JPH0640894A - Anti-hiv agent - Google Patents

Abstract

PURPOSE:To provide the anti-HIV agent containing a specific disulfide as an active ingredient, having a strong multiplication-inhibiting action against cells persistently infected with human immunodeficiency syndrome virus (HIV), and useful for preventing and treating AIDS. CONSTITUTION:The anti-HIV agent contains a disulfide of the formula (R<1> is 2-20C alkenyl; R<2> is 2-20C alkenyl, 1-20C alkyl) (e.g. diallyl sulfide) as an active ingredient. Preferably, 20mg of the disulfide, 60mg of synthetic aluminum silicate, 10mg of light silica, a proper amount of crystalline cellulose, 40mg of carboxymethylcellulose calcium, 10mg of polyvinyl pyrrolidone, 5mg of magnesium stearate, 5mg of polyvinyl acetal diethylaminoacetate, 5mg of hydroxypropylmethylcellulose, and 3mg of macrogol are compounded with each other, granulated by a conventional method, tableted, and subsequently film- coated to provide the anti-HIV agent having a strong multiplication-inhibiting action against persistently HIV-infected cells.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION The present invention relates to acquired immunodeficiency syndrome (AIDS: Acquired ImmuneDefi).
anti-HIV (Human Immunodeficiency) useful for prevention and treatment of circulatory syndrome
energy virus) agent.

[0002]

AIDS is a disease caused by HIV infection, and the number of patients has been increasing rapidly since it was discovered in the United States in 1983. Anti-HIV agents such as azidothymidine (AZT) and didanosine (DDI) are known for the treatment of AIDS.

[0003]

[Problems to be Solved by the Invention] However, AZT
Although a remarkable life-prolonging effect is recognized, there is a problem that side effects such as headache, gastrointestinal disorders, and myelosuppressive effects occur. In addition, AZT and DDI both show a remarkable growth-suppressing effect on HIV-primarily infected cells, but do not exert an effect on cells already infected with HIV. However, it is said that it is not useful for the basic treatment of AIDS, that is, the effect of suppressing cells after HIV infection. Therefore, an object of the present invention is to provide an anti-HIV agent which shows a strong growth inhibitory action not only on HIV primary infected cells but also on HIV persistently infected cells and is useful for treating AIDS after infection.

[0004]

Therefore, the present inventors have proposed that H
As a result of screening the anti-HIV action of various compounds using the growth-suppressing action on the IV persistent-producing strain as an index, a specific disulfide compound has a strong HIV persistent-producing cell growth-suppressing action and is highly safe, and is a treatment for AIDS. The present invention has been completed and the present invention has been completed.

That is, the present invention is represented by the general formula (1): R ¹ -S-S-R ² (1) [wherein R ¹ represents an alkenyl group having 2 to 20 carbon atoms,
R ² is an alkenyl group having 2 to 20 carbon atoms or 1 to 2 carbon atoms.
The present invention provides an anti-HIV agent containing a disulfide represented by the formula 0] as an active ingredient.

Examples of the disulfide which is the active ingredient of the anti-HIV agent of the present invention include diallyl disulfide, allyl methyl disulfide, allyl n-propyl disulfide and the like. Among them, diallyl disulfide is particularly preferable.

Among the above disulfides (1), diallyl disulfide is, for example, garlic (Allium sa).
Tivum), and this compound has been reported to suppress the experimental cancer in rodents (Lee).
WW et al: Cancer Research
49, 2689-2692, 1989), but there are no reports of anti-HIV effects. In addition, this diallyl disulfide is described in the literature (John FB et al.
l: Cancer Research 48, 5937
-5940, 1988), 200 mg / kg in rats
It is highly safe because it does not die even when administered orally and it is a component of garlic.

[0008] Such disulfide (1) is CE, which is known as an HIV persistently infected strain, as shown in Examples below.
It shows a marked inhibitory effect on M / LAV cells. Its anti-H
Although the mechanism of IV action is not clear, transcription of the HIV gene,
It is considered that HIV proliferation is suppressed by participating in the suppression of the replication pathway, that is, the flow of Tat-related genetic information.

The anti-HIV agent of the present invention contains an excipient, a binder, a lubricant, a disintegrating agent, a coating agent, an emulsifying agent, a suspending agent, a solvent, a stabilizer, a disulfide (1), if necessary. It can be obtained by adding an absorption aid, an ointment base or the like as appropriate, or by forming into liposomes and the like and formulating into a dosage form for oral administration, injection administration, rectal administration, etc. by a conventional method.

Preparations for oral administration include granules, tablets,
Dragees, capsules, soft capsules, pills, liquids,
Emulsions, suspensions and the like; preparations for injection administration are preferably intravenous injections, intramuscular injections, subcutaneous injections, preparations for drip injections and the like; preparations for rectal administration are preferably suppository capsules and the like.

The dose varies depending on the route of administration, the age of the patient, symptoms, etc., but is usually 3 mg to 10 g of disulfide (1) per day for an adult, and this is administered once or in several divided doses.

[0012]

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

Example 1 (1) Action on non-infectious CEM cells by continuous administration In culture medium RPMI-1640 (containing 10% FCS),
CEM cells were suspended and the cell number was set to 2.0 × 10 ⁵ cells / ml. 9.9 ml of this CEM cell suspension was placed in a culture bottle and the test drug diallyl disulfide solution (0.01%,
Polyoxyethylene (60) suspended in hydrogenated castor oil)
0.1 ml was added, and the cells were cultured at 37 ° C. in a 5% CO ₂ environment. The number of viable cells was measured by the trypan blue dye exclusion test every 24 hours, at the same time, the cells were recovered by centrifugation at 1200 rpm, and a fresh culture solution and a test drug solution were added to continue the culture. The result is shown in FIG. (2) HIV continuous production CEM / LAV by continuous administration
Action on cells A CEM / LAV cell suspension was prepared in the same manner as in (1) above, and an experiment was conducted. The result is shown in FIG.

As is clear from FIG. 1 and FIG. 2, diallyl disulfide has a weak inhibitory effect on the growth of non-infectious CEM cells when administered at 40 μM, but it does not produce HIV persistent CEM.
/ LAV cell proliferation was completely suppressed. As a result, disulfide (1) suppresses the proliferation of cells after HIV infection,
It turns out that it is useful for AIDS treatment. In addition, about diallyl sulfide, diallyl ether, diethyl disulfide, and di-n-propyl disulfide, Example 1
The effect on CEM / LAV cells was examined in the same manner as in (2), but no growth inhibitory effect was observed at a concentration of 20 to 200 μM.

Example 2 The following components were granulated by a conventional method, tableted and then film-coated to obtain a film-coated tablet containing 100 mg of diallyl disulfide.

[0016]

Table 1 Diallyl disulfide 100 (parts by weight) Hardened oil 40 Microcrystalline cellulose 40 Carboxymethyl cellulose calcium 30 Hydroxypropyl cellulose 20 Magnesium stearate 10

Example 3 The following ingredients were mixed by a conventional method and filled in a hard capsule to obtain a capsule containing 100 mg of diallyl disulfide.

[0018]

[Table 2] Diallyl disulfide 100 (parts by weight) Microcrystalline cellulose 40 Talc 20

[0019]

INDUSTRIAL APPLICABILITY The anti-HIV agent of the present invention has a strong antiproliferative effect on HIV persistently infected cells and is useful for the treatment of AIDS.

[Brief description of drawings]

FIG. 1 is a diagram showing the effect of continuous administration of diallyl disulfide on CEM cells.

FIG. 2 CEM / by continuous administration of diallyl disulfide
It is a figure which shows the influence on a LAV cell.

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[Procedure amendment]

[Submission date] December 22, 1992

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be corrected] 0015

[Correction method] Change

[Correction content]

Example 2 The following ingredients were granulated by a conventional method, tableted and then film-coated to obtain a film-coated tablet containing 20 mg of diallyl disulfide.

[Procedure Amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0016

[Correction method] Change

[Correction content]

[0016]

[Table 1]

[Procedure 3]

[Document name to be amended] Statement

[Correction target item name] 0017

[Correction method] Change

[Correction content]

Example 3 The following components were mixed by a conventional method and filled in a hard capsule to obtain a capsule containing 40 mg of diallyl disulfide.

[Procedure amendment 4]

[Document name to be amended] Statement

[Correction target item name] 0018

[Correction method] Change

[Correction content]

[0018]

[Table 2]

Claims (2)

[Claims] 1. General formula (1): R ¹ —S—S—R ² (1) [In the formula, R ¹ represents an alkenyl group having 2 to 20 carbon atoms,
R ² is an alkenyl group having 2 to 20 carbon atoms or 1 to 2 carbon atoms.
Which represents an alkyl group of 0] as an active ingredient. 2. An anti-HIV agent containing diallyl disulfide as an active ingredient.