Total 145 g According to the above formulation, and were uniformly mixed and mixed by a conventional method. The mixture was mashed, granulated by an extrusion granulator, dried and crushed, and were mixed and compression-molded by a tableting machine to obtain a tablet of 200 mg. 20 mg of Gomisin A is contained in each tablet, and 3 to 10 tablets for adults are to be taken in divided doses.

[Example 4] According to the above prescription, were uniformly mixed, compression-molded by a compression molding machine, crushed by a crusher, and sieved to obtain a granule. 1g of this granule contains 100mg of Gomisin J, and adults take 0.6 to 2g in several divided doses a day.

Example 5 Crystalline Cellulose 86.5 g 10% Hydroxypropyl Cellulose Ethanol Solution 35 g Gomisin A 10 g Total 131.5 g According to the above-mentioned prescription, were uniformly mixed and kneaded. After granulating with an extrusion granulator, it was dried and sieved to obtain granules. 1 g of this granule contains 100 mg of gomisin A, and 0.6 to 2 g of an adult is taken in several divided doses a day.

[Example 6] Corn starch 89.5 g Light anhydrous silicic acid 0.5 g Gomisin J 10 g Total 100 g According to the above-mentioned formulation, 1 to 3 were uniformly mixed, and 200 mg was filled in a No. 2 capsule. One capsule of this capsule contains
It contains 20 mg of Gomisin J, and 3 to 10 capsules for an adult should be taken in divided doses.

[Example 7] Distilled water for injection 89.5g Soybean oil 5g Soybean phospholipid 2.5g Glycerin 2g Gomisin A 1g Total amount 100g An injection was obtained.

Claims (1)

[Claims] 1. The following formula (1) (In the formula, when R ₁ represents a methoxyl group, R ₂ and R ₄ are hydroxyl groups, R ₃ represents a hydrogen atom, and when R ₁ and R ₂ represent a ring by a methylenedioxy group, R ₃ represents a hydroxyl group, R ₄ represents a methoxyl group.) An anti-AIDS agent containing a compound represented by the formula as an active ingredient.