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WO1996007666A1 - Analogues de mononucleotides et de dinucleotides, et leurs intermediaires - Google Patents

Analogues de mononucleotides et de dinucleotides, et leurs intermediaires Download PDF

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Publication number
WO1996007666A1
WO1996007666A1 PCT/GB1995/001986 GB9501986W WO9607666A1 WO 1996007666 A1 WO1996007666 A1 WO 1996007666A1 GB 9501986 W GB9501986 W GB 9501986W WO 9607666 A1 WO9607666 A1 WO 9607666A1
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hydrogen
formula
group
compound according
compound
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PCT/GB1995/001986
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English (en)
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Edward Irving
Anthony David Baxter
Stephen Paul Collingwood
Roger John Taylor
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Novartis Ag
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Priority to AU32629/95A priority Critical patent/AU3262995A/en
Publication of WO1996007666A1 publication Critical patent/WO1996007666A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H23/00—Compounds containing boron, silicon or a metal, e.g. chelates or vitamin B12
    • 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
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • C07H21/04—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with deoxyribosyl as saccharide radical
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates to compounds which are mononucleotide and dinucleotide analogues capable of terminating a replicating strand of a nucleic acid and intermediates therefor, and their preparation.
  • nucleosides substituted at the 3' position by an azido group or other atom or group capable of terminating a replicating strand of a nucleic acid such as fluoro or amino are of continuing interest as therapeutic agents for the treatment of AIDS and other viral diseases.
  • appropriately 3'-substituted mononucleotide and dinucleotide analogues having phosphinic acid, phosphinate ester or phosphine oxide linkages in place of the phosphate ester linkages of natural nucleotides may be prepared.
  • These compounds have good hydrolytic stability, facilitating their use as pharmaceuticals in the treatment of viruses such as HTV, influenza and herpes.
  • R 1 is hydrogen, R l t or a group of formula
  • R 1 is R ⁇ or a protecting group Q
  • R l b is C1-C 20 alkyl, C 2 -C 2 o alkenyl, C 3 -C 10 cycloalkyl, C 6 -C 15 aryl, C 7 -C 16 aralkyl or a 5- or 6- membered heterocyclic group attached by a carbon atom in the heterocyclic group to the indicated phosphorus atom,
  • R 2 is hydrogen, R 2 a or -OR 15 , provided that when R 1 is hydrogen, R 2 is R 2 a or -OR 15 ,
  • R 2 a is a Cj-C2o aliphatic group, a C 3 -C ⁇ 0 cycloaliphatic group, a C 6 -C 15 aromatic group, a
  • R 3 is hydrogen, halogen, hydroxy, R 16 , -OR 16 , OCOR 16 or tri (C, -C 15 hydrocarbyl) silyloxy, or -OSO2R 16 ,
  • R 4 is R a or together with R 6 denotes a valence bond
  • R a is hydrogen, halogen or R 17 ,
  • R 5 is hydrogen, halogen, hydroxy, R 18 , -OR 18 , -OCOR 18 , or tri(C r C 15 hydrocarbyl) silyloxy or -OSO 2 R 18 ,
  • R 6 is hydrogen, halogen or R 19 , or together with R 4 denotes a valence bond,
  • R 7 is hydrogen, or an atom or group capable of terminating a replicating strand of a nucleic acid or of inhibiting viral DNA synthesis, other than a group connected to the indicated furanose ring through an oxygen atom, or together with R 8 denotes a valence bond,
  • R 8 is R 8 migraine or together with R 7 denotes a valence bond
  • R 8 is hydrogen, halogen, hydroxy, R 20 , -OR 20 , -OCOR 20 , -OSO 2 R 20 or tri(C,-C 15 hydroca ⁇ byl)silyloxy,
  • R 9 is a monovalent nucleoside base radical
  • R 10 is hydrogen or R 10heim
  • R 10 t is R 21 , -COR 21 , -SO 2 R 21 or tri(C r C 15 hydrocarbyl)silyl,
  • R 11 is hydrogen, halogen, hydroxy, R 22 , -OR 22 , -OCOR 22 , -OSO2R 22 or Z,
  • R lz is hydrogen, halogen or R 23
  • R 13 is hydrogen or R 13 a , R 13 , is halogen, hydroxy, R 24 , -OR 24 , -OCOR 24 , -OSO 2 R 24 or tri(C r C 15 hydrocarbyl)silyloxy,
  • R 14 is a monovalent nucleoside base radical
  • R 15 is hydrogen or R 15 a ,
  • R 15 is a to C 10 aliphatic group, a C 3 to C 8 cycloaliphatic group, a C 6 to C 15 aromatic group or a C 7 to C 16 araliphatic group,
  • R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 and R 24 are independently a Q to C 10 aliphatic group, a C 3 to Cio cycloaliphatic group, a C 6 to C1 5 aromatic group or a C 7 to C 30 araliphatic group, and Z is substituted or unsubstituted C 6 to Q aryloxythiocarbonyloxy.
  • the aliphatic groups are independently substituted or unsubstituted alkyl or alkenyl groups
  • the cycloaliphatic groups are substituted or unsubstituted cycloalkyl groups
  • the aromatic groups arc substituted or unsubstituted aryl groups
  • the araliphatic groups are substituted or unsubstituted aralkyl groups.
  • the substituted or unsubstituted alkyl groups may be, for example, substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, ten-butyl, n-pentyl, neopentyl, n-hexyl, n-octyl, 2-ethylhexyl or n-decyl.
  • R 1 or R 2 as substituted or unsubstituted Ci to C 2 0 alkyl may additionally be, for example, substituted or unsubstituted n-dodecyl, n-tetradecyl, n-hexadecyl, n-octadecyl or eicosyl.
  • the substituted or unsubstituted alkenyl groups may be, for example, substituted or unsubstituted vinyl, allyl, 1-propenyl, isopropenyl, methallyl, 2-butenyl, 1-butenyl, isobutenyl, pentenyl, hexenyl, octenyl or decenyl.
  • R 1 or R 2 as substituted or unsubstituted alkenyl may additionally be, for example, dodecenyl, hexadecenyl, octadecenyl or eicosenyl.
  • the substituted or unsubstituted cycloalkyl groups may be, for example, substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, methylcyclopentyl, cyclohexyl, methylcyclohexyl, dimethylcyclohexyl, tert-butylcyclohexyl, cycloheptyl or cyciooctyl.
  • the substituted or unsubstituted aryl groups may be, for example, substituted or unsubstituted phenyl, o-tolyl, m-tolyl, p-tolyl, o-xylyl, m-xylyl, p-xylyl, alpha-naphthyl, beta-naphthyl, dimethylnaphthyl or anthryl.
  • R 1 , R 2 or R 15 as substituted or unsubstituted C 7 to C 16 aralkyl may be, for example, substituted or unsubstituted benzyl, 4-methylbenzyl. 2-phenylethyl, 2-phenylpropyl, 3-phenylpropyl or diphenylmethyl.
  • the other substituted or unsubstituted C 7 to C 30 aralkyl groups may be, for example, substituted or unsubstituted benzyl, 4-methylbenzyl, 2-phenylethyl, 2-phenylpropyl, 3-phenylpropyl, diphenylmethyl or triphenylmethyl.
  • the alkyl groups are C ⁇ to C alkyl
  • the alkenyl groups are C 2 to C alkenyl
  • the cycloalkyl groups are C 5 to C 8 cycloalkyl
  • the aryl groups are C 6 to C ⁇ 0 aryl
  • the C 7 to C 16 aralkyl group is C 7 to C 9 aralkyl
  • the C 7 to C 3 o aralkyl groups are C to C 2 o aralkyl, any of which are substituted or unsubstituted.
  • these groups are unsubstituted or substituted by halogen, hydroxy, Cj to C alkoxy, cyano, nitro, amino, Cj to C 4 alkylamino or di ⁇ alkyl) amino, the unsubstituted groups being especially preferred.
  • R 1 in formula I is a protecting group Q
  • this may be any group which is known to be effective in protecting P-H bonds whilst reactions are carried out which would affect such bonds and be readily removable after such reactions to generate a P-H bond.
  • protecting groups may be, for example, those in compounds of formula la of EP 0009348, or those in compounds described in Aust. J. Chem. 33, 292 (1980) or US 4933478.
  • Preferred protecting groups Q are to C 2 o hydrocarbyl groups, preferably alkyl groups, substituted on the carbon atom thereof attached to the indicated phosphorus atom by at least one hydroxy or CI-CH) alkoxy group, including those of formula
  • R 25 is hydrogen, C r C ⁇ 0 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl or C 7 -C ⁇ aralkyl and R 26 and R 27 are independently C ⁇ -C 10 alkyl.
  • Preferred groups of formula HI are those where R 25 is hydrogen or Cj-C 4 alkyl and R 26 and R 27 are each C1-C 4 alkyl.
  • Q is a group of formula HI where R 25 is hydrogen or methyl and R 26 and R 27 are each methyl or ethyl.
  • the tr-iC -C ⁇ hydrocarbyl)silyl radical may be, for example, trialkylsilyl such as trimethylsilyl, triethysilyl, tri-n-propylsilyl, tri-isopropysilyl, tri-n-butylsilyl, tri-isobutysilyl, tri-tert-butylsilyl, isopropyldimethylsilyl, terLbutyldimethylsilyl or 1,1,2,2-tetramethylethyldimethylsilyl (thexyldimethylsilyl), aryldialkylsilyl such as phenyldimethylsilyl, phenyldiethylsilyl, phenyldiisopropylsilyl or phenyl di-tert-butylsilyl, or alkylsilyl such as trimethylsilyl, triethysilyl, tri-n-propylsily
  • R 11 as substituted or unsubstituted C 6 -C 10 aryloxythiocarbonyloxy may be, for example, substituted or unsubstituted phenyloxythiocarbonyloxy, preferably C r C 4 alkyl- or halogen- substituted phenyloxythiocarbonyloxy, especially p-tolyloxythiocarbonyloxy or pentafluorophenoxythiocarbonyloxy.
  • R 9 or R 14 as a monovalent nucleoside base radical may be the same or different and may be a radical of a naturally occuring nucleoside base, such as adeninyl, cytosinyl, thyminyl, guaninyl or uracilyl, which may be unsubstituted or substituted, for example on an amino nitrogen atom by an acyl group such as acetyl, an aralkyl oxyalkyl group such as benzyloxymethyl or an aracyl group such as benzoyl or nitrobenzoyl, or a synthetic analogue thereof.
  • a naturally occuring nucleoside base such as adeninyl, cytosinyl, thyminyl, guaninyl or uracilyl, which may be unsubstituted or substituted, for example on an amino nitrogen atom by an acyl group such as acetyl, an aralkyl oxyalkyl
  • R 9 or R 14 as a monovalent nucleoside base radical is unsubstituted or substituted thyminyl, cytosinyl, guaninyl or adeninyl, especially thyminyl.
  • R 2 as R 2 a is preferably to C 4 alkyl, more preferably methyl or ethyl; C 2 to C alkenyl, more preferably vinyl or allyl; C 5 to C 8 cycloalkyl, more preferably cyclopenryl, cyclohexyl or methylcyclohexyl; C $ to C 10 aryl, more preferably phenyl, tolyl or naphthyl; or C to Co aralkyl, more preferably benzyl.
  • R 2 as R 2 a is especially methyl, cyclohexyl or phenyl.
  • R 15 is preferably hydrogen or to C alkyl. In certain especially preferred compounds R 2 is -OR 15 where R 15 is hydrogen, ethyl or isobutyl or R 2 is methyl.
  • R 3 is hydrogen, halogen (usually fluorine or chlorine), hydroxy, C to C alkyl (more preferably methyl or ethyl), Ci to C 4 alkoxy (more preferably methoxy or ethoxy), C 7 to C aralkyloxy (more preferably benzyloxy), or -OCOR 16 or -OSO 2 R 16 where R 16 is C t to C 4 alkyl, particularly methyl or ethyl, or C 6 to C 10 aryl, particularly phenyl or p-tolyl, or ( to C 6 alkyl) di (C 6 -C 8 aryl) silyloxy, particularly ten-butyl diphenylsilyloxy, and R 4 is hydrogen, halogen (usually fluorine or chlorine) or Cj to C 4 alkyl, particularly methyl or ethyl.
  • halogen usually fluorine or chlorine
  • R 3 and R 4 are each hydrogen.
  • R 5 is hydrogen, halogen (usually fluorine or chlorine), hydroxy, Cito C 4 alkyl (more preferably methyl or ed yl), Ci to C alkoxy (more preferably methoxy or ethoxy), C 7 to C aralkyloxy (more preferably benzyloxy), or -OCOR 18 or -OSO 2 R 18 where R 18 is C j to C 4 alkyl, particularly methyl or ethyl, or C 6 to C 10 aryl, particularly phenyl or p-tolyl, or (Cj -C 6 alkyl) di (C 6 -C 8 aryl) silyloxy, particularly ten-butyldiphenylsilyloxy, and R 6 is hydrogen, halogen (usually fluorine or chlorine) or to C 4 alkyl, particularly methyl or ethyl.
  • R 5 and R 6 are each hydrogen.
  • R 7 may be hydrogen or any atom or group capable of terminating a replicating strand of a nucleic acid or of inhibiting viral DNA synthesis, other than a group connected to the indicated furanose ring through an oxygen atom.
  • atoms and groups are known from the literature and include azido; halogen, generally fluorine or chlorine; mercapto, including alkylmercapto; amino, including alkylamino and dialkylamino; hydroxylamino; cyano; thiocyanate, -SCN; isothiocyanate, -NCS; and an unsubstituted or substituted hydrocarbyl group R 7 a which is to C 10 alkyl, preferably C j to C alkyl, C 2 to C 10 alkenyl, preferably C 2 to C 4 alkenyl, C 3 to C 8 cycloalkyl, preferably C 5 to C 8 cycloalkyl, C 6 to C 10 aryl, preferably C 6 to C 8 aryl
  • R 7 is hydrogen, azido or fluoro, or together with R 8 denotes a valence bond.
  • R 7 is azido or together with R 8 denotes a valence bond.
  • R 8 is preferably hydrogen, hydroxy or -OR 20 , -OCOR 20 or -OSO 2 R 20 where R 20 is substituted or unsubstituted C ⁇ to C alkyl (more preferably methyl or ethyl) or substituted or unsubstituted C 6 to CIQ aryl (more preferably phenyl, tolyl or naphthyl), or together with R 7 denotes a valence bond. In certain especially preferred compounds, R 8 is hydrogen, or together with R 7 denotes a valence bond.
  • R 9 is thyminyl and, where R 1 is a group of formula II, R 14 is also myminyl.
  • R 10 is preferably hydrogen, substituted or unsubstituted Ci to C 4 alkyl (more preferably methyl or ethyl), substituted or unsubstituted C 7 to C 20 aralkyl (more preferably benzyl, diphenylmethyl, triphenylmethyl, methoxytriphenylmethyl or dimethoxytriphenylmethyl), -COR 21 or -SO 2 R 21 where R 21 is substituted or unsubstituted to C 4 alkyl or substituted or unsubstituted C 6 to C 10 aryl (more preferably phenyl, tolyl or naphthyl), or (Cj to C 6 alkyl)di(C 6 -C 8 aryl)silyl.
  • R 10 is hydrogen, benzoyl or ten-butyldiphenylsilyl.
  • R 11 is hydrogen, halogen, hydroxy, -OCOR 22 or -OSO 2 R 22 where R 22 is substituted or unsubstituted Cj to C alkyl or C 6 to o aryl (more preferably methyl, trifluoromethyl, ethyl, phenyl, tolyl or naphthyl), or C1-C 4 alkyl- or halogen- substituted phenyloxythiocarbonyloxy, and R 12 is hydrogen or halogen.
  • R 11 is hydrogen, hydroxy or p-tolyloxythiocarbonyloxy and R 12 is hydrogen.
  • R 13 is hydrogen, hydroxy, or -OR 24 , -OCOR 24 or -OSO 2 R 24 where R 24 is substituted or unsubstituted Cj to C 4 alkyl or C 6 to CI Q aryl (more preferably methyl, ethyl, phenyl, tolyl or naphthyl).
  • R 13 is hydrogen.
  • R 1 is preferably hydrogen, a protecting group Q or a group of formula II where R 10 to R 14 have the preferred meanings hereinbefore defined.
  • R 1 is hydrogen, a protecting group of formula IH where R 25 is hydrogen or methyl and R 26 and R 27 are each methyl or ethyl, or a group of formula II where R 10 is hydrogen or ten-butyldiphenylsilyl, R 11 is hydrogen, hydroxy or p-tolyloxythiocarbonyloxy, R 12 is hydrogen, R 13 is hydrogen and R 14 is thyminyl.
  • R 1 to R 9 certain especially preferred compounds of the invention are those in which R 1 is hydrogen, a protecting group Q of formula III as defined above, or a group of formula ⁇ where R 10 is hydrogen, benzoyl or ten-butyldiphenylsilyl, R 11 is hydrogen, hydroxy or p-tolyloxythiocarbonyloxy, R 12 and R 13 are hydrogen and R 14 is thyminyl; R 2 is methyl, cyclohexyl, phenyl or -OR 15 where R 15 is hydrogen, ethyl or isobutyl; R 3 , R 4 , R 5 and R 6 are each hydrogen; R 7 is hydrogen, azido or fluoro, or together with R 8 denotes a valence bond; R 8 is hydrogen or together with R 7 denotes a valence bond; and R 9 is thyminyl.
  • Compounds of the invention may be in the form of one of the possible isomers, for example as a diastereomer, an optical isomer or a racemate, or a mixture thereof.
  • Preferred isomers of compounds of formula I are those of formula where R 2 to R 9 are as hereinbefore defined and R 1 is hydrogen, R 1 , as hereinbefore defined or a group of formula
  • R 10 to R 14 are as hereinbefore defined.
  • R 10 , R 13 and R 14 are as hereinbefore defined.
  • This reaction may be carried out in the presence of a base, preferably a non-nucleophilic base, for example a hindered amine such as 1, 8-diazabicyclo [5.4.0] undec-7-ene or 1,5-diazabicyclo [4.3.0] non-5-ene, preferably in an amount of 0.1 to 2 equivalents, especially 1 to 1.5 equivalents, or an alkali metal alkoxide such as the ten-butoxide of sodium or potassium.
  • the reaction may be carried out at temperamres of -20 to 100°C, preferably 10 to 30°C.
  • an organic solvent for example a hydrocarbon such as benzene, toluene or xylene, a halohydrocarbon such as dichloroethane or methylene chloride or, preferably, an ether such as diemyl ether, dioxan or, especially, tetrahydrofuran.
  • a hydrocarbon such as benzene, toluene or xylene
  • a halohydrocarbon such as dichloroethane or methylene chloride
  • an ether such as diemyl ether, dioxan or, especially, tetrahydrofuran.
  • R 1 is a group of formula II in which R 11 is hydroxy and R 12 is hydrogen
  • a silylating agent may be, for example, a dialkylhalosilane such as dimethylchlorosilane, trialkylhalosilane such as trimethylchlorosilane or triethylchlorosilane which is reacted with the compound of Formula I where R 1 is hydrogen in the presence of tertiary base such as pyridine or triethylamine.
  • silylating agent which can be used is a bis(trialkylsilyl) derivative of an amide, for example bis(trirnethylsilyl)acetamide or bis(trimethylsilyl)trifluoroacetamide).
  • the reaction between the compound of formula I where R 1 is hydrogen and the silane or the silyl amide may be carried out at temperatures ranging from -20°C to 150°C and can be effected with or without the use of a solvent such as diethylether, tetrahydrofuran, dioxan. dichloromethane or toluene. Alternatively, an excess of the silane can be used as diluent.
  • the silylating agent may alternatively be hexamethyldisilazide, which may be reacted with the compound of Formula I where R 1 is hydrogen in the absence of a solvent at 100-200°C.
  • the reaction of the P(LII) silyl compound with the aldehyde of formula VI may be carried out under conditions conventional for substitution reactions on P(HT) species. It is preferably carried out by the Arbuzov method, e.g. at temperatures between ambient and elevated temperatures such as 160°C, followed by hydrolysis of the intermediate silyl species.
  • the reaction between the aldehyde of formula VI and the compound of formula I where R 1 is hydrogen may be carried out under acid conditions, for example in the presence of a Lewis acid such as boron trifluoride or a titanium (IV) compound, for example a titanium tetrahalide such as TiCl 4 , a titanium dialkoxidedihalide such as Ti(OiPr) 2 Cl 2 or, preferably, a titanium tetraalkoxide such as titanium tetra-isopropoxide.
  • a Lewis acid such as boron trifluoride or a titanium (IV) compound
  • a titanium tetrahalide such as TiCl 4
  • a titanium dialkoxidedihalide such as Ti(OiPr) 2 Cl 2
  • a titanium tetraalkoxide such as titanium tetra-isopropoxide.
  • Aldehydes of formula VI may be prepared by reaction of the conesponding 3'-iodo nucleoside with carbon monoxide and tris(trimethylsilyl)silane in the presence of a free radical initiator such as 2,2'-azobis(isobutyronitrile), by reduction of the corresponding 3'-cyano nucleoside with diisobutylaluminium hydride or otherwise as described in WO 92/20823 and Y.S. Sanghvi et al Tetrahedron Utters 35 (27) 4697-4700 (1994). Aldehydes of formula VI may also be prepared by treatment of the corresponding 3'-amino nucleoside with nitrite as described by S.
  • a free radical initiator such as 2,2'-azobis(isobutyronitrile
  • R 1 is a group of formula II in which R 11 and R 12 are hydrogen
  • deoxygenation which may be effected by conventional methods, for example by reaction with a suitably substituted reagent to allow free radical mediated cleavage, such as by reaction with a substituted or unsubstituted C 6 -C 10 aryloxythiocarbonyl chloride such as p-tolylchlorothionoformate or pentafluorophenylchlorothionoformate to conven the hydroxy group R 11 into a substituted or unsubstituted C 6 -C 1( ) aryloxythiocarbonyloxy group, and then removing this group by reaction with a trialkylstannane such as tri-n-butylstannane, in the presence of a free radical initiator such as azobis(isobutyronit)
  • Such deoxygenation can be carried out using conventional procedures.
  • reaction with the aryloxythiocarbonyl chloride may be carried out in an organic solvent, preferably a halohydrocarbon, an ether or an aromatic solvent, especially dichloromethane, in the presence of a tertiary amine such as triethylamine or dimethylaminopyridine.
  • Removal of the aryloxythiocarbonyloxy group may be effected by heating with the initiator in a hydrocarbon solvent, preferably an aromatic solvent such as benzene, toluene or xylene, at 60 to 140°C, preferably 100-U0°C.
  • a hydrocarbon solvent preferably an aromatic solvent such as benzene, toluene or xylene
  • R 1 is a group of formula II in which R 11 is halogen and R 12 is hydrogen
  • R 11 is hydroxy and R 12 is hydrogen
  • compounds of formula I where R 1 is a group of formula II in which R 11 is fluoro and R 12 is hydrogen may be prepared by reacting a compound of formula I in which R 11 is hydroxy and R 12 is hydrogen with a dialkylaminofluorosulfurane or sulphur tetrafluoride.
  • the dialkylaminofluorosulfurane is preferably a dialkylaminosulphurtrifluoride such as diethylaminosulphurtrifluoride (DAST) and is generally reacted in a non-protic solvent, preferably a halohydrocarbon, an aromatic hydrocarbon or tetrahydrofuran, especially a chlorine-containing solvent such as chloroform or dichloromethane.
  • a non-protic solvent preferably a halohydrocarbon, an aromatic hydrocarbon or tetrahydrofuran, especially a chlorine-containing solvent such as chloroform or dichloromethane.
  • the reaction is preferably carried out at a temperature from -78° to 30°C. Suitable reaction procedures are described by M. Hudlicky, Organic Reactions 35,513 (1988). Suitable reaction procedures for the reaction with sulphur tetrafluoride are described by C.L.J. Wang, Organic Reactions, 34, 319 (1988).
  • R 1 is a group of formula ⁇ in which R 11 is hydroxy and R 12 is hydrogen
  • R 11 is -OR 22 , -OCOR 22 or -OSO 2 R 22 , where R 22 is as hereinbefore defined.
  • they may be converted into corresponding compounds where R 11 is -OSO 2 R 22 by reacton with a sulphonyl chloride of formula R 22 SO 2 Cl in the presence of a tertiary base, preferably triethylamine, pyridine or, especially, dimethylaminopyridine.
  • a tertiary base preferably triethylamine, pyridine or, especially, dimethylaminopyridine.
  • the reaction is generally carried out in an organic non-protic solvent, for example a hydrocarbon, a halohydrocarbon or a cyclic ether, preferably chloroform, tetrahydrofuran or, especially, dichloromethane, and at a temperature from -78°C to 50°C, preferably -20°C to 30°C, especially 0 to 25°C.
  • organic non-protic solvent for example a hydrocarbon, a halohydrocarbon or a cyclic ether, preferably chloroform, tetrahydrofuran or, especially, dichloromethane
  • R 1 is a group of formula II in which R 11 is -OSO 2 R 22 and R 12 is hydrogen, preferably those where R 22 is methyl, rrifluoromethyl orp-tolyl
  • R 1 is a group of formula II in which R 11 is fluoro and R 12 is hydrogen by reaction with a metal fluoride or an ammonium fluoride, preferably an alkali metal fluoride or a quaternary ammonium fluoride such as a tetraalkylammonium fluoride, especially tetrabutylammonium fluoride.
  • the reaction is generally carried out in an organic solvent, preferably a polar aprotic solvent such as a halohydrocarbon, dimethylformamide, dimethylsulphoxide, acetonitrile or an ether, especially tetrahydrofuran, and at a temperature from -30 to 100°C, preferably -20 to 50°C, especially 0 to 30°C.
  • a polar aprotic solvent such as a halohydrocarbon, dimethylformamide, dimethylsulphoxide, acetonitrile or an ether, especially tetrahydrofuran
  • R 1 is hydrogen
  • R 1 is a protecting group Q to replace Q by a hydrogen atom.
  • This deprotection may be carried out using known procedures.
  • the protecting group Q is of formula HI, it may be effected by reaction with a trialkylsilyl halide such as trimethylsilyl chloride, trimethylsilyl bromide or trimethylsilyl iodide.
  • the reaction may be carried out at a temperature of -30°C to 100°C, preferably 0 to 40°C, preferably under anhydrous conditions, in an organic solvent, for example a halohydrocarbon such as chloroform or trichloroethane, an ether such as tetrahydrofuran or an aromatic hydrocarbon such as benzene, toluene or xylene, or a mixture of two or more of such solvents.
  • an organic solvent for example a halohydrocarbon such as chloroform or trichloroethane, an ether such as tetrahydrofuran or an aromatic hydrocarbon such as benzene, toluene or xylene, or a mixture of two or more of such solvents.
  • a trialkylsilyl chloride is used, the reaction is carried out in the presence of an alcohol such as ethanol.
  • R 2 in formula I is -OR 15 a
  • this group may also be affected by the deprotection reaction: in general, use of a trialkylsilyl chloride gives a product in which R 15 a is unchanged, while use of a trialkylsilyl iodide gives a product in which R 15 a is replaced by hydrogen.
  • a trialkylsilyl bromide is used, a mixture of a compound in which R 2 is -OH and a compound in which R 2 is -OR 15 , is generally obtained.
  • Deprotection of compounds of formula I where R 1 is Q, to replace Q by a hydrogen atom can also be effected by treatment with an acid, preferably under anhydrous conditions. It may be carried out with a mineral acid such as hydrochloric acid, in which case when R 2 is -OR 15 , it is also converted to -OH, or with an organic acid such as acetic acid, in which case when R 2 is -OR 15 , the product may be a compound in which R 2 is -OR 15 ,, a compound in which R 2 is -OH or a mixture ⁇ ereof.
  • an acid preferably under anhydrous conditions. It may be carried out with a mineral acid such as hydrochloric acid, in which case when R 2 is -OR 15 , it is also converted to -OH, or with an organic acid such as acetic acid, in which case when R 2 is -OR 15 , the product may be a compound in which R 2 is -OR 15 ,, a compound in which R 2 is
  • R 1 in formula I is Q which is a hydroxyalkyl group
  • hydrolysis to replace Q by a hydrogen atom can be effected by treatment with base, for example by treatment with aqueous ammonia at a temperature from ambient temperature to 100°C.
  • R 2 to R 6 , R 8 , and R 9 are as hereinbefore defined and R 1 is R 1 , or a group of formula ⁇ .
  • Such deoxygenation may be effected by conventional methods, for example as hereinbefore described for the deoxygenation of compounds of formula I where R 1 is a group of formula II in which R 11 is hydroxy and R 12 is hydrogen.
  • R 8 , and R 9 arc as hereinbefore defined, with an organometallic compound of formula where R 1 ,, R 3 and R 4 a are as hereinbefore defined, R 28 is R 2 , or -OR 15 , as hereinbefore defined and M is lithium, ceriumdichloride or magnesium, in die presence of a Lewis acid, preferably a boron trifluoride complex.
  • the reaction is usually carried out at low temperature, generally -120°C to 40°C, preferably -80 to -60°C, in an organic solvent, e.g.
  • organometallic compound of formula DC is preferably formed in situ by reaction of an organolimium, preferably an alkyllithium, a hindered lithium amide such as lithium dusopropylamide or an organomagnesium halide, preferably an alkylmagnesium halide, with a compound of formula
  • R 1 ,, R 3 , R 4 , and R 28 arc as hereinbefore defined.
  • a suitable procedure for reaction of an organometallic compound with a nucleoside oxetane is described in H. Tanaka et al, Tetrahedron Lett., 30,2567 (1989).
  • R 3 and R 4 are as hereinbefore defined and Y denotes a leaving atom or group.
  • R 29 is C j -C alkyl and Q is as hereinbefore defined, with an organomagnesium halide of formula R 28 MgX or an organolithium of formula R ⁇ Li, where R 28 is as hereinbefore defined, using the process described in EPO 501 702.
  • the leaving atom or group Y in formula XLTI may be, for example, a halogen atom or a residue of an organic or inorganic acid after removal of an acidic hydrogen atom therefrom, such as an organic sulphonate group, e.g. a p-toluenesulphonate or trifluoromethanesulphonate group, or a sulphate anion.
  • Y is a halogen atom or an arylsulphonate group, especially a chlorine, bromine or iodine atom or a p-toluenesulphonate group.
  • compounds of formula XLTJ are known or may be prepared by known methods.
  • the reaction between the compound of formula XII and the compound of formula XHT may be carried out under conventional conditions for substitution reactions at a P-H bond, for example using a base such as a tertiary amine, an alkali metal, usually sodium, an organometal of an alkali metal or magnesium, usually an alkyllithium, an alkali metal hydride, usually sodium hydride, or an alkali metal amide such as Li N-fCHfO ⁇ -
  • the reaction may be carried out in an organic solvent, usually an ether such as diethyl ether or tetrahydrofuran, a hydrocarbon such as hexane or toluene or mixtures thereof, and at a temperature from -100°C to 100°C, usually from -80°C to 40°C.
  • R 1 ,, R 2 , R 3 , R 4 overcome R 8 ,, R 9 and R 19 are as hereinbefore defined and R 30 is an optionally substituted acyl, aracyl, alkylsulphonyl or arylsulphonyl group, followed by hydrolysis of the R- ⁇ O- group.
  • the deoxygenation may be effected using deoxygenation procedures hereinbefore described.
  • the hydrolysis of the R 30 O- group may be effected using conventional basic ester hydrolysis procedures.
  • R 30 is preferably acetyl, benzoyl, methanesulphonyl, trifluoromethanesulphonyl or p-toluenesulphonyl.
  • R 8 dirt R 9 , R 19 and R 30 are as hereinbefore defined, optionally in the presence of a Lewis acid such as a boron trifluoride complex, for example under the conditions hereinbefore described for the reaction of compounds of formulae DC and X.
  • a Lewis acid such as a boron trifluoride complex
  • R 8 ,, R 9 and R 30 are as hereinbefore defined, with an organometallic compound of formula R 19 Li or R 19 Mg X where R 19 is as hereinbefore defined and X is halogen, usually chlorine or bromine, generally in an organic solvent, for example an ether such as tetrahydrofuran or diethyl ether, and at a temperature of -120 to 0°C, usually -100 to -60°C, followed by oxidation, for example a Swern oxidation, of the resulting alcohol.
  • organometallic compound of formula R 19 Li or R 19 Mg X where R 19 is as hereinbefore defined and X is halogen, usually chlorine or bromine, generally in an organic solvent, for example an ether such as tetrahydrofuran or diethyl ether, and at a temperature of -120 to 0°C, usually -100 to -60°C, followed by oxidation, for example a Swern oxidation, of the resulting alcohol
  • Aldehydes of formula XVII can be obtained by oxidation of the corresponding 5'-hydroxymethyl compounds using known methods, for example by treatment with a haloacetic acid, dimethyl sulphoxide and dicyclohexylcarbodiimide using the procedure of Jones and Moffat, J. Amer. Chem. See. 90,5337 (1968) or Ranganatham et al, J. Org. Chem. 39,290 0974).
  • the 5'-hydroxymethyl compounds are readily available nucleosides, or substituted derivatives thereof.
  • Compounds of formula VII where R 1 is R 1 ,, R 5 is -OR 18 and R 6 is R 19 may be prepared by etherification of the hydroxyl group in compounds of formula XV by reaction with a halide of formula R 18 X where R 18 is as hereinbefore defined and X is halogen, usually bromine or iodine, followed by hydrolysis of die R 30 O- ester group.
  • the etherification reaction is generally carried out in d e presence of a base e.g. sodium hydride or a hindered amine such as 1,8-diazobicyclo [5.4.0] undec-7-ene in an organic solvent, usually a hydrocarbon such as benzene or toluene.
  • R 1 ,, R 2 , R 3 , R 4 ,, R 8 ,, R 9 and R 30 are as hereinbefore defined, into compounds of formula VII where R 5 is -OR 18 and R 6 is hydrogen.
  • Compounds of formula XVHI can be prepared by reacting an aldehyde of formula XVLT widi a compound of formula DC.
  • the reaction is generally carried out at a temperature of -100 to 0°C, preferably -70 to -80°C, in an organic solvent such as tetrahs drofuran, diethyl ether, ten-butyl methyl ether or toluene, optionally in the presence of a Lewis acid such as a boron trifluoride complex.
  • Compounds of formula I in which R 7 is azido may be prepared by reacting a compound of formula VII with hydrazoic acid in the presence of a tertiary phosphine. preferably a triaryl phosphine such as triphenyl phosphine, and a dialkylazodicarboxylate such as diediylazodicarboxylate or diisopropylazodicarboxylate.
  • the reaction is generally carried out using 1 to 3 mol, preferably 1 to 1.5 mol, of hydrazoic acid per mol of compound of formula VII, in an aptotic solvent such as a hydrocarbon, halohydrocarbon or ether, preferably a mixture of toluene and tetrahydrofuran.
  • the reaction is generally effected at a temperature from -50 to 50°C, preferably -20 to 30°C, especially 15 to 30°C.
  • me compound of formula VII is of formula
  • R 1 to R 6 , R 8 , and R 9 are as defined for formula VII, the sterochemical orientation of the indicated hydroxy group is inverted.
  • the reaction may be carried out using known procedures - see Mitsunobu, Synthesis 1981, 1.
  • R 7 is azido
  • R 7 is azido
  • R 31 is an optionally substituted Cj to C 4 alkyl or C 6 to C 10 aryl group, preferably a methyl, trifluoromethyl or p-tolyl group, with an inorganic azide, preferably an alkali metal azide, especially sodium azide or lidiium azide.
  • the reaction is generally carried out in an organic solvent, preferably an aprotic polar solvent such as acetonitrile, dimethyl sulphoxide or, especially, dimetfiyl formamide, at a temperature from 40 to 200°C, preferably 40 to 120°C.
  • an organic solvent preferably an aprotic polar solvent such as acetonitrile, dimethyl sulphoxide or, especially, dimetfiyl formamide
  • a temperature from 40 to 200°C, preferably 40 to 120°C.
  • 1 to 10 mol of the inorganic azide is used per mol of compound of formula XX.
  • Compounds of formula XX can be prepared by reacting a compound of formula VII with a sulphonyl halide of formula R 31 SO 2 X where X is halogen, usually chlorine, in the presence of a tertiary base such as triethylamine, pyridine or, preferably, dimethylaminopyridine.
  • a tertiary base such as triethylamine, pyridine or, preferably, dimethylaminopyridine.
  • the reaction may be carried out using conventional procedures for the preparation of sulphonyl esters. It is generally carried out in an organic aprotic solvent such as a hydrocarbon, halohydrocarbon or edier, preferably dichloromemane or chloroform, at a temperature from -78°C to 50°, preferably -20 to 30°C, especially 0 to 30°C.
  • Compounds of formula I in which R 7 is fluoro may alternatively be prepared by reacting a compound of formula XX with a metal fluoride or an ammonium fluoride, preferably an alkali metal fluoride or a quaternary ammonium fluoride such as a tetralkylammonium fluoride, especially tetrabutylammonium fluoride. This reaction may be carried using die procedure hereinbefore described for d e corresponding preparation of compounds of formula I where R ⁇ is fluoro and R 12 is hydrogen.
  • a metal fluoride or an ammonium fluoride preferably an alkali metal fluoride or a quaternary ammonium fluoride such as a tetralkylammonium fluoride, especially tetrabutylammonium fluoride.
  • Dehydration of the compound of formula VII may be carried out using known methods for die dehydration of alcohols. For example, it may be effected by treating d e compound widi an acid, preferably an organic acid, especially an aliphatic or aromatic carboxylic acid, generally in an aprotic organic solvent such as a hydrocarbon, halohydrocarbon or ether, preferably toluene, dichloromethane or tetrahydrofuran, preferably at a temperature from -50 to 50°C, especially 15 to 30°C, in me presence of dialkylazodicarboxylate such as diediylazodicarboxylate or diisopropylazodicarboxylate and, preferably, a tertiary phosphine, especially a triarylphosphine such as triphenylphosphine.
  • an acid preferably an organic acid, especially an aliphatic or aromatic carboxylic acid
  • an aprotic organic solvent such as a hydrocarbon, halo
  • Elimination of the R 31 SO 2 O- group from a compound of formula XX can be carried out using known methods for the elimination of such leaving groups. Generally it is carried out by treating d e compound widi a base, preferably an alkali metal alkoxide such as sodium methoxide or potassium ten-butoxide. in a polar aprotic organic solvent such as dime ylformamide or dimethyl sulphoxide. The reaction is generally effected at -70 to 100°C, more usually at -20 - 50°C.
  • R 2 to R 6 and R 9 are as hereinbefore defined for formula I and R 1 is R 1 , or a group of formula II.
  • the reductive elimination may be carried out using known procedures, for example using a zinc/copper couple - see M. J. Robins et al, Tetrahedron Lett. 25,367 (1984).
  • R 1 to R 6 and R 9 are as defined for formula XXLI to a Mattocks reaction (J. Chem. Soc. 1964, 1918) with ⁇ -acetoxyisobutyryl bromide or to a variant diereof using acetyl bromide (Marumoto and Honjo, Chem. Pharm. Bull. 22,128 (1974), or by reacting die compound of formula XXII widi tetraacetoxysilane and phosphorus tribromide in the presence of boron trifluoride edierate using, for example, the procedure of Kondo et al, J. Org. Chem. 42, 3967 0977), to give either a compound of formula XXII or a compound of formula XXLIa, or a mixutre thereof.
  • the acetonide of formula XXVI is reacted widi a compound of formula XII, in die presence of a free radical initiator in an aromatic hydrocarbon solvent such as toluene, at 70-90°C to give a compound of formula
  • R 1 to R 6 and R 9 are as hereinbefore defined for formula I (which can be prepared by esterification of the glycol of formula XXTJI with 1 , 1 l - thiocarbonyldiimidazole - see C. H. Kim et al, J. Med-Chem. 1987, 30,862.), widi a phosphite ester or a diazaphospholidine (Corey- Winter reaction - see Corey and Winter, J. Am. Chem. Soc. 1963, 85, 2677 and Corey et al, Tetrahedron Lett. 1982, 23, 1979).
  • a further method for the preparation of compounds of formula I in which R 7 and R 8 together denote a valence bond is an Eastwood olefination procedure, in which a cyclic orthoformate ester of a glycol of formula XXLLT is heated in the presence of an acid catalyst - see Crank and Eastwood, Aust. J. Chem. 17, 1392 (1964), Ando et al, Chem. Lett. 1986, 879 and Mizutani et al, 13th Heterocyclic Congress, August 11-16, 1991.
  • a yet further method for me preparation of compounds of formula I in which R 7 and R 8 together denote a valence bond is a Barton deoxygenation reaction, in which a bisxanthate derived from a glycol of formula XXIII is treated with tributyltinhydride or an alkyl silane (containing a Si-H bond) - see C.K. Chu et al, J. Org Chem. 1989, 54, 2217 and D.H.R. Barton et al, Tetrahedron lett., 1991, 32, 2569.
  • R 7 and R 8 each denote hydrogen
  • the hydrogenation may be carried out using conventional procedures, for example by catalytic hydrogenation using a transition metal or compound or complex thereof as catalyst, or by reaction with an alkali metal in an alcohol, ammonia or an amine. It is conveniently effected using a palladium -carbon catalyst in an alcohol or ethyl acetate as solvent under a pressure of 0.1 to 10 atmospheres of hydrogen.
  • R 1 is R 1 , or a group of formula ⁇ , R 2 to R 6 and R 9 are as defined for formula I and Ar is an optionally substituted C 6 to C 10 aryl group, such as phenyl, p-tolyl, p-chlorophenyl or, preferably, m-(trifluoromethyl)phenyl.
  • the deoxygenation may be effected by irradiation with a high pressure mercury lamp of the compound in alcohol- water mixtures in the presence of N-metiiylcarbazole as photosensitiser. Suitable procedures are described by Saito et al, J. Am. Chem. Soc, 108, 3115 (1986).
  • Compounds of formula XXX can be obtained by esterification of a glycol of formula XXHl widi an acid of formula Ar COOH or an anhydride or acid halide mereof, using conventional esterification procedures.
  • Compounds of formula I in which R 7 is chloro, bromo or iodo can be prepared by reacting a compound of formula XX widi an inorganic chloride, bromide or iodide respectively, preferably a chloride, bromide or iodide of an alkali metal.
  • Compounds of formula I where R 7 is mercapto, amino, cyano, iocyanate or isothiocyanate can be prepared by reacting a compound of formula XX with a hydrosulphide, amide, cyanide, thiocyanate or isothiocyanate respectively of an alkali metal.
  • Compounds of formula I where R 7 is hydroxylamino may be obtained by reacting a compound of formula XX with a hydroxylamine in which the hydroxyl group is protected, e.g. by a tert-butyldiphenylsilyl group, followed by removal of the protecting group.
  • These reactions of compounds of formula XX with inorganic salts and other nucleophiles may be carried out using conventional procedures for displacement of R 31 SO 2 O- leaving groups from nucleosides.
  • R 7 is an unsubstituted or substituted hydrocarbyl group R 7
  • R 7 can be prepared by reaction of a compound of formula XX with an organomagnesium halide of formula R 7 a MgX or an organoli ium of formula R 7 a Li where R 7 , is as hereinbefore defined and X is halogen.
  • Such a reaction may be carried out using known procedures for reaction of such organometallic compounds with compounds having leaving groups.
  • R 7 as R 7 is Cj to C 10 alkenyl, especially allyl
  • R 7 as R 7 is Cj to C 10 alkenyl, especially allyl
  • a 3'-O- aryloxythiocarbonyl derivative of a compound of formula VTJ with a C ⁇ -C 10 alkenyl-substituted trialkylstannane, particularly allyl-tri-n-butylstannane, in the presence of a free radical initiator such as azobisisobutyronitrile.
  • R 1 is R 1 , or a group of formula II and R 2 to R 6 and R 9 are as hereinbefore defined wid an organomagnesium halide of formula R 7 ,MgX or an organolithium of formula R 7 ,Li where R 7 , is as hereinbefore defined and X is halogen.
  • Alkenyl groups attached to the furanose ring by this method can be reacted further to produce substituted alkyl groups.
  • Compounds of formula XXXI can be prepared by epoxidation of compounds of formula XXI using conventional epoxidation procedures or by treatment of die 2',3 ⁇ - dimethanesulphonyl ester of the compound of formula XXLII with aqueous base following d e procedure of J. F. Codington et al, J. Org. Chem. 27, 163 (1962).
  • Compounds of formula I in which R 1 is a group of formula LI in which R 10 is hydrogen may be prepared by hydrolysing a compound of formula I in which R 10 is R 21 , -COR 21 or hydrocarbyl)silyl. This hydrolysis may be carried out using known procedures for the hydrolysis of ether, ester or silyl ether groups.
  • Compounds of me invention containing salt-forming groups may be in die form of pharmaceutically acceptable, i.e. physiologically tolerable, salts.
  • a compound of formula I in which R 2 is hydroxy, which is a phosphinic acid may in die form of a pharmaceutically acceptable salt with a base.
  • Such salts include alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as magnesium or calcium salts, or ammonium salts with ammonia or organic amines, preferably tertiary monoamines and heterocyclic bases such as triethylamine, tri(2-hydroxyethyl)amine, N-ediylpiperidine or
  • Acids which form suitable salts include hydrohalic acids, for example hydrochloric and hydrobromic acid, sulphuric acid, phosphoric acid, nitric acid or perchloric acid, or aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulphonic acids, such as formic, acetic, propionic, succinic, glycolic, lactic, malic, ta ⁇ aric, citric, fumaric, maleic, hydroxymaleic, oxalic, pyruvic, phenylacetic, benzoic, p-aminobenzoic, andiranilic, p-hydroxybenzoic, salicyclic, p-aminosalicyclic acid, embonic acid, methanesulphonic, eihanesulphonic, hydroxyethanesulphonic, ediylened
  • Salts of the invention may be prepared by conventional salt-forming procedures.
  • diese can be separated by known methods, for example by fractional distillation, crystallisation or chromatography.
  • the invention also relates to the use of compounds of formula I, and dieir pharmaceutically acceptable salts, as pharmaceuticals, particularly as anti-viral agents. Accordingly, the present invention also provides a pharmaceutical composition comprising as active ingredient a compound of formula I or a pharmaceutically acceptable salt thereof.
  • the composition may contain a pharmaceutically acceptable carrier such as one conventionally used in pharmaceutical compositions.
  • the composition may be formulated for enteral or parenteral administration.
  • compositions according to die invention intended for enteral and parenteral administration may be, for example, pharmaceutical compositions in dose unit form, such as drag ⁇ es, tablets, capsules or suppositories, and also ampoules for injection. They may be manufactured using known mediods, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilisa ⁇ ng processes.
  • pharmaceutical compositions for oral administration can be obtained by combining d e active ingredient wid solid carriers, if desired granulating d e resulting mixture and processing me mixture or granulate obtained, if desired or necessary after addition of suitable adjuncts, into tablets, tablet cores, dragees or capsules.
  • compositions of d e invention can be used in die treatment of viruses such as influenza, herpes viruses including Herpes I and II, Herpes CMV, Herpes ERV and Herpes Zoster, and HIV. They are preferably administered orally, by inhalation, intraveneously, subcutaneously or intramuscularly, but otiier methods of administration such as transdermal, topical or intra-lesional methods, and by inclusion in suppositories, can also be useful. Optimum dosages and treatment schedules for individual patients can readily be determined by those skilled in die an. The invention is illustrated by the following Examples.
  • Ph is phenyl and T is l-thyminyl.
  • Trimediylsilylchloride 0-6ml, Dmmole is added to a stirred solution of Compound B (700mg, 1.3mmole) in chloroform (10ml) containing ethanol (0.2ml) under argon. The resulting solution is stood at room temperature for 20 hours and is dien concentrated under vacuum. Purification by flash silica column chromatography (eluant: chloroform /e anol 20:1) gives Compound C as a white foam isolated as a mixture of 2 diastereoisomers.
  • Compound H used in die Examples is the compound prepared in Example 21 of EP 0629 633.
  • Compound J used in die Examples is prepared as follows: To a solution of die compound prepared in Example 25 of EP 0629 633 (0.75g, 0.85mmol) in medianol (6ml) sodium med oxide solution in medianol (25% by weight, 0.55ml, 3.4mmol) is added dropwise. The solution is stirred for 1.5 hours and a sulphonic acidic ion exchange resin is added. The resin is tiien filtered off and die solution evaporated. The crude product is subjected to chromatography on silica gel, during with a gradient of ethyl acetate/edianol. Compound I, a mixture of two diastereoisomers, is obtained as a white solid.
  • T is 1-d ⁇ yminyl
  • Example 5 This Example describes the preparation of die compound of formula
  • This example describes die preparation of die compound of formula
  • T is 1-d ⁇ yminyl
  • Diediylazodicarboxylate (0.42ml, 2.7mmole) is added dropwise over 5 minutes to a stirred solution of Compound A (l.Og, 2.2mmole), triphenylphosphine (0.70g, 2.7mmole) and para-nitrobenzoic acid (0.45g, 2.7mmole) in a toluene - THF mixture (4:1, 20ml) under argon. After standing at room temperature for 18 hours, concentration and purification by flash silica column chromatography (eluant chloroform/edianol 50:1) gives, as well as other products, Compound 11 as a mixture of 2 diastereoisomers.
  • This example describes die preparation of die compound of formula
  • T is 1-d ⁇ yminyl.
  • Trimefhylsilylchloride (1.4ml, llmmol) is added to a stirred solution of Compound 11 (500mg, l.l ⁇ mmol) in chloroform (5ml) containing ethanol 00 pipette drops). After standing at room temperature for 18 hours, concentration gives a white solid which is purified by flash silica column chromatography (eluantxhloroform-edianol 30:1) to give Compound 12, isolated as a mixture of 2 diastereoisomers at phosphorus.
  • Example 13 By a procedure similar to that of Example 12, die pure isomers obtained by chromatography of Compound H are converted into the pure isomers of Compound 13.
  • Compound 7 is tested for antiviral activity against herpes simplex virus type 1(HSV-1) (strain 17i) in vitro.
  • Aqueous solutions of the compound are prepared at concentrations between lO ⁇ M and 50 ⁇ M.
  • the solutions are stored at -70°C after preparation and thawed prior to use in d e antiviral assays. After thawing, the solutions are diluted to die appropriate concentration in the cell-culture medium without prior filtration.
  • Vero cell monolayers are infected widi 20-200 plaque forming units and after virus adsorption die inoculum is replaced by maintenance medium containing different concentrations of the compound under investigation. Virus spread is prevented by die incorporation of 0.5% low gelling temperature agarose. At the end of a set period (2 or 3 days) monolayers are fixed, stained widi methylene blue and plaque numbers determined. The results are as follows: IC 50 >10 ⁇ m ⁇ 50 ⁇ m.

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Abstract

L'invention concerne un composé de la formule (I) ou un sel de celui-ci acceptable sur le plan pharmaceutique. Dans cette formule, R1 est un hydrogène, R1a ou un groupe de la formule (II), R1a est R1b ou un groupe protecteur Q, R1b est un groupe C1-C20 alkyle, C2-C20 alcényle, C3-C10 cycloalkyle, C6-C15 aryle, C7-C16 aralkyle ou un groupe hétérocyclique à 5 ou 6 éléments fixés par un atome de carbone dans le groupe hétérocyclique à l'atome de phosphore indiqué, R2 est un hydrogène, R2a ou -OR15, une condition à satisfaire étant que lorsque R1 est un hydrogène, R?2 soit R2¿a ou -OR15, R2a est un groupe C1-C20 aliphatique, un groupe C3-C10 cycloaliphatique, un groupe C6-C15 aromatique, un groupe C7-C16 araliphatique ou un groupe hétérocyclique à 5 ou 6 éléments fixé par un atome de carbone dans le groupe hétérocyclique à l'atome de phosphore indiqué, R3 est un hydrogène, un halogène, un hydroxy, R?16, -OR16, -OCOR16¿, -OSO¿2R?16, ou un tri(C¿1?-C15 hydrocarbyl)silyloxy, R?4 est R4¿a ou forme ensemble avec R6 une liaison de valence, R4a est un hydrogène, un halogène ou R17, R5 est un hydrogène, un halogène, un hydroxy, R?18, -OR18, -OCOR18¿, --OSO¿2R?18 ou un tri(C¿1?-C15 hydrocarbyl)silyloxy, R?6¿ est un hydrogène, un halogène ou R19 ou forme ensemble avec R4 une liaison de valence, R7 est un hydrogène ou un atome ou groupe capable de terminer un brin de réplication d'un acide nucléique ou d'inhiber une synthèse d'ADN viral autre qu'un groupe relié au cycle du furanose indiqué par un atome d'oxygène ou forme ensemble avec R8 une liaison de valence, R8 est un R8a ou forme ensemble avec R7 une liaison de valence, R8a est un hydrogène, un halogène, un hydroxy, R?20, -OR20, -OCOR20¿, -OSO¿2R?20 ou un tri(C¿1?-C15 hydrocarbyl)silyloxy, R?9¿ est un radical nucléosidique monovalent de base, R10 est un hydrogène ou R10a, R10a est un R?21, -COR21. -SO¿2R21 ou tri(C¿1?-C15 hydrocarbyl)silyle, R?11¿ est un hydrogène, un halogène, un hydroxy, R?22, -OR22, -OCOR22¿, -OSO¿2R?22 ou Z, R12 est un hydrogène, un halogène ou un R23, R13 est un hydrogène ou R13a, R13a est un halogène, un hydroxy, R?24, -OR24, -OCOR24, OSO¿2R24 ou un tri(C¿1?-C15 hydroxycarbyl)silyloxy, R?14¿ est radical nucléosidique monovalent de base, R15 est un hydrogène ou R15a, R15a est un groupe aliphatique en C1 à C10, un groupe cycloaliphatique en C3 à C8, un groupe aromatique en C6 à C15 ou un groupe araliphatique en C7 à C16, R?16, R17, R18, R19, R20, R21, R22, R23 et R24¿ sont d'une manière indépendante un groupe aliphatique en C¿1? à C10, un groupe cycloaliphatique en C3 à C10, un groupe aromatique en C6 à C15 ou un groupe araliphatique en C7 à C30 et Z est un aryloxythiocarbonyloxy en C6 à C10.
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US8324179B2 (en) 2007-02-09 2012-12-04 Gilead Sciences, Inc. Nucleoside analogs for antiviral treatment
US8871737B2 (en) 2010-09-22 2014-10-28 Alios Biopharma, Inc. Substituted nucleotide analogs
US8916538B2 (en) 2012-03-21 2014-12-23 Vertex Pharmaceuticals Incorporated Solid forms of a thiophosphoramidate nucleotide prodrug
US8980865B2 (en) 2011-12-22 2015-03-17 Alios Biopharma, Inc. Substituted nucleotide analogs
US9012427B2 (en) 2012-03-22 2015-04-21 Alios Biopharma, Inc. Pharmaceutical combinations comprising a thionucleotide analog

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US8324179B2 (en) 2007-02-09 2012-12-04 Gilead Sciences, Inc. Nucleoside analogs for antiviral treatment
US8871737B2 (en) 2010-09-22 2014-10-28 Alios Biopharma, Inc. Substituted nucleotide analogs
US9278990B2 (en) 2010-09-22 2016-03-08 Alios Biopharma, Inc. Substituted nucleotide analogs
US8980865B2 (en) 2011-12-22 2015-03-17 Alios Biopharma, Inc. Substituted nucleotide analogs
US9605018B2 (en) 2011-12-22 2017-03-28 Alios Biopharma, Inc. Substituted nucleotide analogs
US8916538B2 (en) 2012-03-21 2014-12-23 Vertex Pharmaceuticals Incorporated Solid forms of a thiophosphoramidate nucleotide prodrug
US9394330B2 (en) 2012-03-21 2016-07-19 Alios Biopharma, Inc. Solid forms of a thiophosphoramidate nucleotide prodrug
US9856284B2 (en) 2012-03-21 2018-01-02 Alios Biopharma, Inc. Solid forms of a thiophosphoramidate nucleotide prodrug
US9012427B2 (en) 2012-03-22 2015-04-21 Alios Biopharma, Inc. Pharmaceutical combinations comprising a thionucleotide analog

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