RU2181049C2 - Use of aminopurine antiviral compounds for treatment and prophylaxis of latent states caused by herpes virus - Google Patents

Abstract

FIELD: medicine, virology, pharmacology, chemotherapy. SUBSTANCE: invention proposes method of prophylaxis as decrease of development or reactivation of latent infection caused by herpes virus. Method involves administration of compound of the formula (A)

or the formula (B)

Description

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

и его соли, фосфатные эфиры и ацильные производные в качестве противовирусных соединений. Гидрат натриевой соли пенцикловира раскрыт в ЕР-А-216459 (Beecham Group p. 1.с.). Пенцикловир и его антивирусная активность описывается также в реферате Р. VII-5, p.l93 публикации "Abstracts of 14th Int. Congress of Microbiology", Manchester, England, 7-13 September 1986 (Boyd et al).In EP-A-141927 (Beecham Group plc.), Penciclovir is disclosed, a compound of formula (A):

and its salts, phosphate esters and acyl derivatives as antiviral compounds. Penciclovir sodium salt hydrate is disclosed in EP-A-216459 (Beecham Group p. 1.c.). Penciclovir and its antiviral activity are also described in abstract R. VII-5, p.l93 of the publication "Abstracts of 14th Int. Congress of Microbiology", Manchester, England, September 7-13, 1986 (Boyd et al).

и их соли и производные определенные формулой (А); в которой Х является C_1-6 алкоксилом, NH₂ или водородом. Соединения формулы (В), в которой Х является C_1-6 алкоксилом или NH₂, раскрыты в ЕР-А-141927, а соединения формулы (В), в которой Х является водородом, раскрытые в ЕР-А-182024 (Beecham Group p.1.с.), являются предпочтительными пролекарствами. Особенно предпочтительным примером соединения формулы (В) является соединение, в котором Х является водородом, и в котором две ОН-группы находятся в форме ацетильного производного, описанное в примере 2 ЕР-А-182024, здесь далее называемое фамцикловиром.Active when taken orally, the biological precursors of the compounds of formula (A) are compounds of the formula

and their salts and derivatives as 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 p.1.s.) 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 reinfection 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) can prevent new cells from becoming latently infected. Then the result will be a radical cure, and after that the patient will not have relapses.

или его биопредшественника или фармацевтически приемлемой соли, фосфатного эфира и/или ацильного производного любого из указанных ранее соединений.Accordingly, the present invention provides a method of treating a latent infection caused by a herpes virus 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 here 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.1.e.).

 Examples of bio-precursors, 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 a syrup, tablet or capsule form. When it is made in the form of tablets, any pharmaceutical carrier suitable for preparing such solid compositions may 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, tablets having a coating that dissolves in the intestine.

 For parenteral administration, liquid dosage forms are prepared in unit dosage form containing a compound and a sterile carrier. 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 will be removed under vacuum.

 Parenteral suspensions are prepared in essentially the same manner, except that the compound is suspended in the vehicle instead of being dissolved 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 a compound will generally range from 0.2 to 40 mg per kg of body weight per day, or more typically from 10 to 20 mg / kg per day. In the case of famciclovir, the unit dose is 125 mg, 250 mg, 500 mg or 750 mg, preferably 125 mg 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 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 present invention further 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 biologically preferred salt, or a pharmaceutically acceptable salt, phosphate ester and / or acyl derivative of any of the compounds, and a pharmaceutically acceptable carrier. Such compositions can 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 encompassed by the scope of this invention.

 The following animal studies illustrate the invention.

HSV-1 infected mouse experiments
A skin infection was created by inoculating HSV-1 mice (SC16) into the earlobe and the effect of famciclovir when orally administered to a latent viral infection was examined.

BALB / c female mice (Bantin and Kingman, Kingston, Hull, UK) were purchased at 3 to 4 weeks old and infected one week later. 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 the 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 on day 10 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 dosing root ganglion (DGG). 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 restrictions at a concentration of 1 mg / ml (approximately 100 mg / kg / day). The results are presented in table. 1.

 Four months later, 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 PCV-treated 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 (where 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 Table 2.

HSV-2 infected mouse experiments
Each infection was created by inoculation in the earlobe of HSV-2 mice (Bru) and the effect of famciclovir when taken orally on a latent viral infection was examined. The treatment consisted of taking 50 mg / kg twice a day for 5 days, starting at 22 hours after infection.

 Table 3 shows the number of mice / group with positive latent infection in the trigeminal or cervical dorsal root ganglion.

Claims (4)

1. A method of reducing the development and reactivation of latent herpes virus infections in humans, characterized in that an effective amount of a drug containing a compound of formula A is administered

or its bioprecursor of formula B

or a pharmaceutically acceptable salt of any of these compounds at least 18 hours after infection.  2. The method according to p. 1, characterized in that the drug is administered to reduce the development and reactivation of latent infections caused by herpes simplex virus type 1.  3. The method according to p. 1, characterized in that the drug is administered to reduce the development and reactivation of latent infections caused by herpes simplex virus type 2.  4. The method according to p. 1, characterized in that the drug is administered at a dose of 125 mg, 250 mg, 500 mg, 750 mg or 1 g once, two or three times a day. Priority on points:
12.12.1994 PP 1, 2, 4;
08.24.1995 under item 3.

Images