JPH06227982A - Antiviral agent - Google Patents

Abstract

PURPOSE:To obtain an antiviral agent highly pharmacodynamically effective against varicella-zoster virus, cytomegalovirus, etc., having high safety, comprising a 1'alpha,2'alpha bis(hydroxymethyl)cyclopropane-1'beta-yl-methylguanine. CONSTITUTION:A compound of the formula (R<1> and R<2> are H or acyl; X is H, OH, halogen, amino or alkyloxy) {e.g. 9-[1'alpha,2'alpha-bis(acetoxymethyl) cyclopropane-1'beta-yl]methylguanine or its pharmaceutically permissible salt as an active ingredient is dissolved in purified water and filtered for sterilization by using a millipore filter. The filtrate is collected in a vial bottle and lyophilized to give a preparation for injection and intravenous drip. The compound is well mixed with lactose, crystalline cellulose and magnesium stearate and tableted by a tableter into tablets to give the objective antiviral agent highly pharmacodynamically effective against varicella-zoster virus and cytomegalovirus, having high safety.

Description

Detailed Description of the Invention

[0001]

The present invention relates to an antiviral agent,
Particularly, it relates to an antiviral agent effective against varicella-zoster virus and cytomegalovirus.

[0002]

[Prior Art] Varicella-Zo Virus (Varicella-Zo)
ster Virus) causes chickenpox with high fever in infants and shingles in adults, causing severe pain such as neuralgia. On the other hand, human cytomegalovirus causes extremely serious symptoms in patients with immunodeficiency such as AIDS, immunosuppressive drugs at the time of organ transplantation and other chemotherapeutics, and often causes blindness and death. Come on. Currently, several antiviral agents such as acyclovir for varicella-zoster virus and gansirovir for human cytomegalovirus are used.
There is a demand for therapeutic agents that are even better in terms of efficacy and safety.

[0003]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a drug having high efficacy and safety against varicella-zoster virus and cytomegalovirus.

[0004]

As a result of various investigations, the present inventors have found that the compound represented by the following chemical formula 2 has an extremely strong antiviral activity against the above viruses, and completed the present invention.

[0005]

[Chemical 2]

In the formula, R ¹ and R ² are the same or different and each represents a hydrogen atom or an acyl group such as an acetyl group or an amino acid acyl group. X is a hydrogen atom; a hydroxyl group; a chlorine atom,
Represents a halogen atom such as a bromine atom; an amino group; and an alkyloxy group such as a methoxy group and an ethoxy group.

Regarding the compound used in the present invention, European Patent Publication No. 502690 (or Japanese Patent Application No. 4-4717) shows that it has a strong activity against the production method and herpes simplex.
No. 8), but the effect on varicella-zoster virus and cytomegalovirus was confirmed for the first time.

A preferred example of the compound used in the present invention is 9- [1'α, 2'α-bis (acetoxymethyl) cyclopropane-1'β-yl] methylguanine 9- [1'α, 2 'α-Bis (hydroxymethyl) cyclopropane-1'β-yl] methylguanine 2-amino-9- [1'α, 2'α-bis (acetoxymethyl) cyclopropan-1'β-yl] methylpurine 2 , 6-Diamino-9- [1'α, 2'α-bis (acetoxymethyl) cyclopropan-1'β-yl] methylpurine 2-amino-6-chloro-9- [1'α, 2'α -Bis (acetoxymethyl) cyclopropan-1'β-yl] methylpurine 2-amino-6-methoxy-9- [1'α, 2'α-bis (acetoxymethyl) cyclopropan-1'β-yl] Methyl purine 2-amino-9- [1'α, 2'α-bis (hydroxymethyl ) Cyclopropan-1′β-yl] methylpurine 2,6-diamino-9- [1′α, 2′α-bis (hydroxymethyl) cyclopropan-1′β-yl] methylpurine 2-amino-6 -Chloro-9- [1'α, 2'α-bis (hydroxymethyl) cyclopropan-1'β-yl] methylpurine 2-amino-6-methoxy-9- [1'α, 2'α-bis (Hydroxymethyl) cyclopropane-1′β-yl] methylpurine and the like can be mentioned.

Among them, 9- [1'α, 2'α-bis (hydroxymethyl) cyclopropan-1'β-yl] methylguanine, especially (-) 9- [1'S, which is an optically active substance thereof. 2 '
R-bis (hydroxymethyl) cyclopropan-1'-yl] methylguanine is particularly preferred.

The present compound forms a salt with an acid or a base, and its salt may be any pharmaceutically acceptable salt, for example, an acid such as hydrochloride, hydrobromide, phosphoric acid or sulfonic acid. And salts with bases such as sodium salt and potassium salt.

When the present compound is used as an antiviral agent, it can be administered intravenously, orally or transdermally, either alone or mixed with an appropriate carrier for formulation. Examples of the dosage form include injections, tablets, granules, fine granules, powders, capsules, creams and suppositories. Examples of the pharmaceutical carrier include lactose, glucose, D-mannitol, starch, crystalline cellulose, calcium carbonate, kaolin, starch, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, ethanol, carboxymethylcellulose, carboxymethylcellulose calcium salt, Magnesium stearate,
Talc, acetyl cellulose, sucrose, titanium oxide, benzoic acid, paraoxybenzoic acid ester, sodium dehydroacetate, gum arabic, tragacanth, methyl cellulose, egg yolk, surfactant, sucrose, simple syrup, citric acid,
There are distilled water, ethanol, glycerin, propylene glycol, macrogol, sodium monohydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate, glucose, sodium chloride, phenol, thimerosal, paraoxybenzoic acid ester, sodium hydrogen sulfite, etc., It is used as a mixture with the present compound depending on the form of the preparation.

Although the content of the present compound in the preparation varies greatly depending on the form of the preparation, it is usually 0.01 to 100% by weight, preferably 2 to 100% by weight based on the total amount of the composition.
Is.

The dose is usually 0.1 to 500 mg / kg · day, though it varies depending on the symptoms, age and administration method of the patient to be administered.

[0014]

EXAMPLES The present invention will be described in detail with reference to examples.

Preparation Example 1 Preparation of preparation for injection and infusion (-) 9- [1'S, 2'R-bis (hydroxymethyl) cyclopropan-1'-yl] methylguanine sodium salt 1g 49g purification Dissolve in water and filter with bacteria using a Millipore filter. 2.5 ml of this filtrate is added to 10 ml
50 liters per vial by freeze-drying
A lyophilized formulation containing mg sodium salt was obtained.

Formulation Example 2 Preparation of tablets (-) 9- [1'S, 2'R-bis (hydroxymethyl) cyclopropan-1'-yl] methylguanine 10 g and 40
lactose, 49 g of crystalline cellulose, 1 g of magnesium stearate were mixed well and tabletted with a tableting machine.
Tablets containing 250 mg per tablet were obtained.

Formulation Example 3 Preparation of granules (-) 9- [1'S, 2'R-bis (hydroxymethyl) cyclopropan-1'-yl] methylguanine 10 g and 90
g of lactose and 100 g of crystalline cellulose were mixed well, compressed by a roll-type compressor, pulverized, and sieved to obtain 20-80 mesh granules.

Test Example 1 Evaluation of anti-varicella-zoster virus activity Human foreskin fibroblasts (HEF) were seeded on a 12-well culture plate and cultured in a 2% carbon dioxide gas atmosphere. Minimal basal medium (MEM) when sub-confluent
Rinse, MEM with 0.5 ml of 2% fetal calf serum
Varicella-zoster virus (DM625), which had been suspended in, was added, and the mixture was cultured at 37 ° C for 2 hours. After lightly washing, 1 ml of the test substance dissolved in the same medium was added, and the mixture was incubated at 37 ° C. for 5 days in a 2% carbon dioxide gas atmosphere. The number of plaques after 5 days was counted, and the drug concentration that reduced the number of plaques by 50% was determined as IC ₅₀ . Cytotoxicity was also measured by MTT assay using the same cells that were not infected with virus. The results are shown in Table 1. (-) 9- [1'S, 2'R-bis (hydroxymethyl) cyclopropan-1'-yl] methylguanine showed stronger antiviral activity than acyclovir.

[0019]

[Table 1]

Test Example 2 Evaluation of anti-human cytomegalovirus activity Dulbecco ME containing 10% fetal bovine serum in a 6-well plate
Human cytomegalovirus (Towne strain) was added to HEL cells grown in M medium at 100 PFU per well.
After infection and adsorption at 37 ° C. for 60 minutes, a medium containing 0.5% agarose containing a drug was added, the mixture was cultured at 37 ° C., and the number of plaques after 7 days was counted. The drug concentration that reduces the number of plaques by 50% was determined as IC ₅₀ . The results are shown in Table 1, and (-) 9- [1'S, 2'R-bis (hydroxymethyl) cyclopropan-1'-yl] methylguanine showed stronger antiviral activity than acyclovir. It was

[0021]

[Table 2]

[0022]

EFFECTS OF THE INVENTION The present compound has strong activity against varicella-zoster virus and cytomegalovirus, and is expected as an antiviral agent against them.

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Satoshi Hattani 1-1 Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa Ajinomoto Co., Inc. Central Research Laboratory (72) Inventor Takaaki Sekiyama 1 Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa -1 Ajinomoto Co., Inc. Central Research Laboratory (72) Inventor Naoshi Tsuji 1-1 Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa 1-1 Ajinomoto Co., Inc. Central Research Laboratory

Claims (2)

[Claims] 1. An antiviral agent against varicella-zoster virus or cytomegalovirus, which comprises a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. [Chemical 1] In the formula, R ¹ and R ² are the same or different and each represents a hydrogen atom or an acyl group, and X represents a hydrogen atom, a hydroxyl group, a halogen atom, an amino group or an alkyloxy group. 2. The antiviral agent according to claim 1, wherein R ¹ and R ² are hydrogen atoms and X is a hydroxyl group.