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WO1998021223A1 - Nucleosides - Google Patents

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Publication number
WO1998021223A1
WO1998021223A1 PCT/SE1997/001903 SE9701903W WO9821223A1 WO 1998021223 A1 WO1998021223 A1 WO 1998021223A1 SE 9701903 W SE9701903 W SE 9701903W WO 9821223 A1 WO9821223 A1 WO 9821223A1
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WO
WIPO (PCT)
Prior art keywords
guanine
mmole
butyl
valyl
mmol
Prior art date
Application number
PCT/SE1997/001903
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English (en)
Inventor
Xiao-Xiong Zhou
Nils-Gunnar Johansson
Original Assignee
Medivir Ab
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Filing date
Publication date
Priority claimed from SE9604165A external-priority patent/SE9604165D0/xx
Priority claimed from SE9604154A external-priority patent/SE9604154D0/xx
Priority claimed from SE9702957A external-priority patent/SE9702957D0/xx
Application filed by Medivir Ab filed Critical Medivir Ab
Priority to EP97913620A priority Critical patent/EP0942916A2/fr
Priority to JP52248098A priority patent/JP2001503767A/ja
Priority to CA002271135A priority patent/CA2271135A1/fr
Priority to AU50759/98A priority patent/AU735438B2/en
Publication of WO1998021223A1 publication Critical patent/WO1998021223A1/fr

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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • 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
    • A61P35/00—Antineoplastic agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures

Definitions

  • This invention relates to the field of nucleosides and nucleoside analogues.
  • the invention provides novel compounds, pharmaceutical compositions comprising these compounds, methods for their manufacture and methods for the treatment or prophylaxis of cancers and viral infections employing these compounds.
  • a second approach to providing prodrugs of acyclic nucleosides involves the preparation of amino acid esters of one or more of the hydroxy groups on the acyclic side chain.
  • European patent EP 99 493 discloses generally amino acid esters of acyclovir and European patent application EP 308 065, published March 22, 1989, discloses the valine and isoleucine esters of acyclovir.
  • European patent application EP 375 329 discloses amino acid ester derivatives of ganciclovir, including the di-valine, di-isoleucine, di- glycine and di-alanine ester derivatives.
  • International patent application WO95/09855, published April 13, 1995 discloses amino acid ester derivatives of penciclovir, including the mono-valine and di-valine ester derivatives.
  • EP 694 547 published January 31, 1996, discloses the mono-L-valine ester of ganciclovir and its preparation from di-valyl-ganciclovir.
  • International patent applications WO 97/27194-27197 describe additional preparations of monovalyl ganciclovir.
  • EP 654 473 published May 24, 1995, discloses various bis amino acid ester derivatives of 9-[ ,2'-bishydroxymethyl)-cyclopropan-l 'yl] methylguanine.
  • acylating antiviral nucleosides bearing at least two free hydroxy groups with a combination of specified amino and particular fatty acid esters produces nucleosides with good bioavailabilities and other beneficial properties.
  • the combined esters of the present invention are generally applicable to nucleosides having at least two free hydroxy groups, preferably in the saccharidic or acyclic moiety of the nucleoside, with the proviso that the nucleoside is not 9-[4-hydroxy- (2-hydroxymethyl)butyl]guanine or its 6-deoxy derivative.
  • B is a natural or unnatural nucleotide base
  • X is O or -CH 2 -
  • R, or R 2 may alternatively or additionally be acylated to the 2'-hydroxy, but it is preferred that R, and R 2 depend from the 3' and 5' positions of the nucleoside or analogue.
  • B, R, and R 2 are as defined above.
  • Representative examples within this group include: 9-[l '-valyloxymethyl-2'-dodecanoyloxymethyl)-cyclopropan- yl] methylguanine, 9- [ 1 ' -valyloxymethyl-2 ' -tetradecanoyloxymethyl)- cyclopropan-1 'yl] methylguanine, 9-[l ' -valyloxymethyl-2 '- hexadecanoyloxymethyl)-cyclopropan-l'yl] methylguanine, 9-[l '-valyloxymethyl- 2'-octadecanoyloxymethyl)-cyclopropan-l 'yl] methylguanine, 9-[l '- valyloxymethyl-2'-eicosanoyloxymethyl)-cyclopropan-l 'yl] methylguanine, 9-[l '- valyloxy
  • R6 is fluoro and R7 is hydrogen or R6 and R7 are both fluoro or R6 and R7 together define an exo-methenyl group.
  • the preferred base is guanine in this alternative.
  • a further group of nucleosides within the scope of the invention has the formula Ic
  • R8 and R9 are fluoro (or one of them is fluoro and the other is hydrogen) or R8 and R9 together define exomethenyl or exomethenyl mono or di-subsituted with fluoro. These nucleosides have anticancer activity.
  • the invention is also applicable to phosphonylated antivirals such as (s)-l-3- hydroxy-2-phosphonyl-methoxypropyl)cytosine (cidofovir, HPMPC), as described in US 5 142 051.
  • one of the R 1 and R 2 may be esterified to an hydroxy group on the phosphonyl moiety, preferably via an intermediate -CH(R a )-O- group where R a may be hydrogen, methyl, isopropyl or the like, whereas the other of R 1 and R 2 may be esterified to the hydroxy group on the 3-hydroxy group.
  • both R 1 and R 2 may be esterified to a respective hydroxy group on the phosphonyl moiety preferably via respective intermediate -CH(R a )-O-groups.
  • This latter arrangement will also be applicable to phosphonylated nucleosides such as 9-[2- (phosphono-methoxy)ethyl]adenine (adefovir, PMEA) as described in US 5 476 938. If a 3-hydroxy group is present, this may optionally be acylated with an additional R 1 or R 2 .
  • the saturated or monounsaturated alkyl component may have from 5 to 21 carbon atoms, viz a fatty acid ester with 6 to 22 carbon atoms including the carbonyl.
  • Preferred compounds of the aspect of the invention described in the paragraph immediately above include 9-[2-(phosphonomethoxy)ethyl]adenine, monovalyloxymethyl, monohexanoyloxymethyl ester; 9-[2-
  • a further application of the combined fatty acid and amino acid esters of the invention is to apply both esters to a common linking group, which linking group is itself esterified to an hydroxyl function of a dihydroxylated nucleoside or nucleoside analogue such as the hydroxyl function marked R 1 or R 2 in Formula I, la, lb or Ic above.
  • the other of R 1 or R 2 will generally be hydrogen, but may also bear an additional linker structure as defined herein or be acylated as for R 1 or R 2 .
  • the common linking group may be configured as in formula II below:
  • R 5 is H or C,-C 3 alkyl; T is a bond, O or NH; m and m' are independently 0, 1 or 2 and n is 0-5,
  • n is 0, 1 or 2 and/or T is a bond or -O-. Especially when T is a bond it is preferred if n is 0 or 1. Conveniently, n and m are not both 0. R 5 is preferably H.
  • the moiety denoted () n preferably comprises an alkane chain but can bear an unsaturated bond.
  • This aspect of the invention contemplates the application of the linking group, such as those of formula II, to nucleosides having at least two hydroxy groups, but outside the scope of formula I, la, lb or Ic, for instance, 9-[3,3-dihydroxymethyl-4- hydroxy-but-1-yl] guanine as described in WO 95/22330 and 9-[4-hydroxy-(2- hydroxymethyl)butyl] guanine as described in EP 343 133.
  • the linking group such as those of formula II
  • the invention also provides pharmaceutical compositions comprising the compounds of the invention, such as those of Formula I, la, lb, Ic or I/II (that is a structure of formula I, la, lb or Ic in conjunction with a structure of the formula II) or mixed esters of phosphonylated antivirals, and their pharmaceutically acceptable salts in conjunction with a pharmaceutically acceptable carrier or diluent.
  • Further aspects of the invention provide the compounds of the invention and their pharmaceutically acceptable salts for use in therapy and the use of these compounds and salts in the preparation of a medicament for the treatment or prophylaxis of cancers and viral infection in humans or animals.
  • an aliphatic amino acid ester for modifying the pharmacokinetics of
  • the compounds of the invention are potent antivirals, especially against herpes infections, such as those caused by Varicella zoster virus, Herpes simplex virus types 1 & 2, Epstein-Barr virus, Herpes type 6 (HHV-6) and type 8 (HHV-8).
  • the compounds of the invention especially cytosine or guanine derivatives where X is oxygen, n is 1 and Y and Z define a ring are also active against certain retroviral infections, notably SIV, HIV-1 and HIV-2, and Hepatitis B virus.
  • the compounds of the invention especially cytosine, guanosine or 6- methoxyguanosine derivatives wherein X is oxygen, n is 0 and Y and Z define an arabinose ring are potent anticancer compounds.
  • the compounds of the invention especially derivatives comprising a 1,2,4-triazole- 3-carboxamide base, where X is O, Y is -CH(OH)-, Z is a bond thereto and n is 0 (ribavirin) are expected to be active against hepatitis C virus (HCV).
  • Compounds comprising a substituted benzimidazole base, where X is O, Y is -CH(OH)-, Z is a bond thereto and n is 0 for instance Glaxo Wellcome's 1263W94 where the base is 2-isopropylamin-5,6-dichloro-benzimidazol-3-yl) are expected to be active against CMV.
  • Compounds comprising an adenine base, where X is O, Y is -CH(OH)-, Z is a bond thereto and n is 0 are expected to be active against HSV encephalitis.
  • Compounds comprising a 2-chloroadenine base with a 2'-deoxyribose sugar are expected to ghave anticancer activity.
  • a further aspect of the invention provides a method for the prophylaxis or treatment of cancers or viral infections in humans or animals comprising the administration of an effective amount of a compound of the invention, such as those of Formula I, la, I/II or mixed esters of phosphonylated antivirals or its pharmaceutically acceptable salt to the human or animal.
  • a compound of the invention such as those of Formula I, la, I/II or mixed esters of phosphonylated antivirals or its pharmaceutically acceptable salt to the human or animal.
  • the nucleoside derivatives of the invention are particularly useful for guanine nucleoside and analogues which tend to have poorer uptake than pyrimidine nucleosides.
  • B is preferably guanine or a guanine derivative.
  • Guanine bases are advantageously modified at the 6 position to define an even more readily soluble 6-deoxy derivative which can be oxidised in vivo (e.g. by xanthine oxidase) to the guanine form.
  • guanine bases can be present in the 6- alkoxy form.
  • Preferred bases when Y and Z are hydrogen or together form a bond include adenine and especially guanine.
  • Other preferred bases include cytosine, especially when X is oxygen, n is 1 and Y and Z define a ring or n is 0 and Y is -C(OH)-..
  • Y is -C(OH)- may define lyxofuranosyl or xylofuranosyl derivatives, but more preferably define arabinose or ribose derivatives.
  • amino acid ester of group R, or R 3 is derived from an L-amino acid, such as leucine, alanine and especially L-valine or L-isoleucine.
  • L-amino acid such as leucine, alanine and especially L-valine or L-isoleucine.
  • the amino acid ester R is preferably located on the 5' position of the nucleoside.
  • Further useful R 2 groups include esters of myristoleic, myristelaidic, palmitoleic, palmitelaidic, n6-octadecenoic, oleic, elaidic, gandoic, erucic or brassidic acids.
  • the fatty acid may optionally be substituted with up to five substituents independently selected from the group consisting of hydroxy, C,-C 6 alkyl, C r C 6 alkoxy, C,-C () alkoxy C r C 6 alkyl, C,-C 6 alkanoyl amino, halo, cyano, azido, oxo, mercapto or nitro, and the like. It is preferred if the fatty acid ester is unsubstituted.
  • Preferred compounds include:
  • Preferred compounds include
  • Further preferred compounds include l-(3'-O-dodecanoyl-5'-O-valyl)- ⁇ -D-ribofuranosyl)-l,2,4-triazole-3-carboxamide, l-(3'-O-tetradecanoyl-5'-O-valyl)- ⁇ -D-ribofuranosyl)-l,2,4-triazole-3-carboxamide,
  • the compounds of the invention can form salts which form an additional aspect of the invention.
  • Appropriate pharmaceutically acceptable salts of the compounds of the invention include salts of organic acids, especially carboxylic acids, including but not limited to acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, isethionate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, palmoate, pectinate, 3- phenylpropionate, picrate, pivalate, proprionate, tartrate, lactobionate, pivolate, camphorate, unde
  • the compounds of the invention are particularly suited to oral administration, but may also be administered rectally, vaginally, nasally, topically, transdermally or parenterally, for instance intramuscularly, intravenously or epidurally.
  • the compounds may be administered alone, for instance in a capsule, but will generally be administered in conjunction with a pharmaceutically acceptable carrier or diluent.
  • the invention extends to methods for preparing a pharmaceutical composition comprising bringing a compound of Formula I, la, lb, Ic, I/II or its pharmaceutically acceptable salt in conjunction or association with a pharmaceutically acceptable carrier or vehicle.
  • Oral formulations are conveniently prepared in unit dosage form, such as capsules or tablets, employing conventional carriers or binders such as magnesium stearate, chalk, starch, lactose, wax, gum or gelatin.
  • Liposomes or synthetic or natural polymers such as HPMC or PVP may be used to afford a sustained release formulation.
  • the formulation may be presented as a nasal or eye drop, syrup, gel or cream comprising a solution, suspension, emulsion, oil-in-water or water-in-oil preparation in conventional vehicles such as water, saline, ethanol, vegetable oil or glycerine, optionally with flavourant and/or preservative and/or emulsifier.
  • the compounds of the invention may be administered at a daily dose generally in the range 0.1 to 200 mg/kg/day, advantageously, 0.5 to 100 mg/kg/day, more preferably 10 to 50mg/kg/day, such as 10 to 25 mg/kg/day.
  • a typical dosage rate for a normal adult will be around 50 to 500 mg, for example 300 mg, once or twice per day for herpes infections and 2 to 10 times this dosage for HIV infections.
  • the appropriate dosage for the compound of the invention can be calculated by referring the pharmacokinetic performance of the present derivative relative to the established dosage regime of the parent compound by techniques well known in the pharmaceutical art.
  • the antiviral compounds of the invention can be administered in combination with other antiviral agents, such as acyclovir, valcyclovir, penciclovir, famciclovir, ganciclovir or foscarnet for herpes indications and AZT, ddl, ddC, d4T, 3TC, foscarnet, ritonavir, indinavir, saquinavir, delaviridine, Vertex VX 478, Agouron AG1343 and the like for retroviral indications.
  • Additional antivirals for hepatitis B indications include 2',3'-deoxy-3'- fluoroguanosine, lamivudine and various interferons.
  • the compounds of the invention can be prepared de novo or esterified from commercially available antivirals such as penciclovir or ganciclovir.
  • the preparation of compounds where X is O, n is 1 and Y/Z define a ring can be prepared as described in WO 95/32983.
  • N-protecting group or “N-protected” as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures.
  • N-protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoracetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, ⁇ -chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl, and the like, carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbon
  • Hydroxy and/or carboxy protecting groups are also extensively reviewed in Greene ibid and include ethers such as methyl, substituted methyl ethers such as methoxymethyl, methylthiomethyl, benzyloxymethyl, t-butoxymethyl, 2- methoxyethoxymethyl and the like, silyl ethers such as trimethylsilyl (TMS), t- butyldimethylsilyl (TBDMS) tribenzylsilyl, triphenylsilyl, t-butyldiphenylsilyl triisopropyl silyl and the like, substituted ethyl ethers such as 1 -ethoxymethyl, 1- methyl-1-methoxyethyl, t-butyl, allyl, benzyl, p-methoxybenzyl, diphenylmethyl, triphenylmethyl and the like, aralkyl groups such as trityl, and pixyl (9-hydroxy-9- phenylx
  • the bases in these start materials such as the 2-amino group of guanine or the carboxamide group of ribavirin derivatives are optionally protected with a conventional protecting group such as acetyl BOC (t-BuO-CO-), Z or CBz (BnO-CO-) or Ph 3 C-.
  • Fmoc may be useful for cytosine.
  • the compounds of Formula I may be prepared from such start materials as described below:
  • the direct acylation method is particularly suitable for achiral or symmetric compounds such as penciclovir or ganciclovir.
  • Scheme A above depicts the acylation of a penciclovir derivative in which G is guanine or 6-deoxyguanine, PG is an optional protecting group or hydrogen, R,* is the fatty acid chain and R 2 * is the valine, isoleucine, leucine, alanine etc side chain.
  • the nucleoside (derivative) preferably reacts in the first step with an activated R, fatty acid derivative, as further described below, in a solvent such as dimethylformamide or pyridine, to give a monoacylated product. Acylating first with the fatty acid, rather than the amino acid is convenient as the lipophilic nature of the acyl facilitates subsequent handling.
  • the R, monoacylated compounds are further acylated in the R 2 position with the appropriate activated amino acid derivative to give di acylated products using similar procedures as for the first esterification step.
  • the R, ⁇ -amino acid may be suitably N-protected with N-BOC, Fmoc, N-CBz or the like.
  • the diester products are subsequently subjected to a conventional deprotection treatment using for example trifluoroacetic acid, HCl(aq)/dioxane or hydrogenation in the presence of catalyst to give the desired compound of Formula I.
  • the compound may be in salt form depending on the deprotection conditions.
  • the activated R,/R 2 acid derivative used in the various acylations may comprise e.g. the acid halide, acid anhydride, activated acid ester or the acid in the presence of coupling reagent, for example dicyclohexylcarbodiimide, where "acid” in each case represents the corresponding R, amino acid or the R, fatty acid.
  • coupling reagent for example dicyclohexylcarbodiimide, where "acid” in each case represents the corresponding R, amino acid or the R, fatty acid.
  • activated acid derivatives include the acid chloride, formic and acetic acid derived mixed anhydrides, anhydrides derived from alkoxycarbonyl halides such as isobutyloxycarbonylchloride and the like, N-hydroxysuccinamide derived esters, N-hydroxyphthalimide derived esters, N-hydroxy-5-norbornene-2,3-dicarboxamide derived esters, 2,4,5-trichlorophenol derived esters and the like.
  • the nucleoside is chiral or where the hydroxy groups are not identical it is possible to preferentially direct the first acylation to a particular hydroxy group with careful control of the reaction conditions, for example, by manipulating the reagent concentrations or rate of addition, especially of the acylating agent, by lowering the temperature or by the choice of solvent.
  • the reaction can be followed by TLC to monitor the controlled conditions.
  • SchemeA-2 shows that the 5-hydroxy group of arabinose nucleosides is preferentially acylated, either with a fatty acid or aliphatic amino acid ester or with a linker group, such as those of formula II.
  • Scheme A-2 Hydroxyls of differential reactivity
  • C is (optionally N-protected) cytosine and R,* and R 2 * etc are as described for scheme A.
  • This technique is particularly suitable for chiral or asymmetric nucleosides where it is desired to direct the fatty acid and amino acid esters to specified hydroxy groups.
  • Scheme B relies on regioselective protection of one of the hydroxy groups with a bulky protecting group.
  • this is depicted as t-butyldiphenylsilyl, but other regioselective protecting groups such as trityl, 9-(9-phenyl)xanthenyl, l,l-bis(4-methylphenyl)-l '-pyrenylmethyl may also be appropriate.
  • the 2'-hydroxy group if present, will generally be sufficiently shielded by the base, but may also be protected with a conventional hydroxy protecting group.
  • the resulting product is acylated at the free hydroxy group using analogous reagents and procedures as described in scheme A above, but wherein the activated acid derivative is the R, fatty acid, for example, myristic, stearic, oleic, elaidic acid chloride, etc.
  • the thus monoacylated compounds are subjected to appropriate deprotection treatment to remove the protecting group which can be done in a highly selective manner with such reagents, depending on the regioselective protecting group, as HF/pyridine and the like and manipulation of the reaction conditions, viz reagent concentration speed of addition, temperature and solvent etc, as elaborated above.
  • the now free hydroxy position is acylated with the activated ⁇ -amino acid in a similar way as described in scheme A above.
  • Additional techniques for introducing the amino acid ester in the above scheme A or B include the 2-oxo-4-aza-cycloalkane-l,3-dione method described in international patent application no WO 94/29311.
  • the common linking group such as those of the formula II with the R 3 and R 4 fatty acid and amino acids already acylated thereon can be introduced to the nucleoside derivative using generally similar directed esterification/carbonyl/amide bonding techniques in conjunction with Scheme A or Scheme B above. It will be generally necessary to protect the free amino group on the amino acid ester with conventional protecting groups such as CBz or BOC.
  • the common linking group of Formula II can be introduced to the 3' or 5' position or, less favourably the 2' position, using generally similar directed esterification/carbonate/amide bonding techniques as Scheme A or Scheme B above in conjunction with the corresponding activated derivative of Formula II and appropriate protection of the non-participating hydroxy function on the sugar or acyclic moiety.
  • the leftmost series of reactions on Scheme 1 shows the situation where R 3 is esterified to position 1 of the glycerol and R 4 is esterified to position 3.
  • Linkers where m is 1, n is alkylene or alkenylene and T is a bond can be prepared as shown in Scheme II above.
  • Other permutations of m, m' and n etc in the linker group of formula II can be prepared analagously to the above with the corresponding starter materials, such as 1 ,2,4-trihydroxybutane (CA registry number 3968-00-6), 3,4-dihydroxybutanoic acid (1518-61-2 & 22329-74-4), (S)-3,4- dihydroxybutanoic acid (51267-44-8), (R)-3,4-dihydroxybutanoic acid (158800-76- 1), 1,2,5-pentanetriol (51064-73-4 & 14697-46-2), (S)-l,2,5-pentanetriol (13942-73- 9), (R)- 1,2,5-pentanetriol (171335-70-9), 4,5-dihydroxypentanoic acid (66679-29-6 & 129725
  • Futher linker structures of Formula II and their placement via acylation or carbonate bonding onto nucleoside analogues are shown in the following examples.
  • a further aspect of the invention thus provides a method for the preparation of the compounds of first aspect of the invention comprising a) optionally protecting the base of a compound of formula I wherein R, and R 2 are each hydrogen,
  • the acylation at step b) or the replacement at step d) may comprise the placement of the amino acid ester via a 2-oxo-4-aza-(5 -isopropyl or 5-isobutyl)-cycloalkane-l,3- dione derivative.
  • a further aspect of the invention provides a method for the preparation of the alternative compounds of the invention comprising
  • Boc-Val-OH (5.47 g; 25.2 mmol) and DCC (3.05 g; 14.8 mmol) in CH 2 C1 2 (240 mL) were stirred for 3 h at room temperature under nitrogen. The mixture was filtrated and the solvent was evaporated. The anhydride was dissolved in DMF (300 mL). Ribavirine (3.0 g; 12.3 mmol) and DMAP (226 mg; 1.85 mmol) were added to this solution and it was stirred for 24 h at room temperature. DMF was evaporated and the residue was purified by chromatography on silica gel by eluting with MeOH/CH 2 Cl 2 5/95 to give 2.5 g of 5'-Boc-valine-ribavirin.
  • N,N-dimethylformamide (1 ml), and pyridine (6 ml) was stirred for lh at room temperature and then cooled to -15°C in an ice-salt bath.
  • a 50% solution of benzyl chloroformate (680 mg; 2.0 mmol) in toluene was added in 3 portions beneath the surface of the reaction mixture, which was kept at room temperature for 0.5h and then cooled in ice-water.
  • Water (5 ml) was added (very slowly initially), then 5 ml of ethyl acetate. After stirring for ten minutes, the aqueous phase was extracted with 5x5 ml of ethyl acetate, and the combined organic phases were evaporated to small volume.
  • N-(benzyloxycarbonyl)-5'-(N-benzyloxycarbonyl-L-valyl)araC A mixture of N-benzyloxycarbonyl-L-valine (302 mg; 1.20 mmol), dicyclohexylcarbodiimide (136 mg; 0.66 mmol), and 4-dimethylaminopyridine (10 mg; 0.08 mmol) in dichloromethane (3 ml) was stirred at room temperature for lh, filtered and evaporated in vacuum to small volume to yield crude N- benzyloxycarbonyl-L-valine anhydride.
  • step a) The intermediate of step a) (174 mg; 0.46 mmol), triethylamine (100 mg; 1.0 mmol), 4-dimethylaminopyridine (10 mg; 0.08 mmol) and N,N-dimethylformamide (2 ml) were added and the mixture was stirred at room temperature. A few minutes later, the new product could be detected by TLC. After 2h the mixture was evaporated in vacuum to small volume and purified on a silica gel column (8 g; ethyl acetate + methanol + water, 15+2+1). The first fractions contained lipophilic byproducts, then the pure title compound was eluted (yield 97.5 mg; 34.6%); finally the unreacted intermediate compound could be recovered.
  • step b) N-(benzyloxycarbonyl)-5 '-(N-benzyloxycarbonyl- -valyl)-3 '-stearoyl-araC.
  • a mixture of the intermediate of step b) (97.5mg; O.l ⁇ mmol), stearoyl chloride (isomer-free; 97mg; 0.32mmol), triethylamine (50 mg; 0.40 mmol), 4- dimethylaminopyridine (10 mg; 0.08 mmol), and N,N-dimethylformamide (3 ml) was stirred at room temperature for 2h and evaporated in vacuum to small volume.
  • aqueous phase with salts was extracted with 2 x 1 ml portions of ethyl acetate - hexane which were also eluted through the 'column'.
  • the combined fractions were evaporated to dryness, yielding 118 mg of a colourless oil which was further purified on a small silica column (ethyl acetate - hexane, 1+1) to give 66.5 mg (47.4%) of pure title compound.
  • step c) 3'-Stearoyl-5'-L-valyl-araC.
  • the intermediate of step c) (67 mg; 0.076 mmol) in 4 ml EtOH and 0.4 ml acetic acid with 20 mg of Pd/C 10% was hydrogenated for 0.5h at room temperature and atmospheric pressure to yield, after filtration through Celite, evaporation in vacuum, and freeze-drying with dioxan, 50 mg (99%) of the title compound as a white powder.
  • Benzyl 2-(hydroxymethyl)-2-(stearoyloxymethyl) propionate (1.86 g, 3.8 mmole) was dissolved in pyridine (30 ml). To the solution were added toluenesulfonic acid (73 mg, 0.39 mmole), N-fluorenylmethoxycarbonyl-L-valine (3.94 g, 11.6 mmole), and DCC (3.58 g, 17.4 mmole). The reaction was kept at 4 °C for 16 hr and then filtered through Celite. The filtrate was poured into sodium hydrogen carbonate aqueous solution and extracted with dichloromethane. The organic phase was collected and evaporated in vacuo.
  • Acetyl chloride (150 ml, 2.1 mol) is added to a magnetically stirred suspension of 9- hydroxy-9-phenylxanthene (20 g 72 mmol) in benzene (100 ml). An homogenous deep red solution is obtained. The solution is stirred for 30 min. at 20 °C. The volatiles are removed under reduced pressure. Excess AcCl is neutralised by careful addition to ethanol. The residue is coevaporated with toluene (2 x 30 ml) and with cyclohexane (2 x 30 ml) to obtain a crystalline residue which is stored airtight.Pixyl chloride is alternatively available from Aldrich.
  • step c) The product of step c) (237 mg, 0.39 mmol), CBz-L-valine (116 mg, 0.46 mmol), DCC (96 mg, 0.46 mmol) and DMAP (4.7 mg, 0.04 mmol) were dissolved in CH 2 C1 2 (4 ml). The mixture was maintained under agitation in a nitrogen atmosphere overnight. After 18 hours the mixture was filtered through a glass filter and chromatographed on a silica gel column (ether - hexane 1 :4) to yield 230 mg with a TLC R f of 0.2
  • step d) Preparation of l-O-stearoyl-2-O-(N-CBz-L-valyl)glycerol
  • the pixyl group in the product of step d) was removed by selective deprotection by the method described in Example 3, step d to yield the title compound.
  • step b) Preparation of 1 -O-(N-CBz-L-valyl)-3-O-pixylglyerol
  • the product of step a) (0.672 g, 20.1 mmol) was dissolved in dry pyridine (3.5 ml) under nitrogen.
  • 9-Chloro-9-phenylxanthene (pixyl chloride, 0.65 g, 22.0 mmol, 1.1 eq - prepared as above) was added and the mixture stirred at room temperature for 1.5 h.
  • MeOH 1.5 ml
  • the aqueous layer was extracted with more ether.
  • pixyl group can be put on by the procedure described by Gaffney et al, Tetrahedron Lett 1997, 38, 2539-2542 using PxOH and acetic acid.
  • Unreacted 1-stearoylglycerol may be recovered by eluting with CH 2 Cl 2 /MeOH
  • Potassium permanganate (756 mg, 4.8 mmole) was dissolved in water (7.5 ml). The solution was kept under strong stirring for 10 min. A solution of l-O-(N- benzyloxycarbonyl-L-valyl)-2-allylyl-3-O-stearoyl-l,3-propandiol (1 g, 1.6 mmol) and tetrabutylammonium bromide (77 mg, 0.24 mmole) in benzene (5 ml) was added. The slurry was stirred for 1.5 hr, and dichloromethane was added. A sodium bisulfite aqueous solution was added to the slurry until the mixture discolored.
  • amino acid is deprotected, for instance with palladium black in a methanol, ethyl acetate, acetic acid solution to yield the nucleoside-O-[l-( L- valyl )-2-stearoyl-3 -propyl oxy carbonyl ]
  • step b) 4'O-[2-Stearoyloxy-l-( L-valyloxymethyl)ethoxycarbonyl]ganciclovir The product of step a) (149 mg; 0.17 mmol) in 5 ml EtOH and 0.5 ml acetic acid with 100 mg of Pd/C 10% was hydrogenated overnight at room temperature and atmospheric pressure to yield, after filtration through Celite and evaporation in vacuum, 110.5 mg (81%) as a solid, the title product 9- ⁇ l-[2-stearoyloxy-l-( L- valyloxymethyl)ethoxycarbonyloxymethyl]-2-hydroxyethoxymethyl ⁇ guanine as the acetate.
  • Ganciclovir sodium salt (280 mg; 1.00 mmol) was suspended in N,N-dimethylformamide (5 ml), and triethylamine (100 mg; 1.0 mmol), 4-dimethylaminopyridine (20 mg; 0.16 mmol), and the crude acid chloride in a small amount of N,N-dimethylformamide were added. The mixture was stirred efficiently for 2 days at room temperature. After filtration through a small amount of silica gel, the filtrate was evaporated in vacuum to small volume.
  • the tablets of Formulation Example 1 are spray coated in a tablet coater with a solution comprising
  • the compound of the invention is dispersed in the lecithin and arachis oil and filled into soft gelatin capsules.
  • samples upon thawing are diluted 1 : 100 in aq dist H 2 O and filtered through an amicon filter with centrifugation at 3000 rpm for 10 minutes.
  • Duplicate 30 ⁇ l samples are chromatographed on an HPLC column; Zorbax SB-C18; 75 x 4.6 mm; 3.5 micron; Mobile phase 0.05M NH 4 PO 4 , 3 - 4 % methanol, pH 3.3 - 3.5; 0.5 ml/min; 254 nm, retention time for PCV/GCV at MeOH 4% and pH 3.33, -12.5 min.
  • Bioavailability is calculated as the measured parent compound recovery from each animal averaged over at least three animals and expressed as a percentage of the averaged 24 hour urinary parent compound recovery from a group of 4 individually weighed rats respectively injected i.vjugularis with 0.1 mmol/kg parent compound in a Ringer's buffer vehicle and analysed as above. Results are presented in Table 1.

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Abstract

Esters mélangés de nucléosides antiviraux, tels que des composés représentés par la formule (I) dans laquelle B représente une base de nucléotide naturelle ou non, X représente O ou CH2, Y et Z représente chacun H ou constituent ensemble une liaison ou Y représente méthylène ou -CH(OH)- et Z représente une liaison avec ces dernières; n est 0 ou 1; un de R1 et de R2 représente le résidu acyle d'un acide amino aliphatique et l'autre représente alkyle -C(=O)C5-C21, et leurs sels acceptables sur le plan pharmaceutique, possédant des propriétés pharmacocinétiques et d'autres propriétés avantageuses.
PCT/SE1997/001903 1996-11-12 1997-11-12 Nucleosides WO1998021223A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP97913620A EP0942916A2 (fr) 1996-11-12 1997-11-12 Nucleosides
JP52248098A JP2001503767A (ja) 1996-11-12 1997-11-12 ヌクレオシド
CA002271135A CA2271135A1 (fr) 1996-11-12 1997-11-12 Nucleosides
AU50759/98A AU735438B2 (en) 1996-11-12 1997-11-12 Nucleosides

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
SE9604165A SE9604165D0 (sv) 1996-11-12 1996-11-12 Antivirals
SE9604165-2 1996-11-12
SE9604154-6 1996-11-12
SE9604154A SE9604154D0 (sv) 1996-11-12 1996-11-12 Anticancer compounds
US79821897A 1997-02-10 1997-02-10
US08/798,218 1997-02-10
US91292797A 1997-08-15 1997-08-15
SE9702957A SE9702957D0 (sv) 1997-08-15 1997-08-15 Antivirals
SE9702957-3 1997-08-15
US08/912,927 1997-08-15

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Cited By (10)

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Publication number Priority date Publication date Assignee Title
WO1999009031A1 (fr) * 1997-08-15 1999-02-25 Medivir Ab Analogues de nucleosides tels que des antiviraux y compris des inhibiteurs de transcriptase inverse retrovirale et l'adn polymerase du virus de l'hepatite b(hbv)
WO1999041275A1 (fr) * 1998-02-13 1999-08-19 Medivir Ab Promedicaments
WO1999051613A1 (fr) * 1998-04-03 1999-10-14 Medivir Ab Promedicaments de produits pharmaceutiques contenant du phosphore
WO2000023455A1 (fr) * 1998-10-16 2000-04-27 Schering Corporation Therapie combinee ribavirine-interferon alpha permettant de supprimer l'arn de vhc pouvant etre detecte chez des patients atteints de l'hepatite c chronique
WO2000023454A1 (fr) * 1998-10-16 2000-04-27 Schering Corporation Therapie combinee ribavirine-interferon alpha permettant de supprimer l'arn de vhc pouvant etre detecte chez des patients atteints de l'hepatite c chronique
US6403564B1 (en) 1998-10-16 2002-06-11 Schering Corporation Ribavirin-interferon alfa combination therapy for eradicating detectable HCV-RNA in patients having chronic hepatitis C infection
US7115578B2 (en) 2000-04-20 2006-10-03 Schering Corporation Ribavirin-interferon alfa combination therapy for eradicating detectable HCV-RNA in patients having chronic hepatitis C infection
US7199151B2 (en) 1996-05-22 2007-04-03 Luitpold Pharmaceuticals, Inc. DHA-pharmaceutical agent conjugates of taxanes
EP1465894A4 (fr) * 2001-11-14 2008-10-08 Teva Pharma Synthese et purification de valacyclovir
US8324381B2 (en) * 2006-03-21 2012-12-04 Cipla Limited Preparation of ester of purine derivatives

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RS114104A (en) * 2002-06-28 2007-02-05 Idenix (Cayman) Limited, 2' and 3'-nucleoside prodrugs for treating flaviviridae infections
KR20050048544A (ko) * 2002-06-28 2005-05-24 이데닉스 (케이만) 리미티드 플라비비리다에 감염 치료용의 변형된 2' 및3'-뉴클레오사이드 프로드럭
DE102017219046A1 (de) 2017-10-25 2019-04-25 BSH Hausgeräte GmbH Haushaltsgerät zur Pflege von Wäschestücken mit einer Unwuchtausgleichsvorrichtung mit verformbarer Bremseinheit und Verfahren zum Betreiben eines derartigen Haushaltsgeräts

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989003837A1 (fr) * 1987-10-28 1989-05-05 Pro-Neuron, Inc. Uridine et cytidine acylees et leurs utilisations
EP0375329A2 (fr) * 1988-12-19 1990-06-27 The Wellcome Foundation Limited Dérivés antiviraux de pyrimidine et de purine, leur procédé de préparation et compositions pharmaceutiques les contenant
WO1994024134A1 (fr) * 1993-04-09 1994-10-27 Hoechst Aktiengesellschaft Nouveaux esters carboxyliques de 2-amino-7-(1,3-dihydroxy-2-propoxymethyl)purine, leur fabrication et leur utilisation
WO1997005154A1 (fr) * 1995-07-25 1997-02-13 Norsk Hydro Asa Agents therapeutiques ameliores
WO1997027197A1 (fr) * 1996-01-26 1997-07-31 F. Hoffmann-La Roche Ag Procede pour la preparation de derives du ganciclovir
WO1997030051A1 (fr) * 1996-02-16 1997-08-21 Medivir Ab Derives de nucleosides acycliques

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989003837A1 (fr) * 1987-10-28 1989-05-05 Pro-Neuron, Inc. Uridine et cytidine acylees et leurs utilisations
EP0375329A2 (fr) * 1988-12-19 1990-06-27 The Wellcome Foundation Limited Dérivés antiviraux de pyrimidine et de purine, leur procédé de préparation et compositions pharmaceutiques les contenant
WO1994024134A1 (fr) * 1993-04-09 1994-10-27 Hoechst Aktiengesellschaft Nouveaux esters carboxyliques de 2-amino-7-(1,3-dihydroxy-2-propoxymethyl)purine, leur fabrication et leur utilisation
WO1997005154A1 (fr) * 1995-07-25 1997-02-13 Norsk Hydro Asa Agents therapeutiques ameliores
WO1997027197A1 (fr) * 1996-01-26 1997-07-31 F. Hoffmann-La Roche Ag Procede pour la preparation de derives du ganciclovir
WO1997030051A1 (fr) * 1996-02-16 1997-08-21 Medivir Ab Derives de nucleosides acycliques

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6458772B1 (en) 1909-10-07 2002-10-01 Medivir Ab Prodrugs
US7199151B2 (en) 1996-05-22 2007-04-03 Luitpold Pharmaceuticals, Inc. DHA-pharmaceutical agent conjugates of taxanes
WO1999009031A1 (fr) * 1997-08-15 1999-02-25 Medivir Ab Analogues de nucleosides tels que des antiviraux y compris des inhibiteurs de transcriptase inverse retrovirale et l'adn polymerase du virus de l'hepatite b(hbv)
US7071173B2 (en) 1998-02-13 2006-07-04 Medivir Ab Antiviral methods employing double esters of 2′, 3′-dideoxy-3′-fluoroguanosine
US7825238B2 (en) 1998-02-13 2010-11-02 Medivir Ab Antiviral methods employing double esters of 2′, 3′-dideoxy-3′-fluoroguanosine
US6974802B2 (en) 1998-02-13 2005-12-13 Medivir Ab Treatment of viral infections using prodrugs of 2′,3-dideoxy,3′-fluoroguanosine
WO1999041275A1 (fr) * 1998-02-13 1999-08-19 Medivir Ab Promedicaments
WO1999051613A1 (fr) * 1998-04-03 1999-10-14 Medivir Ab Promedicaments de produits pharmaceutiques contenant du phosphore
US6277830B1 (en) 1998-10-16 2001-08-21 Schering Corporation 5′-amino acid esters of ribavirin and the use of same to treat hepatitis C with interferon
JP2002527522A (ja) * 1998-10-16 2002-08-27 シェリング・コーポレーション 慢性Ｃ型肝炎感染を有する患者における検出可能ＨＣＶ−ＲＮＡ根絶用リバビリン−インターフェロン−α併用療法
US6403564B1 (en) 1998-10-16 2002-06-11 Schering Corporation Ribavirin-interferon alfa combination therapy for eradicating detectable HCV-RNA in patients having chronic hepatitis C infection
WO2000023454A1 (fr) * 1998-10-16 2000-04-27 Schering Corporation Therapie combinee ribavirine-interferon alpha permettant de supprimer l'arn de vhc pouvant etre detecte chez des patients atteints de l'hepatite c chronique
WO2000023455A1 (fr) * 1998-10-16 2000-04-27 Schering Corporation Therapie combinee ribavirine-interferon alpha permettant de supprimer l'arn de vhc pouvant etre detecte chez des patients atteints de l'hepatite c chronique
US7115578B2 (en) 2000-04-20 2006-10-03 Schering Corporation Ribavirin-interferon alfa combination therapy for eradicating detectable HCV-RNA in patients having chronic hepatitis C infection
EP1465894A4 (fr) * 2001-11-14 2008-10-08 Teva Pharma Synthese et purification de valacyclovir
US8324381B2 (en) * 2006-03-21 2012-12-04 Cipla Limited Preparation of ester of purine derivatives

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KR20000053226A (ko) 2000-08-25
AU735438B2 (en) 2001-07-05
AU5075998A (en) 1998-06-03
CA2271135A1 (fr) 1998-05-22
EP0942916A2 (fr) 1999-09-22

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