JP2009533428A - Intramuscular antiviral treatment - Google Patents

Abstract

The present invention provides unit dosage forms, kits, and methods useful for treating viral infections. In one embodiment, the invention comprises administering to a human by an intramuscular route an effective antiviral amount of a compound of formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof. Methods are provided for treating viral infections (eg, influenza infection) in humans, including. The present invention inhibits neuranimidase in humans, comprising administering to the human by an intramuscular route an effective inhibitory amount of a compound of formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof. A method is also provided.

Description

The influenza virus neuraminidase inhibitor peramivir (peranivir) has significant activity against influenza viruses in mice in vitro and experimentally (Non-Patent Document 1; and Non-Patent Document 2). Unfortunately, clinical trials with peramivir have shown an undesirably low inhibitory effect on influenza in humans after several days of oral administration. Currently, there is a need for methods and formulations that are useful for treating viral infections such as influenza infections.
Govorkova et al. , Antimicrobial Agent and Chemotherapy, 45 (10), 2723-2732 (2001). Smee et al. , Antimicrobial Agent and Chemotherapy, 45 (3), 743-748 (2001).

  It was unexpectedly discovered that single intramuscular administration of peranivir to mice is effective for treating influenza. These findings are unexpected not only due to the high efficacy of a single dose of the compound, but also due to the low dose of the compound that was found to provide effective treatment. Obtaining a therapeutically useful effect with a single dose is important, especially because patient compliance due to the need for multiple doses is minimized by low doses. In addition, administration of low doses is important because it minimizes costs and potential side effects.

  Accordingly, in one embodiment, the present invention provides an effective antiviral amount of a compound of formula I, II, III, or IV:

、あるいはそれらの薬学的に許容される塩を、筋肉内経路によりヒトに投与するステップを含む、ヒトにおけるウイルス感染（例えば、インフルエンザ感染）を処置するための方法を提供する。

Or a pharmaceutically acceptable salt thereof is provided to a method for treating a viral infection (eg, influenza infection) in a human comprising administering to the human by the intramuscular route.

  The present invention inhibits neuranimidase in humans, comprising administering to the human by an intramuscular route an effective inhibitory amount of a compound of formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof. A method is also provided.

  The present invention relates to a unit dosage suitable for intramuscular administration to humans comprising up to about 500 mg (eg, about 150 mg) of a compound of formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof. Also provides a shape.

  The present invention comprises a packaging material, a compound of formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, and instructions for administering the compound to a human by the intramuscular route. A kit containing the same is also provided.

  The present invention exposes an influenza virus source by intramuscular administration of an effective antiviral dose of an agent to each member of a group of mammals, for example, humans, exhibiting clinical symptoms of infection. A compound of formula I, II, III, or IV, or a pharmaceutically acceptable thereof, in the manufacture of an intramuscular injection to increase life expectancy and / or reduce mortality in a given group The use of salt is also provided.

  The present invention increases the life expectancy or reduces mortality in groups exposed to influenza virus sources by intramuscular administration of a dose of a drug to each member of a mammal, eg, a human group There is also provided the use of a compound of formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, in the manufacture of an intramuscular injection drug for

  The influenza virus neuraminidase inhibitor peranivir has long been shown to have significant activity against influenza viruses in mice in vitro and experimentally infected (Govorkova et al., Antimicrobial Agent and Chemotherapy, 45 (10), 2723-2732 (2001); and Smee et al., Antimicrobial Agent and Chemotherapy, 45 (3), 743-748 (2001)). Unfortunately, clinical trials with this drug have shown insufficient inhibitory effects against influenza in humans.

  It has been discovered that single intramuscular injection of peranivir greatly reduces body weight loss and mortality in mice infected with influenza A / H1N1. Thus, single intramuscular injection of peranivir can be used to treat influenza infections and to provide an alternative to oseltamivir during influenza outbreaks.

  Peranivir was tested as a single intramuscular injection in a mouse influenza model and found to be effective when administered intramuscularly. In three different studies of prevention models using two different strains of influenza A virus (H1N1 and H3N2), the efficacy of single intramuscular injection of peranivir was compared with oral treatment with oseltamivir or peranivir (daily x 5 days) Compared. Although oseltamivir for 5 days (twice a day) is commonly used in hospitals for the treatment of influenza, it has been shown to be effective for 5 days once a day. In all three studies, the efficacy of a single intramuscular injection of peranivir at a dose of 10 or 20 mg / kg is comparable to oral treatment with the same dose of oseltamivir or peranivir (daily) in terms of survival, mean survival, and weight loss. × 5 days). As a single intramuscular injection at a dose of 2 mg / kg, peranivir showed comparable efficacy in terms of survival. Nevertheless, the maximum weight loss was greater in the group treated with single intramuscular peranivir than in the group treated with oral (daily x 5 days) oseltamivir. Maximum weight loss for the treatment group was observed around days 8-10. It should be noted that while the lowest dose of peranivir (1 mg / kg) was not effective in terms of survival, there was a large increase in mean survival days. Peranivir was very effective in mice with a viral challenge that caused 70% mortality when treatment was only started 48 hours after infection.

  Single intramuscular injections of peranivir or oseltamivir were also compared in the H1N1 mouse influenza model. Survival data showed that a single intramuscular injection of peranivir is effective and provides complete lethal protection. In contrast, a single intramuscular injection of oseltamivir did not provide significant lethal protection. The weight loss data is consistent with the survival data and, unlike the oseltamivir group, shows that single intramuscular injection of peranivir is effective in preventing weight loss in infected mice. These studies show that peranivir is effective when given as a single intramuscular injection, whereas oseltamivir is not effective by the same route of administration in a mouse influenza model. Single intramuscular injection of oseltamivir carboxylate in mice showed similar effects as single intramuscular injection of oseltamivir.

The IC _{50 for} peranivir and oseltamivir carboxylate is subnanomolar, 0.11 and 0.69 nM for H1N1 (Bantia et al., Antimicrob. Agents Chemother. 45, 1162-1167 (2001)), H3N2, respectively. For 0.59 and 0.55 nM. Despite similar efficacy against the neuranimidase enzyme, a single intramuscular injection of oseltamivir (carboxylate) is not effective. However, peranivir as a single intramuscular injection exceeds oseltamivir (carboxylate) given as a single intramuscular injection. Although the slow off-rate of peranivir was demonstrated by N9 neuranimidase, it would be expected that peranivir binds tightly to both N1 and N2 neuranimidase. This is because amino acid residues in the active site are highly conserved among different neuranimidase subtypes.

  In summary, peranivir is a potent inhibitor of neuranimidase activity. Prophylactic and subsequent single intramuscular administration was effective in preventing mortality and weight loss in a mouse influenza model. In view of in vivo and in vitro data, peranivir is effective as a single intramuscular injection and can be used in the treatment of human influenza virus infection.

  Accordingly, in one embodiment, the present invention comprises administering to a human by intramuscular administration of an effective amount of a compound of formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof. Methods are provided for treating viral infections in humans. In general, an effective amount is administered in a single intramuscular administration. The methods of the present invention provide for high patient compliance because they involve low doses of active agent.

  In one embodiment of the invention, the effective inhibitory amount of a compound of formula I, II, III, or IV is up to about 500 mg (eg, from about 10 mg to about 500 mg).

  In one embodiment of the invention, the effective inhibitory amount of a compound of formula I, II, III, or IV is up to about 150 mg.

  In one embodiment of the invention, the effective inhibitory amount of a compound of formula I, II, III, or IV is about 150 mg.

  According to the methods of the invention, a compound of formula I, II, III, or IV is administered to a human by intramuscular injection. In one embodiment of the invention, the compound of the formula I, II, III or IV is administered once to the human by intramuscular injection. In another embodiment of the invention, the neuraminidase inhibitor administered orally is oseltamivir carboxylate. In one embodiment of the invention, the orally administered neuraminidase inhibitor is a compound of formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof. In one embodiment of the invention, the orally administered neuranimidase inhibitor is a compound of formula Ia, IIa, IIIa, or IVa:

、あるいはそれらの薬学的に許容される塩である。本発明の１つの実施形態において、経口投与されるノイラニミダーゼ阻害剤は、式Ｉａの化合物、それらの薬学的に許容される塩である。

Or a pharmaceutically acceptable salt thereof. In one embodiment of the invention, the orally administered neuraminidase inhibitor is a compound of formula Ia, a pharmaceutically acceptable salt thereof.

  According to the method of the invention, the compound of formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, is an antiviral agent (eg, an agent active against influenza) or an antibiotic. Can also be used in combination with one or more additional therapeutic agents.

  The intramuscular formulations of the present invention may also include one or more additional therapeutic agents such as antiviral agents (eg, agents active against influenza) and antibiotics.

  The compounds used in the present invention are known in the art and can be synthesized by one skilled in the art using available methods (see, eg, US Pat. No. 6,562,861).

  The specific values listed herein for radicals, substituents, and ranges are for illustration only and those values may be defined as other defined values or ranges defined for radicals and substituents. It does not exclude other values.

  Certain compounds of formula I, II, III, or IV are compounds of formula Ia, IIa, IIIa, or IVa:

、あるいはそれらの薬学的に許容される塩である。

Or a pharmaceutically acceptable salt thereof.

  Certain compounds of formula I, II, III, or IV are (1S, 2S, 3R, 4R) -3- (1-acetamido-2-ethylbutyl) -4-guanidino-2-hydroxycyclopentanecarboxylic acid, ( 1S, 2S, 3R, 4R) -3- (1-acetamido-2-propylbutyl) -4-guanidino-2-hydroxycyclopentanecarboxylic acid, (1R, 3R, 4R) -3- (1-acetamido-2 -Propylpentyl) -4-guanidinosicyclopentanecarboxylic acid, or (1R, 3R, 4R) -3- (1-acetamido-2-ethylbutyl) -4-guanidinosicyclopentanecarboxylic acid, or a pharmaceutically It is an acceptable salt.

  A particular compound of formula I is a compound of formula Ia, or a pharmaceutically acceptable salt thereof.

  It will be understood by those skilled in the art that compounds having one or more chiral centers exist and can be isolated in optically active racemic forms. Some compounds may exhibit polymorphism. Of any racemic, optically active, polymorphic, or stereoisomeric form of the compounds of formula I, II, III, and / or IV having the useful properties described herein, or mixtures thereof It should be understood that the invention includes use of how to prepare optically active forms (eg, by resolution of racemic forms by recrystallization, synthesis from optically active starting materials, by chiral synthesis) Or by chromatographic separation using a chiral stationary phase) and using standard tests described herein, or other similar tests that are also well known in the art How to determine antiviral (eg, anti-influenza) activity is well known in the art.

  If the compound is sufficiently basic or acidic to form a stable non-toxic acidic or basic salt, administration of the compound as a salt may be appropriate. Examples of pharmaceutically acceptable salts include organic acid addition salts formed with acids that form physiologically acceptable anions, such as tosylate, methanesulfonate, acetate, citrate, Malonate, tartrate, succinate, benzoate, scorbate, α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts can also be formed, including hydrochloride, sulfate, nitrate, phosphate, bicarbonate, and carbonate.

  Pharmaceutically acceptable salts can be prepared using standard procedures well known in the art, e.g., a sufficiently basic compound, such as an amine, to provide a suitable physiologically acceptable anion. It can be obtained by reacting with an acid. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.

  Compounds of formula I, II, III, and IV are formulated as pharmaceutical compositions and can be administered by intramuscular route to a mammalian host, such as a human patient. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a non-toxic surfactant. Dispersions can also be prepared in glycerin, liquid polyethylene glycols, triacetin, and mixtures thereof and oils. Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. In some embodiments of the invention, the compound of formula I, II, III, and / or IV is formulated with a buffering agent such as citrate, such as sodium citrate.

  Pharmaceutical dosage forms suitable for injection or infusion include sterile aqueous solutions containing the active ingredient which are adapted for the immediate preparation of sterile injectable or injectable solutions or dispersions optionally encapsulated in liposomes. Dispersions or sterile powders can be included. In all cases, the final dosage form should be sterile, liquid and stable under the conditions of manufacture and storage. Liquid carriers or excipients include, for example, solvents or liquid dispersion media containing water, ethanol, polyol (eg, glycerin, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glyceryl esters, and suitable mixtures thereof It can be. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersion or by the use of surfactants. Prevention of the activity of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be more desirable to include isotonic agents, for example, sugars, buffers (eg, sodium citrate) or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by using in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin.

  Sterile injectable solutions can be prepared by mixing the active compound with any other ingredients, such as those listed above, in a suitable solvent, followed by optional filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are the vacuum drying method and the lyophilization method, which, in addition to the active ingredient powder, have been previously sterile filtered. Any additional desired components present in the solution are obtained.

  As used herein, the terms “treat”, “treating” and “treatment” are used before the onset of clinical symptoms of a disease state / situation. Administering a compound to prevent progression of any symptom, and after initiation of one or more clinical symptoms of a disease state / situation, any symptom, appearance or appearance of that disease state / situation Administering a compound so as to reduce or eliminate the feature. Such treatment need not be complete in order to be useful. As exemplified below, the active compound may be administered prior to exposure to the virus. The agent can be administered after exposure to the virus (eg, within 1, 2, 3, 4, or 5 days).

  As used herein, the term “unit dosage form” contains a specific amount (eg, about 10 mg to about 500 mg, eg, about 150 mg) of a drug, in its entirety. It relates to an intramuscular formulation intended to be administered as a single dose. This is in contrast to the supply of non-quantitative medication from which a dose must be metered, for example a bottle of medication.

  The invention is illustrated by the following non-limiting examples.

Example 1. Intramuscular treatment of influenza with peranivir The efficacy of single intramuscular injection of peranivir in a mouse influenza model was evaluated. In summary, peranivir has been found to be effective when administered intramuscularly in a mouse influenza virus infection model. Peranivir potently inhibited neuranimidase enzyme N9 from H1N9 virus at a 50% inhibitory concentration (IC ₅₀ ) of 1.3 ± 0.4 nM in vitro. On-site dissociation studies show that peranivir remains tightly bound to N9 neuraminidase (t _1/2 > 24 h), whereas zanamivir and oseltamivir carboxylate dissociate rapidly from the enzyme (t _1/2 = 1. 25h). Single intramuscular injection of peranivir (10 mg / kg) significantly reduced weight loss and mortality in mice infected with influenza A / H1N1, whereas oseltamivir showed no efficacy with the same treatment regimen There wasn't. An additional efficacy study showed that a single injection of peranivir (2-20 mg / kg) was orally administered x5 daily oral oseltamivir (2-20 mg / kg) in preventing lethality in the H3N2 and H1N1 influenza models. It was shown to be comparable to the daily course. Thus, single intramuscular injection of peranivir can be used to treat influenza infection, providing an alternative to oseltamivir during influenza outbreaks.

Results The ability of peranivir to inhibit N9 neuranimidase activity from H1N9 virus was tested and compared to zanamivir and oseltamivir carboxylate. The IC ₅₀ for peranivir (1.3 +/− 0.4 nM), oseltamivir carboxylate (2.1 +/− 0.4 nM), and zanamivir (1.6 +/− 0.3 nM) for the N9 enzyme was significantly different There wasn't. IC ₅₀ values were 5.0 +/− 1.1 nM for peranivir, 10.4 +/− 0.7 nM for oseltamivir carboxylate and +/− 1.2 nM for zanamivir 10.0.

  In a mouse influenza model, viral infection results in weight loss and high mortality, and this weight loss correlates with lung virus titration and lung injury scores. Thus, the efficacy of peranivir, oseltamivir and zanamivir administered orally and intramuscularly was evaluated based on weight loss, mean survival days and survival, and infection treated relative to untreated infected animals (control) The finished animals were measured for 16 or 21 days after infection.

  In a prophylactic model, a single intramuscular injection of peranivir given 4 hours prior to viral challenge with H1N1 virus was compared to a daily oral treatment with peranivir for 5 days at doses of 1 and 10 mg / kg / day. . Complete lethal protection was observed in mice treated with 10 mg / kg by both treatment regimes. However, at the 1 mg / kg dose, 60% of mice survived in the oral treatment group compared to 40% survival in the intramuscular treatment group. Mice treated with a single intramuscular injection of peranivir (10 mg / kg) did not show any weight loss, whereas mice that received peranivir orally for 5 days at the same dose lost 0.22 g.

  Peranivir was also administered at 2, 10, and 20 mg / kg as a single intramuscular injection 4 hours prior to viral infection with H1N1 virus. Complete lethal protection was observed at all doses. However, none of the 5 saline treated control mice survived. By comparison, complete lethal protection was also observed in mice treated orally with oseltamivir at both 2 and 10 mg / kg (daily x 5 days). No signs of drug-related toxicity were observed when peranivir was administered intramuscularly at the highest dose (20 mg / kg).

  Peranivir and oseltamivir showed a dose-response relationship when they followed weight loss over time in infected mice. On day 8, the maximum mean body weight loss in the 2, 10, and 20 mg / kg peranivir treatment groups was 3.3, 0.98, and 0 g, respectively. In addition, oseltamivir produced a similar effect with a maximum average weight loss of 1.34 and 0 g on day 8 for the 2 and 10 mg / kg groups, respectively. The weight loss on the fifth day shows a similar tendency. In general, lower doses resulted in greater weight loss when compared to higher doses.

  A single intramuscular injection of peranivir or oseltamivir at a dose of 10 mg / kg was evaluated when administered 4 hours after inoculation with H1N1 virus. Oseltamivir provides only 30% protection, which is not significantly different from the control group in which 90% of the mice died. Complete lethal protection was observed in the peranivir treated group. The peranivir group did not show any substantial weight loss (about 1.7% of initial weight). On the other hand, the oseltamivir group lost significant weight, approximately 4 g (25% of the initial weight) and survived only 3 out of 10 mice. In the same model, a single oral treatment comparison of either 10 mg / kg dose of either peranivir or oseltamivir was evaluated. Peranivir provided better protection orally and had a survival rate of 50%, whereas only 10% of mice survived in the oseltamivir group.

  Compare the efficacy of single intramuscular injection of peranivir with oral treatment with oseltamivir (daily x 5 days) in mice infected with H3N2 virus to determine if similar protective effects are observed with different viruses did. In this study, the drug was administered 1 hour prior to virus inoculation. Single intramuscular treatment of peranivir at a 20 mg / kg dose resulted in almost complete lethal protection (9/10 survived). Oseltamivir also showed a similar protective effect (9/10 survived). By day 8, the mean weight loss was calculated in that both oseltamivir treated mice lost 28% (about 5.1 g) of body weight compared to 25% weight loss (4.5 g) in the peranivir group. Identical in the treatment group. In the delayed treatment model, single intramuscular administration of 10 mg / kg peranivir at 24 or 48 hours post infection resulted in complete lethal protection, whereas 70% mortality was observed in the saline group It was done. There was no significant weight loss in the 24 and 48 hour peranivir treated groups, both administered orally (daily x 5 days) and by single intramuscular injection, whereas the saline group received 2.1 g Diminished.

Materials and Methods The influenza A virus used in this study was obtained from the American Type Culture Collection, Manassas, VA, USA (A / NWS / 33; H1N1) and Dr. Robert Sidwell and adapted to mice. Purified N9 crystals from A / H1N9 (NWS / G70) avian virus were obtained from Dr. Graeme Lover, Australian National University, Canberra, Australia.

  Female BALB / c mice (10-19 g) free of specific pathogens were obtained from Charles Rivers Laboratories (Raleigh, NC, USA). The mice were isolated 24 hours prior to infection and maintained with Harlan Tecklad rodent diet and tap water.

  Peranivir, oseltamivir, oseltamivir carboxylate and zanamivir are available from BioCrysta Pharmaceuticals, Inc. (Birmingham, AL, USA). Each compound was prepared in sterile 0.9% sodium chloride for in vivo experiments. A 5% isoflurane / 95% oxygen mixture was administered as anesthesia.

A standard fluorometric assay was used to measure influenza virus neuraminidase activity (Potier et al., Anal. Biochem., 94, 287-296 (1979)). The substrate (2 ′-(4-methylumbelliferyl) -α-D-acetylneuraminic acid, MuNANA) was cleaved with neuranimidase to obtain a fluorescent product that could be quantified. The assay mixture contains various concentrations of inhibitor and neuraminidase enzyme in 32.5 mM MES (2- (N-morpholino) -ethanesulfonic acid) buffer, 4 mM calcium chloride, pH 6.5, Incubated for 30 minutes. The reaction was initiated by the addition of substrate. After 30-120 minutes incubation, fluorescence was recorded (excitation: 360 nm and emission: 450 nm) and the substrate blank was subtracted from the sample reading. IC ₅₀ was calculated by plotting% inhibition of neuranimidase activity against inhibitor concentration. Results are reported as the average of 3 experiments.

  Mice were anesthetized with isoflurane and exposed to 100 μL of virus by nasal drop. In the prevention model, the drug was administered 1 or 4 hours before viral infection, and in the treatment model, the drug was given at the indicated time after viral infection. Each infected, drug and saline treated group contained 5-10 mice. All mice were observed daily for weight change and any death. Parameters for assessing antiviral activity include weight loss, decreased mortality and / or increased mean survival days determined over 16 or 21 days.

  Mice were infected with approximately 70-90% lethal doses of A / NWS / 33 (H1N1) or A / Victoria / 3/75 (H3N2) influenza viruses. Oral treatment with peranivir or oseltamivir (prepared in injection grade saline) started 1 or 4 hours prior to viral exposure (prevention model) and continued once daily for 5 days unless indicated. Single intramuscular treatment was administered 1 or 4 hours prior to virus exposure or when indicated (treatment model). Normal saline treated control mice were included in the same treatment schedule. The parameters studied were a decrease in mortality and / or an increase in mean survival days.

  Data were analyzed with Sigma Plot (Windows (R) Version 4.01, SPSS, Chicago. IL. USA) and Sigma Stat (Windows (R) Version 2.0, Jandel Corporation, San Raphael, CA. USA). did. A t-test was used to assess the difference in mean survival days. To assess differences in weight loss, a one-way analysis of variance (ANOVA) was performed using the Holm-Sidak test for multiple comparisons. Kplan-Meier survival analysis (log rank or Gehan-Broslow test) was applied to the difference in survival numbers.

  These findings, including methods, results, and discussion, are described in Bantia et al. , Antivirus Research, 69, 39-45 (2006).

  All publications, patents and patent applications cited herein are hereby incorporated by reference. In the foregoing detailed description, the invention has been described with reference to specific embodiments thereof, and while numerous details have been presented for purposes of illustration, the invention is susceptible to additional embodiments. It will be apparent to those skilled in the art that some of the details described herein can be varied significantly without departing from the basic principles of the invention.

  The terms “a”, “an”, “the” and similar designations in the context of describing the invention are intended to be used unless otherwise indicated herein or by context. Unless explicitly denied, it should be construed to cover both singular and plural. The terms “comprising”, “having”, “including”, and “containing” are to be interpreted as open-ended terms unless otherwise indicated (ie, Meaning "including but not limited to") the recitation of a range of values herein is individually referred to each individual value falling within that range unless otherwise indicated herein. It is merely intended to serve as a shorthand notation, and each individual value is incorporated into the specification as if it were individually listed herein. All methods described herein may be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of all examples or representative phrases (e.g., “such as”) presented in the specification are merely intended to better illustrate the present invention. Unless otherwise specifically claimed, it is not intended to limit the scope of the invention.

Claims (61)

A method for treating a viral infection in a human, comprising an effective antiviral amount of a compound of formula I, II, III, or IV:

Or administering a pharmaceutically acceptable salt thereof to the human by the intramuscular route. Said compound of formula I, II, III or IV is compound of formula Ia, IIa, IIIa or IVa:

Or a pharmaceutically acceptable salt thereof.   The method according to claim 1 or 2, wherein the viral infection is an influenza infection.   4. The method of claim 3, wherein the viral infection is an influenza A or B infection.   4. The method of claim 3, wherein the influenza is H3N2, H1N1, H5N1, a bird, or seasonal influenza.   6. The method of any one of claims 1-5, wherein the effective antiviral amount is up to about 500 mg.   6. The method of any one of claims 1-5, wherein the effective antiviral amount is up to about 150 mg.   6. The method of any one of claims 1-5, wherein the effective antiviral amount is about 150 mg.   9. The method of any one of claims 1-8, wherein the entire effective dose is administered in a single intramuscular administration.   10. A method according to any one of claims 2 to 9, wherein a compound of formula Ia or a pharmaceutically acceptable salt thereof is administered. A method for inhibiting neuraminidase in a human, comprising an effective inhibitory amount of a compound of formula I, II, III, or IV:

Or administering a pharmaceutically acceptable salt thereof to the human by the intramuscular route. A compound of formula I, II, III, or IV is a compound of formula Ia, IIa, IIIa, or IVa:

Or a pharmaceutically acceptable salt thereof.   13. The method of claim 11 or 12, wherein the effective inhibitory amount is up to about 500 mg.   13. The method of claim 11 or 12, wherein the effective inhibitory amount is up to about 150 mg.   13. The method of claim 11 or 12, wherein the effective inhibitory amount is about 150 mg.   16. A method according to any one of claims 11 to 15, wherein the entire effective inhibitory amount is administered in a single intramuscular administration.   17. A method according to any one of claims 11 to 16, wherein a compound of formula Ia, or a pharmaceutically acceptable salt thereof is administered.   18. The method of any one of claims 1-17, further comprising orally administering a neuraminidase inhibitor to the human.   19. The method of claim 18, wherein the neuraminidase inhibitor administered orally is oseltamivir carboxylate. The neuraminidase inhibitor administered orally is a compound of formula I, II, III, or IV:

The method according to claim 18, or a pharmaceutically acceptable salt thereof. The neuraminidase inhibitor administered orally is a compound of formula Ia, IIa, IIIa, or IVa:

The method according to claim 18, or a pharmaceutically acceptable salt thereof.   24. The method of claim 21, wherein the neuraminidase inhibitor administered orally is a compound of formula Ia or a pharmaceutically acceptable salt thereof.   23. The method of any one of claims 18-22, wherein the neuraminidase inhibitor administered orally is administered for up to 20 days.   23. The method of any one of claims 18-22, wherein the neuraminidase inhibitor administered orally is administered for up to 10 days.   23. The method of any one of claims 18-22, wherein the neuraminidase inhibitor administered orally is administered for up to 5 days. Unit dosage forms suitable for intramuscular administration to humans, up to about 500 mg of a compound of formula I, II, III, or IV:

Or a unit dosage form comprising a pharmaceutically acceptable salt thereof. Said compound of formula I, II, III or IV is compound of formula Ia, IIa, IIIa or IVa:

27. A unit dosage form according to claim 26, which is or a pharmaceutically acceptable salt thereof.   28. A unit dosage form according to claim 26 or 27 comprising up to about 500 mg of the compound or salt.   28. A unit dosage form according to claim 26 or 27 comprising about 150 mg of the compound or salt. Packaging materials and compounds of formula I, II, III, or IV:

Or a pharmaceutically acceptable salt thereof and instructions for administering the compound to a human by the intramuscular route.   32. The kit of claim 30, wherein the compound is provided in a formulation suitable for intramuscular administration.   32. A kit according to claim 30 or 31 comprising up to about 500 mg of the compound or salt.   32. A kit according to claim 30 or 31, comprising up to about 150 mg of the compound or salt.   32. A kit according to claim 30 or 31 comprising about 150 mg of the compound or salt.   35. A kit comprising packaging material, a unit dosage form according to any one of claims 26 to 34, and instructions for administering the compound to a human by the intramuscular route. To increase life expectancy in a group of mammals exposed to a source of influenza virus by intramuscular injection of a dose of drug to each member of the group of mammals presenting with clinical symptoms of infection or mortality A compound of formula I, II, III, or IV in the manufacture of an intramuscular injection to reduce

Or the use of a pharmaceutically acceptable salt thereof. Said compound of formula I, II, III or IV is compound of formula Ia, IIa, IIIa or IVa:

The use according to claim 36, or a pharmaceutically acceptable salt thereof.   38. Use according to claim 36 or 37, wherein the influenza virus is an avian influenza virus.   39. Use according to claim 38, wherein the avian influenza virus is H5N1, or a mutant strain thereof.   40. Use according to any one of claims 36 to 39, wherein each member of the group presenting with symptoms of infection receives only one intramuscular dose of the drug.   41. Use according to any one of claims 36 to 40 for increasing life expectancy or reducing mortality in a group of mammals, wherein the members of the group presenting clinical symptoms of said infection are Use, treated orally with a neuraminidase inhibitor.   42. Use according to claim 41, wherein the neuraminidase inhibitor is oseltamivir carboxylate. The neuraminidase inhibitor is a compound of formula I, II, III, or IV:

42. The use according to claim 41, or a pharmaceutically acceptable salt thereof. The neuranimidase inhibitor is a compound of formula Ia, IIa, IIIa, or IVa:

42. The use according to claim 41, or a pharmaceutically acceptable salt thereof.   42. Use according to claim 41, wherein the neuraminidase inhibitor is a compound of formula Ia, or a pharmaceutically acceptable salt thereof.   46. Use according to any one of claims 36 to 45, wherein the virus source is an infected bird.   46. Use according to any one of claims 36 to 45, wherein the viral source is a mammal presenting with symptoms of infection.   48. Use according to any one of claims 36 to 47, for reducing mortality. Intramuscular injection to increase the life expectancy or reduce mortality in the group of mammals exposed to the influenza virus source by intramuscular injection of a dose of the drug to each member of the group of mammals A compound of formula I, II, III or IV in the manufacture of an injectable medicament:

Or the use of a pharmaceutically acceptable salt thereof. Said compound of formula I, II, III or IV is compound of formula Ia, IIa, IIIa or IVa:

50. The use according to claim 49, which is or a pharmaceutically acceptable salt thereof.   51. Use according to claim 49 or 50, wherein the influenza virus is an avian influenza virus.   52. Use according to claim 51, wherein the avian influenza virus is H5N1, or a mutant thereof.   53. Use according to any one of claims 49 to 52, wherein each member of the group receives a single intramuscular dose of drug.   54. Use according to any one of claims 49 to 53 for increasing life expectancy or reducing mortality in a group of mammals, wherein said group member is orally treated with a neuraminidase inhibitor. Used.   55. Use according to claim 54, wherein the neuraminidase inhibitor is oseltamivir carboxylate. The neuraminidase inhibitor is a compound of formula I, II, III, or IV:

55. The use according to claim 54, which is or a pharmaceutically acceptable salt thereof. The neuranimidase inhibitor is a compound of formula Ia, IIa, IIIa, or IVa:

55. The use according to claim 54, which is or a pharmaceutically acceptable salt thereof.   55. Use according to claim 54, wherein the neuraminidase inhibitor is a compound of formula Ia, or a pharmaceutically acceptable salt thereof.   59. Use according to any one of claims 49 to 58, wherein the viral source is an infected bird.   59. Use according to any one of claims 49 to 58, wherein the viral source is a mammal presenting with symptoms of infection.   61. Use according to any one of claims 49 to 60, for reducing mortality.