WO2008134578A2 - Synthèse d'inhibiteurs de transcriptase inverse radiomarqués actifs optiquement - Google Patents

Synthèse d'inhibiteurs de transcriptase inverse radiomarqués actifs optiquement Download PDF

Info

Publication number
WO2008134578A2
WO2008134578A2 PCT/US2008/061664 US2008061664W WO2008134578A2 WO 2008134578 A2 WO2008134578 A2 WO 2008134578A2 US 2008061664 W US2008061664 W US 2008061664W WO 2008134578 A2 WO2008134578 A2 WO 2008134578A2
Authority
WO
WIPO (PCT)
Prior art keywords
compound
subject
formula
reverse transcriptase
compounds
Prior art date
Application number
PCT/US2008/061664
Other languages
English (en)
Other versions
WO2008134578A3 (fr
Inventor
Dale O. Kiesewetter
Michele Di Mascio
Esther Lim
Original Assignee
The Government Of The United States Of America As Represented By The Secretary Of The Department Of
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Government Of The United States Of America As Represented By The Secretary Of The Department Of filed Critical The Government Of The United States Of America As Represented By The Secretary Of The Department Of
Publication of WO2008134578A2 publication Critical patent/WO2008134578A2/fr
Publication of WO2008134578A3 publication Critical patent/WO2008134578A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs

Definitions

  • FIELD Disclosed herein are radio-isotopically labeled reverse transcriptase derivatives useful for positron emission tomography of subjects infected with a retrovirus.
  • AIDS Acquired immune deficiency syndrome
  • the AIDS virus was first identified in 1983. It has been known by several names and acronyms. It is the third known T-lymphotropic virus (HTLV-III), and it has the capacity to replicate within cells of the immune system, causing profound cell destruction.
  • the AIDS virus is a retrovirus, a virus that uses reverse transcriptase during replication. This particular retrovirus is also known as lymphadenopathy- associated virus (LAV), AIDS-related virus (ARV) and, most recently, as human immunodeficiency virus (HIV).
  • LAV lymphadenopathy- associated virus
  • ARV AIDS-related virus
  • HIV human immunodeficiency virus
  • HIV HIV
  • NRTI nucleoside reverse transcriptase inhibitors
  • NRTI non-nucleoside reverse transcriptase inhibitors
  • radioactive, isotopically labeled reverse transcriptase inhibitors including compounds according to the formula
  • R 1 and R 2 independently are selected from H, lower alkyl, aralkyl, acyl and T) and Z 2 independently form a phosphoester, phosphonamide or phosphonic acid. Also disclosed are methods for synthesizing such compounds in racemic and optically pure forms. In addition, methods are disclosed for using the labeled compounds, for example in positron emission tomography (PET) monitoring of retrovirus activity. The presently disclosed synthetic methods for preparing radio-labeled reverse transcriptase inhibitors is particularly facile and thus is uniquely suited to the preparation of 18 F-labeled compounds for PET imaging.
  • PET positron emission tomography
  • Examples of viral sanctuaries imaged using the presently disclosed radio-labeled compounds include lymphatic tissue, the gastrointestinal tract, tonsils, rectal mucosa, lymph nodes, the central nervous system, the thymus and the testes.
  • FIG. 1 is a graph of the inhibitory activity of ⁇ -PMPA in macaque PBMC cells infected with SIVmac239. (c) (d)
  • FIG. 2 is a graph of the inhibitory activity of ⁇ S-FPMPA in macaque PBMC cells infected with SIVmac239.
  • FIG. 3 is a graph of the inhibitory activity of S-FPMPA in human MT4 cells infected with SHIV D HI2R-
  • FIG. 4 is a graph of the inhibitory activity of ⁇ -FPMPA in human MT4 cells infected with SHIVDHI2R.
  • FIG. 5 is a sample quality control chromatogram of S-FPMPA recorded using an Agilent Eclipse XDB-C- 18 4.6 x 150 mm column and 15% CH 3 CN, 85% 5 mM 11Bu 4 NH 2 PC) 4 as the eluent at a flow rate of 1 mL/min.
  • FIG. 6 includes radiochromatograms of the isolated FPMPA enantiomers recorded using a Luna C-18 4.6 x 250 mm column and 4 mM CuSO 4 , 4 mM L-Phe as the eluent at a flow rate of 1 mL/min. DETAILED DESCRIPTION /. Introduction
  • Reverse transcriptase inhibitors such as tenofovir (PMPA l-(6-amino-9H- purin-9-yl)- propan-2-yloxy)methylphosphonic acid), have been used therapeutically as inhibitors of HIV replication.
  • Tenofovir which is provided therapeutically as its prodrug, tenofovir disopropoxide fumarate, is an orally active inhibitor. This drug belongs to the class of nucleoside analogue reverse transcriptase inhibitors.
  • isotopically labeled analogues of reverse transcriptase inhibitors including radio-labeled tenofovir analogues, as well as methods for synthesizing such inhibitors in both racemic and optically active form.
  • the disclosed radio-labeled inhibitors are used to monitor retroviral load, particularly in viral reservoirs that are not accurately evaluated using conventional RT-PCR assays.
  • the disclosed compounds also are useful for evaluating the efficacy of putative antiretroviral therapies at reducing viral load in reservoir tissues.
  • Derivative refers to a compound or portion of a compound that is derived from or is theoretically derivable from a parent compound.
  • subject includes both human and veterinary subjects.
  • aliphatic group is defined as including alkyl, alkenyl, alkynyl, halogenated alkyl and cycloalkyl groups as described above.
  • a "lower aliphatic” group is a branched or unbranched aliphatic group having from 1 to 10 carbon atoms.
  • alkyl refers to a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, ⁇ -propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like.
  • a "lower alkyl” group is a saturated branched or unbranched aliphatic hydrocarbon having from 1 to 10 carbon atoms.
  • aryl group refers to any carbon-based aromatic group including, but not limited to, benzene, naphthalene, etc.
  • aromatic also includes “heteroaryl group,” which is defined as an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorous.
  • the aryl group can be substituted with one or more groups including, but not limited to, alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ketone, aldehyde, hydroxy, carboxylic acid, or alkoxy, or the aryl group can be unsubstituted.
  • alkyl amino refers to alkyl groups as defined above where at least one hydrogen atom is replaced with an amino group.
  • hydroxyl group is represented by the formula -OH.
  • alkoxy group is represented by the formula -OR, where R can be an alkyl group, optionally substituted with an alkenyl, alkynyl, aryl, aralkyi, cycloalkyl, halogenated alkyl, or heterocycloalkyl group as described above.
  • hydroxyalkyl group refers to an alkyl group that has at least one hydrogen atom substituted with a hydroxyl group.
  • alkoxyalkyl group is defined as an alkyl group that has at least one hydrogen atom substituted with an alkoxy group described above. Where applicable, the alkyl portion of a hydroxyalkyl group or an alkoxyalkyl group can have aryl, aralkyl, halogen, hydroxy and/or alkoxy substituents.
  • amine group is represented by the formula -NRR', where R and R' can be, independently, hydrogen or an alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group described above.
  • amide group is represented by the formula -C(O)NRR', where R and R' independently can be a hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group described above.
  • aralkyl refers to an aryl group having an alkyl group, as defined above, attached to the aryl group.
  • aralkyl groups include, without limitation, benzyl groups and trityl groups.
  • halogenated alkyl or “haloalkyl group” refer to an alkyl group as defined above with one or more hydrogen atoms present on these groups substituted with a halogen (F, Cl, Br, I).
  • Optionally substituted groups refers to groups, such as an alkyl group, having from 1-5 substituents, typically from 1-3 substituents, selected from alkoxy, optionally substituted alkoxy, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, aryl, carboxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, hydroxy, thiol and thioalkoxy.
  • the term “leaving group” refers to a charged or uncharged substituent group on an activated compound which leaves during a substitution, displacement and/or elimination reaction. Suitable examples include, without limitation, halides, such as -Cl, -Br and -I and sulfonates, such as -S(O) 2 R, wherein R is, for example a lower alkyl, haloalkyl or aryl group.
  • pharmaceutically acceptable salt or prodrug is used throughout the specification to describe any pharmaceutically acceptable form (e.g., ester, phosphate ester, salt of an ester or a related group) of an inhibitor compound, which, upon administration to a subject, provides or produces an active compound.
  • the disclosed compounds also encompass salts including, if several salt- forming groups are present, mixed salts and/or internal salts.
  • the salts are generally pharmaceutically-acceptable salts that are nontoxic or substantially nontoxic to a subject.
  • Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids.
  • suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium and magnesium, among numerous other acids well known in the pharmaceutical art.
  • salt-forming acidic groups include, but are not limited to, a carboxyl group, a phosphonic acid group or a boronic acid group, that can form salts with suitable bases.
  • salts can include, for example, nontoxic metal cations which are derived from metals of groups IA, IB, HA and IIB of the periodic table of the elements.
  • alkali metal cations such as lithium, sodium or potassium ions, or alkaline earth metal cations such as magnesium or calcium ions can be used.
  • the salt can also be a zinc or an ammonium cation.
  • the salt can also be formed with suitable organic amines, such as unsubstituted or hydroxyl-substituted mono-, di- or tri-alkylamines, in particular mono-, di- or tri-alkylamines, or with quaternary ammonium compounds, for example with iV-methyl-N-ethylamine, diethylamine, triethylamine, mono-, bis- or tris- (2- hydroxy- lower alkyl)amines, such as mono-, bis- or tris- (2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine or tris(hydroxymethyl)methylamine, N, N-di-lower alkyl-iV-(hydroxy-lower alkyl)amines, such as ⁇ N-dimethyl- ⁇ /-(2- hydroxyethyl)amine or tri-(2- hydroxyethyl)amine, or iV-methyl-D-glucamine, or quaternary ammonium compounds such as
  • Particular compounds possess at least one basic group that can form acid- base salts with inorganic acids.
  • basic groups include, but are not limited to, an amino group or imino group.
  • inorganic acids that can form salts with such basic groups include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid.
  • Basic groups also can form salts with organic carboxylic acids, sulfonic acids, sulfo acids or phospho acids or N-substituted sulfamic acid, for example acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, gluconic acid, glucaric acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, A- aminosalicylic acid, 2- phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid, nicotinic acid or isonicotinic acid, and, in addition, with amino acids, for example with ⁇ -amino acids, and also with methanesulfonic acid, ethanesulfonic acid, 2- hydroxymethanesulfonic acid, ethane- 1,2-disul
  • prodrugs refer to compounds that are metabolized, for example, hydrolyzed or oxidized, in the subject to form an antiviral compound of the present disclosure.
  • Typical examples of prodrugs include compounds that have one or more biologically labile protecting groups on or otherwise blocking a functional moiety of the active compound.
  • Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated to produce the active compound.
  • the compounds of this invention possess antiviral activity against a viral target, or are metabolized to a compound that exhibits such activity.
  • prodrug also is intended to include any covalently bonded carriers that release an active parent drug of the present invention in vivo when the prodrug is administered to a subject. Since prodrugs often have enhanced properties relative to the active agent pharmaceutical, such as solubility and bioavailability, the compounds disclosed herein can be delivered in prodrug form. Thus, also contemplated are prodrugs of the presently claimed compounds, methods of delivering prodrugs and compositions containing such prodrugs. Prodrugs of the disclosed compounds typically are prepared by modifying one or more functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to yield the parent compound.
  • Prodrugs include compounds having a phosphonate and/or amino group functionalized with any group that is cleaved in vivo to yield the corresponding amino and/or phosphonate group, respectively.
  • Examples of prodrugs include, without limitation, compounds having an acylated amino group and/or a phosphonate ester or phosphonate amide group.
  • a prodrug is a lower alkyl phosphonate ester, such as an isopropyl phosphonate ester.
  • Protected derivatives of the disclosed compound also are contemplated.
  • a variety of suitable protecting groups for use with the disclosed compounds are disclosed in Greene and Wuts; Protective Groups in Organic Synthesis; 3rd Ed.; John Wiley & Sons, New York, 1999.
  • protecting groups are removed under conditions which will not affect the remaining portion of the molecule.
  • These methods are well known in the art and include acid hydrolysis, hydrogenolysis and the like.
  • One preferred method involves the removal of an ester, such as cleavage of a phosphonate ester using
  • a second preferred method involves removal of a protecting group, such as removal of a benzyl group by hydrogenolysis utilizing palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof.
  • a t-butoxy-based group, including t-butoxy carbonyl protecting groups can be removed utilizing an inorganic or organic acid, such as HCl or trifluoroacetic acid, in a suitable solvent system, such as water, dioxane and/or methylene chloride.
  • Another exemplary protecting group, suitable for protecting amino and hydroxy functions amino is trityl.
  • Other conventional protecting groups are known, and suitable protecting groups can be selected by those of skill in the art in consultation with Greene and Wuts; Protective Groups in Organic Synthesis; 3rd Ed.; John Wiley & Sons, New York, 1999.
  • radioisotopically labeled reverse transcriptase inhibitors are 18 F-labeled inhibitors.
  • Fluorine has several isotopes in addition to 19 F, all of which are unstable, but only one of these has practical significance: the isotope, 18 F, which is radioactive and has the longest half-life of the unstable isotopes (the other unstable isotopes have half-lives lasting less than 3 minutes).
  • 18 F isotope has a half-life of 110 minutes and is very useful in biological studies and in medicine, but a half-life of less than 2 hours does impose some limits on its utility. Examples of the uses of 18 F include non-invasive measurement of pharmacokinetic phenomena and the localization of tumors with 18 F-labeled 2- fluoro-2-deoxyglucose (e.g. by positron emission tomography).
  • an F-labeled compound In any method in which an F-labeled compound is used, it is generally necessary that its physiological properties (e.g. its properties as a substrate for an enzyme) be similar to the endogenous, non-fluorinated compound it is supposed to mimic.
  • the fluorine atom has the advantage of being fairly small in its covalent radius and hence does not differ too markedly from hydrogen in terms of steric hindrance.
  • a fluorine substituent does differ from other substituents in terms of charge density, due to its high electronegativity and electronic density.
  • I8 F-labeled compounds that can be prepared efficiently and used to image retroviral activity by binding to reverse transcriptase.
  • Certain disclosed 18 F-labeled inhibitors have the structure
  • R 1 and R 2 typically are independently selected from H, lower alkyl, aralkyl and protecting groups.
  • the exocyclic amino group typically is unsubstituted (R 1 and R 2 are H), but different R 1 and R 2 groups can be used to, for example, block undesired side reactions during the synthesis of inhibitor compounds and derivatives thereof.
  • R 1 and R 2 groups also can be used to affect the biodistribution or availability of the compounds.
  • appropriate R 1 and R 2 groups that can be removed in vivo also can be selected to provide inhibitor prodrugs.
  • Exemplary compounds having the formula above are phosphoester or phosphonamide compounds.
  • Z forms any suitable ester or amide phosphonate compound.
  • suitable ester and amide moieties include those heretofore known for use with nucleotide phosphonates.
  • Z forms an ester, it has the structure -OR, wherein R typically is H (Z is hydroxy), although other R ester groups described below are suitable for use as protecting groups or as pro-functionalities for prodrug embodiments of the disclosed 18 F- labeled compounds.
  • Z may be useful to protect the phosphonate moiety against undesired reactions and/or to provide an in vivo prodrug of the compound.
  • the selection of ester or amide may not be critical, depending upon the nature of the reaction involved. All that is needed is that the Z substituent not be removed until the step in synthesis at which this is desired, and if this is not apparent on theoretical grounds, it can be readily determined as is known to those of skill in the art.
  • esters such as lower alkyl, aralkyl and aryl esters, in particular lower alkyl esters, are used to protect the phosphonic acid -OH groups from undesired reaction, such as alkylation.
  • the disclosed labeled antiviral compounds have the formula
  • R 3 and R 4 independently are selected from lower alkyl, aralkyl and aryl.
  • Suitable prodrug esters or amidates optionally are selected based on the substrate specificity of esterases and/or carboxypeptidases expected to be found within cells wherein precursor hydrolysis is desired. To the extent that the specificity of these enzymes is unknown, one will screen a plurality of inhibitor compounds disclosed herein until the desired substrate specificity is found. This will be apparent from the appearance of free phosphonate or antiviral activity. Screening with cells from particular tissues are used to identify precursors that are released in organs susceptible to a target viral or microbial infection, e.g. in the case of liver, precursor drugs capable of hydrolysis in the liver.
  • CMV or HIV optionally are treated with a precursor that is hydrolyzed at substantially the same rate and to substantially the same degree in all tissues.
  • Assays known in the art are suitable for these purposes, including intestinal lumen stability, cell permeation, liver homogenate stability and plasma stability assays. These assays are used to determine the bioavailability characteristics of the precursors.
  • ester and amide substituents Z are found in WO95/07920, WO98/04569 and EP 481214 Al. Any ester or amide genus or species described in these publications can be used as group Z 1 and/or Z 2 herein.
  • Z 1 and Z 2 are the same, for example, both Z 1 and Z 2 are hydroxyl, both form an ester and/or both form an amide. In other words, typically two or no Z groups are hydroxy.
  • phosphonamides formed from naturally occurring amino acids are preferred, and in such embodiments, the free carboxyl(s) of amino acid typically are esterified with a lower alkyl group.
  • the foregoing compounds include an asymmetric center; thus these compounds can exist in two stereoisomeric forms, termed enantiomers.
  • compounds and compositions may be provided as individual pure enantiomers or as stereoisomeric mixtures, including racemic mixtures.
  • the compounds disclosed herein are synthesized in or are purified to be in substantially enantiopure form, such as in a 90% enantiomeric excess, a 95% enantiomeric excess, a 97% enantiomeric excess or even in greater than a 99% enantiomeric excess, such as in enantiopure form.
  • adenine derivative 20 is alkylated with epifluorohydrin 10, to provide N'-alkylated derivative 30.
  • the secondary alcohol of 30 is then selectively alkylated with 40 (wherein X is a leaving group).
  • Phosphate ester 50 is then deprotected to give reverse transcriptase inhibitor 60.
  • Schemes 2 and 3 One embodiment of a facile radiochemical synthesis is depicted in Schemes 2 and 3, below.
  • protected intermediate 70 is selectively deprotected to unmask a primary alcohol 80.
  • Primary alcohol 80 can then be activated by installation of a leaving group in place of the primary hydroxyl moiety.
  • the exocyclic amino group optionally may be protected, but in certain embodiments disclosed herein, amino-protection is not required.
  • activated intermediate compound 90 is treated with a source of nucleophilic 18 F, to give fluorinated, protected compound 100.
  • compound 100 is deprotected to yield labeled reverse transcriptase inhibitor 110.
  • the synthesis set forth in Schemes 2 and 3 is, with the selection of enantiomerically enhanced or enantiopure starting materials, suitable for the production of optically active, labeled reverse transcriptase inhibitors.
  • the subject is administered a radio-labeled reverse transcriptase inhibitor and typically the inhibitor is allowed to partially clear from the subject and to be taken up preferentially by retrovirus-infected tissues and then a portion of the subject containing the tissue of interest is analyzed non-invasively by positron emission tomography (PET). A proportion of the inhibitor will remain in the body, bound to retrovirus or associated with retrovirus-infected cells. Because of the short half-life of radioactive 18 F (110 min), a compromise is reached between having the maximum clearance providing the best signal: noise ratio), and having enough signal to provide adequate image resolution.
  • PET positron emission tomography
  • the viral load of a subject may be quantified using PET imaging of the disclosed reverse transcriptase inhibitors.
  • PET imaging One method for quantitative PET imaging is described by Yao et al. J. Nucl. Med. 1995, 36, 794- 799, which is incorporated herein by reference. Additional methods are known to those of skill in the art and are taught by Wahl, "Regions of Interest in the Venous Sinuses as Input Functions for Quantitative PET," J. Nucl. Med. 1999, 40 1666- 1675; and Fowler, J. S. et al. "PET and Drug Research and Development," J. Nucl. Med. 1999, 40, 1154-1163. The Wahl and Fowler references also are incorporated herein by reference.
  • the disclosed radio-labeled reverse transcriptase inhibitors can be used to determine viral load in a subject.
  • the radiolabeled compounds can be used to directly measure virus presence in particular tissues, which has marked advantages over simply measuring plasma levels.
  • the compounds can be used to test the efficacy of putative antiretroviral therapies, including anti-HIV therapies.
  • the disclosed reverse transcriptase inhibitors can be administered to any subject who is known to be or is suspected of being infected with a retrovirus.
  • Viral infections to be assessed using the disclosed isotopically labeled compounds include infections caused by DNA or RNA viruses such as herpesviruses (CMV, HSV 1, HSV 2, EBV, varicella zoster virus [VZV], bovid herpesvirus type 1, equid herpesvirus type 1, HHV-6, papillomaviruses (HPV types 1-55 including carcinogenic HPV), flaviviruses (including yellow fever virus, African swine fever virus, Japanese encephalitis virus and West Nile virus), togaviruses (including Venezuelan equine encephalomyelitis virus), influenza viruses (types A-C), retroviruses (HIV-I, HIV-2, HTLV-I, HTLV-II, SIV, FeLV, FIV, MoMSV), adenoviruses (types 1
  • the present reverse transcriptase inhibitors also can be used in the assessment of the response of a subject to therapeutic interventions using PET scanning or another external radiation detection technique.
  • the subject can be scanned at more than one time and the data from two or more scans may be compared to determine potential differences in the uptake and/or localization of the inhibitor compound. Comparisons can involve either qualitative image comparison (e.g. contrast of uptake from background) or quantitative indices derived from the imaging or external radiation detection data (e.g. standardized uptake values (SUVs)).
  • a decrease in total radioactive signal (beyond that due to radioactive decay) indicates reduced viral load associated with drug activity, whereas an increase in total radioactive signal (after adjusting for decay), indicates a less effective drug.
  • the efficacy of the drug can be assessed on an organ or tissue specific basis by monitoring the radioactive signal from specific tissues.
  • specific tissues Of specific interest is the effect of drugs on viral sanctuaries, such as the central nervous system, thymus, testes or lymphatic tissue, wherein reduced positron emissions from these tissues indicates that the drug being evaluated is effective at reducing viral load in these tissues.
  • the disclosed labeled reverse transcriptase inhibitors optionally are employed in combination with other therapeutic agents for the assessment or monitoring of the effect of such therapeutic agents on the infections or conditions indicated above. Examples of such further therapeutic agents include agents that are effective for the treatment or prophylaxis of viral infections.
  • nucleoside reverse transcriptase inhibitors 3'-azido-3'- deoxythymidine (zidovudine, AZT), 2'-deoxy-3'-thiacytidine (3TC), 2',3'-dideoxy- 2',3'-didehydrothymidine (D4T), carbovir (carbocyclic 2 l ,3'-dideoxy-2',3 l - didehydroguanosine), abacavir (ABC), 2',3'-dideoxyinosine (D4T), didanosine, 2',3'- dideoxycytidine (ddc, zalcitabine), 3'-azido-2',3'-dideoxyuridine, (E)-5-(2- bromovinyl)-2'-deoxvuridine (BVDU), 2-chloro-2'-deoxyadenosine, 2- deoxycoformycin, 5-fluorouracil,
  • nevirapine delaviridine, efavirens, daparivine, etc.
  • protease inhibitors e.g. saquinavir, indinavir, ritonovir, amprenavir, and the like
  • 2'-nor-cyclicGMP 6-methoxypurine arabinoside (ara-M), 6-methoxypurine arabinoside 2-0-valerate, cytosine arabinoside (ara-C)
  • acyclic nucleosides such as acyclovir, valacyclovir, penciclovir, famciclovir, ganciclovir, acyclic nucleotide analogues such as HPMPC, PMEA, PMEG, PMPA, PMPDAP, FPMPA, HPMPA and HPMPDAP, (2R, 5R)-9-[tetrahydro-5-(phosphonomethoxy)- 2-furanyl] adenine, (2R, 5R)
  • the present analogues can also be used in the assessment or staging of retrovirus infection based on quantitative or qualitative measurements of uptake of the present analogues by tissue.
  • the tissue uptake of the analogue can be determined while the tissue is within the body or outside the body.
  • the uptake measurements can be performed in conjunction with pathologic/histologic/histochemical/ immunohistochemical assessment of the same tissue for classification and evaluation of infection.
  • the method disclosed can be used to determine the degree of infection of a tissue by quantitating the amount of 18 F radioactivity present.
  • the present reverse transcriptase inhibitors also can be used in the anatomical mapping of the distribution of virus in the body using PET or another external radiation detection technique in combination with anatomical images obtained using CT, MRI, and/or ultrasound.
  • the anatomical images can be acquired using a dedicated CT/PET, MRI/PET, PET/ultrasound scanning device or separate PET and CT/MRI/ultrasound scanning devices. If separate PET and CT/MRI/ultrasound imaging devices are used, image analysis techniques can be employed to spatially register the PET images with the anatomical images.
  • the method can be used for intraorgan mapping of viral localization.
  • the disclosed inhibitors also can be used in radiolabeling of virus and in vitro counting of radioactivity.
  • the tracer can be administered in vivo or ex vivo in tissue or cell culture experimental models.
  • the above-described analogues can be used in the assessment of reverse transcriptase inhibitor processing in liver, spleen and kidneys in pathophysiologic conditions that may accompany retroviral infection. Rates of drug transport and metabolism are relatively high in these organs, indicating an importance of drug processing pathways in these tissues. Abnormalities in metabolism can occur in liver, spleen and kidneys, either directly due to diseases that directly influence metabolism, or pathologies that indirectly alter drug processing through morphologic, histologic, or metabolic mechanisms.
  • compositions prepared for administration to a subject which include a therapeutically or diagnostically effective amount of one or more of the currently disclosed compounds.
  • the therapeutically effective amount of a disclosed compound will depend on the route of administration, the species of subject and the physical characteristics of the subject being treated or evaluated. Specific factors that can be taken into account include disease severity and stage, weight, diet and concurrent medications. The relationship of these factors to determining a therapeutically or spectroscopically effective amount of the disclosed compounds is understood by those of skill in the art.
  • a suitable dose for consideration will be in the range of analogous reverse transcriptase inhibitors, taking into account differences in potency in in vitro testing, generally from about 0.1 to 400 mg per kilogram body weight of the subject per dose, such as in a range between about 0.1 mg and about 250 mg/kg/dose in increments of 0.5 mg/kg/dose such as 2.5 mg/kg/dose, 3.0 mg/kg/dose, 3.5 mg/kg/dose, etc), typically in the range 0.5 to 50 mg per kilogram body weight per dose and most usually in the range 1 to 300 mg per kilogram body weight per dose.
  • the presently disclosed isotopically labeled reverse transcriptase inhibitors may be administered in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • compositions for administration to a subject can include carriers, thickeners, diluents, buffers, preservatives, surface active agents and the like in addition to the molecule of choice.
  • Pharmaceutical compositions can also include one or more active ingredients such as antimicrobial agents, anti- inflammatory agents, anesthetics, and the like.
  • Pharmaceutical formulations can include additional components, such as carriers.
  • the pharmaceutically acceptable carriers useful for these formulations are conventional. Remington 's Pharmaceutical Sciences, by E. W. Martin, Mack Publishing Co., Easton, PA, 19th Edition (1995), describes compositions and formulations suitable for pharmaceutical delivery of the disclosed compounds.
  • parenteral formulations usually contain injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle.
  • injectable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle.
  • physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like
  • solid compositions for example, powder, pill, tablet, or capsule forms
  • conventional non-toxic solid carriers can include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate.
  • compositions to be administered can contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate.
  • non-toxic auxiliary substances such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate.
  • an effective amount of the imaging agent such as from about 0.01 mCi to about 50 mCi, for example from about 0.1 mCi to about 30 mCi or from 1 to about 15 mCi may be combined with a pharmaceutically acceptable carrier for use in imaging studies.
  • an effective amount of the imaging agent refers to an amount sufficient to yield an acceptable image using equipment which is available for clinical use.
  • An effective amount of the imaging agent may be administered in more than one injection.
  • Effective amounts of the imaging agent of the invention will vary according to factors such as the degree of susceptibility of the individual, the age, sex, and weight of the individual, idiosyncratic responses of the individual and dosimetry. Effective amounts of the imaging agent of the invention also will vary according to instrument and film-related factors.
  • the radioactive dose allowed is dependent on the radiation exposure to individual organs. This value is first estimated by calculation from biodistribution data obtained from non-human primates. Optimization of such factors is well within the level of skill in the art.
  • the radioactive dose administered to a subject should be in the range of 1 to 100 mCi, preferably from about 5 to about 30 mCi or from about 5 to about 15 mCi and typically from about 2 to about 20 mCi, such as about 10 mCi for each application.
  • disclosed inhibitors are typically administered as an intravenous (IV) bolus.
  • IV intravenous
  • the subject fasts at least 4 hours prior to administration of the analogue.
  • the present analogues can be used in the detection and localization of retrovirus in a subject infected with a retrovirus, such as human immunodeficiency virus (HIV).
  • HIV human immunodeficiency virus
  • the compounds and methods disclosed herein have use in humans and non- human animals.
  • the presently disclosed isotopically labeled reverse transcriptase inhibitors are administered to cats, which may be infected with feline immunodeficiency virus (FIV).
  • FMV feline immunodeficiency virus
  • This example describes the synthesis of ( ⁇ )-Diethyl (l-(6-(tritylamino)-9H- purin-9-yl)-3-(trityloxy)propan-2-yloxy)methylphosphonate (5) as a single stereoisomer.
  • Alcohol 6 (500 mg, 1.39 mmol) was dissolved in 10 mL pyridine and treated with methanesulfonyl chloride (191 mg, 1.67 mmol). The reaction was followed by TLC. After one hour, an additional equivalent of methanesulfonyl chloride was added, followed an hour later by a third equivalent. The pyridine was evaporated; the residue dissolved in ethanol and preabsorbed onto 3.5 gram of silica gel. The material was chromatographed under the following program: 100 % ethyl acetate for 1 minute followed by a gradient over 20 minutes to 100 % (20% (10% NH 4 OH in ethanol) 80% EtOAc). The yield was 455 mg, 75 %. (The S-isomer was similarly obtained in 88% yield).
  • This example describes the synthesis of 18 F radio-labeled reverse transcriptase inhibitors R- or S- (l-(6-Amino-9H-purin-9-yl)-3-[ 18 F]fiuoropropan-2- yloxy)methylphosphonic acid (FPMPA, 9) as well as the corresponding 19 F standard compound.
  • the corresponding chiral methanesulfonates 7 were suspended in CH 3 CN and treated with 3 fold excess of tetramethylammonium bifluoride and heated at 80 °C for 3 hours until TLC indicated consumption of starting material.
  • the product was loaded onto a silica gel column and eluted with 90:9:1 (CHCl 3 :MeOH:NH 4 OH).
  • the major component 8 was dissolved in 0.5 mL DMF and treated with 10 equivalents of bromotrimethylsilane overnight. The DMF and excess bromotrimethylsilane were removed under vacuum, the residue taken up in water and the product precipitated with acetone. The products were about 85% pure by HPLC (Agilent XDB C-18, 85% (5 mM tetrabutylammonium phosphate) 15% CH 3 CN). Higher purity (98%) was obtained after preparative HPLC (Luna C- 18 2% ethanol in 50 mM NH 4 OAc of part of the sample. NMR indicated that the samples contained 1 to 2 equivalents of acetate after drying under vacuum.
  • the solution was loaded onto a short plug of silica gel in a Pasteur pipet; the tube was rinsed with 200 ⁇ L of 15%ethanol/CH3CN. This rinse was added to the column and together with the original solution pushed through the silica gel.
  • the column was further eluted with 600 ⁇ L 15% EtOH/CH 3 CN.
  • the eluate was evaporated under a stream of argon and the residue redissolved in 200 ⁇ L CH 3 CN and treated with 100 ⁇ L bromotrimethylsilane.
  • the resulting solution was heated at 75 °C for one minute then allowed to stand at room temperature for 4 minutes.
  • the solution was evaporated under an argon stream; taken up in HPLC eluant (200 ⁇ L) and injected onto a semipreparative HPLC system (Luna C-18(2) 10 x 250 mm; 2% EtOH, 98% 10 mM NaH 2 PO 4 , 5 mL/min). The peak eluting at about 14 minutes was collected. The radiochemical yield was -30-40% corrected for decay with a total required time of about 60 minutes. Radiochemical purity and specific radioactivity were determined by re-injection onto an analytical HPLC system (Agilent XDB C- 18, 85% (5 mM tetrabutylammonium phosphate) 15% CH 3 CN). Radiochemical purity was >95%. Specific radioactivity was > 1 Ci/ ⁇ mol.
  • This example describes determination of the inhibitory activity of the presently disclosed reverse transcriptase inhibitors.
  • the inhibitory activity of non- radiolabeled racemic (RS)-FVMPA and i ⁇ -PMPA was assessed in macaque peripheral blood mononuclear cells (PBMC) infected with SIVmac239.
  • PBMC peripheral blood mononuclear cells
  • the preparation and infection of macaque PBMC has been previously described by Igarashi T et al. Journal of Virology 2003, 77, 13042-13052; and Imamichi H. et al. Proceedings of the National Academy of Sciences of the United States of America 2002, 99, 13813-13818. Both the Igarashi et al. and Imamichi et al publications are incorporated herein by reference.
  • PBMC peripheral blood mononuclear cells
  • PBMC to assess virus replication by virion-associated reverse transcriptase (RT) assay (Willey et al. Journal of Virology 1988, 62, 139-147).
  • the inhibitory activity of J ⁇ -FPMPA and S-FPMPA was determined in human T- leukemic cells (MT4) (Harada S., Koyanagi Y. ,Yamamoto N., Science 1985, 229, 563-566). infected with SHIVDHI2R. Briefly, MT4 cells were cultured in RPMI 1640 enriched with 10% fetal bovine serum and infected with SHIV D HU R with virus stocks at MOI of 10 "3 . After 2 hours incubation, the cells were washed to remove unbound virions.
  • MT4 human T- leukemic cells
  • the infected cells were cultured for 7 days in the presence of different concentrations of R-FPMPA or S-FPMPA. Each assay was performed in triplicate. On day 7, p24 ELISA assay was performed on culture supernatant to determine viral burden (Zhang Y. M. et al. Journal of Virology 1997, 71, 6662-6670). For both assays, results were expressed as percentage of growth of the virus.
  • IC50 values are determined by non-linear regression analysis using the equation of a sigmoid plot. For each assay, the mean value of the replicates at different concentrations was fitted to the sigmoid curve using the Levenberg- Marquardt Algorithm (Gill P. E., Murray W., Wright M. H. Practical Optimization, Academic Press, London, 1981, pp. 136-137).
  • the best fit theoretical curve was then used to locate the IC 5 O, the concentration of the antiviral compound needed to inhibit 50% of viral growth.
  • the 95% confidence interval of ICs 0 is calculated by bootstrap method (Efron B., Tibshinari R. J. in The bootstrap estimate of standard error, Vol. (Ed. D. R. Cox), Chapman & Hall, New York, 1993, pp. 45-49).
  • the best fit theoretical curve is challenged by the original observed data (mean value of the replicates) by generating surrogate data, obtained by shuffling without replacement the residual difference between the theoretical and the observed data and adding the residual to the observed data. This procedure is repeated 1000 times, and the 95% bootstrap percentile interval is calculated from these bootstrap IC50s.
  • the P value of the difference between estimates of IC 50 in two independent plates was obtained from a permutation test on the distribution of the bootstrap values.
  • This example describes monitoring in vivo biodistribution of the disclosed radio-labeled reverse transcriptase inhibitors.
  • This example demonstrates that the F -labeled compound 9 prepared according to Example 6, mimics the biodistribution of PMPA after in vivo administration.
  • the (S)-[ 18 F]FPMPA was prepared from [18F]fluorxde as described in Example 6. Twelve male Sprague- Dawley rats (250-275 g) were co-injected intravenously through lateral tail vein with 5mg/kg of unlabeled PMPA in 125 ⁇ l, 5 ⁇ Ci of 14 C-PMPA in 50 ⁇ L and 200 ⁇ Ci Of(S)-[ 18 F]FPMPA in 71 ⁇ L.
  • the 12 rats were divided into 4 groups of 3 each and each group was sacrificed by carbon dioxide asphyxiation at 10, 30, 60 and 120 minutes after injection.
  • Samples of submandibular left/right, popliteal left/right and mesenteric lymph nodes, spleen, lungs, kidney, liver, jejunum, colon, Peyer's patches, brain, femur, testes and blood were removed.
  • the collected tissues were weighed into scintillation vials.
  • the [ 18 F]fluoride radioactive content of the blood and various tissues was assayed using automatic gamma counter (PerkinElmer, model 1480 Wallac Wizard).
  • the in vivo biodistribution data demonstrates that 14C-PMPA and (S)- [18F]FPMPA distribution is nearly identical in several organs including femur (tissue with high avidity for unbound fluoride) showing that 18F-fluoride is not a metabolite of FPMPA.
  • Drug accumulation also was observed in the kidneys, which might explain Tenofovir associated nephrotoxicity and demonstrates that the present compounds and methods may be used to determine dosages that avoid nephrotoxicity.
  • Example 10 This example describes the clinical use of the disclosed radio-labeled reverse transcriptase inhibitors.
  • the radio-labeled reverse transcriptase inhibitor is prepared shortly before use, typically within 2 hours of injection, and preferably within less than 1 hour.
  • the presently disclosed synthetic methods for preparing radio-labeled reverse transcriptase inhibitors is particularly facile and thus is uniquely suited to the preparation of 18 F-labeled compounds.
  • the radio-labeled reverse transcriptase inhibitor typically has an activity of at least about 0.1 mCi and typically from about 1 mCi to about 300 mCi, preferably from 2 to about 60 mCi, is injected into the subject as an intravenous bolus, typically within less than 5 minutes, and preferably in 1 minute.
  • An amount of the radio-labeled compound equal to the standard intravenous dose for tenofovir is administered that has an anti-retroviral effect without eliciting significant cytotoxic effects against peripheral blood mononuclear cells.
  • the intravenous dose achieves target tissue concentrations of 0.04-8.5 ⁇ mol/L.
  • an intravenous dose of from 1 mg/kg-3 mg/kg is given.
  • the subject is placed in a PET scanner, and images are obtained using standard techniques known in the art at 5- to 10-minute intervals following the injection, up to at least 60 minutes, preferably 90 minutes, when image quality is satisfactory. Imaging for hours or even a day or more also may be feasible. Variations and improvements in machine technology may permit longer imaging periods, which is desirable.
  • PET scanning can modify the method in such ways as changes and improvements in PET technology require or allow.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne des inhibiteurs de transcriptase inverse marqués de manière isotope, y compris des composés selon la formule (I) dans laquelle R1 et R2 sont sélectionnés indépendamment parmi H, un groupe alkyle inférieur, aralkyle et acyle, et Z1 et Z2 forment indépendamment un phosphoester ou un phosphoamide. Des procédés pour synthétiser de tels composés sous des formes optiquement pures et racémiques sont également décrits. Des procédés d'utilisation des composés marqués, par exemple dans la surveillance par tomographie par émission de positons (PET), de l'activité rétrovirale sont également décrits.
PCT/US2008/061664 2007-04-28 2008-04-25 Synthèse d'inhibiteurs de transcriptase inverse radiomarqués actifs optiquement WO2008134578A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US91473207P 2007-04-28 2007-04-28
US60/914,732 2007-04-28

Publications (2)

Publication Number Publication Date
WO2008134578A2 true WO2008134578A2 (fr) 2008-11-06
WO2008134578A3 WO2008134578A3 (fr) 2008-12-31

Family

ID=39577875

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2008/061664 WO2008134578A2 (fr) 2007-04-28 2008-04-25 Synthèse d'inhibiteurs de transcriptase inverse radiomarqués actifs optiquement

Country Status (1)

Country Link
WO (1) WO2008134578A2 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101928302A (zh) * 2010-04-29 2010-12-29 台州康多利海洋生物保健品有限公司 N-苄基-9-[2-(二烷基磷酰基甲氧基)烷基]腺嘌呤及其制备方法和应用
CN102885846A (zh) * 2011-07-18 2013-01-23 中国医学科学院医药生物技术研究所 2-硫代-6-氮杂尿苷在制备抗hiv-1病毒的药物中的应用
US9593137B2 (en) 2011-12-22 2017-03-14 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
US9908908B2 (en) 2012-08-30 2018-03-06 Jiangsu Hansoh Pharmaceutical Co., Ltd. Tenofovir prodrug and pharmaceutical uses thereof
WO2021055808A1 (fr) * 2019-09-20 2021-03-25 Abbott Rapid Diagnostics International Unlimited Company Anticorps dirigés contre le ténofovir et ses dérivés
US11791060B2 (en) * 2019-03-29 2023-10-17 Jubilant Draximage Inc. Elution protocols and dosages for radiopharmaceutical elution system

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KIESEWETTER ET AL: "Enantiomeric radiochemical synthesis of R and S (1-(6-amino-9H-purin-9-yl)-3-fluoropropan- 2-yloxy)methylphosphonic acid (FPMPA)" JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, vol. 51, 13 March 2008 (2008-03-13), pages 187-194, XP002487665 *
KIESEWETTER ET AL: "Labelling methods and radiosynthesis-Organic positron emitters; (P053) R AND S [18F]FPMPA: NUCLEOTIDE ANALOGUE REVERSE TRANSCRIPTASE INHIBITOR FOR BIODISTRIBUTION STUDIES" JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS SUPPLEMENT: 17TH INTERNATIONAL SYMPOSIUM ON RADIOPHARMACEUTICAL SCIENCES, vol. 50, no. S1, 11 April 2007 (2007-04-11), XP002487635 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101928302A (zh) * 2010-04-29 2010-12-29 台州康多利海洋生物保健品有限公司 N-苄基-9-[2-(二烷基磷酰基甲氧基)烷基]腺嘌呤及其制备方法和应用
CN102885846A (zh) * 2011-07-18 2013-01-23 中国医学科学院医药生物技术研究所 2-硫代-6-氮杂尿苷在制备抗hiv-1病毒的药物中的应用
US9593137B2 (en) 2011-12-22 2017-03-14 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
US10035814B2 (en) 2011-12-22 2018-07-31 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
US10562926B2 (en) 2011-12-22 2020-02-18 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
US11279720B2 (en) 2011-12-22 2022-03-22 Geron Corporation Guanine analogs as telomerase substrates and telomere length affectors
US9908908B2 (en) 2012-08-30 2018-03-06 Jiangsu Hansoh Pharmaceutical Co., Ltd. Tenofovir prodrug and pharmaceutical uses thereof
US11791060B2 (en) * 2019-03-29 2023-10-17 Jubilant Draximage Inc. Elution protocols and dosages for radiopharmaceutical elution system
WO2021055808A1 (fr) * 2019-09-20 2021-03-25 Abbott Rapid Diagnostics International Unlimited Company Anticorps dirigés contre le ténofovir et ses dérivés
CN114761014A (zh) * 2019-09-20 2022-07-15 雅培快速诊断国际无限公司 针对替诺福韦及其衍生物的抗体

Also Published As

Publication number Publication date
WO2008134578A3 (fr) 2008-12-31

Similar Documents

Publication Publication Date Title
ES2903097T3 (es) Formulación farmacéutica que comprende un derivado de fosforamidato de 5-fluoro-2'-desoxiuridina para su uso en el tratamiento del cáncer
ES2536972T5 (es) Profármacos de análogos de nucleótidos de fosfonato y métodos para seleccionar y preparar los mismos
EP2258376B1 (fr) Analogues phosphonates de composés inhibiteurs du VIH
WO2008134578A2 (fr) Synthèse d'inhibiteurs de transcriptase inverse radiomarqués actifs optiquement
CA2645859A1 (fr) Phosphonates de 2'-fluoronucleoside en tant qu'agents antiviraux
Hao et al. Design, synthesis, and activity evaluation of novel acyclic nucleosides as potential anticancer agents in vitro and in vivo
Koszytkowska-Stawińska et al. Synthesis and antiviral activity evaluation of acyclic 2′-azanucleosides bearing a phosphonomethoxy function in the side chain
Kiesewetter et al. Enantiomeric radiochemical synthesis of R and S (1‐(6‐amino‐9H‐purin‐9‐yl)‐3‐fluoropropan‐2‐yloxy) methylphosphonic acid (FPMPA)
Cavaliere Radiochemical synthesis of 18F-radiolabelled ProTides for Positron Emission Tomography
JP2022117326A (ja) プロドラッグ化合物
Velanguparackel Synthetic routes to the tumour proliferation biomarker FLT and ProTide analogues for PET imaging
JP3561272B6 (ja) 抗レトロウィルス性エナンチオマー性ヌクレオチドアナログ
JP3561272B2 (ja) 抗レトロウィルス性エナンチオマー性ヌクレオチドアナログ

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08746966

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08746966

Country of ref document: EP

Kind code of ref document: A2