NZ620421B2 - Tenofovir alafenamide hemifumarate - Google Patents
Tenofovir alafenamide hemifumarate Download PDFInfo
- Publication number
- NZ620421B2 NZ620421B2 NZ620421A NZ62042112A NZ620421B2 NZ 620421 B2 NZ620421 B2 NZ 620421B2 NZ 620421 A NZ620421 A NZ 620421A NZ 62042112 A NZ62042112 A NZ 62042112A NZ 620421 B2 NZ620421 B2 NZ 620421B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- composition
- tenofovir alafenamide
- hiv
- hemifumarate
- inhibitors
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
Abstract
The disclosure relates to a hemifumaiate form of 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine (tenofovir alafenamide), and antiviral therapy using tenofovir alafenamide hemifurnarate (e.g., anti-HTV and anti-HBV therapies). Formula (I). Also disclosed are compositions comprising the salt form, along with its characterisation. ed are compositions comprising the salt form, along with its characterisation.
Description
TITLE
TENOFOVIR ALAFENAMIDE HEMIFUMARATE
Cross-reference to Related Applications
This application claims the benefit of priority from U.S. Provisional
Patent Application No. 61/524,224, filed August 16, 2011, the content of which is
hereby incorporated by reference herein in its entirety.
BACKGROUND OF THE INVENTION
Description of Related Art
U.S. Patent Nos. 7,390,791 and 7,803,788 (the content of each of which
is incorporated by reference herein in its entirety) describe certain prodrugs of
phosphonate nucleotide analogs that are useful in therapy. One such prodrug is
9-[(R)[[(S)-[[(S)
(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine.
This compound is also known by the Chemical Abstract name L-alanine, N-[(S)-
[[(1R)(6-amino-9H-puriny1)methylethoxy]methyl]phenoxyphosphinyl]-,
1-methylethyl ester. U.S. Patent Nos. 7,390,791 and 7,803,788 also disclose a
monofumarate form of this compound and its preparation method (see, e.g.,
Example 4).
SUMMARY OF THE INVENTION
Described is a hemifumarate form of 9-[(R)[[(S)-[[(S)
(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine.
The name for 9-[(R)[[(S)-[[(S)
(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine
is tenofovir alafenamide. The hemifumarate form of tenofovir alafenamide is
also referred to herein as tenofovir alafenamide hemifumarate.
In one embodiment the invention provides tenofovir alafenamide
hemifumarate.
In another embodiment the invention provides a composition comprising
tenofovir alafenamide hemifumarate, wherein the ratio of fumaric acid to
tenofovir alafenamide in said composition is 0.5 ± 0.1, or 0.5 ± 0.05, or 0.5 ±
0.01, or about 0.5.
In one embodiment tenofovir alafenamide hemifumarate is in a solid
form.
In one embodiment the invention provides tenofovir alafenamide
hemifumarate that has an X-ray powder diffraction (XRPD) pattern having 2theta
values of 6.9 ± 0.2° and 8.6 ± 0.2°. In another embodiment tenofovir
alafenamide hemifumarate has an XRPD pattern comprising 2theta values of 6.9
± 0.2°, 8.6 ± 0.2°, 11.0 ± 0.2°, 15.9 ± 0.2°, and 20.2 ± 0.2°.
In one embodiment tenofovir alafenamide hemifumarate has a differential
scanning calorimetry (DSC) onset endotherm of 131 ± 2 °C, or 131 ± 1 °C.
In one embodiment the invention provides a pharmaceutical composition
comprising tenofovir alafenamide hemifumarate and a pharmaceutically
acceptable excipient. Another embodiment provides the pharmaceutical
composition, further comprising an additional therapeutic agent. In a further
embodiment, the additional therapeutic agent is selected from the group
consisting of human immunodeficiency virus (HIV) protease inhibiting
compounds, HIV nonnucleoside inhibitors of reverse transcriptase, HIV
nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of
reverse transcriptase, HIV integrase inhibitors, and CCR5 inhibitors.
Described herein is a method for treating a human immunodeficiency
virus (HIV) infection comprising administering to a subject in need thereof a
therapeutically effective amount of tenofovir alafenamide hemifumarate. Also
described is a method for treating an HIV infection comprising administering to a
subject in need thereof a therapeutically effective amount of a pharmaceutical
composition comprising tenofovir alafenamide hemifumarate. The method
comprises administering to the subject one or more additional therapeutic agents
selected from the group consisting of HIV protease inhibiting compounds, HIV
nonnucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of
reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV
integrase inhibitors, and CCR5 inhibitors.
Also described is a method for treating a hepatitis B virus (HBV)
infection comprising administering to a subject in need thereof a therapeutically
effective amount of tenofovir alafenamide hemifumarate. Also described is a
method for treating an HBV infection comprising administering to a subject in
need thereof a therapeutically effective amount of the pharmaceutical
composition comprising tenofovir alafenamide hemifumarate.
In one embodiment the invention provides a method for preparing a
pharmaceutical composition comprising combining tenofovir alafenamide
hemifumarate and a pharmaceutically acceptable excipient to provide the
pharmaceutical composition.
In one embodiment the invention provides a method for preparing
tenofovir alafenamide hemifumarate comprising subjecting a solution comprising
a suitable solvent; fumaric acid; tenofovir alafenamide; and, optionally, one or
more seeds of tenofovir alafenamide hemifumarate to conditions that provide for
the crystallization of the fumaric acid and the tenofovir alafenamide. In one
embodiment, the solvent comprises acetonitrile. In another embodiment, the
solution is subjected to a temperature in the range of from about 0 °C to
about 75 °C.
In one embodiment the invention provides tenofovir alafenamide
hemifumarate for use in medical therapy.
Described herein is the use of tenofovir alafenamide hemifumarate for the
prophylactic or therapeutic treatment of an HIV infection. Also described is the
use of tenofovir alafenamide hemifumarate to treat an HIV infection. In one
embodiment the invention provides the use of tenofovir alafenamide
hemifumarate for the preparation or manufacture of a medicament for the
treatment of an HIV infection. In another further embodiment the invention
provides tenofovir alafenamide hemifumarate for use in treating an
HIV infection.
Described herein is the use of tenofovir alafenamide hemifumarate for the
prophylactic or therapeutic treatment of an HBV infection. Also described is the
use of tenofovir alafenamide hemifumarate to treat an HBV infection. In one
embodiment the invention provides the use of tenofovir alafenamide
hemifumarate for the preparation or manufacture of a medicament for the
treatment of an HBV infection. In another further embodiment the invention
provides tenofovir alafenamide hemifumarate for use in treating an
HBV infection.
In some embodiments, the methods of treating and the like comprise
administration of multiple daily doses. In other embodiments, the methods of
treating and the like comprise administration of a single daily dose.
In one embodiment the invention provides a composition consisting
essentially of tenofovir alafenamide hemifumarate.
[0018a] The invention also provides a composition consisting essentially of
tenofovir alafenamide hemifumarate having an XRPD pattern that comprises
2theta values of 6.9 ± 0.2° and 8.6 ± 0.2°.
[0018b] The invention also provides pharmaceutical compositions and uses in
medical therapy as set out above, of such compositions consisting essentially of
tenofovir alafenamide.
[0018c] The invention also provides a method for preparing tenofovir alafenamide
hemifumarate comprising the steps of admixing a) aprotic organic solvent; b)
fumaric acid; c) tenofovir alafenamide; and d) one or more seeds of tenofovir
alafenamide hemifumarate; and crystallizing additional tenofovir alafenamide
hemifumarate.
[0018d] The invention also provides a method for preparing tenofovir alafenamide
hemifumarate comprising the steps of: admixing a) a solvent comprising water,
isopropyl alcohol, acetone, acetonitrile, toluene, ethyl acetate, isopropyl acetate,
heptane, tetrahydrofuran, 2-methyl tetrahydrofuran, methyl ethyl ketone, methyl
isobutyl ketone or mixtures thereof; b) fumaric acid; c) tenofovir alafenamide; and
d) one or more seeds of tenofovir alafenamide hemifumarate; and crystallizing
additional tenofovir alafenamide hemifumarate at a temperature from about 0 °C to
about 70 °C.
[0018e] The term 'comprising' as used in this specification and claims means
'consisting at least in part of'. When interpreting statements in this specification
and claims which include the term 'comprising', other features besides the features
prefaced by this term in each statement can also be present. Related terms such as
'comprise' and 'comprised' are to be interpreted in similar manner.
[0018f] In this specification where reference has been made to patent
specifications, other external documents, or other sources of information, this is
generally for the purpose of providing a context for discussing the features of the
invention. Unless specifically stated otherwise, reference to such external
documents is not to be construed as an admission that such documents, or such
sources of information, in any jurisdiction, are prior art, or form part of the
common general knowledge in the art.
[0018g] In the description in this specification reference may be made to subject
matter that is not within the scope of the claims of the current application. That
subject matter should be readily identifiable by a person skilled in the art and may
assist in putting into practice the invention as defined in the claims of this
application.
BRIEF DESCRIPTIONS OF THE DRAWINGS
shows the X-ray powder diffraction (XRPD) pattern of tenofovir
alafenamide hemifumarate.
shows a graph of the DSC analysis of tenofovir alafenamide
hemifumarate.
shows a graph of the thermogravimetric analysis (TGA) data
for tenofovir alafenamide hemifumarate.
shows a graph of the dynamic vapor sorption (DVS) analysis
of tenofovir alafenamide hemifumarate.
DETAILED DESCRIPTION OF THE INVENTION
Specific values listed within the present description 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.
In one embodiment, there is provided a hemifumarate form of tenofovir
alafenamide (i.e., tenofovir alafenamide hemifumarate). In another embodiment,
the invention provides a composition comprising tenofovir alafenamide
hemifumarate wherein the ratio (i.e., a stoichiometric ratio or mole ratio) of
fumaric acid to tenofovir alafenamide of 0.5 ± 0.1, 0.5 ± 0.05, 0.5 ± 0.01, or
about 0.5, or the like.
In one embodiment, the composition consists of fumaric acid and
tenofovir alafenamide in a ratio of 0.5 ± 0.1.
In one embodiment, the composition consists essentially of fumaric acid
and tenofovir alafenamide in a ratio of 0.5 ± 0.1.
In one embodiment, tenofovir alafenamide hemifumarate has an XRPD
pattern comprising 2theta values of 6.9 ± 0.2°, 8.6 ± 0.2°, 10.0 ± 0.2°,
11.0 ± 0.2°, 12.2 ± 0.2°, 15.9 ± 0.2°, 16.3 ± 0.2°, 20.2 ± 0.2°, and 20.8 ± 0.2°.
In one embodiment, tenofovir alafenamide hemifumarate has an XRPD
pattern comprising at least four 2theta values selected from 6.9 ± 0.2°, 8.6 ± 0.2°,
.0 ± 0.2°, 11.0 ± 0.2°, 12.2 ± 0.2°, 15.9 ± 0.2°, 16.3 ± 0.2°, 20.2 ± 0.2°, and
.8 ± 0.2°.
In one embodiment, tenofovir alafenamide hemifumarate has a DSC
onset endotherm of 131 ± 2 °C, or 131 ± 1 °C.
In one embodiment, a tenofovir alafenamide hemifumarate composition
comprises less than about 5% by weight of tenofovir alafenamide monofumarate.
In one embodiment, a tenofovir alafenamide hemifumarate composition
comprises less than about 1% by weight of tenofovir alafenamide monofumarate.
In one embodiment, a tenofovir alafenamide hemifumarate composition
comprises less than about 0.5% by weight of tenofovir alafenamide
monofumarate.
In one embodiment, a tenofovir alafenamide hemifumarate composition
comprises no detectable tenofovir alafenamide monofumarate.
Tenofovir alafenamide (i.e., the compound 9-[(R)[[(S)-[[(S)
(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine)
can be prepared as described in U.S. Patent No. 7,390,791.
Selective Crystallization
In one embodiment, tenofovir alafenamide hemifumarate can be prepared
using selective crystallization. An example of a scheme for this preparation
method is as follows.
N OH
P OP h
P Ph
CH O
The method can be carried out by subjecting a solution comprising: a) a
suitable solvent; b) fumaric acid; c) tenofovir alafenamide; and, optionally, d) one
or more seeds comprising tenofovir alafenamide hemifumarate, to conditions that
provide for the crystallization of fumaric acid and tenofovir alafenamide. The
starting solution can contain the single diastereomer of tenofovir alafenamide or a
mixture of tenofovir alafenamide and one or more of its other diastereomers (e.g.,
GS-7339, as described in U.S. Patent No. 7,390,791).
The selective crystallization can be carried out in any suitable solvent.
For example, it can be carried out in a protic solvent or in an aprotic organic
solvent, or in a mixture thereof. In one embodiment, the solvent comprises a
protic solvent (e.g., water or isopropyl alcohol). In another embodiment, the
solvent comprises an aprotic organic solvent (e.g., acetone, acetonitrile (ACN),
toluene, ethyl acetate, isopropyl acetate, heptane, tetrahydrofuran (THF),
2-methyl THF, methyl ethyl ketone, or methyl isobutyl ketone, or a mixture
thereof). In one embodiment, the solvent comprises ACN or a mixture of ACN
and up to about 50% methylene chloride (by volume). The selective
crystallization also can be carried out at any suitable temperature, for example, a
temperature in the range of from about 0 °C to about 70 °C. In one specific
embodiment, the resolution is carried out at a temperature of about 0 °C.
One major advantage of the hemifumarate form of tenofovir alafenamide
over the monofumarate form is its exceptional capability to purge GS-7339
(i.e., 9-[(R)[[(R)-[[(S)
(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine;
described in, e.g., U.S. Patent No. 7,390,791), which is the major diastereomeric
impurity in the active pharmaceutical ingredient. Thus, the hemifumarate form of
tenofovir alafenamide can be more readily and easily separated from impurities
than the monofumarate form. Other major advantages of tenofovir alafenamide
hemifumarate over the monofumarate form include improved thermodynamic
and chemical stability (including long-term storage stability), superior process
reproducibility, superior drug product content uniformity, and a higher
melting point.
Tenofovir alafenamide hemifumarate is useful in the treatment and/or
prophylaxis of one or more viral infections in man or animals, including
infections caused by DNA viruses. RNA viruses, herpesviruses (e.g., CMV,
HSV 1, HSV 2, VZV), retroviruses, hepadnaviruses (e.g., HBV), papillomavirus,
hantavirus, adenoviruses and HIV. U.S. Patent No. 6,043,230 (incorporated by
reference herein in its entirety) and other publications describe the antiviral
specificity of nucleotide analogs, such as tenofovir disoproxil. Like tenofovir
disoproxil, tenofovir alafenamide is another prodrug form of tenofovir, and can
be used in the treatment and/or prophylaxis of the same conditions.
Tenofovir alafenamide hemifumarate can be administered by any route
appropriate to the condition to be treated. Suitable routes include oral, rectal,
nasal, topical (including ocular, buccal, and sublingual), vaginal, and parenteral
(including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and
epidural). Generally, tenofovir alafenamide hemifumarate is administered orally,
but it can be administered by any of the other routes noted herein.
Accordingly, pharmaceutical compositions include those suitable for
topical or systemic administration, including oral, rectal, nasal, buccal,
sublingual, vaginal, or parenteral (including subcutaneous, intramuscular,
intravenous, intradermal, intrathecal, and epidural) administration. The
formulations are in unit dosage form and are prepared by any of the methods well
known in the art of pharmacy.
For oral therapeutic administration, the tenofovir alafenamide
hemifumarate may be combined with one or more excipients and used in the form
of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups,
wafers, and the like. Such pharmaceutical compositions and preparations will
typically contain at least 0.1% of tenofovir alafenamide hemifumarate. The
percentage of this active compound in the compositions and preparations may, of
course, be varied and may conveniently be between about 2% to about 60% or
more of the weight of a given unit dosage form. The amount of active compound
in such therapeutically useful pharmaceutical compositions is preferably such that
an effective dosage level will be obtained upon administration of a single-unit
dosage (e.g., tablet). Other dosage formulations may provide therapeutically
effective amounts of tenofovir alafenamide hemifumarate upon repeated
administration of subclinically effective amounts of the same. Preferred unit
dosage formulations include those containing a daily dose (e.g., a single daily
dose), as well as those containing a unit daily subclinical dose, or an appropriate
fraction thereof (e.g., multiple daily doses), of tenofovir alafenamide
hemifumarate.
Pharmaceutical compositions suitable for oral administration may be
presented as discrete units such as capsules, cachets, or tablets, each containing a
predetermined amount of tenofovir alafenamide hemifumarate; as a powder or
granules; as a solution or a suspension in an aqueous liquid or a nonaqueous
liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
Tenofovir alafenamide hemifumarate may also be presented as a bolus, electuary,
or paste.
Tenofovir alafenamide hemifumarate is preferably administered as part of
a pharmaceutical composition or formulation. Such pharmaceutical composition
or formulation comprises tenofovir alafenamide hemifumarate together with one
or more pharmaceutically acceptable carriers / excipients, and optionally other
therapeutic ingredients. The excipient(s) / carrier(s) must be “acceptable” in the
sense of being compatible with the other ingredients of the formulation and not
deleterious to the patient. Excipients include, but are not limited to, substances
that can serve as a vehicle or medium for tenofovir alafenamide hemifumarate
(e.g., a diluent carrier). They may be enclosed in hard or soft shell gelatin
capsules, may be compressed into tablets, or may be incorporated directly with
the food of the patient’s diet.
Accordingly, the tablets, troches, pills, capsules, and the like may also
contain, without limitation, the following: a binder(s), such as hydroxypropyl
cellulose, povidone, or hydroxypropyl methylcellulose; a filler(s), such as
microcrystalline cellulose, pregelatinized starch, starch, mannitol, or lactose
monohydrate; a disintegrating agent(s), such as croscarmellose sodium, cross-
linked povidone, or sodium starch glycolate; a lubricant(s), such as magnesium
stearate, stearic acid, or other metallic stearates; a sweetening agent(s), such as
sucrose, fructose, lactose, or aspartame; and/or a flavoring agent(s), such as
peppermint, oil of wintergreen, or a cherry flavoring. When the unit dosage form
is a capsule, it may contain, in addition to materials of the above types, a liquid
carrier, such as a vegetable oil or a polyethylene glycol. Various other materials
may be present as coatings or to otherwise modify the physical form of the solid
unit dosage form. For instance, tablets, pills, or capsules may be coated with
gelatin, polymers, wax, shellac, or sugar and the like. Of course, any material
used in preparing any unit dosage form typically will be pharmaceutically
acceptable and substantially nontoxic in the amounts employed. In addition,
tenofovir alafenamide hemifumarate may be incorporated into sustained-release
preparations and devices.
For infections of the eye or other external tissues, e.g., mouth and skin,
the pharmaceutical compositions are preferably applied as a topical ointment or
cream containing tenofovir alafenamide hemifumarate in an amount of, for
example, 0.01 to 10% w/w (including active ingredient in a range between 0.1%
and 5% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.),
preferably 0.2 to 3% w/w and most preferably 0.5 to 2% w/w. When formulated
in an ointment, the active ingredient may be employed with either a paraffinic or
a water-miscible ointment base. Alternatively, the active ingredient may be
formulated in a cream with an oil-in-water cream base.
Pharmaceutical compositions suitable for topical administration in the
mouth include lozenges comprising tenofovir alafenamide hemifumarate in a
flavored basis, for example, sucrose and acacia or tragacanth; pastilles
comprising the active ingredient in an inert basis such as gelatin and glycerin, or
sucrose and acacia; and mouthwashes comprising the active ingredient in a
suitable liquid carrier.
Formulations for rectal administration may be presented as a suppository
with a suitable base comprising, for example, cocoa butter or a salicylate.
Pharmaceutical formulations suitable for parenteral administration are
sterile and include aqueous and nonaqueous injection solutions that may contain
antioxidants, buffers, bacteriostats, and solutes that render the formulation
isotonic with the blood of the intended recipient; and aqueous and nonaqueous
sterile suspensions that may include suspending agents and thickening agents.
The formulations may be presented in unit-dose or multi-dose containers, for
example, sealed ampoules and vials with elastomeric stoppers, and may be stored
in a freeze-dried (lyophilized) condition requiring only the addition of the sterile
liquid carrier (e.g., water for injections) immediately prior to use. Injection
solutions and suspensions may be prepared from sterile powders, granules, and
tablets of the kind previously described.
In addition to the ingredients particularly mentioned above, the
pharmaceutical compositions / formulations may include other ingredients
conventional in the art, having regard to the type of formulation in question.
In another embodiment, there is provided veterinary compositions
comprising tenofovir alafenamide hemifumarate together with a veterinary carrier
therefor. Veterinary carriers are materials useful for the purpose of administering
the composition to cats, dogs, horses, rabbits, and other animals, and may be
solid, liquid, or gaseous materials that are otherwise inert or acceptable in the
veterinary art and are compatible with the active ingredient. These veterinary
compositions may be administered orally, parenterally, or by any other
desired route.
The tenofovir alafenamide hemifumarate can be used to provide
controlled release pharmaceutical formulations containing a matrix or absorbent
material and an active ingredient of the invention, in which the release of the
active ingredient can be controlled and regulated to allow less frequent dosing or
to improve the pharmacokinetic or toxicity profile of the compound. Controlled
release formulations adapted for oral administration, in which discrete units
comprising a compounds of the invention, can be prepared according to
conventional methods.
Useful dosages of tenofovir alafenamide hemifumarate can be determined
by comparing in vitro activities, and the in vivo activities in animal models.
Methods for the extrapolation of effective amounts / dosages in mice and other
animals to therapeutically effective amounts / dosages in humans are known
in the art.
The amount of tenofovir alafenamide hemifumarate required for use in
treatment will vary with several factors, including but not limited to the route of
administration, the nature of the condition being treated, and the age and
condition of the patient; ultimately, the amount administered will be at the
discretion of the attendant physician or clinician. The therapeutically effective
amount / dose of tenofovir alafenamide hemifumarate depends, at least, on the
nature of the condition being treated, any toxicity or drug interaction issues,
whether the compound is being used prophylactically (e.g., sometimes requiring
lower doses) or against an active disease or condition, the method of delivery,
and the pharmaceutical formulation, and will be determined by the clinician using
conventional dose escalation studies.
In one embodiment, the oral dose of tenofovir alafenamide hemifumarate
may be in the range from about 0.0001 to about 100 mg/kg body weight per day,
for example, from about 0.01 to about 10 mg/kg body weight per day, from about
0.01 to about 5 mg/kg body weight per day, from about 0.5 to about 50 mg/kg
body weight per day, from about 1 to about 30 mg/kg body weight per day, from
about 1.5 to about 10 mg/kg body weight per day, or from about 0.05 to about
0.5 mg/kg body weight per day. As a nonlimiting example, the daily candidate
dose for an adult human of about 70 kg body weight will range from about
0.1 mg to about 1000 mg, or from about 1 mg to about 1000 mg, or from about
mg to about 500 mg, or from about 1 mg to about 150 mg, or from about 5 mg
to about 150 mg, or from about 5 mg to about 100 mg, and may take the form of
single or multiple doses.
The pharmaceutical compositions described herein may further include
one or more therapeutic agents in addition to tenofovir alafenamide
hemifumarate. In one specific embodiment of the invention, the additional
therapeutic agent can be selected from the group consisting of HIV protease
inhibiting compounds, HIV nonnucleoside inhibitors of reverse transcriptase,
HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of
reverse transcriptase, HIV integrase inhibitors, and CCR5 inhibitors.
Therapeutic methods include administering tenofovir alafenamide
hemifumarate to a subject / patient in need of the same as a therapeutic or
preventative treatment. Thus, tenofovir alafenamide hemifumarate may be
administered to a subject / patient having a medical disorder or to a subject who
may acquire the disorder. One of ordinary skill will appreciate that such
treatment is given in order to ameliorate, prevent, delay, cure, and/or reduce the
severity of a symptom or set of symptoms of a disorder (including a recurring
disorder). The treatment may also be given to prolong the survival of a subject,
e.g., beyond the survival time expected in the absence of such treatment. The
medical disorders that may be treated with tenofovir alafenamide hemifumarate
include those discussed herein, including without limitation, HIV infection and
HBV infection.
The following are nonlimiting, illustrative Examples.
Example 1
Tenofovir alafenamide monofumarate solids (5.0 g) and 9-[(R)[[(R)-
[[(S)
(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine
(GS-7339) monofumarate solids (0.75 g) were charged into 35 g MTBE at 22 °C
and the mixture was stirred for 1 hour. A slurry was formed and was dried in a
rotary evaporator. 58 g acetonitrile (ACN) was charged into the solids and the
mixture was heated to reflux to dissolve the solids. The resulting solution was
allowed to cool naturally while agitated. A slurry was formed, and the slurry was
further cooled by ice-water-bath. The solids were isolated by filtration and
washed with 5 g ACN. The solids were dried in a vacuum oven at 40 °C
overnight. 5.52 g off-white solids were obtained. The solids were analyzed by
XRPD and found to contain tenofovir alafenamide monofumarate, GS-7339
monofumarate, and tenofovir alafenamide hemifumarate.
Example 2: Preparation of Tenofovir Alafenamide Hemifumarate via Selective
Crystallization
9-[(R)[[[[(S)
(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine
as a slurry in ACN (9.7 kg slurry, 13.8 wt%, a diastereomeric mixture of 1.0 kg
(2.10 mol, 1 mol equiv) of 9-[(R)[[(S)-[[(S)
(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine
and 0.35 kg of 9-[(R)[[(R)-[[(S)
(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine
was charged into a reactor and rinsed forward with dichloromethane (5 kg). The
mixture was concentrated under vacuum to about 3 L with jacket temperature
below 40 °C. The concentrate was then coevaporated with ACN (6 kg) under
vacuum to about 3 L with jacket temperature below 40 °C. The concentrate was
diluted with ACN (8.5 kg) and warmed to 40-46 °C. The warm mixture was
filtered into a second reactor and the filtrate was cooled to 19-25 °C.
To the above solution was charged fumaric acid (0.13 kg, 1.12 mol,
0.542 mole equiv) followed by ACN (1 kg), and the mixture was heated to
67-73 °C. The hot mixture was transferred into a reactor via a polishing filter,
and then adjusted to 54-60 °C. Seed crystals (5 g) of the hemifumarate form of
tenofovir alafenamide were charged (for example, the mixture can be seeded with
tenofovir alafenamide hemifumarate formed in Example 1 or a subsequent
production), and the resulting mixture was agitated at 54-60 °C for about
minutes. The mixture was cooled over a minimum of 4 hours to 0-6 °C, and
then agitated at 0-6 °C for a minimum of 1 hour. The resulting slurry was filtered
and rinsed with chilled (0-6 °C) ACN (2 kg). The product was dried under
vacuum below 45 °C until loss on drying (LOD) and organic volatile impurities
(OVI) limits were met (LOD ≤ 1.0%, dichloromethane content ≤ 0.19%,
acetonitrile content ≤ 0.19%) to afford the final compound of the hemifumarate
form of tenofovir alafenamide as a white to off-white powder (typical yield is
about 0.95 kg). H NMR (400 MHz, d6 DMSO): δ 1.06 (d, J = 5.6 Hz, 3H),
1.12-1.16 (m, 9H), 3.77 (dd, J = 10.4, 11.6 Hz, 1H), 3.84-3.90 (m, 2H), 3.94 (m,
1H), 4.14 (dd, J = 6.8, 14.8 Hz, 1H), 4.27 (m, 1H), 4.85 (heptet, J = 6.0 Hz, 1H),
.65 (t, J = 11.2 Hz, 1H), 6.63 (s, 1H), 7.05 (d. J = 7.6 Hz, 2H), 7.13 (t, J = 7.2
Hz, 1H), 7.24 (s, 2H), 7.29 (t, J = 7.6 Hz, 2H), 8.13 (t, J = 13.6 Hz, 2H),
P NMR (162 MHz, d6 DMSO): δ 23.3.
Example 3: Preparation of Tenofovir Alafenamide Hemifumarate
To a jacketed reactor equipped with overhead agitator, was charged
9-[(R)[[(S)-[[(S)
(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine
(10 g), fumaric acid (1.22 g), and ACN (100 mL). The mixture was heated to
70-75 °C to dissolve the solids. Any undissolved particulates were removed by
filtration through a cartridge filter. The filtered solution was cooled to 60-65 °C,
and seeded with 1% (by weight) of tenofovir alafenamide hemifumarate. The
slurry was aged for 30 minutes and cooled to 0-5 °C over 2 hours. The
temperature was maintained for 1-18 hours, and the resulting slurry was filtered
and washed with 2 ml of cold ACN (0-5 °C). The solids were dried under
vacuum at 50 °C to provide the hemifumarate form of tenofovir alafenamide,
which was characterized as described below.
Characterization of Tenofovir Alafenamide Hemifumarate from Example 3
Tenofovir alafenamide hemifumarate from Example 3 consists of 9-[(R)-
2-[[(S)-[[(S)
(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine
and one-half an equivalent of fumaric acid. Tenofovir alafenamide hemifumarate
is anhydrous, nonhygroscopic, and has a DSC onset endotherm of about 131 °C.
X-ray Powder Diffraction
The XRPD pattern of tenofovir alafenamide hemifumarate was obtained
in the following experimental setting: 45 KV, 45 mA, Kα1=1.5406 Å, scan range
2. - 40°, step size 0.0084°, counting time: 8.25 s. The XRPD pattern for
tenofovir alafenamide hemifumarate is shown in The characteristic
peaks include: 6.9 ± 0.2°, 8.6 ± 0.2°, 10.0 ± 0.2°, 11.0 ± 0.2°, 12.2 ± 0.2°, 15.9 ±
0.2°, 16.3 ± 0.2°, 20.2 ± 0.2°, and 20.8 ± 0.2°.
Single-Crystal X-ray Diffraction
The crystal size was 0.32 x 0.30 x 0.20 mm . The sample was held at
123 K and the data was collected using a radiation source with a wavelength of
0.71073 Å in the theta range of 1.59 to 25.39°. Conditions of, and data collected
from the single-crystal X-ray diffraction are shown in Table 1.
Table 1. Single-Crystal X-ray Diffraction
Empirical formula C H N O P
23 31 6 7
Formula weight 534.50
Temperature 123(2) K
Crystal size 0.32 x 0.30 x 0.20 mm
Theta range for data collection 1.59 to 25.39°
Wavelength 0.71073 Å
Crystal system Tetragonal
Space group P4(2)2(1)2
Unit cell dimensions a = 18.1185(12) Å α = 90°
b = 18.1185(12) Å β = 90°
c = 17.5747(11) Å γ = 90°
Volume 5769.4(6) Å
Density (calculated) 1.23l g/cm
DSC Analysis
The DSC analysis was conducted using 2.517 mg of tenofovir
alafenamide hemifumarate. It was heated at 10 °C/min over the range of 40-200
°C. The onset endotherm was found to be about 131 °C (.
TGA Data
The TGA data were obtained using 4.161 mg of tenofovir alafenamide
hemifumarate. It was heated at 10 °C/min over the range of 25-200 °C. The
sample lost 0.3% weight before melting (. It was determined to be an
anhydrous form.
DVS Analysis
DVS analysis was conducted using 4.951 mg of tenofovir alafenamide
hemifumarate. The material was kept at 25 °C in nitrogen at humidities ranging
from 10% to 90% relative humidity; each step was equilibrated for 120 minutes.
The sorption isotherm is shown at The material was found to be
nonhygroscopic, and to absorb 0.65% water at a relative humidity of 90%.
Purging of Diastereomeric Impurity
In the prior syntheses of tenofovir alafenamide, one of the major
impurities is typically the diastereomer 9-[(R)[[(R)-[[(S)
(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine.
The hemifumarate form of tenofovir alafenamide from Example 3 has an
exceptional capability to purge this diastereomeric impurity, as compared with
the capability of the monofumarate form (described in U.S. Patent
No. 7,390,791). The data in Table 2 (below) demonstrates that tenofovir
alafenamide hemifumarate (Batch 2) purged the diastereomeric impurity to less
than one-tenth of the starting concentration, whereas the monofumarate form of
tenofovir alafenamide (Batch 1) only slightly purged the diastereomeric impurity.
Table 2. Purging Capability Comparison
Fumaric
Diastereomeric
acid Diastereomeric
Impurity in Product
Batch Solvent charge Impurity in
Starting obtained
(mole Product
Material
equivalent)
Monofumarate
1 9.3% ACN 0.9 7.6%
form
Hemifumarate
2 10.0% ACN 0.5 0.65%
form
Chemical Stability
Chemical stability of the hemifumarate form of tenofovir alafenamide
was compared with the monofumarate form. As shown in Table 3 (below), under
identical conditions, the hemifumarate form of tenofovir alafenamide was
chemically more stable and exhibited better long-term storage stability, with
significantly less degradation (% Total Deg. Products) than the monofumarate
form. Conditions evaluated include temperature, relative humidity (RH), and the
open or closed state of the container cap.
Table 3. Chemical Stability Comparison
Monofumarate form Hemifumarate form
Time
Storage
Points % TA % Total % TA % Total
Condition
(weeks)
Area Deg. Area Deg.
Normalized Products Normalized Products
0 97.1 0.69 98.4 0.05
1 97.0 0.87 98.4 0.14
40°C / 75% RH
2 96.6 1.18 98.5 0.14
Cap Closed
4 96.4 1.49 98.4 0.25
8 95.4 2.36 98.0 0.49
0 97.1 0.69 98.4 0.05
1 96.9 0.90 98.5 0.15
40°C / 75% RH
2 96.6 1.10 98.5 0.14
Cap Open
4 96.2 1.67 98.4 0.26
8 95.0 2.74 98.1 0.50
0 97.1 0.69 98.4 0.05
70°C
2 96.2 1.83 98.5 0.22
Cap Closed
4 93.3 4.78 98.4 0.33
TA is tenofovir alafenamide
Thermodynamic Stability
Stable form screening of tenofovir alafenamide hemifumarate showed
that it is thermodynamically stable in most solvents, such as ACN, toluene, ethyl
acetate, methyl tert-butyl ether (MTBE), acetone, THF, and 2-methyl THF. A
similar stable form screening of the monofumarate form showed that this form is
not thermodynamically stable in the above-listed solvents. When suspended in
these solvents, the monofumarate form of tenofovir alafenamide fully converts to
the hemifumarate form in THF and 2-methyl THF, and partially converts to the
hemifumarate form in ACN, ethyl acetate, MTBE, and acetone, as well as at
ambient temperatures.
Thermal Stability
As shown by the DSC data, the hemifumarate form of tenofovir
alafenamide has a melting point that is about 10 °C higher than that of the
monofumarate form, indicating that the hemifumarate form has improved thermal
stability as compared with the monofumarate form.
All publications, patents, and patent documents are incorporated by
reference herein, as though individually incorporated by reference. The invention
has been described with reference to various specific and preferred embodiments
and techniques. However, it should be understood that many variations and
modifications may be made while remaining within the spirit and scope of the
invention.
Claims (76)
1. Tenofovir alafenamide hemifumarate.
2. A composition comprising tenofovir alafenamide hemifumarate, wherein the ratio of fumaric acid to tenofovir alafenamide in said composition is 0.5 ± 0.1.
3. The composition of claim 2, wherein the ratio of fumaric acid to tenofovir alafenamide is 0.5 ± 0.05.
4. The composition of claim 2, wherein the ratio of fumaric acid to tenofovir alafenamide is 0.5 ± 0.01.
5. The composition of claim 2, wherein the ratio of fumaric acid to tenofovir alafenamide is about 0.5.
6. The hemifumarate of claim 1 that is a solid.
7. The composition of any one of claims 2-5 that is a solid.
8. Tenofovir alafenamide hemifumarate having an X-ray powder diffraction (XRPD) pattern that comprises 2theta values of 6.9 ± 0.2° and 8.6 ± 0.2°.
9. The hemifumarate of claim 8, wherein the XRPD pattern comprises 2theta values of 6.9 ± 0.2°, 8.6 ± 0.2°, 11.0 ± 0.2°, 15.9 ± 0.2°, and 20.2 ± 0.2°.
10. The hemifumarate of claim 1 that has a differential scanning calorimetry (DSC) onset endotherm of 131 ± 2 °C.
11. The hemifumarate of claim 10 that has a DSC onset endotherm of 131 ± 1 °C.
12. A pharmaceutical composition comprising the hemifumarate of any one of claims 1, 6 and 8-11 and a pharmaceutically acceptable excipient.
13. A pharmaceutical composition comprising the composition of any one of claims 2-5 and 7 and a pharmaceutically acceptable excipient
14. The pharmaceutical composition of claim 12 or 13, further comprising an additional therapeutic agent.
15. The pharmaceutical composition of claim 14, wherein the additional therapeutic agent is selected from the group consisting of human immunodeficiency virus (HIV) protease inhibiting compounds, HIV nonnucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, and CCR5 inhibitors.
16 A method for preparing a pharmaceutical composition comprising combining the hemifumarate of any one of claims 1, 6 and 8-11 and a pharmaceutically acceptable excipient to provide the pharmaceutical composition.
17. A method for preparing a pharmaceutical composition comprising combining the composition of any one of claims 2-5 and 7 and a pharmaceutically acceptable excipient to provide the pharmaceutical composition.
18. A method for preparing tenofovir alafenamide hemifumarate comprising subjecting a solution comprising: a) a suitable solvent; b) fumaric acid; c) tenofovir alafenamide; and d) one or more seeds of tenofovir alafenamide hemifumarate, to conditions that provide for the crystallization of the fumaric acid and the tenofovir alafenamide.
19. The method of claim 18, wherein the solvent comprises acetonitrile.
20. The method of claim 18, wherein the solution is subjected to a temperature in the range of from about 0 °C to about 75 °C.
21. The hemifumarate of any one of claims 1, 6 and 8-11 for use in medical therapy.
22. The composition of any one of claims 2-5 and 7 for use in medical therapy.
23. Use of the hemifumarate of any one of claims 1, 6 and 8-11 for the preparation or manufacture of a medicament for the treatment of an HIV infection.
24. Use of the composition of any one of claims 2-5 and 7 for the preparation or manufacture of a medicament for the treatment of an HIV infection.
25. The use of claim 23 or 24, wherein the medicament further comprises one or more additional therapeutic agents selected from the group consisting of HIV protease inhibiting compounds, HIV nonnucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, and CCR5 inhibitors.
26. The hemifumarate of any one of claims 1, 6 and 8-11 for use in treating an HIV infection.
27. The composition of any one of claims 2-5 and 7 for use in treating an HIV infection.
28. The composition of claim 27, wherein the composition further comprises one or more additional therapeutic agents selected from the group consisting of HIV protease inhibiting compounds, HIV nonnucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, and CCR5 inhibitors
29. Use of the hemifumarate of any one of claims 1, 6 and 8-11 for the preparation or manufacture of a medicament for the treatment of an HBV infection in a human.
30. Use of the composition of any one of claims 2-5 and 7 for the preparation or manufacture of a medicament for the treatment of an HBV infection in a human.
31. The hemifumarate of any one of claims 1, 6 and 8-11 for use in treating an HBV infection.
32. The composition of any one of claims 2-5 and 7 for use in treating an HBV infection.
33. The use of claim 23 or 24, wherein the medicament is suitable for administration in multiple daily doses.
34. The use of claim 23 or 24, wherein the medicament is suitable for administration in a single daily dose.
35. The use of claim 29 or 30, wherein the medicament is suitable for administration in multiple daily doses.
36. The use of claim 29 or 30, wherein the medicament is suitable for administration in a single daily dose.
37. The composition of claim 27, wherein the composition is suitable for administration in multiple daily doses.
38. The composition of claim 27, wherein the composition is suitable for administration in a single daily dose.
39. The composition of claim 32, wherein the composition is suitable for administration in multiple daily doses.
40. The composition of claim 32, wherein the composition is suitable for administration in a single daily dose.
41. A composition consisting essentially of tenofovir alafenamide hemifumarate.
42. A composition consisting essentially of tenofovir alafenamide hemifumarate, wherein the ratio of fumaric acid to tenofovir alafenamide is 0.5 ± 0.1.
43. The composition of claim 42, wherein the ratio of fumaric acid to tenofovir alafenamide is 0.5 ± 0.05.
44. The composition of claim 42, wherein the ratio of fumaric acid to tenofovir alafenamide is 0.5 ± 0.01.
45. The composition of claim 42, wherein the ratio of fumaric acid to tenofovir alafenamide is about 0.5.
46. The composition of any one of claims 41-45 that is a solid.
47. A composition consisting essentially of tenofovir alafenamide hemifumarate having an XRPD pattern that comprises 2theta values of 6.9 ± 0.2° and 8.6 ± 0.2°.
48. The composition of claim 47, wherein the XRPD pattern comprises 2theta values of 6.9 ± 0.2°, 8.6 ± 0.2°, 11.0 ± 0.2°, 15.9 ± 0.2°, and 20.2 ± 0.2°.
49. The composition of claim 41 that has a DSC onset endotherm of 131 ± 2 °C.
50. The composition of claim 49 that has a DSC onset endotherm of 131 ± 1 °C.
51. A pharmaceutical composition comprising the composition of any one of claims 41-50 and a pharmaceutically acceptable excipient.
52. The pharmaceutical composition of claim 51, further comprising an additional therapeutic agent.
53. The pharmaceutical composition of claim 52, wherein the additional therapeutic agent is selected from the group consisting of HIV protease inhibiting compounds, HIV nonnucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, and CCR5 inhibitors.
54. A method for preparing a pharmaceutical composition comprising combining the composition of any one of claims 41-50 and a pharmaceutically acceptable excipient to provide the pharmaceutical composition.
55. The composition of any one of claims 41-50 for use in medical therapy.
56. Use of the composition of any one of claims 41-50 for the preparation or manufacture of a medicament for the treatment of an HIV infection.
57. The composition of any one of claims 41-50 for use in treating an HIV infection.
58. The use of claim 56, wherein the medicament further comprises one or more additional therapeutic agents selected from the group consisting of HIV protease inhibiting compounds, HIV nonnucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, and CCR5 inhibitors.
59. The composition of claim 57, wherein the composition further comprises one or more additional therapeutic agents selected from the group consisting of HIV protease inhibiting compounds, HIV nonnucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, and CCR5 inhibitors.
60. Use of the composition of any one of claims 41-50 for the preparation or manufacture of a medicament for the treatment of an HBV infection in a human.
61. The composition of any one of claims 41-50 for use in treating an HBV infection.
62. The use of claim 56, wherein the medicament is suitable for administration in multiple daily doses.
63. The use of claim 56, wherein the medicament is suitable for administration in a single daily dose.
64. The use of claim 60, wherein the medicament is suitable for administration in multiple daily doses.
65. The use of claim 60, wherein the medicament is suitable for administration in a single daily dose.
66. The composition claim 57, wherein the composition is suitable for administration in multiple daily doses.
67. The composition of claim 57, wherein the composition is suitable for administration in a single daily dose.
68. The composition of claim 61, wherein the composition is suitable for administration in multiple daily doses.
69. The composition of claim 61, wherein the composition is suitable for administration in a single daily dose.
70. A method for preparing tenofovir alafenamide hemifumarate comprising the steps of: admixing a) aprotic organic solvent; b) fumaric acid; c) tenofovir alafenamide; and d) one or more seeds of tenofovir alafenamide hemifumarate; and crystallizing additional tenofovir alafenamide hemifumarate.
71. A method for preparing tenofovir alafenamide hemifumarate comprising the steps of: admixing a) a solvent comprising water, isopropyl alcohol, acetone, acetonitrile, toluene, ethyl acetate, isopropyl acetate, heptane, tetrahydrofuran, 2- methyl tetrahydrofuran, methyl ethyl ketone, methyl isobutyl ketone or mixtures thereof; b) fumaric acid; c) tenofovir alafenamide; and d) one or more seeds of tenofovir alafenamide hemifumarate; and crystallizing additional tenofovir alafenamide hemifumarate at a temperature from about 0 °C to about 70 °C.
72. The method of claim 71, wherein the solvent comprises acetonitrile and up to about 50% by volume methylene chloride.
73. Tenofovir alafenamide hemifumarate of claim 1 or 2, substantially as herein described with reference to any example thereof.
74. A composition of any one of claims 2, 12, 13, 41, 42, 47, 51 and 52, substantially as herein described with reference to any example thereof.
75. A method of any one of claims 16-18, 54, 70 and 71, substantially as herein described with reference to any example thereof.
76. A use of any one of claims 23, 24, 29, 30, 56 and 60, substantially as herein described with reference to any example thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161524224P | 2011-08-16 | 2011-08-16 | |
US61/524,224 | 2011-08-16 | ||
PCT/US2012/050920 WO2013025788A1 (en) | 2011-08-16 | 2012-08-15 | Tenofovir alafenamide hemifumarate |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ620421A NZ620421A (en) | 2015-05-29 |
NZ620421B2 true NZ620421B2 (en) | 2015-09-01 |
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