RU2293562C2 - Using aminopurine antiviral compounds for treatment and prophylaxis of latent infections caused by herpes virus - Google Patents

Abstract

FIELD: medicine, infectious diseases.

SUBSTANCE: method involves administration of drug in the effective dose comprising compound of the formula (A) given in the invention description or acyl derivative of a bioprecursor of the formula (B) given in the invention description 18 h after infection. Invention promotes to prophylaxis of viral etiology in mammals, among them, in humans being even with impaired function of the immune system. Invention can be used in treatment and prophylaxis of infections caused by herpes virus.

EFFECT: valuable medicinal properties of compounds.

4 cl, 3 tbl, 3 ex

Description

This invention relates to the treatment of latent infections caused by herpes viruses. When used here, the term “treatment” also includes prophylaxis, when appropriate.

In EP-A-141927 (Beecham Group p.l.c.), penciclovir, a compound of formula (A), is disclosed:

and its salts, phosphate esters and acyl derivatives as antiviral compounds. Penciclovir sodium hydrate is disclosed in EP-A-216459 (Beecham Group p.l.c.). Penciclovir and its antiviral activity are also described in abstract R.VII-5, p. 193, Abstracts of 14th Int. Congress of Microbiology ”, Manchester, England, 7-13 September 1986 (Boyd et al.).

Orally active bioprecursors of a compound of formula (A) are compounds of formula B

and their salts and derivatives, defined by formula (A), in which X is C _1-6 alkoxyl, NH ₂ or hydrogen. Compounds of formula (B) in which X is C _1-6 alkoxyl or NH ₂ are disclosed in EP-A-141927, and compounds of formula (B) in which X is hydrogen are disclosed in EP-A-182024 (Beecham Group plc) are preferred prodrugs. A particularly preferred example of a compound of formula (B) is a compound in which X is hydrogen and in which two OH groups are in the form of an acetyl derivative described in Example 2 EP-A-182024, hereinafter referred to as famciclovir.

The compounds of formulas (A) and (B) and their salts and derivatives are described as useful in the treatment of infections caused by herpes viruses such as Herpes simplex type 1 and Herpes simplex type 2.

Previous work has shown that if antiviral treatment is delayed more than a few hours after infection, latency is established. If the latency of the infection is established, the infection may resume.

It has now been shown in mice that treatment with famciclovir can prevent the establishment of competent latency when treatment begins 18 hours later (first experiment) and up to 4 days (second experiment) after infection. It has now also been shown that latency can be prevented in an experiment in mice with a compromised immune system. A potential clinical advantage is that the patient can be treated with famciclovir within 4 days after contact to prevent not only acute infection, but also the development of latency and thus avoid relapse. In addition, it is believed that a slow, natural loss of latently infected cells may occur and re-infection may be required to maintain the presence of latently infected cells by establishing latency in new cells. Therefore, the overwhelming treatment with famciclovir for an extended period (up to several years) may prevent new cells from becoming latently infected. Then the result will be a radical cure, and after that the patient will not have relapses.

Accordingly, the present invention provides a method of treating latent herpes virus infection in humans, which comprises administering to a person in need of such treatment an effective amount of a compound of formula (A):

or a bioprecursor thereof or a pharmaceutically acceptable salt, phosphate ester and / or acyl derivative of any of the above compounds.

The term “acyl derivative” is used herein to include any derivative of the compounds of formula (A) in which one or more acyl groups are present. Such derivatives are included as bioprecursors of the compounds of formula (A) in addition to those derivatives which are themselves biologically active.

The compound of formula (A) may be in one of the forms disclosed in EP-A-216459 (Beecham Group p.l.c.).

Examples of bioprecursors, pharmaceutically acceptable salts and derivatives are the compounds described in the aforementioned European patents, the subject matter of which is given here for information.

A particular compound of formula (B) of interest is 9- (4-acetoxy-3-acetoxymethylbut-1-yl) -2-aminopurine, known as famciclovir (PCV), a well-absorbed oral form of penciclovir (PCV).

A compound of formula (A), bioprecursors, salts and derivatives can be prepared as described in the aforementioned European patents.

The compound, in particular famciclovir, can be administered to humans parenterally and can be converted into syrup, tablets or capsules. When it is made in the form of tablets, any pharmaceutical carrier suitable for preparing such solid compositions can be used, for example magnesium stearate, starch, lactose, glucose, rice, flour and chalk. The compound may also be presented in the form of swallowable capsules, for example, from gelatin containing the compound, or in the form of a syrup, solution or suspension. Suitable liquid pharmaceutical carriers include ethyl alcohol, glycerin, saline and water, to which flavoring and coloring agents can be added to form a syrup. Sustained release dosage forms are also contemplated, for example, coated tablets that dissolve in the intestine.

For parenteral administration, liquid dosage forms are prepared in unit dosage form containing a compound and a sterile vehicle. The compound, depending on the carrier and concentration, may be either suspended or dissolved. Parenteral solutions are usually prepared by dissolving the compound in a carrier and filter sterilizing before filling either a suitable vessel or ampoule and sealing. Advantageously, adjuvants, such as local anesthetics, preservatives and buffering agents, also dissolve in the vehicle. To increase stability, the composition can freeze after filling the vessels, and water can be removed under vacuum.

Parenteral suspensions are prepared in essentially the same way except that the compound is suspended in the vehicle instead of dissolving and sterilized by exposure to ethylene oxide before being suspended in the sterile vehicle. It is advisable that a surfactant or wetting agent be included in the composition to facilitate uniform distribution of the compound of the invention.

Preferred parenteral dosage forms include aqueous dosage forms using sterile water or physiological saline with a pH of about 7.4 or more, in particular containing penciclovir sodium salt hydrate.

As is usually accepted in practice, compositions are usually accompanied by written or printed instructions for use with appropriate medical treatment.

An appropriate unit dose (dosage form) may contain from 50 mg to 1 g of the active ingredient, for example, 100-500 mg. Such doses can be administered 1-4 times a day or more, usually 2 or 3 times a day. An effective dose of the compound will generally range from 0.2 to 40 mg per kg of body weight per day or more, usually from 10 to 20 mg / kg per day. In the case of famciclovir, the unit dose is 125, 250, 500 or 750 mg, preferably 125 or 250 mg.

To prevent the formation of competent latency, treatment is preferably carried out as soon as possible after contact with the virus, preferably within 18 hours, although it is acceptable to start within 4 days. The treatment period is usually 3-14 days, more usually 5-10 days, often 7 days.

For the treatment of an established recurrent disease, the treatment period is up to 5 years, for example, up to 1, 2, 3, 4 and 5 years.

The present invention also provides the use of a compound of formula (A) or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and / or an acyl derivative of any of these compounds for the manufacture of a medicament for use in the treatment of latent infection caused by herpes viruses. Such treatment can be carried out according to the method described here previously.

The invention also provides a pharmaceutical composition for use in the treatment of latent herpesvirus infection, which comprises an effective amount of a compound of formula (A), or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and / or acyl derivative of any of the compounds, and pharmaceutically acceptable carrier. Such compositions may be made in the same manner as described hereinafter.

The compound of formula (A) and its prodrugs exhibit a synergistic antiviral effect in combination with interferons; and therefore, treatment using combination products comprising these two components for sequential or concomitant administration in the same or different ways is within the scope of this invention.

The following animal studies illustrate the invention.

HSV-1 infected mouse experiments

Skin infection by inoculation of HSV-1 (SC16) mice in the earlobe and the effect of famciclovir when orally administered on latent viral infection was investigated.

BALB / c female mice (Bantin and Kingman, Kingston, Hull, UK) were purchased at 3-4 weeks of age and were infected after a week. A virus suspension (10 μl) containing 5 × 10 ⁴ bouts was inoculated into the skin of the left earlobe. Skin thickness was measured daily in individual mice using a screw micrometer (Nash et al., 1980 J. Gen. Virol. 48, 351-357). These mice were kept for 3 (experiment 1) or 4 (experiment 2) months and then scored. The trigeminal node and cervical dorsal root node were removed and cultured together. Those cultures that showed virus replication were recorded as positive.

Experiment 1

In the first experiment, mice were started to be treated within 18 hours, and treatment was stopped 10 days after infection.

Of the 24 untreated control mice, 12 showed latent infection in the trigeminal ganglion (TG) and 20 revealed a latent infection in the cervical dorsal root ganglion (DCG). All 24 control mice showed either TG or DKG latency. None of the mice treated with FCV showed any latency.

Experiment 2

In the second experiment, antiviral treatment began on the 2nd, 3rd, 4th and 5th day after infection (PI) and stopped on the 10th day of PI Compounds were given with drinking water without restriction at a concentration of 1 mg / ml (approximately 100 mg / kg / day).

The results are presented in the following table:

(Note: Groups 1 and 2 received the same courses of treatment, but the results were analyzed separately).

Table 1 Latency (Group 1) Latency (Group 2) Latency (total) Acute infection (total) Antiviral Therapy (days) TG + ve / 8 DKG + ve / 8 TG + ve / 8 DKG + ve / 8 % of mice with virus + ve ganglion on day 120 (n = 16) L / PTH + DCG % mice with virus + ve ganglion on day 80 (n = 8) L / PTH + DCG L P L P L P L P no 8 four 8 5 8 6 8 2 one hundred one hundred 5-10 four 0 four 0 2 0 2 0 38 one hundred 4-10 2 0 2 0 0 0 0 0 13 one hundred 3-10 0 0 0 0 0 0 0 0 0 0 2-10 0 0 0 0 0 0 0 0 0 0 1-10 0 0 0 0 0 0 0 0 0 0

After 4 months, the latent virus could be reactivated in ganglion explants (ipsilateral and contralateral trigeminal and dorsal root) from all of the 16 control mice. The latent virus did not reactivate from the ganglia of the treated PCV mice, with the exception of the ipsilateral ganglia, and only when the start of therapy was delayed until 4 days p.p. (2/16) or 5 days p.i. (6/16).

Similar results were obtained when the compounds were administered twice daily daily through a probe in an amount of 50 mg / kg per dose.

Experiment 3

Mice were immunosuppressed with cyclosporin A (QiA) from day -2 to day +10 (moreover, day 0 is the day of infection). The groups of mice were: untreated (control) or treated with famciclovir orally at a dose of 50 mg / kg twice a day, starting from 22 hours after infection to 5.5 or 10.5 days. Ganglia were tested for reactivation of the infectious virus after 1 or 4 months, and the results are shown in the table below.

Table 2 LTH (n = 6) PTH (n = 6) LDK (n = 6) MPC (n = 6) The control 6 four 6 3 FCV 0 0 0 0 TG - trigeminal, DKG - dorsal root ganglion, L / R - left / right

HSV-2 infected mouse experiments

A skin infection was created by inoculation of HSV-2 (Bry) mice into the earlobe and the effect of famciclovir by oral administration on latent viral infection was investigated. The treatment consisted of taking 50 mg / kg twice a day for 5 days, starting at 22 hours after infection.

The table shows the number of mice / group with positive latent infection in the trigeminal or cervical dorsal root ganglion.

Table 3 The number of mice with ⁺ ve ganglia / the number of tested mice % of mice giving at least. one ⁺ ve ganglia Group left T / G right T / G left CDK right CDK

control 10/10 10/10 10/10 6/10 one hundred famciclovir 0/10 0/10 0/10 0/10 0 T / G - trigeminal, CDK - cervical dorsal root ganglion.

Claims (4)

1. A method of reducing the development or reactivation of latent herpes virus infection in humans, characterized in that an effective amount of a medication containing a compound of formula (A) is administered

or an acyl derivative of a biological precursor of formula (B)

where X represents hydrogen, and two hydroxyl groups are acetylated, or a pharmaceutically acceptable salt of any of these compounds, even after 18 hours or more after infection. 2. The method according to claim 1, where the drug is administered to reduce the development or reactivation of latent infections caused by herpes simplex virus type 1. 3. The method according to claim 1, where the drug is administered to reduce the development or reactivation of latent infections caused by herpes simplex virus type 2. 4. The method according to claim 1, where the drug is administered in a dose of from 50 mg to 1 g of the active ingredient and where the specified dose is administered from 1 to 4 times a day.