US20220323476A1 - Antiviral prodrugs and formulations thereof - Google Patents

Antiviral prodrugs and formulations thereof Download PDF

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US20220323476A1
US20220323476A1 US17/642,552 US202017642552A US2022323476A1 US 20220323476 A1 US20220323476 A1 US 20220323476A1 US 202017642552 A US202017642552 A US 202017642552A US 2022323476 A1 US2022323476 A1 US 2022323476A1
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compound
esi
phosphate
viral infection
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Arnab K. Chatterjee
Anil K. Gupta
Anders M. ELIASEN
Sean B. JOSEPH
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Scripps Research Institute
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    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/173—Purine radicals with 2-deoxyribosyl as the saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids

Definitions

  • This invention relates to antiviral compounds and compositions useful for the treatment of acquired immunodeficiency syndrome (AIDS).
  • AIDS acquired immunodeficiency syndrome
  • the compound EFdA (MK-8591) is a nucleoside analog known to be effective as an inhibitor of the enzyme reverse transcriptase ( Current Opinion in HIV and AIDS 2018, 13, 294-299)
  • Reverse transcriptase inhibitors can be effective in the treatment of viral infections caused by viruses where reverse transcriptase function is essential for viral replication and production of viral proteins, such as HIV (Human Immunodeficiency Virus) and HBV (Hepatitis B Virus).
  • HIV Human Immunodeficiency Virus
  • HBV Hepatitis B Virus
  • the virus is an RNA virus that uses reverse transcriptase to synthesize DNA reverse transcripts of the vital genome which are translated by the host to provide the viral proteins.
  • HBV a DNA virus
  • the DNA viral polymerase also has a reverse transcriptase function, generating viral DNA from a viral RNA intermediate during replication.
  • An antiviral example of a compound that hits both HIV and HBV is lamivudine.
  • the invention provides, in various embodiments, (1) novel compositions of chemical matter comprising bioactive prodrugs of MK-8591 or pharmaceutically acceptable salt of these prodrugs, and (2) novel formulations of these prodrugs providing therapeutic and prophylactic treatment of patients against viral infections of viruses such as HIV and HBV, wherein inhibition of a reverse transcriptase enzyme (RNA-directed DNA polymerase) slows or blocks the viral infection.
  • RNA-directed DNA polymerase reverse transcriptase enzyme
  • the route of administration for these treatments can include, but not limited to, oral, parenteral and implants (composition and device).
  • the formulations of this invention provide for slow or controlled or sustained release of EFdA from these prodrugs when injected as an aqueous suspension formulation.
  • FIG. 1 shows an X-ray Powder Diffractogram (XPRD) of EFdA.
  • FIG. 2 shows data provided by Differential Scanning Calorimetry (DSC) and Thermo-Gravimetric Analysis (TGA) of EFdA.
  • FIG. 3 shows DSC and TGA data for compound 2.
  • FIG. 4 shows XPRD data for compound 3.
  • FIG. 5 shows DSC data for compound 3.
  • FIG. 6 shows TGA data for compound 3.
  • FIG. 7 shows XPRD data for compound 5.
  • FIG. 8 shows DSC data for compound 5.
  • FIG. 9 shows TGA data for compound 5.
  • FIG. 10 shows in graphic form the data provided in Table 2.
  • FIG. 11 shows in graphic form the data provided in Table 3.
  • FIG. 12 shows in graphic form the data provided in Table 4.
  • the invention provides, in various embodiments, a compound of Formula (I)
  • R is H, (C 1-22 )alkyl, or (C 3-22 )alkenyl wherein the alkenyl can comprise 1-6 unsaturations, or is (C 3-7 )cycloalkyl;
  • R 2 is H or is X-L m , or R 2 is —OCH(R)OP( ⁇ O)OH) 2 or R 2 is a phosphate residue or its derivative residue comprising a monophosphate, a diphosphate, a triphosphate, a phosphonate, a phosphate polyester, a phosphate amidate (mono and di), a phosphorothioate, a phosphoroselenoate, or a phophoroboranoate;
  • R 2 H when R 1 is a phosphate residue or its derivative residue comprising a monophosphate, a diphosphate, a triphosphate, a phosphonate, a phosphate polyester, a phosphate amidate (mono and di), a phosphorothioate, a phosphoroselenoate, or a phophoroboranoate;
  • a compound of Formula (I) can be any of the specific compounds 2-51, shown in Table 1.
  • the invention further provides, in various embodiments, a method of inhibiting viral reverse transcriptase bioactivity, comprising contacting a virus expressing an enzyme with reverse transcriptase bioactivity with an effective amount or concentration of a compound of Formula (I).
  • the invention further provides, in various embodiments, a method of prophylaxis of viremia or treatment of a viral infection in a patient wherein inhibition of a reverse transcriptase is medically indicated, comprising administering to the patient an effective amount or concentration of a compound of Formula (I).
  • the compound of Formula (I) can be administered in a formulation that provides for slow or controlled or sustained release of EFdA from these prodrugs.
  • the compound of Formula (I) can be formulated as aqueous suspension, solutions, and can be encapsulated in particles for slow-release including PLGA and those known in the art.
  • the viral infection can be caused by HIV or HBV.
  • the routes of administration for these prodrugs can include, but not limited to, oral, parenteral and implants (drug delivery composition and device).
  • the method may further comprise an additional anti-HIV and/or anti-HBV agent including but not limited to, cabotegravir, dolutegravir, doravirine, elvitegravir, lersiverine, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate or lamivudine.
  • MS-ESI: m/z 406.57 observed (M + H)+ 41 MS-ESI: m/z 415.47 observed (M + Na)+ 42 MS-ESI: m/z 393.32 observed (M + H)+ 43 MS-ESI: m/z 797.4 observed (M ⁇ H) ⁇ 44 MS-ESI: m/z 562.8 observed (M + H) + 45 MS-ESI: m/z 488.6 observed (M + H)+ 46 MS-ESI: m/z 488.7 observed (M + H)+ 47 MS-ESI: m/z 828.4 observed (M ⁇ H) ⁇ 48 MS-ESI: m/z 604.8 observed (M + H) + 49 MS-ESI: m/z 398.5 observed (M + H) + 50 MS-ESI: m/z 428.3 observed (M + H) ⁇
  • THF tetrahydrofuran
  • DCM dichloromethane
  • MeCN Acetonitrile
  • DMF dimethylsulfoxide
  • TFA trifluoroacetic acid
  • TAA triethylamine
  • DIPEA diisopropylethylamine
  • MeOH methanol
  • EtOAc 4-Dimethylaminopyridine
  • EDC.HCl N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride
  • DCC N,N′-Dicyclohexylcarbodiimide
  • the starting materials and intermediates for the compounds of this invention may be prepared by the application or adaptation of the methods described below, their obvious chemical equivalents, or, for example, as described in literature such as The Science of Synthesis, Volumes 1-8. Editors E. M. Carreira et al. Thieme publishers (2001-2008). Details of reagent and reaction options are also available by structure and reaction searches using commercial computer search engines such as Scifinder (www.cas.org) or Reaxys (www.reaxys.com).
  • the reaction is monitored by LCMS due to the occasional alkylation of NH 2 group observed for elongated reaction time.
  • the reaction mixture was then filtered to remove byproduct urea. Acetonitrile was used to rinse the reaction mixture. Thereafter, the reaction was washed twice with water and once with brine and then the solvent was dried, filtered and evaporated under reduced pressure.
  • the resulting crude material was purified by silica-gel column chromatography using 60-70/% EtOAc in Hexanes to obtain the compound 2 as a glassy solid. The obtained solid was dispersed in minimum amount of isopropanol followed by its rotatory evaporation to obtain pure compound as a white solid (2.5 g, 85% yield).
  • the reaction is monitored by LCMS due to the occasional alkylation of NH 2 group observed for elongated reaction time. Thereafter, the reaction was diluted with EtOAc and washed thrice with water, once with NaHCO 3 and once with brine and then the solvent was dried, filtered and evaporated under reduced pressure. The resulting crude material was purified by silica-gel column chromatography using 60-70/o % EtOAc in Hexanes to obtain the compound 10 as a glassy solid. The obtained solid was dispersed in minimum amount of isopropanol followed by its rotatory evaporation to obtain pure compound as a white solid (372 mg, 70% yield).
  • Step-1 To a solution of intermediate B (400 mg, 0.75 mmol, 1 equiv.) in anhydrous MeCN (12 mL) was added DIPEA (0.6 mL, 3.77 mmol, 5 equiv.) and DMAP (18.4 mg, 0.15 mmol, 0.2 equiv.). To this stirred solution at 0° C. was added dropwise heptanoic anhydride (365 mg, 1.5 mmol, 2 equiv.) in MeCN (5 mL). The resulting mixture was then stirred at rt for 1 h. The reaction is monitored by LCMS.
  • reaction mixture was quenched in ice cold water (20 ml) and was extracted with ethyl acetate (3 ⁇ 20 mL). The combined organic layer was dried, filtered and evaporated under reduced pressure. The resulting crude material was purified by silica-gel column chromatography using 1.5% DCM in MeOH to obtain the intermediate C (430 mg, 88.8% yield).
  • Step-2 To a solution of intermediate C (430 mg, 0.67 mmol, 1 equiv.) in anhydrous MeOH (5 mL) was added NH4F (495 mL, 13.35 mmol, 20 equiv.). The resulting mixture was then stirred at rt for 12 h. The reaction is monitored by LCMS. After completion of reaction, reaction mixture was quenched in ice cold water (20 ml) and was extracted with ethyl acetate (3 ⁇ 20 mL). The combined organic layer was dried, filtered and evaporated under reduced pressure. The resulting crude material was purified by silica-gel column chromatography using 2.5% DCM in MeOH to obtain the compound 24 as an off-white solid (187 mg, 69.1% yield). LC-MS (ESI+): m/z 406.55 [M+H]+.
  • the reaction is monitored by LCMS due to the occasional alkylation of NH 2 group observed for elongated reaction time. Thereafter, the reaction was diluted with EtOAc and washed thrice with water, once with NaHCO 3 and once with brine and then the solvent was dried, filtered and evaporated under reduced pressure. The resulting crude material was purified by silica-gel column chromatography using 1.5% DCM in MeOH to obtain the compound 39 as an off-white solid (1.0 g, 65% yield). LC-MS (ESI+): m/z 476.66 [M+H]+.
  • Compound 43 can be prepared by using the procedure followed for the compound 39 using the acid chloride of known acid dihexadecylglycine.
  • Compound 44 can be prepared by the reaction between EFdA and the corresponding chloroformate in the pyridine as the solvent.
  • Compound 1 (EFdA) was grinded and sieved through #80. 300 mg of 1 was taken in suitable container and a solution of preformed 0.25% sodium carboxymethyl cellulose (Sodium CMC) and 0.1% polyoxyethlene (20) sorbitan monooleate (TWEEN-80) was added to obtain 1 gram (300 mg of 1+ ⁇ 700 mg of polymer solution) of the final formulation ( ⁇ 300 mg/g). The suspension was then bath sonicated for 10 min in an Ice bath. The density of formulation of is 1.064 g/mL. Henceforth, the above formulation suspension will be 319.2 mg/mL concentration of compound 1 (EFdA).
  • Sodium CMC sodium carboxymethyl cellulose
  • TWEEN-80 polyoxyethlene (20) sorbitan monooleate
  • Recrystallized Compound 2 was grinded and sieved through #80. 250 mg of 1 was taken in suitable container and a solution of preformed 0.25% Sodium CMC and 0.1% TWEEN-80 was added to obtain 1 gram (250 mg of 1+ ⁇ 750 mg of polymer solution) of the final formulation ( ⁇ 250 mg/g). The suspension was then probe sonicated for 5 min in an ice bath (Sonication time: 5 min; Pulse Amplitude: 20; Pulse on Time: 30 sec; Pulse off time: 20 sec).
  • Compound 3 was grinded and sieved through #80. 250 mg of 3 was taken in suitable container and a solution of preformed 0.25% Sodium CMC and 0.5% TWEEN-80 was added to obtain 1 gram (250 mg of 3+ ⁇ 750 mg of polymer solution) of the final formulation ( ⁇ 250 mg/g). The suspension was then probe sonicated for 5 min in an ice bath (Sonication time: 5 min; Pulse Amplitude: 20; Pulse on Time: 30 sec; Pulse off time: 20 sec). The density of formulation of is 1.004 g/mL. Henceforth, the above formulation suspension will be 250.88 mg/mL concentration of compound 3 ( ⁇ 150 mg/mL of EFdA).
  • Compound 5 was grinded and sieved through #80. 200 mg of 5 was taken in suitable container and a solution of preformed 0.25% Sodium CMC and 0.5% TWEEN-80 was added to obtain 1 gram (200 mg of 5+ ⁇ 800 mg of polymer solution) of the final formulation ( ⁇ 200 mg/g). The suspension was then probe sonicated for 5 min in an ice bath (Sonication time: 5 min; Pulse Amplitude: 20; Pulse on Time: 30 sec; Pulse off time: 20 sec). The density of formulation of is 1.047 g/mL. Henceforth, the above formulation suspension will be 209.4 mg/mL concentration of compound 5 ( ⁇ 115.97 mg/mL of EFdA).
  • Animals (Male SD rats ⁇ 200-250 g and Male rhesus macaques ⁇ 2-3 kg) were obtained from an approved vendor (SLAC Laboratory Animal Co. Ltd., Shanghai, China and/or Topgene Biotechnology, Wuhan city, Hubei province, China).
  • Acclimation/Quarantine Following arrival, animals were assessed as to their general health by a member of the veterinary staff or other authorized personnel. Animals were acclimated for at least 3 days before being placed on study.
  • Animal Husbandry Animals were group housed during acclimation and individually housed during the study. The animal room environment will be controlled (target conditions: temperature 18 to 26° C., relative humidity 30 to 70%, 12 hours artificial light and 12 hours dark). Temperature and relative humidity were monitored daily.
  • SC Formulation The formulations were prepared according to the procedure given in Examples 52-55 and Table 2-4. The formulations were prepared on the day of dosing. Animals were dosed within four hours after the formulation is prepared. Two 20 ⁇ L aliquots of each formulation were removed from each of the formulation solutions, transferred into 1.5 mL of polypropylene microcentrifuge tubes and run dose validation by LC/UV or LC-MS/MS.
  • the dose formulation was administered via subcutaneous injection following facility SOPs.
  • Plasma samples were processed for plasma by centrifugation at approximately 4° C., 3000 g 15 min within half an hour of collection. Plasma samples was stored in polypropylene tubes, quick frozen over dry ice and kept at ⁇ 70 ⁇ 10° C. until LC/MS/MS analysis.
  • Plasma concentration versus time data was analyzed by non-compartmental approaches using the Phoenix WINNONLIN 6.3 software program.
  • C max , T max , T 1/2 , AUC (0-t) , AUC (0-inf) , MRT (0-t) , MRT (0-inf) , % F and graphs of plasma concentration versus time profile were reported.
  • prodrugs including EFdA (1) as a control were subjected to a single dose rat PK studies via subcutaneous route of administration. All were injected with equivalent doses of 10 mg/kg and concentration of 4 mg/mL of EFdA as an aqueous suspension formulation derived from 0.5% CMC-Na and 0.5% TWEEN-80. While similar exposure was observed, all prodrugs 2, 3 and 5 exhibited plasma levels of EFdA above LLOQ for more than a week with Cmax much lower than EFdA itself.
  • Table 2 shows the rat PK data for compounds 1, 2, 3 and 5 following SC administration at 10 mg/kg equivalent dose of EFdA. The data are shown in graphic form is shown in FIG. 10 .
  • Table 3 shows the rat PK data for compounds 1 and 3 following SC administration at 10 mg/kg and 100 mg/kg equivalent dose of EFdA at high concentration formulation. The data are shown in graphic form in FIG. 11 .
  • Prodrug 5 and EFdA were subjected to a single dose rhesus macaque PK studies via subcutaneous route of administration with equivalent doses of 50 mg/kg of EFdA.
  • the aqueous suspension formulations were derived from 0.25;% CMC-Na and 0.1;%/0.5% TWEEN-80 with equivalent concentration of 116 mg/mL and 319 mg/mL of EFdA for prodrug 5 and EFdA respectively.
  • Prodrugs 5 exhibited plasma levels of EFdA above LLOQ for more than a month with 24-fold lower C max than EFdA itself.
  • Table 4 shows the Rhesus PK data for compounds 1 and 5 following SC administration at 50 mg/kg equivalent dose of EFdA at high concentration formulation. The data are shown in graphic form in FIG. 12 .

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