PROMOIETY STRATEGY TO ENHANCE DRUG ACTIVITY

Abstract

Various nucleoside phosphate and phosphonate analogues are provided for treatment of viral infections. Methods of preparing the analogues, pharmaceutical compositions containing the analogues, and methods of using the analogues as antiviral compounds, especially against adenoviruses, coronaviruses, and varicella zoster viruses, are also provided.

Claims

1. A nucleoside phosphonate (NP) (1) or phosphate (2) of the formula ##STR00005## wherein: B is a purine or pyrimidine base, or a related structure; X is CH.sub.2Ph, CH.sub.2, CH.sub.2CH.sub.2, or CHCH.sub.3; Y is O, NH, CH.sub.2, CHF, CHC.sub.1, CHBr, CF.sub.2, CCl.sub.2, CBr.sub.2, CCH.sub.3, C(CH.sub.3).sub.2, CHN.sub.3, CCH.sub.3N.sub.3 Z is a cyclic or acyclic sugar, such as ribose or deoxyribose, or a related structure m=0-1; m.sub.1=0-3; m.sub.2=0-3 R is H or C(O)R.sub.2, wherein R.sub.2 is lipid-like; and R.sub.1 is H or lipid-like; and NHR.sub.1 in structure (1) may be replaced by OR.sub.3, where R.sub.3=C.sub.1-C.sub.4 alkyl.

2. A nucleoside phosphonate (3) or (4) of the formula ##STR00006##

3. The nucleoside phosphonate of claim 2, wherein B is cytosine or adenine.

4. The NP of claim 1, wherein R.sub.1 is alkyl, alkene, ether or thioether and R.sub.2 is alkyl.

5. The NP of claim 4, wherein R.sub.1 is C.sub.12-18 alkyl, C.sub.nCH═CHC.sub.n1, C.sub.n—O—C.sub.n1 or C.sub.n—S—C.sub.n1, wherein n and/or n1=4-9R.sub.2 is C.sub.8-18 alkyl and.

6-8. (canceled)

9. The nucleoside phosphonate of claim 2, wherein R=H and R.sub.1 is a neutral or positive modifier.

10-15. (canceled)

16. A method of preparing a nucleoside phosphate (NP), comprising conjugation of phosphorylated amino acid with pyrophosphate or pyrophosphate analogues, as outlined in the following reaction scheme: ##STR00007## wherein B is a purine or pyrimidine base; R is H or C(O)NHR.sub.2, wherein R.sub.2 is lipid-like; and R.sub.1 is NHR.sub.1a, wherein R.sub.1a is H or lipid-like.

17. The method of claim 16, wherein the CH.sub.2Ph group is replaced by CH.sub.2, CH.sub.2CH.sub.2, or CHCH.sub.3.

18. The method of claim 17, wherein B is cytosine, guanine, adenine or thymine.

19. The method of claim 17, wherein R.sub.1a is alkyl, alkene, ether or thioether and R.sub.2 is alkyl.

20. The method of claim 17, wherein R.sub.1a is C.sub.12-18 alkyl, C.sub.nCH═CHC.sub.n1, C.sub.n—O—C.sub.n1 or C.sub.n—S—C.sub.n1, wherein n and/or n1=4-9 and R.sub.2 is C.sub.8-18 alkyl.

21-22. (canceled)

23. The method of claim 17, wherein Y is O, NH, CH.sub.2, CHF, CHC.sub.1, CHBr, CF.sub.2, CCl.sub.2, CBr.sub.2, CCH.sub.3, C(CH.sub.3).sub.2, CHN.sub.3, CCH.sub.3N.sub.3 1.

24. A pharmaceutical composition comprising at least one compound of claim 1, and a pharmaceutically acceptable carrier.

25. A method of treating a virus infection comprising administering to the subject an effective amount of at least one nucleoside phosphonate of of claim 1.

26. The method of claim 25, wherein the virus is selected from the group consisting of RNA virus, an DNA virus, a retrovirus, a herpesvirus, an adenovirus, an emerging virus of pandemic potential, VZV, CMV, HPV, and SARS-CoV-2.

27-35. (canceled)

36. A method of treating cancer comprising administering to the subject an effective amount of at least one compound of claim 1.

37-39. (canceled)

40. The compound: A compound selected from the group consisting of: ##STR00008##

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0036] For a more complete understanding of the present invention, reference is now made to the following descriptions taken in conjunction with the accompanying drawings, in which:

[0037] FIG. 1 is a panel showing the structures of CDV, HPMPA and BCV.

[0038] FIG. 2 is a panel showing the structures of USC-505 and USC-087.

[0039] FIG. 3 is a general schematic representation of the prodrug linker platform to increase oral bioavailability and potency of NP drugs. The phosphonic acid group is esterified by the OH side-chain X of an amino acid that has a free (R=H) or modified (R=C(O)NHR.sub.2, R.sub.2=lipophilic modifier) α-amino group or a modified α-carboxyl group where R.sub.1=H, lipid-like.

[0040] FIG. 4 is a table showing embodiments of this invention, in terms of the lipophilic modifier structure (Series A, B), lipid modifier location (Series C), and the linking hydroxy side chain of the esterifying amino acid promoiety (Series D). Range of n and/or n1=4-9.

[0041] FIG. 5 is a panel of known drugs exhibiting termination of the RdRps of SARS-CoV-2 (25).

[0042] FIG. 6 is a panel of general structures of examples of the new lipophilic prodrugs.

[0043] Scheme 1 is a general synthetic scheme for the prodrugs. For Series C, R=H, tBOC is replaced by AlkC(O) and the second step is omitted.

[0044] Scheme 2 is a alternative synthesis of the prodrugs.

[0045] Scheme 3 exemplifies a synthesis of a lipophilic tyrosineamide-modified GS-441524 prodrug.

[0046] Scheme 4 exemplifies a method of preparing certain nucleoside monophosphates.

DETAILED DESCRIPTION

[0047] In methods of treating virus infection or inhibiting virus replication, an effective amount, which can be a therapeutically effective amount, of an acyclic nucleoside phosphonate, or a salt or pharmaceutically acceptable salt thereof, may be administered. A therapeutically effective amount of a compound is an amount that results in an improvement or a desired change in condition for which a compound is administered, when the compound is administered once or over a period of time. For example, with respect to virus infections, the improvement can be a lowering of virus titer, or a reduction in the symptoms or discomfort associated with a viral infection. As is known, the amount will vary depending on such particulars as the type of virus infection, the condition being treated, the specific acyclic nucleoside phosphonate compound utilized, the severity of the condition, and the characteristics of the subject. The subject can be a person or another animal, such as another mammal.

[0048] An antiviral compound such as a nucleoside phosphonate can be prepared as a salt, which may be a pharmaceutically acceptable salt. Pharmaceutically acceptable salts are well known in the art and include salts prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. Suitable non-toxic acids include inorganic and organic acids such as acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid, p-toluenesulfonic acids, and the like. Salts formed with, for example, a POH group, can be derived from inorganic bases including, but not limited to, sodium, potassium, ammonium, calcium or ferric hydroxides, and organic bases including, but not limited to, isopropylamine, trimethylamine, histidine, and procaine.

[0049] Pharmaceutical compositions containing nucleoside phosphonates will typically contain a pharmaceutically acceptable carrier. Although oral administration is a desired route of administration, other means of administration such as nasal, topical (for example, administration to the skin or eye) or rectal administration, or by injection or inhalation, are also contemplated. Depending on the intended mode of administration, the pharmaceutical compositions may be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, drops, ointments, creams or lotions, preferably in unit dosage form suitable for single administration of a precise dosage. The compositions may include an effective amount of a selected compound in combination with a pharmaceutically acceptable carrier and, in addition, may include other pharmaceutical agents such as other anti-viral agents, adjuvants, diluents, buffers, and the like. The compound may thus be administered in dosage formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The amount of active compound administered will be dependent on the subject being treated, the subject's weight, the manner of administration and the judgment of the prescribing physician.

[0050] For solid compositions, conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. Liquid pharmaceutically administrable compositions may, for example, be prepared by dissolving, dispersing, etc., an active compound as described herein and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan mono-laurate, triethanolamine acetate, triethanolamine oleate, etc. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art. For oral administration, the composition will generally take the form of a tablet or capsule, or may be an aqueous or nonaqueous solution, suspension or syrup. Tablets and capsules for oral use will generally include one or more commonly used carriers such as lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. When liquid suspensions are used, the active agent may be combined with emulsifying and suspending agents. If desired, flavoring, coloring and/or sweetening agents may be added as well. Other optional components for incorporation into an oral formulation herein include, but are not limited to, preservatives, suspending agents, thickening agents, and the like.

[0051] In embodiments that include a method of inhibiting viral replication or a method of treating a virus infection, the virus may be an RNA virus, a DNA virus, or a retrovirus, for example. Particular examples of viruses include, but are not limited to, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), varicella zoster virus (VZV), human papililomavirus (HPV), cytomegalovirus (CMV).

[0052] The present invention may be better understood by referring to the accompanying examples, which are intended for illustration purposes only and should not in any sense be construed as limiting the scope of the invention.

EXAMPLE 1

Synthesis of CDV and HPMPA Prodrugs

[0053] Example 1a. General Synthesis of Novel Prodrugs

[0054] The structures of embodiments of this invention are shown in FIG. 4 (Series A-D). As in which structural features are changed to modify biological and pharmacological properties of the prodrugs: i) lipophilic chain length and structure (Series A); by introducing unsaturation at the center of the N-alkyl group; ii) introduction of a polar atom (O or S) at the center of the lipid modifier to create a site for enzymatic cleavage to decrease lipidomimetic properties of the prodrug in the cell prior to P—O ester cleavage or a means to increase prodrug aqueous solubility without reducing the chain length with only a modest (ΔpD˜−1) impact on lipophilicity (Series B); iii) variation in the position of the N-alkyl chain by moving it to the amino side of the promoiety (Series C); this modification converts the prodrug from a zwitterion (more lipidomimetic) to a monoamine PO.sup.− (more soluble in aqueous media); iv) the amino acid P—O ester linkage (O-Tyr, O-Ser, O-Homo-Ser or O-Thr) to vary metabolic activation and other PK properties to tune enzyme-dependent activation of the prodrug by cellular phospholipases/phosphatases (Series D). The person skilled in the art will appreciate that by some of the modifications taught in this invention or similar ones, it is possible to modulate the overall charge on the prodrug molecule and specifically, its promoiety to advantage. For example, introduction of a positive charge by retention of the free amino group and neutralization of the remaining negative charge of the esterified phosphonic acid group by conversion to a cyclic, amido or simple alkyl or aryl ester forms.

Experimental

[0055] General syntheses of the lipidomimetic synthons: Commercially unavailable N-alkyl promoieties can be synthesized by literature methods (30-32).

[0056] Conjugation of the lipidomimetic synthons to (S)-HPMPC and (S)-HPMPA: Prodrugs that incorporate a derivatized single amino acid having a hydroxy side chain in the promoiety portion of the molecule can be prepared following the generalized synthetic pathway shown in Scheme 1 (33). The conjugation of the amino acid promoieties to CDV (or HPMPA) via an internal phosphoester bond in the penultimate synthetic step produces a new chiral center at phosphorus (S.sub.p or R.sub.p), however these cyclic NP intermediates, generated as diastereomeric mixtures, are converted to the same final nucleoside phosphonate analogue in the last step. (The cyclic phosphonate intermediates are themselves active prodrugs (34) but have different metabolic t.sub.1/2 and require an additional purification step for individual isolation. They are considered as further embodiments of this invention, providing a neutral phosphonate group in the final prodrug structure, which may be advantageous as explained in the preceding paragraph. The tBoc-protected amino acid synthons can be prepared by a previously described method (33). Alkenyl lipophilic substituent (Series A) precursors are advantageously 1-aminoalkenes (cis or trans) which can be added to N-tBoc-protected amino acids by reaction with HOBt/EDC in DCM at 25 ° C. Alkoxyalkyl lipophilic substituents (Series B) can be prepared as follows: 1) (example, C.sub.8—O—C.sub.8): 8-bromo-1-octanal is converted to the phtalimide alcohol in DMF, then reacted with 1-bromooctane and NaH in DMF, and deprotected with hydrazine in EtOH; 2) (example, C.sub.8—S—C.sub.8): 1,8-dibromooctane is similarly monoprotected, then reacted with 1-bromooctane and NaOH in thiourea.

Example 1b. Large-scale Syntheses of Analogues.

[0057] For large-scale synthesis, the known chemoselectivity of BTMS-silyldealkylation (35, 36) for alkyl (i.e., ethyl or methyl) vs. aryl (i.e., tyrosinyl) or sterically larger than methyl (i.e. serinyl, homoserinyl, threonilyl) phosphonate esters can be utilized. Elimination of the NH.sub.4OH hydrolysis step in Scheme 1, which typically limits the overall yield (˜50%), makes this method attractive for further scaling development. An important feature of this new method is that it allows the intermediates to be purified by silica gel column chromatography, avoiding preparative HPLC which may be impractical and too time-consuming for large-scale synthesis. After BTMS deprotection, the final products can also be isolated by crystallization, which is highly scalable.

References

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[0095] Although the present invention has been described in connection with the preferred embodiments, it is to be understood that modifications and variations may be utilized without departing from the principles and scope of the invention, as those skilled in the art will readily understand. Accordingly, such modifications may be practiced within the scope of the invention and the following claims.