WO2018100137A1 - Promédicaments de nucléoside triphosphate et d'analogues de nucléoside triphosphate - Google Patents

Promédicaments de nucléoside triphosphate et d'analogues de nucléoside triphosphate Download PDF

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WO2018100137A1
WO2018100137A1 PCT/EP2017/081140 EP2017081140W WO2018100137A1 WO 2018100137 A1 WO2018100137 A1 WO 2018100137A1 EP 2017081140 W EP2017081140 W EP 2017081140W WO 2018100137 A1 WO2018100137 A1 WO 2018100137A1
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substituted
unsubstituted
residue
independently
nucleoside triphosphate
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PCT/EP2017/081140
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Chris Meier
Tobias NACK
Thiago DINIS DE OLIVEIRA
Chenglong ZHAO
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Universität Hamburg
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Priority claimed from LU93331A external-priority patent/LU93331B1/en
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Priority to EP17821806.1A priority Critical patent/EP3548087A1/fr
Publication of WO2018100137A1 publication Critical patent/WO2018100137A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • A61K31/7068—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 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—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 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • A61K31/708—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 having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • 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
    • 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
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • 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
    • 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
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • 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

  • the invention relates to compounds that can be used as nucleoside triphosphate or nucleoside triphosphate analogue prodrugs.
  • nucleoside analogues are used, which can be incorporated into DNA.
  • the nucleoside analogues in general act as chain terminators, i.e. there is no further elongation in the 3'-direction (Balzarini, P. Herdewijn, E. De Clercq; Differential Patterns of intracellular Metabolism of 2 ' ,3 ' -Didehydro-2 ' ,3 ' -dideoxythymidine and 3 ' -Azido- 2 ' ,3 ' -dideoxythymidine, two potent Anti-human Immunodeficiency Virus Compounds; J. Biol. Chem. 1989, 264, 6127-6133).
  • NTP triphosphates
  • nucleoside analogues can not penetrate the cell membrane under physiological conditions due to their charge. It is also not possible to pass the blood brain barrier (BBB) to treat diseases affecting the brain.
  • BBB blood brain barrier
  • nucleoside analogues must either be intracellularly converted into their triphosphates by more or less specific kinases in several stages, or phosphorylated nucleoside analogues must be designed or modified so as to be able to pass through the cell membrane or BBB.
  • the lipophilicity of the drugs has usually to be increased (e.g. RJ Sawchuk, Z. Yang, Investigation of distribution, transport and uptake of anti-HIV drugs to the central nervous system, Advanced Drug Delivery Reviews 1999, 39, 5-31).
  • prodrug systems are precursors of an active agent, releasing the active agent at the desired site of action after biotransformation, e.g. detachment of masking groups.
  • further preconditions for prodrugs are sufficient stability in extracellular medium and the release of non-toxic masks.
  • Enzymatically activatable prodrug systems for nucleoside monophosphates (NMP) have already been described (A. Pompon, I. Lefebvre, J.-L. Imbach, S. Khan, D. Farquhar;
  • nucleoside monophosphate prodrug systems are known and are successfully applied, e.g. Sofosbuvir against Hepatitis C
  • the disadvantage of using NMP prodrugs is that the necessary subsequent phosphorylation to diphosphates and triphosphates in the cell can still be inhibited or completely suppressed.
  • NMP prodrugs a known anti-HIV drug
  • DP diphosphate
  • DP diphosphate
  • NTP nucleoside triphosphates
  • analogues thereof A suitable masking of nucleoside triphosphates (NTP) and analogues thereof is therefore desirable.
  • NTPs nucleoside triphosphates
  • NTPs in contrast to NMPs, in NTPs not only one phosphate group is present, but two energy-rich phosphoric acid anhydride bonds, which must be reversibly masked in the form of the pyrophosphate unit without causing a cleavage in the anhydride bond(s).
  • the pyrophosphate moiety When the pyrophosphate moiety is unmasked, no reaction must take place at the phosphorus atom as this can lead to a break in the pyrophosphate bridge. This essentially differentiates NDP and NTP prodrugs from their NMP relatives. Hydrolysis reactions on the phosphorus atom can also take place.
  • Nucleoside triphosphates may be dephosphorylated very rapidly intracellularly.
  • microbial (pathogen) polymerases viruseses, bacteria or parasites
  • cell-specific polymerases are also inhibited. This can potentially lead to a toxico logical problem.
  • WO 2009/129798 A2 describes symmetrically masked nucleoside diphosphates and triphosphates as well as a process for their preparation.
  • "Symmetric" in this context means that the masks used for masking the charges of the terminal phosphate have the same structure. However, it has been found that the percentage of the desired diphosphate or triphosphate species of the active ingredient released during the chemical or enzymatic hydrolysis depends on the rate of cleavage of the first mask releasing the monomasked intermediate.
  • the corresponding hydrolysis products of the pyrophosphate group were detected as a byproduct, the corresponding nucleoside monophosphates in the case of the nucleoside diphosphate prodrugs, and the corresponding nucleoside diphosphates and the nucleoside monophosphates in case of the nucleoside triphosphates. This ultimately results in a merely nonselective release of the desired target compounds.
  • nucleoside diphosphate analogue (l-[(2R,5S)-5-(hydroxymethyl)- 2,5-dihydrofuran-2-yl]-5-methylpyrimidine-2,4-dion, Stavudine, d4T) with a acyloxybenzyl group and a ⁇ -cyanoethyl group.
  • the ⁇ -cyanoethyl group was rapidly cleaved in biological media.
  • nucleoside and triphosphate compounds are described, which are bioreversibly non-symmetrically masked at the terminal phosphate group, one mask being more labile than the other and, thus, being cleaved more rapidly (see also L. Weinschenk, Anthony Schols, Jan Balzarini, Chris Meier, Nucleoside Diphosphate Prodrugs: Non- symmetric DiP ro-Nucleotides. J. Med. Chem. 2015, 58, 6114-6130).
  • nucleotide or nucleotide analogue prodrugs It is an object of the present invention to provide improved nucleotide or nucleotide analogue prodrugs.
  • the problem is solved according to the invention by a non-symmetric chemical modification of nucleoside triphosphate compounds, or analogues thereof, at the terminal phosphate group or the respective analogous group containing a ⁇ -phosphorus atom, one modification being covalently attaching an intracellularly labile moiety acting as a prodrug masking moiety, while the other modification is covalently attaching an intracellularly stable moiety, which is not supposed to be cleaved neither (photo-)chemically nor enzymatically within the cell.
  • the invention provides nucleotide or nucleotide analogue prodrugs, which are converted intracellularly to ⁇ -phosphate-mono-modified nucleotides or nucleotide analogues.
  • NTP nucleoside triphosphates
  • ⁇ -mono -modified NTPs or analogues thereof are released from the prodrug, which are stable in the intracellular environment.
  • the mono-modified compounds are particularly suitable for the selective inhibition of microbial or viral polymerases, e.g. reverse transcriptase of the human immunodeficiency virus.
  • the modification is carried out only at the terminal phosphate, i.e. at the ⁇ -phosphate. Additional modification of the internal phosphate(s) can be dispensed with.
  • nucleoside triphosphates with one methyl ester unit on the ⁇ -phosphate or an arylphosphonate instead of the ⁇ -phosphate of the nucleo- side triphosphates can be substrates for the viral HIV polymerase in primer extension assays.
  • mono-y-modified nucleoside triphosphates with small aliphatic or aromatic residues can lead to differentiation between different polyme- rases.
  • nucleoside triphosphates are much less or not at all recognized as a substrate by the human DNA polymerases (see, for example, LA Alexandrova, AY Skoblov, MV Jasko, LS Victorova, AA Krayevsky, 2'-Deoxy- nucleosides 5' -triphosphates modified at ⁇ -, ⁇ - and ⁇ -phosphates as substrates for DNA poly- merases, Nucleic Acids Res.
  • the present invention provides a nucleoside triphosphate or nucleoside triphosphate analogue prodrug, or a pharmaceutically acceptable salt thereof, having covalently bound to its terminal phosphate or analogous group a lipophilic moiety A and a lipophilic moiety B, the lipophilic moieties A and B being different from each other, A being an intracellular stable lipophilic moiety, and B being an intracellular labile lipophilic moiety.
  • the nucleoside triphosphate or nucleoside triphosphate analogue prodrug according to the first aspect of the invention is cell-penetrating and permits the intracellular release of an active compound, for example an antivirally or an antitumoral active compound.
  • the moieties A and B at the terminal phosphorus atom differ by their stability within the cell.
  • One of the moieties is intracellularly labile (and is therefore also called mask), for example enzymatically cleavable, e.g. by means of esterases, while the other moiety is intracellularly stable, so that after e.g. enzymatic cleavage of the labile moiety (mask) in the cell a mono-modified nucleotide or nucleotide analogue results.
  • the resulting stably mono-modified compound has high resistance to nucleophilic attack on the phosphoanhydride bond(s) and enzymatic cleavage of the stable moiety A.
  • Both the mask B and the moiety A are lipophilic and thus ensure the necessary lipophilicity in order to ensure entry into the cell.
  • the adjustment of the lipophilicity of these two moieties is known to a person skilled in the art and can, if necessary, be determined by routine experimentation.
  • the lipophilicity of the mask (moiety B) and the stable moiety A can be manipulated by the size or length of a hydrocarbon residue.
  • the stability of the moieties can also be influenced, for example, by the incorporation of heteroatoms.
  • a suitable stable modification at the ⁇ -phosphorus atom of a nucleoside triphosphate or analogue also allows a differentiation in the property of the mono-modified compound resulting after removal of the mask to function as a substrate of microbial/viral and endogenous polymerases.
  • Particularly advantageous is, for example, a ⁇ -mono -modified nucleoside triphosphate analogue, which is used at least predominantly or specifically only by microbial/viral polymerases and not or insignificantly by endogenous polymerases as substrate, as a result of which possible adverse effects on the cell can be avoided or reduced.
  • nucleoside triphosphates and analogues thereof can be introduced directly into the cell, in which they will be released and can also be enriched in a stably mono-modified form so that they can directly be used as a substrate of e.g. viral polymerases.
  • side effects which are caused, for example, by monophosphates can be avoided.
  • R A/DNA e.g. by the mitochondrial DNA polymerase ⁇ .
  • the compounds according to the invention can, for example, find advantageous use in medicinal products both as antiviral and as antitumoral agents. They are particularly suitable as drugs for the treatment of infections by viruses, in particular retroviruses such as HI viruses, influenza, hemorrhagic fever and hepatitis viruses.
  • the intracellularly stable moiety A is thus preferably selected in such a way that it particularly provides for a specificity of the mono-modified compound, i.e. the compound having only the stable moiety A, as a substrate for, for example, viral/microbial enzymes, preferably polymerases, for example reverse transcriptases (EC 2.7.7.49), such as those of the HI virus.
  • the intracellularly for example enzymatically cleavable mask B ensures in particular for sufficient cell uptake of the original dimodified compound and the intracellular formation of the mono-modified compound.
  • the stable moiety A also preferably improves cell membrane penetration by virtue of its lipophilicity.
  • the compounds according to the invention are generally present as salts under physiological conditions.
  • a triphosphate compound or triphosphate analogue la is shown by way of example, where Cat + means cation, for example ammonium, sodium or potassium cation.
  • Nucl stands for nucleoside or nucleoside analogue.
  • nucleoside triphosphate or nucleoside triphosphate analogue refers to nucleoside triphosphates or analogues thereof, a nucleoside triphosphate being a compound according to the following general formula VI
  • nucleoside triphosphate analogue being an analogue of a nucleoside triphosphate.
  • Nucleoside triphosphates are composed of a base component (nucleobase), a sugar component, e.g. a pentose like ribose or deoxyribose, and a triphosphate residue (sometimes also termed “triphosphate bridge") attached to an O atom of the sugar component, e.g. an O atom bound to the 5' atom of a pentose.
  • triphosphate analogue refers to compounds not being triphosphates in a strict sense, because they do not contain three phosphate groups, i.e. groups having a phosphorus atom bound to four oxygen atoms, but contain groups analogous to phosphate groups, e.g. phosphonate groups, instead of one or two phosphate groups.
  • nucleoside triphosphate analogue is a chemical compound, which is structurally and/or functionally similar to a nucleoside triphosphate such that an enzyme, e.g. a viral polymerase, having a nucleoside triphosphate naturally occurring in, for example, a human cell as a substrate would also use said compound as a substrate, analogous to the naturally occurring nucleoside triphosphate.
  • a nucleoside triphosphate analogue may, in relation to a naturally occurring nucleoside triphosphate, be modified in one, two or in each of the above-mentioned components, i.e. the base component, the sugar component or the triphosphate component.
  • terminal phosphate or analogous group refers to the terminal or ⁇ -phosphate ( ⁇ - phosphoryl) group of the triphosphate group, or to the group, e.g. phosphonate, phosphoro- thioate, phosphoroselenoate or boranophosphate group, being analogous to the terminal phosphate group, i.e. the terminal group not being a phosphate group but containing a phosphorus atom.
  • ⁇ -phosphorus atom as used herein relates to the phosphorus atom of the terminal phosphorus containing group of the triphosphate component or the component being analogous thereto.
  • a "non-symmetrically modified nucleoside triphosphate or nucleoside triphosphate analogue prodrug” is understood to mean a nucleoside triphosphate or nucleoside triphosphate analogue being twice, but non-symmetrically, modified at the ⁇ -phosphorus atom thereof, by covalently attaching two different lipophilic groups A and B at the group containing the ⁇ -phosphorus atom.
  • Group B is an intracellularly labile moiety
  • group A is intracellularly stable moiety.
  • a non-symmetrically modified nucleoside triphosphate or nucleoside triphosphate analogue prodrug may thus be a compound according to the following general formula I
  • a and B stand for different chemical structures
  • U is, independently from each other, O, S, Se, or BH 3 , for example O
  • V is, independently from each other, O, CH 2 , NH, CHF, CHC1, CHBr, CF 2 , CC1 2 , CBr 2 or CFC1, for example O
  • R 1 is nucleoside or nucleoside analogue.
  • the terminal phosphorus atom i.e. the ⁇ -phosphorus atom, thus forms a stereogenic centre.
  • the chemical structures A, B neutralize the negative electric charges at the single- bonded oxygen atoms of the terminal phosphate under physiological conditions.
  • an oxygen atom otherwise bound to the terminal phosphorus atom can also be replaced by S or NH.
  • the two organic groups A and B themselves are also not charged under physiological conditions.
  • the term "mono -modified" used here in relation to a nucleoside triphosphate or nucleoside triphosphate analogue exclusively relates to compounds comprising the intracellularly stable moiety A only at the terminal phosphate or the group analogous to the terminal phosphate group, e.g. a terminal phosphonate group.
  • mono-modified triphosphate compounds or triphosphate analogues are released within a cell, e.g. a mammalian cell, by cellular activity, e.g.
  • a compound of the invention having, at the terminal phosphate or analogues group, both an intracellularly stable moiety A and an intracellularly labile moiety (mask) B.
  • the latter compounds i.e. triphosphate compounds or analogues thereof carrying, at their terminal phosphate or analogous group, both the mask B and the stable moiety A, may be referred to as being "dimodified” or as being “monomasked plus mono-modified".
  • intracellularly labile group is understood here to be a chemical group which is, e.g. hydrolytically, cleavable under conditions prevailing in a target cell, preferably a eukaryotic, for example human cell, for example in terms of temperature, pH, salt content, etc., with the aid of enzymes present or, as the case may be, inducible in the target cell.
  • a target cell preferably a eukaryotic, for example human cell, for example in terms of temperature, pH, salt content, etc., with the aid of enzymes present or, as the case may be, inducible in the target cell.
  • the term also encompasses photolabile, i.e. photocleavable moieties, e.g. groups that can be cleaved by irradiation with UV or near-UV light.
  • the term also encompasses those cases in which a mask is degraded in several steps, for example cascade-like, and at least one degrading step takes place
  • a moiety is considered to be intracellularly labile, if the compound masked therewith has a comparatively low half-life in the cell, for example a half-life of ⁇ 4 h, preferably ⁇ 3 h, ⁇ 2 h, ⁇ 1 h, ⁇ 45 min or ⁇ 30 min.
  • an “intracellularly stable moiety” which may also be referred to as “intracellularly stable modification”, “intracellularly stable group”, “intracellularly stable protecting group” or similar terms, is to be understood a modification which is not or at least essentially not cleaved under intracellular conditions, and which is also not cleaved photo chemically.
  • an “intracellularly stable moiety” is understood to be an intracellularly stable modification if the compound modified with it has a high half-life in the cell, for example a half-life of >24 h, preferably >36, >48, >60, >72, >84, >96, >108 or >120 h.
  • nucleoside organic molecules consisting of a sugar residue (sugar component) linked to an organic base (base component), e.g. a heterocyclic organic base, in particular a nitrogen-containing heterocyclic organic base (nucleobase), which are linked via a glycosidic bond.
  • base component e.g. a heterocyclic organic base, in particular a nitrogen-containing heterocyclic organic base (nucleobase), which are linked via a glycosidic bond.
  • base component e.g. a heterocyclic organic base, in particular a nitrogen-containing heterocyclic organic base (nucleobase), which are linked via a glycosidic bond.
  • base component e.g. a heterocyclic organic base, in particular a nitrogen-containing heterocyclic organic base (nucleobase), which are linked via a glycosidic bond.
  • the sugar moiety is often a pentose, e.g. deoxyribose or ribose, but may also be another
  • nucleoside is therefore a compound of the following general formula
  • B is a nitrogen-containing heterocyclic organic base, e.g. a nucleobase
  • R 2 and R 3' are, independently from each other, H or OH.
  • Phosphorylated nucleosides for example nucleoside monophosphates (NMP), nucleoside diphosphates (NDP) and nucleoside triphosphates (NTP), are also referred to as nucleotides.
  • NMP nucleoside monophosphates
  • NDP nucleoside diphosphates
  • NTP nucleoside triphosphates
  • pyrophosphate or triphosphate group is generally linked to the O atom attached to the 5'-C atom of the sugar component of the nucleoside.
  • the invention also encompasses compounds in which the phosphate group(s) is(are) bound to a 2'- or 3'-OH group.
  • nucleoside analogue (or “nucleoside analog”) is to be understood here as an organic compound which is naturally not present in the human body but which is structurally similar to a nucleoside occurring naturally in the human body so that it can be used, for example, by the cell and/or viral enzymes essentially corresponding to the natural nucleoside, for example phosphorylated and incorporated into an RNA or DNA strand.
  • a nucleoside analogue can itself be a nucleoside.
  • nucleoside analogue may also be another compound having the above characteristics, for example a compound of a heterocyclic base and an acyclic residue and/or a residue which is not a sugar, or a compound of a carbocyclic compound and a heterocyclic base.
  • carbocyclic nucleoside analogues for example, the ring oxygen in the sugar component is replaced by a carbon (a methylene group or a substituted methylene group).
  • a carbon atom may also be replaced by a heteroatom, for example the 3 '-carbon atom by sulfur.
  • the 5' hydroxyl group of the sugar component may be replaced by another group, e.g. an amino group, or substituted.
  • a nucleoside analogue may also be composed of a sugar like ribose or deoxyribose and a nucleobase analogue.
  • nucleobase analogues examples include 5-bromouracil, 6-azathymine, 5-fluorouracil and N 6 - hydroxy adenine.
  • Nucleoside analogues are either themselves nucleosides in the above sense or structurally and/or functionally analogous to nucleosides. Since nucleoside analogues do not necessarily have to contain a sugar or base component in the narrow sense, the terms
  • nucleoside analogue component analogous to the (naturally occurring nucleo)base
  • sugar analogue component analogous to the sugar component
  • sugar analogue component analogous to the sugar component
  • AZT 3'-azido-2',3'-dideoxythimidine, azidothymidine
  • 2',3'-dideoxyinosine didanosine
  • 2',3'-dideoxycytidine zalticabine
  • P-L-2',3'-dideoxythiacytidine (lamivudine, 3TC)
  • L- thymidine 2'-methyl-("up")-2'-hydroxyl-("down")-uridine/-cytidine
  • 2'-Methyl-( neglectup")-2'- fluoro-( structuridown")-uridine/-cytidine see, for example, US Pat. No.
  • Nucleoside analogues which inhibit reverse transcriptase from retroviruses such as human immunodeficiency virus (HIV) are also referred to as NRTIs (nucleoside reverse transcriptase inhibitors).
  • HIV human immunodeficiency virus
  • nucleoside phosphate analogue is understood to mean an analogue to a phosphorylated nucleoside, i.e. a nucleotide analogue.
  • nucleoside monophosphate analogue is, for example, understood to mean an analogue to a nucleoside monophosphate.
  • nucleoside monophosphate analogues examples include nucleoside phosphonates, such as, for example, 3- hydroxy-2-phosphonomethoxypropyl (HPMP), 2-phosphonomethoxyethyl (PME), 2',3'- didehydro-2',3'-dideoxythymidine phosphonate (d4TP), (S)9-(3-hydroxy-2- phosphonylmethoxypropyl) adenine (HPMP A) and 9-(2-phosphonylmethoxyethyl) adenine (PMEA, adefovir).
  • HPMP 3- hydroxy-2-phosphonomethoxypropyl
  • PME 2-phosphonomethoxyethyl
  • d4TP didehydro-2',3'-dideoxythymidine phosphonate
  • S 9-(3-hydroxy-2- phosphonylmethoxypropyl) adenine
  • PMEA 9-(2-phosphonyl
  • Nucleoside phosphonates are known to the person skilled in the art, contain a C-P linkage instead of the P-0 linkage of nucleoside phosphates, and can contain, for example, a nucleobase, an acyclic or cyclic aliphatic sugar-analogous component and a phosphonomethyl group CH 2 P(0)(OH) 2 group (see, for example, Pertusati et 2012, Medicinal Chemistry of Phosphonate Prodrugs for Antiviral Therapy, Antivir. Chem. Chem. 22: 181-203, doi: 10.3851 / IMP2012).
  • Phosphorylated nucleoside analogues for example phosphorylated nucleosides with a modified nucleobase, also fall under the terms “nucleoside phosphate analogue” or “nucleotide analogue.”
  • Nucl encompasses both nucleosides and nucleoside analogues.
  • NMP encompass not only nucleoside monophosphates, nucleoside diphosphates and nucleoside triphosphates, but also
  • nucleoside monophosphate analogues i.e. nucleoside monophosphate analogues, nucleoside diphosphate analogues and nucleoside triphosphate analogs, unless explicitly stated otherwise.
  • the indication of a range such as " 1-10", for example, is to be understood as meaning that each intermediate value is also disclosed.
  • an indication which can only affect integers such as, for example, a number of C atoms
  • any narrower range from a broader range is also meant to be disclosed by indicating the broader range, the narrower range also including ranges not comprising any of the boundary values of the broader range (e.g. a range of 2-5 from a range of 1-10).
  • C n -C m or "C n _ m ", where n and m are each positive integers and m is greater than n, means a range indicating the number of carbon atoms of a compound or residue.
  • the expression here expressly includes all integer intermediate values between the range boundaries n and m, in each case independently of one another.
  • “C 1 -10” therefore also comprises, for example, "C 2 _6 M , i.e.
  • this also applies to terms such as "C 2-10 alkenyl", “C4-20 alkenynyl", and the like.
  • aliphatic residue comprises cyclic or acyclic linear (straight chain) or branched, saturated or unsaturated carbon compound residues, other than aromatic residues.
  • heteroaliphatic residue means aliphatic residues in whose carbon skeleton one or more C atoms are replaced by heteroatoms, for example oxygen, sulfur, nitrogen or phosphorus.
  • alkyl comprises saturated aliphatic (non-aromatic) groups including straight-chain (linear) alkyl groups (e.g. methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl), and branched alkyl groups (e.g. isopropyl, tert-butyl, isobutyl).
  • linear alkyl groups e.g. methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl
  • branched alkyl groups e.g. isopropyl, tert-butyl, isobutyl.
  • O, N, S or P alkyl groups e.g., -O-methyl
  • alkyl groups which are bound to a compound via an oxygen, nitrogen, sulfur or phosphorus atom.
  • alkenyl comprises unsaturated aliphatic (non-aromatic) groups having at least one C-C double bond, including straight-chain and branched alkenyl groups.
  • the term also includes 0-, N-, S- or P-alkenyl groups (e.g., -O-propenyl), i.e. alkenyl groups bound to a compound via an oxygen, nitrogen, sulfur or phosphorus atom.
  • alkynyl (or “alkinyl”) includes unsaturated aliphatic (non-aromatic) groups having at least one C-C triple bond, including straight-chain and branched alkynyl groups.
  • alkenynyl (or “alkeninyl”) includes unsaturated aliphatic (non-aromatic) groups having at least one C-C double bond and at least one C-C triple bond, including straight-chain and branched alkenynyl groups.
  • alkenynyl includes unsaturated aliphatic (non-aromatic) groups having at least one C-C double bond and at least one C-C triple bond, including straight-chain and branched alkenynyl groups.
  • the term also includes 0-, N-, S-, or P-alkenynyl groups, i.e. alkenynyl groups bound to a compound via an oxygen, nitrogen, sulfur or phosphorus atom.
  • cycloalkyl includes compounds containing an alicyclic group, i.e. a ring-shaped saturated aliphatic (non-aromatic) group, e.g. cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl group.
  • the term also includes 0-, N-, S- or P-cycloalkyl groups, i.e. cycloalkyl groups bound to a compound via an oxygen, nitrogen, sulfur or phosphorus atom.
  • cycloalkenyl means correspondingly ring- shaped aliphatic (non-aromatic) alkenyls, alkynyls or alkenynyls as defined above, the double and/or triple bond(s) being present within or outside the ring or ring system.
  • heteroalkyl refers to alkyl groups in which one or more carbon atoms of the hydrocarbon structure are replaced by other atoms (heteroatoms), e.g. oxygen, nitrogen, sulfur or phosphorus atoms.
  • heteroatoms e.g. oxygen, nitrogen, sulfur or phosphorus atoms.
  • the term also includes 0-, N-, S- or P-heteroalkyl groups, i.e.
  • heteroalkyl groups which are bound to a compound via an oxygen, nitrogen, sulfur or phosphorus atom.
  • heteroalkyl also includes cycloalkyls in which one or more carbon atoms of the hydrocarbon structure are replaced by other atoms, e.g. oxygen, nitrogen, sulfur or phosphorus atoms.
  • heteroalkenyl means corresponding alkenyls, alkynyls and alkeninyls, as well as cycloalkenyls, cycloalkynyls and cycloalkeninyls, in which one or more carbon atoms of the hydrocarbon skeleton are replaced by other atoms (heteroatoms), e.g. oxygen, nitrogen, sulfur or phosphorus atoms.
  • Ci_2o-heteroalkyl means an alkyl group having 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms and at least one heteroatom.
  • aryl are meant groups with aromaticity, including multi-membered aromatic single ring groups and multicyclic systems with at least one aromatic ring. Examples of aryl groups include benzene, phenyl and naphthalene.
  • the term also includes 0-, N-, S- or P-aryl groups, i.e.
  • heteroaryl aryl groups bound to a compound via an oxygen, nitrogen, sulfur or phosphorus atom.
  • heteroaryl are meant aryl groups having at least one heteroatom in the ring structure, i.e. in which one or more carbon atoms in the ring structure are replaced by other atoms
  • heteroatoms e.g. b oxygen, nitrogen, sulfur or phosphorus atoms.
  • heteroaryls are pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, pyridine, pyrazine, pyridazine and pyrimidine.
  • the term also includes multicyclic, e.g. bicyclic and tricyclic, aryl groups, e.g.
  • benzoxazole benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, indole, benzofuran, purine or benzofuran.
  • the term also includes 0-, N-, S- or P-heteroaryl groups, i.e. heteroaryl groups bound to a compound via an oxygen, nitrogen, sulfur or phosphorus atom.
  • halogen is meant chlorine (CI), fluorine (F), bromine (Br) and iodine (I), particular chlorine (CI) and fluorine (F).
  • substituted means that one or more substituents are present, which replace a hydrogen atom on one or more carbon atoms of the hydrocarbon structure or on one or more heteroatoms in the carbon skeleton.
  • substituents are oxo, hydroxyl, phosphate, cyano, azido and amino groups, but also e.g. halogens (e.g., F, CI, Br), acyl, acyloxy, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl and heteroaryl groups.
  • halogens e.g., F, CI, Br
  • acyl acyloxy, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl and heteroaryl groups.
  • substitution also the terms "residue” or "moiety” may be used here.
  • Electron acceptor is understood here to be a compound, compound residue or functional group which accepts, attracts or withdraws electrons and thus causes a charge displacement, i.e. a polarization, in a compound.
  • a nucleoside triphosphate or nucleoside triphosphate analogue according to the first aspect of the invention preferably is a compound according to the following general formula I
  • a and B are different lipophilic moieties, A being an intracellular stable lipophilic moiety, and
  • U is, independently from each other, O, S, Se, or BH 3 , preferably O,
  • V is, independently from each other, O, CH 2 , NH, CHF, CHC1, CHBr, CF 2 , CC1 2, CBr 2 or
  • CFC1 preferably O
  • nucleoside or nucleoside analog preferably nucleoside analog
  • a nucleoside triphosphate or nucleoside triphosphate analogue according to this preferred embodiment has a structure according to the following general formula la:
  • the residue R 1 is, in the case of a nucleoside or nucleoside analogue, preferably bound via the sugar component or the component analogous to the sugar component, for example via an oxygen atom, e.g. the oxygen atom bound to the 5'-C atom of a pentose.
  • the residue may, however, also be bound to the phosphorus atom via a C atom, preferably a C atom of the sugar component or sugar component analogue, e.g. a 5'-C atom of a pentose or pentose analogue, thus forming a phosphonate group, or via another suitable atom or group, e.g. NH or S.
  • the residue R 1 may, for example, also be bound via an oxygen atom at the 2'- or 3'-carbon atom of a pentose.
  • A is a residue according to formula II
  • R A1 , R A2 and R A4 are, independently from each other, H, a substituted or unsubstituted cyclic, acyclic, linear or branched aliphatic or heteroaliphatic residue, or a substituted or unsubstituted aromatic or heteroaromatic residue, or an electron acceptor,
  • Z is Y or CR A6 R A7 Y, Y being O, S, NH or CR A9 R A10 , and wherein R , R , R and R are, independently from each other, H, a substituted or unsubstituted cyclic, acyclic, linear or branched aliphatic or heteroaliphatic residue, or a substituted or unsubstituted aromatic or heteroaromatic residue, or an electron acceptor,
  • R A3 and R A5 are, independently from each other, H or C(X)R A8 , but are not both H, wherein X is O, S or NH, and
  • R A8 is a substituted or unsubstituted cyclic, acyclic, linear or branched aliphatic or
  • heteroaliphatic residue or a substituted or unsubstituted aromatic or heteroaromatic residue, or
  • A is a substituted or unsubstituted cyclic, acyclic, linear or branched aliphatic or
  • heteroaliphatic residue or a substituted or unsubstituted aromatic or heteroaromatic residue.
  • Non-limiting examples of electron acceptors are N0 2 , CN, SO 3 H, ketone, and halogen.
  • a compound according to the invention can thus, for example, be a compound according to the following general formulas Ibl or Ib2:
  • Y can be O, S, NH or CR R , and is preferably O.
  • the residues R , R and R are, in a compound according to the above formula I, independently from each other H, a substituted or unsubstituted cyclic, acyclic, linear or branched Ci_ 2 o aliphatic or Ci_ 2 o heteroaliphatic residue, or a substituted or unsubstituted C 5 - 2 o aromatic or C 3 - 2 o heteroaromatic residue, or an electron acceptor, especially preferred, independently from each other, H, a substituted or unsubstituted cyclic, acyclic, linear or branched Ci_io aliphatic or Ci_io heteroaliphatic residue, or a substituted or unsubstituted C 5 _ 12 aromatic or C 3 -12 heteroaromatic residue, or an electron acceptor.
  • R A1 , R A2 and R A4 are, in a compound of the invention according to the formula I above, independently from each other selected from the group consisting of H, substituted or unsubstituted Ci_ 2 o alkyl, substituted or unsubstituted C 2 _ 20 alkenyl, substituted or unsubstituted C 2 _ 2 o alkynyl, substituted or unsubstituted C 4 -20 alkenynyl, substituted or unsubstituted C 3 -20 cycloalkyl, substituted or unsubstituted C 3 -20 cycloalkenyl, substituted or unsubstituted C 5 -20 cycloalkynyl, substituted or unsubstituted C 5 -20 cycloalkenynyl, substituted or unsubstituted Ci_ 2 o heteroalkyl, substituted or unsubstituted C 2 _ 20 heteroalkenyl, substituted or unsubstituted
  • R A1 , R A2 and R A4 are, in a compound of the invention according to the formula I above, independently from each other selected from the group consisting of H, substituted or unsubstituted Ci_io alkyl, substituted or unsubstituted C 2 _io alkenyl, substituted or unsubstituted C 2 _io alkynyl, substituted or unsubstituted C 4 -10 alkenynyl, substituted or unsubstituted C 3 -10 cycloalkyl, substituted or unsubstituted C 3 -10 cycloalkenyl, substituted or unsubstituted C 5 -10 cycloalkynyl, substituted or unsubstituted C 5 -10 cycloalkenynyl, substituted or unsubstituted Ci_io heteroalkyl, substituted or unsubstituted C 2 _io heteroalkenyl, substituted or unsubstituted Ci
  • R A8 Preferably, R A8
  • i. is a substituted or unsubstituted cyclic, acyclic, linear or branched Ci_ 2 o aliphatic or Ci_ 2 o heteroaliphatic residue, or a substituted or unsubstituted C5-20 aromatic or C3-20 heteroaromatic residue, or ii. is a substituted or unsubstituted cyclic, acyclic, linear or branched Ci_io aliphatic or Ci_io heteroaliphatic residue, or a substituted or unsubstituted C 5 _ 12 aromatic or C3-12 heteroaromatic residue, or
  • iii. is selected from the group consisting of substituted or unsubstituted Ci_ 2 o alkyl, substituted or unsubstituted C2-20 alkenyl, substituted or unsubstituted C2-20 alkynyl, substituted or unsubstituted C4-20 alkenynyl, substituted or unsubstituted C3-20 cycloalkyl, substituted or unsubstituted C3-20 cycloalkenyl, substituted or unsubstituted C5-20 cycloalkynyl, substituted or unsubstituted C5-20 cycloalkenynyl, substituted or unsubstituted Ci_ 2 o heteroalkyl, substituted or unsubstituted C2-20 heteroalkenyl, substituted or unsubstituted C2-20 heteroalkynyl, substituted or unsubstituted C4-20 hetero alkenynyl, substituted or unsubstituted C5
  • i. are, independently from each other, H, a substituted or unsubstituted cyclic, acyclic, linear or branched Ci_ 2 o aliphatic or Ci_ 2 o heteroaliphatic residue, a substituted or unsubstituted C5-20 aromatic or C3_ 2 o heteroaromatic residue, or an electron acceptor, or
  • ii. are, independently from each other, H, a substituted or unsubstituted cyclic, acyclic, linear or branched Ci_io aliphatic or Ci_io heteroaliphatic residue, or a substituted or unsubstituted C 5 _ 12 aromatic or C3_i 2 heteroaromatic residue, or an electron acceptor, or
  • iii. are, independently from each other, selected from the group consisting of H, substituted or unsubstituted Ci_ 2 o alkyl, substituted or unsubstituted C2-20 alkenyl, substituted or
  • iv. are, independently from each other, selected from the group consisting of H, substituted or unsubstituted Ci_io alkyl, substituted or unsubstituted C 2 _ 10 alkenyl, substituted or
  • v. are all H, or
  • the moiety A i. is a substituted or unsubstituted cyclic, acyclic, linear or branched Ci_ 2 o aliphatic or Ci_ 2 o heteroaliphatic residue, or a substituted or unsubstituted C5-20 aromatic or C3-20 heteroaromatic residue, or
  • ii. is a substituted or unsubstituted cyclic, acyclic, linear or branched Ci_io aliphatic or Ci_io heteroaliphatic residue, or a substituted or unsubstituted C 5 _ 12 aromatic or C3-12 heteroaromatic residue, or
  • iii. is selected from the group consisting of substituted or unsubstituted Ci_ 2 o alkyl, substituted or unsubstituted C2-20 alkenyl, substituted or unsubstituted C2-20 alkynyl, substituted or unsubstituted C4-20 alkenynyl, substituted or unsubstituted C3-20 cycloalkyl, substituted or unsubstituted C3-20 cycloalkenyl, substituted or unsubstituted C5-20 cycloalkynyl, substituted or unsubstituted C5-20 cycloalkenynyl, substituted or unsubstituted Ci_ 2 o heteroalkyl, substituted or unsubstituted C2-20 heteroalkenyl, substituted or unsubstituted C2-20 heteroalkynyl, substituted or unsubstituted C4-20 heteroalkenynyl, substituted or unsubstituted C5
  • the moiety A may be bound via a heteroatom, e.g. an O, N or S atom, or via a C atom to the terminal phosphorus atom.
  • a heteroatom e.g. an O, N or S atom
  • C atom to the terminal phosphorus atom.
  • Moiety A is not a ⁇ -cyanoethyl group -0(CH 2 ) 2 CN.
  • an alkyl or other residue may, however, also be directly attached to the terminal phosphorus atom, i.e. via a C-atom of the residue, as shown below.
  • Z is CR A6 R A7 Y, wherein Y is O, S or NH, preferably O, the residues R A1 , R A2 , R A4 , R A5 , R A6 and R A7 are each H, and R A3 is C(X)R A8 , wherein X is O, S or NH, preferably O, and wherein R A8 is as defined above.
  • R B1 , R B2 and R B4 are, independently from each other, H, a substituted or unsubstituted cyclic, acyclic, linear or branched aliphatic or heteroaliphatic residue, or a substituted or unsubstituted aromatic or heteroaromatic residue, or an electron acceptor
  • R and R are, independently from each other, H, a substituted or unsubstituted cyclic, acyclic, linear or branched aliphatic or heteroaliphatic residue, or a substituted or unsubstituted aromatic or heteroaromatic residue, or an electron acceptor
  • R B3 and R B5 are, independently from each other, H or WC(X)R B8 , but are not both H, wherein W and X are, independently from each other, O, S or NH, preferably both O, and
  • R B8 is a substituted or unsubstituted cyclic, acyclic, linear or branched aliphatic or
  • heteroaliphatic residue or a substituted or unsubstituted aromatic or heteroaromatic residue.
  • Non-limiting examples of electron acceptors are N0 2 , CN, SO 3 H, ketone, and halogen.
  • W and X are, independently from each other, O, S or NH, preferably both O.
  • the compound of the invention has a structure according to the following general formula (Id):
  • residues R A1 , R A2 , R A4 , R B1 , R B2 and R B4 , and preferably also the residues R B6 and R B7 are all the same, preferably all H.
  • residues R A5 and R B5 are also each H, has, for example, the structure according to the following general formula Ie:
  • residues R Ai and R Bi can be each H and the residues R A5 and R 1
  • R A5 can, for example, be C(X)R A8 and R ⁇ can, for example, be W(X)R B8 .
  • W and X can, independently from each other, and in case of X also independently for any occurrence of X, be O, S or NH.
  • W and X are each O.
  • the residue R is
  • W and X can, independently from each other, and in case of X also independently from any occurrence of X, be O, S or NH. Preferably W and X are each O.
  • the two moieties "A” and “B” differ only in the residues R A3 and/or R A5 as well as R B3 and/or R B5 .
  • Z is CR A6 R A7 Y, where Y is O.
  • the residues R A1 and R B1 , R A2 and R B2 , R A4 and R B4 as well as the residues R A6 and R B6 , and the residues R A7 and R B7 are identical among each other, particularly preferably all H.
  • the two moieties differ only in their residues R A3 and R B3 or only in their residues R A5 and R B5 , particularly preferably only in their residues R A3 and R B3 .
  • Such a preferred embodiment has, for example, the structure according to the general formula Ig:
  • R A3 and R B3 are both not H.
  • R A3 is preferably C(X)R A8 , the bond to the phenyl ring being via C, and the residue R is preferably W(X)R B5 , the bond to the phenyl ring being
  • X is preferably, for each of the residues R and R ai independently from each other, O, S or NH, and W in the residue R is preferably O, S or NH.
  • W in the residue R is preferably O, S or NH.
  • X and W are each O.
  • the residues R or R can have the general structure IV shown in the following to the left, and the residues R B3 or R B5 have the general structure V shown in the following on the right:
  • acylbenzyl moiety or "acylbenzyl moiety”, abbreviated as ab moiety or ab group, may also be used.
  • moiety B has the following general structure Ilia
  • AB moiety AB group or AB mask
  • acylbenzyl moiety in which the acyl group (alkanoyl group) is directly linked to the benzyl radical via the C atom of the group, the acyl group in the acyloxybenzyl mask is linked to the benzyl radical via an oxygen atom.
  • a preferred embodiment of the compound according to the invention is, for example, a compound according to the following general formula Ih
  • the residues R A8 and R B8 are preferably, each independently of one another, a substituted or unsubstituted cyclic, acyclic, linear or branched Ci_ 2 o aliphatic residue or Ci_ 2 o heteroaliphatic residue, or a substituted or
  • R A8 and R B8 are, independently from each other, selected from the group consisting of substituted or unsubstituted Ci_ 2 o alkyl, substituted or unsubstituted C 2 _ 20 alkenyl, substituted or unsubstituted C 2 -20 alkynyl, substituted or unsubstituted C4-20 alkenynyl, substituted or unsubstituted C3-20 cycloalkyl, substituted or unsubstituted C3-20 cycloalkenyl, substituted or unsubstituted C3-20 cycloalkynyl, substituted or unsubstituted C 5 -20 cycloalkenynyl, substituted or unsubstituted Ci_ 2 o heteroalkyl, substituted or unsubstituted C 2 -20 hetero alkenyl, substituted or unsubstituted C 2 -20 heteroalkynyl, substituted or unsubstituted C 4 _
  • R B8 are different, and moiety A is an intracellularly stable lipophilic group, and moiety B is an intracellularly labile lipophilic mask.
  • residues R A8 and R B8 are selected from substituted or unsubstituted Ci_ 2 o alkyl and substituted or unsubstituted C 2 _ 2 o alkenyl, with the proviso that the residues R A8 and R B8 are different, and the moiety A is an intracellularly stable lipophilic group and the moiety B is an intracellularly labile lipophilic mask.
  • the compounds according to the invention exhibit good cell penetrability and intracellularly release, for example, mono-modified nucleoside phosphate analogues, which are preferably selectively used by, for example, microbial or viral polymerases, e.g. the reverse transcriptase of the HI virus, as a substrate and lead to chain termination.
  • the compounds according to the invention are thus suitable for use as drugs, in particular as antiviral drugs, for example antiretroviral drug.
  • the compounds according to the invention can advantageously be used in medications for the treatment of HIV, influenza, hepatitis C and B infections, haemorrhagic fever or cancer.
  • the invention therefore also relates in a second aspect to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to the invention and a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers are known to the person skilled in the art and comprise one or more liquid, semi- so lid or solid fillers, diluents or other substances suitable for administration to mammals, including humans.
  • carrier refers to any organic or inorganic, natural or synthetic substance which can be combined with the active ingredient to simplify application.
  • Such carriers include, but are not limited to organic or inorganic solvents, starch, lactose, mannitol, methylcellulose, talc, gelatin, agar agar, calcium phosphate, magnesium stearate, animal and vegetable fats, higher molecular weight fatty acids, or higher molecular weight polymers.
  • pharmaceutically acceptable means any substantially non-toxic material for mammals, especially humans, which does not substantially affect the effectiveness of the biological activity of the active ingredient. Such materials may include pharmaceutically acceptable concentrations of salts, buffers, preservatives, or the like.
  • pharmaceutically acceptable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, ethanol, glycerol, water, buffer solutions.
  • the pharmaceutical composition may also comprise adjuvants and/or diluents.
  • the invention also relates to a pharmaceutical dosage form comprising a compound according to the invention and a pharmaceutically acceptable carrier.
  • a dosage form for oral administration for example a tablet or capsule.
  • a preferred embodiment of a compound according to the invention can be prepared, for exam le, according to the scheme given below
  • FIG. 1 shows schematically the intracellular cleavage of an enzyme-cleavable mask B and intracellular formation of a compound modified with a stable moiety A from a preferred embodiment of a compound according to the invention.
  • Nucl nucleoside or nucleoside analogue
  • Cat + cation
  • E esterase
  • Ti /2 half-life.
  • FIG. 2 Schematic representation of the template (30 nt) and primer (25 nt) used for the primer extension assays.
  • FIG. 3 shows results of primer extension assays with a stable mono-modified nucleoside triphosphate.
  • A Autoradiogram with the polymerase HIV-RT
  • B Autoradiogram with the human polymerase ⁇ .
  • FIG. 4 shows results of primer extension assays with a compound according to the invention.
  • FIG. 5 shows HPLC chromatograms of the hydrolysis of the monomasked C9-ketone-d4TTP in CEM/0 cell extracts after different incubation times.
  • FIG. 1 shows, for an exemplary embodiment of a compound according to the invention, schematically its introduction as a double-modified prodrug into a cell whose cell membrane is indicated here by an arcuate line, as well as the assumed course of release of a NTP derivative, i.e. a nucleoside triphosphate mono-modified with an intracellularly stable moiety A.
  • a NTP derivative i.e. a nucleoside triphosphate mono-modified with an intracellularly stable moiety A.
  • the two otherwise negatively charged oxygen atoms (in bold face type) of the hydroxyl groups of the terminal phosphate ( ⁇ -phosphorus atom) in the NTP prodrug are non-symmetrically substituted, i.e. modified with two different groups A and B.
  • the mask B is here an
  • acyloxybenzyl derivative (AB derivative) and can be cleaved hydrolytically or enzymatically.
  • the labile mask B is therefore rapidly removed after enzymatic attack on the ester group by esterases (E) present in the cell and subsequent spontaneous degradation, resulting in a mono-modified product bearing the intracellularly stable group A.
  • the labile mask B is cleaved at a rate leading to a comparatively short half- life time 12 (1) of the starting prodrug.
  • a nucleophilic attack on the phosphorus anhydride bond(s) with a cleavage thereof does not occur, so that the unwanted formation of the mono- or diphosphate is prevented.
  • the group A in this case an acylbenzyl (ab-derivative), is not, or very much slower, attacked enzymatically, so that there is no or at least essentially no release of the parent nucleoside triphosphate (NTP).
  • thymidine triphosphate was prepared with a stable acylbenzyl group A having a C9 alkyl residue (also referred to as a C9- ab group or C9 ketone group) according to the following scheme:
  • the mono-modified TTP (C9 ketone TTP) prepared as described above was tested in primer extension assays using a 32 P-labeled primer (25 nt) and a 30 nt template for its suitability as a substrate of HIV reverse transcriptase and human polymerases (see FIG. 2).
  • FIGs. 3B and 3C show the results of the reaction with the human DNA polymerases ⁇ and ⁇ .
  • T* the samples containing only the C9 ketone TTP
  • T* no incorporation of TMP out of the C9 ketone TTP is observed (corresponds to the primer, 25 nt). Consequently, the desired differentiation between viral and human polymerase could be achieved.
  • a compound according to the present invention having an unstable, i.e. enzymatically cleavable, C4-acyloxybenzyl mask B (also referred to as C4-AB mask) and a stable acylbenzyl group A with C9-alkyl residue (also referred to as C9-ab group or C9-ketone group) with d4T monophosphate (d4TMP, stavudine monophosphate) as R 1 according to the scheme shown in the following figure.
  • C4-acyloxybenzyl mask B also referred to as C4-AB mask
  • a stable acylbenzyl group A with C9-alkyl residue also referred to as C9-ab group or C9-ketone group
  • d4T monophosphate d4T monophosphate
  • the ⁇ -mono -modified C9-ketone nucleoside triphosphate was selectively generated from the resulting C9-ketone/C4-AB-d4TTP prodrug by enzymatic cleavage of the enzymatically cleavable mask B.
  • FIG. 4A shows the reference samples (-, +) from the reaction with the HIV reverse transcriptase.
  • - 25 nt primer and no polymerase
  • N* includes the stable C9-ketone d4TTP instead of the natural TTP; d4T* includes only the C9 ketone d4TTP).
  • FIGs. 4B and 4C show the results of the reaction with the human DNA polymerases ⁇ .
  • FIG. 4B starting from d4TTP, the comparatively marginal incorporation of d4TMP can be seen in samples three and four sample (Ni* includes d4TTP instead of the natural TTP; d4T includes only the d4TTP).
  • FIG. 4C starting from C9-ketone-d4TTP, no incorporation can be observed (corresponds to the primer, 25 nt) for the corresponding samples three and four. Consequently, the desired substrate specificity was also observed here.
  • ⁇ - ⁇ -modified AZT triphosphates already known from literature had only a half-life of ti/ 2 (l) 17-55 min, depending on the residue on the ⁇ - phosphate ( ⁇ -methylphosphonate, ⁇ -phenylphosphonate, ⁇ -phenyltriphosphate and ⁇ -anilido), in human serum (A. Hofer, GS Cremosnik, AC Miller, R. Giambruno, C. Trefzer, G. Superti- Furga KL Bennett, HJ Jessen, A Modular Synthesis of Modified Phosphoanhydrides, Chem. Eur. J. 2015, 21 , 10116-10122).
  • Table 1 shows data on the antiviral activity of compounds according to the invention according to the following general structure la.
  • Table 1 Antiviral activity of exemplary compounds of the invention.
  • compound 3 with d4T (Stavudine) as a nucleoside, C9-ab (also called “C9 ketone”) as intracellularly stable moiety A and C4-AB as mask B is depicted below:
  • Compounds 3-9 are embodiments of compounds of the invention according to the general formula I.
  • Compound 2 is a compound not according to the invention having two cleavable acyloxybenzyl (AB) masks.
  • Compound 1 is the pure nucleoside d4T.
  • adenosine was used as nucleoside.
  • diphenyl phosphonate (1.2 eq.) was dissolved in 3 mL pyridine and cooled to 0 °C.
  • Alkyl alcohol (1.0 eq.) was added and stirred at 0 °C for 30 min and then heated up to 38 °C.
  • Alkyl alcohol (1.0 eq.) was added and the mixture was stirred for 3 h. Then the solvent was removed in vacuo.
  • the crude product was purified by flash column chromatography (silica) with EtO Ac/petroleum ether/ 0.5% trimethylamine as eluent.
  • the crude product was purified by automatic RP18 flash chromatography, and then followed by ion-exchange to the ammonium form with Dowex 50WX8 cation-exchange resin and a second RP18 chromatography purification step. Product-containing fractions were collected and the organic solvent evaporated. The remaining aqueous solutions were freeze- dried and the desired product obtained as a white solid.
  • the stable moiety A is depicted below the plane of the triphosphate backbone, whereas the labile moiety B, an acyloxybenzyl (AB) moiety, is depicted above the plane of the triphosphate backbone.
  • the stable moiety A is depicted below the plane of the triphosphate backbone, whereas the labile moiety B, an acyloxybenzyl (AB) moiety, is depicted above the plane of the triphosphate backbone.
  • the stable moiety A is depicted below the plane of the triphosphate backbone, whereas the labile moiety B, an acyloxybenzyl (AB) moiety, is depicted above the plane of the triphosphate backbone.
  • Butyldimethylsilyl)oxy)methyl)phenol 2 was described previously (J. L. Sessler, B. Wang, A. Harriman, Journal of the American Chemical Society 1995, 117, 704-714).
  • the synthesis and characterization of (FmO)P(N(i-Pr) 2 ) 2 3 was described previously (A. Hofer, G. S. Cremosnik, A. C. Miiller, R. Giambruno, C. Trefzer, G. Superti-Furga, K. L. Bennett, H. J. Jessen, Chemistry - A European Journal 2015, 21, 10116-10122).
  • the syntheses procedure of non- symmetric (AB,ab)-phosphoramidites were adapted to a literature known procedure (L.
  • GP 2 Syntheses of non-symmetrical (Fm,ab)-phosphoramidites The protocol was adapted to a literature known procedure (A. Hofer, G. S. Cremosnik, A. C. Miiller, R. Giambruno, C. Trefzer, G. Superti-Furga, K. L. Bennett, H. J. Jessen, Chemistry - A European Journal 2015 , 21 , 10116- 10122).
  • GP 3 Syntheses of non symmetric (AB,ab)-TriP ro-NTPs (n-Bu 4 N) 2 -Nucl-DP (1.0 Equiv.) was coevaporated with MeCN, dried in addition to (AB,ab)- phosphoramidite (1.0-2.0 Equiv.) 1-2 h in vacuo and dissolved in MeCN (1-2 mL). To this solution was added a solution of 4,5-dicyanoimidazol (0.25 M in MeCN, 1.2-1.8 equiv.) at rt and stirred for 20-120 min.
  • N-methoxy-N-methyldecanamide 4 N,O-Dimethylhydroxylaminehydrochloride (879 mg, 9.20 mmol, 1.00 equiv.) was dissolved in DCM (24 mL) and cooled to 0 °C. Abs. pyridine (1.65 mL, 20.3 mmol, 2.20 equiv.) and decanoylchloride (1.93 mL, 9.20 mmol, 1.00 equiv.) were added and the solution was stirred for 3 h at 0 °C. Afterwards water and DCM were added, the phases were separated and the aqueous phase extracted with DCM. The combined org.
  • N,O-Dimethylhydroxylaminehydrochloride (595 mg, 6.10 mmol, 1.00 Equiv.) was dissolved in DCM (30 mL) and cooled to 0 °C. Abs. Pyridine (1.04 mL, 12.8 mmol, 2.10 Equiv.) and
  • Phosphoramidit 15 (136 mg, 153 ⁇ , 1.50 Equiv.), 4,5-Dicyanoimidazol (0.25 M in MeCN, 612 ⁇ , 153 ⁇ , 1.50 Equiv.) and t-BuOOH (5.5 M inn-Decan, 28.0 ⁇ , 150 ⁇ mol, 1.50 Equiv.).
  • HMBC 138.8 (C-4"), 135.6 (C-3', HSQC), 129.2 (C-3"), 128.3 (C-2"), 126.4 (C-2', HSQC), 112.2 (C-5, HMBC), 90.3 (C-l ', HSQC), 87.0 (C-4', HSQC), 67.5 (1 "-CH 2 0, HSQC), 67.3 (C-5', HSQC), 39.5 (C-6"), 33.0 (C-12"), 30.6, 30.6, 30.4, 30.4 (C-8"-l l "), 25.7 (C-7"), 23.7 (C-13"*), 14.4 (C-14”), 12.5 (5-CH . 3_).

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Abstract

L'invention concerne des promédicaments de nucléoside triphosphate et d'analogues de nucléoside triphosphate. Un objet de la présente invention est de fournir des promédicaments améliorés de nucléoside triphosphate ou d'analogue de nucléoside triphosphate. Pour atteindre l'objectif, la présente invention concerne, dans un aspect, des composés de nucléoside triphosphate à modification double asymétrique, ou leurs analogues, la modification étant effectuée au niveau de la terminaison, c'est-à-dire le γ-phosphate, ou du groupe analogue correspondant, et la première modification consistant à ajouter un fragment A intracellulaire stable, et la seconde modification consistant à ajouter un masque B intracellulaire labile qui est clivé à l'intérieur de la cellule, de telle sorte qu'un nucléoside triphosphate ou un analogue de celui-ci à modification simple avec la fraction A intracellulaire stable soit libéré dans la cellule.
PCT/EP2017/081140 2016-12-02 2017-12-01 Promédicaments de nucléoside triphosphate et d'analogues de nucléoside triphosphate WO2018100137A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4151646A1 (fr) 2021-09-20 2023-03-22 Universität Hamburg Dérivés de 5-fluorouracile comme promédicaments pour le traitement du cancer
EP4356928A1 (fr) 2022-10-20 2024-04-24 Universität Hamburg Promédicaments de nucléoside diphosphate ou diphosphonate, ou promédicaments de nucléoside analogue diphosphate ou diphosphonate

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WO2009129798A2 (fr) 2008-04-24 2009-10-29 Universität Hamburg Promédicaments à base de diphosphate et de triphosphate, notamment promédicaments à base de nucléoside diphosphate et de nucléoside triphosphate
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4151646A1 (fr) 2021-09-20 2023-03-22 Universität Hamburg Dérivés de 5-fluorouracile comme promédicaments pour le traitement du cancer
WO2023041786A1 (fr) 2021-09-20 2023-03-23 Universität Hamburg Dérivés de 5-fluorouracile en tant que promédicaments pour le traitement du cancer
EP4356928A1 (fr) 2022-10-20 2024-04-24 Universität Hamburg Promédicaments de nucléoside diphosphate ou diphosphonate, ou promédicaments de nucléoside analogue diphosphate ou diphosphonate

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