WO1994005687A1 - Nucleosides pyrimidiniques antiviraux - Google Patents

Nucleosides pyrimidiniques antiviraux Download PDF

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Publication number
WO1994005687A1
WO1994005687A1 PCT/GB1993/001858 GB9301858W WO9405687A1 WO 1994005687 A1 WO1994005687 A1 WO 1994005687A1 GB 9301858 W GB9301858 W GB 9301858W WO 9405687 A1 WO9405687 A1 WO 9405687A1
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Prior art keywords
formula
compound
thio
deoxy
group
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PCT/GB1993/001858
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English (en)
Inventor
John Allen Miller
Robert John Young
Saad George Rahim
David Lawrence Selwood
Richard Walker
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University Of Birmingham
The Wellcome Foundation Limited
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Application filed by University Of Birmingham, The Wellcome Foundation Limited filed Critical University Of Birmingham
Priority to JP6506988A priority Critical patent/JPH08504753A/ja
Priority to AU49733/93A priority patent/AU4973393A/en
Priority to EP94908867A priority patent/EP0658166A1/fr
Publication of WO1994005687A1 publication Critical patent/WO1994005687A1/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
    • 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

  • the compounds according to the invention may be administered to mammals including humans by any route appropriate to the condition to be treated, suitable routes including oral, rectal, nasal, topical (including buccal and sublingual) , vaginal and parenteral -(including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) . It will be appreciated that the preferred route may vary with, for example, the condition of the recipient. For each of the above-indicated utilities and indications the amount required of the individual active ingredients will depend upon a number of factors including the severity of the condition to be treated and the identity of the recipient and will ultimately be at the discretion of the attendant physician.
  • An edible foam or whip formulation as described above may be prepared in a conventional manner, for example by mixing the edible oil, surfactant (s) and any other soluble ingredients, adding the viscosity modifier(s) and milling the mixture to form a uniform dispersion and suspension. The active ingredient is blended into the milled mixture until evenly dispersed. Finally, a metered quantity of propellant is incorporated to the mixture after said mixture has been measured into a suitable dispensing container.
  • Pharmaceutical formulations for topical administration according to the present invention may be formulated as an ointment, cream, suspension, lotion, powder, solution, paste, gel, spray, aerosol or oil.
  • the formulations are preferably applied as a topical ointment or cream containing the active ingredient in an amount of, for example, 0.075 to 20% w/w, preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w.
  • the active ingredients may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream with an oil-in- water cream base.
  • the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents, and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • the formulations of this invention may include other agents conventional in the art having regard to the type of formulation ir. question, for example those suitable for oral administration may include flavoring agents.
  • the compounds according to the invention may be employed alone or in combination with other therapeutic agents for the treatment of the above infections or conditions.
  • Combination therapies according to the present invention comprise the administration of at least one compound of the formula (I) or a physiologically functional derivative thereof and at least one other pharmaceutically active ingredient.
  • the active ingredient (s) and pharmacologically active agents may be administered together or separately and, when administered separately this may occur simultaneously or sequentially in any order.
  • the amounts of the active ingredient (s) and pharmacologically active agent (s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • the combination therapy involves the administration of one compound of the formula (I) or a physiologically functional derivative thereof and one of the agents mentioned herein below.
  • the combination therapy involves the administration of one of the above-mentioned agents and a compound within one of the preferred or more-preferred sub-groups within formula (I) as described above.
  • the combination therapy involves the joint use of one of the above named agents together with one of the compounds of formula (I) specifically named herein.
  • the compounds of formula (I) may be produced by various methods known in the art of organic chemistry in general and nucleoside synthesis in particular. Starting materials are either known and readily available from commercial sources or may themselves be produced by known and conventional techniques.
  • the present invention further provides a process for producing a compound of formula (I) as hereinbefore defined which process comprises: A) reacting a compound of formula (II)
  • R 3a either forms a carbon-carbon bond with R 2 or when R 2 is H, R 3a is hydrogen, hydroxy or a group OZ 3 where Z 3 is a hydroxyl protecting group;
  • the groups R 3a and Z 5 are preferably hydroxyl protecting groups, particularly benzyl, toluoyl or p-nitrotoluoyl groups.
  • the reaction may be performed using standard methods including the use of a Lewis Acid catalyst such as mercuric chloride or bromide or stannic chloride or trimethylsilyltrifluoromethane-sulphonate in solvents such as acetonitrile, 1-2 dichloroethane, dichloromethane, chloroform or toluene at reduced, ambient or elevated temperature such as from -78°C to reflux; or b) reaction of the compound of formula (III) , or a protected form thereof, with a compound of formula (VI)
  • a Lewis Acid catalyst such as mercuric chloride or bromide or stannic chloride or trimethylsilyltrifluoromethane-sulphonate in solvents such as acetonitrile, 1-2 dichloroethane, dichloromethane, chloroform or
  • Acid catalyst such as trimethylsilyltrifluoromethane sulphotonate in a solvent such as acetonitrile.
  • Py is preferably uracil or thymine.
  • silylation 25 by silylation.
  • Suitable silylating agents include bis- (trimethylsilyl) acetamide.
  • Silylation is conducted in a suitable solvent, for example acetonitrile. The reaction may be conducted at from about 20°C to 100°C and is preferably preformed at an elevated temperature, e.g. about 50° to 100°C, e.g. about
  • the compound of formula (V) is reacted with the protected base in the presence of a Lewis acid catalyst such as those mentioned above and, as a co-catalyst a N-halosuccinimide, eg. N- iodosuccinimide or N-bromosuccinimide.
  • a Lewis acid catalyst such as those mentioned above and, as a co-catalyst a N-halosuccinimide, eg. N- iodosuccinimide or N-bromosuccinimide.
  • the Lewis acid is
  • the solvent may be any suitable solvent including chlorinated solvents such as chloroform, dichloromethane, 1-2-dichloromethane but is preferably acetonitrile.
  • the Lewis acid and N-halosuccinimide are preferably used in equimolar proportions, although a range of from 1:5 to 5:1 molar ratio may be used. Desirably, the ratio of Lewis acid to compound of formula (V) is 1:1.
  • nucleoside of formula (VI) When the nucleoside of formula (VI) is protected, it may be deprotected using standard de-esterification reactions, eg by reaction with a base (organic or inorganic) in a suitable solvent such as alcohol (eg. methanol, ethanol or propanol) .
  • a base organic or inorganic
  • suitable solvent such as alcohol (eg. methanol, ethanol or propanol)
  • alcohol eg. methanol, ethanol or propanol
  • 5-Halopyrimidines are commercially available and may be coupled to the 4-thiosugar compound by conventional techniques, for instance by reacting a protected 5-halopyrimidine with a protected 4-thio sugar compound having a leaving group in the 1- position.
  • the leaving group on the 4-thio sugar compound may be a halogen, benzylthio or preferably acetate group.
  • Reaction with iodine and nitric acid also introduces the 5-iodo substituent.
  • Reaction with bromine and acetic acid introduces a 5-bromo substituent to the unprotected nucleoside. Deprotection where necessary is by conventional techniques and is performed as the final step.
  • X is C 2 6 alkenyl
  • 5-Alkenyl compounds may be produced by partial hydrogenation of the corresponding 5-alkynyl pyrimidine of formula (III) or of the nucleoside of formula (II) for instance using Lindlar catalyst poisoned with quinoline, and subsequently, in the case of the pyrimidine, coupling with a 4-thio sugar compound as described above.
  • a 5-iodo nucleoside of formula (II) may be reacted with an appropriate alkenylating agent for example a 2- alkenoic acid ester (for instance the methyl ester) in the presence of palladium (II) acetate and triphenylphosphine to form the 5- (2-methoxycarbonyl alkenyl) derivative.
  • an appropriate alkenylating agent for example a 2- alkenoic acid ester (for instance the methyl ester) in the presence of palladium (II) acetate and triphenylphosphine to form the 5- (2-methoxycarbonyl alkeny
  • the 5- (2-carboxyvinyl) compound may also be produced by treating an unprotected 5- (hydroxymethyl)pyrimidine of formula (III) with an oxidising agent such as persulphate or manganese dioxide to form the corresponding aldehyde and followed by treatment of the aldehyde with malonic acid.
  • an oxidising agent such as persulphate or manganese dioxide
  • the 5- (2-haloalkenyl) base may alternatively be made by a novel route starting with a 2,4-dimethoxy protected 5- bromopyri idine.
  • This may be converted to the corresponding 5- lithium derivative by treatment with an organolithium reagent, preferably n-butyllithium at reduced temperature such as -70°C in an ethereal solvent such as diethylether.
  • Reaction of the lithio derivative j-n situ with an appropriate ester of formic acid, such as ethyl formate at reduced temperature such as -70°C gives rise to the corresponding 5-formyl compound.
  • Treatment of the formyl compound with malonic acid as described above gives rise to the 5- (2-carboxyvinyl) derivative.
  • Similar halogenation gives rise to the required 5- (2-haloalkenyl) compound which is in the 2,4- dimethoxy protected from. Deprotection can then be carried out by conventional techniques.
  • X is C ?f alkyl
  • alkyl eg. 5-ethyl substituted nucleosides may be produced by hydrogenation of the corresponding 5-alkynyl or 5- alkenyl pyrimidine base followed by coupling to the 4-thio sugar compound. Conventional hydrogenation conditions, such as hydrogen over palladium/charcoal catalysts, may be adopted.
  • 5-Fluoroalkyl substituents may be generated from the corresponding 5-hydroxyalkyl substituents, preferably starting from nucleosides having protected sugar hydroxyl groups on the 4- thio sugar moiety.
  • Suitable protecting groups include tert-butyl diphenylsilyloxy groups which may be introduced using tert- butyldiphenylsilylchloride.
  • the protected 5-hydroxyalkyl nucleoside is treated with a fluorinating agent such as diethylaminosulphurtrifluoride followed by deprotection of the hydroxyl groups using tetra-n-butylammonium fluoride to give the monofluoroalkyl derivative.
  • the above 5-hydroxyalkyl nucleoside starting materials where the alkyl group is a methylene are obtained from the corresponding 5-methyl-nucleosides by protection (for instance using tert-butyldiphenylsilylchloride) of the hydroxyl groups of the 4-thio sugar moiety, photolytic bromination (for instance, using bromine, N-bromosuccinimide in carbon tetrachloride) and hydrolysis of the bromoalkyl side chain using sodium bicarbonate.
  • X is nitro or optionally substituted amino
  • Nitro-substituents are introduced at the 5-position of the 5-unsubstituted 4'thio-nucleosides by reaction with a nitrating agent for example nitronium tetrafluoroborate (N0 2 BF 4 ) , and these may be reduced using hydrogen over palladium/charcoal or tin (II) chloride to provide the corresponding amino substituent.
  • a nitrating agent for example nitronium tetrafluoroborate (N0 2 BF 4 )
  • II palladium/charcoal or tin
  • 5-Alkylamino and 5-dialkylamino substituents may be introduced by reacting a suitably protected 5-iodo-nucleoside with a corresponding alkylamine or dialkylamine. Protection is preferably by acylation for example by acetylation using acetic anhydride in pyridine.
  • X is alkoxy
  • alkoxy substituents may be introduced by treatment of the corresponding 5-iodo-4' -thionucleoside with an alkoxylating agent such as sodium alkoxide in an appropriate solvent such as methanol or dimethylformamide or the corresponding alkanol.
  • an alkoxylating agent such as sodium alkoxide in an appropriate solvent such as methanol or dimethylformamide or the corresponding alkanol.
  • Cyano substituents are introduced at the 5-position by reaction of the corresponding 5-iodo 4' -thio-nucleoside with potassium cyanide in the presence of potassium acetate in a suitable solvent such as dimethylformamide, preferably at elevated temperature, for example 80°C-120°C, preferably 100°C
  • X is thiocyanate. alkylthio, mercapto
  • 5-hydroxy-4' -thio-nucleosides may be prepared by the method described above in connection with the preparation of alkoxy compounds.
  • the starting compound, 5-unsubstituted 4'-thio- nucleoside may conveniently be prepared by condensation of the appropriate sugar moiety with commercially available uracil.
  • X is hvdroxy-C 13 alkyl. These compounds may be prepared as described above in connection with the preparation of haloalkyl compounds. Hydroxymethyl uracil itself is commercially available.
  • X is C, ⁇ alkoxyC, 7 alkyl or C /.alkylthiomethyl.
  • X is alkoxymethyl or alkylthiomethyl
  • bases in which the group X is of the formula -CH 2 0H may be made starting from bases in which the group X is of the formula -CH 2 0H.
  • the alkoxymethyl compounds may be made by reacting this starting material with an appropriate alkanol group in the presence of an acid catalyst or an acidic ion exchange resin.
  • the alkylthiomethyl compounds may be made in a similar way but using the appropriate alkylmercaptan group or an appropriate metal salt thereof.
  • the resulting base may be condensed with the desired 4-thio sugar as described herein.
  • alkoxyethyl compounds may be made in an analogous manner starting from the appropriate base in which the group X is hydroxyethyl.
  • These starting bases are either commercially available or may be made as described above in connection with the preparation of haloalkyl compounds.
  • these alkoxyalkyl and alkylthiomethyl compounds may be made from nucleosides of the formula I or a protected derivate thereof in which the group X is -CH 2 L where L is a leaving group, eg halo such as bromo, or alkyl or arylsulphonyloxy such as trifluoromethanesulphonyl or p- toluenesulphonyl or a secondary acyclic or cyclic amino group, such as dimethylamino or pyrrolidinyl.
  • L is a leaving group, eg halo such as bromo, or alkyl or arylsulphonyloxy such as trifluoromethanesulphonyl or p- toluenesulphonyl or a secondary acyclic or cyclic amino group, such as dimethylamino or pyrrolidinyl.
  • the reaction is carried out by treatment of one of these with a suitable nucleophilic
  • the procedure may be performed using methods analogous to those described by Barwolff and Langen, Nucleic Acid Chemistry - Improved and New Synthetic Procedures, Methods and Techniques, Part 1, Eds. L.B. Townsend and R.S. Tipson, p359.
  • the above reference also describes the procedures which may be utilised to make compounds in which L is OH.
  • Such compounds may be used to make compound where L is O-alkyl or S-alkyl using the procedures described above.
  • the compounds where L is dimethylamino or pyrrolidinyl may be prepared by methods analogous to those described by Badman and Reese in J. Chem. Soc. Commun. 1987, 1732-1734 and by Jones et al, Synthesis 1982, 259-260.
  • the 4-thio-sugar compound may be produced by conventional methods prior to coupling with the base or derived by modification of another sugar moiety which is already part of a nucleoside.
  • the process may be carried out using the following procedures to prepare compounds of formula (I) in which R 2 and R 3 have the following meanings include:-
  • R 2 is hydrogen and R 3 is hydroxy.
  • Such compounds may be prepared from a corresponding 3'5' , - anhydro compound for example by treatment with a strong base eg. potassium ter -butoxide.
  • a strong base eg. potassium ter -butoxide.
  • Such 3' ,5' -anhydro compounds may be prepared by treating the corresponding 3 ' , 5' -methanesulphonate diester with a base.
  • the 3' 5' -methanesulphonate diester may be obtained by esterification of the 2-deoxy-L-ribose sugar which may be synthesised by analogous methods to those of Smejkal and Sor , (1964) , Nucleic Acids. Components and their Analogues, part Lii, volume 29, 809.; Genu-Dellac e_t al.
  • acetylated uracil nucleoside (produced for instance by reactions as described above and acetylated using acetic anhydride in pyridine) is treated with p-chlorophenyl- phosphorodichloridate, 1,2,4-triazole and pyridine to produce the 4- (1,2,4-triazol-l-yl) derivative which is then treated with ammonia in dioxane (which also removes the 4-thio sugar protecting group(s) ) to form the corresponding unprotected cytosine 4' -thionucleoside.
  • esters may be prepared by treating a compound of formula (I) with an appropriate esterifying agent, for example, an acyl halide or anhydride.
  • Salts may be prepared by treating a compound of formula (I) with an appropriate base, for example an alkali metal, alkaline earth metal or ammonium hydroxide, or where necessary, an appropirate acid, such as hydrochloric acid or an acetate, eg. sodium acetate.
  • compounds of the formula (V) in which in which R 2 is hydrogen, R 3a is OZ 3 and W is a group -S-CH 2 -Ar as defined above may be made by ring closure of a compound of the formula (VII)
  • Z 3 and Z 5 are hydroxyl protecting groups as defined above, for example optionally substituted benzyl or acyl groups as defined above.
  • the groups Z 3 and Z 5 are acyl groups.
  • the group A is a leaving group, for example an organosulphonyl group such as an optionally substituted alkyl- or aryl-sulphonyl group, for instance methanesulphonyl, a haloalkylsulphonyl group (eg. trifluoromethylsulphonyl) and optionally substituted phenyl- sulphonyl (eg. toluylsulphonyl or bromobenzenesulphonyl) , and Ar is as defined above.
  • A is preferably a methanesulphonyl group.
  • the ring closure may be performed under appropriate basic conditions. Suitable conditions include those described by J. Harness and N.A. Hughes (Chem. Comm. 1971, 811) , which includes the use of sodium iodide and barium carbonate.
  • the compound of the formula (VII) may be made from a compound of formula (VIII) Ar-CH 2 -S.. S-CH 2 -Ar
  • the group M is a group of the formula Ar ** -CO- where Ar 1 is a phenyl group which may be optionally substituted by any of the substituents described above for the group Ar.
  • Removal of this group M may be performed under standard conditions, for example with a base such as an alkali metal alkoxide, for instance sodium methoxide in methanol.
  • a base such as an alkali metal alkoxide, for instance sodium methoxide in methanol.
  • the compounds of formula (IX) may be obtained by the concomitant inversion and derivatization of the 4-hydroxy group of a compound of formula (X) :
  • the inversion and derivatization may be effected by reacting the compound of formula (X) with a derivative of the group M, such as an acid of the formula Ar'-COOH, for example benzoic acid (or a reactive derivative thereof) where Ar 1 is as defined above.
  • a derivative of the group M such as an acid of the formula Ar'-COOH, for example benzoic acid (or a reactive derivative thereof) where Ar 1 is as defined above.
  • the reaction is performed typically at room temperature and under neutral conditions in a suitable polar solvent, for instance tetrahydrofuran.
  • a suitable polar solvent for instance tetrahydrofuran.
  • the Mitsunobu reaction is used for the inversion and derivatization; diethyl azodicarboxylate (DEAD) and triphenylphosphine are used as coreactants together with the acid Ar'COOH.
  • the compound of formula (X) may be made from a glycoside compound of formula (XI)
  • R is a defined above.
  • the hydroxyl groups of the compound of formula (XII) are protected under conventional conditions with the reactive derivative of the groups Z 3 and Z 5 .
  • the bromo derivative may be used.
  • Z 3 and Z 5 are benzyl groups
  • benzyl bromide may be used.
  • the reaction may be performed in an organic solvent such as tetrahydrofuran in the presence of a suitable base such as sodium hydride and a phase transfer catalyst such as tetrabutylammonium iodide.
  • Compounds of the formula (XII) may be made by standard techniques from 2-Deoxy-L-ribose, which can be made by methods described in .J. Robins, T.A.Khwaja, R.K. Robins, J. Org. Chem., 1970, 35(3) 636.
  • 2-Deoxy-L-ribose may be reacted with an alcohol of formula R-OH (where R is as defined above) in the presence of an acid. Hydrochloric acid is suitable.
  • R-OH When R is a methyl group, the alcohol R-OH will be methanol.
  • the compound of the formula (VIII) may also be made directly from the compound of formula (X) using a Mitsunobu reaction under conditions analogous to those described by D.R. Williams et al, JACS (1990) 112, 4552.
  • R, Z 3 and Z ⁇ are as defined for a compound of formula (XI) ; with a compound of the formula Ar-CH 2 -SH where Ar is defined above.
  • the reaction may be conducted using similar conditions to those described above for the preparation of the compound of the formula (X) .
  • the reaction is performed in the presence of an acid, for example an inorganic acid such as HCl or a Lewis acid such as TiCl 4 . TiCl 4 is preferred.
  • the groups Z 3 and Z 5 are preferably acyl groups, in particular p-nitrobenzoyl groups.
  • a compound of the formula Ar-CH 2 -SH which is preferred include p-methoxybenzyl mercaptan.
  • Z n OH is reacted with a compound or compounds of formula Z n OH where Z n is Z 3 and/or Z 5 .
  • Z 3 and Z 5 will be the same and a single compound Z n 0H may be used. If different values of Z 3 and Z 5 are required, then the required mixture of compounds of ZOH may be used, and the desired reaction products separated from the resulting reaction mixture.
  • Preferred compounds of the formula Z n OH are those where Z n is an acyl group as defined above.
  • Z n 0H is p-nitro- benzoic acid, although other benzoic acids may also be used.
  • the reaction is performed in the presence of an azido- carboxylate such as diethylazidodicarboxylate or preferably diisopropylazidodicarboxylate.
  • the solvent for the reaction may be DMF, tetrahydrofuran, dichloromethane or toluene. Toluene is preferred.
  • the reaction may be performed at room temperature.
  • Z 3 and Z 5 are both p-nitrobenzyl.
  • Compounds of the formula (XIV) may be made from 2- deoxyribose using techniques known in the art, for example as described above in connection with the production of compounds of formula (XII) .
  • Compounds of the formula (I) may also be made by reaction of a compound of formula (III) with a compound of formula (XV)
  • L is a leaving group, for example, an acyloxy group such as C alkanoyloxy, for instance, acetoxy
  • P 1 is a protecting group or hydrogen
  • Z is a directing group.
  • Suitable groups P 1 include groups such that P'O is an ether group, e.g. a silyl ether group (such as tertbutyldiphenylsilyl ether or tertbutyldimethylsilyl ether) , a straight or branch chain alkyl ether group, a cyclic ether group (such as tetrahydropyran-2-yl ether) or an optionally substituted aryl ether group (such as benzyl ether, trityl ether or benzhydryl ether) .
  • the group P'O- can also be an ester group e.g.
  • the reaction of the compound of formula (XV) with the base of formula (III) may be carried out for example in the presence of nonafluorobutane sulphonic acid or a Lewis acid catalyst, e.g. tin (IV) chloride, a mercury (II) salt or trimethylsilyl triflate.
  • a Lewis acid catalyst e.g. tin (IV) chloride, a mercury (II) salt or trimethylsilyl triflate.
  • the reaction can be carried out, for example, at a temperature of from 0°C to room temperature in a suitable solvent such as acetonitrile or a chloroalkane.
  • Z is phenylselenyl it may be eliminated under oxidising conditions which are capable of oxidising selenium without oxidising sulphur, e.g. by treatment with m- chloroperbenzoic acid in dichloromethane at -20°C (Toru et al , Tetrahedron Letters, 1986, 22; 1583) .
  • Compounds of the formula (I) in which R 2 and R 3 are both hydrogen may be made by elimination of the group Z (from the reaction product of (XV) and (III) ) under reducing conditions, e.g. using tributyltin. ' hydride and triethyl borane (see Nozaki et al , Tetrahedron Letters-,; 1988, 23; 6125) .
  • EP-A-514 036 describes the production of D-thionucleosides from, inter-alia , the isomer of the compound of formula (XV) which has the D-configuration.
  • the reactions described in EP-A-514 036, the contents of which are incorporated herein by reference, may be applied to the production of compounds of formula (I) .
  • Compounds of the formula (XV) may be made by acylation under standard conditions (eg. acetic anhydride with pyridine) of a compound of formula (XVI) :
  • the compound of formula (XVI) may be made from a compound of formula (XVII) ,
  • E-5- (2-bromovinyl) -2' -deoxy-4' -thio- ⁇ -L-uridine is dissolved in a solution of sodium methoxide in methanol (7.5ml, 0.1m) and the mixture is allowed to stand at 22°C for 24 hours.
  • the solution is neutralised by careful addition of Dowex 50 ion exchange resin (H + form) to pH6. The resin is filtered off and washed with methanol and the filtrate and washings evaporated to a white solid.
  • MeOH-CH 2 Cl 2 (1:1, 18 ml) is added slowly and the mixture allowed to warm to ambient temperature then evaporated. The residue is re-evaporated from MeOH (3x) , taken up in MeOH-CHCl 3 (1:1, 15ml) and the solid collected by filtration, yielding the desired ⁇ -anomer of the product.
  • Benzyl 3,5-di-0-benzyl-2-deoxy-1 , 4-dithio-D-erythro- pentofuranoside (5.6 mmol) is dissolved in CC1 4 (30 ml) and bromine (6.2 mmol) in CC1 4 (30 ml) is added. After stirring for 55 min. at ambient temperature the solvent is evaporated and the residue re-evaporated from CC1 4 (10 ml) to remove excess bromine.
  • This compound is prepared by a method similar to the iodo compound above with the following modifications:
  • the total solvent (MeCN) volume for the reaction is 3 ml.
  • 5-ethynyluracil this compound is prepared in a similar manner to that described in Example 5.
  • 5-ethynyluracil may be prepared from 5-ioduracil using the methodology analogous to that described by M.J. Robins et al (ibid) .
  • E-5- (2-Bromovinyl) -2,4-dimethoxypyrimidine To a solution of E-5- (2-carboxyvinyl) -2,4-dimethoxypyrimidine (0.300 g; 1.43 mmol) in dry DMF (5 ml) was added K 2 C0 3 (0.45 g: 5.25 mmol) . After stirring at ambient temperature for 15 min. a solution of N.-bromosuccinimide (0.258 g; 1.45 mmol) in dry DMF (4 ml) was added dropwise over 10 min. The suspension was immediately filtered, the solid washed with DMF and the filtrate evaporated in high vacuum.
  • the carboxymethyllactone was dissolved in 75 ml of dimethylsulphoxide, to which were added 20 drops of brine. After 2 h at 170°C the reaction was complete. After cooling, the reaction solution was directly transferred onto a pre-packed silica column, and the lactone eluted off with 30% ether in petrol, to give a colourless oil on evaporation.
  • the lactone (7.5 mmol) was reduced by diisobutylaluminiumhydride (7.9 mmol) in 100 ml of dry toluene at -78°C over 3 h, after which the reaction was quenched with 100 ml of saturated ammonium chloride and vigorously stirred for 1 h. After filtering through a hyflo pad, the organic layer was separated and washed twice with brine, dried and evaporated.
  • the crude lactol was dissolved in 200 ml of dichloromethane and treated with 4-dimethylamino pyridine (1.0 g, 8.25 mmol) and acetic anhydride (0.84 g, 8.25 mmol) . Reaction was complete in 2 h at room temperature, then the solution was washed sequentially with water, copper sulphate, water then brine, dried and evaporated. Purification was achieved by on a short flash column.
  • the 2'-selenyl nucleoside was dissolved in dry dichloromethane and cooled to -20°C under nitrogen. To this was added an equivalent of metachloroperoxvbenzoic acid in one portion, and the temperature maintained during the course of the reaction (45 0 min) . 5 eq of pyridine were then added and the solution allowed to warm to room temperature over 1 hour. After dilution with dichloromethane the solution was washed successively with water, copper sulphate (x2) , sodium bicarbonate (x2) , water, and brine, before drying and evaporation. Purification was achieved on a 5 flash column, eluted with methanol/chloroform/ammonia (7:92:1) .
  • silyl ether was stirred in a thf solution with tetraethylammonium fluoride (1.1 eq) for 1 hour at room
  • aqueous layer was further extracted with dichloromethane (3 x 50 ml) , the combined organic layers dried (Na 2 S0 4 ) and evaporated to dryness. Residual pyridine was co-evaporated with ethanol (2 x 50 ml) to give the title compound.
  • N-iodosuccinimide (6 mg, 0.027 mmol) was added and after stirring overnight the reaction mixture was diluted with dichloromethane

Abstract

L'invention concerne des nucléosides antiviraux de la formule (I). Dans cette formule: Y représente un hydroxy ou un amino; X représente un hydrogène, un hydroxy, un mercapto, un halo, un trifluorométhyle, un méthyle, un alkyleC2-6, un haloalkyleC1-6, un hydroxyalkyleC1-3, un formyle, un alcényleC2-6, un haloalcényleC2-6, un alcynyleC2-6, un alcoxyC1-6, un alkylthioC1-6, un alcoxyC1-6alkyleC1-2, un alkylthiométhyleC1-6, un amino, un monoC1-6alkylamino, un diC1-6alkylamino, un cyano, un thiocyanate ou un nitro; R2 représente un hydrogène et R3 représente un hydroxy ou un hydrogène ou R2 et R3 forment ensemble une liaison carbone-carbone. On décrit également des dérivés de ces composés actifs sur le plan physiologique, des compositions contenant ces composés, leur utilisation pour traiter et soigner des maladies virales et des procédés pour produire ces composés.
PCT/GB1993/001858 1992-09-04 1993-09-03 Nucleosides pyrimidiniques antiviraux WO1994005687A1 (fr)

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JP6506988A JPH08504753A (ja) 1992-09-04 1993-09-03 坑ウイルス性ビリミジンヌクレオシド
AU49733/93A AU4973393A (en) 1992-09-04 1993-09-03 Antiviral pyrimidine nucleosides
EP94908867A EP0658166A1 (fr) 1992-09-04 1993-09-03 Nucleosides pyrimidiniques antiviraux

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GB929218810A GB9218810D0 (en) 1992-09-04 1992-09-04 Antiviral pyrimidine nucleosides

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WO1997019686A1 (fr) * 1995-11-30 1997-06-05 Dr. Rentschler Arzneimittel Gmbh & Co. Utilisation d'une combinaison de pentoxifylline et d'interferons de type i pour le traitement de la sclerose en plaques
WO2002018404A2 (fr) * 2000-08-30 2002-03-07 F. Hoffmann-La Roche Ag Derives de nucleosides
WO2002057287A2 (fr) * 2001-01-22 2002-07-25 Merck & Co., Inc. Derives de nucleoside servant d'inhibiteurs de l'arn polymerase virale arn dependante
WO2004078742A1 (fr) * 2003-03-03 2004-09-16 Guilford Pharmaceuticals Inc. Thiolactones
US8481712B2 (en) 2001-01-22 2013-07-09 Merck Sharp & Dohme Corp. Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase
US9061041B2 (en) 2011-04-13 2015-06-23 Merck Sharp & Dohme Corp. 2′-substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases
US9150603B2 (en) 2011-04-13 2015-10-06 Merck Sharp & Dohme Corp. 2′-cyano substituted nucleoside derivatives and methods of use thereof useful for the treatment of viral diseases
US9156872B2 (en) 2011-04-13 2015-10-13 Merck Sharp & Dohme Corp. 2′-azido substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases
US9408863B2 (en) 2011-07-13 2016-08-09 Merck Sharp & Dohme Corp. 5′-substituted nucleoside analogs and methods of use thereof for the treatment of viral diseases
US9416154B2 (en) 2011-07-13 2016-08-16 Merck Sharp & Dohme Corp. 5′-substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases
CN106061959A (zh) * 2014-02-18 2016-10-26 富士胶片株式会社 四氢噻吩骨架型糖化合物的制造方法及四氢噻吩骨架型糖化合物
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US10059734B2 (en) 2014-10-31 2018-08-28 Fujifilm Corporation Thionucleoside derivative or salt thereof, and pharmaceutical composition
US10093645B2 (en) 2012-08-13 2018-10-09 Fujifilm Corporation Synthetic intermediate of 1-(2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl)cytosine, synthetic intermediate of thionucleoside, and method for producing the same
US11141421B2 (en) 2018-01-29 2021-10-12 Fujifilm Corporation Antitumor agent for biliary tract cancer and method for treating biliary tract cancer
WO2022008025A1 (fr) * 2020-07-05 2022-01-13 Since & Technology Development Fund Authority Nucléosides et dérivés de 2-hydroxyiminopyrimidine et utilisations antivirales de ceux-ci
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TW201340971A (zh) * 2012-03-09 2013-10-16 Taiho Pharmaceutical Co Ltd Ｄｎａ損傷劑
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EP0409575A1 (fr) * 1989-07-17 1991-01-23 The University Of Birmingham Pyrimidine nucléosides antiviraux
WO1991004033A1 (fr) * 1989-09-15 1991-04-04 Southern Research Institute 2'-desoxy-4'-thioribonucleosides utiles comme agents antiviraux et anticancereux
EP0421777A1 (fr) * 1989-10-04 1991-04-10 The University Of Birmingham Nucléosides pyrimidiniques antiviraux
WO1991016333A1 (fr) * 1990-04-20 1991-10-31 Southern Research Institute 2'3'-didesoxy-4'-thioribonucleosides utilises comme agents antiviraux et anticancereux
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WO1997019686A1 (fr) * 1995-11-30 1997-06-05 Dr. Rentschler Arzneimittel Gmbh & Co. Utilisation d'une combinaison de pentoxifylline et d'interferons de type i pour le traitement de la sclerose en plaques
WO2002018404A3 (fr) * 2000-08-30 2002-11-14 Hoffmann La Roche Derives de nucleosides
WO2002018404A2 (fr) * 2000-08-30 2002-03-07 F. Hoffmann-La Roche Ag Derives de nucleosides
EP1707571A1 (fr) * 2001-01-22 2006-10-04 Merck & Co., Inc. Derivés de nucléoside comme inhibiteurs de l'ARN polymérase virale ARN-dépendante
WO2002057287A3 (fr) * 2001-01-22 2002-10-10 Merck & Co Inc Derives de nucleoside servant d'inhibiteurs de l'arn polymerase virale arn dependante
WO2002057287A2 (fr) * 2001-01-22 2002-07-25 Merck & Co., Inc. Derives de nucleoside servant d'inhibiteurs de l'arn polymerase virale arn dependante
EA007491B1 (ru) * 2001-01-22 2006-10-27 Мерк Энд Ко., Инк. Производные нуклеозидов в качестве ингибиторов рнк-зависимой рнк вирусной полимеразы
KR100828453B1 (ko) * 2001-01-22 2008-05-13 머크 앤드 캄파니 인코포레이티드 Ｒｎａ 의존성 ｒｎａ 바이러스 폴리머라제의억제제로서의 뉴클레오시드 유도체
HRP20030565B1 (en) * 2001-01-22 2011-12-31 Merck Sharp & Dohme Corp. Nucleoside derivatives as inhibitors of rna-dependent rna viral polymerase
US8481712B2 (en) 2001-01-22 2013-07-09 Merck Sharp & Dohme Corp. Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase
WO2004078742A1 (fr) * 2003-03-03 2004-09-16 Guilford Pharmaceuticals Inc. Thiolactones
US7125907B2 (en) 2003-03-03 2006-10-24 Guilford Pharmaceuticals Inc. Thiolactones
US7553866B2 (en) 2003-03-03 2009-06-30 Eisai Corporation Of North America Thiolactones
US7968593B2 (en) 2003-03-03 2011-06-28 Eisai Inc. Thiolactones
US9156872B2 (en) 2011-04-13 2015-10-13 Merck Sharp & Dohme Corp. 2′-azido substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases
US9061041B2 (en) 2011-04-13 2015-06-23 Merck Sharp & Dohme Corp. 2′-substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases
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JPH08504753A (ja) 1996-05-21
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EP0658166A1 (fr) 1995-06-21
CA2143834A1 (fr) 1994-03-17

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