Prodrugs of L-BHDU and methods for treating viral infections

Abstract

In one embodiment, the present invention relates to a prodrug compound of L-BHDU according to the following chemical structure I: Formula (1), wherein R 1 is ‑(CH2)n‑O‑R 1a Group or ‑(CH2)j‑O‑C(O)O k ‑R 2a Group; R 2 is H, ‑(CH2)n‑O‑R 1a Group or ‑(CH2)j‑O‑C(O)O k ‑R 2a Group; R 1a Independently C6‑C 30 Alkyl, usually C 12 ‑C 22 Alkyl, usually C 14 ‑C 20 Alkyl or C 16 ‑C 18 Alkyl, usually C 16 or C 18 Alkyl; R 2a Independently C1-C 12 alkyl, typically C2-C6 alkyl, C3-C4 alkyl, isopropyl, tert-butyl, or sec-butyl, or isopropyl or tert-butyl; each j is independently 1-6, 1-3, typically 1 or 2; each k is 0 or 1; each n is independently 1-6, 1-4, 2-4, or 2 or 3; or a pharmaceutically acceptable salt, solute, or polymorph thereof. Additional embodiments relate to pharmaceutical compositions based on the disclosed compounds and methods of treating or reducing the likelihood of infection with VZV, HSV-1, or HSV-2. Methods of synthesizing compounds according to the invention represent additional embodiments of the invention.

Description

Technical Field

[0001] The present invention relates to prodrug compounds of β-L-[5-(E-2-bromovinyl)-2-(hydroxymethyl)-1,3-(dioxolan-4-yl)]uracil (L-BHDU), pharmaceutical compounds thereof, and treatment methods for varicella-zoster virus (VZV) and herpes simplex virus (HSV-1 and 2). Methods for synthesizing these compounds are also disclosed.

[0002] Related applications

[0003] This application claims the benefit of priority to U.S. Provisional Application Serial No. US63 / 273,403, filed on October 29, 2021, the entire contents of which are incorporated herein by reference. Background Art

[0004] Varicella-zoster virus (VZV) causes chickenpox (varicella) in primary infection in humans and shingles (zoster) when reactivated during the latent phase. 1 VZV belongs to the gammaherpes family and is partially curable by vaccination with the live attenuated vaccine strain Oka-Merck. 2 While pediatric vaccination has reduced cases of chickenpox, shingles remains a challenge in older adults. Vaccine efficacy decreases by approximately 50% in older adults, quickly leading to reinfection and the painful shingles condition. Postherpetic neuralgia is one of the major complications of shingles. 3 It is characterized by VZV reactivation, which causes a rash accompanied by persistent pain. Due to spontaneous and breakthrough cases of VZV, immunocompromised patients cannot be vaccinated. Consequently, the course of varicella is more likely to begin in immunocompromised patients, particularly those with acquired immunodeficiency syndrome (AIDS), transplant recipients, and cancer patients. In such cases, VZV infection can be life-threatening.

[0005] Current treatments with nucleoside analogs are acyclovir (ACV), valaciclovir (VACV), and famciclovir. 4 However, these drugs show low efficacy and low bioavailability, and long-term use of these therapies is associated with drug resistance.In drug-resistant patients, intravenous administration of foscarnet (sodium foscarnet) to treat drug-resistant VZV is associated with numerous side effects and cytotoxicity. 5Available nucleoside drugs act on viral DNA polymerase in the active triphosphate form and mimic viral replication. Cellular enzymes like thymidine kinase (TK) and cellular kinase (CK) convert the nucleoside drugs to the active triphosphate moiety. 6 Another class of compounds, cyclic derivatives of uridine, have been invented to treat VZV. Herpes zoster ophthalmicus (an eye infection) can be treated with topical trifluridine and ioduridine. 7 First, the bromovinyl analog brivudine (BVDU, E-5-(2-bromovinyl)-2'-deoxyuridine) showed better anti-herpetic activity and was approved in Europe for the treatment of VZV infection. 8 Similarly, BVDU is also converted into 5'-monophosphate and 5'-diphosphate forms by the viral TK enzyme, and ultimately converted into a 5'-triphosphate (BVDU-TP) form by cellular kinases. BVDU-TP selectively interacts with viral DNA polymerase in the form of a competitive inhibitor or is incorporated into the DNA chain, leading to DNA chain termination. BVDU has demonstrated better activity characteristics than acyclovir and its derivatives. Additionally, BVDU's ease of administration makes it more attractive than other drugs for VZV infection in elderly patients. The major disadvantage associated with this drug is that it decomposes into BVD metabolites during metabolism. BVD inhibits dihydropyridine dehydrogenase, which is crucial for the degradation of thymine and uracil. Therefore, cancer patients being treated with 5-fluorouracil (5-FU) cannot be administered with BVDU because the use of BVDU will lead to the accumulation of toxic 5-FU in these patients and cause early death. 9 Due to the described shortcomings and significant side effects of currently prescribed drugs, new antiviral drugs that can prevent the spread of VZV in the skin are highly desirable, particularly since approved drugs have little effect on viral growth.

[0006] Therefore, there is a continuous need for new antiviral drugs against VZV. To address the challenges of current VZV treatment, the present inventors have developed a uridine derivative, β-L-[5-(E-2-bromovinyl)-2-(hydroxymethyl)-1,3-(dioxolan-4-yl)uracil (L-BHDU). 10 L-BHDU expresses VZV-specific EC in human foreskin fibroblasts (HFFS) in vitro 50 The value was 0.22 μM. It was also found to be non-cytotoxic to cells at a concentration of 200 μM and revealed a selectivity index (SI) >909. 11 To increase the cellular bioavailability and cellular uptake of L-BHDU, amino prodrugs of L-BHDU were synthesized. Among these amino prodrugs, L-valyl-L-BHDU exhibited enhanced antiviral activity, EC 50 The value was 0.03 μM, and CC50 At 200 μM, SI>6667. In vivo studies of L-BHDU and L-valyl-L-BHDU showed that VZV growth was significantly reduced compared to ACV and VACV. In addition, L-BHDU studies indicated that it did not inhibit the activity of dihydropyridine dehydrogenase. 11 Therefore, patients receiving cancer treatment with 5-FU may also be administered L-BHDU.

[0007] Encouraged by these findings, the inventors were keen to explore various prodrug approaches to enhance the antiviral efficacy of L-BHDU against VZV. In this application, we describe the synthesis and antiviral evaluation of POM, POC, octadecyl, and hexadecyl prodrugs of L-BHDU. Both the POM and POC groups have demonstrated increased bioavailability and readily convert the active triphosphate form of the parent nucleoside. 12 To date, the US FDA has approved adefovir dipivoxil [bis(pivaloyloxymethyl), POM] 13,14 For HBV, and tenofovir disoproxil fumarate [bis(isopropyloxymethyl carbonate, POC] 15 Used in HIV treatment. During the metabolism of POM prodrugs, the POM ester group first degrades to form an unstable hydroxymethyl alcoholate intermediate, which undergoes chemical rearrangement and releases formaldehyde. Free monophosphate is generated after the second POM ester group is cleaved. 16 Similarly, POC prodrugs are also metabolized by enzymatic degradation. The carbonate of POC is decomposed by esterases and produces an unstable carboxylate intermediate, which then releases carbon dioxide and formaldehyde to produce free nucleotide monophosphates. Considering the frequent conversion of nucleosides to monophosphate forms, the POM (8) and POC (14) prodrugs of L-BHDU (respectively Figure 2 and 3 ) and were evaluated against VZV in vitro and in vivo. These prodrugs have demonstrated superior in vitro and in vivo activity compared to L-BDHU. In addition, POM-L-BHDU was selected for additional in vivo evaluations, where the prodrug demonstrated superior activity compared to the parent molecule.

[0008] The 1-O-hexadecyloxypropyl and 1-O-octadecyloxyethyl groups of cidofovir have been shown to exhibit enhanced activity against cytomegalovirus and herpesvirus. Compared to cidofovir, these prodrugs inhibit viral replication more efficiently. 17These long-chain lipid prodrugs also show improved cellular absorption and oral bioavailability. However, they primarily target nerve cells infected by VZV. Therefore, a more lipophilic L-BHDU is needed. In order to increase the lipophilicity and cellular bioavailability of L-BHDU, octadecyloxyethyl-L-BHDU (ODE-L-BHDU, 5) and hexadecyloxypropyl-L-BHDU (HDP-L-BHDU, 6) were synthesized. Figure 1 Scheme 1 was used and screened for antiviral activity in vitro and in vivo. The esterification of L-BHDU with octadecyloxyethyl (ODE) and hexadecyloxypropyl (HDP) groups was proposed to increase the cellular uptake of L-BHDU-based phospholipids / lipophilic function of cell membranes. The addition of these long hydrocarbon chains may result in potential improvements in the intracellular trafficking of the compounds. However, the enhanced in vitro antiviral activity was unexpected for these analogs. As predicted, HDP-L-BHDU and ODE-L-BHDU have shown lower antiviral activity relative to L-BHDU in vitro. In addition, ODE-L-BHDU (5) was selected for in vivo studies, where this prodrug has shown better antiviral activity compared to L-BHDU.

[0009] Varicella zoster virus (VZV) is an alphaherpesvirus that causes chickenpox and shingles. Acyclovir and its prodrugs brivudine (BVdU) and foscarnet are currently prescribed drugs for VZV infection. There is still a need for new antiviral drugs with enhanced efficacy and specificity to treat VZV, specifically postherpetic neuralgia. β-L-1-[5-(E-2-bromovinyl)-2-(hydroxymethyl)-1,3-(dioxolane-4-yl)]uracil (L-BHDU, 1) was shown to exhibit potential anti-VZV activity in three VZV replication models: primary human foreskin fibroblasts (HFF), skin organ culture (SOC), and SCID-Hu mice with skin xenografts. To improve the potency, cellular bioavailability, and antiviral efficacy of L-BHDU, in this report, long-chain lipid prodrugs octadecyloxyethyl-L-BHDU (ODE-L-BHDU, 5) and hexadecyloxypropyl-L-BHDU (HDP-L-BHDU, 6) were synthesized. Additionally, the synthesis of POM-L-BHDU (8) and POC-L-BHDU (14) phosphate prodrugs was completed, and the antiviral efficacy of these agents was evaluated in ARPE-19 cells infected with VZV-ORF57-Luc in vitro. POM-L-BHDU (8) and POC-L-BHDU (14) have demonstrated significant anti-VZV activity. POM prodrug 8 showed EC 50 was 0.028 μM, and POC prodrug 14 revealed an active EC 50 The CC was 0.034 μM without any cytotoxicity. 50>100 μM. Octadecyl prodrug 5, ODE-L-BHDU showed in vitro activity EC 50 0.068 μM, CC 50 was 32 μM. In vivo studies of POM, POC, and octadecyl prodrugs compared to L-BHDU were conducted in the NuSkin mouse model of VZV replication, and POM-L-BHDU (8) and ODE-L-BHDU (5) were found to be the most active compounds without significant toxicity. These synthetic prodrug analogs containing L-BHDU were also tested in vitro against HSV-1 and HSV-2. All compounds expressed antiviral activity against HSV-1, but only POM-L-BHDU (8) was found to be active against HSV-2, with an EC of 0. 50 1.4 μM, CC 50 Values ​​>100 μM. Summary of the Invention

[0010] In one embodiment, the present invention relates to a prodrug compound of L-BHDU according to the following chemical structure I:

[0011]

[0012] where R 1 Yes - (CH2) n -OR 1a group or -(CH2) j -OC(O)O k -R 2a group;

[0013] R 2 It is H, -(CH2) n -OR 1a group or -(CH2) j -OC(O)O k -R 2a group;

[0014] R 1a Independently C6-C 30 Alkyl, usually C 12 -C 22 Alkyl, usually C 14 -C 20 Alkyl or C 16 -C 18 Alkyl, usually C 16 or C 18 alkyl;

[0015] R 2a Independently C1-C 12Alkyl, typically C2-C6 alkyl, C3-C4 alkyl, isopropyl, tert-butyl or sec-butyl, or isopropyl or tert-butyl;

[0016] Each j is independently 1-6, 1-3, and usually 1 or 2;

[0017] Each n is independently 1-6, 1-4, 2-4, or 2 or 3;

[0018] Each k is independently 0 or 1; or

[0019] A pharmaceutically acceptable salt, solute or polymorph thereof.

[0020] In an embodiment, R 1 Yes - (CH2) n -OR 1a group, n is 2-4, usually 2 or 3, and R 1a It is C 14 -C 20 Alkyl or C 16 -C 18 Alkyl, most commonly C 16 or C 18 In an embodiment, wherein R 1 Yes - (CH2) n -OR 1a Group, R 2 Usually H.

[0021] In an embodiment, R 2 Usually H or -(CH2) j -OC(O)O k -R 2a group.

[0022] In an embodiment, R 2 Yes - (CH2) j -OC(O)O k -R 2a A group wherein j is 1-4, 1 or 2, typically 1, k is 0 or 1, and R 2a It is C1-C 12 Alkyl, C2-C6 alkyl, typically C3 or C4 alkyl, more typically isopropyl or tert-butyl. 1 and R 2 Both are -(CH2) j -OC(O)O k -R 2a A group wherein j is 1-4, 1 or 2, typically 1, k is 0 or 1, and R 2a It is C1-C 12alkyl, C2-C6 alkyl, typically C3 or C4 alkyl, more typically isopropyl, sec-butyl or tert-butyl. In embodiments, k is 1. In embodiments, k is 0. In embodiments, k is 1 and R 2a is a C3 alkyl group, typically isopropyl. In an embodiment, k is 0 and R 2a is C4 alkyl, typically sec-butyl or tert-butyl, most typically tert-butyl. 1 and R 2 Same (not all H).

[0023] In embodiments, the present invention relates to pharmaceutical compositions comprising an effective amount of at least one L-BHDU prodrug compound as described herein in combination with a pharmaceutically acceptable carrier, additive or excipient. In embodiments, the L-BDHU prodrug compound is typically Figure 1 Compound 5 of Scheme 1, Figure 2 Compound 8 of Scheme 2 or Figure 3 Compound 14 of Scheme 3. The pharmaceutical composition can be formulated for oral, parenteral, or other routes of administration, as described herein. In embodiments, the present invention is typically administered by oral or parenteral routes of administration, typically by oral route of administration. In embodiments, the pharmaceutical composition comprises a combination of an L-BHDU prodrug compound as described herein and at least one additional bioactive agent. In embodiments, the additional bioactive agent is acyclovir, brivudine, foscarnet, cidofovir (CDV), valacyclovir, famciclovir, herpes zoster immune globulin (ZIG), vidarabine, or a mixture thereof. In embodiments, the L-BHDU prodrug compound is typically combined with foscarnet and / or cidofovir (CDV) to provide a particularly effective therapy for VZV mutants (TK-, TS-, and TK-TS-). In other embodiments, the additional bioactive agent is an anticancer compound. In other embodiments, the additional bioactive agent is 5-fluorouracil (5FU).

[0024] In embodiments, the present invention relates to methods for treating, inhibiting, or reducing the likelihood of varicella zoster virus (VZV) infection or herpes simplex virus (HSV I and II) infection or its complications, comprising administering to a patient in need thereof an effective amount of a compound as described herein. In embodiments, the infection is a VZV infection (varicella or herpes zoster). In embodiments, the infection is a herpes simplex virus I or II infection (HSV-1 or HSV-2). In embodiments, the methods of treatment utilize a combination of agents, typically a prodrug of L-BHDU as described herein and an optional additional bioactive agent as described herein, which are co-administered to a patient or subject in need thereof.

[0025] In embodiments, the present invention provides methods of synthesizing compounds according to the invention as described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 Scheme 1 shows the chemical synthesis of long-chain lipid phosphates of L-BDHU compounds 5 and 6. Reagents and conditions: (a) 1,2,4-triazole, Et3N, THF, room temperature; (b) ROH, N-methylimidazole (NMI), THF, room temperature; (c) 0.5N NaOH, THF / H2O, 50°C.

[0027] Figure 2 Scheme 2 shows the chemical synthesis of POM-L-BHDU compound 8.

[0028] Reagents and conditions: (a) NMI, THF, 0°C to room temperature.

[0029] Figure 3 Scheme 3 shows the chemical synthesis of the bis-POC-L-BDHU drug. Reagents and conditions: (a) POC-I, Cs2CO3, acetone, room temperature, 24 hours; (b) NaI, acetonitrile, room temperature, 24 hours; (c) POC-I, Cs2CO3, acetone, room temperature, 24 hours; (d) Pd / C, 5-10 psi, room temperature, 2 hours; (e) L-BHDU, BOP-Cl, 3-nitro-1,2,4-triazole, DIPEA, THF, room temperature, 2-3 hours.

[0030] Figure 4 Graph showing the antiviral activity of L-BHDU and its prodrug against VZV-BAC-Luc in ARPE-19 cells.

[0031] Figure 5 The anti-VZV activity of the compounds in ARPE-19 cells is shown in Table 1. In this assay, L-BHDU was found to be 10-fold more potent than in a previous assay using VZV-BAC-Luc infected HFF (0.22 μM for HFF and 22 nM for ARPE-19). 11 L-BHDU revealed good antiviral efficacy, EC 50 0.022μM.

[0032] Figure 6 L-BHDU and its OED-L-BHDU (L-BHDU-C 18), POM-L-BHDU and POC-L-BHDU prodrugs in vivo evaluation. Mice were treated with vehicle or drug, and viral yield was measured by bioluminescent imaging. The VZV growth rate (symbol) of a single mouse and the mean value (column) of the group are shown in (A) and (B). Compared with the vehicle group, the VZV growth rate was significantly reduced, and these two cases indicate sc (A) and po and sc (B). The overall significance at day 10 post-inoculation (DPI 10) was p=0.0352 (one-way ANOVA). For OED-L-BHDU and POM-L-BHDU and (Student's t test and Welch's correction), **p<0.01. The average change fold of the cidofovir group (ip) on DPI 10 was 2-5 (B).

[0033] Figure 7 Body weight change studies are presented, showing that all compounds tested were well tolerated in both male and female mice.

[0034] Figure 8 A graph showing the anti-HSV-1 activity of L-BHDU prodrug in Vero cells.

[0035] Figure 9 Table 2 shows the anti-HSV-1 activity data of L-BHDU prodrug in Vero cells.

[0036] Figure 10 The effects of L-BHDU and its POM, POC, and octadecyl prodrugs on HSV-2 replication in Vero cells compared to acyclovir are shown. HSV-2 productivity was determined by bioluminescence imaging. Each point represents the mean ± standard deviation of three samples.

[0037] Figure 11 Table 3 shows the anti-HSV-2 activities of L-BHDU, its prodrug and acyclovir in Vero cells.

[0038] Figure 12 L-BHDU and its prodrug, L-BHDU-POM, were shown to be highly effective in preventing the spread of VZV and HSV1 in adult skin. Each compound was formulated in cocoa butter and applied topically. POM was formulated at an equimolar concentration of 0.1% L-BHDU. The compounds were nontoxic to the skin (histological results not shown).

[0039] Figure 13The results of antiviral screening of L-BHDU and its C18 (ODE-L-BHDU) POM and POC-L-BHDU against cell-associated VZV-ORF57-Luc, VZV TK-, VZV TS-, and VZV TKTS- are shown. Cidofovir and acyclovir are positive controls. Each symbol represents the average of 6 replicate wells; the line is the best fit curve (error bars omitted for clarity).

[0040] Figure 14 Table 4 shows the antiviral activity of L-BHDU and several prodrugs against cell-associated wild-type and mutant VZV viruses in ARPE-19 cells. DETAILED DESCRIPTION

[0041] The following terms will be used throughout the specification to describe the present invention. When a term is not specifically defined herein, the term should be understood to be used in a manner consistent with how it is used by those of ordinary skill in the art.

[0042] Where a range of values ​​is provided, it will be understood that each intervening value between the upper and lower limits of the range, to the tenth of the unit of the lower limit, unless otherwise expressly stated, and any other stated or intervening values ​​in the range are encompassed within the present invention. The upper and lower limits of these smaller ranges may be independently included in smaller ranges and are also encompassed within the present invention, subject to any exact exclusion of the limits within the stated ranges. Where the range includes one or two limits, the present invention also encompasses the range of any two of the limits included. Where substituents may be present in one or more Markush groups, it will be understood that only those substituents forming stable bonds are used.

[0043] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described.

[0044] It must be noted that, as used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise.

[0045] Unless otherwise indicated, the term "compound" as used herein refers to any specific compound disclosed herein, generally to the prodrug form of β-L-[5-(E-2-bromovinyl)-2-(hydroxymethyl)-1,3-(dioxolan-4-yl)uracil (L-BHDU) as disclosed herein, but may include tautomers, regioisomers, geometric isomers, anomers, and, where applicable, optical isomers (enantiomers) or diastereomers (two chiral centers) thereof of these compounds, as well as pharmaceutically acceptable salts, solvates and / or polymorphs thereof. As used herein, the term compound generally refers to a single compound, but may also encompass other compounds, such as stereoisomers, regioisomers, and / or optical isomers (including racemic mixtures and / or diastereomers as described herein), as well as specific enantiomers, enantiomerically enriched or single diastereomers, or mixtures of disclosed compounds, depending on the context in which the term is used. It should be noted that where carbon ranges are provided for compounds, the ranges indicate that each carbon is individually considered part of the range. For example, C1-C 20 The radical describes groups having a single carbon, two carbon atoms, three carbon atoms, four carbon atoms, etc., up to twenty carbons.

[0046] The term "patient" or "subject" is used throughout this specification to describe an animal, typically a domesticated animal or a human, more typically a human, to whom treatment, including prophylactic treatment, is provided with a composition according to the present invention. For treatment of infections, conditions, or disease states specific to a particular animal, such as a human patient, the term patient refers to that particular animal. Generally, in the present invention, unless otherwise indicated, the term "patient" refers to a human patient. In the present invention, in addition to humans, domesticated animals (e.g., horses, cattle, dogs, cats, etc.) can also be treated with the compounds of the present invention.

[0047] The term "varicella-zoster virus" or "VZV" is used to describe one of eight herpesviruses known to infect humans (and other vertebrates). VZV commonly causes chickenpox in children and both shingles and postherpetic neuralgia in adults. Varicella-zoster virus has many names, including: chickenpox virus, varicella virus, herpes zoster virus, and human herpesvirus 3 (HHV-3). Primary VZV infection causes chickenpox (varicella), but rarely leads to complications, including encephalitis or pneumonia. Even when the clinical symptoms of chickenpox have resolved, VZV remains latent in the infected person's nervous system (viral latency), lurking in the trigeminal nerve and dorsal root ganglia. In approximately 10-20% of cases, VZV reactivates later in life, producing the disease known as herpes zoster or shingles. Serious complications of herpes zoster include postherpetic neuralgia, herpes zoster, myelitis, ocular herpes, or herpes zoster without rash. The compounds according to the present invention can be used to inhibit, treat, or resolve complications associated with these viral infections.

[0048] VZV is closely related to herpes simplex virus (HSV I and II), sharing many genomic homologies. Many known VZV envelope glycoproteins are consistent with those in HSV. Unlike HSV, VZV cannot produce LAT (latency-associated transcript), which plays an important role in establishing the HSV latency period (herpes simplex virus). The virus is very sensitive to disinfectants, especially sodium hypochlorite. In the human body, together with the compounds of the present invention, it can be treated with many drugs and therapeutic agents, including acyclovir, herpes zoster immunoglobulin (ZIG) and vidarabine.

[0049] The terms "herpes simplex virus," "herpes simplex virus-1" (HSV-1), and "herpes simplex virus-2" (HSV-2) refer to two species of the herpes virus family, Herpesviridae, that cause infection in humans. Like other herpesviridae, herpes simplex viruses can produce lifelong infections. They are also known as human herpesviruses 1 and 2 (HHV-1 and HHV-2) and are neurotropic and neuroinvasive viruses; they enter and hide in the human nervous system, which accounts for their persistence in the body. HSV-1 is often associated with facial herpes outbreaks known as cold sores or fever blisters, while HSV-2 is more commonly associated with genital herpes, although each of the two HSV strains may be found in areas usually associated with the other strain.

[0050] Infection with the herpes simplex virus is characterized by complications or symptoms such as blisters that develop on the skin or mucous membranes of the mouth, lips, or genitals. After the lesions heal, scabs, characteristic of herpes disease, appear. However, the infection is persistent, and symptoms may recur periodically with the outbreak of ulcers near the initial site of infection. After the initial or primary infection, HSV becomes latent in the cell bodies of nerves in the area. Some infected people experience sporadic episodes of viral reactivation, after which the virus is transported via the axons of the nerves to the skin, where viral replication and shedding occur. Herpes is contagious if the carrier produces and sheds the virus. This is particularly likely to occur during an outbreak, but it can also occur at other times. There is currently no cure, but there are treatments that can reduce the likelihood of viral shedding.

[0051] Throughout this specification, the term "pharmaceutically acceptable salt" is used to describe, where applicable, one or more salt forms of the compounds described herein that are present to increase the solubility of the compound in the gastric fluid of the patient's gastrointestinal tract, generally to promote dissolution and bioavailability of the compound. Pharmaceutically acceptable salts include salts derived from pharmaceutically acceptable inorganic or organic bases and acids, where applicable. Suitable salts include salts of alkali metals such as potassium and sodium, alkaline earth metals such as calcium, magnesium, and ammonium salts, among many other acids well known in the pharmaceutical field. Sodium and potassium salts are particularly preferred as neutralized salts of the phosphates according to the present invention. Other salts such as base addition salts may also be used in certain embodiments.

[0052] The term "pharmaceutically acceptable derivative" is used throughout the specification to describe any pharmaceutically acceptable prodrug form of the present invention which, when administered to a patient, directly or indirectly provides L-BHDU or an active metabolite of L-BHDU.

[0053] The term "alkyl" in this context shall mean a C1-C 30 , preferably C1-C 20 A straight chain, branched chain or cyclic, usually straight chain or branched, fully saturated hydrocarbon group. It should be noted that where a carbon range is provided, the range means that each carbon is considered to be part of the range. For example, C1-C 20 The group describes groups having a single carbon, two carbon atoms, three carbon atoms, four carbon atoms, etc. The term "ether" shall mean an optionally substituted C1 to C12 radical formed from oxygen and an alkyl group. 20 Ether groups, or alternatively, may also contain at least one oxygen in the alkyl or alkylene chain.

[0054] The term "effective amount" shall mean an amount or concentration of a compound according to the invention that is effective in the context of its administration or use, which may be inhibitory, prophylactic and / or therapeutic. Within this context, all active compounds used in the present invention are used in an effective amount. The compounds of the present invention also encompass combinations of compounds containing an effective amount of each compound used, whether the combination is additive or synergistic in effect, provided that the overall effect of the combination of compounds is to inhibit the growth of a viral infection in a patient, reduce the likelihood of a viral infection in a patient, or treat a viral infection in a patient, as described elsewhere herein.

[0055] As used in the context of the present invention, the term "L-configuration" refers to the configuration of the nucleoside compounds according to the present invention that mimics the unnatural configuration of the sugar moiety, as opposed to the naturally occurring nucleosides or "D" configuration. The term "β" or "β anomeric" is used to describe nucleoside analogs according to the present invention in which the nucleobase is configured (arranged) above the plane of the dioxolane moiety in the compound.

[0056] The term "enantiomerically enriched" is used throughout this specification to describe nucleosides that contain at least about 95%, preferably at least about 96%, more preferably at least about 97%, even more preferably at least about 98%, and even more preferably at least about 100% or more of a single enantiomer of the nucleoside. The prodrug L-BHDU nucleoside compounds according to the present invention are typically β-L-nucleoside compounds. Unless otherwise indicated, when referring to the compounds according to the present invention in this specification, it is assumed that the nucleoside has the L-nucleoside configuration and is enantiomerically enriched (preferably approximately 100% L-nucleoside). The term "diastereomerically pure" is used to describe a single diastereomer of a compound according to the present invention that contains at least 95%, 96%, 97%, 98%, 99%, 99.5%, or 100% by weight of a single diastereomer, including other possible diastereomers.

[0057] The terms "coadminister" and "coadministration" are used synonymously to describe the administration of at least one of the nucleoside compounds according to the present invention in combination with at least one other agent, preferably at least one additional antiviral agent, including other nucleoside antiviral agents specifically disclosed herein, in amounts or concentrations that are considered to be effective amounts at or about the same time. Although coadministration of agents that are administered simultaneously is preferred, the agents may be administered from time to time so that effective concentrations of the two (or more) agents occur simultaneously in the patient for at least a brief period of time. Alternatively, in certain aspects of the present invention, it is possible to have each coadministered agent exhibit its inhibitory or therapeutic effect at different times in the patient, with the end result being inhibition of the virus and treatment of the infections mentioned above. Of course, when there is more than one viral or other infection or other condition, the compounds of the present invention can be combined with agents for treating the other infections or conditions as needed. In certain preferred compositions and methods, the L-BHDU prodrug compounds of the present invention are co-formulated and / or co-administered with at least one additional antiviral agent, preferably wherein the antiviral agent is acyclovir, famciclovir, ganciclovir, valacyclovir, vidarabine, foscarnet, herpes zoster immune globulin (ZIG), and mixtures thereof. The present invention also contemplates co-administration with 5-fluorouracil (5-FU).

[0058] The term "independently" is used herein to indicate variables that are independently applied, varying independently from application to application.

[0059] Therefore, the present invention also relates to pharmaceutical compositions comprising an effective amount of a compound as described above, optionally in combination with a pharmaceutically acceptable carrier, additive, or excipient. In alternative embodiments, the pharmaceutical composition may further contain one or more additional antiviral agents as described elsewhere herein in combination with additives, carriers, or excipients.

[0060] Methods of treatment represent additional embodiments according to the present invention. In this regard, methods of treating viral infections or their secondary disease states or conditions, specifically viral infections or reducing the likelihood of VZV, HSV-1 or HSV-2 infections from patients in need of therapy or at risk of infection or its secondary disease states or conditions, comprise administering to said patient an effective amount of a compound or composition as described elsewhere above. Alternative embodiments rely on co-administering a compound according to the present invention in combination with another antiviral agent to said patient. In a preferred aspect, methods of treating VZV or HSV-1 or HSV-2 (including drug-resistant strains thereof or secondary diseases or conditions occurring due to VZV, HSV-1 or HSV-2) or reducing the likelihood thereof involve administering to a patient in need thereof an effective amount of a compound according to the present invention as described herein, or a pharmaceutically acceptable salt, solvate or polymorph thereof.

[0061] Pharmaceutical compositions based on nucleoside compounds according to the present invention include an effective amount of one or more of the compounds described above for treating or reducing the likelihood of viral infection (particularly VZV, HSV-1 or HSV-2 infection) in a patient in need of therapy thereof, optionally in combination with a pharmaceutically acceptable additive, carrier or excipient. One of ordinary skill in the art will recognize that the therapeutically effective amount will vary depending on the infection or condition to be treated, its severity, the treatment regimen to be adopted, the pharmacokinetics of the agent used, and the patient or subject (animal or human) to be treated.

[0062] In terms of the medicine according to the present invention, the compound according to the present invention is preferably mixed with a pharmaceutically acceptable carrier and formulated. Generally, the pharmaceutical composition is preferably administered orally, but some formulations can be administered parenterally, intravenously, intramuscularly, transdermally, buccally, intranasally, subcutaneously, by inhalation, by suppository or other routes. Intravenous and intramuscular formulations are usually administered in sterile saline. In some cases, topical or transdermal administration can be used. Of course, those of ordinary skill in the art can modify the formulation within the instructions of the specification to provide a variety of formulations for specific routes of administration without making the composition of the present invention unstable or compromising its therapeutic activity. Specifically, the modification of the compound of the present invention makes it more soluble in water or other vehicles, for example, it can be easily achieved by minor modifications (salt formulations, etc.) well known to those of ordinary skill in the art. It is also within the skill of the technician to change the route of administration and dosage regimen of a particular compound to manage the pharmacokinetics of the compound of the present invention so as to obtain the maximum beneficial effect in the patient.

[0063] In some pharmaceutical dosage forms, monophosphate and various salt forms of the compounds of this invention may be preferred. In an embodiment, phosphate diester and triester are used. Those of ordinary skill in the art will recognize how to easily modify the compounds of this invention to enhance prodrug-compound according to the present invention, thereby promote the delivery of active compound to the targeted site in host organisms or patients. When the compounds of this invention are delivered to the targeted site in host organisms or patients, the technician will also utilize the favorable pharmacokinetic parameters (if applicable) of prodrug-form to maximize the expected effect of the compound.

[0064] The amount of the compound included in the active formulation according to the present invention is an effective amount for treating an infection or condition, specifically a viral infection as described elsewhere herein. Typically, the therapeutically effective amount of the compound of the present invention in a pharmaceutical dosage form is typically in the range of about 0.05 mg / kg to about 100 mg / kg per day for a patient, more preferably slightly less than about 1 mg / kg to about 25 mg / kg per day or quite a bit more, depending on the compound used, the condition or infection being treated, and the route of administration. The active nucleoside compound according to the present invention is typically administered in an amount ranging from about 0.5 mg / kg to about 25 mg / kg per day for a patient, depending on the pharmacokinetics of the agent in the patient's body. This dosage range typically produces an effective blood level concentration of the active compound, which can range from about 0.05 to about 100 micrograms / cc in the patient's blood. For purposes of the present invention, the preventive or prophylactic effective amount (i.e., the amount that effectively reduces the likelihood of a patient contracting a viral infection risk) of the composition according to the present invention falls within the same concentration range of the above-mentioned therapeutically effective amount, and is often / usually the same as the therapeutically effective amount.

[0065] The range of administration of the active compound can be continuous (intravenous drip) to oral administration several times a day at most (e.g., once a day, or four times a day or QID) or transdermal administration, and can include oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (possibly containing a penetration enhancer), buccal and suppository administration and other routes of administration. Enteric-coated oral tablets can also be used to enhance the bioavailability of compounds from oral administration routes. The most effective dosage form will depend on the bioavailability / pharmacokinetics of the selected particular agent and the severity of the patient's disease and the patient's size and weight. Oral dosage forms are particularly preferred, as are topical dosage forms, because of the ease of administration and expected favorable patient compliance.

[0066] In order to prepare the pharmaceutical composition according to the present invention, one or more of the compounds according to the present invention of therapeutically effective amount are preferably closely mixed with a pharmaceutically acceptable carrier to produce a dosage according to conventional drug mixing technology (conventional pharmaceutical compounding technique). According to the formulation form required for administration, for example, oral or parenteral, the carrier can be in various forms. When preparing the pharmaceutical composition of oral dosage form, any conventional pharmaceutical medium can be used. Therefore, for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives can be used, including water, ethylene glycol, oil, alcohol, flavorings, preservatives, coloring agents, etc. For solid oral preparations such as powders, tablets, capsules, and for solid preparations such as suppositories, suitable carriers and additives can be used, including starch, sugar carriers such as glucose, mannitol, lactose and related carriers, diluents, granulating agents, lubricants, adhesives, disintegrants, etc. If necessary, tablets or capsules can be enteric-coated or sustained-released by standard technology to advantageously affect the pharmacokinetics and / or bioavailability of the administered drug. Using these dosage forms can significantly enhance the bioavailability of the compound in the patient's body.

[0067] For parenteral formulations, the carrier will generally comprise sterile water or aqueous sodium chloride solution, but may also contain other ingredients, including ingredients that aid dispersion. Of course, where sterile water is used and sterility is maintained, the composition and carrier must also be sterilized. Injectable suspensions may also be prepared, in which case suitable liquid carriers, suspending agents, etc. may be employed.

[0068] Liposomal suspensions (comprising liposomes targeting viral antigens) can also be prepared by conventional methods to produce pharmaceutically acceptable carriers. This may be suitable for delivery of free nucleosides, acyl / alkyl nucleosides or phosphate prodrug forms of nucleosides or other compounds used according to the present invention.

[0069] In particularly preferred embodiments according to the present invention, the compounds and compositions are used to treat, prevent, reduce the likelihood of, or delay the onset of viral infections, such as those disclosed elsewhere herein (VZV, HSV-1, or HSV-2). Preferably, to treat, prevent, reduce the likelihood of, or delay the onset of these infections or disease states and / or conditions secondary to these viral infections, the compositions will be administered in an oral dosage form in a dosage range of about 250 micrograms up to about 500 mg-1 gram or more, at least once a day and up to four times a day. In embodiments, the compounds are formulated in a sustained-release form and are administered less frequently. The compounds of the present invention are preferably administered orally, but can generally be administered parenterally, topically, or in the form of suppositories.

[0070] In the case of co-administration of a compound of the present invention in combination with another compound for treating a viral infection, specifically a viral infection such as VZV, HSV-1 or HSV-2 infection, the amount of the prodrug nucleoside compound according to the present invention is administered in a range of about 1 mg / kg patient to about 500 mg / kg patient or more or quite a bit more, depending on the efficacy of the second agent to be co-administered and its efficacy for each of the viral infections to be inhibited, the condition or infection to be treated, and the route of administration. In the case of co-administration, the other antiviral agent may preferably be administered in an amount ranging from about 100 μg / kg (micrograms per kilogram) to about 500 mg / kg. In certain preferred embodiments, these compounds may preferably be administered in an amount ranging from about 1 mg / kg to about 50 mg / kg or more (usually up to about 100 mg / kg), which generally depends on the pharmacokinetics of the two agents in the patient. These dosage ranges generally produce effective blood level concentrations of the active compound in the patient. Typical antiviral agents that can be co-administered with the compounds according to the present invention include acyclovir, famciclovir, ganciclovir, valacyclovir, vidarabine, herpes zoster immune globulin (ZIG), and mixtures thereof. 5-FU is also frequently co-administered with the compounds according to the present invention.

[0071] The compounds according to the present invention can be advantageously used prophylactically to prevent or reduce the likelihood of a viral infection, or to prevent or reduce the likelihood of the onset of clinical symptoms associated with a viral infection, or to prevent or reduce the likelihood of a viral infection spreading to another person. Thus, the present invention also encompasses methods for the prophylactic treatment of VZV, HSV-1, or HSV-2 infection. In accordance with this aspect of the present invention, the compositions of the present invention can be used to prevent, reduce the likelihood of, and / or delay the onset of a viral infection or a viral-related disease state or condition, or to prevent, reduce, and / or delay the spread of the infection to another person. Such prophylactic methods comprise administering a compound according to the present invention, alone or in combination with another antiviral, to a patient in need of such treatment, or at risk of developing a VZV, HSV-1, or HSV-2 infection, including a viral-related disease state or condition, or to an infected patient for whom it is desired to prevent or reduce the likelihood of the viral infection spreading to another person, in an amount effective to alleviate, prevent, reduce the likelihood of, or delay the onset of a viral infection. In prophylactic treatment according to the present invention, the antiviral compound used is preferably as low in toxicity as possible and preferably non-toxic to the patient. In this aspect of the invention, it is particularly preferred that the compound used should be most effective against the virus and should exhibit minimal toxicity to the patient. In the case of compounds of the invention for the prophylactic treatment of viral infections, these compounds can be administered as a prophylactic agent in the same dosage range used for therapeutic treatment (i.e., for oral dosage forms, from about 250 micrograms up to about 500 mg or more, one to four times a day) to prevent the proliferation of the viral infection, or alternatively, to prolong the onset of or reduce the likelihood of a patient contracting a viral infection that manifests as clinical symptoms.

[0072] In addition, compound according to the present invention can be used alone or in combination with other medicaments that comprise other compounds of the present invention. According to some compound of the present invention, can effectively enhance the biological activity of some medicament according to the present invention by reducing the metabolism, catabolism or inactivation of other compounds, and therefore, for this expected effect jointly-use.

[0073] Chemical

[0074] In general, compounds according to the present invention are readily synthesized from L-BHDU according to Schemes 1, 2, and 3 presented below. A skilled practitioner can readily adapt the specific synthetic steps to provide a convenient synthesis of all compounds disclosed herein without undue experimentation.

[0075] ODE-L-BHDU and HDP-L-BHDU

[0076] Octadecyloxyethyl-L-BHDU (ODE-L-BHDU, 5) and hexadecyloxypropyl-L-BHDU (HDP-L-BHDU, 6) prodrugs were synthesized according to the protocol described by the present inventors. 18 These long-chain lipid phosphates of L-BHDU were synthesized using the phosphotriester method, e.g. Figure 1 As shown in Scheme 1, the synthesis of L-BHDU was performed by a previously reported method. 10 L-BHDU was condensed with 2-chlorophenyl dichlorophosphate (2) in the presence of 1,2,4-triazole and triethylamine to provide the coupled intermediate. Without further purification, the intermediate was treated with a long-chain lipid alcohol (3-hexadecyloxy-1-propanol or 2-octadecyloxy-1-ethanol) in THF in the presence of N-methylimidazole (NMI) to give the fully protected corresponding phosphotriesters (3 and 4) in 64% yield, which were separated in good yield by flash chromatography. The phosphotriesters (3 or 4) were separated in good yield by flash chromatography in the presence of 1,2,4-triazole and triethylamine to provide the coupled intermediate. 31 P NMR shows two distinct signals. The presence of diastereomers is also evident from 1 To remove the 2-chlorophenyl group, the phosphate triester was dissolved in THF and treated with 0.5 N NaOH at 50 °C for 1.5 h to afford the desired prodrugs 5 and 6 in approximately 85 to 90% yield.

[0077] POM-L-BHDU

[0078] The synthesis of POM-L-BHDU Figure 2 The reaction is shown in Scheme 2 and initiated by coupling L-BHDU with chlorobis(POM)phosphate (7), as shown in Scheme 2. All chemical syntheses and reagents are disclosed in the figure legends. Chlorobis(POM)phosphate (7) was synthesized according to the protocol reported by Hawang Y. et al. 19 L-BHDU was treated with 7 in the presence of NMI in THF at 0°C to room temperature to produce POM-L-BHDU in 71% yield.

[0079] The synthesis of the bis-POC-L-BHDU (14) prodrug was initiated with compound 9. Figure 3As shown in Scheme 3, 9 was alkylated with POC-I in cesium carbonate (Cs2CO3) in THF to give the POC alkylated ester 10. Initially, an attempt was made to convert 10 to 11 following hydrogenation conditions over Pd / C. In this attempt, selective monobenzyl deprotection was not achieved and a major bis-debenzylated product was obtained. Therefore, selective monobenzyl deprotection was performed with LiBr, but this conversion was very low yielding and only 7-9% of compound 11 was obtained. Therefore, the reaction was repeated and carried out with sodium iodide (NaI) in acetonitrile, which in this case only gave 11 in 92% yield. Repeated alkylation of 11 was accomplished by POC-I in THP in the presence of Cs2CO3 to give intermediate 12 in 70% yield. Final benzyl deprotection of 12 was performed over Pd / C under 5 psi of hydrogen to give the key intermediate 13 in 85% yield. Intermediate 13 was coupled with L-BDHU in THF at 0°C to room temperature in the presence of diisopropylamine (DIPEA), bis(2-oxo-3-oxazolidinyl)phosphine chloride (BOP-Cl) and 3-nitro-1,2,4-triazole to provide the final Bis-POC-L-BHDU (14) in 22% yield. The product was characterized by ESI high resolution mass spectrometry (ESI-HRMS), 1 H-NMR, 13 C-NMR and 31 P-NMR confirmed the identity of all prodrugs. These prodrugs were subsequently used in the biological experiments described below.

[0080] Antiviral activity

[0081] L-BHDU has antiviral activity against VZV and HSV-1. The antiviral efficacy of L-BHDU was tested in a SCID-Hu mouse model of VZV replication using human fetal skin and was effective at 15 mg / kg. 11 L-BHDU was well tolerated up to 150 mg / kg and reached high levels in mouse organs, but not in the brain. The antiviral activity of L-BHDU depended on phosphorylation of thymidine kinase encoded by VZV and HSV-1, and resistance mapped to this gene. 20

[0082] To enhance the antiviral activity, octadecyloxyethyl-L-BHDU (ODE-L-BHDU, 5) and hexadecyloxypropyl-L-BHDU (HDP-L-BHDU, 6), POM-L-BHDU (8) and POC-L-BDHU (14) were synthesized ( Figure 1-3(Schemes 1-3) prodrug, modified to increase bioavailability and cell permeability. Its antiviral activity was evaluated in ARPE-19 cells infected with the novel reporter virus VZV-ORF57-Luc. In this assay, L-BHDU was found to be 10-fold more potent than in a previous assay using HFFs infected with VZV-BAC-Luc (0.22 μM in HFFs and 22 nM in ARPE-19). 11 L-BHDU revealed good antiviral efficacy, EC 50 0.022 μM (see Figure 4 and Figure 5 , Table 1). POM-L-BHDU and POC-L-BHDU analogs showed good antiviral efficacy against VZV-ORF57-Luc in ARPE-19 cells. POM-L-BHDU showed EC 50 is 0.028 and SI is 3619. This is consistent with the EC 50 The antiviral efficacy of parent L-BHDU and POC-L-BHDU was similar with an EC of 0.034 μM and an SI of 2915. The long-chain phospholipid prodrugs OED-L-BHDU (5) and HDP-L-BHDU (6) showed 50 0.068 and 0.90 μM, respectively, with SI of 479 and 111.

[0083] The cytotoxicity of the synthesized analogs was determined on low-passage human fibroblast (HFF) cells by performing 72-hour neutral red dye uptake and MTT cell proliferation assays. L-BHDU and its POM and POC prodrugs were found to be non-cytotoxic (CC 50 >100μM) and did not affect cell proliferation. The long-chain phospholipid octadecyl and hexadecyl prodrugs of L-BHDU showed CC 50 The cytotoxicity values ​​were 32.5 and 10 μM respectively. Figure 5 Table 1.

[0084] Encouraged by the in vitro antiviral data, the present inventors subsequently attempted to evaluate the in vivo antiviral efficacy of these L-BHDU prodrugs. After evaluating the in vitro data for the synthesized compounds, the compound was not further tested in vivo due to its high toxicity and low selectivity. In the NuSkin mouse model of VZV replication, the octadecyl ( Figure 1 Scheme 1, compound 5), POM ( Figure 2 Scheme 2, compound 8) and POC ( Figure 3Scheme 3, compound 14) in vivo antiviral efficacy was compared with L-BHDU, and the model used athymic Nude mice implanted with adult skin xenografts. A group of 10 mice (5 males, 5 females) with skin xenografts were inoculated with VZV-ORF57-Luc, and then treatment was started subcutaneously 3 days later. The vehicle group received only Cremophor-DMSO-saline, and the positive control group received HPMPC (cidofovir) 10 mg / kg. The test compound was formulated in CDS at an equimolar concentration with HPMPC, ranging from 11.4 to 24.9 mg / kg according to its molecular weight. Mice were treated once a day from day 3 to day 9 after infection. They were weighed daily and scanned by an in vivo imaging system (IVIS) to measure viral spread on days 3-14. Antiviral activity was evaluated based on viral yield measured by doubling the total flux compared to the value on day 3.

[0085] Based on previous in vivo analysis with L-BHDU, the inventors expected that these prodrug analogs would have antiviral activity. In vivo examination of these derivatives showed that among the selected prodrug analogs, OED-L-BHDU and POM-L-BHDU have demonstrated antiviral efficacy superior to L-BHDU without any cytotoxicity. Both prodrugs of L-BHDU were effective in vivo at a dose of approximately 25 mg / kg / day subcutaneous injection (sc). This is equimolar to cidofovir 10 mg / kg. The parent compounds L-BHDU and POC-L-BHDU were found to be ineffective ( Figure 6 A). It is worth mentioning that L-BHDU-POM is equally effective when taken orally (ip route, Figure 6 B). L-BHDU is expected to exhibit lower in vivo efficacy due to its poor pharmacokinetics. However, POC-L-BDHU ester may not be stable enough at physiological pH to achieve effective concentrations inside cells. This may explain the reduced in vivo efficacy of the POC prodrug. Mice (both male and female) were also well tolerated for all tested compounds and did not show significant weight loss ( Figure 7 ).

[0086] Following these findings, OED-L-BHDU (L-BHDU-C18) and (POM-L-BHDU, 37) were selected for repeated in vivo evaluations with the standard reference cidofovir (10 mg / Kg intravenous route (iv)). In repeated in vivo studies of L-BHDU-C18 and POM-L-BHDU prodrugs, the prodrugs were found to be more active than cidofovir by subcutaneous (sc) as well as oral (op) routes ( Figure 6(b) POM-L-BHDU and L-BHDU-C18 have shown good in vivo efficacy and have been selected for additional pharmacokinetic / pharmacodynamic (PK / PD) studies, mechanism of action, and toxicology studies. Additionally, the potential interaction of POM-L-BHDU with 5-fluorouracil catabolism needs to be evaluated, a concern with brivudine that is not present with L-BHDU. 11 According to preliminary findings, L-BHDU interferes with pyrimidine biosynthesis induced by VZV infection in non-dividing cells. 22

[0087] Additionally, all synthesized compounds were also tested in vitro against herpes simplex virus (HSV-1, oral herpes) in Vero cells. Figure 8 L-BHDU and its octadecyl OED-L-BHDU and POC-L-BHDU prodrugs showed good activity against HSV-1. L-BHDU showed EC 50 is 0.007 μM, and SI is greater than 12,903 ( Figure 9 , Table 2).

[0088] POM-L-BHDU expresses EC 50 The antiviral efficacy of POC-L-BHDU was 0.028 μM, and the SI was > 3546. 50 The minimum effective EC of the octadecyl prodrug was found to be 0.0260 μM, with SI>3,846 compared to all the synthesized analogs. 50 The results showed that L-BHDU and its POM and POC prodrugs were superior to acyclovir (EC 50 =0.0736μM) and no toxic CC 50 >100 μM. However, the octadecyl prodrug showed cytotoxicity at a concentration of 20 μM.

[0089] Furthermore, the antiviral activity of these analogs against HSV-2 (genital herpes) in vitro was tested in Vero cells using acyclovir as a standard drug reference. Interestingly, it was reported that POM-L-BHDU was found to be active only against HSV-2, EC 50 1.4 μM, SI>71( Figure 10 All other analogs containing L-BDHU were found to be ineffective against HSV-2 ( Figure 11, Table 3). Following these findings, it was determined that POM-L-BHDU (37) has potential against both HSV-1 and HSV-2. Additional in vivo evaluation of the POM prodrug of L-BDHU will confirm activity. The POM prodrug of L-BHDU can demonstrate excellent antiviral efficacy against HSV-2 in an in vivo mouse model.

[0090] Furthermore, POM-L-BHDU was evaluated as a topical treatment for VZV and HSV in a human skin explant model and was highly effective against both viruses when formulated at 0.2% in cocoa butter ( Figure 12 Importantly, topical L-BHDU-POM 0.2% was more effective than topical acyclovir 0.5% for HSV1 ( Figure 12 , right small picture).

[0091] Since L-BHDU, ODE-L-BHDU, POM-L-BHDU, and POC-L-BHDU have some of the best antiviral properties against VZV-ORF57-Luc, the prodrugs were screened against the VZV mutants VZV TK (thymidine kinase-deficient, -TK), VZV TS (thymidylate synthase-deficient, -TS), and VZV TKTS (thymidylate kinase and thymidylate synthase-deficient, -TKTS). These studies were performed in the same manner as the efficacy studies described above, except that cell-associated VZV-ORF57-Luc, VZV-ORF57-ΔTK, VZV-ORF57-ΔTS, and VZV-ORF57-ΔTKTS were used to infect ARPE-19 cells. As before, CDV and ACV were used as positive controls. The EC values ​​for each compound against cell-associated VZV were 0.01, 0.02, and 0.06, respectively. 50 ECs obtained with cell-free VZV 50 Similar or slightly higher ( Figure 13 In most cases, L-BHDU and its prodrugs were more potent against VZV-ORF57-Luc than against CDV or ACV. The exception was ODE-L-BHDU, which was less potent than CDV but 9 times more potent than ACV ( Figure 14 , Table 4).

[0092] in conclusion

[0093] In summary, the present inventors have synthesized POM, POC and long-chain phospholipid prodrugs of L-BHDU. These prodrugs exhibited significant anti-VZV activity. Compared to L-BHDU, POM-L-BHDU (8) showed enhanced antiviral efficacy, while OED-L-BHDU (5) and HDP-L-BHDU (6) exhibited lower in vitro activity against VZV than the parent molecules. In addition, the in vitro effective compound POM-L-BHDU maintained its antiviral efficacy in an in vivo mouse model without cytotoxicity. In addition, the long-chain phospholipid prodrug OED-L-BHDU (compound 5) also exhibited significantly enhanced in vivo antiviral activity compared to L-BHDU. From this study, it can be concluded that POM-L-BDHU (8) and OED-L-BHDU (5) should be developed as drug candidates against VZV. Additional biological studies including anti-VZV activity against drug-resistant mutants, pharmacokinetic studies, molecular mechanism of action studies, and tissue distribution studies are needed to evaluate the full potential of these 8 and 9 promising L-BHDU prodrugs. It is worth mentioning that all synthetic prodrugs in this study showed good antiviral activity against HSV-1 (oral herpes). POM-L-BDHU (8) also showed significant activity against HSV-2 (genital herpes), while all other prodrug analogs containing L-BDHU were found to be inactive against this virus. Overall, POM-L-BDHU (8) and OED-L-BHDU (5) are effective, safe, and well tolerated, making them good candidates for drug therapy. In addition, POM-L-BDHU (8) showed activity consistent with the development of this compound as a good drug candidate against HSV-2 (genital herpes), which is a prerequisite for current treatment.

[0094] Experimental part

[0095] General analytical methods

[0096] Reagents and anhydrous solvents were purchased and used without further purification. Reactions were monitored by thin layer chromatography plates (TLC silica gel GF 250 microns) visualized with a UV lamp (254 nm) and developed with a solution of 15% sulfuric acid in methanol. Melting points were recorded on a digital melting point apparatus and are uncorrected. Tetramethylsilane (TMS) was used as an internal standard and recorded at 500 MHz. 1 H NMR, 19 F NMR, recorded at 202 MHz 31 P-NMR and recorded at 125 MHz 13C NMR nuclear magnetic resonance spectra. Chemical shifts (δ) are quoted as s (singlet), bs (broad singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (double doublet), and dt (double triplet). Optical rotations were measured on a digital polarimeter. ESI high-resolution mass spectra were recorded on a Q-TOF mass spectrometer. Thin-layer chromatography was performed on silica gel-coated glass plates.

[0097] L-BHDU-5'-[(2-octadecyloxyethyl)phosphate](5). To a solution of 1,2,4-triazole (0.28 g, 4.1 mmol) and triethylamine (0.57 mL, 4.1 mmol) in anhydrous THF (10 mL) was added a solution of 2-chlorophenyl dichlorophosphate (2, 0.5 g, 2.0 mmol) in THF (10 mL). The reaction mixture was stirred at room temperature for 30 minutes and then filtered. To the filtrate were added 20 mL of THF, L-BHDU (1, 0.49 g, 1.5 mmol) and 1-methylimidazole (0.17 mL, 2.0 mmol) in sequence. After 1 hour, 2-(octadecyloxy)ethanol (0.48 g, 1.5 mmol) was added to the mixture and stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (3% MeOH / DCM) to give L-BHDU 5'-[(2-chlorophenyl 2-octadecyloxyethyl)phosphate] (3, 0.45 g, 64% yield). 1 H-NMR (500MHz, CDCl3) δ9.13 (bs, 1H, NH), 7.71 (d, J = 2.5Hz, 1H), 7.48-7.38 (m, 3H), 7.20 (t, J = 16. 0&8.5Hz,1H),7.10(t,J=15.5&8.0Hz,1H),6.72(dd,J=13.5&4.5Hz,1H);6.33(dd,J=16.5&7.5Hz, 1H),5.17-5.16(m,1H),4.55-4.43(m,2H),4.37-4.32(m,2H),4.22-4.16(m,2H),3.66-3.64(m,2H ),3.42(t,J=13.5&8.0Hz,2H),1.52-1.48(m,2H),1.29-1.23(m,30H),0.86(t,J=14.0&7.0Hz,3H); 31 P NMR (202MHz, CDCl3): δ-6.10,-6.36; 13C-NMR (125 MHz, CDCl3) δ 160.9, 149.3, 146.3, 130.9, 130.5, 128.2, 127.6, 126.6, 126.0, 125.5, 112.1, 110.8, 110.4, 81.5, 81.4, 81.2, 71.5, 71.4, 68.3, 31.9, 29.7, 29.5, 29.4, 26.0, 22.7, 14.2. The obtained intermediate 3 was dissolved in THF, and 0.5 N NaOH solution (1.5 mL) was added at 0 ° C. The mixture was stirred at 50 ° C for 2 hours and neutralized with 1 N HCl at 0 ° C. The volatiles were removed under reduced pressure, and the residue was purified by silica gel column chromatography (10% MeOH / DCM) to give 5 in 90% yield. Mp 115-117 °C; 1 H-NMR (500MHz, DMSO-d6) δ11.59(s,1H),8.20(s,1H),7.39(d,J=13.5Hz,1H),7.26(d,J =14.0Hz,1H),6.18(d,J=4.5Hz,1H),5.04-5.03(m,1H),4.23(d,J=9.5Hz,1H),4.08(t, J=10.0&4.5Hz,1H),3.91-3.93(m,2H),3.72-3.69(m,2H),3.43(t,J=10.0&4.5Hz,2H), 3.35-3.34(m,2H),1.46-1.43(m,2H),1.28-1.23(m,30H),0.85(t,J=13.5&8.6Hz,3H); 31 P NMR (202MHz, DMSO-d6): δ-1.06; 13 C{ 1 H}NMR(125MHz,CD3OD)δ162.3,150.0,138.6(d,J=21.5Hz),111.2,108.3,107.8,81.55(d ,J=34.4Hz),70.9,64.6,46.7,31.7,29.4,29.2,29.1,25.8,22.4,13.1,13.0; HRMS(EI)(C 30 H 52 BrN2O9P+Na) + The calculated value is 717.2492, and the experimental value is 717.2485.

[0098] Compound 6 (50 mg) was synthesized in qualitative yield according to the same procedure as compound 5. Yield 85%; mp 122-123°C; 1H-NMR (500MHz, CD3OD) δ8.02(s,1H),7.46(d,J=14.0Hz,1H),7.04(d,J=13.5Hz,1H),6.32( dd,J=7.5&1.5Hz,1H),5.19(s,1H),4.29(dd,J=7.0&2.0Hz,1H),4.22-4.19(m,1H),4.15-4. 14(m,2H),3.99(d,J=6.5&2.0Hz,2H),3.55(t,J=13.0&7.0Hz,2H),3.43(t,J=13.0&6.5Hz, 2H),1.92-1.89(m,2H),1.56-1.52(m,2H),1.37-1.31(m,26H),0.93(t,J=13.5&7.0Hz,3H); 31 P NMR (202 MHz, CD3OD): δ 0.58; 13 C{ 1 H}NMR (125MHz, CD3OD) δ162.3,150.0,138.6(d,J=20.1Hz),129.6,129.1,111.2,108.3,107.8,104.5,103.9,81.5(d,J=34.6Hz) ,71.1(d,J=31.5),70.7,67.0,63.6,62.4,31.7,30.8,30.7,30.6,29.4,29.3,29.1,25.9,22.4,13.0(d,J=12.0Hz); HRMS(EI)(C 29 H 50 BrN2O9P+H) + The calculated value is 681.2516, and the experimental value is 681.1507.

[0099] Procedure for the synthesis of bis(POM)phosphorylation of L-BHDU: To a stirred solution of L-BHDU (30 mg, 0.094 mmol) and N-methylimidazole (0.61 mL, 0.75 mmol) in dry THF (3 mL) was added chlorobis(POM)phosphate 7 (154 mg, 0.473 mmol) dissolved in 3 mL of THF at 0 ° C and stirred for 15 minutes. Afterwards, the reaction was warmed to room temperature and stirred for 3 hours. The mixture was quenched with methanol, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (0.5% MeOH / DCM) to give 8 (42.0 mg, 71% yield) as a colorless viscous oil. 1H NMR (500MHz, CDCl3) δ8.55(bs,1H),7.70(bs,1H),7.43(d,J=15.0Hz,1H),6.78(d,J=10.0Hz,1H),6.35(d,J =10.0Hz,1H),5.71-5.64(m,4H),5.14(d,J=1.5Hz,1H),4.42-4.30(m,2H),4.25-4.17(m,2H),1.22(s,18H); 13 C-NMR (125MHz, CDCl3) δ176.8,160.9,149.4,137.3,128.3,112.2,110.6,102.9,100.0,83.1,81.4,71.5,65.1,38.8,26.9; 31 P-NMR(202MHz,CDCl3)δ-3.02,HRMS(EI)(C 22 H 32 BrN2O 12 P+H) + Calculated value 627.0954, found value m / z 627.0953.

[0100] ((Bis(benzyloxy)phosphoryl)oxy)methyl isopropyl carbonate (10). To a stirred mixture of compound 9 (560 mg, 1.99 mmol) and cesium carbonate (1.6 g, 4.97 mmol) in acetone (10 mL) was added POC-I (610 mg, 2.38 mmol) dropwise at room temperature and stirred overnight. The reaction mixture was filtered through a Buchner funnel, and the obtained filtrate was concentrated under reduced pressure. The obtained residue was purified on silica gel column chromatography (20% EtOAc / hexane) to produce 650 mg of compound 10 as a colorless oil with a yield of 82%. 1 H NMR (500MHz, CDCl3) δ7.35-7.30 (m, 10H), 5.61-5.58 (d, J = 15.0Hz, 2H), 5.07-5.05 (d, J = 10.0Hz, 4H), 4.90-4.85 (s, 1H), 1.29-1.28 (d, J = 5.0Hz, 6H); 31 P-NMR (202MHz, CDCl3)δ–2.02

[0101] (((Benzyloxy)(hydroxy)phosphoryl)oxy)methyl isopropyl carbonate (11). To a stirred solution of compound 10 (1.0 g, 2.54 mmol) in acetonitrile (20 mL) was added NaI (0.76 g, 5.07 mmol) and stirred at 45 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the crude product obtained was washed with dry ether and dried under high vacuum. After drying, the residue was used in the next step without further purification.

[0102] ((Phenoxyphosphoryl)bis(oxy))bis(methylene)diisopropylbis(carbonate) (12). To a stirred mixture of compound 11 (231 mg, 0.75 mmol) and cesium carbonate (371 mg, 1.13 mmol) in acetone (10 mL) was added POC-I (240 mg, 0.98 mmol) dropwise at room temperature and stirring was continued overnight. The reaction mixture was filtered through a Buchner funnel, and the obtained filtrate was concentrated under reduced pressure. The residue was purified on silica gel column chromatography (15% EtOAc / hexanes) to give 30 mg of compound 12 as a colorless oil in 70% yield. 1 H NMR (500MHz, CDCl3) δ7.38-7.33(m,5H),5.64-5.62(d,J=10.0Hz,4H),5.13-5.12(d,J=5.0Hz,2H),4.94-4.86(s,2H),1.30-1.28(t,J=10.0Hz,6H); 31 P NMR (202MHz, CDCl3) δ–3.77.

[0103] ((Hydroxyphosphoryl)bis(oxy))bis(methylene)diisopropylbis(carbonate) (13). A suspension of compound 12 (300 mg, mmol) and 10% Pd / C (30 mg) in methanol at ambient temperature was treated with H2 at 5 psi for 2 hours. The mixture was passed through a bed of celite and concentrated under reduced pressure to give 200 mg of 13 in 85% yield as a colorless viscous liquid. Compound 13 was used as such in the next step reaction without further purification. 1 H-NMR (500MHz, CDCl3) δ7.99 (bs, 1H), 5.63-5.60 (d, J=15.0Hz, 4H), 4.95-4.88 (s, 2H), 1.31-1.30 (t, J=5.0&2.0Hz, 6H); 13 C-NMR (125MHz, CDCl3) δ153.19,85.46,73.44,21.66; 31 P-NMR (202MHz, CDCl3) δ–3.36.

[0104] Bis(POC) prodrug L-BHDU (14) compound 13 (92 mg, 0.282 mmol) was dissolved in TEA (1 mL) and pyridine (0.5 mL) and stirred at room temperature for 10 minutes. The contents were then concentrated under reduced pressure and co-evaporated with toluene (3 mL). The residue was dissolved in dry THF (3 mL) and cooled to 0°C, after which L-BHDU (30 mg, 0.094 mmol) was added, followed by DIPEA (0.05 mL, 0.282 mmol), BOP-Cl (48.0 mg, 0.189 mmol), and 3-nitro-1,2,4-triazole (21 mg, 0.189 mmol). The mixture was stirred at the same temperature for 2 hours and diluted with ethyl acetate (50 mL). The organic layer was washed with saturated NaHCO solution (20 mL x 2), followed by brine solution (10 mL), and dried over NaSO. The solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (0.8% methanol / DCM) to give Compound 14 (13 mg, 22% yield) as a colorless sticky solid. 1 H-NMR (500MHz, CDCl3) δ8.59(bs,1H),7.69(s,1H),7.44-7.41(d,J=15.0MHz,1H),6.79-6.76(d,J=15.0MHz,1H),6.35-6.34(d,J=5.0 MHz,1H),5.71-5.64(m,4H),5.15(s,1H),4.95-4.88(s,2H),4.45-4.35(m,2H),4.33-4.17(m,2H),1.31-1.29(t,J=15.0&7.0Hz,6H); 13 C-NMR(125MHz, CDCl3):160.95,153.05,149.4,137.3,128.3,112.2,110.5,102.9,85.8,81.4,77.4 73.7,71.5,65.2,21.7; 31 P-NMR(202MHz, CDCl3)–3.14; HRMS(EI)(C 20 H 28 BrN2O 14 P+H) + The calculated value is 631.0540, and the experimental value is 631.0538.

[0105] References

[0106] 1. Gershon, AA; Breuer, J.; Cohen, JI; Cohrs, RJ; Gershon, MD; Gilden, D.; Grose, C.; Hambleton, S.; Kennedy, PGE; Oxman, MN; Seward, JF; Yamanishi, K. Varicella zoster virus infection. Nat Rev Dis Primers 2015, 1.

[0107] 2. Marin, M.; Leung, J.; Gershon, AA. Transmission of Vaccine-Strain Varicella-Zoster Virus: A Systematic Review. Pediatrics, 2019, 144(3).

[0108] 3. Sampathkumar, P.; Drage, LA; Martin, DP. Herpes zoster / shingles and postherpetic neuralgia. Mayo Clin Proc, 2009, 84(3), 274-280.

[0109] 4. Field, HJ; Hodge, RAV. Recent developments in anti-herpesvirus drugs. British Med Bull 2013, 106(1), 213-249.

[0110] 5. Lee, MY; Kim, KS; Lee, WK. Intravitreal Foscarnet for the Treatment of Acyclovir-resistant Acute Retinal Necrosis Caused by Varicella Zoster Virus. Ocul Immunol Inflamm, 2011, 19(3), 212-213.

[0111] 6. Andrei, G.; Snoeck, R., Advances and Perspectives in the Management of Varicella-Zoster Virus Infections. Molecules, 2021, 26(4).

[0112] 7. Hoffman, J., Overview of antiviral medications used in ophthalmology. Community Eye Health. 2020, 33(108), 85-88.

[0113] 8. De Clercq, E., (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU). Med Res Rev 2005, 25(1), 1-20.

[0114] 9. De Clercq, E., Discovery and development of BVDU (brivudine) as a therapeutic for the treatment of herpes zoster. Biochem Pharmacol, 2004, 68(12), 2301-2315.

[0115] 10. Choi, Y.; Li, L.; Grill, S.; Gullen, E.; Lee, C.S.; Gumina, G.; Tsujii, E.; Cheng, Y.C.; Chu, C.K. Structure-activity relationships of (E)-5-(2-bromovinyl)uracil and related pyrimidine nucleosides as antiviral agents for herpes viruses. J Med Chem 2000, 43(13), 2538-2546.

[0116] 11. De, C.; Liu, D. M.; Zheng, B.; Singh, U. S.; Chavre, S.; White, C.; Arnold, R. D.; Hagen, F. K.; Chu, C. K.; Moffat, J. F. Beta-L-1-[5-(E-2-bromovinyl)-2-(hydroxymethyl)-1,3-(dioxolan-4-yl)]uracil (L-BHDU) prevents varicella-zoster virus replication in a SCID-Hu mouse model and does not interfere with 5-fluorouracil catabolism. Antivir. Res)》2014,110,10-19.

[0117] 12. Pradere, U.; Garnier-Amblard, EC; Coats, SJ; Amblard, F.; Schinazi, RF. Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs. Chem Rev, 2014, 114(18), 9154-9218.

[0118] 13. Naesens, L.; Neyts, J.; Balzarini, J.; Bischofberger, N.; Declercq, E., In-Vivo Antiretroviral Efficacy of Oral Bis(Pom)-Pmea, the Bis(Pivaloyloxymethyl) Prodrug of 9-(2-Phosphonylmethoxyethyl)Adenine(Pmea). Nucleos Nucleot, 1995, 14(3-5), 767-770.

[0119] 14.Marcellin,P.Chang,T.Lim,SGTong,MJSievert,W.Shiffman,MLJeffers,L.Goodman,Z.Wulfsohn,MS.Xiong,S.Fry,J.Brosgart, CL,Afdhal,N.O'Conner,C.Andreone,P.Cursaro,C.Angus,P.Vaughan,R.Bain,V.Gutfreund,K.Barange,K.Duffant,M.Barnes,E.B ennett,M.;Pressman,J.Bernstein,D.Bonino,F.Coco,B.Borum,M.Schuck,S.Bourliere,M.Benali,S.Boyer,N.Castelnau,C.Brown ,R.Scales,S.Buggisch,P.Peterson,J.Cooksley,G.MacDonald,G.Couzigou,P.Foucner,D.Crawford,D outas,A.DiBisceglie,A.Bacon,B.Dieterich,D.Goldman,D.Dusheiko,G.Enriquez,J.Gallego,A.Esposito,S.Lemieszewski,J.Es teban,R.Buti,M.Faust,T.Wherity,K.Francavilla,A.Malcangi,F.Fried,M.Nakayama,C.Gilson,R.Lascar,M.Gish,R.Trinh,H. Gordon,S ,J.Hsing,A.Nonaka-Wong,S.Kraus,M.Jen,CMKaita,K.Koval,G.Parrish,H.Kowdley,K.Kronborg,I.Nicoll,A.Kullavanijaya,P.Amonrattanakosol,J.Lao-Tan,J.Garcia,L.Liaw,YFChien,RNLok,A.Richtmyer,P.Luengrojanakul,P.Tanwandee,T.Manns,M.Sch ueler,A.andMartin,P.Peacock,V.McCaughan,G.Strasser,S.McHutchison,J.Pockros,P.Merican,I.Lachmanan,S.Mohamed,R.Naccar ato,R..Fagiuoli,S.Nelson,M.Higgs,C.Pastore,G.Perrillo,R.Denham,C.Pol,S.Fontaine,H.Riely,C.Litley,D.Rizzetto,M.L agget,M.Rodriguez,M.Espiga,M.Rustgi,V.Lee,P.Sacks,S.Farley,J.Samuel,D.Feray,C.Sasadeusz,J.Gioupouki,M.Shaw,D.Le Mire, M. Shelton, D. Sherman, M. Bartolucci, A. Schiff, E. Siebert, A. Sollano, J. and Dy, F.Thuluvath,P.Tong,L.Trepo,C.Maynard,M.Trinchet,JCCarrie,N.Vetter,D.Metz ger,S.Vierling,J.Clarke-Platt,J.Wakil,E.Bzowej,N.Warnes,T.Wright,T.Kwong ,A.Young,YY;Zarski,JP;Leroy,V.Grp,ADS; Grp,RFVH,Observation of the active ingredient(Adefovir). dipivoxil for the treatment ofhepatitis B and antigen-positive chronic hepatitis B).

[0120] 15. Fung, HB; Stone, EA; Piacenti, FJ. Tenofovir disoproxil fumarate: A nucleotide reverse transcriptase inhibitor for the treatment of HIV infection. Clin Ther, 2002, 24(10), 1515-1548.

[0121] 16. Wiemer, AJ; Wiemer, DF. Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier. Top Curr Chem, 2015, 360, 115-160.

[0122] 17. Beadle, JR; Hartline, C.; Aldern, KA; Rodriguez, N.; Harden, E.; Kern, ER; Hostetler, KY. Alkoxyalkyl esters of cidofovir and cyclic cidofovir exhibit multiple-log enhancement of antiviral activity against cytomegalovirus and herpesvirus replication in vitro. Antimicrob Agents Ch, 2002, 46(8), 2381-2386.

[0123] 18. Liang, Y.; Narayanasamy, J.; Schinazi, R. F.; Chu, C. K. Phosphoramidate and phosphate prodrugs of (-)-beta-D-(2R,4R)-dioxolane-thymine: synthesis, anti-HIV activity and stability studies. Bioorg Med Chem, 2006, 14(7), 2178-89.

[0124] 19. Hwang, YS; Cole, PA. Efficient synthesis of phosphorylated prodrugs with bis(POM)-phosphoryl chloride. Organic Letters, 2004, 6(10), 1555-1556.

[0125] 20. De, C.; Liu, D.; Singh, U.S.; Chu, C.K.; Moffat, J.F. β-L-1-[5-(E-2-Bromovinyl)-2-(Hydroxymethyl)-1,3-(Dioxolan-4-yl)]Uracil (L-BHDU) Inhibits Varicella Zoster Virus Replication by Depleting the Cellular dTTP Pool. bioRxiv, 2020, 02.13.948216.

[0126] 21. De, C.; Liu, D.; Depledge, D.; Breuer, J.; Singh, US; Hartline, C.; Prichard, MN; Chu, CK; Moffat, JF. β-L-1-[5-(E-2-Bromovinyl)-2-(hydroxymethyl)-1,3-(dioxolan-4-yl)]uracil (L-BHDU) effectiveness against varicella-zoster virus and herpessimplex virus type 1 depends on thymidine kinase activity. BioPreprint Repository 2020, 02.13.948190.

Claims

1. A prodrug compound of L-BHDU according to the following chemical structure I: where R 1 Yes - (CH2) n -OR 1a group or -(CH2) j -OC(O)O k -R 2a group; R 2 It is H, -(CH2) n -OR 1a group or -(CH2) j -OC(O)O k -R 2a group; R 1a It is C6-C 30 alkyl; R 2a It is C1-C 12 alkyl; Each j is independently 1-6; Each k is 0 or 1; Each n is independently 1-6; or or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein R 1a It is C 12 -C 22 alkyl.

3. The compound according to claim 1, wherein R 1a It is C 14 -C 20 alkyl.

4. The compound according to claim 1, wherein R 1a It is C 16 -C 18 alkyl.

5. The compound according to claim 1, wherein R 1a It is C 16 or C 18 alkyl.

6. The compound according to claim 1, wherein R 1 Yes - (CH2) n -OR 1a group, and n is 2 or 3.

7. The compound according to claim 6, wherein R 1a It is C 14 -C 20 Alkyl or C 16 -C 18 alkyl, and n is 2 or 3.

8. The compound according to claim 7, wherein R 1a It is C 16 Alkyl or C 18 Alkyl, and R 2 It’s H.

9. The compound according to claim 8, wherein R 1a It is C 18 alkyl, and n is 2.

10. The compound according to claim 8, wherein R 1a It is C 16 alkyl, and n is 2.

11. The compound according to claim 1, wherein R 1 Yes - (CH2) n -OR 1a group, and R 2 is H or -(CH2) n -OR 1a group.

12. The compound of claim 1, wherein each j is independently 1-3.

13. The compound of claim 1, wherein each j is independently 1 or 2.

14. The compound according to claim 1, wherein R 1 Yes - (CH2) j -OC(O)O k -R 2a group, and R 2 is H or -(CH2) j -OC(O)O k -R 2a group.

15. The compound according to claim 14, wherein R 2 Yes - (CH2) j -OC(O)O k -R 2a group, and j is 1-4.

16. The compound according to claim 15, wherein j is 1 or 2, and R 2a It is C1-C 12 alkyl.

17. The compound according to claim 16, wherein j is 1 or 2, and R 2a It is a C2-C6 alkyl group.

18. The compound of claim 17, wherein j is 1, and R 2a It is a C3 or C4 alkyl group.

19. The compound of claim 17, wherein j is 2, and R 2a It is a C3 or C4 alkyl group.

20. The compound according to claim 1, wherein R 1 Yes - (CH2) j -OC(O)O k -R 2a .

21. The compound of claim 20, wherein j is 1.

22. The compound of claim 21, wherein k is 0.

23. The compound of claim 21, wherein k is 1.

24. The compound according to claim 14, wherein R 1 and R 2 same.

25. A compound according to the following chemical structure: where R 1 Yes - (CH2) n -OR 1a group, n is 2 or 3, R 1a It is C 16 or C 18 alkyl, and R2 is H, or a pharmaceutically acceptable salt thereof.

26. The compound of claim 25, wherein n is 2, and R 1a It is C 18 alkyl.

27. The compound of claim 25, wherein n is 3, and R 1a It is C 16 alkyl.

28. A compound according to the following chemical structure: where R 1 and R 2 Each is -(CH2) j -OC(O)O k -R 2a group; R 2a is independently isopropyl or tert-butyl; Each j is independently 1 or 2; Each k is 0 or 1; or or a pharmaceutically acceptable salt thereof.

29. The compound according to claim 28, wherein R 1 and R 2 are the same, j is 1, k is 1, and R 2a It is isopropyl.

30. The compound according to claim 28, wherein R 1 and R 2 are the same, j is 1, k is 0, and R 2a It is tert-butyl.

31. A pharmaceutical composition comprising an effective amount of a compound according to claim 1, claim 25 or claim 28 in combination with a pharmaceutically acceptable carrier, additive or excipient.

32. The composition of claim 31 further comprising an additional bioactive agent.

33. The composition of claim 32, wherein the bioactive agent is acyclovir, brivudine, foscarnet, cidofovir, valacyclovir, famciclovir, herpes zoster immune globulin, vidarabine, or a mixture thereof.

34. The composition of claim 32, wherein the bioactive agent is 5-fluorouracil.

35. The composition of claim 33, wherein the bioactive agent is foscarnet, cidofovir, or a mixture thereof.

36. Use of the composition of claim 31 in the preparation of a medicament for treating a viral infection in a patient in need thereof, wherein the viral infection is varicella-zoster virus infection, herpes simplex virus I infection, or herpes simplex virus II infection.

37. The use according to claim 36, wherein the viral infection is a VZV infection.

38. The use according to claim 37, wherein the viral infection is caused by wild-type VZV or mutant VZV.

39. The use according to claim 37, wherein the viral infection is caused by VZV TK, VZV TS or VZV TKTS.

40. The use according to claim 36, wherein the viral infection is an HSV-1 infection.

41. The use according to claim 36, wherein the viral infection is an HSV-2 infection.

42. Use of a compound according to claim 1, claim 25 or claim 28 in the preparation of a medicament for treating a viral infection in a patient in need thereof, wherein the viral infection is varicella-zoster virus infection, herpes simplex virus I infection or herpes simplex virus II infection.

43. The use according to claim 42, wherein the compound is: Where R is C 18 H 37 O(CH2)2-,R 2 Yes - (CH2) j -OC(O)O k -R 2a Group; R 2a is independently isopropyl or tert-butyl; each j is independently 1 or 2; each k is 0 or 1; or or a pharmaceutically acceptable salt thereof.

44. Use of a compound according to claim 1, 25 or 28 in the preparation of a medicament for reducing the likelihood of a viral infection in a patient in need thereof, wherein the viral infection is varicella zoster virus infection, herpes simplex virus I infection or herpes simplex virus II infection.

45. The use according to claim 44, wherein the viral infection is a VZV infection.

46. ​​The use according to claim 44, wherein the viral infection is an HSV-1 infection.

47. The use according to claim 44, wherein the viral infection is an HSV-2 infection.

Images