Note: Descriptions are shown in the official language in which they were submitted.
CA 02642260 2014-09-03
INTRAVENOUS ANTIVIRAL TREATMENTS
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.
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
etal.,
Antimicrobial Agents and Chemotherapy, 45(3), 743-748 (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
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 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
peramivir to
humans provides high plasma concentrations of peramivir with an extended half-
life.
In one aspect, of the invention provides use of a compound of formula I:
1
CA 02642260 2015-06-18
11214N+,.,1411
142=4
.214
011
NIICOCHI
or a pharmaceutically acceptable salt thereof; in an effective anti-viral
amount, in the
manufacture of a medicament for single intravenous administration, for
treatment of a
viral infection in a human.
In another aspect, the invention provides use of a compound of formula I or a
pharmaceutically acceptable salt thereof, in an effective anti-viral amount,
or such
compound for use, for treatment of a viral infection in a human, wherein the
compound is
formulated for single intravenous administration.
In another aspect, the invention provides use of a compound of formula Ia:
H2 N NH
HN
CO2
NHCOCH3 OH
1 0 (la)
or a pharmaceutically acceptable salt thereof; in an effective anti-viral
amount, in the
manufacture of a medicament for single intravenous administration, for
treatment of
seasonal influenza in a human.
2
CA 02642260 2015-11-06
In another aspect, the invention provides use of a compound of formula Ia or a
pharmaceutically acceptable salt thereof, in an effective anti-viral amount,
or such
compound for use, for treatment of seasonal influenza in a human, wherein the
compound
is formulated for single intravenous administration.
In another aspect, the invention provides use of a compound of formula I or a
pharmaceutically acceptable salt thereof, in an effective inhibitory amount,
in the
manufacture of a medicament for single intravenous administration, for
inhibition of a
neuraminidase in a human.
In another aspect, the invention provides use of a compound of formula I or a
pharmaceutically acceptable salt thereof, in an effective inhibitory amount,
or such
compound for use, for inhibition of a neuraminidase in a human, wherein the
compound
is formulated for single intravenous administration.
In another aspect, the invention provides use of a compound of formula I or a
pharmaceutically acceptable salt thereof, in the manufacture of a medicament
for single
intravenous administration, for increasing life expectancy or reducing
mortality in a
group of mammals exposed to a source of an influenza virus, in each member of
the
group who presents clinical symptoms of infection.
In another aspect, the invention provides use of a compound of formula I or a
pharmaceutically acceptable salt thereof, or such compound for use, for
increasing life
expectancy or reducing mortality in a group of mammals exposed to a source of
an
influenza virus, wherein the compound is formulated for single intravenous
administration, in each member of the group who presents clinical symptoms of
infection.
In another aspect, the invention provides use of a compound of formula I or a
pharmaceutically acceptable salt thereof, in the manufacture of a medicament
for single
intravenous administration, for increasing life expectancy or reducing
mortality in a
group of mammals exposed to a source of an influenza virus, in each member of
the
group.
In another aspect, the invention provides use of a compound of formula I or a
pharmaceutically acceptable salt thereof, or such compound for use, for
increasing life
expectancy or reducing mortality in a group of mammals exposed to a source of
an
3
CA 02642260 2015-12-11
,
influenza virus, wherein the compound is formulated for single intravenous
administration, in each member of the group.
In another aspect, the invention provides use of a compound of formula I or a
pharmaceutically acceptable salt thereof, in the manufacture of a medicament
for single
intravenous administration, for achieving a plasma concentration of the
compound in a
human that is effective to treat a virus.
In another aspect, the invention provides a unit dosage form for a single
intravenous administration to a human, comprising up to 800 mg of a compound
of
formula I or a pharmaceutically acceptable salt thereof.
In another aspect, the invention provides a kit, comprising packaging
materials, a
compound of formula I or a pharmaceutically acceptable salt thereof, and
instructions for
administering the compound to a human by a single administration via an
intravenous
route, wherein the compound is provided in a formulation for intravenous
administration.
In another aspect, the invention provides use of a compound of formula I or a
pharmaceutically acceptable salt thereof, in an effective anti-viral amount,
for treatment
of a viral infection in a human, wherein the compound is formulated for single
intravenous administration per day over the course of treatment.
3a
CA 02642260 2015-06-19
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.
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 etal., (2001)). Unfortunately,
clinical trials
using this drug showed an inadequate 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 herein
indicates that a
single treatment of peramivir given i.v. will protect mice infected with an
influenza virus.
3b
CA 02642260 2008-08-12
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:
NH = = r- H2N NH
' HN HN
111 = CO2H CO2H
NHCOCH3 OH NHCOCH3 OH
(I) =
HN = HN
CO2H CO2H
NHCOCH3 NHCOCH3
(III) (IV),
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, Ma, or Wa:
H2N.`r NH NH
.000O2H 0,0,µµCO2H
NHCOCH3 OH NHCOCH3 OH
(Ia) (Ha)
Hrt
= ,,,,,,,,,,,,
..0,00O2H
=
NHCOCH3 NHCOCH3
(Ma) (IVa),
4
CA 02642260 2008-08-12
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
virus represented by the formula HõNy 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. hi certain embodiments, the effective anti-viral amount is up to about 400
mg. In certain embodiments, the effective anti-viral amount is up to about 300
rug. 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
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 IC50 of the virus causing the viral infection 12 hours
following
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:
H2N
H2N
HN HN =
.2.
=
NHCOCH3 OH NHCOCH3 OH
(I) (11)
=
5
CA 02642260 2008-08-12
WO 2007/095218
PCT/US2007/003755
H2N =
NH H2N\r.NH
HN HN
41, co,. .02.
NHCOCH3 NHCOCH3
(III) (V),
or a pharmaceutically acceptable salt thereof, to the human by an intravenous
route. =
In certain embodiments, the compound of formula I, II, HI, or IV is a
compound of formula Ia, Ha, Ina, or Na:
H,N
NH
.00,402H
CO2H
NHCOCH3 OH NHCOCH3 OH
(Ia) (Ha)
H2N
µCO2H ssoCO2H
NHCO'CH3 NHCOCH3
(Ma) (IVa),
or a pharmaceutically acceptable salt thereof.
In certain embodiments, the effective inhibitory amount is up to about
800 mg. In certain embodiments, the effective inhibitory amount is up to about
400 mg. In certain embodiments, the effective inhibitory amount is up to about
300 mg. In certain embodiments, the effective inhibitory amount is up to about
200 mg.
In certain embodiments, the entire effective inhibitory dose is
administered in one intravenous administration. In certain embodiments, the
6
CA 02642260 2008-08-12
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.
-
=
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 oseltarnivir carboxylate.
In certain embodiments, the neuraminidase inhibitor that is administered
orally is a compound of formula I, H, III, or IV:
Hats' NH 112N\ NH
HN UN
No, .02.
NHCOCH3 OH NHCOCH3 OH
(II)
H2N
UN HN
CO2H CO2H
NHCOC H3 NH000H3
= am (IV),
or a pharmaceutically acceptable salt thereof.
In certain embodiments, the neuraminidase inhibitor that is administered
orally is a compound of formula Ia, Ha, Ma, or IVa:
H2N = H2NNN
= 000O211
CO,H
NHCOC H3 OH NHCOCH3 OH
(Ia) =(Ha)
7
CA 02642260 2008-08-12
WO 2007/095218 PCT/US2007/003755
=
=
H2N\r.t1H
=
HN_
= ,,,,,,
\ CO211
NHCOCH3 NHCO CH3
(Ma) (IVa),
= or a pharmaceutically acceptable salt thereof.
In certain embodiments, the neuraminidase inhibitor that is administered
=
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
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:
H3N H2N'r.NH
HN HN
CO2H = CO2H
NHCOCH3 OH NHCOCH3 OH
H2N
-
HN HN
CO2H CO2H
NHCOCH3 NHCOCH3
(III) (IV),
or a pharmaceutically acceptable salt thereof.
In certain embodiments, the compound of formula I, II, III, or IV is a
compound of formula Ia, Ha, Ma, or IVa:
=
8
CA 02642260 2008-08-12
WO 2007/095218
PCT/US2007/003755
H2ni
NH H2N
NCO2H \CO2H
NHCOCH3 OH NHCOCH3 OH
(Ia) (Ha).
H2N=====,,,NH
HN
00O2H 00O2H
=
NHCOCH3 NHCOCH3
(IIIa) (1Va),
or a pharmaceutically acceptable salt thereof.
In certain embodiments, the unit dosage form comprises up to about 400
mg of the compound or salt. In certain embodiments, the unit dosage form
comprises up to about 300 mg of the compound or salt. In certain embodiments,
the unit dosage form comprises up to about 200 mg of the compound or salt.
Certain embodiments of the present invention provide a kit, comprising
packaging materials, a compound of formula I, II, III, or IV:
=
NH
HN HN
C 02H = CO2H
NHCOC H3 OH NHCOCH3 OH
(I) (II)
H2N H2N
NH
HN HN
400 CO2H CO2H
=
NHCOCH3 NHCOCH3
(III) (IV),
9
CA 02642260 2008-08-12
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.
In certain embodiments, the kit comprises up to .about 800 mg of the
=
compound or salt. In certain embodiments, the kit comprises up to about 400 mg
=
of the compound or salt. In certain embodiments, the kit comprises up to about
300 mg of the compound or salt. In certain embodiments, the kit comprises up
to about 200 mg of the compound or salt.
Certain embodiments of the present invention provide a kit comprising
packaging materials, a unit dosage form as described herein, and instructions
for
administering the compound to a human by an intravenous route.
Certain embodiments of the present invention provide a use of a
compound of formula I, II, III, or IV:
HzNNH
RN * CO2H
NHCOCH3 OH NHCO CH3 OH
=
(I)
H2N
H2NNH
.,
HNRN
CO2H * COaH
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 sourbe of an influenza virus, by
intravenous injection of a dose of the medicament into each member of the
group
presenting clinical symptoms of infection.
=
CA 02642260 2008-08-12
WO 2007/095218 PCT/US2007/003755
In certain embodiments, the compound of formula I, II, III, or IV is a
compound of formula Ia, Ha, Ma, or IVa:
H,N 1-1,N
- -
MN,
µCO2H osACO2H
NHCOCH3 OH NHCOCH3 OH
=
(Ia) (Ha)
1-12N
HN" HN,
NµCO2H = ..so.0O2H
NHCO1H3 NHCOCH3
(Ma) (rVa),
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
represented by the formula HõNy 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
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
certain embodiments, the neurarninidase inhibitor is a compound of formula I,
II,
III, or IV:
11 =
=
CA 02642260 2008-08-12
WO 2007/095218
PCT/US2007/003755
HN HN
CO2H * CO2H
=
NHCOCH3 OH NH000H3 OH
(I) (II)
H2N NH H2N \rN1-1
HN HN
lop coõ
NH000H3 NHCOCH3
= (111)
(V),
or a pharmaceutically acceptable salt thereof. In certain embodiments, the
neuraminidase inhibitor is a compound of formula Ia, Ha, Ma, or IVa:
= H2N
=
frt..
1;
NHCO CH3 OH NHCO CH3 OH
(Ia) (Ha)
Hztki***.r. NH
H
µµCO2H , so\
CO2H
NHCO.CH3 NHCOCH3
= (Ina)
(IVa),
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 =
CA 02642260 2008-08-12
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.
Certain embodiments of the present=invention provide a use of a
compound of formula I, II, III, or IV:
H2N 'sr NH
HN HN
10, CO2H
CO2H
NHCOCH3 OH NHCOCH3 OH
(II)
H2NNH t4H
MN HN
11110 CO2H CO2H
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.
In certain embodiments, the compound of formula I, II, III, or IV is a
compound of formula Ia, IIa, Ma, or TVa:
H2N
H2
00O2H
02H
NHCOCH3 OH NHCOCH3 OH
(la) = (Ha)
13 =
CA 02642260 2008-08-12
WO 2007/095218 PCT/US2007/003755
=
H2 NH
.,,ACO2H
,NCO2H
NHC07.'CH3 NHCO CH3
.(IIIa) (IVa),
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 HõNy wherein X is an integer from 1-16 and Y is an
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,
H1N1, 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
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 neurarninidase
inhibitor
is oseltamivir carboxylate. In certain embodiments, the neuraminidase
inhibitor
is a compound of formula I, II, III, or IV:
=
H2N
NH
HN 14N
ecop = .2.
NHCOCH3 OH NHCOCH3 OH
(I) (II)
=
= 14
CA 02642260 2008-08-12
WO 2007/095218 PCT/US2007/003755
NH
HN HN
CO2H CO2H
NHCOCH3 NHCOCH3
=
(III) (IV),
or a pharmaceutically acceptable salt thereof. In certain embodiments, the
neuraminidase inhibitor is a compound of formula Ia, Ha, Ina, or IVa:
H N H-3N
2 \
HN, HN,
0402H ..000O2H
NHCOCH3 OH NHCOCH3 OH
(Ia) (Ha)
H2N***N.NH
Hrst.., Wk.
.0ACO2H 0µµCO2H
NHCOCH3 NHCOCH3
(Ina) (IVa),
or a pharmaceutically acceptable salt thereof. In certain embodiments, the
neuraminidase inhibitor is a compound of formula Ia, or a pharmaceutically
acceptable salt thereof.
In certain embodiments, the source of the virus is an infected bird. In
certain embodiments, the source of the virus is a mammal presenting symptoms
of infection.
In certain embodiments, the use is for reducing mortality.
Certain embodiments of the present invention provide a use of a
compound of formula I, II, III, or IV:
CA 02642260 2008-08-12
WO 2007/095218
PCT/US2007/003755
=
Ha
= r`i-NrNH
= HN HN
CO2H CO211
NHCOCH3 OH NHCOCH3 OH
HN HN
1111 CO2H CO2H
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.
Certain embodiments of the present invention provide a use of a
compound of formula I, II, III, or IV:
= H,N
-NH
HN HN
= CO2H CO2H
NHCOCH3 OH NHCOCH3 OH
(I) (II)
H N
2
HN HN
CO2H = CO2H
NHCOCH3 NHCOCH3
(III) (IV),
16
CA 02642260 2008-08-12
WO 2007/095218 PCT/US2007/003755
=
=
. NH = ' H2N NH
=
CO2H
=
NHCOCI-13 NHCoCH3
(Illa) (IVa),
or a pharmaceutically acceptable salt thereof.
A specific compound of formula I, II, III, or IV is (1S,2S,3R,4R)-3-(1-
Acetamido-2-ethylbuty1)-4-guanidino-2-hydroxycyclopentane-carboxylic acid;
(1S,2S,3R,4R)-3-(1-Acetamido-2-propylpenty1)-4-guanidino-2- =
hydroxycyclopentanecarboxylic acid; (1R,3R,4R)-3-(1-Acetamido-2-
propylpenty1)-4-guanidinocyclopentanecarboxylic acid; or (1R,3R,4R)-3-(1-
Acetamido-2-ethylbuty1)-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
one or more chiral centers may exist in and be isolated in optically active
and
racemic forms. Some compounds may exhibit polymorphism. It is to be
understood that the present invention encompasses the use of any racemic,
optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of
a
compound of formula I, II, III, or IV, which possess the useful properties
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
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
CA 02642260 2008-08-12
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.
In certain embodiments, the plasma concentration of the compound is =
=
higher than the IC50 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 iv. 1 hour pre-virus exposure with peramivir at doses of
20,
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
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
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, Ill, or IV is a compound of formula
Ia, IIa, Ma, or IVa:
112N-Nr.NH H2N"rNH
=
HNI,
= 0 soNCO2H
=CO H
NHCOCH3 OH NHCOCI-13 01-1
(Ia) (ha)
=
17 =
CA 02642260 2008-08-12
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.
= 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
made.
The compounds of formula I, II, III, 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.
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
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
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
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
CA 02642260 2008-08-12
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.
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,
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
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
(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
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
amount is administered in a single intravenous administration. In some
embodiments, the effective amount is administered in multiple administrations.
CA 02642260 2008-08-12
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 1,11, Ill, or IV is up to about 1,000 mg.
= In one embodiment of the invention, the effective inhibitory.amount of
the compound of formula I, H, III, or IV is up to about 800 mg.
In one embodiment of the invention, the effective inhibitory amount of
=
the compound of formula I, II, III, or IV is up to about 600 mg.
= -in one embodiment of the invention, the effective inhibitory,amount of
the compound of formula I, H, HI, or IV is up to about 500 mg.
In one embodiment of the invention, the effective inhibitory amount of
=
the compound Of formula I, II, III, or IV is up to about 400 mg.
In one embodiment of the invention, the effective inhibitory amount of
the compound of formula I, II, III, or IV is up to about 300 mg.
In one embodiment of the invention, the effective inhibitory amount of
= the compound of formula 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
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, H, HI, or IV is administered once to a
human intravenously. In another embodiment of the invention, a neuraminidase
= 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
CA 02642260 2008-08-12
PCT/US2007/003755
WO 2007/095218
020 NH
=
= HP
HN HN
CO2H
CO2H
NHCOCH3 OH NHC9CH3 OH
=(I) = = = (II)
= NH H2N..Nr NH
HN HN
= CO2H
CO2H
NHCOCH3 NHCOCH3
(III) = . (IV),
=
or a pharmaceu' tically acceptable salt thereof. In one embodiment of the
invention, the neuraminidase inhibitor that is administered orally is a.
compound
= of formula Ia, Ila, lila, or IVa:
H2NN-...,NH
Hit
CO3H
.,0µµ
= NHCOCH3 OH NHCOC H3 OH
(Ia) (Ha)
NH 112N
HN
Htt.,
CO2H .00µCO2H
=
NHCO'C. H3
NHCOCH3
(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
CA 02642260 2014-09-03
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.
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
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. Further, as described
herein,
it has been unexpectedly discovered that intravenous and 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" 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
CA 02642260 2008-08-12
WO 2007/095218 PCT/US2007/003755
= =
Table 1
Ni N2 N3 N4 N5 ¨N6 N7 N8 N9
= H1 H1N1 H1N2 H1N3 H1N4 HIN5 H1N6 H1N7 H1N8 H1N9
. _
H2 H2N1 H2N2 H2N3 H2N4 H2N5 H2N6 H2N7 H2N8 H2N9
H3 H3N1 - H3N2 1-13N3 H3N4. H3N5 H3N6 H3N7 H3N8 H3N9 .
= = H4 H4N1 H4N2 H4N3 H4N4 H4N5 H4N6. H4.1\17 H4N8 H4N9 - =
= H5 H5N1 H5N2 H5N3 H5N4 H5N5 115N6 H5N7 H5N8 1-15N9
_
.
H6 H6N1 - H6N2 H6N3 H6N4 H6N5 H6N6 H6N7 H6N8 H6N9 =
H7 H7N1 H7N2 H7N3 H7N4 H7N5 H7N6 H7N7 H7N8 H7N9 =
H8 H8N1 H8N2 H8N3 H8N4 H8N5 H8N6 H8N7 H8N8 H8N9
H9 H9NI H9N2 1-19N3 H9N4 H9N5 119N6 H9N7 H9N8 H9N9 =
= H10 H1ON1 H1ON2 H1ON3 H1ON4 H1ON5 H1ON6 HION7 H1ON8 H1ON9
_
H11 Hi 1N1 HI1N2 H11N3 HI 1N4 H11N5 H11N6 1-111N7 H11N8 HI1N9
H12 H12N1 - H12N2 H12N3 H12N4 H12N5 = H12N6 H12N7 H12N8 H12N9
H13 1113N1 H13N2 H13N3 HI3N4 H13N5 HI 3N6 H13N7 1-113N8 H13N9
H14 H14N1 H14N2 H14N3 H14N4 H14N5 H14N6 H14N7 H14N8 H14N9
H15 H15N1 H1 5N2 H15N3 H15N4 H15N5 H15N6 H15N7 HI5N8 H15N9
1116 H16N1 H16N2 H16N3 H16N4 H16N5 H16N6 1-116N7 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
forms of the avian virus.
Certain embodiments of the present invention provide the use of a
compound of formula I, 11, 111, or IV:
H2N 112N NH
PINHN
= ..2.=
NHCOCH3 OH NHCOCH 3 OH
=
(II)
24
CA 02642260 2008-08-12
WO 2007/095218 PCT/US2007/003755
H2N
=
= I-IN HN
=
CO2H . 1110, CO2H
=
NHCOCH3NHCOCH3 .
=
(111) (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 compouhd that is effective to treat a virus by intravenous
injection
of a dose of the medicament into the human.
=
Certain embodiments of the present invention also provide the use of a
compound of formula 1, II, HI, or IV:
' 10
H2N"NH
HN HN
= CO2H CO2H
NHCOCH3 OH NHCOCH3 OH
(I) (1)
=
NH = H2N
FIN = HN
CO2H CO2H
NHCOCH3NHC0CH3
=
(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 compound that is effective to treat a virus by intramuscular
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
=
CA 02642260 2008-08-12
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
comprising peramivir formulated for intramuscular administration to a human.
Certain embodiments of the invention also provide compositions comprising
peramivir formulated for intramuscular administration for use in treating a
virus
by achieving a plasma concentration in a human of peramivir that is effective
to =
treat the virus.
In certain embodiments of the invention, the plasma concentration of the
compound is higher than the 1050 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 IC50 of the virus at least about 24 hoprs
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 36 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 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. =
In certain embodiments of the invention, the plasma concentration of the
compound is higher than the IC50 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
certain embodiments of the invention, the virus is H5N1, or a mutant strain
thereof,
=
26
=
CA 02642260 2008-08-12
WO 2007/095218
PCT/US2007/003755
= The invention will now be illustrated by the following non-limiting
=
Examples.
Example I. Effect of IV Treatment with Peramivir on Influenza A Virus.
=
5. Infection
Experiment Design: Mice were infected th. 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 i.V. in parallel with the above to 20
infected
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
treatment. Five normal controls were weighed.
=
. .
=
=
27 =
CA 02642260 2008-08-12
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
Treatment (mg/kg) Total Total SD
Peramivir 20 . 3/3 10/10** >21.0
=
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 Well tolerated in this experiment.
These data indicate that peramivir is a significant influenza inhibitor
when used in a single i.v. injection.
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 =
CA 02642260 2014-09-03
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.
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 IC50 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 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
peramivir are higher than the IC50 values for all the influenza virus strains
tested.
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.
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
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 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
CA 02642260 2008-08-12
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
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.
=
