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Publication numberUS20040224916 A1
Publication typeApplication
Application numberUS 10/757,122
Publication dateNov 11, 2004
Filing dateJan 13, 2004
Priority dateJan 14, 2003
Also published asCA2512319A1, CA2512475A1, CA2512475C, CN102670629A, CN102670629B, CN105596356A, DE602004014470D1, EP1583542A1, EP1583542B1, EP1583542B9, EP1585527A1, EP1923063A2, EP1923063A3, EP3025718A1, US8592397, US8716264, US9457036, US9744181, US20040224917, US20060234982, US20060246130, US20090036408, US20090143314, US20140213556, US20150111855, US20150111856, US20170232019, WO2004064845A1, WO2004064845A8, WO2004064846A1
Publication number10757122, 757122, US 2004/0224916 A1, US 2004/224916 A1, US 20040224916 A1, US 20040224916A1, US 2004224916 A1, US 2004224916A1, US-A1-20040224916, US-A1-2004224916, US2004/0224916A1, US2004/224916A1, US20040224916 A1, US20040224916A1, US2004224916 A1, US2004224916A1
InventorsTerrance Dahl, Mark Menning, Reza Oliyai
Original AssigneeGilead Sciences, Inc.
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Compositions and methods for combination antiviral therapy
US 20040224916 A1
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-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one (emtricitabine, (−)-cis FTC, Emtriva™) 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.
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Claims(57)
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]-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)-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]-phenoxyphosphinyl]methoxy]propyl]adenine (GS-7340) or a physiologically functional derivative thereof, and a compound of the formula:
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, O6-methylguanine, N6-methyladenine, O4-methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, and a pyrazolo[3,4-D]pyrimidine; and
R is selected from H, C1-C18 alkyl, C1-C18 substituted alkyl, C2-C18 alkenyl, C2-C18 substituted alkenyl, C2-C18 alkynyl, C2-C18 substituted alkynyl, C6-C20 aryl, C6-C20 substituted aryl, C2-C20 heterocycle, C2-C20 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-hydroxymethyl-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)-pyrimidin-2-one.
12. The method according to claim 1 wherein the combination comprises a physiologically functional derivative of GS-7340 which has the structure:
wherein R5 is H or CH3; R6 and R8 are independently selected from H, C1-C6 alkyl, C1-C6 substituted alkyl, C6-C20 aryl, C6-C20 substituted aryl, C6-C20 arylalkyl, and C6-C20 substituted arylalkyl; R7 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; R11 is amino, alkylamino, oxo, or dialkylamino; and R12 is amino or H;
or a pharmaceutically acceptable salt or solvate thereof.
13. The method according to claim 12 wherein R7 is H, CH3 or CH(CH3)2.
14. The method according to claim 12 wherein R6 is phenyl.
15. The method according to claim 12 wherein R8 is CH3, CH2CH3, or CH(CH3)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-(isopropoxycarbonyl)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)-pyrimidin-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:
wherein R5 is H or CH3; R6 and R8 are independently selected from H, C1-C6 alkyl, C1-C6 substituted alkyl, C6-C20 aryl, C6-C20 substituted aryl, C6-C20 arylalkyl, and C6-C20 substituted arylalkyl; R7 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; R11 is amino, alkylamino, oxo, or dialkylamino; and R12 is amino or H;
or a pharmaceutically acceptable salt or solvate thereof.
38. The pharmaceutical formulation according to claim 37 wherein R7 is H, CH3 or CH(CH3)2.
39. The pharmaceutical formulation according to claim 37 wherein R6 is phenyl.
40. The pharmaceutical formulation according to claim 37 wherein R8 is CH3, CH2CH3, or CH(CH3)2.
41. A patient pack comprising at least one active ingredient selected from 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-hydroxymethyl-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™, 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-α. However, it must be noted that combinations of compounds can give rise to increased cytotoxicity. For example, AZT and recombinant interferon-α 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]methoxy]propyl]adenine (GS-7340) and (2R, 5S, cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-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™), 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]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.
  • [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 (—CH3), ethyl, Et (—CH2CH3), acetylenic (—C≡CH), ethylene, vinyl (—CH═CH2), 1-propyl, n-Pr, n-propyl (—CH2CH2CH3), 2-propyl, i-Pr, i-propyl (—CH(CH3)2), allyl (—CH2CH═CH2), propargyl (—CH2C≡CH), cyclopropyl (—C3H5), 1-butyl, n-Bu, n-butyl (—CH2CH2CH2CH3), 2-methyl-1-propyl, i-Bu, i-butyl (—CH2CH(CH3)2), 2-butyl, s-Bu, s-butyl (—CH(CH3)CH2CH3), 2-methyl-2-propyl, t-Bu, t-butyl (—C(CH3)3), 1-pentyl, n-pentyl, (—CH2CH2CH2CH2CH3), 2-pentyl (—CH(CH3)CH2CH2CH3), 3-pentyl (—CH(CH2CH3)2), 2-methyl-2-butyl (—C(CH3)2CH2CH3), cyclopentyl (—C5H9), 3-methyl-2-butyl (—CH(CH3)CH(CH3)2), 3-methyl-1-butyl (—CH2CH2CH(CH3)2), 2-methyl-1-butyl (—CH2CH(CH3)CH2CH3), 1-hexyl (—CH2CH2CH2CH2CH2CH3), 5-hexenyl (—CH2 CH2CH2CH2CH═CH2) 1-hexyl (—CH(CH3)CH2CH2CH2CH3), 3-hexyl (—CH(CH2CH3)(CH2CH2CH3)), cyclohexyl (—C6H11), 2-methyl-2-pentyl (—C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (—CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (—CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (—C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (—CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (—C(CH3)2CH(CH3)2), and 3,3-dimethyl-2-butyl (—CH(CH3)C(CH3)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 sp3 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—, —NR2, —NR3, =NR, —CX3, —CN, —OCN, —SCN, —N═C═O, —NCS, —NO, —NO2, =N2, —N3, NC(═O)R, —C(═O)R, —C(═O)NRR—S(═O)2O, —S(═O)2OH, —S(═O)2R, —OS(═O)2OR, —S(═O)2NR, —S(═O)R, —OP(═O)O2RR, —P(═O)O2RR —P(═O)(O)2, —P(═O)(OH)2, —C(═O)R, —C(═O)X, —C(S)R, —C(O)OR, —C(O)O, —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-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine, and has the structure:
  • [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 μM. 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 μM 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:
  • [0046]
    The chemical names of PMPA include: (R)-9-(2-phosphonylmethoxypropyl)adenine; and phosphonic acid, [[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]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:
  • [0048]
    PMEA (R5=H) and PMPA (R5=CH3). R6 and R8 are independently selected from H, C1-C6 alkyl, C1-C6 substituted alkyl, C6-C20 aryl, C6-C20 substituted aryl, C6-C20 arylalkyl, C6-C20 substituted arylalkyl. R7 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, R7 may be H, CH3 or CH(CH3)2. R11 is amino, alkylamino, oxo, or dialkylamino. R12 is amino or H. Exemplary embodiments include where R is methyl, R6 is phenyl, and R8 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 R5 may be the R or S enantiomer when R5 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™), 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:
  • [0052]
    The chemical names for emtricitabine include: (−)-cis-FTC; β-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-pyrimidin-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-oxathiolan-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)-(1H)-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:
  • [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, 2nd Edition, (1996) Oxford University Press, pp. 15-81).
  • [0057]
    Also in the 1,3 oxathiolane nucleoside structure above, R is H, C1-C18 alkyl, C2l-C18 substituted alkyl, C2-C18 alkenyl, C2-C18 substituted alkenyl, C2-C18 alkynyl, C2-C18 substituted alkynyl, C6-C20 aryl, C6-C20 substituted aryl, C2-C20 heterocycle, C2-C20 substituted heterocycle, phosphonate, phosphophosphonate, diphosphophosphonate, phosphate, diphosphate, triphosphate, polyethyleneoxy, or a prodrug moiety
  • [0058]
    Physiologically functional derivatives of emtricitabine also include 3TC (lamivudine, Epivir®), a reverse transcriptase inhibitor approved in the United States for the treatment of HIV-1 infection in combination with AZT (Zidovudine) as Combivir® (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:
  • [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 C1-C18 alkyl (for example, methyl, n-propyl, t-butyl, or n-butyl); C3-C12 cycloalkyl; alkoxyalkyl (for example, methoxymethyl); arylalkyl (for example, benzyl); aryloxyalkyl (for example, phenoxymethyl); C5-C20 aryl (for example, phenyl optionally substituted by, for example, halogen, C1-C4 alkyl, C1-C4 alkoxy, or amino; acyloxymethyl esters —CH2C(═O)R9 (e.g. POM) or acyloxymethyl carbonates —CH2C(═O)OR9 (e.g. POC) where R9 is C1-C6 alkyl, C1-C6 substituted alkyl, C6-C20 aryl or C6-C20 substituted aryl. For example, ester groups may be pivaloyloxymethoxy, POM, —CH2C(═O)C(CH3)3; —CH2C(═O)OC(CH3)3; or POC, —CH2C(═O)OCH(CH3)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™ 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 NX4 + (wherein X is C1-C4 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+ and NX4 + (wherein X is independently selected from H or a C1-C4 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 μM. 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 μg 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 μg 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 μg 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™ (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.
    TABLE 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 ®
    Acyclovir, ACV; 9-(2-hydroxyethoxylmethyl)guanine
    Adefovir dipivoxil, Hepsera ®
    amdoxivir, DAPD
    Amprenavir, Agenerase ®
    araA; 9-β-D-arabinofuranosyladenine (Vidarabine)
    atazanivir sulfate (Reyataz ®)
    AZT; 3′-azido-2′,3′-dideoxythymdine, Zidovudine, (Retrovir ®)
    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-β-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-β-L-arabino-furanosyluracil
    Combivir ® (lamivudine/zidovudine)
    Cytallene; [1-(4′-hydroxy-1′,2′-butadienyl)cytosine]
    d4C; 3′-deoxy-2′,3′-didehydrocytidine
    DAPD; (−)-β-D-2,6-diaminopurine dioxolane
    ddA; 2′,3′-dideoxyadenosine
    ddAPR; 2,6-diaminopurine-2′,3′-dideoxyriboside
    ddC; 2′,3′-dideoxycytidine (Zalcitabine)
    ddI; 2′,3′-dideoxyinosine, didanosine, (Videx ®, Videx ® EC)
    Delavirdine, Rescriptor ®
    Didanosine, ddI, Videx ®; 2′,3′-dideoxyinosine
    DXG; dioxolane guanosine
    E-5-(2-bromovinyl)-2′-deoxyuridine
    Efavirenz, Sustiva ®
    Enfuvirtide, Fuzeon ®
    F-ara-A; fluoroarabinosyladenosine (Fludarabine)
    FDOC; (−)-β-D-5-fluoro-1-[2-(hydroxymethyl)-1,3-dioxolane]cytosine
    FEAU; 2′-deoxy-2′-fluoro-1-β-D-arabinofuranosyl-5-ethyluracil
    FIAC; 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-iodocytosine
    FIAU; 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-iodouridine
    FLG; 2′,3′-dideoxy-3′-fluoroguanosine
    FLT; 3′-deoxy-3′-fluorothymidine
    Fludarabine; F-ara-A; fluoroarabinosyladenosine
    FMAU; 2′-Fluoro-5-methyl-β-L-arabino-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 ®
    Indinavir, Crixivan ®
    Kaletra ® (lopinavir/ritonavir)
    Lamivudine, 3TC, Epivir ™; (2R, 5S, cis)-4-amino-
     1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-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 ®
    Nevirapine, Viramune ®
    Oxetanocin A; 9-(2-deoxy-2-hydroxymethyl-β-D-erythro-
    oxetanosyl)adenine
    Oxetanocin G; 9-(2-deoxy-2-hydroxymethyl-β-D-erythro-
    oxetanosyl)guanine
    Penciclovir
    PMEDAP; 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine
    PMPA, tenofovir; (R)-9-(2-phosphonylmethoxypropyl)adenine
    PPA; phosphonoacetic acid
    Ribavirin; 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide
    Ritonavir, Norvir ®
    Saquinavir, Invirase ®, Fortovase ®
    Sorivudine, BvaraU; 1-β-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil
    Stavudine, d4T, Zerit ®; 2′,3′-didehydro-3′-deoxythymidine
    Trifluorothymidine, TFT; Trifluorothymidine
    Trizivir ® (abacavir sulfate/lamivudine/zidovudine)
    Vidarabine, araA; 9-β-D-arabinofuranosyladenine
    Viread ®, 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 ®, ddC; 2′,3′-dideoxycytidine
    Zidovudine, AZT, Retrovir ®; 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®, 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:
  • [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-phosphanonanedioic 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® (Gilead Science, Inc.) is the fumarate salt of tenofovir disoproxil. Viread® 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 EC50 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.
    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.
    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.
    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.
    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.
    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° 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° 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° C. At a temperature of 38° C. to 40° C., 2.02 g of the mixture is filled into suitable, 2 mL plastic molds. The suppositories are allowed to cool to room temperature.
    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 5th 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:
  • [0137]
    wherein R5 is H or CH3; R6 and R8 are independently selected from H, C1-C6 alkyl, C1-C6 substituted alkyl, C6-C20 aryl, C6-C20 substituted aryl, C6-C20 arylalkyl, and C6-C20 substituted arylalkyl; R7 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; R11 is amino, alkylamino, oxo, or dialkylamino; and R12 is amino or H;
  • [0138]
    or a physiologically functional derivative thereof;
  • [0139]
    in combination with an effective amount of a compound of the formula
  • [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, O6-methylguanine, N6-methyladenine, O4-methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, and a pyrazolo[3,4-D]pyrimidine; and
  • [0141]
    R is selected from H, C1-C18 alkyl, C1-C18 substituted alkyl, C2-C18 alkenyl, C2-C18 substituted alkenyl, C2-C18 is alkynyl, C2-C18 substituted alkynyl, C6-C20 aryl, C6-C20 substituted aryl, C2-C20 heterocycle, C2-C20 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, R7 is H, CH3 or CH(CH3)2.
  • [0144]
    C. A composition of embodiment A wherein, in formula 1, R6 is phenyl.
  • [0145]
    D. A composition of embodiment A wherein, in formula 1, R8 is CH3, CH2CH3, or CH(CH3)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.
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US7827042Jul 31, 2007Nov 2, 2010The Invention Science Fund I, IncMethods and systems related to transmission of nutraceutical associated information
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Classifications
U.S. Classification514/47, 514/269
International ClassificationA61K31/675, A61K31/513, A61K45/06, A61K31/7076
Cooperative ClassificationA61K31/683, A61K31/675, A61K31/7076, A61K9/2013, A61K9/2054, A61K45/06, A61K9/2018, A61K9/2009, A61K9/2059, A61K31/513
European ClassificationA61K31/7076, A61K31/513, A61K31/675, A61K45/06
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Owner name: GILEAD SCIENCES, INC., CALIFORNIA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:DAHL, TERRENCE C.;MENNING, MARK M.;OLIYAI, REZA;REEL/FRAME:014635/0994;SIGNING DATES FROM 20040426 TO 20040429