ANTIVIRAL PRODRUGS AND THEIR PHARMACEUTICAL COMPOSITIONS

Abstract

4'-ethynyl-2-fluoro-2'-deoxyadenosine diesters and aqueous parenteral suspensions thereof provide extended in vivo viral suppression of the human immunodeficiency virus (HIV).

Description

Antiviral prodrugs and their pharmaceutical compositions. Cross-reference to related applications RRQznn / zznz / E / viAi This application claims the benefit of U.S. Provisional Application Serial No. 62 / 898.679, filed on September 11, 2019, which is incorporated herein by reference in its entirety. Field of invention The present invention relates to antiviral compounds and compositions useful for the treatment of acquired immunodeficiency syndrome (AIDS). Background of the invention 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) (MK-8591) represented by Formula I: It is a nucleoside analogue effective as a nucleoside reverse tryptase inhibitor (Current Opinion on HIV and AIDS 2018, 13, 294-299) and is useful as an antiretroviral in the treatment and pre-exposure prophylaxis of HIV-1 infection. EFdA is metabolized in cells into an active triphosphate anabolic (EFdA-TP) that inhibits HIV reverse transcriptase. However, EFdA has relatively high water solubility and a relatively short plasma concentration time course. As a result, EFdA can provide only a limited duration of viral suppression when administered to a patient for the treatment of human immunodeficiency virus (HIV) infection or for pre-exposure prophylaxis. Consequently, there is a need for formulations that can extend the duration of viral suppression after administration. The pharmaceutical compounds and preparations of the present invention satisfy this need. Compendium of the invention The antiviral compounds of the present invention are EFdA diesters and have limited water solubility. While EFdA has an aqueous solubility of 0.877 mg / mL at physiological pH, the present EFdA diesters have an aqueous solubility of less than 0.03 mg / mL at physiological pH, preferably less than 0.002 mg / mL. These EFdA diesters are crystalline, useful for providing extended duration of HIV suppression, and can be administered parenterally as a suspension in a pharmaceutically acceptable carrier. A preferred prophylactic dose for a human subject is in the range of approximately 80 mg to approximately 800 mg of the administered EFdA diester. RRQznn / zznz / E / YiAi parenterally at intervals of approximately six months in a dose volume of approximately 0.5 to approximately 4 milliliters per dose. A preferred treatment dose for a human subject is in the range of approximately 80 mg to approximately 800 mg of EFdA diester administered parenterally at intervals of approximately three months in a dose volume of approximately 0.5 to approximately 4 milliliters per dose. Parenteral formulations containing the antiviral compound of the present invention may be dry formulations comprising the antiviral compound together with pharmaceutically acceptable excipients or stable suspensions of the antiviral compound in an aqueous or oil-based medium. Brief description of the drawings In the drawings: Figure 1 shows an X-ray powder diffractogram (XPRD) of EFdA. Figure 2 shows data provided by Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA) of EFdA. Figure 3 shows the DSC and TGA data for Compound 2. Figure 4 shows the XPRD data for Compound 3. RRQznn / zznz / E / YiAi Figure 5 shows the DSC data for Compound 3. Figure 6 shows the TGA data for Compound 3. Figure 7 shows the XPRD data for Compound 5. Figure 8 shows the DSC data for Compound 5. Figure 9 shows the TGA data for Compound 5. Figure 10 graphically displays the data provided in Table 2. Figure 11 graphically displays the data provided in Table 3. Figure 12 graphically displays the data in Table 4. Figure 13 graphically displays the data from Example 10. Figure 14 shows the XPRD data for Compound 2. Figure 15 shows the XPRD data for Compound 6. Description of preferred embodiments Extended in vivo viral suppression is achieved by RRQznn / zznz / E / viAi diesters represented by Formula (II): RRQznn / zznz / E / v where R1 and R2 are independently -C(=O)R3 and R3 is a group member consisting of isopropyl, 3-pentyl, cyclopentyl, and phenylmethyl. The preceding diesters are prepared by reacting EFdA with the desired acid or acid anhydride and recovering the diester as a crystalline compound. The Examples below illustrate the preparation of the preferred diesters. Preparation of (2R,3S,5R)-5-(6-amino-2fluoro-9H-purin-9-yl)-2-ethynyl-2-((isobutyryloxy)methyl)tetrahydrofuran-3-yl isobutyrate EFdA o (6 equiv) DMAP (0.4 equiv) DCC (4 equiv) DMF.t.a., 5h Isobutyric acid (8.4 g, 27.3 mmol, 6 equiv.) was added dropwise to a mixture of EFdA (Compound 1) (3 g, 6.8 mmol, 1 equiv.) and 4-dimethylaminopyridine (DMAP) (499 mg, 2.73 mmol, 0.4 equiv.) in anhydrous dimethylformamide (DMF) (100 mL) at room temperature. The reaction was stirred for 5 h at room temperature. The reaction was monitored by LC-MS due to occasional alkylation of the NH2 group observed after a prolonged reaction time. The reaction mixture was then filtered to remove urea derivatives. Acetonitrile was used to rinse the reaction mixture. The reaction mixture was then washed twice with water and once with brine, and the solvent was dried, filtered, and evaporated under reduced pressure. The resulting crude material was purified by silica gel column chromatography using 60-70% ethyl acetate (EtOAc) in hexanes to obtain Compound 2 as a glassy solid.The vitreous solid obtained was dispersed in a minimal amount of isopropanol followed by rotary evaporation to obtain pure Compound 2 as a white solid (2.5 g, 85% yield). LC-MS (ESI+): m / z 434.49 [M+H]+. Approximately 250 mg / g of Compound 2 was suspended in an aqueous solution of 0.25% CMC-Na / 0.5% TWEEN-80 (26-gauge syringe) and subjected to stability testing for 2 weeks at 40°C / 75% relative humidity. Figure 14 provides XPRD data for Compound 6 from the incubated suspension, before incubation (bottom graph), after one week (middle graph), and after two weeks (top graph). RRQznn / zznz / E / viAi superior), showing that the compound retains good crystallinity in suspension. Preparation of 2-ethylbutanoate of (2R,3S,5R)-5-(6-amino2-fluoro-9H-purin-9-yl)-2-(((2-ethylbutanoyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-yl RRQznn / zznz / E / v EFdA oo (b equiv) DMAP (0.2 equiv) TEA (8 equiv) MeCN.ta, 5h 4-Dimethylaminopyridine (DMAP) was added (83 mg, 0.68 mmol, 0.2 equiv.) at 0°C to a mixture of EFdA (1 g, 3.4 mmol, 1 equiv.), 2-ethylbutanoic anhydride (4.4 g, 20.4 mmol, 6 equiv.), triethanolamine (TEA) (3.8 mL, 27.2 mmol, 8 equiv.) in anhydrous acetonitrile (MeCN) (43 mL) and cooled to 0°C. The resulting mixture was stirred for 0.5 h at 0°C and then for 5 h at room temperature. The reaction was monitored by LC-MS due to occasional alkylation of the NH2 group observed after prolonged reaction times. The reaction mixture was quenched with methanol and the solvent evaporated under reduced pressure. The resulting crude material was purified by silica gel column chromatography using 608 70% ethyl acetate (EtOAc) in hexanes to obtain Compound 3 as a glassy solid. The resulting glassy solid was dispersed in a minimal amount of isopropanol followed by rotary evaporation to obtain pure Compound 3 as a white solid (1.33 g, 80% yield). LC-MS (ESI+): m / z 490.56 [M+H]+. Preparation of (2R,3S,5R)-5(6-amino-2-fluoro-9H-purin-9-yl)-2-(((cyclopentanecarbonyl)oxy)methyl)-2-ethynyltetrahydrofuran-310yl cyclopentanecarboxylate RRQznn / zznz / E / viAi Compound 4 was prepared using the procedure followed for Compound 2 but using cyclopentanoic acid instead of isobutyric acid. LC-MS (ESI+): m / z 486, 44 [M+H]+. Preparation of (2R,3S,5R)-5-(6-amino-2fluoro-9H-purin-9-yl)-2-ethynyl-2-((2phenylacetoxy)methyl)tetrahydrofuran-3-yl 2-phenylacetate EFdA (6 equiv) DMAP (0.2 equiv) TEA (8 equiv) MeCN.ta, 3h RRQznn / zznz / E / v 4-Dimethylaminopyridine (DMAP) (42 mg, 0.34 mmol, 0.2 equiv.) was added at 0°C to a mixture of EFdA (499 mg, 1.7 mmol, 1 equiv.), 2-phenylacetic anhydride (2.6 g, 10.2 mmol, 6 equiv.), and triethanolamine (TEA) (1.9 mL, 13.6 mmol, 8 equiv.) in anhydrous acetonitrile (MeCN) (22 mL) and cooled to 0°C. The reaction was stirred for 0.5 h at 0°C and then for up to 3 h at room temperature. The reaction was monitored by LC-MS due to occasional alkylation of the NH2 group observed after prolonged reaction times. The reaction mixture was quenched with methanol, and the solvent was evaporated under reduced pressure. The resulting crude material was purified by silica gel column chromatography using 60-70% ethyl acetate (EtOAc) in hexanes to obtain Compound 5 as a glassy solid.The vitreous solid obtained was dispersed in a minimal amount of isopropanol followed by rotary evaporation to obtain pure Compound 5 as a white solid (694 mg, 77% yield). LC-MS (ESI+): m / z 530.52 [M+H]+. Table 1 presents the characterization data of the compound obtained by nuclear magnetic resonance (NMR) and liquid chromatography - mass spectrometry (LC-MS). (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9yl)-2-((benzoyloxy)methyl)-2-ethynyltetrahydrofuran-3-yl benzoate, 5 Compound 6 Compound 6 was prepared using a procedure similar to that used for Compound 2 using 4.5 equiv of the corresponding acid. LC-MS (ESI+): m / z 502.41 [M+H]+. Approximately 275 mg / g of Compound 6 was suspended in an aqueous solution of 0.25% CMC-Na / 0.5% TWEEN-80 (26-gauge syringe) and subjected to stability testing for 2 weeks at 40°C / 75% relative humidity. Figure 15 provides XPRD data for Compound 6 from the incubated suspension, before incubation (lower graph), after one week (middle graph), and after two weeks (upper graph), showing that the compound retains good RRQznn / zznz / E / YiAi crystallinity in suspension. Table 1: Preferred Compounds Comp. No. Structure Characterization data (NMR and LC-MS) 2 Π cv / \ ,,ζ^ζ ΤΗ NMR (4 00 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.96 (s, 1H), 7.87 (s, 1H), 6.35 (t, J = 6.6 Hz, 1H), 5.68 (t, J = 5.6 Hz, 1H), 4.40 (dd, J = 11.9, 1.5 Hz, 1H), 4.21 (d, J = 10.4 Hz, 1H), 3.81 (s, 1H), 3.18 (dt, J = 13.6, 6.8 Hz, 1H) , 2.69 - 2.57 (m, 2H), 1.2-1.1 (m, 6H), Characterization data (NMR and LC-MS) 1,08 - 0,98 (m, 6H). MS-ESI: m / z 434,49 observada (M+H)+ Análisis calculado para C20H24FN5O5: C, 55,42; H, 5,58; N, 16,16. Encontrado: C, 55,48; H, 5,73; N, 15,94 Solubilidad acuosa (pH 7,4): 0,028 mg / mLXH NMR (4 00 MHz, DMSO-de) δ” 8,35 (s, 1H) , 7,91 (d, J = 39,8 Hz, 2H) , 6,35 (t, J = 6,8 Hz, 1H) , 5,73 (t, J = 6,5 Hz, 1H), 4,38 (dd, J = 11,8, 2,5 Hz, 1H), 4,24 (dd, J = 11,7, 2,5 Hz, 1H), 3,81 (s, 1H) , 3,20 (dt, J = 13,5, 6,8 Hz, 1H) , 2,61 (dt, J = 13,2, 6,6 Hz, 1H), 2,29 (ddd, J = 8,3, 5,6, 2,6 Hz, 1H), 2,13 (tt, J = 8,9, 5,9 Hz, 1H) , 1,72 1,31 (m, 8H) , 0,88 (td, J = 7,5, 2,3 Hz, 6H) , 0,80 0,66 (m, 6H) . MS-ESI: m / z 490,56 observada (M+H)+Solubilidad acuosa (pH 7,4): <0,002 mg / mL NMR (4 00 MHz, DMSO-free) δ 8.34 (s, 1H), 7.92 (d, J = 36.1 Hz, 2H) , 6.34 (t, J = 6.8 Hz, 1H) , 5.68 (t, J = 6.1 Hz), t 4, 1 1.8 Hz, 1H), 4.21 (dd, J = 11.6, 2.4 Hz, 1H), 3.81 (s, 1H) , 3.18 (dt, J = 13, 9, 6, 9 Hz, 1H) , 2.90 -2.7 1.78 (m 2H) , 1.93 – 1.44 (m, 16H) . MS-ESI: m / z 486.44 observed (M+H)+Aqueous solubility (pH RRQznn / zznz / E / YiAi Comp. No. Structure Characterization data (NMR and LC-MS) 7,4): <0.001 mg / mL 5 X 0. Vo οχ Z^Z'' <n ) ( z—( 'Z θ*) LL !H NMR (4 00 MHz, DMSO-d6) δ 8,31 (s, 1H) , 7,93 (d, J = 37,3 Hz, 2H), 7,39 - 7,12 (m, 10H) , 6, 35 (t, J = 6, 7 Hz, 1H) , 5,71 (t, J = 6,0 Hz, 1H), 4,41 (d, J = 11,7 Hz, 1H) , 4,25 (d, J = 11, 3 Hz, 1H) , 3,88 - 3,71 (m, 3H) , 3,63 (q, J = 15,8 Hz, 2H) , 3,11 (dt, J = 14,0, 7,0 Hz, 1H), 2,63 (dt, J = 12,5, 6,4 Hz, 1H). MS-ESI: m / z 530,52 observada (M+H)+ Solubilidad acuosa (pH 7,4): <0,002 mg / mL 6 °Ύ° οχ o— ζ^ζ'χ / ^ο i* / \ u_ !H NMR (4 00 MHz, DMSO-de) δ 8,38 (s, 1H) , 8,09 (dt, J = 8,6, 1,4 Hz, 2H), 8,02 7,83 (m, 4H) , 7,76 - 7,68 (m, 1H), 7,66 (td, J = 7,4, 1,5 Hz, 1H), 7,59 (td, J= 7,6, 7,1, 1,7 Hz, 2H), 7,53 -7,44 (m, 2H), 6,54 (t, J = 6,8 Hz, 1H) , 6,16-6,08 (m, 1H), 4,72 (d, J = 11,6 Hz, 1H), 4,59 (d, J = 11,5 Hz, 1H), 3,84 (s, 1H), 3,41 - 3,32 (m, 1H) , 2,85 (dt, J = 13,4, 6,3 Hz, 1H).MS-ESI: m / z 502.41 observed (M+H)+ Aqueous solubility (pH 7.4): <0.002 mg / mL. The preceding discussion and examples are illustrative and should not be considered limiting. Other variations within the spirit of the present invention are possible and will be readily apparent to those skilled in the art. Synthesis of stable crystalline forms Example 1 Compound 2 (~200 mg) was completely dissolved in a minimal amount of acetone with stirring. The solvents were then slowly evaporated at room temperature. This resulted in a recrystallized sample as a white powder. Other solvents, including ethyl acetate, methanol, and tetrahydrofuran, can also be used. General examples for the formulation of compounds of the invention All formulation protocols generated a stable aqueous suspension with 26 gauge syringeability. Formulation of the EFdA. The EFdA was ground and sieved through a No. 80 sieve. A 0.25% solution of preformed sodium carboxymethylcellulose (sodium CMC) and 0.1% polyoxyethylenated sorbitan monooleate (20) (TWEEN-80) was added to approximately 300 mg of EFdA (Compound 1) to provide a suspension of approximately 1 gram (300 mg of 1 + ~700 mg of polymer solution) of the final formulation (approximately 300 mg / g). The suspension was then subjected to a sonication bath for 10 min in an ice bath. The density of the formulation was 1.064 g / mL and it provided a concentration of 319.2 mg / mL of RRQznn / zznz / E / YiAi EFdA. Example 2 The recrystallized Compound 2 was milled and sieved through a No. 80 sieve, US Standard Series of Sieves for Wire Cloth Panels (nominal sieve opening 0.180 mm). 250 mg of Compound 2 was taken into a suitable container and a preformed 0.25% sodium carboxymethylcellulose (CMC) and 0.1% TWEEN80 solution was added to obtain 1 gram (250 mg of Compound 2 ± 750 mg of polymer solution) of the final formulation (~250 mg / g). The suspension was then sonicated with a probe for 5 min in an ice bath (Sonication time: 5 min; Pulse amplitude: 20; Pulse application time: 30 sec; Pulse pause time: 20 sec). Example 3 Compound 3 was ground and sieved using No. 80 sieves, US Standard Series of Sieves for Wire Fabric Panels (nominal sieve opening 0.180 mm). 250 mg of Compound 3 was taken into a suitable container and a preformed 0.25% sodium CMC and 0.5% TWEEN-80 solution was added to obtain 1 gram (250 mg of Compound 3 ± 750 mg of polymer solution) of the final suspension (-250 mg / g). The suspension was then sonicated with a probe for 5 min in an ice bath (Sonication time: 5 min; Pulse amplitude: 20; Pulse application time: 30 sec; Pulse pause time: 20 sec). The density of the suspension was RRQznn / zznz / E / viAi of 1.004 g / mL. The previous suspension contained 250.88 mg / mL of Compound 3 (~150 mg / mL of EFdA). Example 4 Compound 5 was ground and sieved through a No. 80 sieve, US Standard Series of Sieves for Wire Cloth Panels (nominal sieve opening 0.180 mm). 200 mg of Compound 5 was placed in a suitable container, and a preformed 0.25% sodium CMC and 0.5% TWEEN-80 solution was added to obtain 1 gram (200 mg of Compound 5 ± 800 mg of polymer solution) of the final suspension (~200 mg / g). The suspension was then sonicated with a probe for 5 min in an ice bath (Sonication time: 5 min; Pulse amplitude: 20; Pulse application time: 30 sec; Pulse pause time: 20 sec). The density of the suspension was 1.047 g / mL. The previous suspension contained 209.4 mg / mL of Compound 5 (-115.97 mg / mL of EFdA). Pharmacokinetic (PK) studies Animals: The animals (male SD rats -200-250 kg and male Rhesus macaques -2-3 kg) were obtained from an approved supplier (SLAC Laboratory Animal Co. Ltd., Shanghai, China and / or Topgene Biotechnology, Wuhan, Hubei Province, China). Acclimation / Quarantine: Upon arrival, the animals' general health was assessed by a veterinary staff member or other authorized personnel. The animals were acclimated for at least 3 days before being placed. RRQznn / zznz / E / viAi in the studio. Animal housing: The animals were housed in groups during acclimatization and individually during the study. The animal room environment was controlled (target conditions: temperature 18 to 26°C, relative humidity 30 to 70%, 12 hours of artificial light and 12 hours of darkness). Temperature and relative humidity were monitored daily. Cannulation of animals: No The animals fasted for at least 12 hours before administration. All animals had access to the Certified Rodent and Non-Rodent Diet (Catalog No. M01F, SLAC Laboratory Animal C1. Ltd., Shanghai, China) ad libitum 4 hours after dosing. The water was autoclaved before being provided to the animals ad libitum. Periodic water analyses were performed and the results archived. There were no known contaminants in the diet or water that, at detection levels, were expected to interfere with the purpose, conduct, or outcome of the study. . Dose formulation SC formulation: The suspensions were prepared on the day of dosing according to the procedure described in Examples 2-5 above, and Tables 2-4. The animals were dosed within four hours of the RRQznn / zznz / E / viAi Suspension preparation. Two 20 pL aliquots of each prepared suspension were transferred to 1.5 mL polypropylene microcentrifugation tubes and dose validation was performed by LC / UV or LC-MS / MS. Dose administration The suspensions were administered by subcutaneous (SC) injection following the facility's standard operating procedures (SOPs). Sample collection Approximately 200 pL of blood were collected from the saphenous vein at each time point for rats and 0.5 mL for rhesus macaques. All blood samples were transferred to microcentrifugation tubes containing 4 pL of K2EDTA (0.5M) as an anticoagulant and placed on moist ice until processed to obtain plasma. Blood / plasma processing Blood: Blood samples were processed to obtain plasma by centrifugation at approximately 4°C, 3000 g for 15 min within half an hour of collection. Plasma samples were stored in polypropylene tubes, rapidly cooled on dry ice, and maintained at -70 ± 10°C until analysis by LC / MS / MS. Analysis of the samples RRQznn / zznz / E / YiAi Dose concentration verification The aliquots of the prepared suspension were collected in the middle position of each suspension in duplicate. The concentration of the active ingredient in each aliquot was determined using the LC / UV or LC / MS / MS method. Bioanalytical method and sample analysis The LC-MS / MS methods for the quantitative determination of the active ingredient (test compound) in a corresponding biological matrix were not subject to GLP (Good Laboratory Practices). A calibration curve was applied with 8 non-zero calibration standards for the method that includes a lower limit of quantitative determination (LLOQ). A set of quality control (QC) samples consisting of low, medium, and high concentrations was applied to the method. The study sample analysis will be performed simultaneously with a set of calibration standards and two sets of CC samples using the LC-MS / MS method (if the number of samples was greater than 48, then two calibration curves were applied with 2 sets of CC samples). Acceptance criteria: Linearity: a minimum of 6 calibration standards were recalculated with +20% of their nominal values ​​in plasma RRQznn / zznz / E / viAi Accuracy: A minimum of 4 out of 6 CC samples were recalculated to within ±20% of their nominal plasma values. Specificity: The average calculated concentration in the blank single matrix should be 0.5 times the LLOQ. Sensitivity: the LLOQ will target 1~3 ng / mL. Carryover: The average calculated carryover concentration in the single blank matrix immediately after the highest standard injection should be LLOQ. If the carryover could not meet the criteria, then the carryover percentage should be estimated following internal bioanalytical SOPs. Data analysis Plasma concentration data were analyzed over time using non-compartmental approaches with the Phoenix WinNonlin 6.3 software program. Cmax, Tmax, T^, AUC(Ut), AUC(o-in±), MRT(Ut>, MRT(U-inf) , %F and plasma concentration graphs over time profile were generated. Example 5: Several prodrugs, including EFdA (1) as a control, were subjected to single-dose rat PK studies via subcutaneous administration. All animals were injected with equivalent doses of 10 mg / kg and a concentration of 4 mg / mL of EFdA as an aqueous suspension in 0.5% CMC-Na and 0.5% TWEEN-80. Although similar exposure was observed, compounds 2, 3, and 5 exhibited plasma levels of EFdA above the lower limit of quantitative determination (LLOQ) for more than one week with a much lower Cmax than for EFdA. Table 2 shows the rat PK data for the Compounds 1, 2, 3, and 5 after subcutaneous (SC) administration at a dose equivalent to 10 mg / kg of the EFdA. Data are shown graphically in Figure 10. Table 2: SC rat PK: EFdA levels for EFdA, Compounds 1, 2, 3 and 5 RRQznn / zznz / E / viAi SC Comp 1 (EFdA) SC Comp 2 SC Comp 3 SC Comp 5 EFdA Dose (mg / kg) 10 10 10 10 EFdA Concentration (mg / kg) 4 4 4 4 Excipients 0.5% CMC-Na / 0.5% TWEEN-80 Ti / 2 (h) 1.3 ± 0.2 17 + 4 NC 12 + 4 MRTo-ultimate (11) 1.6 + 0.1 12 ± 1.2 20 ± 4 13 + 3 Tmax (11) 0.5 2 ± 1.1 4 ± 2.3 7 ± 0 Cmax (nM) 11.548 ± 3.173 1.795 ± 337 287 ± 177 968 ± 374 AUCo-last (nM*h) 22,528 ± 1,680 19,771 ± 1,219 6,475 ± 2,909 18,516 ± 4,409 AUCo-inf (nM*h) 23,235 ± 2,000 22,745 + 748 NC 19,993 + 3,525 Example 6: After optimization, PK studies in SC rats were again performed at a high equivalent dose of 100 mg / kg at an equivalent concentration of 120 mg / mL for Compound 3, 116 mg / mL for Compound 5, and 319 mg / mL for EFdA, respectively. Compound 3 provided a delayed Cmax and a Cmax 100 times lower than EFdA. In addition, improved half-life and mean residence time were observed, making Compound 3 and Compound 5 suitable for prophylaxis. Table 3A and Table 3B show the PK data for rats for Compounds 1, 3, and 5 after SC administration. Data for Compound 3 are shown graphically in Figure 11. Table 3A: Rat SC PK: EFdA levels for EFdA and Compound 3 RRQznn / zznz / E / viAi SC Comp 3 SC Comp 3 SC Comp 1 (EFdA) SC Comp 1 (EFdA) Dose of EFdA (mg / kg) 10 100 100 10 Excipients 0.5% CMC-Na / 0.5% TWEEN-80, 0.25% Na / CMC- 0.80% TWE / Na 0.1% TWEEN-80 0.5% CMCNa / 0.5% TWEEN-80 Conc. of EFdA (mg / mL) 4,120,319 4 Ti / 2 (h) NC 474 ± ​​168 99 ± 13 1.3 ± 0, 2 MRTo-last (h) 20 ± 4 456 ± 17 67 + 24 1.6 ± o, 1 Tmax (11) ±nM 4 + 2.3 312 +2x 0 1 177 66 ± 21 7,429 ± 1,584 11,548 ± 3,173 AUCo-last (nM*h) 6,475 ± 2909 38,306 ± 101 158,500 ± 17 22,528 ± UC (An*h*inf) 52,531 ± 39 159,373 ± 16 23,235 ± 2,000 RRQznn / zznz / E / v Table 3B: Rat PK SC: EFdA Levels for EFdA and Compound 5 SC Comp 5 SC Comp 1 (EFdA) EFdA dose (mg / kg) 100 100 Excipients 0.25% CMC-Na / 0.1% TWEEN-80 EFdA conc. (mg / mL) 116 319 Ti / 2 (h) 363 ± 411 99 ± 13 MRTo-last (11) 225 ± 64 67 ± 24 Cmax (nM) 244 ± 54 7,429 ± 1,584 AUCo-last (nM*h) 68,848 + 16,728 158,500 ± 17 AUCo-inf (nM*h) 129,209 ± 117,423 159,373 ± 16 Example 7: Following the rat pharmacokinetic (PK) analysis, the approach shifted to non-rodents, specifically rhesus macaques. Compound 5 and EFdA were subjected to single-dose, 5-dose PK studies in rhesus macaques via subcutaneous administration, with an equivalent dose of 50 mg / kg of EFdA. Aqueous suspensions contained 0.25% CMC-Na and 0.1% / 0.5% TWEEN-80, with equivalent concentrations of 116 mg / mL and 319 mg / mL of EFdA for Compound 5 and EFdA, respectively. With Compound 5, plasma levels of EFdA were observed above the LLOQ for more than one month, with a Cmax 24 times lower than that of EFdA. Table 4 shows the PK data for Rhesus Compounds 1 and 5 after SC administration at a dose equivalent to 50 mg / kg of EFdA. The data are shown graphically in Figure 12. Table 4: Rhesus SC PK: Plasma levels of EFdA after dosing of EFdA or Compound 5 in plasma RRQznn / zznz / E / YiAi EFdA SC EFdA (Plasma) Compound 5 SC EFdA (Plasma) EFdA Dose (mg / kg) 50 50 Excipients 0.25% CMC-Na 0.1% TWEEN-80 0.25% CMC-Na 0.5% TWEEN-80 EFdA Conc. (mg / mL) 319 116 Ti / 2 (h) 165 ± 56 1,063 ± 608 MRTo-ultimate (h) 79 ± 37 1,449 ± 517 Tmax (ti) 4 1 3.6 264 + 125 Cmax (nM) 3,060 ± 1,058 128 ± 52 C42days (llM) 0.6 ± 0.3 60 + 16 AUCo-ultimate (nM*h) 135,691 ± 22,574 143,330 ± 33,727 AUCo-inf (nM*h) 135,748 ± 22,594 145,643 ± 32,180 RRQznn / zznz / E / v The suspension medium for the compounds herein may be an aqueous vehicle such as water for injection (WFI) or a vegetable oil vehicle such as sesame oil, olive oil, and the like. The suspension medium may also contain pharmaceutically acceptable excipients such as nonionic surfactants, suspending or flocculating agents, preservatives, buffer solutions, toxicity adjusters, chelating agents, antioxidants, and the like. For prophylaxis, a preferred prophylactic dose for a human subject is in the range of approximately 80 mg to approximately 800 mg of the antiviral compound administered parenterally at intervals of approximately six months (semi-annually) in a dose volume of approximately 0.5 to 15 milliliters (mL) per dose. For the treatment of a human patient, the effective amount of the antiviral compound of the present invention preferably ranges from approximately 80 mg to approximately 800 mg at a dose volume of approximately 0.5 to approximately 4 mL per dose, more preferably an effective amount in the range of approximately 200 to approximately 400 mg, for a three-month dosing regimen. However, the dosing regimen may vary, depending on the time interval between doses administered in a particular dosing regimen. The term "effective quantity" as used herein and in the claims means a quantity of the antiviral compound sufficient to inhibit HIV reverse transcriptase, inhibit HIV replication, exert a prophylactic effect and / or exert a therapeutic effect after administration. The term administration and its variants, for example, the expression administering a compound, with reference to the claimed treatment method means providing the antiviral compound to the patient and includes self-administration as well as administration to the patient by another person. Preferably, parenteral suspensions suitable for injection contain the present antiviral compound in an amount ranging from approximately 3 to 45 percent by weight, based on the weight of the suspension. The preferred particle size is no larger than approximately 50 micrometers (µm), more preferably an average particle size in the range of approximately 6 µm to approximately RRQznn / zznz / E / YiAi pm. The preferred flocculating or suspending agents are linear polymers, particularly substituted celluloses such as methylcellulose, carboxymethylcellulose (CMC), hydroxypropylcellulose, hydroxypropylmethylcellulose and the like. The preferred surfactants are nonionic surfactants. The particularly preferred surfactant is polyoxyethylenated sorbitan monooleate (20) (TWEEN-80). In addition to parenteral dosage forms, the compounds herein may also be administered in oral dosage forms and as implants. The dosage forms containing the compounds herein may also include additional anti-HIV and / or anti-HBV agents such as cabotegravir, dolutegravir, doravirine, evilegravir, lesiverine, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, lamivudine, and the like. The invention further provides, in several embodiments, a method for prophylactic treatment of viremia or for the treatment of a viral infection in a patient where the inhibition of a reverse transcriptase is medically indicated, comprising administering to the patient an effective amount or concentration of a compound of Formula (II). More specifically, the compound of Formula (II) may RRQznn / zznz / E / v may be administered in a formulation that provides a slow, controlled, or sustained release of EFdA from these prodrugs. More specifically, the compound of Formula (II) may be formulated as an aqueous suspension, a solution, and may be encapsulated in particles for release, including PLGA and other materials known in the art. More specifically, the viral infection may be caused by HIV or HBV. Routes of administration for these prodrugs may include, but are not limited to, oral, parenteral, and implant release (composition and drug delivery device). In the method for the treatment or prevention of the viral infection, the method may further comprise an additional anti-HIV and / or anti-HBV agent, including, but not limited to, cabotegravir, dolutegravir, doravirine, elvitegravir, lersiverine, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, lamivudine, and similar agents. Example 8 The surfactant concentration was optimized with 0.3% and 0.5% methylcellulose in a formulation containing 400 mg / g of micronized Compound 5. Formulations were prepared with different concentrations of TWEEN-80 (0.1, 0.2, and 0.3%). No significant effect of surfactant concentration on viscosity, flow, or redispersion time was observed in the formulations after 10 days of storage. RRQznn / zznz / E / viAi observations are indicated in Table 5. Table 5: Optimization of surfactant concentration with 400 mg / g of Compound 5 Composition Concentration of surfactant TWEEN-80 Syringability (26G) Viscosity Flow Time to resuspend 0.3% methylcellulose 0.1% z ++ + + + + + + 2.2 min. 0.2% z ++ + + + + + + 2.5 min. 0.3% z ++++ +++ + 2.3 min. 0.5% methylcellulose 0.1% z ++ + + + + + + 2.5 min. 0.2% z + + + + + + + + 2.5 min. 0.3% z ++++ +++ + 3.0 min. Viscosity: ++++ Slightly viscous, +++ Viscous, ++ Very viscous, + Semi-solid Flow: + No flow, ++ Less flow, +++ Good flow, i / flow: Applicable with syringe ++++ Very good Example 9 A bulk batch (40 g) of the Compound 5 suspension was prepared with a concentration of 0.3% methylcellulose and 0.2% TWEEN-80. Although the polymer and surfactant concentrations were optimized with a 40 wt% drug concentration, a bulk batch with a 35 wt% drug concentration was also prepared during accelerated and long-term stability studies. The composition of the formulation loaded into a stability chamber is provided in Table 6. A detailed manufacturing procedure for the preparation and composition of the formulation is provided below. RRQznn / zznz / E / viAi Table 6: Formulation Composition Ingredient Amount (mg / g) Amount, g / 40 g Compound 5 350 14 Methylcellulose 3 0.120 TWEEN-80 2 0.08 Water for Injection (WFI) 645 25.8 Methylcellulose was slowly added to the required amount of water for injection (WFI) in a glass flask with continuous stirring. The resulting mixture was stirred until the solution was clear and free of lumps using a magnetic stirrer. TWEEN-80 (0.08 g) was added to the resulting solution and stirred thoroughly. Micronized Compound 5 (14 g; average particle size 11 µm) was slowly added to the prepared polymer surfactant solution under vigorous stirring at 1400 rpm using a magnetic stirrer. After complete addition of Compound 5, the resulting suspension was stirred (600 rpm) for 20 minutes to ensure uniform particle dispersion. The prepared formulation was characterized by various physicochemical properties such as assay, pH, % purity, redispersibility, injectability, polymorphic shape, and particle size. The results are presented in Table 7. Table 7: Physicochemical characterization of the formulation under preparation Test Parameter Appearance White dispersion pH 5.78 HPLC Assay (% indicated on label) 108.8% Purity % 99.34% Redispersibility Yes Injectability Yes Polymorphic form Equal to API Average particle size 14 pm The formulation shown in Table 6 was considered acceptable based on the characteristics shown in Table 7. Example 10 Aqueous suspensions of EFdA and Compounds 3 and 5 were administered subcutaneously to rhesus macaques, and periodically retrieved peripheral blood mononuclear cells (PBMCs) and pharmacokinetic data were evaluated. The 10 observed results are presented in Tables 8, 9, and 10 for both compounds and in Figure 13 for Compound 5. Table 8: PK of Rhesus SC: PBMC levels of EFdA-TP after dosing of Compound 5 or EFdA Compound 5 SC: EFdA-TP (PBMC) EFdA SC: EFdA-TP (PBMC) Nominal EFdA Dose (mg / kg) 50 50 Formulation 0.25% CMC-Na / 0.5% TWEEN-80 0.25% CMC-Na / 0.1% TWEEN-80 EFdA conc. (mg / mL) 116 319 Dose volume (mL / kg) 0.43 (tot. vol. 1.39 mL) 0.16 (tot. vol. 0.47 mL) Ti / 2 (d) 31 ± 17 12 ± 5 MRT O-last (Ó) 72 ± 19 6 + 1 MRT o-inf (d) 73 + 21 6 + 1 Tmax (d) 21 ± 13 2 ± 0 Cmax (μΜ) 192 ± 96 789 ± 154 Quitimo (μΜ) 0.71 0.03 AUCo-ultima (pM*h) 233.2743 ± 37.553 127.176 ± 29. 205 AUCo-inf (pM*h) 234.062 ± 37.077 127.201 + 29. 225 RRQznn / zznz / E / viAi Table 9: PK of Rhesus SC: Plasma levels of EFdA and PBMC of EFdA-TP after dosing of Compound 3 Compound 3 SC: EFdA (Plasma) Compound 3 SC: EFdA-TP (PBMC) Nominal dose of EFdA (mg / kg) 50 Formulation 0.25% CMC-Na / 0.5% TWEEN80 EFdA concentration (mg / mL) 150 Dose volume (mL / kg) 0.335 (total vol. 1.57 mL) Ti / 2 (h) 566 ± 344 1.022 ± 463 MRTo-ultimate (ti) 1.071 ± 488 394 ± 36 Tmax (ti) 440 + 270 784 + 485 Cmax (nM) 40 ± 28 627 ± 60 AUCo-ultimate (nM*h) 35,385 ± 18,522 807,473 ± 519,381 AUCo-inf (nM*h) 45,293 ± 14,840 1,447,998 ± 576,163 ββοζηη / ζζηζ / E / γ Table 10: PK of Rhesus SC: EFdA levels for the Compounds 3 and 5 in Plasma EFdA SC EFdA (Plasma) Compound 5 SC: EFdA (Plasma) Compound 3 SC: EFdA (Plasma) Nominal EFdA Dose (mg / kg) 50 50 50 Formulation 0.25% CMC-Na / 0.1% Tween 80 0.25% CMC-Na / 0.5% Tween 80 0.25% CMC-Na / 0.5% Tween 80 EFdA Conc. (mg / mL) 319 116 150 Ti / 2 (h) 165 ± 56 1,063 ± 608 566 + 344 MRTo-ultimate (Ir) 79 ± 37 1,449 ± 517 1,071 ± 488 Tmax (h) 4 ± 3, 6 264 ± 125 440 + 270 Cmax (nM) 3060 ± 1058 128 ± 52 40 ± 28 AU C 0 - last (nM*h) 135,691 + 22,574 143,330 + 33,727 35,385 + 18,522 AUCo-inf (nM*h) 135,748 ± 22,594 145,643 ± 32,180 45,293 ± 14,840

Claims

1. A compound of Formula (II): RRQznn / zznz / E / viAi wherein R1 and R2 are independently -C(=O)R3 and R3 is selected from the group consisting of isopropyl, 3-pentyl, cyclopentyl, phenyl, and phenylmethyl.

2. The compound of claim 1, which is crystalline (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2((isobutyryloxy)methyl) tetrahydrofuran-3-yl isobutyrate.

3. The compound of claim 1, which is crystalline (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-911)-2-(((2-ethylbutanoyl)oxy)methyl)-2-ethynyltetrahydrofuran-3yl 2-ethylbutanoate.

4. The compound of claim 1, which is crystalline (2R,3S,5R)-5-(6-amino-2-fluoro-9Hpurin-9-yl)-2-(((cyclopentanecarbonyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-yl cyclopentanecarboxylate.

5. The compound of claim 1, which is crystalline (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9yl)-2-ethynyl-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl 2phenylacetate.

6. An aqueous parenteral suspension comprising a compound of Formula (II): RRQznn / zznz / E / viAi wherein R1 and R2 are independently -C(=O)R3 and R3 is selected from the group consisting of isopropyl, 3-pentyl (1-ethoxypropyl, cyclopentyl and phenylmethyl; a nonionic surfactant; a suspending agent; and water.

7. The aqueous parenteral suspension of claim 6, wherein said compound is present in an amount in the range of approximately 3 to 4.5 percent by weight of the suspension, said nonionic surfactant is present in an amount in the range of approximately 0.1 to approximately 0.5 percent by weight of the suspension, and said suspending agent is present in an amount in the range of approximately 0.1 to approximately 0.5 percent by weight of the suspension.

8. The aqueous parenteral suspension of claim 6, wherein the non-ionic surfactant is polyoxyethylenated sorbitan monooleate (20).

9. The aqueous parenteral suspension of claim 6, wherein the suspending agent is selected from the group consisting of methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose.

10. The aqueous parenteral suspension of claim 6, wherein the compound is crystalline (2R,3S,5R)-5-(6amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-((2phenylacetoxy)methyl)tetrahydrofuran-3-yl 2-phenylacetate.

11. The aqueous parenteral suspension of claim 6, wherein the compound is crystalline (2R,3S,5R)-5(6-amino-2-fluoro-9H-purin-9-yl)-2-(((2ethylbutanoyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-yl 2-ethylbutanoate.

12. A method for in vivo suppression of the human immunodeficiency virus in a patient comprising parenterally administering to the patient an effective amount of the compound of claim 1 in an aqueous suspension.

13. The method of claim 12, wherein the administration is a three-month dosing regimen.

14. The method of claim 12, wherein said effective amount is a dose in the range of approximately 80 to approximately 800 mg.

15. The method of claim 12, wherein said effective amount is a dose in the range of approximately 200 to approximately 400 mg.

16. The method of claim 12, wherein the RRQznn / zznz / E / viAi compound is crystalline (2R,3S,5R)-5-(6-amino-2-fluoro9H-purin-9-yl)-2-ethynyl-2-((2phenylacetoxy)methyl)tetrahydrofuran-3-yl 2-phenylacetate.

17. The method of claim 12, wherein the compound is crystalline (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-(((2-ethylbutanoyl)oxy)methyl)-2-ethyni1-tetrahydrofuran-3-yl 2-ethylbutanoate.

18. A method for the prophylaxis of HIV infection in a human subject not infected with HIV comprising parenterally administering to the human subject an effective amount of the compound of claim 1 in an aqueous suspension on a semi-annual dosing regimen.

19. The method of claim 18, wherein said compound is administered in a unit dose quantity in the range of approximately 80 to approximately 800 mg.

20. The method of claim 18, wherein said compound is administered in a dose volume in the range of approximately 0.5 to approximately 4 mL per dose.

21. The aqueous parenteral suspension of claim 6 or claim 7, wherein the non-ionic surfactant is polyoxyethylenated sorbitan monooleate (20).

22. The aqueous parenteral suspension of any of claims 6, 7 or 21, wherein the suspending agent is selected from the group consisting of methylcellulose, carboxymethylcellulose, hydroxypropylcellulose and RRQznn / zznz / E / viAi 37 hydroxypropylmethylcellulose.

23. The aqueous parenteral suspension of any of claims 6, 7, 21 or 22, wherein the compound is crystalline (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl 2-phenylacetate or crystalline (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-(((2-ethylbutanoyl)oxy)methyl)-2-ethynyltetrahydrofuran-3-yl 2-ethylbutanoate.

24. A method for in vivo suppression of the human immunodeficiency virus (HIV) in a patient comprising parenterally administering to the patient an effective amount of the compound of any of claims 1 to 5 in an aqueous suspension.

25. The method of claim 24, wherein the administration is a three-month dosing regimen.

26. A method for the prophylaxis of HIV infection in a human subject not infected with HIV comprising parenterally administering to the human subject an effective amount of the compound of any of claims 1 to 5 in an aqueous suspension on a semi-annual dosing regimen.

27. The method of any of claims 24 to 26, wherein said effective amount is a dose in the range of approximately 80 to approximately 800 mg.

28. The method of any of claims 24 to RRQznn / zznz / E / viAi 27, wherein said compound is administered in a dose volume in the range of approximately 0.5 to approximately 4 mL per dose.

29. The method of any of claims 24 to 28, wherein administration of the compound provides a slow, controlled, or sustained release of EFdA from the compound in vivo.

30. The method of any one of claims 24 to 29, wherein the route of administration for the compound is selected from the group consisting of oral, parenteral, subcutaneous injections, intravenous, intramuscular, intrasternal injection, infusion, and release from an implant.

31. The method of any of claims 24 to 30, wherein the compound is formulated as an aqueous suspension, a solution, or encapsulated in particles for slow release.

32. The method of any of claims 24 to 31, wherein the viral infection is caused by HIV.

33. The method of any of claims 24 to 31, wherein the viral infection is caused by HBV.

34. The method of any of claims 24 to 33, further comprising administering an additional anti-HIV and / or anti-HBV agent.

35. The method of claim 34, wherein the additional agent is selected from the group consisting of cabotegravir, dolutegravir, doravirine, elvitegravir, lersiverine, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, and lamivudine.

36. The use of a compound of any of the 5 claims 1 to 11 for the treatment and prevention of HIV or HBV viral infection.