EP0445201A1 - Nucleoside analogues - Google Patents

Nucleoside analogues

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Publication number
EP0445201A1
EP0445201A1 EP90900225A EP90900225A EP0445201A1 EP 0445201 A1 EP0445201 A1 EP 0445201A1 EP 90900225 A EP90900225 A EP 90900225A EP 90900225 A EP90900225 A EP 90900225A EP 0445201 A1 EP0445201 A1 EP 0445201A1
Authority
EP
European Patent Office
Prior art keywords
ratio
phosphate
azidothymidine
diastereoisomers
nucleoside analogue
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP90900225A
Other languages
German (de)
English (en)
French (fr)
Inventor
Christopher Mcguigan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University College London
Medical Research Council
Original Assignee
University College London
Medical Research Council
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 University College London, Medical Research Council filed Critical University College London
Publication of EP0445201A1 publication Critical patent/EP0445201A1/en
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • 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
    • 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

Definitions

  • This invention relates to nucleosides and in particular to nucleoside phosphate triesters and processes for their preparation.
  • Nucleoside analogues of general formula (I) are currently of considerable interest for use as therapeutic agents in the treatment of viral infections and in particular acquired immunodeficiency syndrome (AIDS) .
  • AIDS acquired immunodeficiency syndrome
  • AZT Mitsubishi et al., 1985
  • HCV human immunodeficiency virus
  • nucleoside analogues have found widespread use in the treatment of a number of viral infections; for example, 9- /3-D-arabinofuranosyladenine (araA) in the treatment of herpes simplex encephalitis and disseminated herpes zoster (North et al.I, 1979).
  • HIV HIV was first recognised as a distinct clinical entity in 1981 (Gott Kunststoff , et al., 1981).
  • the main target in anti-AIDS treatment has been the causative agent itself, the HIV virion.
  • HIV depends on a unique viral enzyme, reverse transcriptase (RT) , to proliferate. This enzyme has long been considered an attractive target for an attack on retroviruses (Smith et al., 1974; Chandra et al., 1977).
  • RT reverse transcriptase
  • AZT As an inhibitor of HIV in lymphocytes has been studied in detail (Furman et al., 1986) .
  • AZT requires conversion to its 5 1 - triphosphate ( arqar et al. , 1984; Cooney et al., 1986).
  • the nucleoside is monophosphorylated by a nucleoside kinase enzyme present in the cell. Further kinase enzymes convert the monophosphate to the corresponding triphosphate product, which is the bioactive form.
  • the bioactive form efficiently and selectively inhibits the HIV reverse transcriptase and its incorporation into DNA results in termination of DNA synthesis.
  • nucleoside analogues suffer from a number of problems in relation to their anti-viral activity.
  • the compounds are rapidly deactivated.
  • deactivation of nucleosides may occur by cleavage of the glycosidic bond by phosphorylase enzymes.
  • Phosphorylases are known to cleave the glycosidic bond in natural nucleosides (Stryer, 1981) . Furthermore, phosphorylases have been specifically implicated in the degradation of nucleoside analogues with therapeutic applications (Birnie et al., 1963; Saffhill et al., 1986).
  • the nucleosides may be deactivated by deaminase enzymes.
  • Deaminases cause the loss of the amine group from the base portion (B) of the nucleoside.
  • adehosine deaminase mediates in the deactivation of araA by converting it to arahypoxanthine (Bryson et al., 1976 and Haskell, 1977).
  • potent inhibitors of deaminase enzymes have been sought (Cha, 1976; Schaeffer et al., 1974) .
  • nucleoside compounds may be improved in the presence of deaminase inhibitors (Agarwal et al., 1978; Sloan et al., 1977), the inhibitors themselves may have undesirable toxic side effects (North et al.II, 1979).
  • deamination resistant compounds have been sought.
  • a major substrate requirement of adenosine deaminase is a free 5 1 - hydroxyl group (Bloch et al., 1967).
  • Many 5 1 - modified adenosine nucleosides have been prepared and are indeed resistant to adenosine deaminase (Declercq et al., 1977).
  • a second problem leading to poor clinical response to the nucleosides results from dependence on nucleoside kinases to effect monophosphorylation of the nucleoside. Poor intracellular phosphorylation may result in a poor clinical response to the nucleoside. In some cases a dependence on the virally-coded kinases is advantageous since it leads to enhanced antiviral selectivity (Furman et al., 1979). However, in most cases it is deleterious. There are now many reports of the absence, low activity or deletion of the kinase leading to a poor clinical response to the nucleoside analogue (Reichard P. et al., 1962; Morse P.A. et al., 1965; and Bapat A.R. et al ; 1983 ) .
  • a further problem relating to the clinical use of nucleosides is their poor physical properties, in particular their low solubility in water and poor membrane penetrability.
  • the triester compounds (II) show increased stability to deactivation by enzymes such as deaminases and may be expected to possess the desired lipophilicity to facilitate crossing of the cell membrane.
  • the compounds require hydrolytic cleavage of -the two 'R'-groups. It is postulated that the disappointing bio-activity of these compounds is a consequence of the cells, inability to effect such a hydrolytic cleavage. This is probably a consequence of the general lack of triesterase activity in cells.
  • a first aspect of the present invention provides a nucleoside analogue of the formula:
  • R 1 ,R 2 ,R 3 ,R 4 and R 5 are the same or different and are selected from -H, alkyl, aryl, acyl, substituted alkyl, substituted aryl and substituted acyl.
  • the base portion may be any organic base; for . example, purine or pyrimidine bases.
  • the base is adenine, thymine, guanine or cytosine. Most preferably the base is thymine.
  • the phosphate group is an asymmetric chiral centre. Consequently the compound may be a single diastereomer or a mixture of diastereomers with respect to the phosphate chiral centre.
  • the biological activity of the individual or mixed diastereomers may be different.
  • the compounds of the present invention are single diastereomers. More preferably the compounds of the present invention are the most biologically active diastereomers. For example,
  • -X may be selected from either -H or -N 3 .
  • X - N 3 .
  • the nucloside analogue of the present invention may be particularly useful in the treatment of AIDS.
  • nucleoside analogues of the present invention have been shown in .in vitro assays to be excellent inhibitors of HIV proliferation.
  • an assay in which the nucleoside analogues of the present invention, suitable host cells, and HIV are incubated together indicates that the IC 50 of the compounds (i.e. concentration of the compound required to produce a 50% reduction in the formation of HIV antigen) is typically between 0.05 and 100 ⁇ M.
  • IC 50 of the compounds i.e. concentration of the compound required to produce a 50% reduction in the formation of HIV antigen
  • Enhanced inhibition may be observed in an assay in which the compounds and host cells are preincubated prior to addition of HIV.
  • nucleoside analogues of the present invention are excellent ij vitro inhibitors of HIV proliferation the nucleoside analogues present low toxicity towards uninfected cells.
  • the compounds of the present invention overcome the above-mentioned problems associated with the bioactivity of nucleoside analogues in a number of ways.
  • the compounds possess enhanced stability towards deactivation;
  • the phosphorylated structure of the compounds leads to a reduced dependence on kinase enzymes to phosphorylate the nucleoside;
  • third, the uncharged nature of the compounds enables them to cross the lipophilic cell membranes.
  • the nitrogen-phosphorus amide bond is hydrolysed, possibly by protease enzymes.
  • the resulting phosphate diester may then be further hydrolysed by, for example, diesterase enzymes, to yield the corresponding monophosphate.
  • the monophosphate is then a substrate for transformation by kinase enzymes to the corresponding triphosphate, as shown in Reaction Scheme I.
  • the bioactive form of the nucleoside is produced. It is not intended to limit this disclosure to this postulate explaining the surprisingly efficacious nature of the compounds of the present invention.
  • -Y may be -OR 3 or -NR 4 R 5 .
  • Y -OR 3 .
  • R 1 ,R 2 ,R 3 ,R 4 and R 5 are the same or different and are selected from hydrogen, alkyl, aryl, acyl, substituted alkyl, substituted aryl and substituted acyl groups.
  • the alkyl, aryl, acyl, substituted alkyl, substituted aryl and substituted acyl groups from which R 1 ,R 2 ,R 3 , R 4 and R 5 may be selected comprise C ⁇ to C 10 alkyl, aryl, acyl, substituted alkyl, substituted aryl and substituted acyl groups.
  • the groups may be branched or unbranched.
  • R 3 is a substituted alkyl group. More preferably, R 3 is a 2,2,2-trihaloethyl group, a 2,2- dihaloethyl group or a 2-haloethyl group. More preferably, R 3 is a 2,2,2-trichloroethyl group such that the compound of the present invention is a 2,2,2-trichloroethyl phosphate ester. In vitro assays have shown compounds of this type to be particularly effective inhibitors of HIV proliferation.
  • nucleoside analogue varies the individual substituents -X,-Y,-Z and -B enables the nucleoside analogue's properties to be tuned to the optimum combination for biological activity.
  • modification of the structure may enhance the selectivity of hydrolysis in the infected cell; the substituents may also be chosen to enhance the physical characteristics of the nucleoside analogue, for example to increase the lipophilicity and thereby enhance its transport across the cell membrane or to increase the solubility of the nucleoside analogue.
  • R 7 may be selected include amino acids, oligopeptides and polypeptides.
  • R 2 and/or R 3 cause large variations in the biological activity of the nucleoside analogue.
  • the alkyl, aryl, acyl, substituted alkyl, substituted aryl and substituted acyl groups from which R 6 and R 7 may be selected comprise C ⁇ to C 10 alkyl, aryl, acyl, substituted alkyl, substituted aryl and substituted- acyl groups.
  • the groups may be branched or unbranched.
  • R ⁇ may be selected from 1 to C 3 alkyl groups. More preferably R 6 is methyl or iso-propyl.
  • diastereomers corresponding to D- and L- amino acids, about the ⁇ -carbon atom may exist.
  • the nucleoside analogue of the present invention may be single diastereomers or a mixture of diastereomers about the ⁇ -carbon asymmetric centre.
  • the nucleoside analogue of the present invention are single diastereomers. More preferably, the nucleoside analogue of the present invention is the most biologically active diastereomer.
  • nucleoside analogue of the present invention has the nucleoside analogue of the present invention.
  • R 3 Me, Et, Pr, Bu, Hex, 2,2,2-trichloroethyl,
  • nucleoside analogue of the present invention is selected from:
  • the nucleoside analogue of the present invention is 3 ' -azidothymidine-5 '-(2,2, 2-trichloroethyl methoxyalaninyl) phosphate.
  • a second aspect of the present invention provides a process for the preparation of a nucleoside analogue according to the first aspect of the present invention.
  • the nucleoside analogue according to the first aspect of the present invention may be prepared according to the scheme outlined in Reaction Scheme II.
  • Reaction Scheme II Reaction of the phosphorodichloridate (III) with the amine HNR 1 R 2 yields the aminophosphorochloridate (IV) .
  • Reaction of the aminophosphorochloridate (IV) with a nucleoside yields a nucleoside monophosphate triester (VI) of the present invention.
  • the phosphorodichloridate (III) may be prepared by conventional means.
  • Preparation of the amino phosphorochloridate (IV) may be accomplished by reaction of the phosphordichloridate (III) and an amine (HNR 1 R ) under standard conditions (Van Boom et al., 1975; Michaelis, 1903). For example, by the dropwise addition of the amine (R 1 R 2 NH) to the phosphorodichloridate (III) in ether solution at -40°C followed by warming to ambient temperature.
  • Reaction of (IV) and (V) to give (VI) may be performed in pyridine as solvent. However, the reaction is slow. Preferably the reaction is performed in THF in the presence of N-methylimidazole.
  • nucleoside (V) and 2 equivalents of aminophosphorochloridate (IV) are stirred together for 16 hours at room temperature in THF solution (5 ml/mmol) in the presence of 4 equivalents of N-methylimidazole.
  • the nucleoside monophosphate triester (VI) may be isolated by a conventional extractive work up and chromatographic purification.
  • a third aspect of the present invention comprises a chemical compound of the formula
  • R2 -CHR 6 C0 2
  • R 3 ,R 6 ,R 7 are the same or different and are selected from -H, alkyl, aryl, acyl, substituted alkyl, substituted acyl and substituted aryl groups.
  • the alkyl, aryl, subsituted alkyl and substituted aryl groups from which R , R and R 7 may be selected comprise C ⁇ to C 10 alkyl, aryl, substituted alkyl and substituted aryl groups.
  • the groups may be branched or unbranched.
  • the third aspect of the present invention provides the compounds methylmethoxyvalinyl phosphorochloridate, ethylmethoxyvalinyl phosphorochloridate, propylmethoxyvalinyl phosphorochloridate, buty lme hoxy va 1 i ny 1 phosphorochloridate, hexylmethoxyvalinyl phosphorochloridate, ethylmethoxyalaninyl phosphorochloridate, ethylme hoxyphenylalaninyl phosphorochloridate, ethylmethoxyleucinyl phosphorochloridate, ethylmethoxyisoleuciny1 phosphorochloridate, 2,2,2-trichloroethyl methoxyalaniny1 phosphorochloridate.
  • a compound of the third aspect of the present invention may be prepared by reaction of an alkoxy phosphorodichloridate R 3 0P(0)C1 2 with an amino acid ester H 2 NCHR ⁇ C0 2 R 7 , for example, by the dropwise addition of the amino acid ester to the alkoxy phosphorodichloridate in ether solution at -40°C followed by warming to ambient temperature.
  • a compound of the third aspect of the present invention may be used in the preparation of a nucleoside analogue of the first aspect of the present invention.
  • a fourth aspect of the present invention provides a pharmaceutical composition comprising a nucleoside analogue according to the first aspect of the present invention in association with a pharmaceutically acceptable excipient.
  • a fifth aspect of the present invention provides a nucleoside analogue according to the first aspect of the present invention in a form suitable for parenteral or oral administration.
  • a sixth aspect of the present invention provides a nucleoside analogue according to the first aspect of the present invention for use as a pharmaceutical.
  • a seventh aspect of the present invention provides a process for the preparation of a pharmaceutical composition comprising bringing a nucleoside analogue of the first aspect of the present invention into association with a pharmaceutically acceptable excipient.
  • An eighth aspect of the present invention provides a method of treatment comprising the administration, to a human or animal in need of such treatment, of an effective amount of a nucleoside analogue according to the first aspect of the present invention.
  • the eighth aspect of the present invention provides a method of treatment of a viral infection. More preferably the viral infection is human immunodeficiency virus.
  • a ninth aspect of the present invention provides use of a nucleoside analogue according to the first aspect of the present invention for the manufacture of a medicament for the treatment of a viral infection.
  • the viral infection is human immunodeficiency virus.
  • a tenth aspect of the present invention provides a pharmaceutically acceptable salt or addition compound of a nucleoside analogue according to the first aspect of the present invention.
  • the mixture of diastereomers (UCL 12) was partially separated to give fast and slow running fractions (UCL 19 and UCL - 20 respectively) .
  • Partial separation was accomplished by HPLC, employing a Waters system using a 25cm x 4.6mm Partisil 5 silica column, and a mobile phase of 90% ethyl acetate/10% petroleum spirit, with a flow rate of 2.0cm 3 /min. Detection was by UV at 254nm.
  • 2,2,2-Trichloroethyl methoxyalaninyl phosphorochloridate (0.37g, 1.12mmol) was added to a solution of AZT (0.10g, 0.37mmol) in anhydrous THF (5ml) containing N- methylimidazole (0.42 ml, 5.24 mmol), and the mixture stirred for 16h at ambient temperature. The solvent was removed under reduced pressure, and the residue dissolved in chloroform (30ml) , and extracted with saturated sodium bicarbonate solution (15ml) , and then with water (2x15ml) . The organic phase was dried over magnesium sulphate, and concentrated under reduced pressure.
  • Ethyl propylamino phosphorochloridate (0.35g, 1.87mmol) was added to a solution of AZT (0.20g, 0.74mmol) in anhydrous THF (5mL) containing N-methylimidazole (0.30mL, 3.75mmol), and the mixture stirred for 16h at ambient temperature.
  • the solvent was removed under reduced pressure, and the residue dissolved in chloroform (30mL) , extracted with saturated sodium bicarbonate solution (15mL) , and then with water (2xl5mL) .
  • the organic phase was dried over magnesium sulphate, and concentrated under reduced pressure.
  • the residue was precipitated from chloroform (lOmL) , by the addition of petroleum ether (400mL; bp 30-40) .
  • TCD50 HTLV III (RF) is added to the total number of cells required (10 7 - 10 8 ) and absorbed to the cells for 90 Min. at 37°C.
  • the cells (2xl0 5 /l.5ml) are then cultured in 6 ml tubes with drugs at two concentrations (100 and l ⁇ M) for 72h.
  • tissue culture supernatant from each sample is assayed for HIV antigen using a commercial ELISA.
  • cells (2x105/1.5ml) are cultured in 6 ml tubes with drugs only at half log dilutions (100 - 0.01 ⁇ M) for 72H.
  • the cells are harvested, washed and 14 C incorporation measured .
  • the assay results are summarised in Table 1 in which IC 50 ( ⁇ M) for each compound is the micromolar concentration of that compound required to inhibit HIV antigen formation by 50%.
  • IC 50 ( ⁇ M) for each compound is the micromolar concentration of that compound required to inhibit HIV antigen formation by 50%.
  • the results clearly show that the compounds UCL 11 to UCL 17, UCL 19 to UCL 24 and UCL 89 are effective In vitro inhibitors of HIV, even at concentrations of less than 100 ⁇ M. No assessment of inhibition of HIV antigen formation was performed at concentrations of the compounds above lOO ⁇ l.

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EP90900225A 1988-11-23 1989-11-23 Nucleoside analogues Withdrawn EP0445201A1 (en)

Applications Claiming Priority (2)

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GB888827337A GB8827337D0 (en) 1988-11-23 1988-11-23 Nucleoside analogues
GB8827337 1988-11-23

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EP (1) EP0445201A1 (ja)
JP (1) JPH04502006A (ja)
KR (1) KR900701814A (ja)
AU (1) AU626360B2 (ja)
DK (1) DK95791A (ja)
FI (1) FI912489A7 (ja)
GB (1) GB8827337D0 (ja)
WO (1) WO1990005736A2 (ja)

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CA2001401A1 (en) * 1988-10-25 1990-04-25 Claude Piantadosi Quaternary amine containing ether or ester lipid derivatives and therapeutic compositions
CA2164717C (en) * 1993-06-10 2009-10-20 Louis S. Kucera Method of combatting hepatitis b virus infection
US7135584B2 (en) 1995-08-07 2006-11-14 Wake Forest University Lipid analogs for treating viral infections
JP4259611B2 (ja) 1994-08-29 2009-04-30 ウェイク フォレスト ユニバーシティ ウィルス感染を治療するための脂質アナログ
US5981507A (en) * 1995-12-14 1999-11-09 Advanced Magnetics, Inc. Polymeric carriers linked to nucleotide analogues via a phosphoramide bond
US6475985B1 (en) 1998-03-27 2002-11-05 Regents Of The University Of Minnesota Nucleosides with antiviral and anticancer activity
US7026469B2 (en) 2000-10-19 2006-04-11 Wake Forest University School Of Medicine Compositions and methods of double-targeting virus infections and cancer cells
US7309696B2 (en) 2000-10-19 2007-12-18 Wake Forest University Compositions and methods for targeting cancer cells
KR100871648B1 (ko) 2001-08-31 2008-12-03 톰슨 라이센싱 조건부 액세스 시스템을 구현하는 방법, 컨텐트를 전송하는 방법 및 그 장치 및 컨텐트를 수신하고 처리하는 방법 및 그 장치
WO2006063149A1 (en) 2004-12-09 2006-06-15 Regents Of The University Of Minnesota Nucleosides with antiviral and anticancer activity

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US1414252A (en) * 1921-12-29 1922-04-25 William A Brubaker Cushion tire
US3082203A (en) * 1960-02-10 1963-03-19 American Cyanamid Co Novel nucleotide coenzymes
US3280104A (en) * 1964-04-13 1966-10-18 Syntex Corp 2', 3'-dideoxyribonucleoside and 2', 3'-dideoxyribonucleotide derivatives
US3284440A (en) * 1964-06-12 1966-11-08 Merck & Co Inc Phosphate esters of cytosine arabinoide and process for preparing same
US3534017A (en) * 1967-03-14 1970-10-13 Kyowa Hakko Kogyo Kk Process for the preparation of nucleoside-5'-diphosphates and triphosphates and mono- and oligo-nucleotidyl-nucleoside-5'-diphosphates and triphosphates
DE2460051A1 (de) * 1974-12-19 1976-07-01 Bayer Ag Einteilige pannensichere reifen
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DE3148313C2 (de) * 1981-12-07 1983-11-03 Paul Vom Stein & Co, 5632 Wermelskirchen Laufrolle für Apparate, Möbel od. dgl.
CA1239854A (en) * 1984-04-16 1988-08-02 Uniroyal, Inc. Non-pneumatic tire with supporting and cushioning members
ES8801303A1 (es) * 1985-05-15 1987-12-16 Wellcome Found Un procedimiento para preparar una formulacion farmaceutica que contiene un 2'3'-didesoxi-nucleosido.
DE3650741T2 (de) * 1985-09-17 2000-10-12 The Wellcome Foundation Ltd., Greenford Kombination therapeutische Nukleoside mit weiteren therapeutisch wirksamen Komponenten.

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DK95791D0 (da) 1991-05-22
JPH04502006A (ja) 1992-04-09
FI912489A0 (fi) 1991-05-22
DK95791A (da) 1991-05-22
WO1990005736A2 (en) 1990-05-31
GB8827337D0 (en) 1988-12-29
AU4654289A (en) 1990-06-12
FI912489A7 (fi) 1991-05-22
KR900701814A (ko) 1990-12-04
WO1990005736A3 (en) 1990-07-12
AU626360B2 (en) 1992-07-30

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