Prodrugs of L-BHDU and methods for treating viral infections

Abstract

In one embodiment, the present invention provides a prodrug compound of L-BHDU according to chemical structure I, 1 is -(CH2) n -OR 1a Group or -(CH2) j -O.C.(O)O k -R 2a R 2 is H, -(CH2) n -OR 1a group, or -(CH2) j -O.C.(O)O k -R 2a R 1a Independently, C6-C 30 Alkyl groups, often C 12 -C 22 Alkyl groups, often C 14 -C 20 Alkyl group or C 16 -C 18 Alkyl groups, often C 16 or a Cis alkyl group, R 2a are independent, C1-C 12 wherein each j is independently 1 to 6, 1 to 3, often 1 or 2, each k is 0 or 1, and each n is independently 1 to 6, 1 to 4, 2 to 4, or 2 or 3, or a pharma- ceutically acceptable salt, solute, or polymorph thereof. Further embodiments relate to pharmaceutical compositions and methods based on the disclosed compounds for treating or reducing the likelihood of VZV, HSV-1, or HSV-2 infection. Methods of synthesizing the compounds according to the invention represent further embodiments of the invention. [Formula 1] TIFF2024543812000006.tif65150

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 compositions thereof, and methods of treatment against varicella zoster virus (VZV) and herpes simplex virus (HSV-1 and 2). Methods for synthesizing these compounds are also disclosed.

[0002] Related Applications This application claims the benefit of priority to U.S. Provisional Application No. 63 / 273,403, filed October 29, 2021, the entire contents of which are incorporated herein by reference. [Background technology]

[0003] The varicella zoster virus (VZV) causes chickenpox (varicella) in humans upon primary infection, and causes shingles (zoster) upon reactivation during the latent stage. 1 VZV belongs to the gamma herpes family and is partially curable by vaccination with the live attenuated vaccine strain Oka-Merck. 2 However, while childhood vaccination has reduced chickenpox cases, shingles in the elderly remains a challenge. In the elderly, the effectiveness of the vaccine is reduced by about 50%, which quickly leads to reinfection and the painful condition shingles. Postherpetic neuralgia is one of the major complications of shingles. 3 It is characterized by a persistent, painful skin rash due to VZV reactivation. Due to spontaneous and breakthrough cases of VZV, immunocompromised patients cannot receive the vaccine. Therefore, the course of chickenpox is more likely to begin in immunocompromised patients, especially those suffering from acquired immune deficiency syndrome (AIDS), transplant recipients, and cancer patients. In these conditions, VZV infection can be life-threatening.

[0004] The current therapeutic agents that are nucleoside drug analogs are acyclovir (ACV), valacyclovir (VACV), and famciclovir. 4 However, these drugs have low efficacy and low bioavailability, and long-term use of these therapies is associated with drug resistance. In drug-resistant patients, foscarnet (phosphonoformic acid) is administered intravenously to treat resistant VZV, but it is associated with numerous side effects and cytotoxicity. 5 Available nucleoside drugs act in their active triphosphate form on viral DNA polymerase, mimicking viral replication. Cellular enzymes such as thymidine kinase (TK) and cytokinin 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 (eye infection) can be treated with topical trifluridine and idoxuridine. 7 First, the bromovinyl analog brivudine (BVDU, E-5-(2-bromovinyl)-2'-deoxyuridine) showed better antiherpetic activity and has been approved in Europe for the treatment of VZV infections. 8 Similarly, BVDU is also converted to 5'-monophosphate and 5'-diphosphate forms by viral TK enzymes and finally to 5'-triphosphate (BVDU-TP) form by cellular kinases. BVDU-TP selectively interacts with viral DNA polymerase either in the form of a competitive inhibitor or incorporated into the DNA chain, resulting in DNA chain termination. BVDU has shown a better activity profile than acyclovir and its derivatives. Additionally, the ease of administration of BVDU makes it more attractive among elderly patients compared to other drugs used for VZV infection. The main drawback associated with this drug is that it is cleaved into BVD metabolites during metabolism. BVD inhibits dihydropyridine dehydrogenase, which is essential for the breakdown of thymidine and uracil. Therefore, cancer patients treated with 5-fluorouracil (5-FU) cannot be administered BVDU because its use causes the accumulation of toxic 5-FU in these patients, resulting in early death. 9Due to the described drawbacks and significant adverse effects of currently prescribed drugs, there is a great demand for new antiviral drugs that can inhibit the spread of VZV in the skin, especially since the approved drugs have little effect on viral replication.

[0005] Therefore, there is a continuing need for new antiviral drugs against VZV. To address the current challenges of VZV treatment, the present inventors developed a uridine derivative, β-L-[5-(E-2-bromovinyl)-2-(hydroxymethyl)-1,3-(dioxolan-4-yl)uracil (L-BHDU). 10 L-BHDU had an EC50 of 0.22 μM against VZV in human foreskin fibroblasts (HFFS). 50 The potency of this antibody was expressed in vitro. It was also found to be non-cytotoxic to cells at a concentration of 200 μM and exhibited a selectivity index (SI) of >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 showed an EC of 0.03 μM with an SI of >6667. 50 value and 200 μM CC 50 and showed enhanced antiviral activity. In vivo testing of L-BHDU and L-valyl-L-BHDU shows a significant reduction in VZV growth compared to ACV and VACV. Furthermore, testing of L-BHDU showed that it does not inhibit the activity of dihydropyridine dehydrogenase. 11 Therefore, L-BHDU can be administered to patients undergoing cancer treatment with 5-FU.

[0006] Encouraged by these findings, the inventors focused on exploring various prodrug approaches to improve the antiviral potency of L-BHDU against VZV. This application describes the synthesis and antiviral evaluation of POM, POC, octadecyl, and hexadecyl prodrugs of L-BHDU. Both the POM and POC groups have been shown to exhibit increased bioavailability and demonstrated facile access to the conversion of the active triphosphate form of the parent nucleoside. 12 To date, the U.S. FDA has approved adefovir dipivoxil [bis(pivaloyloxymethyl), POM] for HBV. 13,14 , and tenofovir disoproxil fumarate [bis(isopropyloxymethyl carbonate, POC]] for the treatment of HIV. 15 In the metabolism of POM prodrugs, the first POM ester group decomposes to form an unstable hydroxymethyl alcoholate intermediate, which undergoes chemical rearrangement to release formaldehyde. After cleavage of the second POM ester group, the free monophosphate is generated. 16 Similarly, POC prodrugs are also metabolized by enzymatic degradation. The carbonate of POC is decomposed by esterases to generate unstable carboxylate intermediates, followed by the successive release of carbon dioxide and formaldehyde to generate free nucleotide monophosphates. In view of these frequent conversions of nucleosides to monophosphate forms, POM(8) ​​and POC(14) prodrugs of L-BHDU (Figures 2 and 3, respectively) were synthesized and evaluated against VZV in vitro and in vivo. These prodrugs showed superior in vitro and in vivo activity compared to L-BDHU. Furthermore, POM-L-BHDU was selected for further in vivo evaluation, and this prodrug showed superior activity compared to the parent molecule.

[0007] It has been demonstrated that the 1-O-hexadecyloxypropyl and 1-O-octadecyloxyethyl prodrugs of cidofovir exhibit enhanced activity against cytomegalovirus and herpesvirus, and these prodrugs inhibit viral replication more efficiently than cidofovir. 17These long chain lipid prodrugs also show improved cellular absorption and oral bioavailability. However, we are targeting neuronal cells, which are predominantly infected by VZV. Therefore, a more lipophilic nature of L-BHDU was required. 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) (Figure 1, Scheme 1) were synthesized and screened in vitro and in vivo for antiviral activity. Esterification of L-BHDU with octadecyloxyethyl (ODE) and hexadecyloxypropyl (HDP) was meant to engineer to increase the cellular uptake / cell membrane lipophilic function of L-BHDU-based phospholipids. The addition of these long hydrocarbon chains may provide a potential improvement for the intracellular transport of compounds. However, the enhanced antiviral activity in vitro for these analogs was unexpected. As expected, HDP-L-BHDU and ODE-L-BHDU expressed lower antiviral activity in vitro compared to L-BHDU. Furthermore, ODE-L-BHDU (5) was selected for in vitro testing, and this prodrug showed superior antiviral activity compared to L-BHDU.

[0008] Varicella zoster virus (VZV) is an alphaherpesvirus that causes chickenpox and shingles. Acyclovir and its prodrug brivudine (BVdU), as well as foscarnet, are currently prescribed drugs against VZV infection. New antiviral drugs with enhanced potency and specificity are still needed to treat VZV, especially for treating postherpetic neuralgia. We have shown that β-L-1-[5-(E-2-bromovinyl)-2-(hydroxymethyl)-1,3-(dioxolan-4-yl)]uracil (L-BHDU, 1) exerted potent anti-VZV activity in three VZV replication models: primary human foreskin fibroblasts (HFFs), skin organ cultures (SOCs), and SCID-Hu mice bearing skin xenografts. To increase the potency, cellular bioavailability, and antiviral effect of L-BHDU, in this report, the 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 ester prodrugs was achieved, and these drugs were evaluated for their in vitro antiviral potency in ARPE-19 cells infected with VZV-ORF57-Luc. POM-L-BHDU (8) and POC-L-BHDU (14) showed significant anti-VZV activity. POM-prodrug 8 had an EC of 0.028 μM. 50 and POC-prodrug 14 showed no cytotoxicity (CC 50 >100μM), activity EC of 0.034μM 50 The octadecyl prodrug, ODE-L-BHDU, 5, showed an in vitro activity EC 50 indicates CC 50The EC value was 32 μM. In vivo testing of POM, POC, and octadecyl prodrugs compared to L-BHDU in the NuSkin mouse model of VZV replication found that POM-L-BHDU (8) and ODE-L-BHDU (5) were the most active compounds without significant toxicity. These synthetic prodrug analogs, including 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 (EC of 1.4 μM). 50 , >100 μM CC 50 value). Summary of the Invention

[0009] In one embodiment, the present invention provides a prodrug compound of L-BHDU according to chemical structure I. [ka] (In the formula, R 1 is -(CH 2 ) n -OR 1a group or -(CH 2 ) j -O.C.(O)O k -R 2a It is based on R 2 is H, -(CH 2 ) n -OR 1a group or -(CH 2 ) j -O.C.(O)O k -R 2a It is based on R 1a is independently 6 -C 30 Alkyl groups, often C 12 -C 22 Alkyl groups, often C 14 -C 20 Alkyl group or C 16 -C 18 Alkyl groups, often C 16Or C 18 is an alkyl group, R 2a is independently 1 -C 12 Alkyl groups, often C 2 -C 6 Alkyl group, C 3 -C 4 an alkyl group, an isopropyl group, a t-butyl group, or a sec-butyl group, or an isopropyl group or a t-butyl group; each j is independently 1 to 6, 1 to 3, often 1 or 2; each n is independently 1 to 6, 1 to 4, 2 to 4, or 2 or 3; each k is independently 0 or 1; or It relates to a pharma- ceutically acceptable salt, solute, or polymorph thereof.

[0010] In embodiments, R 1 is -(CH 2 ) n -OR 1a group, n is 2 to 4, often 2 or 3, and R 1a is C 14 -C 20 Alkyl or C 16 -C 18 Alkyl groups, most often C 16 Or C 18 It is an alkyl group. 1 Ga-(CH 2 ) n -OR 1a In embodiments where R is a group 2 is often H.

[0011] In embodiments, R 2 is often H or -(CH 2 ) j -O.C.(O)O k -R 2a It is based on

[0012] In embodiments, R 2 is -(CH 2 ) j-O.C.(O)O k -R 2a group, where j is 1 to 4, 1 or 2, often 1; k is 0 or 1; R 2a is C 1 -C 12 Alkyl group, C 2 -C 6 Alkyl groups, often C 3 Or C 4 An alkyl group, more often isopropyl or t-butyl. In embodiments, R 1 and R 2 are both -(CH 2 ) j -O.C.(O)O k -R 2a group, j is 1 to 4, 1 or 2, often 1, k is 0 or 1, R 2a is C 1 -C 12 Alkyl group, C 2 -C 6 Alkyl groups, often C 3 Or C 4 In an embodiment, k is 1. In an embodiment, k is 0. In an embodiment, k is 1 and R 2a is C 3 In an embodiment, k is 0 and R 2a is C 4 The alkyl group is often sec-butyl or t-butyl, most often t-butyl. In embodiments, R 1 and R 2 are the same as (neither is H).

[0013] In an embodiment, the present invention relates to a pharmaceutical composition comprising an effective amount of at least one L-BHDU prodrug compound as described herein in combination with a pharma- ceutically acceptable carrier, additive, or excipient. In an embodiment, the L-BDHU prodrug compound is often compound 5 of FIG. 1, Scheme 1, compound 8 of FIG. 2, Scheme 2, or compound 14 of FIG. 3, Scheme 3. The pharmaceutical composition may be formulated for oral, parenteral, or other routes of administration as described herein. In an embodiment, the present invention is often administered via oral or parenteral routes of administration, often via oral routes of administration. In an embodiment, the pharmaceutical composition comprises an L-BHDU prodrug compound as described herein in combination with at least one additional bioactive agent. In an embodiment, the additional bioactive agent is acyclovir, brivudine, foscarnet, cidofovir (CDV), valacyclovir, famciclovir, zoster immune globulin (ZIG), vidarabine, or a mixture thereof. In embodiments, L-BHDU prodrug compounds are often combined with foscarnet and / or cidofovir (CDV) to provide particularly effective treatment against VZV mutants (TK-, TS-, and TK-TS-). In other embodiments, the additional bioactive agent is an anti-cancer compound. In other embodiments, the additional bioactive agent is 5-fluorouracil (5FU).

[0014] In embodiments, the invention relates to a method of treating, inhibiting, or reducing the likelihood of a Varicella Zoster Virus (VZV) infection, or a Herpes Simplex (HSV I and II) infection, or complications thereof, 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 shingles). In embodiments, the infection is a Herpes Simplex Virus I or II infection (HSV-1 or HSV-2). In embodiments, the treatment method utilizes a combination of agents, often a prodrug of an L-BHDU as described herein, and any additional bioactive agent as described herein, co-administered to a patient or subject in need thereof.

[0015] In an embodiment, the present invention provides a method of synthesizing a compound according to the invention described herein. [Brief description of the drawings]

[0016] [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, EtN, THF, room temperature; (b) ROH, N-methylimidazole (NMI), THF, room temperature; (c) 0.5 N NaOH, THF / HO, 50° C. [Diagram 2] Scheme 2 shows the chemical synthesis of POM-L-BHDU, compound 8. Reagents and conditions: (a) NMI, THF, 0° C. to room temperature. [Diagram 3] Scheme 3 shows the chemical synthesis of bisPOC-L-BDHU prodrug. 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. [Figure 4] 1 shows a graph of the antiviral activity of L-BHDU and its prodrugs against VZV-BAC-Luc in ARPE-19 cells. [Diagram 5] Table 1 shows the anti-VZV activity of the compounds in ARPE-19 cells. In this assay, L-BHDU was found to be 10 times more potent than in the previous assay using HFFs infected with VZV-BAC-Luc (0.22 μM in HFFs, 22 nM in ARPE-19). 11L-BHDU showed a good antiviral potency EC50 of 0.022 μM. [Figure 6]Shown are the in vivo evaluations of L-BHDU, and its OED-L-BHDU (L-BHDU-C18), POM-L-BHDU, and POC-L-BHDU prodrugs. Mice were treated with vehicle or drug, and virus yields were measured by bioluminescence imaging. The VZV growth rates of individual mice (symbols) and the group means (bars) are shown in (A) and (B). A significant reduction in the VZV growth rate compared to the vehicle group is shown for both subcutaneous (s.c) (A) and oral (p.o) and subcutaneous (s.c) (B). The overall significance at 10 days post-inoculation (DPI10) is p = 0.0352 (one-way ANOVA). **OED-L-BHDU and POM-L-BHDU are <p0.01 (Student's t-test with Welch's correction). The cidofovir group (intraperitoneal (i.p)) has an average fold change of 2 - 5 at DPI10. (B). [Figure 7] Presented is a weight change test showing that all test compounds were well tolerated in both male and female mice. [Figure 8] Shown is a graph of the anti-HSV-1 activity of the L-BHDU prodrug in Vero cells. [Figure 9] Table 2 shows the data of the anti-HSV-1 activity of the L-BHDU prodrug in Vero cells. [Figure 10] Shown is the effect of L-BHDU, and its POM, POC, and octadecyl prodrugs, on HSV-2 replication in Vero cells compared to acyclovir. The yield of HSV-2 was determined by bioluminescence imaging. Each point represents the mean ± standard deviation of three samples. [Figure 11] Table 3 shows the anti-HSV-2 activities of L-BHDU, its prodrugs, and acyclovir in Vero cells. [Figure 12] Shown is that L-BHDU and its prodrug L-BHDU-POM were very effective in preventing the spread of VZV and HSV1 in adult human skin. Each compound was formulated in cocoa butter and applied topically. POM was formulated at equimolar concentrations up to 0.1% L-BHDU. The compounds showed no toxicity to the skin (histological results not shown). [Figure 13] Antiviral screening results are shown for 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-. Cidofovir and acyclovir are positive controls. Each symbol represents the average of six replicate wells. The line is the best fit curve (error bars omitted for clarity). [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 OF THE PREFERRED EMBODIMENTS

[0017] The following terms shall be used throughout the specification to describe the present invention. If a term is not specifically defined herein, it shall be understood that the term is used in a manner consistent with its usage by those of ordinary skill in the art.

[0018] Where a range of values ​​is provided, it is understood that each intervening value between the upper and lower limits of that range, to the tenth of the unit of the lower limit, and any other stated or intervening value in that stated range, is encompassed within the invention unless the context clearly dictates otherwise. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, subject to any specifically excluded limits in the stated range, and are also encompassed within the invention. Where a stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention. Where substituents are possible in one or more Markush groups, it is understood that only those substituents that form stable bonds are used.

[0019] 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 this 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.

[0020] Please note that as used in this specification and the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise.

[0021] The term "compound," as used herein, unless otherwise indicated, refers to any specific compound disclosed herein and generally refers to the prodrug form of β-L-[5-(E-2-bromovinyl)-2-(hydroxymethyl)-1,3-(dioxolan-4-yl)uracil (L-BHDU) disclosed herein, but may include tautomers, regioisomers, geometric isomers, anomers, and, where applicable, optical isomers (enantiomers) or diastereomers (two chiral centers) of these compounds, as well as pharmaceutically acceptable salts, solvates, and / or polymorphs thereof. In its use in context, the term compound generally refers to a single compound, but may also include other compounds, such as stereoisomers, regioisomers, and / or optical isomers (including racemic mixtures and / or diastereomers described herein), as well as specific enantiomers, enantiomerically enriched or individual diastereomers, or mixtures of the disclosed compounds, depending on the context in which the term is used. Note that when a range of carbons is provided for a compound, the range means that every carbon is considered individually as part of the range. For example, C 1 -C 20 Groups illustrate groups having 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., up to 20 carbons.

[0022] The term "patient" or "subject" is used throughout the present specification to describe an animal, often a domestic animal or a human, more often a human, to whom treatment, including prophylactic treatment, with a composition according to the present invention is provided. For treatment of an infection, condition, or pathology that is specific to a particular animal, such as a human patient, the term patient refers to that particular animal. Generally, in the present invention, the term patient refers to a human patient, unless otherwise stated. In addition to humans, in the present invention, domestic animals (e.g., horses, cows, dogs, cats, etc.) can also be treated with the compounds according to the present invention.

[0023] The term "varicella zoster virus" or "VZV" is used to describe one of eight herpes viruses known to infect humans (and other vertebrates). VZV commonly causes chickenpox in children and both shingles and postherpetic neuralgia in adults. Varicella zoster virus is known by many names, including chickenpox virus, varicella (varicella) virus, varicella zoster virus, and human herpesvirus type 3 (HHV-3). Primary VZV infection causes chickenpox (varicella) and can rarely lead to complications including encephalitis and pneumonia. Even after the clinical symptoms of chickenpox have resolved, VZV remains dormant in the nervous system of an infected individual in the trigeminal ganglion and dorsal root ganglion (viral latency). In approximately 10-20% of cases, VZV reactivates later in life, causing a disease known as herpes zoster or shingles. Serious complications of shingles include postherpetic neuralgia, multiplex zoster, myelitis, ocular herpes, or serotinous zoster. The compounds according to the present invention are useful for inhibiting, treating, or resolving complications associated with these viral infections.

[0024] VZV is closely related to herpes simplex virus (HSV I and II) and shares many genomic homologies. Many of the known envelope glycoproteins of VZV correspond to those of HSV. Unlike HSV, VZV cannot produce LAT (latency associated transcript), which plays a key role in establishing HSV (herpes simplex virus) latency. The virus is highly susceptible to disinfectants, especially sodium hypochlorite. In humans, it can be treated with several drugs and therapeutic agents, including acyclovir, zoster immune globulin (ZIG), and vidarabine, along with the compounds of the present invention.

[0025] The terms "herpes simplex virus", "herpes simplex virus-1" (HSV-1) and "herpes simplex virus-2" (HSV-2) are two species of the Herpesviridae family that cause infection in humans. Like other Herpesviridae families, Herpes simplex viruses can cause lifelong infections. They are also called human herpesviruses 1 and 2 (HHV-1 and HHV-2), and are neurotropic and neuroinvasive viruses that invade and hide in the human nervous system, which is why they persist in the human body. HSV-1 is commonly associated with facial herpes outbreaks known as cold sores or fever blisters, while HSV-2 is often associated with genital herpes, although each of the two types of HSV can be found in areas normally associated with the other type.

[0026] Infection with herpes simplex virus is characterized by the complication or symptom of blisters on the skin or mucous membranes of the mouth, lips, or genitals. The lesions heal with the scabs characteristic of herpes disease. However, the infection is persistent and symptoms may periodically recur as sore outbreaks near the original infection site. After the initial or primary infection, HSV lies dormant in the cell bodies of nerves in the area. Some infected individuals experience sporadic episodes of viral reactivation, after which the virus is transported via nerve axons to the skin, where viral replication and release occurs. Herpes is contagious if the carrier is producing and releasing the virus. This is especially likely during an outbreak, but may occur at other times as well. There is no cure yet, but there are treatments that reduce the likelihood of viral release.

[0027] The term "pharmaceutically acceptable salt" is used throughout the present specification to describe one or more salt forms of the compounds described herein, which are often presented to increase the solubility of the compound in the gastric juices of the patient's digestive tract, in order to facilitate the dissolution and bioavailability of the compound, if applicable. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases, and, if applicable, acids. Suitable salts include those derived from 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 art. Sodium and potassium salts are particularly preferred as neutral salts of phosphate salts according to the present invention. Other salts, such as base addition salts, may also be used in certain embodiments.

[0028] The term "pharmaceutically acceptable derivative" is used throughout this specification to describe any pharmaceutically acceptable prodrug form of the present invention that, upon administration to a patient, directly or indirectly provides L-BHDU or an active metabolite of L-BHDU.

[0029] The term "alkyl" in this context means 1 -C 30 , preferably C1 -C 20 It is intended to mean a straight chain, branched chain, or cyclic, often fully saturated, hydrocarbon radical that is straight chain or branched chain. Note that when a range of carbons is provided, the range means that every carbon is considered to be part of the range. For example, C 1 -C 20 The group describes groups having 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc. The term "ether" refers to an optionally substituted C alkyl group formed from an oxygen and an alkyl group, or alternatively, which may contain at least one oxygen within the alkyl or alkylene chain. 1 -C 20 It is understood to mean an ether group.

[0030] The term "effective amount" refers to the amount or concentration of a compound according to the present invention that is effective in the context of its administration or use and may be inhibitory, preventive, and / or therapeutic. Depending on the context, all active compounds used in the present invention are used in effective amounts. The compounds of the present invention also relate to combinations of compounds that contain an effective amount of each of the compounds used, regardless of whether the effect of the combination is additive or synergistic, provided that the overall effect of the combination of compounds is to inhibit the development of, reduce the likelihood of, or treat viral infection in a patient, as described elsewhere herein.

[0031] The term "L-configuration" as used in the context of the present invention refers to a configuration of a nucleoside compound according to the present invention that mimics the non-natural configuration of the sugar moiety, as opposed to the naturally occurring nucleosides or the "D" configuration. The term "β" or "β anomer" is used to describe nucleoside analogs according to the present invention in which the nucleoside base is configured (arranged) above the plane of the dioxolane moiety in the compound.

[0032] The term "enantiomerically enriched" is used throughout the present specification to describe a nucleoside that contains at least about 95%, preferably at least about 96%, more preferably at least about 97%, even more preferably at least about 98%, even more preferably at least about 100% or more of a single enantiomer of that nucleoside. The prodrug L-BHDU nucleoside compounds according to the present invention are generally β-L-nucleoside compounds. When the compounds of the present invention according to the present invention are referred to herein, unless otherwise stated, the nucleoside is presumed to have the L-nucleoside configuration and to be enantiomerically enriched (preferably about 100% of the L-nucleoside). The term "diastereomerically pure" is used to describe a single diastereomer of the compounds according to the present invention that contains at least 95%, 96%, 97%, 98%, 99%, 99.5%, or 100% by weight of a single diastereomer, and includes other possible diastereomers.

[0033] The terms "co-administer" and "co-administration" are used interchangeably to describe the simultaneous or near-simultaneous 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 an amount or concentration that is considered to be an effective amount. Although co-administered agents are preferably administered simultaneously, the agents may be administered at a time such that effective concentrations of both (or more) agents are present in the patient at the same time, at least for a short period of time. Alternatively, in certain aspects of the present invention, it may be possible for each co-administered agent to exhibit its inhibitory or therapeutic effect in the patient at different times, with the end result being the inhibition of the virus and the treatment of the aforementioned infection. Of course, if more than one virus, or other infections, or other conditions are present, the compounds of the present invention may be combined with agents for treating the other infections or conditions, as appropriate. In certain preferred compositions and methods, the L-BHDU prodrug compounds of the invention are coformulated and / or coadministered with at least one additional antiviral agent, preferably the antiviral agent is acyclovir, famciclovir, ganciclovir, valacyclovir, vidaribine, foscarnet, zoster immune globulin (ZIG), and mixtures thereof. Coadministration with 5-fluorouracil (5-FU) is also contemplated by the invention.

[0034] The term "independently" is used herein to indicate that a variable that is independently applied varies independently from application to application.

[0035] The present invention also relates to pharmaceutical compositions comprising an effective amount of the above compounds, optionally in combination with a pharma- ceutically acceptable carrier, excipient, or vehicle. In alternative embodiments, the pharmaceutical compositions may also contain one or more additional antiviral agents, as described elsewhere herein, in combination with an excipient, carrier, or vehicle.

[0036] A method of treatment represents a further embodiment according to the invention. In this aspect, a method of treating or reducing the likelihood of a viral infection or its secondary pathology or condition, in particular a viral infection due to VZV, HSV-1 or HSV-2 infection, in a patient in need of treatment or at risk of infection or its secondary pathology or condition, comprises administering an effective amount of the compound or composition as otherwise described above. An alternative embodiment relies on the simultaneous administration of a compound according to the invention to the patient in combination with an additional antiviral agent. In a preferred aspect, a method of treating or reducing the likelihood of VZV, or HSV-1 or HSV-2 (including drug-resistant strains thereof, or secondary diseases or conditions resulting from VZV, HSV-1 or HSV-2) involves administering an effective amount of a compound according to the invention as described herein, or a pharma- ceutically acceptable salt, solvate or polymorph thereof, to a patient in need thereof.

[0037] Pharmaceutical compositions based on nucleoside compounds according to the invention comprise an effective amount of one or more of the above compounds to treat or reduce the likelihood of a viral infection, particularly a VZV, HSV-1, or HSV-2 infection, in a patient in need of such treatment, optionally in combination with a pharma- ceutically acceptable additive, carrier, or excipient. Those skilled in the art will recognize that a therapeutically effective amount will vary depending on the infection or condition being treated, its severity, the treatment regimen being used, the pharmacokinetics of the drug being used, and the patient or subject (animal or human) being treated.

[0038] In the pharmaceutical aspects according to the present invention, the compounds according to the present invention are preferably formulated in admixture with a pharma- ceutically acceptable carrier. In general, it is preferred to administer the pharmaceutical composition in an orally administrable form, but certain formulations may be administered parenterally, intravenously, intramuscularly, transdermally, bucally, intranasally, subcutaneously, by inhalation, as a suppository, or by other routes. Intravenous and intramuscular formulations are often administered in sterile saline. In some cases, topical or transdermal administration may be used. Of course, those skilled in the art can modify the formulations within the teachings of this specification to provide a number of formulations for a particular route of administration without destabilizing the compositions of the present invention or compromising their therapeutic activity. In particular, those modifications to make the compounds of the present invention more soluble in water or other vehicles, for example, can be easily achieved by minor modifications (such as salt formulations), which are well within the capabilities of those skilled in the art. It is also well within the capabilities of those of ordinary skill in the art to modify the route of administration and the dosage regimen of a particular compound in order to manage the pharmacokinetics of the compounds of the present invention to provide the greatest beneficial effect to the patient.

[0039] In certain pharmaceutical dosage forms, monophosphate esters and various salt forms of the compounds of the present invention may be preferred. In embodiments, phosphodiesters and triesters are used. Those skilled in the art will recognize how to easily modify the compounds of the present invention to enhance the prodrug compounds according to the present invention in order to facilitate the delivery of the active compound to the target site in the host organism or patient. Those skilled in the art will also take advantage of the favorable pharmacokinetic parameters of the prodrug form when delivering the compounds of the present invention to the target site in the host organism or patient in order to maximize the intended effect of the compound.

[0040] The amount of compound contained in the active formulation according to the invention is an effective amount for treating an infection or condition, particularly a viral infection as described elsewhere herein. In general, the therapeutically effective amount of the compound of the invention in a pharmaceutical dosage form is usually in the range of about 0.05 mg / kg to about 100 mg / kg / day or more per patient per day, more preferably about 1 mg / kg to less than about 25 mg / day per patient per day, or significantly more, depending on the compound used, the condition or infection being treated, and the route of administration. The active nucleoside compound according to the invention is often administered in an amount ranging from about 0.5 mg / kg to about 25 mg / kg / day per patient per day, depending on the pharmacokinetics of the drug in the patient. This dosage range generally results in an effective blood concentration level of the active compound, which may range from about 0.05 to about 100 micrograms / cc of the patient's blood. For purposes of the present invention, a prophylactically effective amount or prophylactically effective amount (i.e., an amount effective to reduce the likelihood of a patient at risk of contracting a viral infection) of a composition according to the present invention will be in the same concentration range as set forth above for the therapeutically effective amount, and often / usually will be the same as the therapeutically effective amount.

[0041] Administration of the active compound can range from continuous administration (intravenous drip) to up to several oral doses per day (e.g., once a day, or four times a day or QID) or transdermal administration, including oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include a penetration enhancer), buccal, and suppository administration, among other routes of administration. Enteric-coated oral tablets can also be used to enhance the bioavailability of the compound from the oral route of administration. The most effective dosage form depends on the severity of the disease in the patient, as well as the size and weight of the patient, as well as the bioavailability / pharmacokinetics of the particular agent selected. Oral dosage forms are particularly preferred, as are topical dosage forms, due to ease of administration and the potential for good patient compliance.

[0042] To prepare pharmaceutical compositions according to the present invention, a therapeutically effective amount of one or more of the compounds according to the present invention is mixed intimately with a pharma- ceutically acceptable carrier, preferably according to conventional pharmaceutical compounding techniques, to produce a dose. The carrier may take a wide variety of forms, depending on the form of preparation desired for administration, e.g., oral or parenteral. When preparing pharmaceutical compositions in oral dosage form, any of the usual pharmaceutical media may be used. Thus, for liquid oral preparations such as suspensions, elixirs, and solutions, suitable carriers and additives may be used, including water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like. For solid oral preparations such as powders, tablets, capsules, and solid preparations such as suppositories, suitable carriers and additives may be used, including starches, sugar carriers, e.g., dextrose, mannitol, lactose, and related carriers, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like. If desired, the tablets or capsules may be enteric coated by standard techniques or sustained release to favorably affect the pharmacokinetics and / or bioavailability of the administered drug. The use of these dosage forms can significantly enhance the bioavailability of the compound in the patient.

[0043] For parenteral formulations, the carrier usually comprises sterile water or aqueous sodium chloride solution, but other ingredients, including those that aid dispersion, may also be included. Of course, if sterile water is used and maintained as sterile, the composition and carrier must also be sterilized. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspensions, and the like may be used.

[0044] Liposomal suspensions (including liposomes targeted to viral antigens) may also be prepared by conventional methods to produce pharma- ceutically acceptable carriers, which may be suitable for delivery of free nucleosides, acyl / alkyl nucleosides, or phosphate ester prodrug forms of nucleosides, or other compounds used in accordance with the present invention.

[0045] In a particularly preferred embodiment according to the invention, the compounds and compositions are used to treat, prevent, reduce the likelihood of, or delay the onset of viral infections (VZV, HSV-1, or HSV-2) as otherwise disclosed herein. Preferably, to treat, prevent, reduce the likelihood of, or delay the onset of these infections, or pathologies and / or conditions secondary to these viral infections, the compositions are administered in oral dosage form in amounts ranging from about 250 micrograms up to about 500 mg, 1 gram or more, at least once a day, up to a maximum of four times a day. In an embodiment, the compounds are formulated in sustained release form and administered less frequently. The compounds of the invention are preferably administered orally, but often can be administered parenterally, topically, or in suppository form.

[0046] When the compounds of the present invention are co-administered in combination with another compound used to treat a viral infection, specifically a viral infection such as a VZV, HSV-1, or HSV-2 infection, the amount of the prodrug nucleoside compound according to the present invention administered ranges from about 1 mg / kg of patient to about 500 mg / kg of patient or more, or even more, depending on the second agent co-administered and its potency against each of the viral infections being inhibited, the condition or infection being treated, and the route of administration. When co-administered, the other antiviral agent may be administered in an amount preferably ranging from about 100 μg / kg (micrograms per kilogram) to about 500 mg / kg. In certain preferred embodiments, these compounds may be administered in an amount preferably ranging from about 1 mg / kg to about 50 mg / kg or more (usually up to about 100 mg / kg), generally depending on the pharmacokinetics of the two agents in the patient. These dosage ranges generally result in effective blood concentration levels of the active compound in the patient. Exemplary antiviral agents that may be co-administered with the compounds of the invention include acyclovir, famciclovir, ganciclovir, valacyclovir, vidaribine, zoster immune globulin (ZIG), and mixtures thereof. 5-FU is also often co-administered with the compounds of the invention.

[0047] The compounds according to the invention can be advantageously used to prevent or reduce the possibility of viral infection, or to prevent or reduce the possibility of the occurrence of clinical symptoms associated with viral infection, or to prevent or reduce the possibility of spreading viral infection to other humans. Thus, the invention also encompasses a method for prophylactic treatment of VZV, HSV-1, or HSV-2 infection. In this aspect according to the invention, the compositions of the invention can be used to prevent, reduce the possibility, and / or delay the onset of viral infection, or a pathology or condition associated with the virus, or the spread of infection to other humans. This prophylactic method comprises administering to a patient in need of such treatment, or to a person at risk of developing VZV, HSV-1, or HSV-2 infection, including a pathology or condition associated with the virus, or to an infected patient who wishes to prevent or reduce the possibility of spreading viral infection to other humans, an amount of a compound according to the invention, alone or in combination with another antiviral agent effective in alleviating, preventing, reducing the possibility, or delaying the onset of viral infection. In the prophylactic treatment according to the invention, it is preferred that the antiviral compound utilized should have low toxicity, preferably non-toxic to the patient. Particularly preferred in this aspect of the invention, the compound used should be maximally effective against the virus and show minimal toxicity to the patient. In the case of the compounds of the invention for the prophylactic treatment of viral infections, these compounds can be administered in the same dosage range as therapeutic treatment (i.e., in the case of oral dosage forms, from about 250 micrograms up to about 500 mg or more, 1 to 4 times per day) as a prophylactic agent to prevent the proliferation of viral infections, or alternatively to postpone or reduce the likelihood of a patient suffering from a clinically manifested viral infection.

[0048] In addition, compounds according to the present invention may be administered alone or in combination with other agents, including other compounds of the present invention. Certain compounds according to the present invention may be effective in enhancing the biological activity of certain agents according to the present invention by reducing the metabolism, catabolism, or inactivation of the other compounds, and are therefore co-administered for this intended effect.

[0049] chemistry In general, compounds according to the present invention are readily synthesized from L-BHDU according to Schemes 1, 2, and 3 shown below. One of skill in the art can readily adapt the specific synthetic steps to provide for facile synthesis of all of the compounds disclosed herein without engaging in undue experimentation.

[0050] ODE-L-BHDU and HDP-L-BHDU Octadecyloxyethyl-L-BHDU (ODE-L-BHDU, 5) and hexadecyloxypropyl-L-BHDU (HDP-L-BHDU, 6) prodrugs were synthesized according to protocols described by the inventors. 18 These long-chain lipid phosphates of L-BHDU were synthesized using the phosphotriester approach shown in Scheme 1 of Figure 1. The synthesis of L-BHDU was carried out by the method we previously reported. 10 L-BHDU was condensed with 2-chlorophenyl dichlorophosphate (2) in the presence of 1,2,4-triazole and triethylamine to give the coupled intermediate. Without further purification, the intermediate was treated with long chain lipid alcohol (3-hexadecyloxy-1-propanol or 2-octadecyloxy-1-ethanol) in the presence of N-methylimidazole (NMI) in THF to give the corresponding fully protected phosphotriesters (3 and 4) in 64% yield, which were isolated in good yield by flash chromatography. The phosphotriesters (3 or 4) were 31 P NMR showed two clearly distinct signals corresponding to the two diastereomers. 1This was also evident from H NMR spectroscopy. To remove the 2-chlorophenyl group, the phosphotriester was dissolved in THF and treated with 0.5 N NaOH at 50 °C for 1.5 h to give the target prodrugs 5 and 6 in approximately 85–90% yield.

[0051] POM-L-BHDU The synthesis of POM-L-BHDU is shown in Scheme 2 of Figure 2, and started with the coupling of L-BHDU with chlorobis(POM)phosphate (7) as shown in Scheme 2. The reagents and conditions for all chemical syntheses are disclosed in the brief description of the figures. Chlorobis(POM)phosphate (7) was synthesized according to the protocol reported by Hawang Y. et al. 19 Treatment of L-BHDU with 7 in the presence of NMI in THF at 0 °C–room temperature afforded POM-L-BHDU in 71% yield.

[0052] The synthesis of the bisPOC-L-BHDU (14) prodrug began with compound 9, which is shown in Scheme 3 of FIG. 3. The alkylation of 9 was carried out using cesium carbonate (Cs 2 CO 3 ) to give the POC alkylated ester 10. Initially, the conversion of 10 to 11 was attempted following hydrogenation conditions on Pd / C. In this attempt, selective monobenzyl deprotection was not achieved, and the major didebenzylated product was obtained. Hence, selective monobenzyl deprotection was performed with LiBr, but this conversion gave very low yields, only 7–9% of compound 11. Therefore, this reaction was revisited and carried out with sodium iodide (NaI) in acetonitrile, which in this case exclusively gave 11 in 92% yield. Repeated alkylation of 11 was performed using Cs in THP. 2 CO 3This was achieved by POC-I in the presence of 1, affording intermediate 12 in 70% yield. Final benzyl deprotection of 12 was carried out on Pd / C in hydrogen at 5 psi to afford key intermediate 13 in 85% yield. Intermediate 13 was coupled with L-BDHU in the presence of diisopropylamine (DIPEA), bis(2-oxo-3-oxazolidinyl)phosphine chloride (BOP-Cl), and 3-nitro-1,2,4-triazole in THF at 0 °C to room temperature to afford the final Bis-POC-L-BHDU (14) in 22% yield. The identity of all prodrugs was confirmed by ESI high resolution mass spectrometry (ESI-HRMS), 1 H-NMR, 13 C-NMR, and 31 The results were confirmed by P-NMR. These prodrugs were then used in the biological experiments described later in this specification.

[0053] Antiviral activity L-BHDU has antiviral activity against VZV and HSV-1. The antiviral potential 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 was dependent on phosphorylation by thymidine kinase encoded by VZV and HSV-1, and resistance was mapped to this gene. 20

[0054] To enhance 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) (Figure 1-3, Scheme 1-3) prodrugs were synthesized with modifications to increase bioavailability and cell permeability. Their antiviral activity was evaluated in ARPE-19 cells infected with a new reporter virus, VZV-ORF57-Luc. In this assay, L-BHDU was found to be 10-fold more potent (0.22 μM in HFFs and 22 nM in ARPE-19) than in previous assays using HFFs infected with VZV-BAC-Luc. 11 L-BHDU has a good antiviral activity of EC 0.022 μM 50 (See Figures 4 and 5, Table 1). POM-L-BHDU and POC-L-BHDU analogs showed good antiviral effects against VZV-ORF57-Luc in ARPE-19 cells. POM-L-BHDU had an EC 50 This showed an EC of 0.034 μM with an SI of 2915. 50 The antiviral effects of the parent L-BHDU and POC-L-BHDU were similar to those of the parent L-BHDU and POC-L-BHDU, which showed EC of 0.068 and 0.90 μM, respectively, with SIs of 479 and 111. 50 showed.

[0055] The cytotoxicity of the synthetic analogs was determined in low passage human fibroblasts (HFFs) by performing a 72-h neutral red dye uptake assay and an MTT cell proliferation assay. L-BHDU and its POM and POC prodrugs were non-cytotoxic (CC 50 >100 μM) and had no effect on cell proliferation. On the other hand, the long-chain phospholipid octadecyl and hexadecyl prodrugs of L-BHDU showed CC values ​​of 32.5 μM and 10 μM, respectively. 50 The concentrations of these compounds showed cytotoxicity (see Table 1 in FIG. 5).

[0056] Encouraged by the in vitro antiviral data, we then sought to evaluate the in vivo antiviral efficacy of these L-BHDU-prodrugs. After evaluating the in vitro data of the synthesized compounds, HDP-L-BHDU (compound 6) was excluded from further in vivo testing due to its higher toxicity and lower selectivity. The in vivo antiviral efficacy of octadecyl (Figure 1, scheme 1, compound 5), POM (Figure 2, scheme 2, compound 8), and POC (Figure 3, scheme 3, compound 14) prodrugs was compared to L-BHDU in the NuSkin mouse model of VZV replication using athymic nude mice implanted with adult human skin xenografts. Groups of 10 mice (5 males, 5 females) bearing skin xenografts were inoculated with VZV-ORF57-Luc, then treatment was initiated 3 days later via the subcutaneous route. The vehicle group received Cremophor-DMSO-saline alone, and the positive control group received HPMPC (cidofovir) 10 mg / kg. Test compounds were formulated in CDS at equimolar concentrations with HPMPC, ranging from 11.4 to 24.9 mg / kg based on their molecular weight. Mice were treated once daily on days 3–9 post-infection. Mice were weighed daily and scanned by an In vivo Imaging System (IVIS) on days 3–14 to measure viral spread. Antiviral activity was assessed based on viral yield, measured as the fold increase in total flux compared to the value on day 3.

[0057] Based on previous in vivo assays with L-BHDU, we expected that these prodrug analogs would have antiviral activity. In vivo testing of these derivatives revealed that among the selected prodrug analogs, OED-L-BHDU and POM-L-BHDU exhibited superior antiviral potency compared to L-BHDU without any cytotoxicity. Both prodrugs of L-BHDU were effective in vivo at a subcutaneous (sc) dose of approximately 25 mg / kg / day, which is equimolar to 10 mg / kg of cidofovir. The parent compound L-BHDU and POC-L-BHDU were found to be ineffective (Figure 6A). It is also worth mentioning that L-BHDU-POM is equally effective orally compared to cidofovir (ip route, Figure 6B). L-BHDU is predicted to have shown lower in vivo efficacy due to its poor pharmacokinetics. However, POC-L-BDHU esters may not be stable enough at physiological pH to reach effective concentrations in cells. This may explain the reduced in vivo efficacy of POC prodrugs. All tested compounds were also well tolerated by mice (both males and females) and did not show significant weight loss (Figure 7).

[0058] Following these findings, OED-L-BHDU (L-BHDU-C18) and (POM-L-BHDU, 37) were selected for repeated in vivo evaluation with the standard reference cidofovir (10 mg / Kg intravenous route (iv)). Repeated in vivo testing of L-BHDU-C18 and POM-L-BHDU prodrugs found them to be more active than cidofovir via subcutaneous (sc) and oral (op) routes (as shown in Figure 6b). POM-L-BHDU and L-BHDU-C18 showed good in vivo efficacy and were selected for further studies: pharmacokinetic / pharmacodynamic (PK / PD), mechanism of action, and toxicological studies. Additionally, evaluation of POM-L-BHDU for potential interactions with the catabolism of 5-fluorouracil (which is a concern for brivudine but not for L-BHDU) is also warranted. 11Our preliminary findings suggest that L-BHDU interferes with pyrimidine biosynthesis induced by VZV infection in non-dividing cells. 22

[0059] Additionally, all synthesized compounds were tested in vitro against herpes simplex virus (HSV-1, oral herpes) in Vero cells ( FIG. 8 ). L-BHDU and its octadecyl OED-L-BHDU and POC-L-BHDU prodrugs showed good activity against HSV-1. L-BHDU had an EC of 0.007 μM with an SI of over 12,903. 50 (Figure 9, Table 2).

[0060] POM-L-BHDU has an EC of 0.028 μM with an SI of >3546. 50 In contrast, however, POC-L-BHDU expressed a higher antiviral effect, EC of 0.0260 μM, with an SI of >3,846. 50 The octadecyl prodrug was the least potent compared to all synthetic analogues with an SI of 26.5 and an EC of 0.7573 μM. 50 L-BHDU and its POM and POC prodrugs did not show any cytotoxicity (CC 50 >100μM), acyclovir (EC 50 = 0.0736 μM). However, the octadecyl prodrug exhibited cytotoxicity at a concentration of 20 μM.

[0061] Furthermore, the antiviral activity of these analogs was tested in vitro against HSV-2 (genital herpes) in Vero cells using acyclovir as the standard reference drug. It is interesting to report that POM-L-BHDU was found to be active only against HSV-2 (EC of 1.4 μM with an SI of >71). 50) (Figure 10). All other analogs, including 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 HSV-1 and HSV-2. Further in vivo evaluation of the POM prodrug of L-BDHU will confirm activity. The POM prodrug of L-BHDU may show superior antiviral efficacy against HSV-2 in an in vivo mouse model.

[0062] Furthermore, when POM-L-BHDU was evaluated as a topical treatment against VZV and HSV in a human skin explant model, it was highly effective against both viruses at 0.2% formulated in cocoa butter (Figure 12). Importantly, with regard to HSV1, topical L-BHDU-POM 0.2% was more effective than topical acyclovir 0.5% (Figure 12, right panel).

[0063] Because L-BHDU, ODE-L-BHDU, POM-L-BHDU, and POC-L-BHDU had the best antiviral profile against VZV-ORF57-Luc, these prodrugs were screened against the VZV mutants VZV TK (thymidine kinase deficient, -TK), VZV TS (thymidylate synthase deficient, -TS), and VZV TKTS (thymidine kinase and thymidylate synthase deficient, -TKTS) mutants. These tests were performed in the same manner as the efficacy tests 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 of each compound against cell-associated VZV was 1.25 μg / mL. 50were similar to or slightly higher than those obtained with cell-free VZV (Figure 13). In most cases, L-BHDU and its prodrugs were more potent against VZV-ORF57-Luc than CDV or ACV. The exception was ODE-L-BHDU, which was less potent compared to CDV but 9-fold more potent compared to ACV (Figure 14, Table 4).

[0064] conclusion In summary, we have synthesized POM, POC, and long-chain phospholipid prodrugs of L-BHDU. These prodrugs showed significant anti-VZV activity. POM-L-BHDU (8) showed enhanced antiviral potency compared to L-BHDU, whereas OED-L-BHDU (5) and HDP-L-BHDU (6) showed lower in vitro activity against VZV than the parent molecules. Furthermore, the in vitro potent compound POM-L-BHDU retained its antiviral potency in an in vivo mouse model without showing cytotoxicity. Moreover, the long-chain phospholipid prodrug OED-L-BHDU (compound 5) also shows significantly enhanced in vivo antiviral activity compared to L-BHDU. From this study, it is concluded that POM-L-BDHU (8) and OED-L-BHDU (5) should be developed as drug candidates against VZV. Further biological testing, including anti-VZV activity against drug-resistant mutants, pharmacokinetic studies, molecular mechanism of action studies, and tissue distribution studies, are warranted to evaluate the full potential of these promising L-BHDU prodrugs 8 and 9. Of note, all of the synthesized 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, including L-BDHU, were found to be inactive against this virus. Overall, POM-L-BDHU (8) and OED-L-BHDU (5) are potent, safe, and well tolerated, making them good options for drug therapy. POM-L-BDHU (8) also showed activity consistent with the development of this compound as a good drug candidate against HSV-2 (genital herpes), which is currently required for treatment.

[0065] Experimental Section Common analytical methods 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 using a UV lamp (254 nm) and developed with a 15% solution of sulfuric acid in methanol. Melting points were recorded on a digital melting point apparatus and were uncorrected. Nuclear magnetic spectra were determined using tetramethylsilane (TMS) as an internal standard. 1 H NMR, 19 500MHz for F NMR; 31 For P-NMR, 202MHz, 13 C NMR was recorded at 125 MHz. Chemical shifts (δ) are indicated 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 with 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.

[0066] 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 min 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) successively. After 1 h, 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 resulting crude was purified by silica gel column chromatography (3% MeOH / DCM) to give L-BHDU 5'-[(2-chlorophenyl 2-octadecyloxyethyl)phosphate] (3, 0.45 g, yield 64%). 1 H-NMR (500MHz, CDCl 3)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),3.4 2(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, CDCl 3 ):δ-6.10,-6.36; 13 C-NMR (125MHz, CDCl 3 ) 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 0.5N NaOH solution (1.5 mL) was added at 0 °C. The mixture was stirred at 50 °C for 2 h and neutralized with 1N 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-d 6)δ11.59(s,1H),8.20(s,1H),7.39(d,J=13.5Hz,1H),7.26(d,J=14.0Hz,1H),6.1 8(d,J=4.5Hz,1H),5.04-5.03(m,1H),4.23(d,J=9.5Hz,1H),4.08(t,J=10.0&4.5 Hz,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-d 6 ):δ-1.06; 13 C{ 1 H}NMR (125MHz, CD 3 OD)δ162.3,150.0,138.6(d,J=21.5Hz),111.2,108.3,107.8,81.55(d,J=3 4.4Hz),70.9,64.6,46.7,31.7,29.4,29.2,29.1,25.8,22.4,13.1,13.0; 30 H 52 BrN 2 O 9 P+Na) + HRMS(EI) calculated value 717.2492, found value 717.2485

[0067] Compound 6 (50 mg) was synthesized in qualitative yield following the same procedure as compound 5. Yield 85%; mp 122-123°C; 1 H-NMR (500MHz, CD 3OD)δ8.02(s,1H),7.46(d,J=14.0Hz,1H),7.04(d,J=13.5Hz,1H),6.32(dd,J=7.5&1.5 Hz,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 (202MHz, CD 3 OD):δ0.58; 13 C{ 1 H}NMR (125MHz, CD 3 OD)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);(C 29 H 50 Bn 2 O 9 P+H) + The calculated value of HRMS (EI) is 681.2516 and the measured value is 681.1507.

[0068] Synthesis procedure for 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), chlorobis(POM)phosphate 7 (154 mg, 0.473 mmol) was added by dissolving in 3 mL of THF at 0° C. and stirred for 15 min. The reaction was then warmed to room temperature and stirred for 3 h. The mixture was quenched with methanol and the solvent was removed under reduced pressure. The crude was purified by silica gel column chromatography (0.5% MeOH / DCM) to give 8 as a colorless viscous oil (42.0 mg, 71% yield). 1 HNMR (500MHz, CDCl 3 )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, CDCl 3 )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, CDCl 3 ) δ-3.02,(C 22 H 32 BrN 2 O 12 P+H) + HRMS(EI) calculated value 627.0954, observed value m / z 627.0953.

[0069] ((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), POC-I (610 mg, 2.38 mmol) was added dropwise at room temperature and stirred overnight. The reaction mixture was filtered through a Buchner funnel, the filtrate obtained was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (20% EtOAc / Hexane) to give 650 mg of compound 10 as a colorless oil in 82% yield. 1 H NMR (500 MHz, CDCl 3 )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, CDCl 3 ) δ-2.02

[0070] (((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), NaI (0.76 g, 5.07 mmol) was added and stirred at 45° C. for 12 h. The reaction mixture was concentrated under reduced pressure and the resulting crude was washed with dry ether and dried under high vacuum. After drying, the residue was used directly in the next step without further purification.

[0071] ((Benzoloxyphosphoryl)bis(oxy))bis(methylene)diisopropyl bis(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), POC-I (240 mg, 0.98 mmol) was added dropwise at room temperature and stirred overnight. The reaction mixture was filtered through a Buchner funnel, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (15% EtOAc / Hexane) to give 30 mg of compound 12 as a colorless oil in 70% yield.1 H NMR (500 MHz, CDCl 3 )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, CDCl 3 )δ-3.77.

[0072] ((Hydroxyphosphoryl)bis(oxy))bis(methylene)diisopropyl bis(carbonate) (13). A suspension of compound 12 (300 mg, mmol) and 10% Pd / C (30 mg) in methanol at ambient temperature was heated at 5 psi for 2 h under H 2 The mixture was passed through a bed of Celite and concentrated under reduced pressure to give 200 mg of 13 as a colorless viscous liquid in 85% yield. Compound 13 was used directly in the next step reaction without further purification. 1 H-NMR (500MHz, CDCl 3 )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, CDCl 3 ) δ 153.19, 85.46, 73.44, 21.66; 31 P-NMR (202MHz, CDCl 3 )δ-3.36.

[0073] Bis(POC) Prodrug L-BHDU (14) Compound 13 (92 mg, 0.282 mmol) was taken up in TEA (1 mL) and pyridine (0.5 mL) and stirred at room temperature for 10 min, then the contents were concentrated under reduced pressure and coevaporated 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) 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 h and diluted with ethyl acetate (50 mL). The organic layer was washed with saturated NaHCO 3 After washing with solution (20 mL x 2), it was washed with brine solution (10 mL) and then with Na 2 SO 4 The solvent was removed under reduced pressure and the resulting crude was purified by silica gel column chromatography (0.8% methanol / DCM) to give compound 14 as a colorless sticky solid (13 mg, 22% yield). 1 H-NMR (500MHz, CDCl 3 )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=5.0MHz,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, CDCl 3 ):160.95,153.05,149.4,137.3,128.3,112.2,110.5,102.9,85.8,81.4,77.473.7,71.5,65.2,21.7; 31 P-NMR (202MHz, CDCl 3 )-3.14;(C 20 H 28 BrN 2 O 14 P+H) +HRMS(EI) calculated value: 631.0540, measured value: 631.0538.

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Claims

1. Prodrug compounds of L-BHDU according to chemical structure I 【Chemistry 1】 (In the formula, R １ is -(CH ２ ) ｎ -O-R １ａ group or -(CH ２ ) ｊ -O-C(O)O ｋ -R ２ａ It is the basis, R ２ is H, -(CH ２ ) ｎ -O-R １ａ group or -(CH ２ ) ｊ -O-C(O)O ｋ -R ２ａ It is the basis, R １ａ are independently ６ -C ３０ Alkyl groups, often C １２ -C ２２ Alkyl groups, often C １４ -C ２０ Alkyl group or C １６ -C １８ Alkyl groups, often C １６ or C １８ is an alkyl group, R ２ａ are independently １ -C １２ Alkyl groups, often C ２ -C ６ Alkyl group, C ３ -C ４ an alkyl group, an isopropyl group, a t-butyl group, or a sec-butyl group, or an isopropyl group or a t-butyl group; each j is independently 1 to 6, 1 to 3, often 1 or 2; each k is 0 or 1; each n is independently 1 to 6, 1 to 4, 2 to 4, or 2 or 3); or A pharmaceutically acceptable salt, solute, or polymorph thereof.

2. R １ Ga-(CH ２ ) ｎ -O-R １ａ 2. The compound of claim 1, wherein n is a group and n is 2 or 3.

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

4. R １ａ is C １６ or C １８ and R ２ 3. The compound of claim 1 or 2, wherein is H.

5. R １ａ is C １８ and n is 2.

6. R １ａ is C １６ and n is 2.

7. R １ Ga-(CH ２ ) ｎ -O-R １ａ is a group, and R ２ is H or -(CH ２ ) ｎ -O-R １ａ 3. The compound according to claim 1 or 2, wherein

8. R ２ is H or -(CH ２ ) ｊ -O-C(O)O ｋ -R ２ａ The compound of claim 1 , wherein the compound is a group.

9. R ２ Ga-(CH ２ ) ｊ -O-C(O)O ｋ -R ２ａ The compound according to claim 1 or 8, wherein j is a group and j is 1 to 4.

10. j is 1 or 2, and R ２ａ is C １ -C １２ 9. The compound of claim 1 or 8, which is an alkyl group.

11. j is 1 or 2, and R ２ａ is C ２ -C ６ 9. The compound of claim 1 or 8, which is an alkyl group.

12. j is 1 and R ２ａ is C ３ or C ４ 9. The compound of claim 1 or 8, which is an alkyl group.

13. j is 2 and R ２ａ is C ３ or C ４ 9. The compound of claim 1 or 8, which is an alkyl group.

14. R １ Ga-(CH ２ ) ｊ -O-C(O)O ｋ -R ２ａ 9. The compound of claim 1 or 8, wherein:

15. 9. The compound of claim 1 or 8, wherein j is 1.

16. 9. The compound of claim 1 or 8, wherein k is 0.

17. 9. The compound of claim 1 or 8, wherein k is 1.

18. R １ and R ２ The compound according to any one of claims 1, 2 and 8, wherein

19. A compound with the following chemical structure: 【Chemistry 2】 (In the formula, R １ Ha-(CH ２ ) ｎ -O-R １ａ group, n is 2 or 3, and R １ａ is C １６ Or C １８ is an alkyl group, and R ２ is H), or a pharmaceutically acceptable salt, solvate, or polymorph thereof.

20. n is 2 and R １ａ is C １８ 20. The compound of claim 19, which is an alkyl group.

21. n is 3 and R １ａ is C １６ 20. The compound of claim 19, which is an alkyl group.

22. A compound with the following chemical structure: 【Transformation 3】 (In the formula, R １ and R ２ are respectively -(CH ２ ) ｊ -O-C(O)O ｋ -R ２ａ It is the basis, R ２ａ are independently an isopropyl or t-butyl group; each j is independently 1 or 2; each k is 0 or 1), or A pharmaceutically acceptable salt, solute, or polymorph thereof.

23. R １ and R ２ and are identical, j is 1, k is 1, and R ２ａ 23. The compound of claim 22, wherein is an isopropyl group.

24. R １ and R ２ and are identical, j is 1, k is 0, and R ２ａ The compound of claim 22, wherein is a tert-butyl group.

25. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1, 2, 8, 19-24 in combination with a pharmaceutically acceptable carrier, excipient, or vehicle.

26. 26. The pharmaceutical composition of claim 25, further comprising an additional bioactive agent.

27. 27. The pharmaceutical composition of claim 26, wherein the bioactive agent is acyclovir, brivudine, foscarnet, cidofovir (CDV), valacyclovir, famciclovir, zoster immune globulin (ZIG), vidarabine, or a mixture thereof.

28. 27. The pharmaceutical composition of claim 26, wherein the bioactive agent is 5-fluorouracil.

29. 28. The pharmaceutical composition of claim 27, wherein the bioactive agent is foscarnet, cidofovir, or a mixture thereof.

30. 26. Use of the pharmaceutical composition of claim 25 in the manufacture of a medicament for treating a viral infection in a patient in need thereof, wherein the viral infection is a varicella-zoster virus (VZV) infection, a herpes simplex virus type 1 (HSV-1) infection, or a herpes simplex virus type 2 (HSV-2) infection.

31. 26. Use of a compound according to any one of claims 1, 2, 8, 19-24 in the manufacture of a medicament for treating a viral infection in a patient in need thereof, wherein the viral infection is a varicella zoster virus (VZV) infection, a herpes simplex virus type 1 (HSV-1) infection, or a herpes simplex virus type 2 (HSV-2) infection.

32. 31. The use of claim 30, wherein the compound is compound 5 of Figure 1, Scheme 1, compound 8 of Figure 2, Scheme 2, or compound 14 of Figure 3, Scheme 3.

33. 26. Use of the pharmaceutical composition of claim 25 in the manufacture of a medicament for reducing the likelihood of a viral infection in a patient in need thereof, wherein the viral infection is a varicella-zoster virus (VZV) infection, a herpes simplex virus type 1 (HSV-1) infection, or a herpes simplex virus type 2 (HSV-2) infection.

34. 26. Use of a compound according to any one of claims 1, 2, 8, 19-24 in the manufacture of a medicament for inhibiting or eliminating a complication of VZV infection in a patient or subject in need thereof, wherein the complication is selected from the group consisting of postherpetic neuralgia, multiplex zoster, myelitis, ocular herpes, and varicella zoster.

35. Use of the pharmaceutical composition of claim 25 in the manufacture of a medicament for inhibiting or eliminating a complication of VZV infection in a patient or subject in need thereof, wherein the complication is selected from the group consisting of postherpetic neuralgia, multiplex zoster, myelitis, ocular herpes, and varicella-zoster.

36. 35. The use of claim 34, wherein the compound is compound 5 of Figure 1, Scheme 1, compound 8 of Figure 2, Scheme 2, or compound 14 of Figure 3, Scheme 3.

37. The use of claim 35, wherein the compound is compound 5 of Figure 1, Scheme 1, compound 8 of Figure 2, Scheme 2, or compound 14 of Figure 3, Scheme 3.

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