BRPI0707769A2 - intravenous antiviral treatments - Google Patents

Abstract

Intravenous anti-viral treatments. The present invention relates to unit dosage forms, kits, and methods useful for treating viral infections.

Description

Descriptive Report of the Invention Patent for "INTRAVENOUS ANTIVIAL TREATMENTS".

Related Patent Applications

This patent document claims the priority benefit of United States Patent Application No. 60 / 772,748, filed February 13, 2006, and International Patent Application PCT / US2006 / 013535, filed April 12, 2006, from Patents are incorporated herein by reference.

Background

The peramivir neuraminidase influenza virus inhibitor has marked activity against the influenza virus in vitro and in experimentally infected mice (Govorkova et al., Antimicrobial Agentsand Chemotherapy, 45 (10), 2723-2732 (2001); and Smee et al., Antimicrobial Agents and Chemotherapy. , 45 (3), 743-748 (2001)) Unfortunately, clinical trials using this drug have shown a subideal therapeutic effect on influenza infection in humans following oral administration over a period of days. There is currently a need for methods and formulations that are useful for treating viral infections (e.g., influenza infections) in humans.

Summary of the Invention

It has been unexpectedly found that a single intravenous administration of peramivir to a mouse is effective for treating influenza. These findings are unexpected not only because of the high efficacy of a single administration of the compound, but also because of the low dose of the compound that has been found to provide effective treatment. The ability to achieve therapeutically useful effects with a single administration is important among other things because it minimizes consequences of patient compliance resulting from the need for multiple administrations. Additionally, administering a download is important because it minimizes cost and the potential for side effects. It has also been unexpectedly found that intravenous and intramuscular injections of peramivir to humans provide high concentrations of peramivir plasma with a prolonged half life.

Accordingly, in one embodiment, the invention provides a method for treating a viral infection (e.g., an influenza infection) in a human comprising administering an effective antiviral amount of a compound of formula I, II, III, or IV:

<formula> formula see original document page 3 </formula>

or a pharmaceutically acceptable salt thereof, to humans by an intravenous routine.

The invention also provides a method for inhibiting a neuraminidase in a human comprising administering an effective inhibitory amount of a compound of formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, to the human by an intravenous routine.

The invention also provides a unit dosage form which is suitable for intravenous administration to a human comprising up to about 400 mg of a compound of formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof.

The invention also provides a unit dosage form which is suitable for intravenous administration to a human being comprising up to about 1,000 mg (e.g., up to about 800, 600,500, 400, 300, 200, 150, 100, or 75 mg) of a compound of formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof.

The invention also provides a kit comprising packaging materials, a compound of formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, and instructions for administration to a human by intravenous routine.

The invention also provides the use of a compound of formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, in the manufacture of an intravenous injection medicament to increase life expectancy or reduce mortality in a group of mammals exposed to a source of an influenza virus by intravenously injecting a dose of the drug into each member of the group who has clinical symptoms of infection.

The invention also provides the use of a compound of formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, in the manufacture of an intravenous injection medicament to increase life expectancy or reduce mortality in a group of mammals exposed to a source of an influenza virus by intravenously injecting a dose of the drug into each member of the group.

Brief Description of the Figures

Figure 1. Figure 1 represents plasma peramivir concentration-time curves after 15 minutes of intravenous infusions of peramivir to healthy human volunteers.

Figure 2. Figure 2 represents plasma peramivir concentration-time curves after intramuscular injections to healthy human volunteers.

Detailed Description

The peramivir neuraminidase influenza virus inhibitor has previously been found to have marked activity against invitro influenza viruses and experimentally infected mice (Govorkova et al. (2001); and Smee et al. (2001)). Unfortunately, clinical trials using this drug showed an inappropriate inhibitory effect on eminfluenza in humans. This effect was attributed to poor drug adsorption when administered once daily orally in patients.

Peramivir has been found to be well-adsorbed when administered intravenously (i.v.) in mice and that the compound remains at relatively high plasma levels for at least 6 hours. A series of experiments presented here indicate that a single peramivir treatment given i.v. will protect mice infected with the influenza virus.

Accordingly, certain embodiments of the present invention provide a method for treating a viral infection in a human comprising administering an effective antiviral amount of a compound of formula I, II, III, or IV:

<formula> formula see original document page 5 </formula>

or a pharmaceutically acceptable salt thereof, to humans by an intravenous routine.

In certain embodiments, the compound of formula I, II, III, or IV is a compound of formula Ia, IIa, 11a, or IVa:

<formula> formula see original document page 5 </formula>

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the viral infection is a deinfluenza infection. In certain embodiments, the viral infection is a type A or type B influenza infection. In certain embodiments, the viral infection is caused by a virus strain represented by the formula HxNy where X is an integer from 1 to 16 and Y is an integer. from 1 to 9. In certain embodiments, influenza is an H3N2, H1N1, H5N1, avian, or seasonal influenza.

In certain embodiments, the effective antiviral amount is up to about 800 mg. In certain embodiments, the effective antiviral amount is up to about 400 mg. In certain embodiments, the effective antiviral amount is up to about 300 mg. In certain embodiments, the effective antiviral amount is up to about 200 mg.

In certain embodiments, the full effective dose is administered intravenously. In certain embodiments, the full effective dose is administered in multiple intravenous administrations.

In certain embodiments, a compound or formula Ia, or a pharmaceutically acceptable salt thereof, is administered.

In certain embodiments, the plasma concentration of the compound is greater than the IC50 of the virus causing a viral infection 12 hours after compound administration.

Certain embodiments of the present invention provide a method for inhibiting a neuraminidase in a human comprising administering an effective inhibitory amount of a compound of formula I, II, III, or IV:

<formula> formula see original document page 6 </formula> or a pharmaceutically acceptable salt thereof, to humans by an intravenous routine.

In certain embodiments, the compound of formula I, II, III, or IV is a compound of formula Ia1 IIa, 11a, or Iva:

<formula> formula see original document page 7 </formula>

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the effective inhibitory amount is up to about 800 mg. In certain embodiments, the effective inhibitory amount is up to about 400 mg. In certain embodiments, the effective inhibitory amount is up to about 300 mg. In certain embodiments, the effective inhibitory amount is up to about 200 mg.

In certain embodiments, the full effective inhibitory dose is administered intravenously. In certain embodiments, integral effective inhibitory adose is administered in intravenous multiple administrations.

In certain embodiments, a compound of formula Ia, or a pharmaceutically acceptable salt thereof, is administered.

In certain embodiments, the methods may further comprise orally administering a human naser neuraminidase inhibitor.

In certain embodiments, the orally administered neuraminidase inhibitor is oseltamivir carboxylate.

In certain embodiments, the orally administered neuraminidase inhibitor is a compound of formula I, II, III, or IV:

<formula> formula see original document page 7 </formula> <formula> formula see original document page 8 </formula>

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the orally administered neuraminidase inhibitor is a compound of formula Ia, IIa, 11a, or IVa:

<formula> formula see original document page 8 </formula>

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the orally administered neuraminidase inhibitor is a compound of formula Ia1 or a pharmaceutically acceptable salt thereof.

In certain embodiments, the orally administered neuraminidase inhibitor is administered for up to 20 days. In certain embodiments, the orally administered neuraminidase inhibitor is administered for up to 10 days. In certain embodiments, the deneuraminidase inhibitor that is administered orally is administered for up to 5 days.

Certain embodiments of the present invention provide a unit dosage form which is suitable for intravenous administration to a human, comprising up to about 800 mg of a compound of formula.

<formula> formula see original document page 8 </formula> <formula> formula see original document page 9 </formula>

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of formula I, II, III, or IV is a compound of formula Ia, II, 11a, or IVa:

<formula> formula see original document page 9 </formula>

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the unit dosage form comprises up to about 400 mg of the compound or salt. In certain embodiments, the unit dosage form comprises up to about 300 mg of the compound or salt. In certain embodiments, the unit dosage form comprises up to about 200 mg of the compound or salt.

Certain embodiments of the present invention provide Kit comprising packaging materials, a compound of formula I, II, III, or IV:

<formula> formula see original document page 9 </formula>

or a pharmaceutically acceptable salt thereof, and instructions for administering the compound to a human by an intravenous routine.

In certain embodiments, the compound is provided in a formulation suitable for intravenous administration.

In certain embodiments, the kit comprises up to about 800 mg of the compound or salt. In certain embodiments, the kit comprises up to about 400 mg of the compound or salt. In certain embodiments, the kit comprises up to about 300 mg of the compound or salt. In certain embodiments, the kit comprises up to about 200 mg of the compound or salt.

Certain embodiments of the present invention provide a kit comprising packaging materials, a unit dosage form as described herein, and instructions for administering the compound to a human by an intravenous routine.

Certain embodiments of the present invention provide a use of a compound of formula I, II, III, or IV:

<formula> formula see original document page 10 </formula>

or a pharmaceutically acceptable salt thereof, in the manufacture of an intravenous injection drug to increase due expectancy or reduce mortality in a group of mammals exposed to an influenza virus source, by intravenously injecting a dose of the drug into each member of the group that presents clinical symptoms of infection.

In certain embodiments, the compound of formula I, II, III, or IV is a compound of formula Ia, IIa, 11a, or IVa:

<formula> formula see original document page 10 </formula> <formula> formula see original document page 11 </formula>

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the influenza virus is an influenza virus. In certain embodiments, the influenza virus is an influenza A or type B virus. In certain embodiments, the influenza virus is H5N1, or a cepamutant thereof. In certain embodiments, the influenza virus is a virus strain represented by the formula HxNy wherein X is an integer from 1 to 16 and Y is an integer from 1 to 9. In certain embodiments, the influenza virus is an H3N2, H1N1, H5N1, avian, or seasonal.

In certain embodiments, each member of the group who has symptoms of infection receives only one intravenous dose of medication. In certain embodiments, each member of the group who has symptoms of infection receives multiple intravenous doses of the drug.

In certain embodiments, members of the group who have clinical symptoms of infection are treated orally with a deneuraminidase inhibitor. In certain embodiments, the neuraminidase inhibitor is oseltamivir carboxylate. In certain embodiments, the deneuraminidase inhibitor is a compound of formula I, II, III, or IV:

<formula> formula see original document page 11 </formula>

or a pharmaceutically acceptable salt thereof. In certain embodiments, the neuraminidase inhibitor is a compound of formula Ia, Na, 11Ia, or IVa: <formula> formula see original document page 12 </formula>

or a pharmaceutically acceptable salt thereof. In certain embodiments, the neuraminidase inhibitor is a compound of formula Ia, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the source of the virus is an infected bird. In certain embodiments, the source of the virus is a mammal with symptoms of infection.

In certain embodiments, use is for reducing mortality.

Certain embodiments of the present invention provide a use of a compound of formula I, II, III, or IV:

<formula> formula see original document page 12 </formula>

or a pharmaceutically acceptable salt thereof, in the manufacture of an intravenous injection drug to increase due expectancy or reduce mortality in a group of mammals exposed to an influenza virus source by intravenously injecting a dose of the drug into each member of the group.

In certain embodiments, the compound of formula I, II, III, or IV is a compound of formula Ia, IIa, IIIa, or IVa: <formula> formula see original document page 13 </formula>

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the influenza virus is an influenza virus. In certain embodiments, the avian influenza virus is H5N1, or a mutant strain thereof. In certain embodiments, the influenza virus is a virus strain represented by the formula HxNy wherein X is an integer from 1 to 16 and Y is an integer from 1 to 9. In certain embodiments, the influenza virus is an influenza A or A B. In certain embodiments, influenza ovirus is an H3N2, H1N1, H5N1, avian, or seasonal influenza virus.

In certain embodiments, each member of the group receives only one intravenous dose of the drug. In certain embodiments, each group member receives multiple intravenous doses of the drug.

In certain embodiments, group members are orally treated with a neuraminidase inhibitor. In certain embodiments, the neuraminidase inhibitor is oseltamivir carboxylate. In certain embodiments, the neuraminidase inhibitor is a compound of formula I, II, III, or IV:

<formula> formula see original document page 13 </formula>

or a pharmaceutically acceptable salt thereof. In certain embodiments, the neuraminidase inhibitor is a compound of formula Ia, la, IIIa1 or IVa:

(IIIa) (IVa) l

or a pharmaceutically acceptable salt thereof. In certain embodiments, the neuraminidase inhibitor is a compound of formula Ia, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the source of the virus is an infected bird. In certain embodiments, the source of the virus is a mammal with symptoms of infection.

In certain embodiments, the use is to reduce mortality.

Certain embodiments of the present invention provide a use of a compound of formula I, II, III, or IV:

<formula> formula see original document page 14 </formula> or a pharmaceutically acceptable salt thereof, in the manufacture of an intravenous injection drug to obtain a human plasma concentration of the compound that is effective for treating a virus through intravenous injection of a dose of the medicine in humans.

Certain embodiments of the present invention provide a use of a compound of formula I, II, III, or IV:

<formula> formula see original document page 14 </formula> <formula> formula or original pharmaceutically acceptable salt thereof, in the manufacture of an intramuscular injection drug to obtain a plasma concentration in a human of the compound that is effective for treating a virus by intramuscular injection of a dose of the drug into humans.

In certain embodiments, the plasma concentration of the compound is greater than virus IC50 12 hours after compound injection.

Influenza A / duck / MN / 1525/81 (H5N1) virus infected mice were treated once i.v. 1 hour pre-exposure to the virus with peramivir at doses of 20, 10 and 3 mg / kg. Peramivir was significantly protective of mice at the two highest dosages used, as seen by death prevention, decreased lung consolidation, and inhibition of pulmonary virus titers. The 3mg / kg dose was moderately inhibitory to pulmonary parameters. Compost appeared well tolerated in concomitantly conducted toxicity controls. These data indicate that a single i.v. peramivir treatment is effective in influenza virus infected mice.

The compounds used in the invention are known in the art and may be synthesized by the artisan using available methods (see, for example, United States Patent No. 6,562,861).

Specific values listed here for radicals, substituents, and bands are for illustration only; they do not exclude other defined values or other values within defined ranges for the substituent radicals. A specific compound of formula I, II, III, or IV is a compound of formula Ia, IIa, IIIa, or IVa:

<formula> formula see original document page 16 </formula> or a pharmaceutically acceptable salt thereof.

A specific compound of formula I, II, III, or IV is Acid

(1S, 2S, 3f, 4f) -3- (1-acetamido-2-ethylbutyl) -4-guanidino-2-hydroxycyclopentane carboxylic acid; (1S, 2S, 3f, 4f ') -3- (1-acetamido-2-propylpentyl) -4-guanidino-2-hydroxycyclopentanecarboxylic acid; (1fl, 3fl, 4fl) -3- (1-acetamido-2-propylpentyl) -4-guanidinocyclopentanecarboxylic acid; or (1 H, 3 H, 4 H) -3- (1-acetamido-2-ethylbutyl) -4-guanidinocyclopentanecarboxylic acid; or a salt

A specific compound of formula I is a compound of formula, or a pharmaceutically acceptable salt thereof. One or more chiral centers may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses the use of any racemic, optically active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of formula I, II, III, or IV, which has the useful properties described herein. It is known in the art to prepare optically active forms (e.g., by resolution of racemic form by recrystallization techniques, by synthesis of optically active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine antiviral activity (e.g. antiinfluenza) using the patterns described herein, or using other similar tests that are well known in the art.

It will be appreciated by those skilled in the art that compounds In cases where compounds are sufficiently basic or acidic to form stable non-toxic acid or base salts, administration of the compounds as salts may be appropriate. Examples of pharmaceutically acceptable salts are acid-formed organic acid addition salts which form a physiological acceptable anion, for example tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate, and α-glycerophosphate. Suitable salts may also be formed, including hydrochloride, sulfate, nitrate, phosphate, bicarbonate, and carbonate salts.

Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reaction of a sufficiently basic compound such as an amine with a suitable acid providing a physiologically acceptable anion. Salts of alkali metal (eg sodium, potassium or lithium) or alkaline earth metal (eg calcium) of carboxylic acids may also be produced.

The compounds of formula I, II, III, and IV may be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient, via intravenous routines. Solutions of the active compound or salts thereof may be prepared in water, optionally mixed with a non-toxic surfactant. Dispersions may also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary storage and use conditions, these preparations contain a preservative to prevent the development of microorganisms.

Suitable pharmaceutical dosage forms for injection or infusion may include sterile or post-sterile aqueous solutions or dispersions comprising the active ingredient (s) which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the final dosage form must be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or carrier may be a liquid solvent or dispersion medium comprising, for example, water, ethanol, a polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, non-toxic glycerylanester esters, and mixtures. of these. Proper flowability can be maintained, for example, by liposome formation, maintaining the required particle size in the case of dispersions or detensive use. Prevention of the action of microorganisms can be accomplished by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions may be accomplished by use in the compositions of absorbing retarding agents, for example aluminum monostearate and gelatin.

Sterile injectable solutions may be prepared by incorporating the active compound (s) in an appropriate solvent with the other optional ingredients listed above, optionally followed by filter sterilization. In the case of sterile powders for preparation of sterile injectable desolutions, preferred methods of preparation are vacuum drying techniques and freeze drying, which produces an active ingredient powder plus any additional desired ingredient present in the previously sterile filtered solutions.

As used herein the terms "treating", "treating" and "treatment" include administering a compound prior to the onset of clinical symptoms of a disease state / condition to prevent the development of any symptoms as well as administering a compound afterwards. initiating one or more clinical symptoms of a disease state / condition in order to reduce or eliminate any such disease state symptom, aspect or feature. Such treatment need not be absolute to be useful. As illustrated below, the active compounds may be administered prior to exposure to the virus. Agents may also be administered subsequent (for example, within 1, 2, 3, 4, or 5 days) to exposure to the virus.

As used herein the term "unit dosage form" refers to an intravenous formulation containing a specific amount of a drug, all of which is intended to be administered as a single dose. It is distinguished from a supply of an indefinite amount of a drug, for example a drug dose, from which a dose must be measured.

In one embodiment, the invention provides a method for treating a viral infection in a human comprising administering an effective amount of a compound of formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, to human by intravenous administration. Typically, the effective amount is administered in a single intravenous administration. In some embodiments, the effective amount is administered in multiple administrations. Consequently, the methods of the invention provide high patient compliance and they require a low dose of effective agent.

In one embodiment of the invention, the effective inhibitory amount of the compound of formula I, II, III, or IV is up to about 1,000 mg.

In one embodiment of the invention, the effective inhibitory amount of the compound of formula I, II, III, or IV is up to about 800 mg.

In one embodiment of the invention, the effective inhibitory amount of the compound of formula I, II, III, or IV is up to about 600 mg.

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

In one embodiment of the invention, the effective inhibitory amount of the compound of formula I, II, III, or IV is up to about 400 mg.

In one embodiment of the invention, the effective inhibitory amount of the compound of formula I, II, III, or IV is up to about 300 mg.

In one embodiment of the invention, the effective inhibitory amount of the compound of formula II, III, or IV is up to about 200 mg.

In one embodiment of the invention, the effective inhibitory amount of the 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 the compound of formula I, II, III, or IV is up to about 75 mg. According to the methods of the invention a compound of formula I, II, III, or IV is administered to a intravenously. In one embodiment of the invention, the compound of formula I, II, III, or IV is administered once to a human intravenously. In another embodiment of the invention, a neuraminidase inhibitor is also administered to humans orally. In one embodiment of the invention, the orally administered neuraminidase inhibitor is deoseltamivir carboxylate. In one embodiment of the invention, the orally administered neuraminidase inhibitor is a compound of formula I, II, III, or IV:

<formula> formula see original document page 20 </formula>

or a pharmaceutically acceptable salt thereof. In one embodiment of the invention, the orally administered neuraminidase inhibitor is a compound of formula Ia, IIa, 11a, or IVa:

<formula> formula see original document page 20 </formula>

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

In accordance with the methods of the invention, the compound of formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, may also be administered in combination with one or more additional therapeutic agents, such as antiviral agents (e.g., counter-influenza active agents. ) or antibiotics.

Intravenous formulations of the invention may also comprise one or more additional therapeutic agents, such as antiviral agents (e.g., influenza active agents) and antibiotics.

Accordingly, intravenous administration of peramivir to treat a viral infection is described herein. Intramuscular administration of peramivir to treat a viral infection is also described herein (see, for example, Example 2), which also exemplifies intramuscular administration of peramivir to treat a viral infection as described in International Application No. PCT / US2006 / 013535, filed on April 12, 2006, the description of which is incorporated by reference. Furthermore, as described herein, it has been unexpectedly found that intravenous and intramuscular injections of peramivir to humans provide higher concentrations of peramivir plasma with an extended plasma half-life.

As described herein, the compounds described herein may be used to treat a virus, for example an influenza virus. For example, the compounds may be used to treat any or any of the following strains. In the table below, "H" represents a type of hemagglutinin, and "N" represents a type of neuraminidase. The formula HxNyem where X is an integer from 1 to 16 and Y is an integer from 1 to 9, can also be used to describe the combinations given in the table.

Table 1

<table> table see original document page 21 </column> </row> <table> <table> table see original document page 22 </column> </row> <table>

The virus may be, for example, an avian virus or a humanized avian virus. Accordingly, the term "avian virus" includes both avian forms of the virus and humanized forms of the avian virus.

Certain embodiments of the present invention provide the use of a compound of formula I, II, III, or IV:

<table> table see original document page 22 </column> </row> <table>

or a pharmaceutically acceptable salt thereof, in the manufacture of an intravenous injection drug to obtain a human plasma concentration of the compound that is effective for treating a virus through intravenous injection of a dose of the medicament into the human.

Certain embodiments of the present invention also provide the use of a compound of formula I, II, III, or IV:

<table> table see original document page 22 </column> </row> <table>

or a pharmaceutically acceptable salt thereof, in the manufacture of an intramuscular injection drug to obtain a human plasma concentration of the compound that is effective for treating a virus by intramuscular injection of a dose of the drug into the human.

Certain embodiments of the invention also provide compositions comprising peramivir formulated for intravenous administration to a human. Certain embodiments of the invention also provide compositions comprising peramivir formulated for intravenous administration for use in treating a virus by obtaining a plasma concentration in a human of peramivir that is effective for treating the virus.

Certain embodiments of the invention also provide compositions comprising peramivir formulated for intramuscular administration to a human. Certain embodiments of the invention also provide compositions comprising peramivir formulated for intramuscular administration for use in treating a virus by obtaining a plasma concentration in a human of peramivir which is effective for treating the virus.

In certain embodiments of the invention, the plasma concentration of the compound is greater than the IC50 of the virus at least about 12 hours after injection.

In certain embodiments of the invention, the plasma concentration of the compound is greater than the IC50 of the virus at least about 24 hours after injection.

In certain embodiments of the invention, the plasma concentration of the compound is greater than the IC50 of the virus at least about 36 hours after injection.

In certain embodiments of the invention, the plasma concentration of the compound is greater than the virus IC50 at least about 48 hours after injection.

In certain embodiments of the invention, the compound plasma concentration is greater than the IC50 of the virus at least about 60 hours after injection.

In certain embodiments of the invention, the plasma concentration of the compound is greater than the IC50 of the virus at least about 72 hours after injection.

In certain embodiments of the invention, the virus is an influenza virus. In certain embodiments of the invention, the virus is an influenza virus. In certain embodiments of the invention, the virus is H5N1, or a cepamutant thereof.

The invention will now be illustrated by the following non-limiting Examples.

Example 1. Effect of IV Treatment with Peramivir on Influenza A Virus Infection

Experiment Design: Mice were infected i.n.com a dose believed to be the influenza virus LD100. Groups of 10 mice were treated i.v. with peramivir at dosages of 20, 10 and 3mg / kg only once 1 hour pre-exposure to the virus. Placebo (sterile saline) was administered i.v. in part allel with the above to 20 infected mice. Drug-treated and placebo-controlled infected mice were observed daily during death for 21 days. As toxicity controls, 3 uninfected mice were treated with the highest dose of the compounds in part of the infected animals. All toxicity controls were observed during death for 21 days and were weighed immediately before the initial treatment and 18 h after the final treatment. Five normal controls were heavy.

Table 2. Single I.V. Treatment Effect with Peramivir on an Influenza A Virus Infection in Mice.

<table> table see original document page 24 </column> </row> <table> <table> table see original document page 25 </column> </row> <table>

bAverage day for death of mice dying before day 21.

** P <0.01; *** P <0.001 compared to saline treated controls.

Infection induced in this experiment was lethal to 55% of mice (Table 1), with an average day to death of 9.1 days. Single iv injection with peramivir at 20 and 10 mg / kg was highly protective to infected animals, with 100% infection survivors (P <0.01). Partodeel-led toxicity controls all survived and gained weight indicating that the compound was well tolerated in this experiment.

These data indicate that peramivir is a significant influenzas inhibitor when used in a single i.v. injection.

Example 2. Effects of IV and IM Treatment with Peramivir on Humans

Peramivir was studied in a placebo-controlled phase I clinical study in healthy human volunteers to evaluate safety and pharmacokinetic parameters using intramuscular intravenous administrations. Blood samples were collected from the subjects at different times after drug administration to determine drug concentration in plasma. Time course plots are shown in Figure 1 and Figure 2 for intramuscular intravenous administrations respectively.

In the intravenous study, peramivir concentrations followed linear kinetics with an extended plasma half-life rarely greater than 12 hours. At doses of 2 mg / kg and above, the level of peramivir emplasma at 48 hours post-dose is higher than IC50 for all influenza virus strains tested, including H5 virus types. For doses higher than 4 mg / kg, still within 72 hours, drug levels are higher than IC50 values.

In the intramuscular study, peramivir concentrations also followed linear kinetics with rarely extended plasma half-life. Still at 72 hours post-dosing, peramivir levels are greater than IC50 values for all influenza virus strains tested.

The long plasma half-life and high levels of peramivir in human volunteers are extraordinary and unexpected findings and indicate that intravenous and intramuscular administration of peramivirs are beneficial in the treatment of influenza in humans.

All publications, patents and patent applications cited herein are incorporated herein by reference. Although in the foregoing disclosure report this invention has been described with respect to certain embodiments thereof, and many details have been presented for illustration purposes, it will be apparent to those skilled in the art that the invention is susceptible to additional embodiments and that certain details described herein may be varied considerably without departing. basic principles of the invention.

The use of the terms "one, one" and "one, one (an)" and "o," similar references in the context of describing the invention should be construed to encompass both the singular and the plural unless otherwise stated. way indicated here or clearly contradicted by the context. The terms "comprising," "possessing," "including," and "containing" shall be construed as open terms (that is, meaning "including, but not limited to") unless otherwise stated. Mention of value ranges herein is merely intended to serve as a method of reference handwriting individually for each separate value that includes this range, unless otherwise indicated herein, and each separate value is incorporated into the descriptive report as if it were individually specified here. All methods described herein may be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any of the examples, or exemplary language (for example, "as") provided herein, is intended to further clarify the invention and does not represent a limitation on the scope of the invention unless otherwise claimed.

Claims (80)

1. Method for treating a viral infection in a human being comprising administering an effective antiviral amount of a compound of formula I, II, III, or IV: or a pharmaceutically acceptable salt thereof, to the human being by an intravenous routine. The method according to claim 1, wherein the compound of formula I, II, III, or IV is a compound of formula Ia, IIa, IIia, or IVa: <formula> formula see original document page 28 </formula> or a pharmaceutically acceptable salt thereof. A method according to claim 1 or 2, wherein the viral infection is an influenza infection. The method of claim 3, wherein the viral infection is a type A or type B influenza infection. A method according to claim 1 or 2, wherein the viral infection is caused by a virus strain represented by the formula wherein X is an integer from 1-16 and Y is an integer from 1-9. The method of claim 3, wherein the influenza is an H3N2, H1N1, H5N1, avian, or seasonal influenza. A method according to any one of claims 1 to 6, wherein the antiviral effective amount is up to about 800 mg. The method of claim 7, wherein the effective antiviral amount is up to about 400 mg. The method of claim 8, wherein the effective antiviral amount is up to about 300 mg. The method of claim 9, wherein the effective antiviral amount is up to about 200 mg. A method according to any one of claims 1 to 10, wherein the entire effective dose is administered in intravenous administration. A method according to any one of claims 1 to 10, wherein the entire effective dose is administered in multiple intravenous administrations. A method according to any one of claims 2 to 12, wherein a compound of formula Ia, or a pharmaceutically acceptable salt thereof, is administered. A method according to any one of claims 1 to 13, wherein the plasma concentration of the compound is greater than the IC5 of the virus causing viral infection 12 hours after compound administration. A method for inhibiting neuraminidase in a human comprising administering an effective inhibitory amount of a compound of formula I, II, III, or IV: (III) (IV), or a pharmaceutically acceptable salt thereof, to humans by an intravenous routine. The method according to claim 15, wherein the compound of formula I, II, III, or IV is a compound of formula Ia, IIa, 11a, or IVa: <formula> formula see original document page 30 </formula> or a pharmaceutically acceptable salt thereof. The method of claim 15 or 16, wherein the effective inhibitory amount is up to about 800 mg. The method of claim 17, wherein the effective inhibitory amount is up to about 400 mg. The method of claim 18, wherein the effective inhibitory amount is up to about 300 mg. The method of claim 19, wherein the effective inhibitory amount is up to about 200 mg. A method according to any one of claims 15 to 20, wherein the entire effective inhibitory dose is administered as an intravenous administration. A method according to any one of claims 15 to 20, wherein the entire effective inhibitory dose is administered and multiple intravenous administrations. A method according to any one of claims 16 to 22, wherein a compound of formula Ia1 or a pharmaceutically acceptable salt thereof is administered. A method according to any one of claims 1 to 23, further comprising orally administering a deneuraminidase inhibitor to humans. The method of claim 24, wherein the orally administered neuraminidase inhibitor is oseltamivir carboxylate. The method according to claim 24, wherein the orally administered neuraminidase inhibitor is a compound of formula I, II, III, or IV: or a pharmaceutically acceptable salt. of this one. The method according to claim 24, wherein the orally administered neuraminidase inhibitor is a compound of formulaulea, 11a, 11a, or IVa: or a pharmaceutically acceptable salt. of this one. The method of claim 27, wherein the orally administered neuraminidase inhibitor is a compound of formulaulala, or a pharmaceutically acceptable salt thereof. A method according to any one of claims 24-25 to 28, wherein the orally administered neuraminidase inhibitor is administered for up to 20 days. The method of claim 29, wherein the orally administered neuraminidase inhibitor is administered for up to 10 days. The method of claim 30, wherein the orally administered neuraminidase inhibitor is administered for up to 5 days. 32. Unit dosage form which is suitable for intravenous administration to a human, comprising up to about -800 mg of a compound of formula I, II, III, or IV: <formula> formula see original document page 32 </formula> or a pharmaceutically acceptable salt thereof. A unit dosage form according to claim 32, wherein the compound of formula I, II, III, or IV is a compound of formula Ia, IIa, 11a, or IVa: <formula> formula see original document page 32 </formula> or a pharmaceutically acceptable salt thereof. A unit dosage form according to claim 32 or 33 comprising up to about 400 mg of the compound or salt. The unit dosage form of claim 34, comprising up to about 300 mg of the compound or salt. A unit dosage form according to claim 35 comprising up to about 200 mg of the compound or salt. 37. Kit comprising packaging materials, a compound of formula I, II, III, or IV: <formula> formula or original pharmaceutically acceptable salt thereof, and instructions for administering the compound to a human by an intravenous routine. The kit of claim 37, wherein the compound is provided in a formulation suitable for intravenous administration. A kit according to claim 37 or 38 comprising up to about 800 mg of the compound or salt. The kit of claim 39, comprising up to about 400 mg of the compound or salt. The kit of claim 40, comprising up to about 300 mg of the compound or salt. A kit according to claim 41, comprising up to about 200 mg of the compound or salt. A kit comprising packaging materials, a unit dosage form as defined in any one of claims 32 to 36, and instructions for administering the compound to a human by an intravenous routine. Use of a compound of formula I, II, III, or IV: (formula) (III) (IV), or a pharmaceutically acceptable salt thereof, in the manufacture of an injection drug intravenously to increase life expectancy or reduce mortality in a group of mammals exposed to an influenza virus source by intravenously injecting a single dose into each member of the group showing clinical symptoms of infection. Use according to claim 44, wherein the compound of formula I, II, III, or IV is a compound of formula Ia, IIa, IIIa, or IVa: <formula> formula see original document page 34 </formula> or a pharmaceutically acceptable salt thereof. Use according to claim 44 or 45, wherein an influenza virus is an avian influenza virus. Use according to claim 44 or 45, wherein an influenza virus is a type A or type B influenza virus. Use according to claim 44 or 45, wherein an influenza virus is H5N1, or a mutant strain thereof. Use according to claim 44 or 45, wherein an influenza virus is a virus strain represented by the formula HxNy wherein X is an integer from 1-16 and Y is an integer from 1-9. Use according to claim 44 or 45, wherein an influenza virus is an H3N2, H1N1, H5N1, avian, or seasonal influenza virus. Use according to any one of claims 44 to 50, wherein each member of the group exhibiting symptoms of infection receives only one intravenous dose of the medicament. Use according to any one of claims 44 to 50, wherein each member of the group exhibiting symptoms of infection receives multiple intravenous doses of the medicament. Use according to any one of claims 44 to 52, to increase life expectancy or reduce mortality in a mammalian group, where members of the group who have clinical symptoms of infection are treated orally with a deneuraminidase inhibitor. Use according to claim 53, wherein the deneuraminidase inhibitor is oseltamivir carboxylate. Use according to claim 53, wherein the deneuraminidase inhibitor is a compound of formula I, II, III, or IV: or a pharmaceutically acceptable salt thereof. The use according to claim 53, wherein the deneuraminidase inhibitor is a compound of formula Ia, IIa, IIIa, or IVa: <formula> <formula> <formula> formula see original document page </formula> or a pharmaceutically acceptable salt thereof. Use according to claim 56, wherein the de-neuraminidase inhibitor is a compound of formula Ia, or a pharmaceutically acceptable salt thereof. Use according to any one of claims 44 to 57, wherein the source of the virus is an infected bird. Use according to any one of claims 44 to 57, wherein the source of the virus is a mammal with symptoms of infection. Use according to any one of claims 44 to 59, which is to reduce mortality. 61. Use of a compound of formula I, II, III, or IV: <formula> formula see original document page 36 </formula> or a pharmaceutically acceptable salt thereof in the manufacture of an intravenous injection drug to increase life expectancy or reduce mortality in a group of mammals exposed to a source of an influenza virus by intravenously injecting a single dose into each group member. Use according to claim 61, wherein the compound of formula I, II, III, or IV is a compound of formula Ia, IIa, IIIa, or IVa: <formula> formula see original document page 37 </formula> or a pharmaceutically acceptable salt thereof. Use according to claim 61 or 62, wherein the influenza virus is an avian influenza virus. Use according to claim 63, wherein the avian influenza virus is H5N1, or a mutant strain thereof. Use according to claim 61 or 62, wherein an influenza virus is a virus strain represented by the formula HxNy wherein X is an integer from 1-16 and Y is an integer from 1-9. Use according to claim 61 or 62, wherein an influenza virus is a type A or type B influenza virus. Use according to claim 61 or 62, wherein an influenza virus is an H3N2, Η1Ν1, H5N1, avian, or seasonal influenza virus. Use according to any one of claims 61 to 67, wherein each member of the group receives only one intravenous dose of the drug. Use according to any one of claims 61 to 67, wherein each member of the group receives multiple intravenous doses of drug. Use according to any one of claims 61 to 69 to increase life expectancy or reduce mortality in a mammalian group in which group members are orally treated with a neuraminidase inhibitor. Use according to claim 70, wherein the deneuraminidase inhibitor is oseltamivir carboxylate. Use according to claim 70, wherein the deneuraminidase inhibitor is a compound of formula I, II, III, or IV: or a pharmaceutically acceptable salt thereof. Use according to claim 70, wherein the deneuraminidase inhibitor is a compound of formula Ia1a, Ilia, or IVa: or a pharmaceutically acceptable salt thereof. Use according to claim 73, wherein the deneuraminidase inhibitor is a compound of formula Ia1 or a pharmaceutically acceptable salt thereof. Use according to any one of claims 61 to 74, wherein the source of the virus is an infected bird. Use according to any one of claims 61 to 74, wherein the source of the virus is a mammal with symptoms of infection. Use according to any one of claims 61 to 76, which is to reduce mortality. 78. Use of a compound of formula I, II, III, or IV: <formula> formula see original document page 39 </formula> or a pharmaceutically acceptable salt thereof, in the manufacture of an intravenous injection drug to obtain a plasma concentration in a human compound that is effective for treating a virus by intravenously injecting a dose of the medicament into a human. 79. Use of a compound of formula I, II, III, or IV: <formula> formula see original document page 39 </formula> or a pharmaceutically acceptable salt thereof in the manufacture of an intramuscular injection drug to obtain a plasma concentration in a human of the compound that is effective for treating a virus by intramuscular injection of a dose of the medicament into a human. Use according to claim 78 or 79, wherein the plasma concentration of the compound is greater than a virus IC50 of 12 hours after compound injection.