U.S. patent application number 10/757122 was filed with the patent office on 2004-11-11 for compositions and methods for combination antiviral therapy.
This patent application is currently assigned to GILEAD SCIENCES, INC.. Invention is credited to Dahl, Terrance C., Menning, Mark M., Oliyai, Reza.
Application Number | 20040224916 10/757122 |
Document ID | / |
Family ID | 32776014 |
Filed Date | 2004-11-11 |
United States Patent
Application |
20040224916 |
Kind Code |
A1 |
Dahl, Terrance C. ; et
al. |
November 11, 2004 |
Compositions and methods for combination antiviral therapy
Abstract
The present invention relates to therapeutic combinations of
[9-[R-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]-phenoxyphosphinyl]-
methoxy]propyl]adenine (GS-7340) and (2R,5S,
cis)-4-amino-5-fluoro-1-(2-hy-
droxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one
(emtricitabine, (-)-cis FTC, Emtriva.TM.) and their physiologically
functional derivatives. The combinations may be useful in the
treatment of HIV infections, including infections with HIV mutants
bearing resistance to nucleoside and/or non-nucleoside inhibitors.
The present invention is also concerned with pharmaceutical
compositions and formulations of said combinations of GS-7340 and
emtricitabine, and their physiologically functional derivatives, as
well as therapeutic methods of use of those compositions and
formulations.
Inventors: |
Dahl, Terrance C.;
(Sunnyvale, CA) ; Menning, Mark M.; (San
Francisco, CA) ; Oliyai, Reza; (San Carlos,
CA) |
Correspondence
Address: |
Mark Bosse
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City
CA
94404
US
|
Assignee: |
GILEAD SCIENCES, INC.
|
Family ID: |
32776014 |
Appl. No.: |
10/757122 |
Filed: |
January 13, 2004 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
60440308 |
Jan 14, 2003 |
|
|
|
60440246 |
Jan 14, 2003 |
|
|
|
Current U.S.
Class: |
514/47 ;
514/269 |
Current CPC
Class: |
A61K 31/683 20130101;
A61P 31/18 20180101; A61K 31/7076 20130101; A61P 43/00 20180101;
A61P 31/12 20180101; A61K 31/513 20130101; A61K 45/06 20130101;
A61K 9/2018 20130101; A61K 9/2059 20130101; A61K 9/2054 20130101;
A61K 31/675 20130101; A61K 9/2013 20130101; A61K 9/2009 20130101;
A61P 31/00 20180101; A61K 31/675 20130101; A61K 2300/00 20130101;
A61K 31/7076 20130101; A61K 2300/00 20130101; A61K 31/513 20130101;
A61K 2300/00 20130101 |
Class at
Publication: |
514/047 ;
514/269 |
International
Class: |
A61K 031/7076; A61K
031/513 |
Claims
We claim:
1. A method for the treatment or prevention of the symptoms or
effects of an HIV infection in an infected animal which comprises
administering to said animal a therapeutically effective amount of
a combination comprising
9-[R-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]-phenoxyp-
hosphinyl]methoxy]propyl]adenine (GS-7340) or a physiologically
functional derivative thereof, and
(2R,5S,cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1-
,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one (emtricitabine) or a
physiologically functional derivative thereof.
2. The method according to claim 1 wherein the combination
comprises GS-7340 and emtricitabine.
3. The method according to claim 2 wherein the combination
comprises about 150 mg of GS-7340 and about 200 mg of
emtricitabine.
4. The method according to claim 1 wherein GS-7340 or a
physiologically functional derivative thereof and emtricitabine or
a physiologically functional derivative thereof are present in a
ratio of about 1:50 to about 50:1 by weight.
5. The method according to claim 1 wherein GS-7340 or a
physiologically functional derivative thereof and emtricitabine or
a physiologically functional derivative thereof are present in a
ratio of about 1:10 to about 10:1 by weight.
6. The method according to claim 1 wherein GS-7340 or a
physiologically functional derivative thereof and emtricitabine or
a physiologically functional derivative thereof are each present in
an amount from about 1 mg to about 1000 mg per unit dosage
form.
7. The method according to claim 1 wherein GS-7340 or a
physiologically functional derivative thereof and emtricitabine or
a physiologically functional derivative thereof are each present in
an amount from about 100 mg to about 300 mg per unit dosage
form.
8. A method according to claim 1 wherein GS-7340 is a fumarate
salt.
9. A method for the treatment or prevention of the symptoms or
effects of an HIV infection in an infected animal which comprises
administering to said animal a therapeutically effective amount of
a combination comprising
9-[R-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]-phenoxyp-
hosphinyl]methoxy]propyl]adenine (GS-7340) or a physiologically
functional derivative thereof, and a compound of the formula:
10wherein B is selected from adenine, guanine, cytosine, uracil,
thymine, 7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine,
7-deaza-8-azaadenine, inosine, nebularine, nitropyrrole,
nitroindole, 2-aminopurine, 2-amino-6-chloropurine,
2,6-diaminopurine, hypoxanthine, pseudouridine, 5-fluorocytosine,
5-chlorocytosine, 5-bromocytosine, 5-iodocytosine, pseudocytosine,
pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine,
7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothymine,
4-thiouracil, O.sup.6-methylguanine, N.sup.6-methyladenine,
O.sup.4-methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil,
4-methylindole, and a pyrazolo[3,4-D]pyrimidine; and R is selected
from H, C.sub.1-C.sub.18 alkyl, C.sub.1-C.sub.18 substituted alkyl,
C.sub.2-C.sub.18 alkenyl, C.sub.2-C.sub.18 substituted alkenyl,
C.sub.2-C.sub.18 alkynyl, C.sub.2-C.sub.18 substituted alkynyl,
C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20 substituted aryl,
C.sub.2-C.sub.20 heterocycle, C.sub.2-C.sub.20 substituted
heterocycle, phosphonate, phosphophosphonate, diphosphophosphonate,
phosphate, diphosphate, triphosphate, polyethyleneoxy, and a
prodrug moiety.
10. The method according to claim 9 wherein the combination
comprises a physiologically functional derivative of emtricitabine
which is (2R, 5S,
cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one
(3TC).
11. The method according to claim 1 wherein the combination
comprises a physiologically functional derivative of emtricitabine
which is a racemic mixture of the enantiomers (2R, 5S,
cis)-4-amino-5-fluoro-1-(2-hydroxymet-
hyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one and (2S, 5R,
cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimi-
din-2-one.
12. The method according to claim 1 wherein the combination
comprises a physiologically functional derivative of GS-7340 which
has the structure: 11wherein R.sup.5 is H or CH.sub.3; R.sup.6 and
R.sup.8 are independently selected from H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 substituted alkyl, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.6-C.sub.20 arylalkyl, and
C.sub.6-C.sub.20 substituted arylalkyl; R.sup.7 is the side chain
of any naturally-occurring or pharmaceutically acceptable amino
acid and where if the side chain comprises carboxyl, the carboxyl
group is optionally esterified with an alkyl or aryl group;
R.sup.11 is amino, alkylamino, oxo, or dialkylamino; and R.sup.12
is amino or H; or a pharmaceutically acceptable salt or solvate
thereof.
13. The method according to claim 12 wherein R.sup.7 is H, CH.sub.3
or CH(CH.sub.3).sub.2.
14. The method according to claim 12 wherein R.sup.6 is phenyl.
15. The method according to claim 12 wherein R.sup.8 is CH.sub.3,
CH.sub.2CH.sub.3, or CH(CH.sub.3).sub.2.
16. The method according to claim 1 wherein GS-7340 or a
physiologically functional derivative thereof, and emtricitabine or
a physiologically functional derivative thereof are administered
sequentially.
17. The method according to claim 1 wherein the combination is
administered as a single combined formulation.
18. The method according to claim 17 wherein the single combined
formulation is administered once per day to an infected human.
19. The method according to claim 1 in which said animal is a
human.
20. The method according to claim 1 wherein the combination further
comprises a third active ingredient selected from a protease
inhibitor (PI), a nucleoside reverse transcriptase inhibitor
(NRTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI),
and an integrase inhibitor.
21. The method according to claim 20 wherein the third active
ingredient is tenofovir disoproxil fumarate.
22. The method according to claim 1 wherein the combination further
comprises a pharmaceutically acceptable glidant selected from
silicon dioxide, powdered cellulose, microcrystalline cellulose, a
metallic stearate, sodium aluminosilicate, sodium benzoate, calcium
carbonate, calcium silicate, corn starch, magnesium carbonate,
asbestos free talc, stearowet C, starch, starch 1500, magnesium
lauryl sulfate, magnesium oxide, and combinations thereof.
23. The method according to claim 22 wherein the metallic stearate
is selected from calcium stearate, magnesium stearate, zinc
stearate, and combinations thereof.
24. A pharmaceutical formulation comprising
9-[R-2-[[(S)-[[(S)-1-(isopropo-
xycarbonyl)ethyl]amino]-phenoxyphosphinyl]methoxy]propyl]adenine
(GS-7340) or a physiologically functional derivative thereof and
(2R, 5S,
cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimi-
din-2-one (emtricitabine) or a physiologically functional
derivative thereof.
25. The pharmaceutical formulation according to claim 24 further
comprising one or more pharmaceutically acceptable carriers or
excipients.
26. The pharmaceutical formulation according to claim 25 wherein
the pharmaceutically acceptable carriers or excipients are selected
from pregelatinized starch, croscarmellose sodium, povidone,
lactose monohydrate, microcrystalline cellulose, and magnesium
stearate; and combinations thereof.
27. The pharmaceutical formulation according to claim 24 wherein
GS-7340 or a physiologically functional derivative thereof and
emtricitabine or a physiologically functional derivative thereof
are present in a ratio of 1:50 to 50:1 by weight.
28. The pharmaceutical formulation according to claim 24 wherein
GS-7340 or a physiologically functional derivative thereof and
emtricitabine or a physiologically functional derivative thereof
are present in a ratio of 1:10 to 10:1 by weight.
29. The pharmaceutical formulation according to claim 24 in unit
dosage form.
30. The pharmaceutical formulation according to claim 29 wherein
GS-7340 or a physiologically functional derivative thereof and
emtricitabine or a physiologically functional derivative thereof
are each and individually present in an amount from 100 mg to 1000
mg per unit dosage form.
31. The pharmaceutical formulation according to claim 24 comprising
GS-7340 and emtricitabine.
32. The pharmaceutical formulation according to claim 31 comprising
about 150 mg of GS-7340 and about 200 mg of emtricitabine.
33. The pharmaceutical formulation according to claim 24 suitable
for oral administration.
34. The pharmaceutical formulation according to claim 30 in the
form of a tablet or capsule.
35. The pharmaceutical formulation according to claim 30 suitable
for administration once per day to an infected human.
36. The pharmaceutical formulation according to claim 24 comprising
a physiologically functional derivative of emtricitabine which is
(2R, 5S,
cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one
(3TC).
37. The pharmaceutical formulation according to claim 24 comprising
a physiologically functional derivative of GS-7340 which has the
structure: 12wherein R.sup.5 is H or CH.sub.3; R.sup.6 and R.sup.8
are independently selected from H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 substituted alkyl, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.6-C.sub.20 arylalkyl, and
C.sub.6-C.sub.20 substituted arylalkyl; R.sup.7 is the side chain
of any naturally-occurring or pharmaceutically acceptable amino
acid and where if the side chain comprises carboxyl, the carboxyl
group is optionally esterified with an alkyl or aryl group;
R.sup.11 is amino, alkylamino, oxo, or dialkylamino; and R.sup.12
is amino or H; or a pharmaceutically acceptable salt or solvate
thereof.
38. The pharmaceutical formulation according to claim 37 wherein
R.sup.7 is H, CH.sub.3 or CH(CH.sub.3).sub.2.
39. The pharmaceutical formulation according to claim 37 wherein
R.sup.6 is phenyl.
40. The pharmaceutical formulation according to claim 37 wherein
R.sup.8 is CH.sub.3, CH.sub.2CH.sub.3, or CH(CH.sub.3).sub.2.
41. A patient pack comprising at least one active ingredient
selected from
9-[R-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]-phenoxyphosphinyl]m-
ethoxy]propyl]adenine (GS-7340) and (2R,5S,
cis)-4-amino-5-fluoro-1-(2-hyd-
roxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one
(emtricitabine), and an information insert containing directions on
the use of GS-7340 and emtricitabine together in combination.
42. The patient pack according to claim 41 comprising a
co-formulated pill, tablet, caplet, or capsule of 100 to 1000 mg of
GS-7340 and 100 to 1000 mg of emtricitabine.
43. The patient pack according to claim 41 comprising a
co-formulated pill, tablet, caplet, or capsule of 300 mg of GS-7340
and 200 mg of emtricitabine.
44. The patient pack according to claim 41 comprising a separate
pill, tablet, caplet, or capsule of 100 to 1000 mg of GS-7340 and
100 to 1000 mg of emtricitabine.
45. The patient pack according to claim 44 comprising a separate
pill, tablet, caplet, or capsule of 150 mg of GS-7340 and 200 mg of
emtricitabine.
46. A chemically stable combination of GS-7340 and
emtricitabine.
47. The chemically stable combination of claim 46 wherein the
combination is a pharmaceutical dosage form.
48. The chemically stable combination of claim 47 wherein the
dosage form is oral.
49. The chemically stable combination of claims 46-48 which further
comprises a third antiviral agent.
50. The chemically stable combination of claim 49 where in the
third antiviral agent is an NNRTI or PI.
51. The chemically stable combination of claim 50 wherein the third
antiviral agent is a PI.
52. The chemically stable combination of Clam 50 wherein the third
antiviral agent is an NNRTI.
53. The chemically stable combination of claim 49 wherein the third
antiviral agent is selected from Reyataz, Kaletra or Sustiva.
54. A chemically stable oral pharmaceutical dosage form comprising
GS-7340 and emtricitabine.
55. A chemically stable oral pharmaceutical dosage form comprising
GS-7340, emtricitabine and Reyataz.
56. A chemically stable oral pharmaceutical dosage form comprising
GS-7340, emtricitabine and Kaletra.
57. A chemically stable oral pharmaceutical dosage form comprising
GS-7340, emtricitabine and Sustiva.
Description
[0001] This non-provisional application claims the benefit of
Provisional Application Nos. 60/440,308 and 60/440,246, both filed
Jan. 14, 2003, which is incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The invention relates generally to combinations of compounds
with antiviral activity and more specifically with anti-HIV
properties. In particular, it relates to chemically stable
combinations of structurally diverse anti-viral agents.
BACKGROUND OF THE INVENTION
[0003] Human immunodeficiency virus (HIV) infection and related
diseases are a major public health problem worldwide. Human
immunodeficiency virus type 1 (HIV-1) encodes at least three
enzymes which are required for viral replication: reverse
transcriptase (RT), protease (Prt), and integrase (Int). Although
drugs targeting reverse transcriptase and protease are in wide use
and have shown effectiveness, particularly when employed in
combination, toxicity and development of resistant strains have
limited their usefulness (Palella, et al N. Engl. J. Med. (1998)
338:853-860; Richman, D. D. Nature (2001) 410:995-1001). Human
immunodeficiency virus type 1 (HIV-1) protease (Prt) is essential
for viral replication and is an effective target for approved
antiviral drugs. The HIV Prt cleaves the viral Gag and Gag-Pol
polyproteins to produce viral structural proteins (p17, p24, p7 and
p6) and the three viral enzymes. Combination therapy with RT
inhibitors has proven to be highly effective in suppressing viral
replication to unquantifiable levels for a sustained period of
time. Also, combination therapy with RT and Prt inhibitors (PI)
have shown synergistic effects in suppressing HIV replication.
Unfortunately, a high percentage, typically 30 to 50% of patients
currently fail combination therapy due to the development of drug
resistance, non-compliance with complicated dosing regimens,
pharmacokinetic interactions, toxicity, and lack of potency.
Therefore, there is a need for new HIV-1 inhibitors that are active
against mutant HIV strains, have distinct resistance profiles,
fewer side effects, less complicated dosing schedules, and are
orally active. In particular, there is a need for a less onerous
dosage regimen, such as once per day oral dosing, optimally with as
few pills as possible.
[0004] The use of combinations of compounds can yield an equivalent
antiviral effect with reduced toxicity, or an increase in drug
efficacy. Lower overall drug doses can reduce the frequency of
occurrence of drug-resistant variants of HIV. Many different
methods have been used to examine the effects of combinations of
compounds acting together in different assay systems (Furman WO
02/068058). Lower doses predict better patient compliance when pill
burden decreases, dosing schedules are simplified and, optionally
if synergy between compounds occurs (Loveday, C. "Nucleoside
reverse transcriptase inhibitor resistance" (2001) JAIDS Journal of
Acquired Immune Deficiency Syndromes 26:S1O--S24). AZT
(zidovudine.TM., 3'-azido, 3'-deoxythymidine) demonstrates
synergistic antiviral activity in vitro in combination with agents
that act at HIV-1 replicative steps other than reverse
transcription, including recombinant soluble CD4 castanospermine
and recombinant interferon-.alpha.. However, it must be noted that
combinations of compounds can give rise to increased cytotoxicity.
For example, AZT and recombinant interferon-.alpha. have an
increased cytotoxic effect on normal human bone marrow progenitor
cells.
[0005] Chemical stability of combinations of antiviral agents is an
important aspect of co-formulation success and the present
invention provides examples of such combinations.
[0006] There is a need for new combinations of orally-active drugs
for the treatment of patients infected with certain viruses, e.g.
HIV, that provide enhanced therapeutic safety and efficacy, impart
lower resistance, and predict higher patient compliance.
SUMMARY OF THE INVENTION
[0007] The present invention provides combinations of antiviral
compounds, in particular compositions and methods for inhibition of
HIV. In an exemplary aspect, the invention includes a combination
of GS-7340 and emtricitabine which has anti-HIV activity. The
combination of GS-7340 and emtricitabine is both chemically stable
and either synergistic and/or reduces the side effects of one or
both of GS-7340 and emtricitabine. Increased patient compliance is
likely in view of the lower pill burden and simplified dosing
schedule.
[0008] The present invention relates to therapeutic combinations of
9-[R-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]-phenoxyphosphinyl]m-
ethoxy]propyl]adenine (GS-7340) and (2R, 5S,
cis)-4-amino-5-fluoro-1-(2-hy-
droxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one
(emtricitabine), and their use in the treatment of HIV infections
including infections with HIV mutants bearing resistance to
nucleoside and/or non-nucleoside inhibitors. The present invention
is also concerned with pharmaceutical compositions and formulations
of said combinations of GS-7340 and emtricitabine. Another aspect
of the invention is a pharmaceutical formulation comprising a
physiologically functional derivative of GS-7340 or a
physiologically functional derivative of emtricitabine, including
FTC and 3TC.
[0009] FTC is
4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H-
)-pyrimidin-2-one and includes all diastereomers, enantiomers, and
mixtures thereof, in any proportion. For example, FTC includes the
single enantiomer emtricitabine.
[0010] Therapeutic combinations and pharmaceutical compositions and
formulations of the invention include the combination of
phosphonamidate PMEA or PMPA compounds with FTC or
(2R,5S,cis)-4-amino-1-(2-hydroxymethyl-
-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one (3TC, Lamivudine,
Epivir.TM.), and their use in the treatment of HIV infections.
[0011] One aspect of the invention is a method for the treatment or
prevention of the symptoms or effects of an HIV infection in an
infected animal which comprises administering to, i.e. treating,
said animal with a therapeutically effective amount of a
formulation comprising
9-[R-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]-phenoxyphosphinyl]m-
ethoxy]propyl]adenine (GS-7340) or a physiologically functional
derivative thereof, and
(2R,5S,cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiol-
an-5-yl)-(1H)-pyrimidin-2-one (emtricitabine) or a physiologically
functional derivative thereof.
[0012] Another aspect of the invention is a unit dosage form of a
therapeutic combination comprising GS-7340 and emtricitabine, or
physiological functional derivatives thereof. The unit dosage form
may be formulated for administration by oral or other routes and is
unexpectedly chemically stable in view of the properties of the
structurally diverse components.
[0013] Another aspect of the invention is directed to a chemically
stable combination antiviral compositions comprising GS-7340 and
emtricitabine. In a further aspect of the invention, the chemically
stable combinations of GS-7340 and emtricitabine further comprise a
third antiviral agent. In this three-component mixture, the unique
chemical stability of GS-7340 and emtricitabine is taken advantage
of in order to enable the combination with the third antiviral
agent. Particularly useful third agents include, by way of example
and not limitation, those of Table A. Preferably, the third
component is an agent approved for antiviral use in humans, more
preferably, it is an NNRTI or a protease inhibitor (PI), more
preferably yet, it is an NNRTI. In a particularly preferred
embodiment, the invention is directed to a combination of the
chemically stable mixture of GS-7340 and emtricitabine together
with efavirenz.
[0014] Another aspect of the invention is a patient pack comprising
at least one, typically two, and optionally, three active
ingredients selected from GS-7340, emtricitabine, and other
antiviral agents, and an information insert containing directions
on the use of GS-7340 and emtricitabine together in
combination.
[0015] Another aspect of the invention is a process for preparing
the combinations hereinbefore described, which comprises bringing
into association GS-7340 and emtricitabine of the combination in a
medicament to provide an antiviral effect. In a further aspect of
the present invention, there is provided the use of a combination
of the present invention in the manufacture of a medicament for the
treatment of any of the aforementioned viral infections or
conditions.
DETAILED DESCRIPTION OF THE INVENTION
[0016] While the invention will be described in conjunction with
the enumerated embodiments, it will be understood that they are not
intended to limit the invention to those embodiments. On the
contrary, the invention is intended to cover all alternatives,
modifications, and equivalents, which may be included within the
scope of the present invention as defined by the claims.
[0017] Definitions
[0018] Unless stated otherwise, the following terms and phrases as
used herein are intended to have the following meanings:
[0019] When tradenames are used herein, applicants intend to
independently include the tradename product and the active
pharmaceutical ingredient(s) of the tradename product.
[0020] The term "chemical stability" means that the two primary
antiviral agents in combination are substantially stable to
chemical degradation. Preferably, they are sufficiently stable in
physical combination to permit commercially useful shelf life of
the combination product. Typically, "chemically stable" means that
a first component of the mixture does not act to degrade a second
component when the two are brought into physical combination to
form a pharmaceutical dosage form. More typically, "chemically
stable" means that the acidity of a first component does not
catalyzes or otherwise accelerate the acid decomposition of a
second component. By way of example and not limitation, in one
aspect of the invention, "chemically stable" means that GS-7340 is
not substantially degraded by the acidity of emtricitabine.
"Substantially" in this context means at least about less than
about 10%, preferably less than about 1%, more preferably less than
about 0.1%, more preferably yet, less than about 0.01% acid
degradation of GS-7340 over a 24-hour period when the products are
in a pharmaceutical dosage form.
[0021] The terms "synergy" and "synergistic" mean that the effect
achieved with the compounds used together is greater than the sum
of the effects that results from using the compounds separately,
i.e. greater than what would be predicted based on the two active
ingredients administered separately. A synergistic effect may be
attained when the compounds are: (1) co-formulated and administered
or delivered simultaneously in a combined formulation; (2)
delivered by alternation or in parallel as separate formulations;
or (3) by some other regimen. When delivered in alternation
therapy, a synergistic effect may be attained when the compounds
are administered or delivered sequentially, e.g. in separate
tablets, pills or capsules, or by different injections in separate
syringes. In general, during alternation therapy, an effective
dosage of each active ingredient is administered sequentially, i.e.
serially, whereas in combination therapy, effective dosages of two
or more active ingredients are administered together. A synergistic
anti-viral effect denotes an antiviral effect which is greater than
the predicted purely additive effects of the individual compounds
of the combination.
[0022] The term "physiologically functional derivative" means a
pharmaceutically active compound with equivalent or near equivalent
physiological functionality to GS-7340 or emtricitabine when
administered in combination with another pharmaceutically active
compound in a combination of the invention. As used herein, the
term "physiologically functional derivative" includes any
physiologically acceptable salt, ether, ester, prodrug, solvate,
stereoisomer including enantiomer, diastereomer or
stereoisomerically enriched or racemic mixture, and any other
compound which upon administration to the recipient, is capable of
providing (directly or indirectly) such a compound or an
antivirally active metabolite or residue thereof.
[0023] "Bioavailability" is the degree to which the
pharmaceutically active agent becomes available to the target
tissue after the agent's introduction into the body. Enhancement of
the bioavailability of a pharmaceutically active agent can provide
a more efficient and effective treatment for patients because, for
a given dose, more of the pharmaceutically active agent will be
available at the targeted tissue sites.
[0024] The compounds of the combinations of the invention may be
referred to as "active ingredients" or "pharmaceutically active
agents."
[0025] The term "prodrug" as used herein refers to any compound
that when administered to a biological system generates the drug
substance, i.e. active ingredient, as a result of spontaneous
chemical reaction(s), enzyme catalyzed chemical reaction(s), and/or
metabolic chemical reaction(s).
[0026] "Prodrug moiety" means a labile functional group which
separates from the active inhibitory compound during metabolism,
systemically, inside a cell, by hydrolysis, enzymatic cleavage, or
by some other process (Bundgaard, Hans, "Design and Application of
Prodrugs" in Textbook of Drug Design and Development (1991), P.
Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood Academic
Publishers, pp. 113-191). Prodrug moieties can serve to enhance
solubility, absorption and lipophilicity to optimize drug delivery,
bioavailability and efficacy. A "prodrug" is thus a covalently
modified analog of a therapeutically-active compound.
[0027] "Alkyl" means a saturated or unsaturated, branched,
straight-chain, branched, or cyclic hydrocarbon radical derived by
the removal of one hydrogen atom from a single carbon atom of a
parent alkane, alkene, or alkyne. Typical alkyl groups consist of
1-18 saturated and/or unsaturated carbons, such as normal,
secondary, tertiary or cyclic carbon atoms. Examples include, but
are not limited to: methyl, Me (--CH.sub.3), ethyl, Et
(--CH.sub.2CH.sub.3), acetylenic (--C.ident.CH), ethylene, vinyl
(--CH.dbd.CH.sub.2), 1-propyl, n-Pr, n-propyl
(--CH.sub.2CH.sub.2CH.sub.3- ), 2-propyl, i-Pr, i-propyl
(--CH(CH.sub.3).sub.2), allyl (--CH.sub.2CH.dbd.CH.sub.2),
propargyl (--CH.sub.2C.ident.CH), cyclopropyl (--C.sub.3H.sub.5),
1-butyl, n-Bu, n-butyl (--CH.sub.2CH.sub.2CH.sub.2CH.sub.3),
2-methyl-1-propyl, i-Bu, i-butyl (--CH.sub.2CH(CH.sub.3).sub.2),
2-butyl, s-Bu, s-butyl (--CH(CH.sub.3)CH.sub.2CH.sub.3),
2-methyl-2-propyl, t-Bu, t-butyl (--C(CH.sub.3).sub.3), 1-pentyl,
n-pentyl, (--CH.sub.2CH.sub.2CH.sub.2CH.- sub.2CH.sub.3), 2-pentyl
(--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3), 3-pentyl
(--CH(CH.sub.2CH.sub.3).sub.2), 2-methyl-2-butyl
(--C(CH.sub.3).sub.2CH.sub.2CH.sub.3), cyclopentyl
(--C.sub.5H.sub.9), 3-methyl-2-butyl
(--CH(CH.sub.3)CH(CH.sub.3).sub.2), 3-methyl-1-butyl
(--CH.sub.2CH.sub.2CH(CH.sub.3).sub.2), 2-methyl-1-butyl
(--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3), 1-hexyl
(--CH.sub.2CH.sub.2CH.s- ub.2CH.sub.2CH.sub.2CH.sub.3), 5-hexenyl
(--CH.sub.2 CH.sub.2CH.sub.2CH.sub.2CH.dbd.CH.sub.2) 1-hexyl
(--CH(CH.sub.3)CH.sub.2C- H.sub.2CH.sub.2CH.sub.3), 3-hexyl
(--CH(CH.sub.2CH.sub.3)(CH.sub.2CH.sub.2- CH.sub.3)), cyclohexyl
(--C.sub.6H.sub.11), 2-methyl-2-pentyl
(--C(CH.sub.3).sub.2CH.sub.2CH.sub.2CH.sub.3), 3-methyl-2-pentyl
(--CH(CH.sub.3)CH(CH.sub.3)CH.sub.2CH.sub.3), 4-methyl-2-pentyl
(--CH(CH.sub.3)CH.sub.2CH(CH.sub.3).sub.2), 3-methyl-3-pentyl
(--C(CH.sub.3)(CH.sub.2CH.sub.3).sub.2), 2-methyl-3-pentyl
(--CH(CH.sub.2CH.sub.3)CH(CH.sub.3).sub.2), 2,3-dimethyl-2-butyl
(--C(CH.sub.3).sub.2CH(CH.sub.3).sub.2), and 3,3-dimethyl-2-butyl
(--CH(CH.sub.3)C(CH.sub.3).sub.3.
[0028] "Aryl" means a monovalent aromatic hydrocarbon radical of
6-20 carbon atoms derived by the removal of one hydrogen atom from
a single carbon atom of a parent aromatic ring system. Typical aryl
groups include, but are not limited to, radicals derived from
benzene, substituted benzene, naphthalene, anthracene, biphenyl,
and the like.
[0029] "Arylalkyl" refers to an acyclic alkyl radical in which one
of the hydrogen atoms bonded to a carbon atom, typically a terminal
or sp.sup.3 carbon atom, is replaced with an aryl radical. Typical
arylalkyl groups include, but are not limited to, benzyl,
2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl,
2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl,
2-naphthophenylethan-1-yl and the like. The arylalkyl group 6 to 20
carbon atoms e.g., the alkyl moiety, including alkanyl, alkenyl or
alkynyl groups, of the arylalkyl group is 1 to 6 carbon atoms and
the aryl moiety is 5 to 14 carbon atoms.
[0030] "Substituted alkyl", "substituted aryl", and "substituted
arylalkyl" mean alkyl, aryl, and arylalkyl respectively, in which
one or more hydrogen atoms are each independently replaced with a
substituent. Typical substituents include, but are not limited to,
--X, --R, --O--, --OR, --SR, --S--, --NR.sub.2, --NR.sub.3, =NR,
--CX.sub.3, --CN, --OCN, --SCN, --N.dbd.C.dbd.O, --NCS, --NO,
--NO.sub.2, =N.sub.2, --N.sub.3, NC(.dbd.O)R, --C(.dbd.O)R,
--C(.dbd.O)NRR--S(.dbd.O).sub.2O.sup.-, --S(.dbd.O).sub.2OH,
--S(.dbd.O).sub.2R, --OS(.dbd.O).sub.2OR, --S(.dbd.O).sub.2NR,
--S(.dbd.O)R, --OP(.dbd.O)O.sub.2RR, --P(.dbd.O)O.sub.2RR
--P(.dbd.O)(O.sup.-).sub.2, --P(.dbd.O)(OH).sub.2, --C(.dbd.O)R,
--C(.dbd.O)X, --C(S)R, --C(O)OR, --C(O)O.sup.-, --C(S)OR, --C(O)SR,
--C(S)SR, --C(O)NRR, --C(S)NRR, --C(NR)NRR, where each X is
independently a halogen: F, Cl, Br, or I; and each R is
independently --H, alkyl, aryl, heterocycle, or prodrug moiety.
[0031] "Heteroaryl" and "Heterocycle" refer to a ring system in
which one or more ring atoms is a heteroatom, e.g. nitrogen,
oxygen, and sulfur. Heterocycles are described in: Katritzky, Alan
R., Rees, C. W., and Scriven, E. Comprehensive Heterocyclic
Chemistry (1996) Pergamon Press; Paquette, Leo A.; Principles of
Modern Heterocyclic Chemistry W. A. Benjamin, New York, (1968),
particularly Chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of
Heterocyclic Compounds, A series of Monographs" (John Wiley &
Sons, New York, 1950 to present), in particular Volumes 13, 14, 16,
19, and 28. Exemplary heterocycles include but are not limited to
substituents, i.e. radicals, derived from pyrrole, indole, furan,
benzofuran, thiophene, benzothiophene, 2-pyridyl, 3-pyridyl,
4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 2-imidazole,
4-imidazole, 3-pyrazole, 4-pyrazole, pyridazine, pyrimidine,
pyrazine, purine, cinnoline, pthalazine, quinazoline, quinoxaline,
3-(1,2,4-N)-triazolyl, 5-(1,2,4-N)-triazolyl, 5-tetrazolyl,
4-(1-0,3-N)-oxazole, 5-(1-0,3-N)-oxazole, 4-(1-S, 3-N)-thiazole,
5-(1-S, 3-N)-thiazole, 2-benzoxazole, 2-benzothiazole,
4-(1,2,3-N)-benzotriazole, and benzimidazole.
[0032] Stereochemical definitions and conventions used herein
generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of
Chemical Terms (1984) McGraw-Hill Book Company, New York; and
Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds
(1994) John Wiley & Sons, Inc., New York. Many organic
compounds exist in optically active forms, i.e., they have the
ability to rotate the plane of plane-polarized light. In describing
an optically active compound, the prefixes D and L or R and S are
used to denote the absolute configuration of the molecule about its
chiral center(s). The prefixes R and S, d and l or (+) and (-) are
employed to designate the sign of rotation of plane-polarized light
by the compound, with (-) or 1 or S meaning that the compound is
levorotatory. A compound prefixed with (+) or d or R is
dextrorotatory. For a given chemical structure, these compounds,
called stereoisomers, are identical except that they are mirror
images of one another. A specific stereoisomer is also referred to
as an enantiomer, and a mixture of such isomers is often called an
enantiomeric mixture. A 50:50 mixture of enantiomers is referred to
as a racemic mixture or a racemate. The terms "racemic mixture" and
"racemate" refer to an equimolar mixture of two enantiomeric
species, devoid of optical activity.
[0033] The term "chiral" refers to molecules which have the
property of non-superimposability of the mirror image partner,
while the term "achiral" refers to molecules which are
superimposable on their mirror image partner.
[0034] The term "stereoisomers" refers to compounds which have
identical chemical constitution, but differ with regard to the
arrangement of the atoms or groups in space.
[0035] "Diastereomer" refers to a stereoisomer with two or more
centers of chirality and whose molecules are not mirror images of
one another. Diastereomers have different physical properties, e.g.
melting points, boiling points, spectral properties, and
reactivities. Mixtures of diastereomers may separate under high
resolution analytical procedures such as electrophoresis and
chromatography.
[0036] "Enantiomers" refer to two stereoisomers of a compound which
are non-superimposable mirror images of one another.
[0037] Active Ingredients of the Combinations
[0038] The present invention provides novel combinations of two or
more active ingredients being employed together. In some
embodiments, a synergistic antiviral effect is achieved. In other
embodiments, a chemically stable combination is obtained. The
combinations include at least one active ingredient selected from
(1) GS-7340 and physiologically functional derivatives, and at
least one active ingredient selected from (2) emtricitabine and
physiologically functional derivatives. The term "synergistic
antiviral effect" is used herein to denote an antiviral effect
which is greater than the predicted purely additive effects of the
individual components (a) and (b) of the combination.
[0039] GS-7340 is an antiviral prodrug known as:
9-[(R)-2-[[(S)-[[(S)-1-(i-
sopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine,
and has the structure: 1
[0040] CAS Registry Numbers for GS-7340 include: 379270-37-8 and
for GS-7340 fumarate include: 379270-38-9.
[0041] The prodrug GS-7340 is the subject of commonly owned,
pending application, U.S. Ser. No. 09/909,560, filed Jul. 20, 2001
and Becker et al WO 02/08241. GS-7340 is an isopropyl alanyl
phosphonamidate, phenyl ester prodrug of tenofovir (PMPA). In vivo
and in vitro characterization shows that selective intracellular
activation of GS 7340 leads to preferential distribution in
lymphatic tissues (Lee W, He G, Mulato A, Delaney W, Eisenberg E,
Cihlar T, Xiong S, Miller M, Gill S, Shibata R, Gibbs C
Internatiional Conference on Retroviruses and Opportunistic
Infections 2002, 9th Conf:February 24-28, Abs 384-T; "Evaluation of
Cidofovir, Adefovir, Tenofovir and Related Phosphonate Analogs for
Inhibition of Orthopoxvirus Replication." Keith K A, Hitchcock M J
M, Lee W A, Holy A, Kern E R (2002) Antiviral Research, 53:3, Abs
95; "Structure and activity relationship for tenofovir amidates,
novel intracellular prodrugs for tenofovir" He G X, Eisenberg E J,
Cihlar T, Chapman H, Lee W A Antiviral Research 2001, 50:1, Abs
123)
[0042] Preclinical data on tenofovir prodrugs were presented at the
15th ICAR meeting in Prague, Czech Republic. It was demonstrated
that GS-7340 is active against both cowpox and vaccinia viruses at
concentrations of 20 to 100 .mu.M. GS-7340 is 1000 times more
effective than tenofovir against HIV in culture. GS-7340 has an
S-configuration at the phosphorus. This S-configuration
diastereomer is 10-fold more effective than the diastereomer with
the R-configuration (Nucleosides, Nucleotides and Their Biological
Applications--XIV International Roundtable (Part II), San
Francisco, Calif., USA). The large-scale separation of GS-7340
diastereomers and enantiomers has been achieved ("Practical
synthesis, separation, and stereochemical assignment of the PMPA
prodrug GS-7340" Chapman et al (2001) Nucleosides, Nucleotides
& Nucleic Acids, 20(4-7):621-628.
[0043] In vitro data showed that GS-7340 was effective against HIV
and HBV in a variety of cell types. In vivo studies in dogs and
rhesus monkeys revealed that the compound is orally bioavailable
(20%), stable in plasma and selectively hydrolyzed inside lymphatic
tissue. In vitro, the most potent compounds displayed an EC50 value
of 0.0008 .mu.M against HIV, and a half-life of 103 min in plasma.
The prodrugs have demonstrated oral bioavailability, stability and
ability to rapidly convert to tenofovir inside lymphatic cells.
GS-7340 is 100-fold more effective than tenofovir against HIV in
culture, and the diastereomer with an S-configuration at the P
group is 10-fold more effective than that with an R-configuration.
GS-7340 is in phase I/II trials for the potential treatment of HIV
and other viral infections.
[0044] The term "GS-7340" includes all combinations of
stereochemistry at the three designated centers as well as all
diasteromeric and racemic mixtures. Examples include R,R,R; R,R,S;
R,S,R; S,R,R; R,S.S; S,R.S; S,S,R; and S,S,S compounds and their
racemic, enantiomerically enriched and partially racemic
mixtures.
[0045] PMPA (U.S. Pat. Nos. 4,808,716, 5,733,788, 6057305) has the
structure: 2
[0046] The chemical names of PMPA include:
(R)-9-(2-phosphonylmethoxypropy- l)adenine; and phosphonic acid,
[[(1R)-2-(6-amino-9H-purin-9-yl)-1-methyle- thoxy]methyl]. The CAS
Registry number is 147127-20-6.
[0047] Physiologically functional derivatives of GS-7340 include
phosphonamidate PMEA (adefovir,
9-((R)-2-(phosphonomethoxy)ethyl)adenine) and PMPA compounds.
Exemplary combinations include a phosphonamidate PMEA or PMPA
compound in combination with emtricitabine or a physiologically
functional derivative. Phosphonamidate PMEA and PMPA compounds have
the structures: 3
[0048] PMEA (R.sup.5=H) and PMPA (R.sup.5=CH.sub.3). R.sup.6 and
R.sup.8 are independently selected from H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 substituted alkyl, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.6-C.sub.20 arylalkyl,
C.sub.6-C.sub.20 substituted arylalkyl. R.sup.7 is the side chain
of any naturally-occurring or pharmaceutically acceptable amino
acid and which, if the side chain comprises carboxyl, the carboxyl
group is optionally esterified with an alkyl or aryl group. For
example, R.sup.7 may be H, CH.sub.3 or CH(CH.sub.3).sub.2. R.sup.11
is amino, alkylamino, oxo, or dialkylamino. R.sup.12 is amino or H.
Exemplary embodiments include where R is methyl, R.sup.6 is phenyl,
and R.sup.8 is methyl, ethyl, or isopropyl.
[0049] Phosphonamidate PMEA and PMPA compounds may be prepared from
the corresponding dialkyl phosphonates which may be prepared
according to the methods of: Quast et al (1974) Synthesis 490;
Stowell et al (1990) Tetrahedron Lett. 3261; U.S. Pat. No.
5,663,159.
[0050] The phosphonamidate PMEA and PMPA compound may be
enantiomerically-enriched or purified (single stereoisomer) where
the carbon atom bearing R.sup.5 may be the R or S enantiomer when
R.sup.5 is not H. The phosphonamidate PMEA and PMPA compound may be
a racemate, i.e. a mixture of R and S stereoisomers. The invention
includes all enantiomers, diastereomers, racemates, and enriched
stereoisomer mixtures of phosphonamidate PMEA and PMPA
compounds.
[0051] Emtricitabine ((-)-cis-FTC, Emtriva.TM.), a single
enantiomer of FTC, is a potent nucleoside reverse transcriptase
inhibitor approved for the treatment of HIV (U.S. Pat. Nos.
5,047,407, 5,179,104, 5,204,466, 5,210,085, 5,486,520, 5,538,975,
5,587,480, 5,618,820, 5,763,606, 5,814,639, 5,914,331, 6,114,343,
6,180,639, 6,215,004; WO 02/070518). The single enantiomer
emtricitabine has the structure: 4
[0052] The chemical names for emtricitabine include: (-)-cis-FTC;
.beta.-L-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane;
(2R,5S)-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine;
and
4-amino-5-fluoro-1-(2-hydroxymethyl-[1,3]-(2R,5S)-oxathiolan-5-yl)-1H-pyr-
imidin-2-one. The CAS Registry numbers include: 143491-57-0;
143491-54-7. It should be noted that FTC contains two chiral
centers, at the 2 and 5 positions of the oxathiolane ring, and
therefore can exist in the form of two pairs of optical isomers
(i.e. enantiomers) and diastereomeric and racemic mixtures thereof.
Thus, FTC may be either a cis or a trans isomer or mixtures
thereof. Mixtures of cis and trans isomers are diastereomers with
different physical properties. Each cis and trans isomer can exist
as one of two enantiomers or mixtures thereof including racemic
mixtures. The invention includes all enantiomers, diastereomers,
racemates, and enriched stereoisomer mixtures of emtricitabine, and
physiologically functional derivatives thereof. For example, the
invention includes physiological functional derivatives such as the
1:1 racemic mixture of the enantiomers (2R, 5S,
cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxa-
thiolan-5-yl)-(1H)-pyrimidin-2-one (emtricitabine) and its mirror
image (2S, 5R,
cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1-
H)-pyrimidin-2-one, or mixtures of the two enantiomers in any
relative amount. The invention also includes mixtures of cis and
trans forms of FTC.
[0053] It will be appreciated that GS-7340 and emtricitabine may
exist in keto or enol tautomeric forms and the use of any
tautomeric form is within the scope of this invention. GS-7340 and
emtricitabine will normally be utilized in the combinations of the
invention substantially free of the corresponding enantiomer, that
is to say no more than about 5% w/w of the corresponding enantiomer
will be present.
[0054] Physiologically functional derivatives of emtricitabine
include 1,3 oxathiolane nucleosides having the structure: 5
[0055] In the 1,3 oxathiolane nucleoside structure above, B is a
nucleobase including any nitrogen-containing heterocyclic moiety
capable of forming Watson-Crick hydrogen bonds in pairing with a
complementary nucleobase or nucleobase analog, e.g. a purine, a
7-deazapurine, or a pyrimidine. Examples of B include the naturally
occurring nucleobases: adenine, guanine, cytosine, uracil, thymine,
and minor constituents and analogs of the naturally occurring
nucleobases, e.g. 7-deazaadenine, 7-deazaguanine,
7-deaza-8-azaguanine, 7-deaza-8-azaadenine, inosine, nebularine,
nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropurine,
2,6-diaminopurine, hypoxanthine, pseudouridine, 5-fluorocytosine,
5-chlorocytosine, 5-bromocytosine, 5-iodocytosine, 5-alkylcytosine,
e.g. 5-methylcytosine, pseudocytosine, pseudoisocytosine,
5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine,
2-thiopyrimidine, 6-thioguanine, 4-thiothymine, 4-thiouracil,
06-methylguanine, N6-methyladenine, 04-methylthymine,
5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole,
pyrazolo[3,4-D]pyrimidines (U.S. Pat. Nos. 6,143,877 and 6,127,121;
WO 01/38584), and ethenoadenine (Fasman (1989) in Practical
Handbook of Biochemistry and Molecular Biology, pp. 385-394, CRC
Press, Boca Raton, Fl).
[0056] Nucleobases B may be attached in the configurations of
naturally-occurring nucleic acids to the 1,3 oxathiolane moiety
through a covalent bond between the N-9 of purines, e.g.
adenin-9-yl and guanin-9-yl, or N-1 of pyrimidines, e.g.
thymin-1-yl and cytosin-1-yl (Blackburn, G. and Gait, M. Eds. "DNA
and RNA structure" in Nucleic Acids in Chemistry and Biology,
2.sup.nd Edition, (1996) Oxford University Press, pp. 15-81).
[0057] Also in the 1,3 oxathiolane nucleoside structure above, R is
H, C.sub.1-C.sub.18 alkyl, C.sub.2l-C.sub.18 substituted alkyl,
C.sub.2-C.sub.18 alkenyl, C.sub.2-C.sub.18 substituted alkenyl,
C.sub.2-C.sub.18 alkynyl, C.sub.2-C.sub.18 substituted alkynyl,
C.sub.6-C.sub.20 aryl, C.sub.6-C.sub.20 substituted aryl,
C.sub.2-C.sub.20 heterocycle, C.sub.2-C.sub.20 substituted
heterocycle, phosphonate, phosphophosphonate, diphosphophosphonate,
phosphate, diphosphate, triphosphate, polyethyleneoxy, or a prodrug
moiety
[0058] Physiologically functional derivatives of emtricitabine also
include 3TC (lamivudine, Epivir.RTM.), a reverse transcriptase
inhibitor approved in the United States for the treatment of HIV-1
infection in combination with AZT (Zidovudine) as Combivir.RTM.
(GlaxoSmithKline). U.S. Pat. Nos. 5,859,021; 5,905,082; 6,177,435;
5,627,186; 6,417,191. 3TC (U.S. Pat. Nos. 5,587,480, 5,696,254,
5,618,820, 5,756,706, 5,744,596, 568,164, 5,466,806, 5,151,426) has
the structure: 6
[0059] For example and for some therapeutic uses, 3TC may be a
physiologically functional derivative of emtricitabine in
combination with GS-7340 or a physiologically functional derivative
of GS-7340.
[0060] Prodrugs
[0061] The invention includes all prodrugs of GS-7340 and
emtricitabine. Whereas GS-7340 is a prodrug form of a PMPA
compound, GS-7340 may bear additional prodrug moieties which confer
advantageous properties. A large number of structurally-diverse
prodrugs have been described for phosphonic acids (Freeman and Ross
in Progress in Medicinal Chemistry 34: 112-147 (1997). A commonly
used prodrug class is the acyloxyalkyl ester, which was first used
as a prodrug strategy for carboxylic acids and then applied to
phosphates and phosphonates by Farquhar et al (1983) J. Pharm. Sci.
72: 324; also U.S. Pat. Nos. 4,816,570, 4,968,788, 5,663,159 and
5,792,756. Subsequently, the acyloxyalkyl ester was used to deliver
phosphonic acids across cell membranes and to enhance oral
bioavailability. A close variant of the acyloxyalkyl ester
strategy, the alkoxycarbonyloxyalkyl ester, may also enhance oral
bioavailability as a prodrug moiety in the compounds of the
combinations of the invention. Aryl esters of phosphorus groups,
especially phenyl esters, are reported to enhance oral
bioavailability (DeLambert et al (1994) J. Med. Chem. 37: 498).
Phenyl esters containing a carboxylic ester ortho to the phosphate
have also been described (Khamnei and Torrence, (1996) J. Med.
Chem. 39:4109-4115). Benzyl esters are reported to generate the
parent phosphonic acid. In some cases, substituents at the ortho-
or para-position may accelerate the hydrolysis. Benzyl analogs with
an acylated phenol or an alkylated phenol may generate the phenolic
compound through the action of enzymes, e.g. esterases, oxidases,
etc., which in turn undergoes cleavage at the benzylic C--O bond to
generate the phosphoric acid and the quinone methide intermediate.
Examples of this class of prodrugs are described by Mitchell et al
(1992) J. Chem. Soc. Perkin Trans. I 2345; Brook et al WO 91/19721.
Still other benzylic prodrugs have been described containing a
carboxylic ester-containing group attached to the benzylic
methylene (Glazier et al WO 91/19721). Thio-containing prodrugs are
reported to be useful for the intracellular delivery of phosphonate
drugs. These proesters contain an ethylthio group in which the
thiol group is either esterified with an acyl group or combined
with another thiol group to form a disulfide. Deesterification or
reduction of the disulfide generates the free thio intermediate
which subsequently breaks down to the phosphoric acid and
episulfide (Puech et al (1993) Antiviral Res., 22: 155-174;
Benzaria et al (1996) J. Med. Chem. 39: 4958). Cyclic phosphonate
esters have also been described as prodrugs of
phosphorus-containing compounds.
[0062] Prodrug esters in accordance with the invention are
independently selected from the following groups: (1) mono-, di-,
and tri-phosphate esters of GS-7340 or emtricitabine or any other
compound which upon administration to a human subject is capable of
providing (directly or indirectly) said mono-, di, or triphosphate
ester; (2) carboxylic acid esters (3) sulfonate esters, such as
alkyl- or aralkylsulfonyl- (for example, methanesulfonyl); (4)
amino acid esters (for example, alanine, L-valyl or L-isoleucyl);
(5) phosphonate; and (6) phosphonamidate esters.
[0063] Ester groups (1)-(6) may be substituted with; straight or
branched chain C.sub.1-C.sub.18 alkyl (for example, methyl,
n-propyl, t-butyl, or n-butyl); C.sub.3-C.sub.12 cycloalkyl;
alkoxyalkyl (for example, methoxymethyl); arylalkyl (for example,
benzyl); aryloxyalkyl (for example, phenoxymethyl);
C.sub.5-C.sub.20 aryl (for example, phenyl optionally substituted
by, for example, halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, or amino; acyloxymethyl esters --CH.sub.2C(.dbd.O)R.sup.9
(e.g. POM) or acyloxymethyl carbonates --CH.sub.2C(.dbd.O)OR.sup.9
(e.g. POC) where R.sup.9 is C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
substituted alkyl, C.sub.6-C.sub.20 aryl or C.sub.6-C.sub.20
substituted aryl. For example, ester groups may be
pivaloyloxymethoxy, POM, --CH.sub.2C(.dbd.O)C(CH.sub.3).sub.3;
--CH.sub.2C(.dbd.O)OC(CH.sub.3).sub.3; or POC,
--CH.sub.2C(.dbd.O)OCH(CH.- sub.3).sub.2.
[0064] An exemplary aryl moiety present in such esters comprises a
phenyl or substituted phenyl group. Many phosphate prodrug moieties
are described in U.S. Pat. No. 6,312,662; Jones et al (1995)
Antiviral Research 27:1-17; Kucera et al (1990) AIDS Res. Hum.
Retro Viruses 6:491-501; Piantadosi et al (1991) J. Med. Chem.
34:1408-14; Hosteller et al (1992) Antimicrob. Agents Chemother.
36:2025-29; Hostetler et al (1990) J. Biol. Chem. 265:611127; and
Siddiqui et al (1999) J. Med. Chem. 42:4122-28.
[0065] Pharmaceutically acceptable prodrugs refer to a compound
that is metabolized in the host, for example hydrolyzed or
oxidized, by either enzymatic action or by general acid or base
solvolysis, to form an active ingredient. Typical examples of
prodrugs of the active ingredients of the combinations of the
invention have biologically labile protecting groups on a
functional moiety of the active compound. Prodrugs include
compounds that can be oxidized, reduced, aminated, deaminated,
esterified, deesterified, alkylated, dealkylated, acylated,
deacylated, phosphorylated, dephosphorylated, or other functional
group change or conversion involving forming or breaking chemical
bonds on the prodrug.
[0066] Chemical Stability of a Pharmaceutical Formulation
[0067] The chemical stability of the active ingredients in a
pharmaceutical formulation is of concern to minimize the generation
of impurities and ensure adequate shelf-life. The active
ingredients, GS-7340 and emtricitabine, in the pharmaceutical
formulations of the invention have relatively low pKa values,
indicative of the potential to cause acidic hydrolysis of the
active ingredients. Emtricitabine, with a pKa of 2.65 (Emtriva.TM.
Product Insert, Gilead Sciences, Inc. 2003, available at
gilead.com) is subject to hydrolytic deamination of the 5-fluoro
cytosine nucleobase to form the 5-fluoro uridine nucleobase.
Tenofovir, with a pKa of 3.8 (Yuan L. et al "Degradation Kinetics
of Oxycarbonyloxymethyl Prodrugs of Phosphonates in Solution",
Pharmaceutical Research (2001) Vol. 18, No. 2, 234-237), is subject
also to hydrolytic deamination of the exocyclic amine of the
adenine nucleobase, and to hydrolysis of one or both of the amidate
and ester groups (U.S. Pat. No. 5,922,695). It is desirable to
formulate a therapeutic combination of GS-7340 and emtricitabine,
and the physiological functional derivatives thereof, with a
minimum of impurities and adequate stability.
[0068] The combinations of the present invention provide
combination pharmaceutical dosage forms which are chemically stable
to acid degradation of: (1) a first component (such as GS-7340, and
physiological functional derivatives; (2) a second component (such
as emtricitabine, and physiological functional derivatives; and (3)
optionally a third component having antiviral activity. The third
component includes anti-HIV agents and include: protease inhibitors
(PI), nucleoside reverse transcriptase inhibitors (NRTI),
non-nucleoside reverse transcriptase inhibitors (NNRTI), and
integrase inhibitors. Exemplary third active ingredients to be
administered in combination with first and second components are
shown in Table A. First and second components are as defined in the
above section entitled: ACTIVE INGREDIENTS OF THE COMBINATIONS.
[0069] Salts
[0070] Any reference to any of the above compounds also includes a
reference to a physiologically acceptable salt thereof. Examples of
physiologically acceptable salts of GS-7340, emtricitabine and
their physiologically acceptable derivatives include salts derived
from an appropriate base, such as an alkali metal (for example,
sodium), an alkaline earth (for example, magnesium), ammonium and
NX.sub.4.sup.+ (wherein X is C.sub.1-C.sub.4 alkyl).
Physiologically acceptable salts of an hydrogen atom or an amino
group include salts of organic carboxylic acids such as acetic,
benzoic, lactic, fumaric, tartaric, maleic, malonic, malic,
isethionic, lactobionic and succinic acids; organic sulfonic acids,
such as methanesulfonic, ethanesulfonic, benzenesulfonic and
p-toluenesulfonic acids; and inorganic acids, such as hydrochloric,
sulfuric, phosphoric and sulfamic acids. Physiologically acceptable
salts of a compound of an hydroxy group include the anion of said
compound in combination with a suitable cation such as Na.sup.+ and
NX.sub.4.sup.+ (wherein X is independently selected from H or a
C.sub.1-C.sub.4 alkyl group).
[0071] For therapeutic use, salts of active ingredients of the
combinations of the invention will be physiologically acceptable,
i.e. they will be salts derived from a physiologically acceptable
acid or base. However, salts of acids or bases which are not
physiologically acceptable may also find use, for example, in the
preparation or purification of a physiologically acceptable
compound. All salts, whether or not derived from a physiologically
acceptable acid or base, are within the scope of the present
invention.
[0072] Administration of the Formulations
[0073] While it is possible for the active ingredients of the
combination to be administered alone and separately as
monotherapies, it is preferable to administer them as a
pharmaceutical co-formulation. A two-part or three-part combination
may be administered simultaneously or sequentially. When
administered sequentially, the combination may be administered in
one, two, or three administrations.
[0074] Preferably, two-part or three-part combinations are
administered in a single pharmaceutical dosage form. More
preferably, a two-part combination is administered as a single oral
dosage form and a three-part combination is administered as two
identical oral dosage forms. Examples include a single tablet of
GS-7340 and emtricitabine, or two tablets of GS-7340,
emtricitabine, and efavirenz.
[0075] It will be appreciated that the compounds of the combination
may be administered: (1) simultaneously by combination of the
compounds in a co-formulation or (2) by alternation, i.e.
delivering the compounds serially, sequentially, in parallel or
simultaneously in separate pharmaceutical formulations. In
alternation therapy, the delay in administering the second, and
optionally a third active ingredient, should not be such as to lose
the benefit of a synergistic therapeutic effect of the combination
of the active ingredients. By either method of administration (1)
or (2), ideally the combination should be administered to achieve
peak plasma concentrations of each of the active ingredients. A one
pill once-per-day regimen by administration of a combination
co-formulation may be feasible for some HIV-positive patients.
Effective peak plasma concentrations of the active ingredients of
the combination will be in the range of approximately 0.001 to 100
.mu.M. Optimal peak plasma concentrations may be achieved by a
formulation and dosing regimen prescribed for a particular patient.
It will also be understood that GS-7340 and emtricitabine, or the
physiologically functional derivatives of either thereof, whether
presented simultaneously or sequentially, may be administered
individually, in multiples, or in any combination thereof. In
general, during alternation therapy (2), an effective dosage of
each compound is administered serially, where in co-formulation
therapy (1), effective dosages of two or more compounds are
administered together.
[0076] Formulation of the Combinations
[0077] When the individual components of the combination are
administered separately they are generally each presented as a
pharmaceutical formulation. Techniques and formulations generally
are found in Remington's Pharmaceutical Sciences (Mack Publishing
Co., Easton, Pa.). The references hereinafter to formulations refer
unless otherwise stated to formulations containing either the
combination or a component compound thereof. It will be understood
that the administration of the combination of the invention by
means of a single patient pack, or patient packs of each
formulation, within a package insert diverting the patient to the
correct use of the invention is a desirable additional feature of
this invention. The invention also includes a double pack
comprising in association for separate administration, formulations
of GS-7340 and emtricitabine, or a physiologically functional
derivative of either or both thereof.
[0078] The combination therapies of the invention include: (1) a
combination of GS-7340 and emtricitabine or (2) a combination
containing a physiologically functional derivative of either or
both thereof.
[0079] The combination may be formulated in a unit dosage
formulation comprising a fixed amount of each active pharmaceutical
ingredient for a periodic, e.g. daily, dose or subdose of the
active ingredients.
[0080] Pharmaceutical formulations according to the present
invention comprise a combination according to the invention
together with one or more pharmaceutically acceptable carriers or
excipients and optionally other therapeutic agents. Pharmaceutical
formulations containing the active ingredient may be in any form
suitable for the intended method of administration. For example,
tablets, troches, lozenges, aqueous or oil suspensions, dispersible
powders or granules, emulsions, hard or soft capsules, syrups or
elixirs may be prepared for oral administration (Remington's
Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.).
Compositions intended for oral use may be prepared according to any
method known to the art for the manufacture of pharmaceutical
compositions and such compositions may contain one or more agents
including antioxidants, sweetening agents, flavoring agents,
coloring agents and preserving agents, in order to provide a
palatable preparation. Tablets containing the active ingredient in
admixture with non-toxic pharmaceutically acceptable excipient
which are suitable for manufacture of tablets are acceptable. These
excipients may be, for example, inert diluents, such as calcium or
sodium carbonate, lactose, lactose monohydrate, croscarmellose
sodium, povidone, calcium or sodium phosphate; granulating and
disintegrating agents, such as maize starch, or alginic acid;
binding agents, such as cellulose, microcrystalline cellulose,
starch, gelatin or acacia; and lubricating agents, such as
magnesium stearate, stearic acid or talc. Tablets may be uncoated
or may be coated by known techniques including microencapsulation
to delay disintegration and absorption in the gastrointestinal
tract and thereby provide a sustained action over a longer period.
For example, a time delay material such as glyceryl monostearate or
glyceryl distearate alone or with a wax may be employed.
[0081] Formulations for oral use may be also presented as hard
gelatin capsules where the active ingredient is mixed with an inert
solid diluent, for example pregelatinized starch, calcium phosphate
or kaolin, or as soft gelatin capsules wherein the active
ingredient is mixed with water or an oil medium, such as peanut
oil, liquid paraffin or olive oil.
[0082] Aqueous suspensions of the invention contain the active
materials in admixture with excipients suitable for the manufacture
of aqueous suspensions. Such excipients include a suspending agent,
such as sodium carboxymethylcellulose, methylcellulose,
hydroxypropyl methylcelluose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing
or wetting agents such as a naturally occurring phosphatide (e.g.,
lecithin), a condensation product of an alkylene oxide with a fatty
acid (e.g., polyoxyethylene stearate), a condensation product of
ethylene oxide with a long chain aliphatic alcohol (e.g.,
heptadecaethyleneoxycetanol), a condensation product of ethylene
oxide with a partial ester derived from a fatty acid and a hexitol
anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous
suspension may also contain one or more preservatives such as ethyl
or n-propyl p-hydroxybenzoate, one or more coloring agents, one or
more flavoring agents and one or more sweetening agents, such as
sucrose, sucralose, or saccharin.
[0083] Oil suspensions may be formulated by suspending the active
ingredient in a vegetable oil, such as arachis oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as liquid
paraffin. The oral suspensions may contain a thickening agent, such
as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such
as those set forth above, and flavoring agents may be added to
provide a palatable oral preparation. These compositions may be
preserved by the addition of an antioxidant such as ascorbic acid,
BHT, etc.
[0084] Dispersible powders and granules of the invention suitable
for preparation of an aqueous suspension by the addition of water
provide the active ingredient in admixture with a dispersing or
wetting agent, a suspending agent, and one or more preservatives.
Suitable dispersing or wetting agents and suspending agents are
exemplified by those disclosed above. Additional excipients, for
example sweetening, flavoring and coloring agents, may also be
present.
[0085] The pharmaceutical compositions of the invention may also be
in the form of oil-in-water emulsions or liposome formulations. The
oily phase may be a vegetable oil, such as olive oil or arachis
oil, a mineral oil, such as liquid paraffin, or a mixture of these.
Suitable emulsifying agents include naturally-occurring gums, such
as gum acacia and gum tragacanth, naturally occurring phosphatides,
such as soybean lecithin, esters or partial esters derived from
fatty acids and hexitol anhydrides, such as sorbitan monooleate,
and condensation products of these partial esters with ethylene
oxide, such as polyoxyethylene sorbitan monooleate. The emulsion
may also contain sweetening and flavoring agents. Syrups and
elixirs may be formulated with sweetening agents, such as glycerol,
sorbitol or sucrose. Such formulations may also contain a
demulcent, a preservative, a flavoring or a coloring agent.
[0086] The pharmaceutical compositions of the invention may be in
the form of a sterile injectable preparation, such as a sterile
injectable aqueous or oleaginous suspension. This suspension may be
formulated according to the known art using those suitable
dispersing or wetting agents and suspending agents which have been
mentioned above. The sterile injectable preparation may also be a
sterile injectable solution or suspension in a non-toxic
parenterally acceptable diluent or solvent, such as a solution in
1,3-butane-diol or prepared as a lyophilized powder. Among the
acceptable vehicles and solvents that may be employed are water,
Ringer's solution and isotonic sodium chloride solution. In
addition, sterile fixed oils may conventionally be employed as a
solvent or suspending medium. For this purpose any bland fixed oil
may be employed including synthetic mono- or diglycerides. In
addition, fatty acids such as oleic acid may likewise be used in
the preparation of injectables.
[0087] The pharmaceutical compositions of the invention may be
injected parenterally, for example, intravenously,
intraperitoneally, intrathecally, intraventricularly,
intrastemally, intracranially, intramuscularly or subcutaneously,
or they may be administered by infusion techniques. They are best
used in the form of a sterile aqueous solution which may contain
other substances, for example, enough salts or glucose to make the
solution isotonic with blood. The aqueous solutions should be
suitably buffered (preferably to a pH of from 3 to 9), if
necessary. The preparation of suitable parenteral formulations
under sterile conditions is readily accomplished by standard
pharmaceutical techniques well known to those skilled in the
art.
[0088] The pharmaceutical compositions of the invention may also be
administered intranasally or by inhalation and are conveniently
delivered in the form of a dry powder inhaler or an aerosol spray
presentation from a pressurized container or a nebuliser with the
use of a suitable propellant, e.g. dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetrafluoroethane, a
hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFC 134a),
carbon dioxide or other suitable gas In the case of a pressurized
aerosol, the dosage unit may be determined by providing a valve to
deliver a metered amount. The pressurized container or nebuliser
may contain a solution or suspension of the composition, e.g. using
a mixture of ethanol and the propellant as the solvent, which may
additional contain a lubricant, e.g. sorbitan trioleate. Capsules
and cartridges (made, for example, from gelatin) for use in an
inhaler or insufflator may be formulated to contain a powder mix of
a compound of the formula (I) and a suitable powder base such as
lactose or starch. Aerosol or dry powder formulations are
preferably arranged so that each metered dose or "puff" contains
from 20 .mu.g to 20 mg of a composition for delivery to the
patient. The overall daily dose with an aerosol will be in the
range of from 20 .mu.g to 20 mg which may be administered in a
single dose or, more usually, in divided doses throughout the
day.
[0089] The amount of active ingredient that may be combined with
the carrier material to produce a single dosage form will vary
depending upon the host treated and the particular mode of
administration. For example, a time-release formulation intended
for oral administration to humans may contain approximately from
about 1 to 1000 mg of active material compounded with an
appropriate and convenient amount of carrier material which may
vary from about 5 to about 95% of the total compositions
(weight:weight). The pharmaceutical composition can be prepared to
provide easily measurable amounts for administration. For example,
an aqueous solution intended for intravenous infusion may contain
from about 3 to 500 .mu.g of the active ingredient per milliliter
of solution in order that infusion of a suitable volume at a rate
of about 30 mL/hr can occur. As noted above, formulations of the
present invention suitable for oral administration may be presented
as discrete units such as capsules, cachets or tablets each
containing a predetermined amount of the active ingredient; as a
powder or granules; as a solution or a suspension in an aqueous or
non-aqueous liquid; or as an oil-in-water liquid emulsion or a
water-in-oil liquid emulsion. The active ingredient may also be
administered as a bolus, electuary or paste.
[0090] The combinations of the invention may conveniently be
presented as a pharmaceutical formulation in a unitary dosage form.
A convenient unitary dosage formulation contains the active
ingredients in amounts of from about 1 mg to 1 g each, for example,
100 mg to 300 mg. The synergistic effects of GS-7340 in combination
with emtricitabine may be realized over a wide ratio, for example
1:50 to 50:1 (GS-7340: emtricitabine). In one embodiment, the ratio
may range from about 1:10 to 10:1. In another embodiment, the
weight/weight ratio of GS-7340 to emtricitabine in a co-formulated
combination dosage form, such as a pill, tablet, caplet or capsule
will be about 1, i.e. an approximately equal amount of GS-7340 and
emtricitabine. In other exemplary co-formulations, there may be
more or less GS-7340 than emtricitabine. Conveniently each compound
will be employed in the combination in an amount at which it
exhibits antiviral activity when used alone. For example, 150 mg
GS-7340 and 200 mg emtricitabine can be co-formulated in a ratio of
0.75:1 (GS-7340: emtricitabine). In one embodiment, each compound
will be employed in the combination in an amount at which it
exhibits antiviral activity when used alone. Exemplary Formulations
A, B, C, D, E, and F (Examples) have ratios of 0.125:1 to 1.5:1
(GS-7340:emtricitabine). Exemplary Formulations A, B, C, D, E, and
F use amounts of GS-7340 and emtricitabine ranging from 25 mg to
200 mg. Other ratios and amounts of the compounds of said
combinations are contemplated within the scope of the
invention.
[0091] A unitary dosage form may further comprise GS-7340 and
emtricitabine, or physiologically functional derivatives of either
thereof, and a pharmaceutically acceptable carrier.
[0092] It will be appreciated by those skilled in the art that the
amount of active ingredients in the combinations of the invention
required for use in treatment will vary according to a variety of
factors, including the nature of the condition being treated and
the age and condition of the patient, and will ultimately be at the
discretion of the attending physician or health care practitioner.
The factors to be considered include the route of administration
and nature of the formulation, the animal's body weight, age and
general condition and the nature and severity of the disease to be
treated. For example, in a Phase 1111 monotherapy study of
emtricitabine, patients received doses ranging from 25 mg to 200 mg
twice-a-day for two weeks. At each dose regimen greater or equal to
200 mg, a 98-percent (1.75 log10) or greater viral suppression was
observed. A once-a-day dose of 200 mg of emtricitabine reduced the
viral load by an average of 99 percent (1.92 log10). Emtriva.TM.
(emtricitabine) has been approved by the FDA for the treatment of
HIV as a 200 mg oral tablet.
[0093] It is also possible to combine any two of the active
ingredients in a unitary dosage form for simultaneous or sequential
administration with a third active ingredient. The three-part
combination may be administered simultaneously or sequentially.
When administered sequentially, the combination may be administered
in two or three administrations. Third active ingredients have
anti-HIV activity and include protease inhibitors (PI), nucleoside
reverse transcriptase inhibitors (NRTI), non-nucleoside reverse
transcriptase inhibitors (NNRTI), and integrase inhibitors.
Exemplary third active ingredients to be administered in
combination with GS-7340, emtricitabine, and their physiological
functional derivatives are shown in Table A.
1TABLE A 5,6 dihydro-5-azacytidine 5-aza 2'deoxycytidine
5-azacytidine 5-yl-carbocyclic 2'-deoxyguanosine (BMS200,475) 9
(arabinofuranosyl)guanine; 9-(2' deoxyribofuranosyl)guanine
9-(2'-deoxy 2'fluororibofuranosyl)-2,6-- diaminopurine 9-(2'-deoxy
2'fluororibofuranosyl)guanine 9-(2'-deoxyribofuranosyl)-2,6
diaminopurine 9-(arabinofuranosyl)-2,6 diaminopurine Abacavir,
Ziagen .RTM. Acyclovir, ACV; 9-(2-hydroxyethoxylmethyl)guanine
Adefovir dipivoxil, Hepsera .RTM. amdoxivir, DAPD Amprenavir,
Agenerase .RTM. araA; 9-.beta.-D-arabinofuranosyladenine
(Vidarabine) atazanivir sulfate (Reyataz .RTM.) AZT;
3'-azido-2',3'-dideoxythymdine, Zidovudine, (Retrovir .RTM.) BHCG;
(.+-.)-(1a,2b,3a)-9-[2,3-bis(hydroxymethyl)cyclobutyl]guanine
BMS200,475; 5-yl-carbocyclic 2'-deoxyguanosine Buciclovir; (R)
9-(3,4-dihydroxybutyl)guanine BvaraU; 1-.beta.-D-arabinofuranosyl--
E-5-(2-bromovinyl)uracil (Sorivudine) Calanolide A Capravirine CDG;
carbocyclic 2'-deoxyguanosine Cidofovir, HPMPC; (S)-9-(3-hydroxy-
2-phosphonylmethoxypropyl)cytosine Clevudine, L-FMAU;
2'-Fluoro-5-methyl-.beta.-L-arabino-furanosyluracil Combivir .RTM.
(lamivudine/zidovudine) Cytallene;
[1-(4'-hydroxy-1',2'-butadienyl)cytosine] d4C;
3'-deoxy-2',3'-didehydrocytidine DAPD; (-)-.beta.-D-2,6-diaminopur-
ine dioxolane ddA; 2',3'-dideoxyadenosine ddAPR;
2,6-diaminopurine-2',3'-dideoxyriboside ddC; 2',3'-dideoxycytidine
(Zalcitabine) ddI; 2',3'-dideoxyinosine, didanosine, (Videx .RTM.,
Videx .RTM. EC) Delavirdine, Rescriptor .RTM. Didanosine, ddI,
Videx .RTM.; 2',3'-dideoxyinosine DXG; dioxolane guanosine
E-5-(2-bromovinyl)-2'-deoxyuridine Efavirenz, Sustiva .RTM.
Enfuvirtide, Fuzeon .RTM. F-ara-A; fluoroarabinosyladenosine
(Fludarabine) FDOC; (-)-.beta.-D-5-fluoro-1-[2-(hydroxymethyl)-1,3-
-dioxolane]cytosine FEAU;
2'-deoxy-2'-fluoro-1-.beta.-D-arabinofura- nosyl-5-ethyluracil
FIAC; 1-(2-deoxy-2-fluoro-.beta.-D-arabinofuran-
osyl)-5-iodocytosine FIAU;
1-(2-deoxy-2-fluoro-.beta.-D-arabinofura- nosyl)-5-iodouridine FLG;
2',3'-dideoxy-3'-fluoroguanosine FLT; 3'-deoxy-3'-fluorothymidine
Fludarabine; F-ara-A; fluoroarabinosyladenosine FMAU;
2'-Fluoro-5-methyl-.beta.-L-arabin- o-furanosyluracil FMdC
Foscarnet; phosphonoformic acid, PFA FPMPA;
9-(3-fluoro-2-phosphonylmethoxypropyl)adenine Gancyclovir, GCV;
9-(1,3-dihydroxy-2-propoxymethyl)guanine GS-7340;
9-[R-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]-
phenoxyphosphinyl]methoxy]propyl]adenine HPMPA;
(S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine HPMPC;
(S)-9-(3-hydroxy-2- phosphonylmethoxypropyl)cytosine (Cidofovir)
Hydroxyurea, Droxia .RTM. Indinavir, Crixivan .RTM. Kaletra .RTM.
(lopinavir/ritonavir) Lamivudine, 3TC, Epivir .TM.; (2R, 5S,
cis)-4-amino- 1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1-
H)-pyrimidin-2-one L-d4C; L-3'-deoxy-2',3'-didehydrocytidine L-ddC;
L-2',3'-dideoxycytidine L-Fd4C; L-3'-deoxy-2',3'-didehydro--
5-fluorocytidine L-FddC; L-2',3'-dideoxy-5-fluorocytidine Lopinavir
Nelfinavir, Viracept .RTM. Nevirapine, Viramune .RTM. Oxetanocin A;
9-(2-deoxy-2-hydroxymethyl-.beta.-D-erythro- oxetanosyl)adenine
Oxetanocin G; 9-(2-deoxy-2-hydroxymethyl-.- beta.-D-erythro-
oxetanosyl)guanine Penciclovir PMEDAP;
9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine PMPA, tenofovir;
(R)-9-(2-phosphonylmethoxypropyl)adenine PPA; phosphonoacetic acid
Ribavirin; 1-.beta.-D-ribofuranosyl-1,2,4-tri- azole-3-carboxamide
Ritonavir, Norvir .RTM. Saquinavir, Invirase .RTM., Fortovase .RTM.
Sorivudine, BvaraU;
1-.beta.-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil Stavudine,
d4T, Zerit .RTM.; 2',3'-didehydro-3'-deoxythymidine
Trifluorothymidine, TFT; Trifluorothymidine Trizivir .RTM.
(abacavir sulfate/lamivudine/zidovudine) Vidarabine, araA;
9-.beta.-D-arabinofuranosyladenine Viread .RTM., tenofovir
disoproxil fumarate (DF), Bis POC PMPA, TDF;
2,4,6,8-Tetraoxa-5-phosphanonanedioic acid, 5-[[(1R)-
2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]-,
bis(1-methylethyl) ester, 5-oxide, (2E)-2-butenedioate (1:1)
Zalcitabine, Hivid .RTM., ddC; 2',3'-dideoxycytidine Zidovudine,
AZT, Retrovir .RTM.; 3'-azido-2',3'-dideoxythymdine Zonavir;
5-propynyl-1-arabinosyluracil
[0094] Another aspect of the present invention is a three-part
combination comprising GS-7340, emtricitabine, and tenofovir.
Tenofovir DF (also known as Viread.RTM., Tenofovir disoproxil
fumarate, Tenofovir disoproxil, Tenofovir, TDF, Bis-POC-PMPA (U.S.
Pat. Nos. 5,935,946, 5,922,695, 5,977,089, 6,043,230, 6,069,249)
has the structure: 7
[0095] The chemical names for Tenofovir disoproxil (DF) include:
[2-(6-amino-purin-9-yl)-1-methyl-ethoxymethyl]-phosphonic acid
diisopropoxycarbonyloxymethyl ester; and
2,4,6,8-tetraoxa-5-phosphanonane- dioic acid,
5-[[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]-,
bis(1-methylethyl) ester, 5-oxide. The CAS Registry numbers
include: 201341-05-1; 202138-50-9; 206184-49-8. It should be noted
that the ethoxymethyl unit of tenofovir (PMPA) has a chiral center.
The R (rectus, right handed configuration) enantiomer is shown.
However, the invention includes the S isomer, as well. The
invention includes all enantiomers, diastereomers, racemates, and
enriched stereoisomer mixtures of tenofovir and physiologically
functional derivatives thereof.
[0096] Tenofovir DF is a new nucleotide reverse transcriptase
inhibitor recently approved in the United States for the treatment
of HIV-1 infection in combination with other antiretroviral agents.
Tenofovir disoproxil fumarate or Viread.RTM. (Gilead Science, Inc.)
is the fumarate salt of tenofovir disoproxil. Viread.RTM. may be
named as: 2,4,6,8-Tetraoxa-5-phosphanonanedioic acid,
5-[[(1R)-2-(6-amino-9H-purin-- 9-yl)-1-methylethoxy]methyl]-,
bis(1-methylethyl) ester, 5-oxide, (2E)-2-butenedioate (1:1). The
CAS Registry number is 202138-50-9.
[0097] For example, a typical unitary dosage may contain 1 mg to
1000 mg of GS-7340, 1 mg to 1000 mg of emtricitabine, and 1 mg to
1000 mg of the third active ingredient. A unitary dosage form may
further comprise GS-7340, emtricitabine, the third active
ingredient, or physiologically functional derivatives of any of the
active ingredients thereof, and a pharmaceutically acceptable
carrier.
[0098] Combinations of the present invention enable patients
greater freedom from multiple dosage medication regimens and ease
the needed diligence required in remembering and complying with
complex daily dosing times and schedules. By combining GS-7340 and
emtricitabine into a single dosage form, the desired daily regimen
may be presented in a single dose or as two or more sub-doses per
day. The combination of co-formulated GS-7340 and emtricitabine may
be administered as a single pill, once per day.
[0099] A further aspect of the invention is a patient pack
comprising at least one active ingredient GS-7340, emtricitabine or
a physiologically functional derivative of either of the
combination and an information package or product insert containing
directions on the use of the combination of the invention.
[0100] Segregation of active ingredients in pharmaceutical powders
and granulations is a widely recognized problem that can result in
inconsistent dispersions of the active ingredients in final dosage
forms. Some of the main factors contributing to segregation are
particle size, shape and density. Segregation is particularly
troublesome when attempting to formulate a single homogenous tablet
containing multiple active ingredients having different densities
and different particle sizes. Glidants are substances that have
traditionally been used to improve the flow characteristics of
granulations and powders by reducing interparticulate friction. See
Lieberman, Lachman, & Schwartz, Pharmaceutical Dosage Forms:
Tablets, Volume 1, p. 177-178 (1989), incorporated herein by
reference. Glidants are typically added to pharmaceutical
compositions immediately prior to tablet compression to facilitate
the flow of granular material into the die cavities of tablet
presses. Glidants include: colloidal silicon dioxide, asbestos free
talc, sodium aluminosilicate, calcium silicate, powdered cellulose,
microcrystalline cellulose, corn starch, sodium benzoate, calcium
carbonate, magnesium carbonate, metallic stearates, calcium
stearate, magnesium stearate, zinc stearate, stearowet C, starch,
starch 1500, magnesium lauryl sulfate, and magnesium oxide.
Exemplary Tablet Formulation A has colloidal silicon dioxide
(Examples). Glidants can be used to increase and aid blend
composition homogeneity in formulations of anti-HIV drugs (U.S.
Pat. No. 6,113,920). The novel compositions of the present
invention may contain glidants to effect and maintain homogeneity
of active ingredients during handling prior to tablet
compression.
[0101] The present invention provides pharmaceutical formulations
combining the active ingredients GS-7340 and emtricitabine, or
physiologically functional derivatives thereof, in a sufficiently
homogenized form, and a method for using this pharmaceutical
formulation. An object of the present invention is to utilize
glidants to reduce the segregation of active ingredients in
pharmaceutical compositions during pre-compression material
handling. Another object of the present invention is to provide a
pharmaceutical formulation combining the active ingredients GS-7340
and emtricitabine, or physiologically functional derivatives
thereof, with a pharmaceutically acceptable glidant, resulting in a
mixture characterized by a pharmaceutically acceptable measure of
homogeneity.
[0102] Formulations include those suitable for oral, rectal, nasal,
topical (including transdermal, buccal and sublingual), vaginal or
parenteral (including subcutaneous, intramuscular, intravenous and
intradermal) administration. The formulations may conveniently be
presented in unit dosage form and may be prepared by any methods
well known in the art of pharmacy. Such methods represent a further
feature of the present invention and include the step of bringing
into association the active ingredients with the carrier which
constitutes one or more accessory ingredients. In general, the
formulations are prepared by uniformly and intimately bringing into
association the active ingredients with liquid carriers or finely
divided solid carriers or both, and then if necessary shaping the
product.
[0103] Formulations of the present invention suitable for oral
administration may be presented as discrete units such as capsules,
caplets, cachets or tablets each containing a predetermined amount
of the active ingredients; as a powder or granules; as a solution
or a suspension in an aqueous or non-aqueous liquid; or as an
oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The
active ingredient may also be presented as a bolus, electuary or
paste.
[0104] A tablet may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared by compressing in a suitable machine the active
ingredients in a free-flowing form such as a powder or granules,
optionally mixed with a binder (e.g. povidone, gelatin,
hydroxypropyl methylcellulose), lubricant, inert diluent,
preservative, disintegrant (e.g. sodium starch glycollate,
cross-linked povidone, cross-linked sodium carboxymethyl cellulose)
surface-active or dispersing agent. Molded tablets may be made by
molding a mixture of the powdered compound moistened with an inert
liquid diluent in a suitable machine. The tablets may optionally be
coated or scored and may be formulated so as to provide slow or
controlled release of the active ingredients therein using, for
example, cellulose ether derivatives (e.g., hydroxypropyl
methylcellulose) or methacrylate derivatives in varying proportions
to provide the desired release profile. Tablets may optionally be
provided with an enteric coating, to provide release in parts of
the gut other than the stomach.
[0105] Formulations suitable for topical administration in the
mouth include lozenges comprising the active ingredients in a
flavored base, usually 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
salicylates. Topical administration may also be by means of a
transdermal iontophoretic device.
[0106] Formulations suitable for vaginal administration may be
presented as pessaries, tampons, creams, gels, pastes, foams or
spray formulations containing in addition to the active ingredient
such carriers as are known in the art to be appropriate.
[0107] Formulations suitable for penile administration for
prophylactic or therapeutic use may be presented in condoms,
creams, gels, pastes, foams or spray formulations containing in
addition to the active ingredient such carriers as are known in the
art to be appropriate.
[0108] Pharmaceutical formulations suitable for rectal
administration wherein the carrier is a solid are most preferably
presented as unit dose suppositories. Suitable carriers include
cocoa butter and other materials commonly used in the art. The
suppositories may be conveniently formed by admixture of the active
combination with the softened or melted carrier(s) followed by
chilling and shaping in moulds.
[0109] Formulations suitable for parenteral administration include
aqueous and nonaqueous isotonic sterile injection solutions which
may contain anti-oxidants, buffers, bacteriostats and solutes which
render the formulation isotonic with the blood of the intended
recipient; and aqueous and non-aqueous sterile suspensions which
may include suspending agents and thickening agents; and liposomes
or other microparticulate systems which are designed to target the
compound to blood components or one or more organs. The
formulations may be presented in unit-dose or multi-dose sealed
containers, for example, ampoules and vials, and may be stored in a
freeze-dried (lyophilized) condition requiring only the addition of
the sterile liquid carrier, for example water for injection,
immediately prior to use. Extemporaneous injection solutions and
suspensions may be prepared from sterile powders, granules and
tablets of the kind previously described.
[0110] Exemplary unit dosage formulations are those containing a
daily dose or daily subdose of the active ingredients, as
hereinbefore recited, or an appropriate fraction thereof. It should
be understood that in addition to the ingredients particularly
mentioned above the formulations of this invention may include
other agents conventional in the art having regard to the type of
formulation in question, for example, those suitable for oral
administration may include such further agents as sweeteners,
thickeners and flavoring agents.
[0111] The compounds of the combination of the present invention
may be obtained in a conventional manner, known to those skilled in
the art. Tenofovir disoproxil fumarate can be prepared, for
example, as described in U.S. Pat. No. 5,977,089. Methods for the
preparation of FTC are described in WO 92/14743, incorporated
herein by reference.
[0112] Composition Use
[0113] Compositions of the present invention are administered to a
human or other mammal in a safe and effective amount as described
herein. These safe and effective amounts will vary according to the
type and size of mammal being treated and the desired results of
the treatment. Any of the various methods known by persons skilled
in the art for packaging tablets, caplets, or other solid dosage
forms suitable for oral administration, that will not degrade the
components of the present invention, are suitable for use in
packaging. The combinations may be packaged in glass and plastic
bottles. Tablets, caplets, or other solid dosage forms suitable for
oral administration may be packaged and contained in various
packaging materials optionally including a dessicant, e.g. silica
gel. Packaging may be in the form of unit dose blister packaging.
For example, a package may contain one blister tray of GS-7340 and
another blister tray of emtricitabine pills, tablets, caplets, or
capsule. A patient would take one dose, e.g. a pill, from one tray
and one from the other. Alternatively, the package may contain a
blister tray of the co-formulated combination of GS-7340 and
emtricitabine in a single pill, tablet, caplet or capsule. As in
other combinations and packaging thereof, the combinations of the
invention include physiological functional derivatives of GS-7340
and emtricitabine.
[0114] The packaging material may also have labeling and
information related to the pharmaceutical composition printed
thereon. Additionally, an article of manufacture may contain a
brochure, report, notice, pamphlet, or leaflet containing product
information. This form of pharmaceutical information is referred to
in the pharmaceutical industry as a "package insert." A package
insert may be attached to or included with a pharmaceutical article
of manufacture. The package insert and any article of manufacture
labeling provides information relating to the pharmaceutical
composition. The information and labeling provides various forms of
information utilized by health-care professionals and patients,
describing the composition, its dosage and various other parameters
required by regulatory agencies such as the United States Food and
Drug Agencies.
[0115] Assays of the Combinations
[0116] The combinations of the inventions may be tested for in
vitro activity against HIV and sensitivity, and for cytotoxicity in
laboratory adapted cell lines, e.g. MT2 and in peripheral blood
mononuclear cells (PBMC) according to standard assays developed for
testing anti-HIV compounds, such as WO 02/068058 and U.S. Pat. No.
6,475,491. Combination assays may be performed at varying
concentrations of the compounds of the combinations to determine
EC.sub.50 by serial dilutions.
EXAMPLES
[0117] The following examples further describe and demonstrate
particular embodiments within the scope of the present invention.
The examples are given solely for illustration and are not to be
construed as limitations as many variations are possible without
departing from spirit and scope of the Invention. The following
examples are intended for illustration only and are not intended to
limit the scope of the invention in any way. "Active ingredient"
denotes GS-7340, emtricitabine, or a physiologically functional
derivative of either thereof.
[0118] Tablet Formulation
[0119] The following exemplary formulations A, B, C, D, E, and F
are prepared by wet granulation of the ingredients with an aqueous
solution, addition of extragranular components and then followed by
addition of magnesium stearate and compression.
2 mg/tablet Formulation A: GS-7340 150 emtricitabine 200
Microcrystalline Cellulose 200 Lactose Monohydrate 325 Sodium
Starch Glycollate 60 Pregelatinized Starch 50 Colloidal silicon
dioxide 5 Magnesium Stearate 10 1000 Formulation B: GS-7340 150
emtricitabine 200 Microcrystalline Cellulose 200 Lactose
Monohydrate 330 Croscarmellose Sodium 60 Pregelatinized Starch 50
Magnesium Stearate 10 1000 Formulation C: GS-7340 50 emtricitabine
200 Microcrystalline Cellulose 200 Lactose Monohydrate 330
Croscarmellose Sodium 60 Pregelatinized Starch 50 Magnesium
Stearate 10 900 Formulation D: GS-7340 25 emtricitabine 200
Microcrystalline Cellulose 200 Lactose Monohydrate 330
Croscarmellose Sodium 60 Pregelatinized Starch 50 Magnesium
Stearate 10 875 Formulation E: GS-7340 150 emtricitabine 100
Microcrystalline Cellulose 200 Lactose Monohydrate 330
Croscarmellose Sodium 60 Pregelatinized Starch 50 Magnesium
Stearate 10 900 Formulation F: GS-7340 100 emtricitabine 100
Microcrystalline Cellulose 200 Lactose Monohydrate 330
Croscarmellose Sodium 60 Pregelatinized Starch 50 Magnesium
Stearate 10 850
[0120] Formulation G (Controlled Release Formulation):
[0121] This formulation is prepared by wet granulation of the
ingredients with an aqueous solution, followed by the addition of
magnesium stearate and compression.
3 mg/tablet GS-7340 300 emtricitabine 200 Hydroxypropyl
Methylcellulose 112 Lactose B.P. 53 Pregelatinized Starch B.P. 28
Magnesium Stearate 7 total: 700
[0122] Drug release takes place over a period of about 6-8 hours
and is complete after 12 hours.
[0123] Capsule Formulations
[0124] Formulation H:
[0125] A capsule formulation is prepared by admixing the
ingredients and filling into a two-part hard gelatin or
hydroxypropyl methylcellulose capsule.
4 mg/capsule Active Ingredient 500 Microcrystalline Cellulose 143
Sodium Starch Glycollate 25 Magnesium Stearate 2 total: 670
[0126] Formulation I (Controlled Release Capsule):
[0127] The following controlled release capsule formulation is
prepared by extruding ingredients a, b, and c using an extruder,
followed by spheronization of the extrudate and drying. The dried
pellets are then coated with release-controlling membrane (d) and
filled into a two-piece, hard gelatin or hydroxypropyl
methylcellulose capsule.
5 mg/capsule (a) Active Ingredient 500 (b) Microcrystalline
Cellulose 125 (c) Lactose B.P. 125 (d) Ethyl Cellulose 13 total:
763
[0128] Formulation J (Oral Suspension):
[0129] The active ingredients are admixed with the ingredients and
filling them as dry powder. Purified water is added and mixed well
before use.
6 Active Ingredient 500 mg Confectioner's Sugar 2000 mg Simethicone
300 mg Methylparaben 30 mg Propylparaben 10 mg Flavor, Peach 500 mg
Purified Water q.s. to 5.00 ml
[0130] Formulation K (Suppository):
[0131] One-fifth of the Witepsol H15 is melted in a steam-jacketed
pan at 45.degree. C. maximum. The active ingredients are sifted
through a 200 micron sieve and added to the molten base with
mixing, using a Silverson fitted with a cutting head, until a
smooth dispersion is achieved. Maintaining the mixture at
45.degree. C., the remaining Witepsol H15 is added to the
suspension and stirred to ensure a homogenous mix. The entire
suspension is passed through a 250 micron stainless steel screen
and, with continuous stirring, is allowed to cool to 40.degree. C.
At a temperature of 38.degree. C. to 40.degree. C., 2.02 g of the
mixture is filled into suitable, 2 mL plastic molds. The
suppositories are allowed to cool to room temperature.
7 mg/Suppository Active Ingredient 500 Hard Fat, B.P. (Witepsol H15
- Dynamit 1770 Nobel) total 2270
[0132] A fixed dose combination tablet of GS-7340 and
emtricitabine, or their physiologically functional derivatives, may
be formulated using a wet granulation/fluid-bed drying process
using conventional methods. See: U.S. Pat. No. 5,935,946; L. Young
(editor). Tableting Specification Manual 5.sup.th ed., American
Pharmaceutical Association, Washington, D.C., (2001); L. Lachman,
H. Lieberman (editors). Pharmaceutical Dosage Forms: Tablets (Vol
2), Marcel Dekker Inc., New York, 185-202 (1981); J. T. Fell and J.
M. Newton, J. Pharm. Pharmacol. 20, 657-659 (1968); US Pharmacopeia
24-National Formulary 19, "Tablet Friability", Chapter
<1216>, Page 2148 (2000).
[0133] All publications and patent applications cited herein are
incorporated by reference to the same extent as if each individual
publication or patent application was specifically and individually
indicated to be incorporated by reference.
[0134] Although certain embodiments are described in detail above,
those having ordinary skill in the art will clearly understand that
many modifications are possible in the embodiments without
departing from the teachings thereof. All such modifications are
intended to be encompassed within the claims of the invention.
[0135] Embodiments of the Invention:
[0136] A. A pharmaceutical composition comprising an effective
amount of a compound of the formula: 8
[0137] wherein R.sup.5 is H or CH.sub.3; R.sup.6 and R.sup.8 are
independently selected from H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 substituted alkyl, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.6-C.sub.20 arylalkyl, and
C.sub.6-C.sub.20 substituted arylalkyl; R.sup.7 is the side chain
of any naturally-occurring or pharmaceutically acceptable amino
acid and where if the side chain comprises carboxyl, the carboxyl
group is optionally esterified with an alkyl or aryl group;
R.sup.11 is amino, alkylamino, oxo, or dialkylamino; and R.sup.12
is amino or H;
[0138] or a physiologically functional derivative thereof;
[0139] in combination with an effective amount of a compound of the
formula 9
[0140] wherein B is selected from adenine, guanine, cytosine,
uracil, thymine, 7-deazaadenine, 7-deazaguanine,
7-deaza-8-azaguanine, 7-deaza-8-azaadenine, inosine, nebularine,
nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropurine,
2,6-diaminopurine, hypoxanthine, pseudouridine, 5-fluorocytosine,
5-chlorocytosine, 5-bromocytosine, 5-iodocytosine, pseudocytosine,
pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine,
7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothymine,
4-thiouracil, O.sup.6-methylguanine, N.sup.6-methyladenine,
O.sup.4-methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil,
4-methylindole, and a pyrazolo[3,4-D]pyrimidine; and
[0141] R is selected from H, C.sub.1-C.sub.18 alkyl,
C.sub.1-C.sub.18 substituted alkyl, C.sub.2-C.sub.18 alkenyl,
C.sub.2-C.sub.18 substituted alkenyl, C.sub.2-C.sub.18 is alkynyl,
C.sub.2-C.sub.18 substituted alkynyl, C.sub.6-C.sub.20 aryl,
C.sub.6-C.sub.20 substituted aryl, C.sub.2-C.sub.20 heterocycle,
C.sub.2-C.sub.20 substituted heterocycle, phosphonate,
phosphophosphonate, diphosphophosphonate, phosphate, diphosphate,
triphosphate, polyethyleneoxy or a physiologically functional
derivative thereof; and
[0142] a pharmaceutically acceptable carrier.
[0143] B. A composition of embodiment A wherein, in formula 1,
R.sup.7 is H, CH.sub.3 or CH(CH.sub.3).sub.2.
[0144] C. A composition of embodiment A wherein, in formula 1,
R.sup.6 is phenyl.
[0145] D. A composition of embodiment A wherein, in formula 1,
R.sup.8 is CH.sub.3, CH.sub.2CH.sub.3, or CH(CH.sub.3).sub.2.
[0146] E. A composition of embodiments A through D wherein, in
formula 2, B is cytosine or a 5-halocytosine and R is H.
[0147] F. A composition of embodiments A through E wherein, in
formula 2, B is 5-fluorocytosine and R is H.
[0148] G. A pharmaceutical formulation of embodiments A through F
further comprising a third active ingredient selected from the
group consisting of a protease inhibitor, a nucleoside or
nucleotide reverse transcriptase inhibitor, a non-nucleoside
reverse transcriptase inhibitor, and an integrase inhibitor.
[0149] H. A pharmaceutical formulation of embodiments A through G
in unit dosage form.
[0150] I. A method for the treatment or prevention of the symptoms
or effects of an HIV infection in an infected animal which
comprises administering to said animal a pharmaceutical composition
of embodiments A through G.
* * * * *