AU2007215156A1

AU2007215156A1 - Intravenous antiviral treatments

Info

Publication number: AU2007215156A1
Application number: AU2007215156A
Authority: AU
Inventors: Shane Arnold; Yarlagadda Sudhakara Babu; Shanta Bantia; Pooran Chand; John Michael Kilpatrick
Original assignee: Biocryst Pharmaceuticals Inc
Current assignee: Biocryst Pharmaceuticals Inc
Priority date: 2006-02-13
Filing date: 2007-02-12
Publication date: 2007-08-23
Also published as: MX2020002008A; MY166063A; JP2013256527A; JP6073202B2; KR20080096829A; BRPI0707769A2; KR20230003248A; KR20200143519A; JP2015180695A; KR20190072681A; EA025483B1; WO2007095218A1; CA2642260A1; KR101992585B1; EP1986626A1; KR101992585B9; KR20180024027A; KR20210135632A; KR20210076189A; EA200870263A1

Description

WO 2007/095218 PCT/US2007/003755 INTRAVENOUS ANTIVIRAL TREATMENTS 5 Related Applications This patent document claims the benefit of priority of U.S. Application No. 60/772,748, filed February 13, 2006, and of International Application No. PCT/US2006/013535, filed April 12,2006, which applications are herein incorporated by reference. 10 Background The influenza virus neuraminidase inhibitor peramivir has marked activity against the influenza virus in vitro and in experimentally infected mice (Govorkova et al., Antimicrobial Agents and Chemotherapy, 45(10), 2723-2732 (2001); and Smee el al., Antimicrobial Agents and Chemotherapy, 45(3), 743 15 748 (2001)). Unfortunately, clinical trials using this drug showed a suboptimal' therapeutic effect on influenza infection in humans following oral administration over a period of days. Currently there is a need for methods and formulations that are useful for treating viral infections (e.g., influenza infections) in humans. Summary of the Invention 20 It has unexpectedly been-discovered that a single intravenous administration of peramivir to a mouse is effective to treat influenza. These findings are unexpected not only because of the high effectiveness of a single administration of the compound, but also because of the low dose of the compound that was found to provide effective treatment. The ability to obtain 25 therapeutically useful effects with a single administration is important inter alia because it minimizes patient compliance issues resulting from the need for multiple administrations. Additionally, the administration of a low dose is important because it minimizes cost and the potential for side-effects. It has also been unexpectedly discovered that intravenous and intramuscular injections of 30 peramivir to humans provides high plasma concentrations of peramivir with an extended 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 WO 2007/095218 PCT/US2007/003755 administering an effective anti-viral amount of a compound of formula I, II, III, or IV:

H

2 N H2N NH HN HN C02H CO2H

NHCOCH

3 OH NHCOCHa OH (I) (II) 5

H

z N " NH

H

2 N NH HN HN CO2H COH . NHCOCHs

NHCOCH

3 (III) (IV), or a pharmaceutically acceptable salt thereof, to the human by an intravenous 10 route. 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 route. 15 The invention also provides a unit dosage form that 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 that is suitable for 20 intravenous administration to a human 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, I, III, or IV, or a pharmaceutically acceptable salt 2 WO 2007/095218 PCT/US2007/003755 thereof, and instructions for administering the compound to a human by an intravenous route. The invention also provides the use of a compound of formula I, 11, n, or IV, or a pharmaceutically acceptable salt thereof, in the manufacture of a 5 medicament for intravenous injection for increasing life expectancy or reducing mortality in a group of mammals exposed to a source of an influenza virus, by intravenous injection of a dose of the medicament into each member of the group presenting clinical symptoms of infection. The invention also provides the use of a compound of formula I, IL, mII, or 10 IV, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for intravenous injection for increasing life expectancy or reducing mortality in a group of mammals exposed to a source of an influenza virus, by intravenous injection of a dose of the medicament into each member of the group. 15 Brief Description of the Figures. Figure 1. Figure 1 depicts plasma peramivir concentration time curves after 15 minute intravenous infusions of peramivir to healthy human volunteers. Figure 2. Figure 2 depicts plasma peramivir concentration time curves after intramuscular injections of peramivir to healthy human volunteers. 20 Detailed Description The influenza virus neuraminidase inhibitor peramivir has been previously shown to have marked activity against influenza virus in vitro and in experimentally infected mice (Govorkova et al., (2001); and Smee et al., (2001)). Unfortunately, clinical trials using this drug showed an inadequate 25 inhibitory effect on influenza in humans. This effect was attributed to a poor adsorption of the drug when administered once daily orally in patients. It has been discovered that peramivir is well adsorbed when administered intravenously (i.v.) in mice and that the compound remains at relatively high levels in the plasma for at least 6 hours. A series of experiments presented 30 herein indicates that a single treatment of peramivir given i.v. will protect mice infected with an influenza virus. 3.

WO 2007/095218 PCT/US2007/003755 Accordingly, certain embodiments of the present invention provide a method for treating a viral infection in a human comprising administering an effective anti-viral amount of a compound of formula I, II, III, or IV:

H

2 N NH - H2N NH HN HN COzH C0 2 H 5 NHCOCH, OH NHCOCHz OH (I) (II) H2N NH H2N NH HN HN CO-H

CO

2 H > 7NHCOCH 3 NHCOCH3 (II) (IV), 10 or a pharmaceutically acceptable salt thereof, to the human by an intravenous route. In certain embodiments, the compound of formula I, II, III, or IV is a compound of formula la, Ha, iIIa, or IVa: 15

H

2 N N H

H

2 N * NH HN. MN HCO2H Hg CO 2 H NHCOCH OH NHCOCH OH (la) (Hla)

H

2 N NH H2N HN. HN ",,,\IC02,..,,CH

~CO

2 H pGO2H > NHCOCH 3 NHCOCH 3 20 (HIa) (IVa), 4 WO 2007/095218 PCT/US2007/003755 or a pharmaceutically acceptable salt thereof. In certain embodiments, the viral infection is an influenza infection. In certain embodiments, the viral infection is an influenza type A or type B infection. In certain embodiments, the viral infection is caused by a strain of 5 virus represented by the formula HxNy wherein X is an integer from 1-16 and Y is an integer from 1-9. In certain embodiments, the influenza is an H3N2, H1N1, H5N1, avian, or seasonal influenza. In certain embodiments, the effective anti-viral amount is up to about 800 mg. In certain embodiments, the effective anti-viral amount is up to about 400 10 mg. In certain embodiments, the effective anti-viral amount is up to about 300 mg. In certain embodiments, the effective anti-viral amount is up to about 200 mg. In certain embodiments, the entire effective dose is administered in one intravenous administration. In certain embodiments, the entire effective dose is 15 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 higher than the ICs 50 of the virus causing the viral infection 12 hours following 20 administration of the compound. 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:

H

2 N NH

H

2 N NH HN HN

CO

2 H COH 25 NHCOCH 3 OH NHCOCH 3 OH (I) (II) 5 WO 2007/095218 PCT/US2007/003755 H2N U H2N N HN HN COH C0 2 H NHCOCH, NHCOCHa (III) (IV), or a pharmaceutically acceptable salt thereof, to the human by an intravenous 5 route. In certain embodiments, the compound of formula I, II, III, or IV is a compound of formula Ia, Ha, IIIa, or IVa: HN NH H2N NH HN HN ,#CO2H CO2H NHCOCH, OH NHCOCH3 OH 10 (Ia) (Ha)

H

2 N r NH HN NH NH NH HN HN CO2H ,COH > NHCOCH3 NHCOCH3 (IIIa) (IVa), 15 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 20 200 mg. In certain embodiments, the entire effective inhibitory dose is administered in one intravenous administration. In certain embodiments, the 6 WO 2007/095218 PCT/US2007/003755 entire effective inhibitory dose is administered in multiple intravenous administrations. In certain- embodiments, a compound of formula Ia, or a pharmaceutically acceptable salt thereof, is administered. 5 In certain embodiments, the methods may further comprise orally administering a neuraminidase inhibitor to the human. In certain embodiments, the neuraminidase inhibitor that is administered orally is oseltamivir carboxylate. In certain embodiments, the neuraminidase inhibitor that is administered 10 orally is a compound of formula I, II, III, or IV: H2N NH

H

2 N NH HN HN

CO

2 H CO2H NHCOCHa OH NHCOCH, OH (I) (II) H2N NH H2N NH HN HN. COH CO2H 15 NHCOCHz NHCOCH3 (iI) (IV), or a pharmaceutically acceptable salt thereof. In certain embodiments, the neuraminidase inhibitor that is administered orally is a compound of formula Ia, HIa, MIa, or IVa: HN NH H2N NH HN HN . ,CO2H ,CO.H 20 NHCOCH3 OH /NHCOCHa OH (Ia) (IHa) 7 WO 2007/095218 PCT/US2007/003755

H

2 N NH HN NH ,,,COH ,\\CO2H NHCOCH, NHCOCHa (IIa) (IVa), or a pharmaceutically acceptable salt thereof. In certain embodiments, the neuraminidase inhibitor that is administered 5 orally is a compound of formula la, or a pharmaceutically acceptable salt thereof. In certain embodiments, the neuraminidase inhibitor that is administered orally is administered for up to 20 days. In certain embodiments, the neuraminidase inhibitor that is administered orally is administered for up to 10 days. In certain embodiments, the neuraminidase inhibitor that is administered 10 orally is administered for up to 5 days. Certain embodiments of the present invention provide a unit dosage form that is suitable for intravenous administration to a human, comprising up to about 800 mg of a compound of formula I, II, III, or IV: H2N NH

H

2 N NH HN HN CO2H CO2H NHCOCH3 OH NHCOCH3 OH 15 (I) (II) HH2N ' NH HN HN CO2H COH NHCOCHa NHCOCH3 (II) (IV), 20 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of formula I, II, III, or IV is a compound of formula Ia, IIa, IIIa, or IVa: 8 WO 2007/095218 PCT/US2007/003755 H2N " NH HN ' NH H% HN H N, H N

HCO

2 H g,

\

CO

2 H

NHCOCH

3 OH NHCOCH 3 OH (Ia) - (IIa). HN NH H2N : NH HN HN

\\CO

2 H 0CO 2 H S NHCOCH3 NHCOCH3 5 (IIIa) (IVa), 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 10 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 a kit, comprising packaging materials, a compound of formula I, II, III, or IV: HN ' NH H2N NH HN HN COH C0 2 H 15 NHCOCH 3 OH NHCOCH, OH (I) (II) H2N NH H2N NH HN CO2H CO2H

NHCOCH

3 NHCOCH, (III) (IV), 20 9 WO 2007/095218 PCT/US2007/003755 or a pharmaceutically acceptable salt thereof, and instructions for administering the compound to a human by an intravenous route. In certain embodiments, the compound is provided in a formulation suitable for intravenous administration. 5 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. 10 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 route. Certain embodiments of the present invention provide a use of a compound of formula I, II, III, or IV; 15 HzN NH HN ' NH HN HN CO2H CO 2H NHCOCH3 OH NHCOCH3 OH (i) (II) H2N NH H2N NH HN HN CO2H CO2H NHCOCH, NHCOCH, 20 (III) (IV), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for intravenous injection for increasing life expectancy or reducing mortality in a group of mammals exposed to a source of an influenza virus, by 25 intravenous injection of a dose of the medicament into each member of the group presenting clinical symptoms of infection. 10 WO 2007/095218 PCT/US2007/003755 In certain embodiments, the compound of formula I, II, I1, or IV is a compound of formula Ia, HIa, Illa, or IVa: H2N ' NH H2N "rN N COH 2 - COH NHCOCH3 OH >NHCOCH 3 OH 5 (Ia) (HIa) HN NH H2N NH HN HN 2,COH C02H > NHCOCH 3 NHCOCH 3 (IIIa) (IVa), 10 or a pharmaceutically acceptable salt thereof. In certain embodiments, the influenza virus is an avian influenza virus. In certain embodiments, the influenza virus is an influenza type A or type B virus. In certain embodiments, the influenza virus is H5N1, or a mutant strain thereof. In certain embodiments, the influenza virus is a strain of virus 15 represented by the formula HxNy wherein X is an integer from 1-16 and Y is an integer from 1-9. In certain embodiments, the influenza virus is an H3N2, H1N1, H5N1, avian, or seasonal influenza virus. In certain embodiments, each member of the group presenting symptoms of infection receives only one intravenous dose of the medicament. In certain 20 embodiments, each member of the group presenting symptoms of infection receives multiple intravenous doses of the medicament. In certain embodiments, the members of the group presenting clinical symptoms of infection are treated orally with a neuraminidase inhibitor. In certain embodiments, the neuraminidase inhibitor is oseltamivir carboxylate. In 25 certain embodiments, the neuraminidase inhibitor is a compound of formula I, II, III, or IV: 11 WO 2007/095218 PCT/US2007/003755

H

2 N NH

H

2 N NH HN HN

CO

2 H CO2H

NHCOCH

3 OH NHCOCHa OH (I) (II) H2N NH H2N NH HN HN CO2H COH 5 NHCOCHa

NHCOCH

3 (III) (IV), or a pharmaceutically acceptable salt thereof. In certain embodiments, the neuraminidase inhibitor is a compound of formula Ia, IIa, Ilia, or IVa:

H

2 N " NH

H

2 N NH HN HN CO2H ,COH 10 NHCOCHa OH NHCOCH3 OH (Ia) (Ha) H2N NH H2N NH HN HN 2\CO 2 H .,,,COOH > NHCOCH. NHCOCH3 (IlIa) (IVa), 15 or a pharmaceutically acceptable salt thereof. In certain embodiments, the neuraminidase inhibitor is a compound of formula Ia, or a pharmaceutically acceptable salt thereof. 12 WO 2007/095218 PCT/US2007/003755 In certain embodiments, the source of the virus is an infected bird. In certain embodiments, the source of the virus is a mammal presenting symptoms of infection. In certain embodiments, the use is for reducing mortality. 5 Certain embodiments of the present-invention provide a use of a compound of formula I, 11, III, or IV:

H

2 N N H HzN NH HN HN CO2H C02 H NHCOCH3 OH NHCOCH3 OH (I) (II) 10

H

2 N NH

H

2 N NH HN HN COH COH NHCOCH3 NHCOCH3 (III) (iv), or a pharmaceutically acceptable salt thereof, in the manufacture of a 15 medicament for intravenous injection for increasing life expectancy or reducing mortality in a group of mammals exposed to a source of an influenza virus, by intravenous injection of a dose of the medicament into each member of the group. In certain embodiments, the compound of formula I, II, I, or IV is a 20 compound of formula Ia, IHa, IIIa, or IVa: H2N NH

H

2 N NH HN HN\ .',COH COH NHCOCH, OH NHCOCH3 OH (la) (IIa) 13 WO 2007/095218 PCT/US2007/003755 H2N NH

H

2 N : NH HN HN , 1\C02H CO 2 H

NHCOCH

3 NHCOCHa (IlIa) (IVa), 5 or a pharmaceutically acceptable salt thereof. In certain embodiments, the influenza virus is an avian influenza virus. In certain embodiments, the avian influenza virus is H5N1, or a mutant strain thereof. In certain embodiments, the influenza virus is a strain of virus represented by the formula HxNy wherein X is an integer from 1-16 and Y is an 10 integer from 1-9. In certain embodiments, the influenza virus is an influenza type A or type B virus. In certain embodiments, the influenza virus is an H3N2, HIN1, H5N1, avian, or seasonal influenza virus. In certain embodiments, each member of the group receives only one intravenous dose of the medicament. In certain embodiments, each member of 15 the group receives multiple intravenous doses of the medicament. In certain embodiments, the members of the group are treated orally 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, M, or IV: 20

H

2 N NH

H

2 N NNH HN HN

CO

2 H CO2H NHOCH OH NHCOCH OH OH (I) (II) 14 WO 2007/095218 PCT/US2007/003755 H2N NH H2N N H HN HN COH CO2H > NHCOCHa

NHCOCH

3 (III) (IV), or a pharmaceutically acceptable salt thereof. In certain embodiments, the 5 neuraminidase inhibitor is a compound of formula Ia, Ila, IIIa, or IVa: NH HN ... sgC2H H COH NHCOCH, OH NHCOCHa OH (la) (Ha) H2N T NH HNT NH HN HN .,ssCO2H QCO2H 10 NHCOCH, NHCOCH, (IIa) (IV a), or a pharmaceutically acceptable salt thereof. In certain embodiments, the neuraminidase inhibitor is a compound of formula Ia, or a pharmaceutically 15 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 presenting symptoms of infection. In certain embodiments, the use is for reducing mortality. 20 Certain embodiments of the present invention provide a use of a compound of formula I, II, III, or IV: 15 WO 2007/095218 PCT/US2007/003755 H2 NH HzN NH HN HN

CO

2 H

CO

2 H

NHCOCH

3 OH NHCOCH3 OH (I) (II)

H

2 N NH

H

2 N NH NHN

CO

2 H

CO

2 H

-NHCOCH

3 NHCOCH 3 5(I) (IV), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for intravenous injection for achieving a plasma concentration in a .human of the compound that is effective to treat a virus by intravenous injection 10 of a dose of the medicament into the human. Certain embodiments of the present invention provide a use of a compound of formula I, II, III, or IV: HN N NH H2N N NH MN MN COH COH

NHCOCH

3 OH

NHCOCH

3 OH 15 (1) I)

H

2 N NH H2N NH HN HN COH

CO

2 H NHCOCH, NHCOCH3 (III) (IV), 16 WO 2007/095218 PCT/US2007/003755 H2N NH HN NH H\ H\ .#g CO 2 H .C02H > NHCOCH3 NHCOCHa (IIIa) (iVa), or a pharmaceutically acceptable salt thereof. 5 A specific compound of formula I, II, III, or IV is (1S,2S,3R,4R)-3-(1 Acetamido-2-ethylbutyl)-4-guanidino-2-hydroxycyclopentane-carboxylic acid; (1S,2S,3R,4R)-3-(1-Acetamido-2-propylpentyl)-4-guanidino-2 hydroxycyclopentanecarboxylic acid; (1R,3R,4R)-3-(1-Acetamido-2 propylpentyl)-4-guanidinocyclopentanecarboxylic acid; or (1R,3R,4R)-3-(1 10 Acetamido-2-ethylbutyl)-4-guanidinocyclopentanecarboxylic acid; or a pharmaceutically acceptable salt thereof. A specific compound of formula I is a compound of formula Ia, or a pharmaceutically acceptable salt thereof. It will be appreciated by those skilled in the art that compounds having 15 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, IlI, or IV, which possess the useful properties 20 described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine anti-viral (e.g. anti-influenza) activity using the standard tests 25 described herein, or using other similar tests which are well known in the art. In cases where compounds are sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compounds as salts may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for 18 WO 2007/095218 PCT/US2007/003755 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for intramuscular injection for achieving a plasma concentration in a human of the compound that is effective to treat a virus by intramuscular injection of a dose of the medicament into the human. 5 In certain embodiments, the plasma concentration of the compound is higher than the IC 50 of the virus 12 hours following injection of the compound. Mice infected with influenza A/Duck/MN/1525/81 (H5N1) virus were treated a single time i.v. 1 hour pre-virus exposure with peramivir at doses of 20, 10 10 and 3 mg/kg. Peramivir was significantly protective to the mice at the two highest dosages used, as seen by prevention of deaths, lessening of lung consolidation, and inhibition of lung virus titers. The 3 mg/kg dose was moderately inhibitory to lung parameters. The compound appeared well tolerated in concomitantly run toxicity controls. These data indicate that a single 15 i.v. peramivir treatment is efficacious in influenza virus-infected mice. The compounds used in the invention are known in the art and can be synthesized by the art worker using available methods (see, e.g., U.S. Patent No. 6,562,861). Specific values listed herein for radicals, substituents, and ranges, are for 20 illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents A specific compound of formula I, II, I, or IV is a compound of formula Ia, Ila, iIa, or IVa: H2N NH HzN NH H\ \\\COH - COH 25 NHCOCH3 OH NHCOCH3 OH (Ia) (Ila) 17.

WO 2007/095218 PCT/US2007/003755 example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, a-ketoglutarate, and a-glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, phosphate, bicarbonate, and carbonate salts. 5 Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic Compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be 10 made. The compounds of formula I, II, IIl, and IV can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient, by intravenous routes. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. 15 Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The pharmaceutical dosage forms suitable for injection or infusion can 20 include sterile aqueous solutions or dispersions or sterile powders 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 ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or 25 vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in 30 the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, 19 WO 2007/095218 PCT/US2007/003755 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 can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. 5 Sterile injectable solutions can be prepared by incorporating the active compound(s) into an appropriate solvent with the other optional ingredients enumerated above, optionally followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying techniques, 10 which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions. As used herein the terms "treat", "treating" and "treatment" include administering a compound prior to the onset of clinical symptoms of a disease state/condition so as to prevent the development of any symptom, as well as 15 administering a compound after the onset of one or more clinical symptoms of a disease state/condition so as to reduce or eliminate any such symptom, aspect or characteristic of the disease state/condition. Such treating need not be absolute to be useful. As illustrated hereinbelow, the active compounds can be administered prior to exposure to the virus. The agents can also be administered subsequent 20 (e.g., within 1, 2, 3, 4, or 5 days) to exposure to the virus. As used herein the term "unit dosage form" relates to an intravenous formulation containing a specific amount of a drug, the whole of which is intended to be administered as a single dose. It is distinguished from a supply of an indefinite amount of a medicament, e.g., a bottle of medicine, from which a 25 dose has to be measured out. 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 the human by intravenous administration. Typically, the effective 30 amount is administered in a single intravenous administration. In some embodiments, the effective amount is administered in multiple administrations. 20 WO 2007/095218 PCT/US2007/003755 Accordingly, the methods of the invention provide for high patient compliance and they require a low dose of the 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. 5 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 10 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. 15 In one embodiment of the invention, the effective inhibitory amount of the compound of formula I, 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 20 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 human 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 25 inhibitor is also administered to the human orally. In one embodiment of the invention, the neuraminidase inhibitor that is administered orally is oseltamivir carboxylate. In one embodiment of the invention, the neuraminidase inhibitor that is administered orally is a compound of formula I, II, III, or IV: 21 WO 2007/095218 PCT/US2007/003755 HN NH H 2 N NH HN CO2H

CO

2 H NHCOCH3 OH NHCOCH, OH (I) (II) H2N NH H2N NH HN HN CO2H COH NHCOCH3 NHCOCH, (I) (IV), or a pharmaceutically acceptable salt thereof. In one embodiment of the invention, the neuraminidase inhibitor that is administered orally is a.compound of formula Ia, IIa, IIIa, or IVa: 10 H2N NH H2N NH HN HN ,,,COzH ,,COH NHCOCH OH >NHCOCHa OH (Ia) (HIa) H2N NH H2N N H HN HN\"

,

.

3 CO..H CO2H > NHCOCH3 NHCOCH, 15 (Ma) (IVa), or a pharmaceutically acceptable salt thereof. In one embodiment of the invention, the neuraminidase inhibitor that is administered orally is a compound of formula Ia, or a pharmaceutically acceptable salt thereof. 22 WO 2007/095218 PCT/US2007/003755 According to the methods of the invention, the compound of formula I, •II, III, or IV, or a pharmaceutically acceptable salt thereof, can also be administered in combination with one or more additional therapeutic agents, such as anti-viral agents (e.g., agents active against influenza) or antibiotics. 5 The intravenous formulations of the invention can also comprise one or more additional therapeutic agents, such as anti-viral agents (e.g., agents active against influenza) and antibiotics. Thus, intravenous administration of peramivir to treat a viral infection is described herein. Intramuscular administration of peramivir to treat a viral 10 infection is also described herein (see, e.g., Example 2), which further exemplifies intramuscular administration ofperamivir. to treat a viral infection, as is described in International Application No. PCT/US2006/013535, filed April 12, 2006, the disclosure of which is incorporated by reference. Further, as described herein, it has been unexpectedly discovered that intravenous and -15 intramuscular injections of peramivir to humans provides high plasma concentrations of peramivir with an extended plasma half-life. SAs described herein, the compounds described herein can be used to treat a virus, e.g., an influenza virus. For example, the compounds can-be used to treat any one or combination of the following strains. In the table below, the "H" 20 stands for a type of hemagglutinin, and the "N" stands for a type of neuraminidase. The formula HxNy wherein X is an integer from 1-16 and Y is an integer from 1-9, can also be used to describe the combinations presented in the table. 23 WO 2007/095218 PCT/US2007/003755 Table 1 N1 N2 N3 N4 N5 N6 N7 N8 N9 H1 H1NI HIN2 H1N3 HIN4 HIN5 HIN6 HIN7 H1N8 .J11N9 H2 H2NI H2N2 H2N3 H2N4 H2N5 H2N6 H2N7 H2N8 H2N9 H3 H3NI H3N2 H3N3 H3N4 H3N5 H3N6 H3N7 H3N8 H3N9. H4 H4NI H4N2 H4N3 H4N4 H4N5 H4N6. H4N7 H4N8 H4N9 H5 H5NI H5N2 HSN3 H5N4 H5N5 H5N6 H5N7 H5N8 H5N9 H6 H6N1 H6N2 H6N3 H6N4 H6NS H6N6 H6N7 H6N8 H6N9 H7 H7N1 H7N2 H7N3 H7N4 H7N5 H7N6 H7N7 H7N8 H7N9 H8 H8NI H8N2 HSN3 H8N4 H8N5 H8N6 H8N7 H8N8 H8N9 H9 H9NI H9N2 H9N3 H9N4 H9N5 H9N6 H9N7 H9N8 H9N9 H10O HION1 HION2 HION3 HION4 HIONS HION6 HION7 HION8 HION9 H11 HIlNI HIIN2 H11N3 HIIN4 HIIN5 HIIN6 HIIN7 HIIN8 141IN9 H12 HI2NI HI2N2 H12N3 H12N4 HI2N5 .H12N6 HI2N7 HI2N8 HI2N9 H13 H13N1 H13N2 HI3N3 HI3N4 H13N5 HI3N6 HI3N7 H]3N8 HI13N9 H14 HI4N1 H14N2 H14N3 HI4N4 H14N5 HI4N6 H14N7 H14N8 HI4N9 H15 H15NI H15N2 H15N3 H15N4 H15N5 H15N6 H15N7 H15N8 HI5N9 H16 H16N1 H16N2 H16N3 H16N4 H16N5 H16N6 IH16N7 HI6N8 H16N9 The virus may be, for example, an avian virus or a humanized avian virus. Thus, the term "avian virus" includes both avian forms of the virus and humanized 5 forms of the avian virus. Certain embodiments of the present invention provide the use of a compound of formula I, II, III, or IV:

H

2 N ; N H

H

2 N N H HN HN CO2H CO2H NHCOCH3 OH NHCOCH, OH 10 (I) (II) 24 WO 2007/095218 PCT/US2007/003755

H

2 N NH

H

2 N NH HN .HN

CO

2 H. COH

-NHCOCH

3 NHCOCH 3 . (Ill) (IV), or a pharmaceutically acceptable salt thereof, in the manufacture of a 5 medicament for intravenous injection for achieving a plasma concentration in a human of the compound that is effective to treat a virus by intravenous injection of a dose of the medicament into the human. Certain embodiments of the preserit invention also provide the use of a compound of formula I, II, 111, or IV: 10

H

2 N ' N H H2N NH HN HN

CO

2 H COH NHCOCH3 OH NHCOCH3 OH I). - (II) H2N NH H2N NH HN • HN COH COH NHCOCH, .

NHCOCH

3 15 (I) (IV), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for intramuscular injection for achieving a plasma concentration in a human of the compound that is effective to treat a virus by intramuscular 20 injection of a dose of the medicament 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 25 WO 2007/095218 PCT/US2007/003755 peramivir formulated for intravenous administration for use in treating a virus by achieving a plasma concentration in a human of peramivir that is effective to treat the virus. Certain embodiments of the invention also provide compositions 5 comprising peraminivir 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 achieving a plasma concentration in a human of peramivir that is effective to treat the virus. 10 In certain embodiments of the invention, the plasma concentration of the compound is higher than the ICso 50 of the virus at least about 12 hours following the injection. In certain embodiments of the invention, the plasma concentration of the compound is higher than the ICs 50 of the virus at least about 24 hours following 15 the injection. In certain embodiments of the invention, the plasma concentration of the compound is higher than the IC 50 of the virus at least about 36 hours following the injection. In certain embodiments of the invention, the plasma concentration of the 20 compound is higher than the IC 50 of the virus at least about 48 hours following the injection. In certain embodiments of the invention, the plasma concentration of the compound is higher than the ICs 50 of the virus at least about 60 hours following the injection. 25 In certain embodiments of the invention, the plasma concentration of the compound is higher than the IC 50 of the virus at least about 72 hours.following the injection. In certain embodiments of the invention, the virus is an influenza virus. In certain embodiments of the invention, the virus is an avian influenza virus. In 30 certain embodiments of the invention, the virus is H5N1, or a mutant strain thereof. 26 WO 2007/095218 PCT/US2007/003755 The invention will now be illustrated by the following non-limiting Examples. Example 1. Effect of IV Treatment with Peramivir on Influenza A Virus. 5. Infection Experiment Design: Mice were infected iLi. with a dose thought to be the LD 100 of influenza virus. Groups of 10 mice were treated i.v. with peramivir at dosages of 20, 10 and 3 mg/kg a single time 1 hour pre-virus exposure. Placebo -(sterile saline) was administered i.v. in parallel with the above to 20 infected 10 mice. Drug-treated infected mice and placebo-treated controls were observed daily for death through 21 days. As toxicity controls, 3 uninfected mice were treated with the highest dose of the compounds in parallel to the infected animals. All toxicity controls were observed for death through 21 days and were weighed immediately prior to the initial treatment and 18"h after the final 15 treatment. Five normal controls were weighed. 27 WO 2007/095218 PCT/US2007/003755 Table 2. Effect of Single I.V. Treatment with Peramivir on an Influenza A Virus Infection in Mice. Animals: Female 18-21 gram Treatment schedule: Peramivir,: Single BALB/c mice treatment 1 hour pre-virus exposure Virus: Influenza Treatment route: Peramivir i.v.; A/Duck/MN/152518 (H5N1) Drug diluent: Sterile Saline Expt. duration: 21 days Tox Infected, Treated Mice Controls Mean Day Dose Surv/ Surv/ to Deathb :L Treatment (mg/kg) Total Total SD Peramivir 20 3/3 10/10** >21.0 = 0.0*** 10 3/3 10/10** >21.0 0.0*** 3 3/3 5/10 9.6 1.3 Saline - - 9/20 9.1 1.4 Normal - 5/5 Controls bMean day to death of mice dying prior to day 21. 5 **P<0.01; .***P<0.001 compared to saline-treated controls. The infection induced in this experiment was lethal to 55% of the mice (Table 1), with a mean day to death of 9.1 days. The single i.v. injection with peramivir at 20 and 10 mg/kg was highly protective to the infected animals, with 100% 10 surviving the infection (P<0.01). Toxicity controls run in parallel all survived and gained weight, indicating compound was vell tolerated in this experiment. These data indicate that peramivir is a significant influenza inhibitor when used in a single i.v. injection. 15 Example 2. Effects of IV and IM Treatment with Peramivir in Humans Peramivir was studied in a placebo-controlled phase I clinical study in healthy human volunteers to evaluate safety and pharmacokinetic parameters using intravenous and intramuscular administrations. Blood samples were 28 WO 2007/095218 PCT/US2007/003755 collected from the subjects at different time points after drug administration to determine the concentration of the drug in plasma. The time course plots are shown in Figure 1 and Figure 2 for intravenous and intramuscular administrations respectively. 5 In the intravenous study, peramivir concentrations followed linear kinetics with an unusually extended plasma half life of greater than 12 hours. At doses of 2 mg/kg and above, the level of peramivir in plasma at 48 hours post dose is greater than the ICso for all strains of influenza virus tested, including H5 virus types. For doses greater than 4 mg/kg, even at 72 hours, the levels of the 10 drug are greater than the IC 50 values. In the intramuscular study, peramivir concentrations also followed linear kinetics with an unusually extended plasma half life. Even at 72 hours post dosing, the levels of peramivir are higher than the ICso 50 values for all the influenza virus strains tested. 15 The long plasma half-life and the high levels of peramivir in human volunteers are unusual and unexpected findings and indicate that intravenous and intramuscular administrations of peramivir are beneficial in the treatment of -influenza in humans. All publications, patents and patent applications cited herein are 20 incorporated herein by reference. While in the foregoing specification this inventionhas been described in relation to certain embodiments thereof, and many details have been set forth for purposes of illustration, it will be apparent to those skilled in the art that the invention is susceptible to additional embodiments and that certain of the details described herein may be varied 25 considerably without departing from the basic principles of the invention. The use of the terms "a" and "an" and "the" and similar.referents in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" are to 30 be construed as open-ended terms (i.e., meaning "including, but not limited to") unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate 29 WO 2007/095218 PCT/US2007/003755 value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by 5 context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. 30

Claims

1. A method for treating a viral infection in a human comprising administering an effective anti-viral amount of a compound of formula I, II, HI, or IV: HN NH H2N NH HN HN CO2H CO 2 H NHCOCH3 OH NHCOCHs OH (I) (II) H 2 N NH H2N NH HN HN COH COH NHCOCH3 NHCOCH, (I) (IV), or a pharmaceutically acceptable salt thereof, to the human by an intravenous route.

2. The method of claim 1, wherein the compound of formula I, II, m, or IV is a compound of formula Ia, HIa, mIa, or IVa: H2N NH H2N NH HN\ \COH ' H CO2H NHCOCH OH NHCOCH, OH (Ia) (HIa) 31 WO 2007/095218 PCT/US2007/003755 H2N NH H2N NH ..,\CO2H .- ,C02H > NHCOCH3 NHCOCH 3 (lia) (IVa), or a pharmaceutically acceptable salt thereof.

3. The method of 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 type A or type B infection.

5. The method of claim 1 or 2, wherein the viral infection is caused by a strain of virus represented by the formula HxNy wherein X is an integer from 1 16 and Y is an integer from 1-9.

6. The method of claim 3, wherein the influenza is ari H3N2, H1NI, H5N1, avian, or seasonal influenza.

7. The method of any one of claims 1-6, wherein the effective anti-viral amount is up to about 800 mg.

8. The method of claim 7, wherein the effective anti-viral amount is up to about 400 mg.

9. The method of claim 8, wherein the effective anti-viral amount is up to about 300 mg.

10. The method of claim 9, wherein the effective anti-viral amount is up to about 200 mg. 32 WO 2007/095218 PCT/US2007/003755

11. The method of any one of claims 1-10, wherein the entire effective dose is administered in one intravenous administration.

12. The method of any one of claims 1-10, wherein the entire effective dose is administered in multiple intravenous administrations.

13. The method of any one of claims 2-12, wherein a compound or formula Ia, or a pharmaceutically acceptable salt thereof, is administered.

14. The method of any one of claims 1-13, wherein the plasma concentration of the compound is higher thanthe IC 50 of the virus causing the viral infection 12 hours following administration of the compound.

15. 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: HN NH HN NH HN HN C02H ' CO 2 H NHCOCH 3 OH NHCOCH, OH (I) (II) H2N NH H 2 N NH HN HN CO2H COH NHCOCH, NHCOCH, (III) (IV), or a pharmaceutically acceptable salt thereof, to the human by an intravenous route. 33 WO 2007/095218 PCT/US2007/003755

16. The method of claim 15, wherein the compound of formula I, H, III, or IV is a compound of formula Ia, IHa, lia, or IVa: H 2 N NH H 2 N NH HN, HN .,,,,CO2H .,CO 2 H NHCOCH OH NHCOCH, OH (Ia) (HIa) H2N N H H2N NH ,,,\CO 2 H gCO2H NHCOCH9 NHCOCH, (IIIa) (IVa), or a pharmaceutically acceptable salt thereof.

17. The method of claim 15 or 16, wherein the effective inhibitory amount is Sup to about 800 mg.

18. The method of claim 17, wherein the effective inhibitory amount is up to about 400 mg.

19. The method of claim 18, wherein the effective inhibitory amount is up to about 300 mg.

20. The method of claim 19, wherein the effective inhibitory amount is up to about 200 mg.

21. The method of any one of claims 15-20, wherein the entire effective inhibitory dose is administered in one intravenous administration. 34 WO 2007/095218 PCT/US2007/003755

22. The method of any one of claims 15-20, wherein the entire effective Sinhibitory dose is administered in multiple intravenous administrations.

23. The method of any one of claims 16-22, wherein a compound of formula Ia, or a pharmaceutically acceptable salt thereof, is administered.

24. The method of any one of claims 1-23, further comprising orally administering a neuraminidase inhibitor to the human.

25. The method of claim 24, wherein the neuraminidase inhibitor that is administered orally is oseltamivir carboxylate.

26. The method of claim 24, wherein the'neuraminidase inhibitor that is administered orally is a compound of formula I, II, III, or IV: HN NH H2N NH HN HN C0O" CO 2 H NHCOCHa OH NHCOCH, OH (I) (11) H2N NH H2N' NH HN HN CO2H CO2H NHCOCH3 NHCOCH3 (El) (IV), or a pharmaceutically acceptable salt thereof.

27. The method of claim 24, wherein the neuraminidase inhibitor that is administered orally is a compound of formula Ia, IHa, IIIa, or IVa: 35 WO 2007/095218 PCT/US2007/003755 H2N NH H2N NH HN\ HN ,,COH CO 2 H NHCOCH3 OH NHCOCH3, OH (Ia) (IHa) H2N NH H2N NH H\N,. HN .,#\CO 2 H ,C\\CO 2 H SINHCOCH3 NHCOCH3 (IIIa) (IVa), or a pharmaceutically acceptable salt thereof.

28. The method of claim 27, wherein the neuraminidase inhibitor that is administered orally is a compound of formula Ia, or a pharmaceutically acceptable salt thereof.

29. The method of any one of claims 24-28, wherein the neuraminidase inhibitor that is administered orally is administered for up to 20 days.

30. The method of claim 29, wherein the neuramninidase inhibitor that is administered orally is administered for up to 10 days.

31. The method of claim 30, wherein the neuraminidase inhibitor that is administered orally is administered for up to 5 days.

32. A unit dosage form that is suitable for intravenous administration to a Human, comprising up to about 800 mg of a compound of formula I, II, III, or IV: HN ",- H H 2 N NH HN * HN CO2H C02H NHCOCH, OH NHCOCH, OH 36 WO 2007/095218 PCT/US2007/003755 (I) (LI) H 2 N N H H 2 N NH HN HN CO 2 H CO2H NHCOCH3 NHCOCH, (III) (IV), or a pharmaceutically acceptable salt thereof.

33. The unit dosage form of claim 32, wherein the compound of formula I, II, III, or IV is a compound of formula Ia, IIa, IIla, or IVa: H 2 N r NH H2N NH HN HN ,,,CO 2 H * COH NHCOCH3 OH NHCOCH, OH (Ia) ([a) H2N NH. H2N H\N HN- HN, ,,\\CO 2 H CO2H NHCOCH3 NHCOCH 3 (IIIa) (IVa), or a pharmaceutically acceptable salt thereof.

34. The unit dosage form of claim 32 or 33 that comprises up to about 400 mg of the compound or salt.

35. The unit dosage form of claim 34 that comprises up to about 300 mg of the compound or salt. 37 WO 2007/095218 PCT/US2007/003755

36. The unit dosage form of claim 35 that comprises up to about 200 mg of the compound or salt.

37. A kit, comprising packaging materials, a compound of formula I, II, III, or IV: H2N N- N H2N NH HN HN COH COaH NHCOCH OH > NHCOCH, OH -(I) (II) H2N NH H2N NH HN HN CO2H COH NHCOCH3 NHCOCH3 (III) (IV), or a pharmaceutically acceptable salt thereof, and instructions for administering the-compound to a human by an intravenous route.

38. The kit of claim 37, wherein the compound is provided in a formulation suitable for intravenous administration.

39. The kit of claim 37 or 38 that comprises up to about 800 mg of the compound or salt.

40. The kit of claim 39 that comprises up to about 400 mg of the compound or salt. 38 WO 2007/095218 PCT/US2007/003755

41. The kit of claim 40 that comprises up to about 300 mg of the compound or salt.

42. The kit of claim 41 that comprises utp to about 200 mg of the compound or salt.

43. A kit, comprising packaging materials, a unit dosage form as described in any one of claims 32-36, and instructions for administering the compound to a human by an intravenous route.

44. Use of a compound of formula I, II, III, or IV: H 2 N ' NH H2N NH NHCOCH3 OH NHCOCH 3 OH (I) (II) H2N NH H 2 N NH HN HN CO2H COH NHCOCH3 NHCOCH3 (III) (IV), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for intravenous injection for increasing life expectancy or reducing mortality in a group of mammals exposed to a source of an influenza virus, by intravenous injection of a dose of the medicament into each member of the group presenting clinical symptoms of infection.

45. Use as in claim 44, wherein.the compound of formula I, II, III, or IV is a compound of formula Ia, IHa, lia, or IVa: 39 WO 2007/095218 PCT/US2007/003755 H 2 N NH HN NH HN N%~ COH COH NHCOCH3 OH >NHCOCHa OH (la) (IHa) H2N NH H 2 N NH HN HN ,\CO 2 H ,,\CO 2 H NHCOCH, NHCOCH, (Ilia) (IVa), or a pharmaceutically acceptable salt thereof.

46. Use as claimed in claim 44 or 45, wherein the influenza virus is an avian influenza virus.

47. Use as claimed in claim 44 or 45, wherein the influenza virus is an influenza type A or type B virus.

48. Use as claimed in claim 44 or 45, wherein the influenza virus is H5N1, or a mutant strain thereof.

49. Use as claimed in claim 44 or 45, wherein the influenza virus is a strain of virus represented by the formula HxNy wherein X is an integer from 1-16 and Y is an integer from 1-9.

50. Use as claimed in claim 44 or 45, wherein the influenza virus is an H3N2, HIN1, H5N1, avian, or seasonal influenza virus. 40 WO 2007/095218 PCT/US2007/003755

51. Use as claimed inany one of claims 44-50, in which each member of the group presenting symptoms of infection receives only one intravenous dose of the medicament.

52. Use as claimed in any one of claims 44-50, in which each member of the group presenting symptoms of infection receives multiple intravenous doses of the medicament.

53. -Use as claimed in any one of claims 44-52, for increasing life expectancy or reducing mortality in a group of mammals, wherein the members of the group presenting clinical symptoms of infection are treated orally with a neuraminidase inhibitor.

54. Use as claimed in claim 53, in which the neuraminidase inhibitor is oseltamivir carboxylate.

55. Use as claimed in claim 53, in which the neuraminidase inhibitor is a compound of formula I, II, III, or IV: H2N NH H2N NH HN HN COH CO2H NHCOCHa OH NHCOCHs OH () (II) H2N NH H2N NH HN HN CO 2 H CO2H NHCOCH3 NHCOCHz (III) (IV), or a pharmaceutically acceptable salt thereof. 41 WO 2007/095218 PCT/US2007/003755

56. Use as claimed in claim 53, in which the neuraminidase inhibitor is a compound of formula Ia, Ha, lia, or IVa: HN NH HN NH HN HN\ ,,gCO2H s co"H ",,,\,CO2 .,,,,,,,,co2H NHCOCH3 OH NHCOCHa OH (Ia) (IHa) H 2 N NH HN N H HH HNCO2H NHCOCH 3 NHCOCH 3 (IIIa) (IVa), or a pharmaceutically acceptable salt thereof.

57. Use as claimed in claim 56, in which the neuraminidase inhibitor is a compound of formula Ia, or a pharmaceutically acceptable salt thereof.

58. Use as claimed in any one of claims 44-57, in which the source of the virus is an infected bird.

59. Use as claimed in any one of claims 44-57, in which the source of the virus is a mammal presenting symptoms of infection.

60. Use as claimed in any one of claims 44-59, which is for reducing mortality.

61. Use of a compound of formula I, II, III, or IV: 42 WO 2007/095218 PCT/US2007/003755 H 2 N NH HN NH 'T HN HN HN CO 2 H CO 2 H NHCOCH, OH NHCOCH 3 OH (1) (II) H 2 N NH H2N NH HN HN CO 2 H CO 2 H NHCOCH 3 NHCOCH 3 (II) (IV), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for intravenous injection for increasing life expectancy or reducing mortality in a group of mammals exposed to a source of an influenza virus, by intravenous injection of a dose of the medicament into each member of the group.

62. Use as in claim 61, wherein the compound of formula I, II, III, or IV is a compound of formula Ia, Ha, Ila, or IVa: H2N " NH H2N* NH HN HN, CO 2 H ,,,,CO 2 H NHCOCH OH NHCOCH OH (la) (IHa) H 2 N " NH H2N NH H N _ HN ,-a0 2 C2HH >NHCOCH 3 NHCOCH3 (IlIa) (IVa), 43 WO 2007/095218 PCT/US2007/003755 or a pharmaceutically acceptable salt thereof.

63. Use as claimed in claim 61 or 62, in which the'influenza virus is an avian influenza virus.

- 64. Use as claimed in claim 63, in which the avian influenza virus is H5N1, or a mutant strain thereof.

65. Use as claimed in claim 61 or 62, wherein the influenza virus is a strain of virus represented by the formula HxNy wherein X is an integer from 1-16 and Y is an integer from 1-9.

66. Use as claimed in claim 61 or 62, wherein the influenza virus is an influenza type A or.type B virus.

67. Use as claimed in claim 61 or 62, wherein the influenza virus is an H3N2, HIN1, H5N1, avian, or seasonal influenza virus.

68. Use as claimed in any one of claims 61-67, in which each member of the group receives only one intravenous dose of the medicament.

69. Use as claimed in any one of claims 61-67, in which each member of the group receives multiple intravenous doses of the medicament.

70. Use as claimed in any one of claims 61-69, for increasing life expectancy or reducing mortality in a group of mammals wherein the members of the group are treated orally with a neuraminidase inhibitor.

.71. Use as claimed in claim 70, in which the neuraminidase inhibitor is oseltamivir carboxylate. 44 WO 2007/095218 PCT/US2007/003755

72. Use as claimed in claim 70, in which the neuraminidase inhibitor is a compound of formula I, II, III, or IV: H 2 N NH .*HN NH HN HN CO02H CO2H NHCOCH 3 OH >NHCOCH OH (I) - (I) H2N N H H2N NH HN HN COH CO2H NHCOCHP NHCOCH3 (m) (IV), or a pharmaceutically acceptable salt thereof.

73. Use as claimed in claim 70, in which the neuraminidase inhibitor is a compound of formula Ia, IIa, IIIa, or IVa: H2N NH H2N N HN HN ,yCO 2 H ~CO2H NHCOCH3 OH NHCOCH, OH (la) (Ha) H 2 N NH H2N NH HN _ HN - yCO 2 H C~g ,,,,, co." " ,,,,N,,e2" NHCOCH3 NHCOCH3 (Ila) (IVa), 45- WO 2007/095218 PCT/US2007/003755 or a pharmaceutically acceptable salt thereof.

74. Use as claimed in claim 73, in which the neuraminidase inhibitor is a compound of formula Ia, or a pharmaceutically acceptable salt thereof.

75. Use as claimed in any one of claims 61-74, in which the source of the. virus -is an infected bird.

76. Use as claimed in any one of claims 61-74, in which the source of the virus is a mammal presenting symptoms of infection.

77. Use as claimed in any one of claims 61-76, which is for reducing mortality.

78. Use of a compound of formula I, II, III, or IV: H04 NH HN NH HN HN C02H COH NHCOCH3 OH NHCOCH 3 OH (I) (II) H 2 N " :NH HNIN NH HN HN CO2H 002H NHCOCH3 NHCOCH3 (III) (IV), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for intravenous injection for achieving a plasma concentration in a human of the compound that is effective to treat a virus by intravenous injection of a dose of the medicament into the human. 46 WO 2007/095218 PCT/US2007/003755

79. Use of a compound of formula I, II, III, or IV: H2N NH HzN N H HN iHN CO2H CO 2 H NHCOCH 3 OH >NHCOCH 3 OH (I) (II). H2i NH H 2 N NH HN iHN CO2H CO2H > 7NHCOCH 3 NHCOCH, (III) (IV), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for intramuscular injection for achieving a plasma concentration in a human of the compound that is effective to treat a virus by intramuscular injection of a dose of the medicament into the human.

80. The use of claim 78 or 79, wherein the plasma concentration of the compound is higher than the IC 50 of the virus 12 hours following injection of the compound. 47