JPH0616561A - Antiretroviral agent - Google Patents

Abstract

(57) [Summary] [Object] The present invention aims to provide a drug having an antiretroviral activity and useful as an antiviral agent. [Structure] The present inventors have found that compounds such as Cibacron Brilliant Red 3B-A, which have been used as pigments, are anti-HI.
It was found to have V activity. The present invention is based on the above findings, and is based on Cibacron Brilliant Red 3B.
-An antiviral agent containing 13 kinds of pigments such as A as an active ingredient.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an antiretroviral agent effective in treating various viral diseases caused by retroviruses.

[0002]

2. Description of the Related Art As researches on viruses have been conducted, therapeutic methods for viral diseases are gradually being established.

In particular, HIV (Human Immunodeficienc) that causes acquired immunodeficiency syndrome (AIDS), which has recently become a problem
y Virus) is known as a retrovirus.

Retroviruses are RNAs in viral particles.
It is a virus containing dependent DNA synthase (hereinafter, referred to as reverse transcriptase), and propagates as follows.

After infecting a host cell, viral RNA is first transcribed into DNA by reverse transcriptase.

This DNA is integrated into the host cell chromosome, and then mRNA is synthesized by the RNA synthase of the host cell.

Various viral proteins are produced by this mRNA.

It has been desired to develop a drug having an epoch-making therapeutic effect on the human disease caused by this retrovirus.

[0009]

Means for Solving the Problems The present inventors have conducted various studies on the retroviral growth inhibitory effect of various compounds, and as a result, several compounds used as pigments have a retroviral growth inhibitory effect. After finding out that there was something, the present invention was completed.

That is, the present invention provides the following formulas I, II, III and I
It is an antiretroviral agent containing the compounds represented by V, V, VI, VII and VIII as an active ingredient. Formula I (However, in the formula, R ₁ is Or Indicates. Formula II (However, R ₂ in the formula is And R ₃ represents a hydrogen atom or a methyl group. ). Formula III (However, in the formula, R ₄ represents a hydrogen atom or a sodium atom, and R ₅ represents Indicates. ) Formula IV Formula V Formula VI Formula VII Formula VIII

Hereinafter, the compounds represented by the formulas I to VIII are referred to as the compounds of the formula.

To specifically exemplify the compound of the formula:
The compounds shown in 1 are mentioned, and may be referred to by the compound numbers below.

[0013]

[Table 1]

All compounds of the above formula are commercially available from Aldrich Chemical Campany Inc.

The compound of the formula has been conventionally used for colorimetric determination of metals and dyeing, but it has never been known to have an antiretroviral effect.

Next, the fact that the compound of the formula has an antiretroviral effect will be described with reference to experimental examples.

Experimental Example <Anti-AIDS virus activity test using MT-4 cells (T cell line system)>

2 × 10 ⁴ MT-4 cells (T cell line system) were placed per well in a 96-well microplate. Then, human immunodeficiency virus (H9 / HTLV-III B cell supernatant) was added to each of these holes at 10 to 20 TCID ₅₀ (50% of Tissue Culture In
Inhibition Dose) was put in and infected. Next, serially diluted test substances were placed in each hole. After culturing this plate at 37 ° C. under 5% carbon dioxide for 5 days, the cytotoxicity was measured by the MTT method, and the 50% inhibitory concentration (IC ₅₀ , μg / ml) of the compound of the formula was determined.

In the absence of human immunodeficiency virus, the cytotoxic concentration (CC ₅₀ , μg / ml) was determined, and the ratio of 50% inhibitory concentration to cytotoxic concentration (SI, CC ₅₀ / IC ₅₀ ) was calculated. did.

The results are shown in Table 2.

[0020]

[Table 2]

From the results of the experimental example, it was confirmed that the compound of the formula has an antiretroviral effect.

The compound of formula can be applied to any virus as long as it is a retrovirus, and specific examples of the retrovirus include leukemia virus, sarcoma virus, breast cancer virus, visna virus, maedi virus, HIV. (Human Immunodeficiency Virus), HTLV-I (Hu
man T cell Leukemia Virus Type I) and the like.

Next, the fact that the compound of the formula has low toxicity and high safety is demonstrated by showing the results of acute toxicity experiments.

[0024] Acute toxicity test was conducted using 100 mg / kg of Compounds 1 to 13.
Was intraperitoneally administered to 5 mice each, and the survival number of the mice was examined 7 days later. As a result, no death was observed for Compounds 1 to 13.

From the results of the acute toxicity experiment, these compounds were shown to have low toxicity and high safety.

The dosage and formulation of the compound of formula will now be described.

The compounds of formula can be administered to animals and humans neat 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 agents such as tablets, capsules, granules, fine granules and powders, parenteral agents such as injections and suppositories. To be

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 10 mg to 1 g as the weight of the compound of formula is administered to an adult several times daily. It seems appropriate to take them separately.

In the present invention, oral preparations such as tablets, capsules, granules and the like are produced by a conventional method using, for example, starch, lactose, sucrose, mannitol, carboxymethyl cellulose, corn starch, inorganic salts and the like.

In addition to the above-mentioned excipients, a binder, a disintegrant, 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 preparation. You can
Specific examples of each are as shown below.

[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.

The compounds of formula can also be administered as suspensions, emulsions, syrups and elixirs, and these various dosage forms may contain flavoring agents and coloring agents.

In order to exert the desired effect as a parenteral agent, it depends on the age, body weight and degree of disease of the patient.
In general, it is considered that intravenous injection, intravenous infusion, subcutaneous injection, and intramuscular injection of 0.5 to 50 mg per day as the weight of the compound in an adult are considered 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 bactericide, a preservative, and a stabilizer may be added. Further, from the viewpoint of stability, this parenteral preparation may be filled in a vial or the like and then frozen, the water content may be removed by a usual freeze-drying technique, and a liquid preparation may be re-prepared from the freeze-dried product immediately before use. Further, an isotonicity agent, a stabilizer, a preservative, a soothing agent and the like may be added as needed.

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, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

Example 1 According to the above prescription, the ingredients (1) to (4) were uniformly mixed and compression-molded with a tableting machine to give tablets (200 mg each).

Each tablet contains 20 mg of compound 1, and 3 to 10 tablets for adults are to be taken in several divided doses.

Example 2 According to the above formulation, a part of and was uniformly mixed, compression-molded, then crushed, and the remaining amount of was added and mixed, and compression-molded with a tableting machine to obtain a tablet of 200 mg. .

Each tablet contains 20 mg of Compound 2, and 3 to 10 tablets for adults are to be taken in several divided doses.

Example 3 Crystalline cellulose 34.5 g 10% Hydroxypropyl cellulose ethanol solution 50 g Carboxymethyl cellulose calcium 5 g Magnesium stearate 0.5 g Compound 3 10 g Total 100 g According to the above formulation, and were uniformly mixed and mixed by a conventional method. Then, after granulating with an extrusion granulator, drying and crushing, and were mixed and compression-molded with a tableting machine, one tablet of 200 mg was obtained.

Each tablet contains 20 mg of Compound 3, and 3 to 10 tablets for adults are to be taken in several divided doses.

Example 4 Corn starch 84 g Magnesium stearate 0.5 g Carboxymethylcellulose calcium 5 g Light anhydrous silicic acid 0.5 g Compound 4 10 g Total 100 g According to the above recipe, the Were pulverized and sieved to obtain granules.

1 g of this granule contains 100 mg of compound 4, and 0.6 to 2 g of an adult is taken in several divided doses per day.

Example 5 Crystalline cellulose 55 g 10% Hydroxypropyl cellulose ethanol solution 35 g Compound 5 10 g Total 100 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 Compound 5, and 0.6 to 2 g of an adult is taken in several divided doses per day.

Example 6 According to the above formulation, was mixed uniformly and 200 mg was filled in No. 2 capsule.

Compound 6 is contained in one capsule of this capsule.
It contains 20 mg, and 3 to 10 capsules for an adult should be taken in several divided doses.

Example 7 After dissolving and in distilled water for injection, the mixture was poured into a 5 ml ampoule and autoclaved at 121 ° C. for 15 minutes to obtain an injection.

Claims (8)

[Claims] 1. The following formula I (However, in the formula, R ₁ is Or An antiretroviral agent comprising a compound represented by as an active ingredient. 2. The following formula II (However, R ₂ in the formula is And R ₃ represents a hydrogen atom or a methyl group. An antiretroviral agent containing a compound represented by the formula (1) as an active ingredient. 3. The following formula III (However, in the formula, R ₄ represents a hydrogen atom or a sodium atom, and R ₅ represents Indicates. An antiretroviral agent containing a compound represented by the formula (1) as an active ingredient. 4. The following formula IV An antiretroviral agent comprising a compound represented by as an active ingredient. 5. The following formula V An antiretroviral agent comprising a compound represented by as an active ingredient. 6. The following formula VI An antiretroviral agent comprising a compound represented by as an active ingredient. 7. The following formula VII An antiretroviral agent comprising a compound represented by as an active ingredient. 8. The following formula VIII An antiretroviral agent comprising a compound represented by as an active ingredient.