AU2013216632A1

AU2013216632A1 - Intravenous antiviral treatments

Info

Publication number: AU2013216632A1
Application number: AU2013216632A
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: 2013-08-14
Publication date: 2013-08-29
Anticipated expiration: 2027-02-12
Also published as: MX2020002008A; MY166063A; JP2013256527A; JP6073202B2; KR20080096829A; BRPI0707769A2; KR20230003248A; KR20200143519A; JP2015180695A; KR20190072681A; EA025483B1; WO2007095218A1; CA2642260A1; KR101992585B1; EP1986626A1; KR101992585B9; KR20180024027A; KR20210135632A; KR20210076189A; EA200870263A1

Abstract

The invention provides unit dosage forms, kits and methods useful for treating viral infections.

Description

INTRAVENOUS ANTIVIRAL TREATMENTS Related Applications The present application is a divisional from parent Australian application 2007215156, the entire disclosure of which is incorporated herein by reference. The parent application 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. Throughout the description and the claims of this specification the word "comprise" and 5 variations of the word, such as "comprising" and "comprises" is not intended to exclude other additives, components, integers or steps. A reference herein to a patent document or other matter which is given as prior art is not to be taken as an admission that that document or matter was known or that the information it contains was part of the common general knowledge as at the priority date of any of the claims. 10 Backaround 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 et dl., 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. Summona 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 alla 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 1 WO 2007/095218 PCT/US2007/003755 administering an effective anti-viral amount of a compound of formula I, I, IIl, or IV: IN N HN NH HN N<%NH CHcc3 oH NHOCHa H 5 HN NK H2N"- NH > INH$ NHCoCHa Off) (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, H, I, or IV, or a pharmaceutically acceptable salt thereof, to the human by an intravenous route. 15 The invention also provides a unit dosage forn that is suitable for -intravenous administration to a human comprising up to about 400 mg of a compound of formula I, U, I, 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, R, III, or IV, or a phatmaceutically acceptable salt thereof. The invention also provides a kit comprising packaging materials, a compound of. formula I, H, 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, I, II, 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, li, III, 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 peranivir 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 at., (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 , U, In, or IV: N% r- H2N H cam 5 NHCOCI% H NHCOCH H HIN N Nw HM NHCOC~aNHCuale (ID) (IV), 10 or a pharmaceutically acceptable salt thereof, to the human by an intravenous route. In certain embodiments, the compound of formula I, II, IM, or IV is a compound of formula la, HIa, Ia, or IVa: 15 aN NH NHCI-I, OH NHCO0C4a (Ia) .(IHa) N H NHC0C~aHOCa NHCOGN OH G=OWN 20 (1Ia) (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 HNy wherein X is an integer from 1-16 and Y is an integer from 1-9. In certain embodiments, the influenza is an H3N2, H1NI, 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 tp 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 IC 5 o 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, 11, 111, or IV: HaN NH 25 NHQOCHs II NHCOON H (1) (11) 5 WO 2007/095218 PCT/US2007/003755 COmH G08 HwCOC HCOCHN (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, Ila, Ma, or IVa: IN HN H~a CHN, OH 10 (Ia) (Ila) H2HORN NHOOCH, - NOH, (IIma) (Ia), 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/US2007/00375 5 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, II, III, or V: NHOH H OCH H MM H HH oa 20**"" *.NHCOCHZ OH (I) (1I1) 24$H H0 2 15 NHCCCHz HOH or a pharmaceutically acceptable salt thereof. In certain embodiments, the neuraminidase inhibitor that is administered orally is a compound of formula Ia, Ha, M~a, or Wa: H-N H1\ 20 2424008 OH Hi ONH (1a) (la) 7 WO 2007/095218 PCT/US2007/003755 NcoO- . NHCOCH3 (IIfa) (IVa), or a pharmaceutically acceptable salt thereof. In certain embodiments, the neuraminidase inhibitor that is administered 5 orally is a compound of formula Ia, 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, I, III, or IV: COIH HOaN H H a H 15 (I)0) HzN NH K C0" COIN NCOCHH (MI) (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 la, Ila, lla, or IVa: 8 WO 2007/095218 PCT/US2007/00375 5 MOODMw3 OH NHH-OOOI%01 (Ia) a). ~Can ~COaH NHCtI2804 5 (Ia) (Va), 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, 11, I1, or IV: HIN HN 15 NGOCH, MNO4 (1) (II) C~hH C02H NHOOCM NHCOO (III) OV), 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 MHCI, NNCOCH,' (I) (II) H co "

NHCOQH

3 HOC4, 20 (I) (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, 11, 1I, or IV is a compound of formula la, la, Ia, or IVa: asces o NCQCH* H 5 (1a) (IIa) $OHGOOaH NNGOOM, OCH3 (IlIa) (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 HNy 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, HINI, H5NI, 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, Im, or IV: 11 WO 2007/095218 PCT/US2007/003755 H COIN HOCH. OM NHCOC~s OH (I) (U)

H

2 N N Ha NC 00 2 H CCOH 5 NHCOH NHCOCHa gLI (IV), or a pharmaceutically acceptable salt thereof. In certain embodiments, the neuraminidase inhibitor is a compound of formula la, Ila, Ma, or IVa: 10 soces HGOOHs OH (Ia) (Ha) NH HOOCH NHCOCHa (Ia) (Iva), 15 or a pharnaceutically 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, II, III, or IV: HAN Ha M MN NH

H

2 NNC NHCOCOa H OH (I) (U) 10 NH N HoHH NHOCHC? HHOOCHS (111) (V), 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 o.f a dose of the medicament into each member of the group. In certain embodiments, the compound of formula I, II, III, or IV is a 20 compound of formula Ia, IHa, IIa, or IVa: NHOCxCa

NHCOOH

3 OH (Ia) (IIa) 13 WO 2007/095218 PCT/US2007/003755

H

N Mr NNDaCH 1 HOCNs (Iia) (Va), 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 HNy 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, H1IN, 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, III, or IV: 20 H0 1 NHCOCH3 H NHGOCMS (1)( 14 WO 2007/095218 PCT/US2007/003755

H

2 N NHN HHN COH GOH NMcO0Ma NiCOCH3 or a pharmaceutically acceptable salt thereof. In certain embodiments, the 5 neuraminidase inhibitor is a compound of formula Ia, Ia, Ila, or IVa: NHHNH OCHS. 0 HCH (Ia) (Ha) HN NH N1 N OAH H 10 - fiCccaH NWO006 (Illa) or a pharmaceutically acceptable salt thereof. In certain embodiments, the neuraminidase inhibitor is a compound of formula la, 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 Man COiH la NHCCCHNCC~ COC NHCCC 1 H OIH 5 (M) (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 1, I, II, or IV:

-

2 N HZN HhNH NHCOCH H NHCOWC4 H '5 (I) (II) HaN HaN H CH COH NCOCIa NHCCt (III) (IV), 16 WO 2007/095218 PCTUS2007/003755 NH, Hr NEICOc~ coca (Ia) (Ia), or a pharmaceutically acceptable salt thereof. 5 A specific compound of formula I, II, III, or IV is (IS,2S,3R,4R)-3-(1 Acetamido-2-ethylbutyl)-4-guanidino-2-hydroxycyclopentane-carboxylic acid; (IS,2S,3R,4R)-3-(1-Acetamido-2-propylpentyl)-4-guanidino-2- hydroxycyclopentanecarboxylic acid; (lR,3R,4R)-3-(l-Acetamido-2 propylpentyl)-4-guanidinocyclopentanecarboxylic acid; or (lR,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 1, 11, III, 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/US2007/00375 5 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 5 o qf the virus 12 hours following injection of the compound. Mice infected with influenza A/Duck/MN/i 525/81 (H5NI) 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 1, 11, III, or IV is a compound of formula Ia, Ila, Ma, or Ia: ~C0NH 25 X0H HCOC4 OH (Ia) (IHa) 17- WO 2007/095218 PCT/US2007/00375 5 example, tosylate, methanesulfonate, acetate, citrate, malonats, tartarate, 'succinate, benzoate, ascorbate; a-ketoglutarate, and CE-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, II, 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 PCTIUS2007/003755 and the like. In many cases, it will be preferable to include isqtonic 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 prepare< by incorporating the active compound(s) into an appropriate solvent with the other o-ptional 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, I, IM, or IV is up to about 1,000 mg. 5 In one embodiment of the invention, the effective inhibitory.amount of the compound of fonula I II, IH, or IV is up to about 800 mg. In one embodiment of the invention, the effective inhibitory amount of the compound of formula I, If, M, 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, H, mI, or IV is up to about 500 mg. In one embodiment of the invention, the effective inhibitory amount of the compound of formula I , I1, or IV is up to about 400 mg. In one embodiment of the invention, the effective inhibitory amount of the compound of formula 1, H, 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 1, II, Il, or IV is up to about 200 mg. In one embodiment of the invention, the effective inhibitory amount of the compound of fonnula I, 11, I1, or IV is up to about 150 mg. In one embpdiment of the invention, the effective inhibitory amount of 20 the compound of formula I, 11, HI, or IV is up to about 75 mg. According to the methods of the invention a compound of formula 1, 11, . III, or IV is administered to a human intravenously. In one embodiment of the invention, the compound of formula I,1U, m1, 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, U, Il, or IV: 21 WO 2007/095218 PCT/US2007/003755 NHa CONNH CO2H COiH N-eocIq NKCQCH3 ON (I) . (II) N~NH NH *J H~i COH COsH 5 ( ) .(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, la, IIma, or IVa: 10 HMM NHCOCNE HC (Ia) (Ila) H N r H N ' NHCOCN~ , NHCOCH 15 (11a) (Ia), 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 PCTIUS2007/003755 According to the methods of the invention, the compolind of fonnula I, -U, 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 mbre additional ther'peutic agents, such as anti-viral agents (e.g., agents active against influenza) and antibiotics. .Thus, intravenous administration of peramnivir 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 of peramivir 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. - As 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 H.Ny 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/US2007/00375 5 Table 1 Ni N2 N3 N4 N5 N6 N7 N8 N9 H1 HIN1 HIN2 HIN3 HIN4 HIN5 HIN6 H1N7 BINS *IlN9 - H2 H2NI H2N2 H2N3 H2N4 H2N5 H2N6 12N7 H2N8 H2N9 113 H3NI H3N2 H3N3 H3N4. H3N5 H3N6 H3N7 H3N8 H3N9, H4 H4N1 H4N2 H413 H4N4 H4N5 H4N6. H4N7 H4N8 H4N9 H5 H5NI H5N2 H5N3 H5N4 H5N5 H5N6 H5-N7 H5N8 H5N9 116 H6NI H6N2 H6N3 H6N4 H6N5 H6N6 H6N7 H6N8 H6N.9 H7 H7NI H7N2 H7N3 H7N4 H7N5 H7N6 H7N7 H7N8 H7N9 H8 H8N1 H8N2 HSN3 HSN4 H8N5 H8N6 H8N7 H8N8 H8N9 R9 H9N1 119N2 19N3 H9N4 H9N5 H9N6 H9N7 H9N8 H9N9 H110 HIONI H11N2 H11N3 H11N4 110N5 HION6 H11N7 H11N8 H1ON9 H111 HINI I1111142 H11143 111114 H11145 HI11N6 BI11147 11114 1N14N9 H12 H12NI1 1112N2 H12N3 H12N4 H12N5 H12N6. H12N7 H12N8 H12N9 113 H1H1 13N2 H133 H13N4 H13N.5 H13N6 113N7 H13N8 H13N9 H14 H14N1 H14N2 H14N3 H14N4 H14N5 H14N6 H14N7 H114N8 H14N9 HIS H15N H15N2 H15N3 H15N4 H15N5 H15N6 H15N7 H15N8 H15N9 H116 H16N1 H16N2 H16N3 H16N4 H16N5 H16N6 H16N7 H16N8 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, 11, UI, or IV: HNN H NHCOCWs 4 NICOH3 NCO O 1 H 10 (I) 24 WO 2007/095218 PCT/US2007/003755 H H COH. -OaH OHHCOCH,. (III) - (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 compoulid 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, I, or IV: 10 NH . NHCOCH'J OHMHO~ H NH NN H Cop com 15 (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 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 peranivir 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 peranivir 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 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 IC 50 of the virus at least about 24 hours following 15 the injection. In certain embodiments of thb invention, the plasma concentration of the compound is higher than the IC50 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 IC5D 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 IC50 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 IJso 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 H5Ni, 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: Mige were infected i.h. with a dose thought to be the LD100 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 iV. 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 181h after the final 15 treatment. Five normal controls were weighed. 27 WO 2007/095218 PCTIUS2007/003755 Table 2. Effect of Single I.V. Treatment with Perarnivir 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 Death Z Treatment (mg/kg) Total Total SD Peramivir 20 . 3/3 10/10** >21.0 . 0.0*** 10 3/3 10/10** >21.0d 0.0*** -3 3/3 5/10 9.6- 1.3 Saline - - 9/20 9.1 L 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<0.0 1). 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 1 clincal 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.IC5o 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 IC50 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 perarnivir are higher than the ICso 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 invention-has 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 1, I 11L, or IV: HN HN COH C2 NHCOCH3 OH NHCOCHs Oil (I) (H) H2N NH NH HNHN CO 2 H COH NHCOCH 3 NHCOCH . (UI) (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, U, HIl, or IV is a compound of formula Ia, Ha, ma, or IVa: HN NH C~aH COH NHCOCHS OH NHOOCHS OH ga) (Ea) 31, WO 2007/095218 PCT/US2007/003755 NHCCH NH (II9a) (IWa), or a pharmaceutically acceptable salt thereof.

3. The method of claim I 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 HNy wherein X is an integer from I 16 and Y is an integer from 1-9.

6. The method of claim 3, wherein the influenza is an H3N2, HINI, 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/tJS2007/003755 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 phannaceutically acceptable salt thereof, is administered.

14. The method of any one of claims 1-13, wherein the plasma concentration of the compound is higher than the IC 5 0 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 1, IU, 1, or IV: H 2 N NH HN HN HN COH CO2H NSCOCHa HNHD3 (I) HN NH HTN NH HNHN NHGOcH, NHCOCH, (111) (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 1, 11, I, or IV is a compound of formula la, Ha, Ia, or IVa: NHCOCH) H NHCOCH3 H (Ia) (Ha) H2N N -H2 N SCO2H\Ca NHCOCH, NHCOCH3 (Ia) (IVa), or a pharmaceutically acceptable salt thereof.

17. The method of claim 15 or 16, wherein the effective inhibitory amount is up 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 inhibitory 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 hwman.

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, I, III, or IV: NH HiiN N HN HN NHCOCa, OH NHCOCH3 OH (I) (II) HN H H,N NH HN HN CO2H C~yH NHCOCR, NHOH, (III) ,(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, Ha, IIa, or IVa: 35 WO 2007/095218 PCT/US2007/003755 H 2 N H2N NH TNH H\ HN CO2H CO 2 H NHCOCH3 OH NHCOCH.4 oH (la) (Ila) H2 H -H2N NH CHCO2H NHCOCH2 NHCOCH, (IIa) (Va), 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 neuraminidase 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, II, or IV: H2N NH H 2 N NH HNHN CO H CO2I HCOCHa OH NHCCCH OH 36 WO 2007/095218 PCT/US20071/003755 (I) (TI) H2N HN NH NH HN HN NHCOCH' N"COca, (HIl) (IV), or a pharmaceutically acceptable salt thereof.

33. The unit dosage form of claim 32, wherein the compound of formula 1, H, I, or IV is a compound of formula la, la, HIla, or IVa: NHCOCH3 ON IJHOOCH3 O a) (Ha) NHCOCH1, NHCQCH3 (Hla) (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 1, 11, I, or IV: HaN H2MN HN HN CO2H COaH NHOCr-4 OH NHCGOCHZ OH (II) H2.N NiH2,N N HN HN 2H ~C02H HoocH, NHOCH 3 (rIV), or a pharmaceutically acceptable salt thereof, and instructions for administering thecompound 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 nip 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: COaH C2 NHCOCH3 OH NHCOC5, OH (1) (II) N2" NH HN HN COH C02 NHCOCH' 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 1, 11, M, or IV is a compound of formula la, Ila, IlIa, or IVa: 39 WO 2007/095218 PCT/US2007/003755 HaN HaN N NH MH NHNO CO (Ia) (ha) HoN HN CO 2 H Cz NHICOCHa -HO~ (lIla) (IWa) 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 H5NI, 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 HNy 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, HINI, 15N1, avian, or seasonal influenza virus. 40 WO 2007/095218 PCT/US20071003755

51. Use as claimed in any 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, 11, 111, or TV: NHCOC~s OH-NH3H HN CO2H CO2H NHNHCOCH NHCOCH (II) .(I), FRI HN C02H C 2 H 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 la, Ila, ila, or IVa: HM NH H2N "r NH HN, NHCOCH, OH NHCOCH3 OH (Ia) (Ila) H2N NHH2N H 2 NH CO2H CO2H NHQOCH, NHICOCH, (RIa) (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. 6L. Use of a compound of formula I, II, III, or IV: 42 WO 2007/095218 PCTI/US2007/003755 H2N NH NH HN HN CO2H C02H NHOO100, OH NH1OCH1 OHf (I).. .(I H7NNH H2N NH HN HN CO CO2H. 4HooCH NsNcooH2 (ll) (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 1, HL I, or IV is a compound of formula Ia, Ila, Ia, or IVa: H2N NH NH NHCOCHN OH . (Ia) (IHa) H2NrNH HN---N HoCH NHOCHa (IMa) (IVa), 43 WO 2007/095218 PCTUS2007/003755 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 virs is a strain of virus represented by the formula H4,Ny 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 ortype B virus.

67. Use as claimed in claim 61 or 62, wherein the influenza virus is an H3N2, HINI, 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 oseltarnivir carboxylate. 44 WO 20071095218 PCT/US2007/003755

72. Use as claimed in claim 70, in which the neuramninidase inhibitor is a compound of formula 1, H~, 111, or IV: H 2 N *H2N" N HN 4 WHOOCH, ~N.6COCH (I) (I), HN~r. H:ZN NH HNN COH, NHCOCH3 NHCOCH3 (111) (IV),. or phrmceuicllyaceptbl sat herof 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.111, or IV: HzH NHNH HN NHCOCH, OH OH (I) (II) H 2 N N NH HN HN C 002 NHCOH ONCOCH 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, 11, III, or IV: H z NN NH HIN C02" C02H NHCOCH, H >N HC OC H, 0 H (I) ' (II). H2N H2N NH _NH HN H C02H C02H r'~HCOH, NHCOCH3 (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 IC5o of the virus 12 hours following injection of the compound. 47