JPH04139130A - Antiviral composition - Google Patents

Abstract

PURPOSE:To obtain an antiviral composition by combining 9-(2-deoxy-2- hydroxymethyl-beta-D-erythroxetanocyl)guanines (oxetanocin G) with an acyclovir or carbocyclic oxetanocin. CONSTITUTION:An antiviral composition containing 9-(2-deoxy-2- hydroxymethyl-beta-D-erythroxetanocyl)guanine (oxetanocin G) expressed by formula I or a pharmacologically permissible salt thereof, 9-(2-hydroxyethoxymethyl) guanine (acyclovir) expressed by formula II or a pharmacologically permissible salt thereof or (+)-9-[1R,2R,3R)-2,3-bis(hydroxymethyl)cyclobutyl]guanine (carbocyclic oxetanocin) expressed by formula III or a pharmacologically permissible salt thereof. The aforementioned composition has excellent effects especially on herpes 1 type or 2 type.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field] The present invention relates to novel antiviral compositions having selective and synergistic antiviral activity.

[Conventional technology]

Herpes type 1 and type 2 viruses cause encephalitis and herpes virus infections of the cornea, lips, and genitals in infants and adults, causing serious illness, especially in young children.

In recent years, the herpesvirus group (herpesvi)
rus group) is known to cause serious infections.

Currently, for diseases caused by these herpesviruses,
9-(2-Hydroxyethoxymethyl)guanine (hereinafter referred to as acyclovir or AeV) is used in boat fishing. Recently, the combination of acyclovir and bromovinyldeoxyuridine (BVDU) (Japanese Patent Application Laid-open No. 6O-12
0814) and the combination of acyclovir with a bonucleotide reductase inhibitor (Japanese Patent Application Laid-Open No. 2-45423).

[Invention or problem to be solved]

However, there are no satisfactory results in terms of effectiveness or side effects. Therefore, it is desired to develop an antiviral agent that is more effective and less toxic.

[Means to solve problems]

As a result of various studies, the inventors found that (a) Structural formula (■): 9-(2-deoxy-2-hydroxymethyl-β-D-
erythrooxetanosyl)guanine (hereinafter abbreviated as oxetanosine G or OXT-G) or a pharmacologically acceptable salt thereof; and (b) acyclovir or a pharmacologically acceptable salt thereof represented by the structural formula or (+) −9−((IR,2R,3S)−2
, 3-bis(hydroxymethyl)cyclobutylcoguanine (hereinafter referred to as rubocyclic oxetanosine G or C-0)
It's called XT-G. ) or a pharmacologically acceptable salt thereof has an excellent antiviral effect against herpes viruses, especially herpes type I or type 2, and is significantly superior to each single agent. It has been found that the compound can be used as an anti-herpesvirus composition since it has a complementary effect.

The present invention was completed based on the above findings. All of the compounds used in the present invention are known compounds; for example, oxetanosine G is used in JP-A-1-100192 (E
Acyclovir is currently commercially available as an antiviral agent, and Proc.
Natl, Acad, Sci, vol. 74, 57
16 (1977), and carbocyclic oxetanosine G is a known compound disclosed in JP-A-1-269073.

(a) component dioxetanosine G and (b) in the present invention
The ratio of the ingredient niacyclovir or carbocyclic oxetanosine G varies depending on the type of herpes virus or the type of drug used.The weight ratio is 250: 1 to 1.
:20, preferably about 150:1 to 1:10. Oxetanosine G, acyclovir and carbocyclic, Oxetanosine G forms a salt with an acid, or the acid forming the salt may be any pharmacologically acceptable acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, etc. is preferred.

Also, sodium or potassium adducts can be produced by using an alkaline solution such as sodium hydroxide or potassium hydroxide.

The antiviral composition of the present invention is usually mixed with excipients or carriers and administered as an injection, oral preparation, or halved solution. Pharmaceutically acceptable excipients and carriers are selected, and their types and compositions are determined by the route and method of administration. For example, water, alcohol, animal or vegetable oils such as soybean oil, peanut oil, rubber oil, mineral oil, or synthetic oils are used as liquid carriers. As solid carriers, sugars such as maltose and sucrose, cellulose derivatives such as amino acids hydroxypropylcellulose, and organic acid salts such as magnesium stearate are used. In the case of injections, physiological saline, various buffer solutions, saccharide solutions such as glucose, inositol, and mannitol, and glycols such as ethyl glycol and polyethylene glycol are generally preferred. In addition, it can be made into a lyophilized preparation with excipients such as sugars such as inositol, mannitol, glycose, mannose, maltose, and sucrose, and amino acids such as phenylalanine, and then used in a suitable injection solvent such as sterile water or physiological saline at the time of administration. It can also be administered by dissolving it in a liquid for intravenous administration such as water, glucose solution, electrolyte solution, amino acid, or the like.

(a) Component Oxetanosine G and (b) in the formulation
) The total content of both components (aciclovir or carbocyclic oxetanosine G) varies depending on the formulation, but is usually 0.1 to 100% by weight, preferably 1 to 90% by weight.
It is. For example, in the case of an injection solution, it is usually 0.
It may contain 1 to 5% by weight of component (a) and component (b). When administered orally, tablets, capsules, powders,
It is used in the form of granules, liquids, dry syrups, etc. In the case of capsules, tablets, granules, and powders, the total content of both is generally about 3 to 100% by weight, preferably 5 to 90% by weight.
and the remainder is the carrier.

The dosage is determined depending on the patient's age, weight, symptoms, therapeutic purpose, etc., but the therapeutic dose is generally 1 to 50 m
g/kg (total amount of both is the same)/day, and oral administration is 5 to 50 mg/kg/day.

Oxetanosine G and acyclovir or carbocyclic oxetanosine G are characterized by low toxicity, and each compound is characterized by low toxicity accumulation upon continuous administration. For example, no signs of toxicity were observed when oxetanosine G was intraperitoneally administered once to mice at a dose of 400 mg/kg.

Next, examples of formulations of the present invention will be shown.

Formulation Example 1 Purified water was added to 250 parts by weight of each of oxetanosine G and acyclovir or calsulic oxetanosine G, the pH was adjusted to 13-14, the total amount was 2.00 parts, and the mixture was dissolved and filtered using a Millipore filter GS type. Filter to sterilize using 2 g of this filtrate was placed in a 10-sized vial, lyophilized, and 1 vial was filled with oxetanosine G and acyclovir or carbocyclic oxetanosine G.
Freeze-dried injections containing 50 mg each were obtained.

Formulation Example 2 Granules 50 parts by weight of each of oxetanosine G and acyclovir or carbocyclic oxetanosine G, 600 parts of lactose, 330 parts of crystalline cellulose and 20 parts of hydroxypropyl cellulose were thoroughly mixed, and the mixture was thoroughly mixed using a roll compactor (roller compactor). ), crushed, and sieved to obtain granules between 16 mesh and 60 mesh.

Formulation Example 3 50 parts by weight each of tablet oxetanosin G and acyclovir or carbocyclic oxetanosin G, 1 part by weight of crystalline lactose
20 parts of microcrystalline cellulose, 147 parts of magnesium stearate, and 3 parts of magnesium stearate were compressed into tablets using a V-type mixture, each tablet weighing 300 mg (
Tablets containing approximately 50 mg each were obtained.

Next, a test example of the combined effect of the composition of the present invention on suppressing the growth of herpes simplex type 1 and type 2 viruses will be explained in more detail.

(1) Growth inhibitory effect measurement method Eagle's minimal medium (MEM-) containing lO% newborn calf serum
Create a monolayer cell culture of green monkey kidney cells (vero cells) in a 24-well microplate using C3IO),
Herpes simplex type I (H3V-1) or type 2 (H3V-1)
-2) was inoculated at 50 PFU 10.1 mJ/well.

After adsorption at 37°C for 1 hour, cells of each type were washed with phosphate buffered saline (PBS) and serially diluted with 0XT-G or ACV alone or in MEM-containing 0.5% methylcellulose. C32 was overlaid and cultured at 37°C for 12 days. After discarding the overlay medium and fixing the cells with formalin, they were stained with crystal leaf fluid and the number of plaques for each type was counted. Calculate the percentage (% value) of the number of plaques at each drug concentration with respect to the number of control (no drug added) plaques, which is 50%.
A graph of the percentage value of the drug concentration against which the plaque inhibition concentration (1c5o) was measured was created.

(2) Results (Note) In Tables 1 to 3, the percentages in parentheses after each drug concentration were calculated from the IC6° value (50% inhibitory concentration) for each drug alone. Calculated inhibition rate alone.

Effect As is clear from the results of the above test examples, when the (a) component and (B) component are used in combination, the best effect is when the calculated inhibition rate is 18-20%, but in reality it is 50%. %
It can be seen that a remarkable mutual effect has been achieved in the present invention.

Patent applicant: Nippon Kayaku Co., Ltd.

Claims (1)

[Claims] (1) (a) Structural formula (I): ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) 9-(2-deoxy-2-hydroxymethyl-β-D-
erythrooxetanosyl)guanine (oxetanosine G
) or a pharmacologically acceptable salt thereof and (b) Structural formula (II): ▲Mathematical formula, chemical formula, table, etc. ▼(II) 9-(2-hydroxyethoxymethyl)guanine (acyclovir) or its drug Physically acceptable salts or structural formula (III): ▲Mathematical formulas, chemical formulas, tables, etc.▼(III) (+)-9-[(1R,2R,3S)-2,3-bis(
An antiviral composition characterized by containing hydroxymethyl)cyclobutyl]guanine or a pharmacologically acceptable salt thereof