EP0523110A1 - Nucleoside derivatives - Google Patents

Nucleoside derivatives

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Publication number
EP0523110A1
EP0523110A1 EP91906957A EP91906957A EP0523110A1 EP 0523110 A1 EP0523110 A1 EP 0523110A1 EP 91906957 A EP91906957 A EP 91906957A EP 91906957 A EP91906957 A EP 91906957A EP 0523110 A1 EP0523110 A1 EP 0523110A1
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EP
European Patent Office
Prior art keywords
group
formula
groups
compounds
fluoro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP91906957A
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German (de)
French (fr)
Inventor
Jo Klaveness
Kjell Undheim
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GE Healthcare AS
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Nycomed Imaging AS
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Priority claimed from GB909007650A external-priority patent/GB9007650D0/en
Priority claimed from GB909007566A external-priority patent/GB9007566D0/en
Priority claimed from GB909007651A external-priority patent/GB9007651D0/en
Application filed by Nycomed Imaging AS filed Critical Nycomed Imaging AS
Publication of EP0523110A1 publication Critical patent/EP0523110A1/en
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals

Definitions

  • This invention relates to antiviral compounds and more particularly to esters, ethers and amides of nucleoside derivatives which are active against human immunodeficiency virus (HIV) , the retrovirus which causes the disease AIDS, or other viruses such as herpes simplex virus (HSV) .
  • HIV human immunodeficiency virus
  • HSV herpes simplex virus
  • Clinical symptoms are weight loss, chronic diarrhoea, persisting fever and opportunistic infections due to loss of T-cells, thus upsetting the overall balance of the immune system.
  • the patient loses his/her ability to combat otherwise insignificant infections.
  • Many substances interfering with replication have been tried, e.g.
  • 3'-azido - 3*-deoxythymidine (AZT) , 2' ,3 '-dideoxyadenosine, 3*-fluoroarabinosyladenine, 2' ,3'-dideoxycytidine, 2'-chloro-2'3'-dideoxyadenosine, 2* ,3'-dideoxyguanosine, 2' ,3'-dideoxyinosine, 2' ,3'- dideoxy - 2 • ,3'-didehydrothymidine, 3*-azido- 2',3*,- dideoxyuridine, 3'-azido - 2• ,3'-dieoxy-5-ethyl-uridine, 1-(2'-deoxy-2'-fluoro-3-D-arabinofuranosyl)-5- ethyluracil, 2,6-diamino-9-(3'-azido-2• ,3
  • European Patent Application No. 0196185A describes pharmaceutical compositions containing AZT, a known compound which has shown great promise in the treatment of AIDS and AIDS- related complex. It is believed that AZT works by inhibiting reverse transcriptase.
  • G is the residue of the glycone moiety of the nucleoside
  • Y is a hydrogen atom or a physiologically acceptable group of the formula
  • n O or 1
  • m 0 or 1
  • R is an optionally substituted alkyl or aryl group or an N-(C alkyl)-1,4-dihydropyridin- 3-yl group or, where n is 0, a hydrogen atom; R 2 and R3 are independently hydrogen atoms or lower alkyl groups or R 2 and R3 together are an alkylidene group; and X is a group selected from
  • R 4 is a hydrogen atom or a group -NY3Y4, where Y3 and Y 4 have the above meani.ngs and R5 i.s a hydrogen or halogen atom or a lower alkyl or trifluoromethyl group, with the. following provisos
  • 1(G) are hydrogen and Y 4 i.s R1CO, then Y1 i.s a group Rl(O) .CO. (OCR2R3) i.n whi.ch n and/or m is 1,
  • the glycone group - G - is not a 2 ',3'- dideoxyribosyl group or such a group having 3 *- fluorine or 3*-azido substituent nor a 2*,3'- dehydro-dideoxyribosyl group) and/or salts thereof.
  • glycone moiety G will normally be of the formula
  • glycone moieties include the 2,3-dideoxy- 2-halo-pentofuranosyl group, for example the 2-chloro- and 2-fluoro-analogues, especially when the group has the threo configuration:
  • Another preferred moiety is the 2,2-difluoro-2-deoxy- pentofuranosyl group
  • Y 5 is a hydrogen atom or an acyl or acyloxy-alkyl group as defined above for Y 1 . It is known that 2,2- difluoro-2-deoxy-nucleosides are active against herpes simplex virus (HSV) and accordingly the compounds according to the invention having this glycone moiety will find application in treatment of herpes infections.
  • HSV herpes simplex virus
  • Protected hydroxy groups will in general be groups of the formula Y 1O- where Y1 has the above meaning.
  • compositions for the treatment or prophylaxis of virus infections, in particular neurotropic viruses and especially retroviruses such as HIV.
  • compositions also form part of the invention.
  • the group R is preferably an alkyl group containing 1-20 carbon atoms which may be straight or branched, or an aryl group which may contain 6 to 20 carbon atoms and may be mono- or poly-cyclic.
  • Substituents which may be present on the alkyl groups R 1 include aryl groups preferably having 6-10 carbon atoms (as in aralkyl groupings) , hydroxy, alkoxy and carboxy groups.
  • Aryl groups include 5- or 6-membered heterocyclic aryl groups having one or more heteroato s selected from 0, N and S, such as furyl, imidazolyl, pyrrolyl, pyridinyl and thienyl groups.
  • Substituents which may be present on aryl groups include alkyl groups, e.g. having 1-6 carbon atoms, hydroxy and carboxy groups. Examples of such groups include methyl, ethyl, propyl, t-butyl, pentyl, stearyl, palmityl, carboxyethyl and benzyl groups.
  • the lower alkyl groups R 2, R3 and R5 preferably contain 1-6 carbon atoms. However, R 2 preferably
  • R 3 represents a hydrogen atom.
  • R is preferably a hydrogen atom or more preferably a methyl group.
  • R 5 i.s a halogen atom it may be a fluorine, chlorine, bromine or
  • R is preferably a hydrogen or chlorine atom or a methyl group.
  • R in any of the groups Y , Y , Y or Y 4 is an N-alkyl-l,4-dihydropyridin-3-yl group the alkyl group is preferably methyl.
  • the compounds of the invention may carry more than one of the groups Y 1, Y2, Y 3 and Y4.
  • the compounds of formula (I) D,E, I and
  • Groups Y are preferably of the formula
  • the salts of the compounds of formula (I) may be acid addition salts with organic or inorganic acids, for instance hydrochloric or phosphoric acid or methanesulphonic acid, ethane disulphonic acid, 2-naphthylsulphonic acid, pivalic acid and pamoic acid.
  • Antiviral counter-ions such as phosphonoformate or suramin may also be used.
  • Organic or inorganic base salts may be formed with acidic groups present in the molecule; suitable counter-ions include alkali metal ions such as sodium and potassium ions, divalent ions such as calcium and zinc ions and organic ions such as tetraalkylammonium and choline or ions derived from meglumine or ethylenediamine. Salts according to the invention may be formed by reaction of the compound of formula (I) with an appropriate acid or base.
  • compositions according to the invention may be used in the treatment and/or prophylaxis of virus infections, in particular HIV infections, and such a method forms a further feature of the invention. They may be formulated in conventional manner by admixture of one or more compounds of formula (I) as defined above with excipients and/or carriers.
  • the compounds of formula (I) may themselves be inhibitors of reverse transcriptase when the 5'- hydroxy group is free, it is possible that they are converted jln vivo to the desacyl or desalkyl nucleosides. Nevertheless the substitution at the respective O- and N- atoms gives surprising advantages in terms of uptake and sustained activity.
  • the compounds of formula (I) are more lipophilic than the parent compounds and this permits rapid and efficient absorption from the gastro-intestinal tract; the absorption rate may be optimised by careful choice of the substituent group to give the desired balance of lipophilicity and hydrophilicity.
  • the lipophilic nature of the compunds of formula (I) also gives the molecules the ability to penetrate the cell membranes more easily and leads to higher intracellular concentrations, giving an improved dose/effect ratio.
  • the steady hydrolysis of the compounds ensures a sustained concentration of the active compound in the cell and thereby permits longer intervals between doses, overcoming a significant drawback of the prior art compounds.
  • the compounds according to the invention can penetrate the blood-brain barrier and thus permit treatment of the neurological disorders which have been observed to be related to the presence of neurotropic viruses, e.g. retroviruses such as HIV, and lentiviruses (Yarchoan et al. The Lancet, January 17, 1987, page 132). This is a significant advantage compared to the corresponding unsubstituted compounds or other antiviral compounds and is not referred to anywhere in the prior art. Attempts have been made to treat these neurological disorders with AZT but with limited success.
  • the invention thus further provides a method of treatment of neurological disorders caused by neurotropic viruses wherein an effective dose of a compound of formula (I) or a salt thereof is administered to a patient suffering from such a disorder.
  • Compounds of formula (I) may be prepared in any convenient way, for example, by reaction of a compound of formula (II)
  • Y 1 is as hereinbefore defined and XB is as hereinbefore defined for X except that any of the groups Y 1, Y2, Y3 and Y4 may each additionally represent a protecting group, with the proviso that at least one of Y 1, Y2, Y3 and Y4 i.s a hydrogen atom] with a reagent serving to introduce a group R 1(0) CO. (OCR2R3) as defined above followed where required by removal of any protecting groups and/or unwanted substituents so introduced.
  • OCR2R3 group R 1(0) CO.
  • acylation or alkylation is effected while one or more groups Y 1, Y2, Y 3 and Y4 remain as hydrogen atoms
  • Such protecting groups may, in fact, be conventional N- or O-protecting groups including groups R OCO- which may be selectively removed in the presence of the group(s) intended to remain.
  • an N-benzyloxycarbonyl may be used to protect an exocylic amino group and if the group which is intended to remain is not one which is removable by reduction, for example a straight chain alkoxycarbonyl group, the
  • N-benzyloxycarbonyl group can readily be removed selectively using hydrogen and a noble metal catalyst such as palladium.
  • Trisubstituted silyl groups may also be used as protecting groups, especially for the 5'-oxygen atom, and include trialkylsilyl e.g. trimethylsilyl, dimethyl- t-butylsilyl, and thexyldimethyl silyl groups.
  • the reagent introduces a group R 1(O) .CO. (OCR2R3) - only into the purine or pyrimidine base then it will be convenient to protect all of the hydroxyl groups present in the glycone, if any; adjacent hydroxyl groups can be protected with a bidentate protecting group such as the
  • 1,1,3,3-tetraisopropyldisilox-l,3-diyl group In general, where more than one of Y 1, Y2, Y3 and Y 4 are hydrogen, and a mixture of compounds is produced, the individual components may readily be separated, for example by chromatography.
  • 2' ,3•-dideoxy derivatives i.e. introduction of a group Y 1 i.n whi.ch m i.s 1
  • i.t is especially effective to form a dianion of the nucleoside (e.g. by reacting with sodium hydride) and to react this with one equivalent of the alkylating agent.
  • Monoalkylation of a hydroxy group other than the 5'-hydroxy group in the sugar moiety is carried in a similar fashion using a 5'-protected nucleoside. It is of course, still possible to use protected forms of the nucleoside, for example by acylation of a nucleophilic nitrogen atom before salt formation with sodium hydride.
  • Suitable acylating agents for use in the reaction have the formula Ac-L where L is a leaving group.
  • suitable acylating agents include the acid halides and acid anhydrides advantageously in the presence of a base;
  • acylating agents include the haloformate esters and reactive carbonic acid diesters.
  • the halogen may, for example, be chlorine or bromine.
  • the base for use in the reaction with the acid halide or anhydride may, for example, be a heterocyclic base such as pyridine or 4-dimethylamino- pyridine.
  • a heterocyclic base such as pyridine or 4-dimethylamino- pyridine.
  • the latter increases the speed of the reaction and may be used advantageously with pyridine.
  • the reaction will normally be carried out in the presence of an inert solvent e.g. a substituted amide solvent such as dimethylformamide, dimethyl- acetamide or a halogenated hydrocarbon such as dichloromethane.
  • N-acyl groups R CO- may be removed selectively, for example by reaction with a phenol such as p-methyl-phenol. Where multiple substitution is to be effected, a stronger base such as sodium hydride may be advantageous.
  • Suitable acyloxyalkylating agents for use in the invention will in general be of the formula R 1 C0.0.CR R 3 L or R O.CO.O.CR 2 R L, where L is a leaving group.
  • the group L may for example, be a halogen atom such as a chlorine or bromine atom or a hydrocarbon-sulphonyloxy group such as a tosyloxy or mesyloxy group.
  • alkylation reaction will normally be effected in the presence of a base, conveniently an inorganic carbonate such as potassium carbonate or an alkali metal hydride such as sodium hydride.
  • a base conveniently an inorganic carbonate such as potassium carbonate or an alkali metal hydride such as sodium hydride.
  • Bases as used for acylation may also be useful.
  • Perbenzoylated l-(2-fluoro-2-deoxy-3-D-arabino- furanosyl)cytosine C. H. Tann, P. H. Brodfeuhrer, S. P. Brundidge, C. Sapino. H. G. Howell J. Or ⁇ . Chem. 50 (1985)3644.
  • compositions according to the invention may be formulated conventionally by means well known in the art, and may be administered by any convenient route, for instance orally, rectally, vaginally, intraveneously or intramuscularly.
  • suitable formulations include tablets and capsules, aqueous formulations for intravenous injection and oil-based formulations for intramuscular injection. Suitable dosages will lie in the range 0.1 to lOOmg per kilogram of bodyweight per 24 hour period.
  • the compositions according to the invention may also contain other active antivirals for instance acyclovir. phosphonoformate, suramin, Evans Blue, interferons or AZT.
  • N-Benzyloxycarbonyl-l-(2-fluoro-5-0-pivaloyloxymethyl- 2,3-dideoxy-?-D-threo-pentofuranosyl)cytosine (1.0 mmol) is added to a suspension of 5% palladium on charcoal (8mg) in ethanol (4ml) .
  • the hydrogenolysis is run at atmospheric presure using a Brown apparatus where the hydrogen gas is generated in a controlled manner by the addition of 3N HC1 to a solution of sodium hydride in a separate compartment.
  • the reaction is run at ambient temperature and is monitored by TLC in order to ensure that overreduction in the heterocyclic ring does not occur.
  • the reaction time is about 1 hour.
  • the mixture is then filtered through a thin bed of Celite, the filtrate evaporated and the product purified by chromatography on silica gel using chloroform-ethanol (9:1).
  • N 6 -B ⁇ nzyloxycarbonyl-9-(2-fluoro-5-0-pivaloyloxymethyl- 2,3-dideoxy- ⁇ -D-threo-pentofuranosyl)adenine (0.1 mmol) is added to a suspension of 5% palladium on charcoal (8mg) in ethanol (4ml) .
  • the hydrogenolysis is run at atmospheric pressure using a Brown apparatus where the hydrogen gas is generated in a controlled manner by the addition of 3N HC1 to a solution of sodium hydride in a separate compartment.
  • the reaction is run at ambient temperature and is monitored by TLC in order to ensure that overreduction in the heterocyclic ring does not occur.
  • the reaction time is about 1 hour.
  • the mixture is then filtered through a thin bed of Celite, the . filtrate evaporated and the product purified by chromatography on silica gel using chloroform-ethanol (9:1).
  • 1,1,3,3-tetraisopropyldisiloxane (0.2mmol) are added to pyridine (2ml) , the reaction mixture stirred at ambient temperature for 8 hours, the solvent removed at reduced pressure, chloroform (15 ml) added to the residue, washed with aqueous bicarbonate and with water, and the dried (MgS0 4 ) solution evaporated. The residue is chromatographed on silica gel using ethyl acetate-hexane to furnish 2' .2 '-difluoro-3' .5'-O-(1.1,3,3- tetraisopropyldisilox-1.3-diyl)thymidine.
  • the silyl group is removed by dissolution of the product thus obtained (lmmol) in THF (lml) and adding 0.25 M solution of tetrabutylammonium fluoride in THF (lml) .
  • the silyl group is removed by dissolution of the product thus obtained (lmmol) in THF (lml) and adding 0.25 M solution of tetrabutylammonium fluoride in THF (lml) .
  • the mixture is stirred at ambient temperature for 30 minutes, the solvent evaporated, the residue dissolved in chloroform (10ml) , washed with water (2ml) , dried (MgSO ) , evaporated, and the product purified by chromatography on silica gel using chloroform:methanol 95:5.
  • 1-(2-Fluoro-2-deoxy-, ⁇ -D-arabinofuranosyl)-5-iodocytosine (0.2mmol) is dissolved in a mixture of pyridine (0.5ml) and DMF (0.5ml), the solution cooled to 0 ⁇ C, isobutyl chloroformate (0.5mmol) and 4-N,N-dimethylaminopyridine (0.2mmol) added, the mixture stirred at ambient temperature for 12 hours, water (4ml) added, the mixture evaporated at reduced pressure, and the residue chromatographed on silica gel. The product is eluted with chloroform:ethanol (98:2).
  • Potassium carbonate (7 mmol) was added to a solution of 3',5'-bis-O- (thexyldimethylsilyl)-2',2'-difluorothymidine (6 mmol) in dry DMF (20 ml), the mixture stirred at 60°C for 1 h, cooled to 0°C, chloromethyl pivalate (10 mmol) added and the mixture stirred at 60°C for 2 h. Water was added and the mixture freeze-dried and the residue subjected to flash chromatography on silica gel using EtOAc:hexane (5:7).
  • Potassium carbonate (0.25 mmol) was added to a solution of 3',5'-bis-O- (thexyldimethylsilyI)-2 ' ,2'-difluorothymidine (0.2 mmol) in DMF (4 ml), the mixture was stirred at room temperature for 1.5 hours, cooled to 0°C, 1-chloroethyl ethyl carbonate (0.25 mmol) added and the mixture stirred at 40°C for 2 days before the solvent was removed at reduced pressure. The residue was dissolved in hexane: EtOAc (7:5) and the filtrate subjected to flash cromatography using the above eluant.

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Abstract

Composés nucléosidiques répondant à la formule (I): Y1O-G-X dans laquelle Y1 est un atome d'hydrogène ou un groupe acyle ou acyloxyméthyle; G est le résidu de la moitié glycone du nucléoside; et X est une base de purine ou de pyrimidine ou un dérivé ester, amide ou acyloxyalkyle de cette base. Les composés présentent une activité antivirale.Nucleoside compounds corresponding to formula (I): Y1O-G-X in which Y1 is a hydrogen atom or an acyl or acyloxymethyl group; G is the residue of the glycone half of the nucleoside; and X is a purine or pyrimidine base or an ester, amide or acyloxyalkyl derivative of this base. The compounds exhibit antiviral activity.

Description

NUCLEOSIDE DERIVATIVES
This invention relates to antiviral compounds and more particularly to esters, ethers and amides of nucleoside derivatives which are active against human immunodeficiency virus (HIV) , the retrovirus which causes the disease AIDS, or other viruses such as herpes simplex virus (HSV) . Since the recognition of AIDS as a new clinical entity in 1981 nearly five hundred thousand cases of the disease have probably been diagnosed, while the number of HIV infected persons is estimated to be between 5 million and 10 million. AIDS is fatal, more than 50% of all diagnosed cases having ended in death. HIV and AIDS are today and will remain a worldwide health problem for many years to come.
Clinical symptoms are weight loss, chronic diarrhoea, persisting fever and opportunistic infections due to loss of T-cells, thus upsetting the overall balance of the immune system. The patient loses his/her ability to combat otherwise insignificant infections. Many substances interfering with replication have been tried, e.g. 3'-azido - 3*-deoxythymidine (AZT) , 2' ,3 '-dideoxyadenosine, 3*-fluoroarabinosyladenine, 2' ,3'-dideoxycytidine, 2'-chloro-2'3'-dideoxyadenosine, 2* ,3'-dideoxyguanosine, 2' ,3'-dideoxyinosine, 2' ,3'- dideoxy - 2• ,3'-didehydrothymidine, 3*-azido- 2',3*,- dideoxyuridine, 3'-azido - 2• ,3'-dieoxy-5-ethyl-uridine, 1-(2'-deoxy-2'-fluoro-3-D-arabinofuranosyl)-5- ethyluracil, 2,6-diamino-9-(3'-azido-2• ,3 *-dideoxy-β-D- erythropentofuranosyl)purine, suramin, Evans Blue, fuchsin acid, 5-chloro-3*-fluoro-2* ,3•-dideoxy-uridine, hypericin, I-aurothioglucose, carbovir, dextran sulfate, interferon alpha, monoclonal antibodies against the HIV envelope, peptide T, phosphonoformate (foscarnet) , phosphorothioate oligodeoxynucleotides, protease inhibitors, ribavirin and soluble CD4 receptor.
European Patent Application No. 0196185A, for instance, describes pharmaceutical compositions containing AZT, a known compound which has shown great promise in the treatment of AIDS and AIDS- related complex. It is believed that AZT works by inhibiting reverse transcriptase.
We have now found that acylation or alkylation of oxygen atoms in the glycone (sugar moiety) or in the purine or pyrimidine ring and/or acylation or alkylation of exocylic or endocyclic nitrogen atoms present in the purine or pyrimidine ring can give significant advantages in terms of uptake, overall activity and site of action. Our PCT Application WO88/07532 describes certain esters and amides of this type carrying acyl groups at the 5• position or on nitrogens in the aglycone moiety nitrogens; the present invention extends this principle to a wider range of related compounds. Thus according to one feature of the invention we provide nucleosides of the general formula
γ1 0 _ G _ (!)
(wherein G is the residue of the glycone moiety of the nucleoside, Y is a hydrogen atom or a physiologically acceptable group of the formula
where n is O or 1, m is 0 or 1 and
R is an optionally substituted alkyl or aryl group or an N-(C alkyl)-1,4-dihydropyridin- 3-yl group or, where n is 0, a hydrogen atom; R 2 and R3 are independently hydrogen atoms or lower alkyl groups or R 2 and R3 together are an alkylidene group; and X is a group selected from
(where the groups Y 2, Y3 and Y4 are as defined for Y1 ι and may be the same as or different from Y or each other, R 4 is a hydrogen atom or a group -NY3Y4, where Y3 and Y 4 have the above meani.ngs and R5 i.s a hydrogen or halogen atom or a lower alkyl or trifluoromethyl group, with the. following provisos
1 2 3 4 .
(a) at least one of the groups Y , Y , Y and Y is other than hydrogen,
(b) when all of those groups Y 2, Y3 and Y4 which are present are hydrogen or all of those groups Y 2 , Y3 and R 5 which are present in formulae 1(C), 1(F) and
1(G) are hydrogen and Y 4 i.s R1CO, then Y1 i.s a group Rl(O) .CO. (OCR2R3) i.n whi.ch n and/or m is 1,
(c) the glycone group - G - is not a 2 ',3'- dideoxyribosyl group or such a group having 3 *- fluorine or 3*-azido substituent nor a 2*,3'- dehydro-dideoxyribosyl group) and/or salts thereof.
In general, compounds in which m and/or n is 1 are preferred, that is the group R1(0) .CO. (0CR2R3)- is other than a simple acyl group R 1CO-.
Compounds in which X is a group of formula (D) ,
(E) , (G) , (H) , (I) or (J) wherein the groups Y 2 and/or
3 Y are other than hydrogen are of particular interest. It will be appreciated that some of the groups X,
2 for example those in which Y is a hydrogen atom, are tautomers of other of the groups X and exist in equilibrium with them
The glycone moiety G will normally be of the formula
_ with the group Y in the 5'-position and the group X in the l*-position. The remaining positions may be substituted, for example, by one or more halogen atoms such as chlorine or, more particularly fluorine; or by hydroxyl, protected hydroxy or azido groups. There may be a bond joining the 2*- and 3'-positions to form a 2 ' ,3 •-didehydro glycone. The sterochemistry of the glycone moiety may be that of any pentose but will generally be that of ribose or arabinose. Preferred glycone moieties include the 2,3-dideoxy- 2-halo-pentofuranosyl group, for example the 2-chloro- and 2-fluoro-analogues, especially when the group has the threo configuration:
Another preferred moiety is the 2,2-difluoro-2-deoxy- pentofuranosyl group
where Y5 is a hydrogen atom or an acyl or acyloxy-alkyl group as defined above for Y1. It is known that 2,2- difluoro-2-deoxy-nucleosides are active against herpes simplex virus (HSV) and accordingly the compounds according to the invention having this glycone moiety will find application in treatment of herpes infections.
Protected hydroxy groups will in general be groups of the formula Y 1O- where Y1 has the above meaning.
According to a further feature of the invention we provide for the use of compounds of formula (I) as hereinbefore defined, and/or salts thereof, in the manufacture of a composition for the treatment or prophylaxis of virus infections, in particular neurotropic viruses and especially retroviruses such as HIV. Such compositions also form part of the invention.
The group R is preferably an alkyl group containing 1-20 carbon atoms which may be straight or branched, or an aryl group which may contain 6 to 20 carbon atoms and may be mono- or poly-cyclic. Substituents which may be present on the alkyl groups R 1 include aryl groups preferably having 6-10 carbon atoms (as in aralkyl groupings) , hydroxy, alkoxy and carboxy groups. Aryl groups include 5- or 6-membered heterocyclic aryl groups having one or more heteroato s selected from 0, N and S, such as furyl, imidazolyl, pyrrolyl, pyridinyl and thienyl groups. Substituents which may be present on aryl groups include alkyl groups, e.g. having 1-6 carbon atoms, hydroxy and carboxy groups. Examples of such groups include methyl, ethyl, propyl, t-butyl, pentyl, stearyl, palmityl, carboxyethyl and benzyl groups. * The lower alkyl groups R 2, R3 and R5 preferably contain 1-6 carbon atoms. However, R 2 preferably
3 . represents a hydrogen atom. R is preferably a hydrogen atom or more preferably a methyl group. Where R 5 i.s a halogen atom it may be a fluorine, chlorine, bromine or
5 . iodine atom. However, R is preferably a hydrogen or chlorine atom or a methyl group. When R 2 and R3 together form an alkyidene group this suitably contains
1-6 carbon atoms. Where R in any of the groups Y , Y , Y or Y4 is an N-alkyl-l,4-dihydropyridin-3-yl group the alkyl group is preferably methyl.
It will be noted that the compounds of the invention may carry more than one of the groups Y 1, Y2, Y 3 and Y4. In the compounds of formula (I) D,E, I and
4 . J, it is preferred that m in the group Y is 0 (zero) .
2 Groups Y are preferably of the formula
R1.C0-, R1C0.0.CR2R3 or R1.O.CO.O.CR2R3-.
The salts of the compounds of formula (I) may be acid addition salts with organic or inorganic acids, for instance hydrochloric or phosphoric acid or methanesulphonic acid, ethane disulphonic acid, 2-naphthylsulphonic acid, pivalic acid and pamoic acid. Antiviral counter-ions such as phosphonoformate or suramin may also be used. Organic or inorganic base salts may be formed with acidic groups present in the molecule; suitable counter-ions include alkali metal ions such as sodium and potassium ions, divalent ions such as calcium and zinc ions and organic ions such as tetraalkylammonium and choline or ions derived from meglumine or ethylenediamine. Salts according to the invention may be formed by reaction of the compound of formula (I) with an appropriate acid or base.
The compositions according to the invention may be used in the treatment and/or prophylaxis of virus infections, in particular HIV infections, and such a method forms a further feature of the invention. They may be formulated in conventional manner by admixture of one or more compounds of formula (I) as defined above with excipients and/or carriers.
While the compounds of formula (I) may themselves be inhibitors of reverse transcriptase when the 5'- hydroxy group is free, it is possible that they are converted jln vivo to the desacyl or desalkyl nucleosides. Nevertheless the substitution at the respective O- and N- atoms gives surprising advantages in terms of uptake and sustained activity. The compounds of formula (I) are more lipophilic than the parent compounds and this permits rapid and efficient absorption from the gastro-intestinal tract; the absorption rate may be optimised by careful choice of the substituent group to give the desired balance of lipophilicity and hydrophilicity. The lipophilic nature of the compunds of formula (I) also gives the molecules the ability to penetrate the cell membranes more easily and leads to higher intracellular concentrations, giving an improved dose/effect ratio. The steady hydrolysis of the compounds ensures a sustained concentration of the active compound in the cell and thereby permits longer intervals between doses, overcoming a significant drawback of the prior art compounds. Finally, the compounds according to the invention can penetrate the blood-brain barrier and thus permit treatment of the neurological disorders which have been observed to be related to the presence of neurotropic viruses, e.g. retroviruses such as HIV, and lentiviruses (Yarchoan et al. The Lancet, January 17, 1987, page 132). This is a significant advantage compared to the corresponding unsubstituted compounds or other antiviral compounds and is not referred to anywhere in the prior art. Attempts have been made to treat these neurological disorders with AZT but with limited success.
The invention thus further provides a method of treatment of neurological disorders caused by neurotropic viruses wherein an effective dose of a compound of formula (I) or a salt thereof is administered to a patient suffering from such a disorder. Compounds of formula (I) may be prepared in any convenient way, for example, by reaction of a compound of formula (II)
γ--0 _ G _ χB (H)
[wherein Y 1 is as hereinbefore defined and XB is as hereinbefore defined for X except that any of the groups Y 1, Y2, Y3 and Y4 may each additionally represent a protecting group, with the proviso that at least one of Y 1, Y2, Y3 and Y4 i.s a hydrogen atom] with a reagent serving to introduce a group R 1(0) CO. (OCR2R3) as defined above followed where required by removal of any protecting groups and/or unwanted substituents so introduced. It should be noted that where, in the starting material, more than one of Y 1, Y2, Y3 and Y4 is hydrogen, multiple reactions may occur.
Where it is desired to ensure that acylation or alkylation is effected while one or more groups Y 1, Y2, Y 3 and Y4 remain as hydrogen atoms, it may be desirable to protect the latter first, to form a compound of formula (I) in which one or more of Y 1, Y2, Y3 and Y4 are protecting groups, these being removed after introduction of the desired acyl or ether group. Such protecting groups may, in fact, be conventional N- or O-protecting groups including groups R OCO- which may be selectively removed in the presence of the group(s) intended to remain. Thus, for example, an N-benzyloxycarbonyl may be used to protect an exocylic amino group and if the group which is intended to remain is not one which is removable by reduction, for example a straight chain alkoxycarbonyl group, the
N-benzyloxycarbonyl group can readily be removed selectively using hydrogen and a noble metal catalyst such as palladium. Trisubstituted silyl groups may also be used as protecting groups, especially for the 5'-oxygen atom, and include trialkylsilyl e.g. trimethylsilyl, dimethyl- t-butylsilyl, and thexyldimethyl silyl groups. Where it is desired that the reagent introduces a group R 1(O) .CO. (OCR2R3) - only into the purine or pyrimidine base then it will be convenient to protect all of the hydroxyl groups present in the glycone, if any; adjacent hydroxyl groups can be protected with a bidentate protecting group such as the
1,1,3,3-tetraisopropyldisilox-l,3-diyl group. In general, where more than one of Y 1, Y2, Y3 and Y 4 are hydrogen, and a mixture of compounds is produced, the individual components may readily be separated, for example by chromatography.
Where 5•-0-monoalkylation is to be effected in
2' ,3•-dideoxy derivatives (i.e. introduction of a group Y 1 i.n whi.ch m i.s 1) i.t is especially effective to form a dianion of the nucleoside (e.g. by reacting with sodium hydride) and to react this with one equivalent of the alkylating agent. Monoalkylation of a hydroxy group other than the 5'-hydroxy group in the sugar moiety is carried in a similar fashion using a 5'-protected nucleoside. It is of course, still possible to use protected forms of the nucleoside, for example by acylation of a nucleophilic nitrogen atom before salt formation with sodium hydride.
Suitable acylating agents for use in the reaction have the formula Ac-L where L is a leaving group. When the acyl group Ac- is derived from a carboxylic acid, i.e. is of formula R -CO-, then suitable acylating agents include the acid halides and acid anhydrides advantageously in the presence of a base; when the acyl group is derived from a carbonic acid, i.e. is of formula R .O.CO-, then acylating agents include the haloformate esters and reactive carbonic acid diesters. In such reagents, the halogen may, for example, be chlorine or bromine. The base for use in the reaction with the acid halide or anhydride may, for example, be a heterocyclic base such as pyridine or 4-dimethylamino- pyridine. The latter increases the speed of the reaction and may be used advantageously with pyridine. The reaction will normally be carried out in the presence of an inert solvent e.g. a substituted amide solvent such as dimethylformamide, dimethyl- acetamide or a halogenated hydrocarbon such as dichloromethane. In general, we have found that using acid anhydrides as acylating agents to introduce a group R 1CO, O-acylation in the glycone takes place more readily than N-acylation, whereas using acid halides, N-acylation or even N-diacylation predominates. However, N-acyl groups R CO- may be removed selectively, for example by reaction with a phenol such as p-methyl-phenol. Where multiple substitution is to be effected, a stronger base such as sodium hydride may be advantageous.
Suitable acyloxyalkylating agents for use in the invention will in general be of the formula R1C0.0.CR R3L or R O.CO.O.CR2R L, where L is a leaving group. Thus, the group L may for example, be a halogen atom such as a chlorine or bromine atom or a hydrocarbon-sulphonyloxy group such as a tosyloxy or mesyloxy group.
The "alkylation reaction will normally be effected in the presence of a base, conveniently an inorganic carbonate such as potassium carbonate or an alkali metal hydride such as sodium hydride. Bases as used for acylation may also be useful.
The starting compounds of formula (II) wherein Y , Y 2, Y3 and Y4 are all hydrogen atoms are well described in the literature (see for example the literature references cited in the introduction hereto) . Starting compounds wherein one or more of Y 1, Y2, Y3 and Y4 are other than hydrogen may be prepared by preliminary reactions as described above.
The following literature references are of particular interest in describing the preparation of nucleoside starting materials:
2 '-Fluoro-2 •-deoxyarabinofuranosylpyrimidine nucleosides: K. A. Watanabe, U. Reichman, K. Hirota, C. Lopez, J.J. Fox J. Med. Chem. 22 (1979)21.
5-Substituted (2-Deoxy-2-halogeno-,9-D- arabinofuranosyl)cytosines and -uracils. (2-halogeno = F, Cl, Br ara, and 2-F ribo) :
K. A. Watanabe, T.-L-Su, R. S. Klein, C. K. Chu, A. Matsuda, M. W. Chun, C. Lopez, J. J. Fox J. Med. Chem. 26 (1983) 152.
1-(2-Deoxy-2-fluoro-/3-D-arabinofuranosyl)-5-ethyl(or methyl)uracil:
M. M. Mansuri, I. Ghazzouli, M. S. Chen, H. G. Howell, P. R. Brodfuehrer, D. A. Benigni, J. C. Martin J. Med. Chem.30 (1987)867.
Perbenzoylated l-(2-fluoro-2-deoxy-3-D-arabino- furanosyl)cytosine: C. H. Tann, P. H. Brodfeuhrer, S. P. Brundidge, C. Sapino. H. G. Howell J. Orα. Chem. 50 (1985)3644.
9-(2-Deoxy-2-β-fluoroarabinofuranosyl)guanine (2'-ara- fluoroguanosine) :
A. D. Borthwick, S. Butt, K. Biggadike, A. M. Exall, S.
M. Roberts, P. M. Yods, B. E. Kirk, B. R. Booth, J. M.
Cameron, S. W. Cox, C. L. P. Marr, M. D. Shill . Chem.
Soc. Chem. Commun. (1988)656.
1-(2-Fluoro-2,3-dideoxy-fi-D-ervthro-pentofuranosyl)- thymine and 1-(2-Fluoro-2.3-dideoxy-β-D-threo- pentofuranosyl)-thymine
A. V. Aerschot, P. Herdewijn, J. Balzarini, R. Pauwels, E. De Clercq J.Med.Chem.32 (1989)1743.
9-(2-Chloro-2,3-dideoxy-β-D-threo-pentofuranosyl)adenine and its bromo analogue:
P. Herdewijn, J. Balzarini, M. Baba, R. Pauwels, A. V. Aerschot, G. Janssen, E. De Clercq . Med. Chem. 31(1988)2040.
1-(2,3-Dideoxy-2-fluoro-/3-D-arabinofuranosyl)-cytosine: EP-A-292033 and EP-A-349928.
The pharmaceutical compositions according to the invention may be formulated conventionally by means well known in the art, and may be administered by any convenient route, for instance orally, rectally, vaginally, intraveneously or intramuscularly. Examples of suitable formulations include tablets and capsules, aqueous formulations for intravenous injection and oil-based formulations for intramuscular injection. Suitable dosages will lie in the range 0.1 to lOOmg per kilogram of bodyweight per 24 hour period. The compositions according to the invention may also contain other active antivirals for instance acyclovir. phosphonoformate, suramin, Evans Blue, interferons or AZT.
The invention is illustrated by the following Examples.
Example 1
l-(2-Fluoro-2,3-dideoxy-<3-D-threo-pentofuranosyl)-3- piva1oyloxy ethy1-thymine
1-(2-Fluoro-2,3-dideoxy-β-D-threo-pentofuranosyl)thymine (0.2 mmol) and imidazole (0.5 mmol) are dissolved in DMF (0.5 mmol). Thexyldimethylsilyl chloride (0.25 mmol) is added, and the reaction mixture is stirred at ambient temperature for 24 hours. The solvent is removed at reduced pressure, chloroform (15 ml) added to the residue, washed with water (5ml x 2) and the dried (MgSO ) solution evaporated. The residue is chromatographed on silica gel using ethyl acetate-hexane to furnish 1-(2-Fluoro-5-0-thexyldimethylsilyl-2,3- dideoxy-β-D-threo-pentofuranosyl)-thvmine. The product thus prepared (0.1 mmol) and potassium carbonate (0.12 mmol) are added to DMF (1ml), the mixture stirred for 1.5 hours at ambient temperature, cooled to 0βC, chloromethyl pivalate (0.12 mmol) added, the mixture stirred at ambient temperature for 18 hours, the solvent evaporated at reduced pressure, and the residue chromatographed on silica gel using ethyl acetate-hexane to furnish 1-(2-Fluoro-5-θ-thexyl- dimethylsilyl-2.3-dideoxy-g-D-threo-pentofuranosyl)-3- piva1oyloxymethy1-thy ine
The silyl group is removed by dissolution of the product thus obtained (1 mmol) in THF (1ml) and adding 0.25 M solution of tetrabutylammonium fluoride in THF (1ml) . The mixture is stirred at ambient temperature for 30 minutes, the solvent evaporated, the residue dissolved in chloroform (10ml) , washed with water (2ml) , dried (MgSO ) , evaporated and the residue purified by preparative chromatography on silica gel plates using diethyl ether. The product is extracted from the main band by chloroform-methanol. Example 2
5-Chloro-3- -fEthyloxycarbonyloxy)ethyl-l-(2-fluoro-5-Q- propionyl-2,3-dideoxy-ff-D-threo-pentofuranosyl)uracil
5-Chloro-l-(2-fluoro-2,3-dideoxy-?-D-threo- pentofuranosyl) racil (0.2mmol) and 4-N,N- dimethylaminopyridine (0.25mmol) are dissolved in pyridine (3ml), the solution cooled to 0°C, propionic anhydride (0.3mmol) added, the mixture stirred at ambient temperature for 24 hours, the solvent evaporated at reduced pressure, toluene added, the mixture reevaporated at reduced pressure, and the residue chromatographed on silica using chloroform and subsequently chloroform-methanol. The product obtained is 5-Chloro-l-(2-fluoro-5-0-propionyl-2,3-dideoxy-3-D- threo-pentofuranosyl)uracil
5-Chloro-l-(2-fluoro-5-0-propionyl-2,3-dideoxy-3-D- threo-pentofuranosyl)uracil (0.2mmol) and potassium carbonate (0.25mmol) are suspended in DMF (2ml), the mixture stirred at ambient temperature under nitrogen for 1.5 hours, cooled to 0°C, 1-chloroethyl ethyl carbonate (0.25 mmol) added, the mixture stirred at 0°C for 30 minutes, at ambient temperature for 2 hours, at 60βC for 24 hours, and the solvent evaporated at reduced pressure. The product is purified by chromatography of the residue on silica gel using ethyl acetate-hexane.
Example 3
1-(2-Fluoro-5-pivaloyloxymethyl-2.3-dideoxy-β-D-threo- pentofuranosyl)thymine
A mixture of 1-(2-fluoro-2.3-dideoxv-3-D-threo- pentofuranosyl)thymine (0.1 mmol) and sodium hydride (0.2 mmol) in DMF (1.5ml) is stirred at 0βC for 1.5 hours, chloromethyl pivalate (O.llmmol) added, the mixtvre stirred for 1 hour at ambient temperature, acetic acid (lmmol) added, the solvent evaporated at reduced pressure, and the residue chromatographed on silica gel. The product is eluted with chlorofor - methanol.
Example 4
N-Benzyloxycarbonyl-l-(2-fluoro-5-0-pivaloyloxymethyl- 2,3-dideoxy-g-D-threo-pentofuranosyl)cytosine
1-(2-Fluoro-2,3-dideoxy-jS-D-theo-pentσfuranosyl)cytosine (0.2mmol) is dissolved in a mixture of pyridine (0.5 ml) and DMF (0.5 ml), the solution cooled to CC,benzyl chloroformate (0.5 mmol) and 4-N,N-dimethylaminopyridine (0.2 mmol) added, the mixture stirred at ambient temperature for 12 hours, water (4 ml) added, the mixture evaporated at reduced pressure, and the residue chromatographed on silica gel. The product,1^^ benzyloxycarbonyl-1-(2-fluoro-2.3-dideoxy-g-D-threo- pento uranosyl)cytosine is eluted with chloroform:ethanol (99:1
A mixture of N^-benzyloxycarbonyl-l-(2-fluoro-2,3- dideoxy-ff-D-threo-pentofuranosyl)cytosine (0.lmmol) and sodium hydride (0.2lmmol) in DMF (2ml) is stirred at ambient temperature for 1.5 hours, the mixture cooled to -50°C, chloromethyl pivalate (0.11 mmol) added, the mixture stirred at -50βC for 4 hours, saturated ammonium chloride solution (1ml) added, the mixture evaporated at reduced pressure, and the residue chromatographed on silica. The product is eluted with chloroform-methanol. Example 5"
1-(2-Fluoro-5-Q-pivaloyloxymethyl-2,3-dideoxy-ff-D-threo- pentofuranosyl)cytosine
N-Benzyloxycarbonyl-l-(2-fluoro-5-0-pivaloyloxymethyl- 2,3-dideoxy-?-D-threo-pentofuranosyl)cytosine (1.0 mmol) is added to a suspension of 5% palladium on charcoal (8mg) in ethanol (4ml) . The hydrogenolysis is run at atmospheric presure using a Brown apparatus where the hydrogen gas is generated in a controlled manner by the addition of 3N HC1 to a solution of sodium hydride in a separate compartment. The reaction is run at ambient temperature and is monitored by TLC in order to ensure that overreduction in the heterocyclic ring does not occur. The reaction time is about 1 hour. The mixture is then filtered through a thin bed of Celite, the filtrate evaporated and the product purified by chromatography on silica gel using chloroform-ethanol (9:1).
Example 6
N6-Benzyloxycarbonyl-9- (2-fluoro-5-0-pivaloyloxymethyl- 2 .3 -dideoxy-jg-D-threo-pentof uranosyl ) adenine
A solution of 9-(2-fluoro-2.3-dideoxv-g-D-threo- pentofuranosyl)adenine (0.2 mmol) and 4-N.N- dimethylaminopyridine (0.2mmol) in pyridine (4ml) is cooled to 0°C, benzyl chloroformate (0.4mmol) added., the mixture stirred under nitrogen at room temperature for 24 hours, the same amounts of N.N-dimethylpyridine and benzyl chloroformate added, and the stirring continued for 48 hours. The solvent is removed at reduced pressure, the residue chromatographed on silica using chloroform:methanol (99:1 which is gradually changed to 9:1). Evaporation gives the product N6- Benzyloxycarbonyl-9-(2-fluoro-2,3-dideoxy-β-D-threo- pentofuranosyl)adenine
The product (0.15mmol) thus obtained is dissolved in DMF (3ml), sodium hydride (80% in oil, 0.33 mmol) added, the mixture stirred at room temperature for 1 hour, cooled to -50°C and chloromethyl pivalate (0.16mmol) added, the mixture stirred at room temperature for 4 hours before the reaction is stoped by addition of acetic acid (2mmol) . The mixture is evaporated to dryness at reduced pressure and the product isolated by chromatography on silica gel using chloroform:methanol (99:1) .
Example 7
9-(2-Fluoro-5-Q-pivaloyloxymethyl-2.3-dideoxy-β-D-threo- pentofuranosyl)adenine
N6-Bεnzyloxycarbonyl-9-(2-fluoro-5-0-pivaloyloxymethyl- 2,3-dideoxy-β-D-threo-pentofuranosyl)adenine (0.1 mmol) is added to a suspension of 5% palladium on charcoal (8mg) in ethanol (4ml) . The hydrogenolysis is run at atmospheric pressure using a Brown apparatus where the hydrogen gas is generated in a controlled manner by the addition of 3N HC1 to a solution of sodium hydride in a separate compartment. The reaction is run at ambient temperature and is monitored by TLC in order to ensure that overreduction in the heterocyclic ring does not occur. The reaction time is about 1 hour. The mixture is then filtered through a thin bed of Celite, the . filtrate evaporated and the product purified by chromatography on silica gel using chloroform-ethanol (9:1). Example 8
2' ,2 '-Difluoro-3-pivaloyloxymethylthvmidine
2' ,2'-Difluorothymidine (0.2 mmol) and 1,3-dichloro-
1,1,3,3-tetraisopropyldisiloxane (0.2mmol) are added to pyridine (2ml) , the reaction mixture stirred at ambient temperature for 8 hours, the solvent removed at reduced pressure, chloroform (15 ml) added to the residue, washed with aqueous bicarbonate and with water, and the dried (MgS04) solution evaporated. The residue is chromatographed on silica gel using ethyl acetate-hexane to furnish 2' .2 '-difluoro-3' .5'-O-(1.1,3,3- tetraisopropyldisilox-1.3-diyl)thymidine. The product thus prepared (0.1 mmol) and potassium carbonate (0.12 mmol) are added to DMF (1ml) , the mixture stirred for 1.5 hours at ambient temperature, cooled to 0βC, chloromethyl pivalate (0.12 mmol) added, the mixture stirred at ambient temperature for 18 hours, the solvent evaporated at reduced pressure, and the residue chromatographed on silica gel using ethyl acetate-hexane to furnish 2' .2'-difluoro-3' ,5'-O- (1.1.3.3-tetraisopropyldisilox-l.3-diyl)-3- pivaloyloxymethylthvmidine. The silyl group is removed by dissolution of the product thus obtained (lmmol) in THF(lml) and adding 0.25 M solution of tetrabutylammonium fluoride in THF (lml) . The mixture is stirred at ambient temperature for 30 minutes, the solvent evaporated, the residue dissolved in chloroform (10ml) , washed with water (2ml) , dried (MgS04) , evaporated, and the product purified by chromatography on silica gel using chloroform:methanol 95:5. Example 9
3-α-(Ethyloxycarbonyloxy)ethyl-2 ' .2 '-difluorothymidine
2 ' ,2 '-Difluoro-3 ' ,5'-0-(l,1,3,3-tetraisopropyldisilox- 1,3-diyl)thymidine (0.2mmol) and potassium carbonate (0.25 mmol) are suspended in DMF (2ml), the mixture stirred at ambient temperature under nitrogen for 1.5 hours, cooled to 0°C, 1-chloroethyl ethyl carbonate (0.25 mmol) added, the mixture stirred at 0°C for 30 minutes, at ambient temperature for 2 hours, at 60°C for 24 hours, and the solvent evaporated at reduced pressure. The product 3-et-(Ethyloxycarbonyloxy)ethyl- 2 ' .2 '-difluoro-3 ' ,5'-0-(l, 1.3.3-tetraisopropyldisilox- 1,3-diyl)thymidine is purified by chromatography on silica gel using ethyl acetate-hexane.
The silyl group is removed by dissolution of the product thus obtained (lmmol) in THF (lml) and adding 0.25 M solution of tetrabutylammonium fluoride in THF (lml) .
The mixture is stirred at ambient temperature for 30 minutes, the solvent evaporated, the residue dissolved in chloroform (10 ml) , washed with water (2ml) , dried (MgSOA) , evaporated, and the product purified by chromatography on silica gel using chloroform:methanol
95:5.
Example 10
N4-Benzyloxycarbonyl-2 ' .2 '-difluoro-2 '-deoxycytidine
2 • ,2 '-difluoro-2 '-deoxycytidine (0.2mmol) is dissolved in a mixture of pyridine (0.5ml) and DMF (0.5ml) , the solution cooled to 0°C, benzyl chloroformate (0.5 mmol) and 4-N,N-dimethylaminopyridine (0.2mmol) added, the mixture stirred at ambient temperature for 12 hours. water (4ml) added, the mixture evaporated at reduced pressure, and the residue chromatographed on silica gel. The product is eluated with chloroformrethanol (99:1)
Example 11
l-(2-Fluoro-2-deoxy-fl-D-arabinofuranosyl)-3- pivaloyloxymethylthymine
1-(2-Fluoro-2-deoxy-?-D-arabinofuranosyl)thymine (0.2mmol) and 1,3-dichloro-l,1,3,3- tetraisopropyldisiloxane (0.2mmol) are added to pyridine (2ml) , the reaction mixture stirred at ambient temperature for 8 hours, the solvent removed at reduced pressure, chloroform (15ml) added to the residue, washed with aqueous bicarbonate and with water, and the dried (MgSO.) solution evaporated. The residue is chromatographed on silica gel using ethyl acetate-hexane to furnish l-r2-fluoro-2-deoxy-/?-D-arabinofuranosyl-3,5- 0-(1.1.3.3-tetraisopropyldisilox-l.3-diyl) 1thymine.
The product thus prepared (0.lmmol) and potassium carbonate (0.12mmol) are added to DMF (lml), the mixture stirred for 1.5 hours at ambient temperature, cooled to 0°C, chloromethylpivalate (0.12mmol) added, the mixture stirred at ambient temperature for 18 hours, the solvent evaporated at reduced pressure, and the residue chromatographed on silica gel using ethyl acetate-hexane to furnish l-r2-fluoro-2-deoxy-β-D-arabinofuranosyl-3,5- 0-(l.l,3,3-tetraisopropyldisilox-1.3-diyl) 1-3- pivaloyloxymethylthymine.
The silyl group is removed by dissolution of the product thus obtained (lmmol) in THF (lml) and adding 0.25 M solution of tetrabutylammonium fluoride in THF (lml) . The mixture is stirred at ambient temperature for 30 minutes, the solvent evaporated, the residue dissolved in chloroform (10ml) , washed with water (2ml) , dried (MgSO ) , evaporated, and the product purified by chromatography on silica gel using chloroform:methanol 95:5.
Example 12
3-α-(Ethyloxycarbonyloxy)ethyl-1-(2-fluoro-2-deoxy-β-D- arabinofuranosyl)thymine
1-[2-Fluoro-2-deoxy-3-D-arabinofuranosyl-5-0-(1,1,3,3- tetraisopropyldisilox-1,3-diyl)]thymine (0.2mmol) and potassium carbonate (0.25mmol) are suspended in DMF (2ml) , the mixture stirred at ambient temperature under nitrogen for 1.5 hours, cooled to 0°C, 1-chloroethyl ethyl carbonate (0.25mmol) added, the mixture stirred at 0°C for 30 minutes, at ambient temperature for 2 hours, at 60°C for 24 hours, and the solvent evaporated at reduced pressure. The product 3-β-(ethyloxy- carbonyloxy)ethyl-1-f (2-fluoro-2-deoxy-g-D- arabinofuranosyl-3.5-0-(1.1.3.3)-tetraisopropyldisilox- 1.3-diyl) 1thymine is purified by chromatography on silica gel using ethyl acetate-hexane.
The silyl group is removed by dissolution of the product thus obtained (lmmol) in THF (lml) and adding 0.25M solution of tetrabutylammonium fluoride in THF (lml) . The mixture is stirred at ambient temperature for 30 minutes, the solvent evaporated, the residue dissolved in chloroform (10ml) , washed with water (2ml) , dried (MgSO.) , evaporated, and the product purified by chromatography on silica gel using chloroform:methanol 95:5. Example 13
l-(2-Fluoro-2-deoxy-3-pivaloyloxymethyl-β-D- arabinofuranosyl)thymine
A mixture of 4-anisylchlorodiphenylmethane (1.05mmol) and l-(2-fluoro-2-deoxy-3-D-arabinofuranosyl)thymine (lmmol) in dry pyridine is stirred at room temperature for 4 hours, the reaction stopped by addition of a few drops of methanol, the solution evaporated at reduced pressure, the residue extracted into chloroform, the chloroform solution washed and dried (MgSO.) , the solvent evaporated, and the crude product, l-(2-fluoro- 2-deoxy-5-0-monomethoxytrityl-3-D- arabinofuranosyl)thymine purified by chromatography on silica using chloroform:Me0H 98:2.
A mixture of l-(2-fluoro-2-deoxy-5-0-monomethoxytrityl- /3-D-arabinofuranosyl)thymine (0.2mmol), sodium hydride
0.42mmol; 80% in oil) in DMF (4ml) is stirred at 0°C for 1 hour, chloromethyl pivalate (0.2lmmol) added, the mixture stirred at 0βC for 5 hours. The reaction is stopped by addition of 1 M aqueous ammonium chloride (10ml) . The mixture is extracted with diethyl ether, the ether extracts washed (saturated NaCl) , dried, evaporated and the product fractionated by silica gel chromatography. The product 1-(2-fluoro-2-deoxy-5-0- monomethoxytrityl-3-pivaloyloxymethyl-/3-D- arabinofuranosyl)thymine is eluted by chloroform: ethanol (99:1).
The product thus obtained is detritylated by heating a solution in 80% acetic acid at 60 ' C for 15 minutes, the solution evaporated at reduced pressure, and the desired product isolated by chromatography on silica gel using chloroform:ethanol 95:5. Example 14
NA-Isobutyloxycarbonyl 1-(2-fluoro-2-deoxy-g-D- arabinofuranosyl)-5-iodocytosine
1-(2-Fluoro-2-deoxy-,β-D-arabinofuranosyl)-5-iodocytosine (0.2mmol) is dissolved in a mixture of pyridine (0.5ml) and DMF (0.5ml), the solution cooled to 0βC, isobutyl chloroformate (0.5mmol) and 4-N,N-dimethylaminopyridine (0.2mmol) added, the mixture stirred at ambient temperature for 12 hours, water (4ml) added, the mixture evaporated at reduced pressure, and the residue chromatographed on silica gel. The product is eluted with chloroform:ethanol (98:2).
Example 15 N6-Ethyloxycarbonyl-N6-pivaloyloxymethyl-9-(2-fluoro-2,3-dideoxy-β-arabino- furanosvpadenine ■
a) 9-(2-Fluoro-5-O-thexyldimethylsilyl-2-deoxy-6-D-arabinofuranosyl)adenine: Thexyldimethylsilyl chloride (840 mg, 4.7 mmol) was added to a solution of 9-(2- deoxy-2-fluoro-β-D-arabinofuranosyl)adenine (320 mg, 1.28 mmol) and imidazole (650 mg, 9.55 mmol) in pyridine (8 ml) and the mixture stirred at R.T. for 30 min. The reaction was stopped by addition to ice-water (30 ml), the mixture stirred for 10 min and extracted with chloroform (2 x 30 ml). The washed and dried (MgSO ) chloroform solution was evaporated and the residue subjected to flash chromatography on silica gel using CHC13 : EtOH (9 : 1); yield 236 mg (47%). »H NMR (200 MHz, CDCI3): δ 0.23 (Me2Si), 0.85 (thexyl), 1.7 (1H), 3.9 (2H, m, H5'), 4.05 (1H, m), 4.65 (1H, m, H3'), 5.1 (1H, m, H2'), 5.80 (NH2), 6.50 (1H, dd, HI'), 8.10 (1H, d, H8), 8.32 (1H, s, H2).
b) 9-(3-O-Phenoxythiocarbonyl-5-O-thexyldimethylsilyl-2-deoxy-2-fluoro-β-D-arabino- furanosvPadenine:
A solution of 9-(2-fluoro-5-O-thexyldimethylsilyl-2-deoxy-2-fluoro-β-D-arabino- furanosyl)adenine (136 mg, 0.35 mmol), 4-dimethylaminopyridine (95 mg, 0.82 mmol) and phenoxythiocarbonyl chloride (58 μl) in acetonitrile (5 ml) was stirred at R.T. under N2 for 16 h. The solvent was then removed at reduced pressure and the residue purified by flash chromatography using CHC13 : EtOH (9 : 1), yield 116 mg (63%). lH NMR (200 MHz, CDCI3) : δ 0.21 (MeSi), 0.89 (thex.), 1.6 (1H), 4.0 (CH2-5'), 4.3 (H4'), 5.4 (H2'), 5.90 (NH2), 6.0 (H3'), 6.5 (HI'), 7.1-7.5 (Ph), 8.13 (d, H8), 8.40 (s, H2).
c) 9-(2-Fluoro-5-O-thexyldimethylsilyl-2.3-dideoxy-β-D-arabinofuranosyl)-adenine: Nitrogen was bubbled for 15 min through a solution of 9-(2-fluoro-5-O- thexyldimethylsilyl-2-deoxy-β -D-arabinofuranosyl)adenine (116 mg, 0.22 mmol), tributylstannane (70 μl) and azobisisobutyronitrile (7 mg) in toluene (6 ml). The mixture was stirred at 75 °C under N2 for 3 h and the solvent evaporated. The product was isolated by flash chromatography on silica gel using CHC13 : EtOH (9 : 1); yield 82 mg (98%). »H NMR (200 MHz, CDC13): δ 0.22 (Me2Si), 0.90 (thexyl), 1.5 (1H), 2.4 (CH2-3'), 3.8 (CH2- 5'), 4.3 (H4'), 5.3 (H2'), 5.90 (NH2), 6.3 (HI'), 8.20 (d, H8), 8.35 (s, H2).
d) N^-Ethyloxycarbonyl-9-(2-fluoro-5-O-thexyldimetylsilyl-2.3-dideoxy-β-D-arabino- furanosvPadenine:
A solution of 9-(2-fluoro-5-O-thexyldimethylsilyl-2,3-dideoxy-β-D-arabino-furanosyl)- adenine (50 mg, 0.13 mmol) in dichloromethane (1.5 ml) was added dropwise to a solution of N-methylimidazole ( 0.5 ml) and ethyl chloroformate (70 ml, 0.75 mmol) in dichloromethane (1.5 ml). The mixture was stirred at room temperature for 20 h, the solvent evaporated and the residue subjected to flash chromatography using CHCI3 : EtOH (9:1); yield 37 mg (64%). tø-NMR (200 MHz, CDCI3): δ 0.15 ( Me2Si), 0.9 (thex) 1.40 and 4.30 (EtO), 1.5 (1H), 2.5 (CH2-3'), 3.8 (CH2-5'), 5.3 (H2'), 6.4 (HI'), 8.30 (d, H8), 8.65 (NH), 8.75 (s, H2).
e) N6-Ethyloxycarbonyl-N6-pivaloyloxymethyl-9-(2-fluoro-5-O-thexyldimethvIsilyl- 2.3-dideoxy-β-D-arabinofuranosyl)adenine:
Chloromethyl pivalate (30 mg, 0.20 mmol) was added to a mixture of N6- ethyloxycarbonyl-9-(2-fluoro-5-O-thexyldimethylsilyl-2,3-dideoxy-β-D-arabinofurano- syl)adenine (30 mg, 0.067 mmol) and potassium t-butoxide (24 mg, 0.20 mmol) in dry DMF (2 ml) under nitrogen atmosphere. The mixture was stirred at R.T. for 7 h, evaporated, the residue subjected to flash chromatography using CHCl3:Et2O:EtOH (5:4: 1); yield 28 mg (76 %). -1H-NMR (200 MHz, CDCI3): δ 0.15 (Me2Si), 0.85 (thex), 1.30 (piv), 1.40 and 4.33 (OEt), 1.6 (1H), 2.5 (CH2-3'), 3.8 (CH2-5'), 5.3 (H2'), 6.05 (OCH2N), 6.5 (HI'), 8.35 (H8), 8.79(s, H2).
f) N6-Ethyloxycaιbonyl-N6-pivaloyloxymethyl-9-(2-fluoro-2.3-dideoxy-β-D-arabino- furanosvDadenine:
A solution of tetrabutylammonium fluoride (0.5 M, 50 μl) in dry THF was added dropwise to a solution of N6-ethyloxycarbonyl-N6-pivaloyloxymethyl-9-(2-fluoro-5-O- thexyldimethylsilyl-2,3-dideoxy-β-D-arabinofuranosyl) adenine (18 mg, 0.032 mmol) in dry THF (lml). The mixture was stirred under nitrogen atmosphere at R.T. for 30 min. Saturated aqueous ammonium chjoride solution (1 ml) was added, the mixture was stirred for 5 min and evaporated. The product was isolated by flash chromatography using chloroform:Et2O:ethanol (5:4: 1); yield 60%. -tø[ NMR (200 MHz, CDCI3): 1.3 (piv), 1.4 and 4.3 (OEt), 6.1 (OCH2N), 8.3 (H8), 8.8 (H2).
Example 16 2' t2'-Difluoro-3-pivaloyloxymethylthymidine
a) 3.5-Bis -O-(thexyldimethylsilvI)-2-deoxy-2.2-difluoro-l-oxoribose: Thexyldimethylsilyl chloride (1.00 ml, 5.1 mol) was added to a solution of 2-deoxy-2,2- difluoro-1-oxoribose (2.5 mmol) and imidazole (10 mmol) in dry DMF (15 ml). The mixture was stirred at room temperature for 4 h before the solvent was removed under reduced pressure. The product was purified by flash-chromatography on silica gel using chloroform:ethanol (8:1); yield 80%. *H-NMR (200 MHz, CDCI3) δ 0.1, 0.9 and 1.6 (2x thexSiMe^, 3.8-4.05 (CH2), 4.3 (H3), 4.5-4.7 (H4). b) 3.5-Bis-O-(thexyldimethylsilyl)-l-O-(methanesulphonyl)-2-deoxy-2.2-difluoro- ribose:
The above lactone was reduced to the corresponding ribose by diisobutylaluminum hydride and mesylated by methanesulphonyl chloride essentially as described for the corresponding t-butylsilyl analogue by Hertel et. al. (J. Org. Chem. 53 (1988) 2406.). 1H-NMR (200 MHz, CDC13): δ 0.1, 0.9 and 1.6 (2 x thexSiMe2), 3.1 (MeOSO2-), 3.7- 3.9 (CH2), 4.2-4.3 (H3), 4.3-4.6(H4), 5.8-5.9 (HI).
c) 3'.5'-Bis -O-(thexyldimethylsilyl)-2'.2'-difluorothvmidine:
A mixture of 3,5-bis-O-(thexyldimethysilyl)-l-O-methanesuIphonyl-2-deoxy-2,2- difluororibose (3.0 g) and 2,4-bis-O-(trimethyIsiIyl)thymine ( 2.5 g) in dry dichloromethane (100 ml) together with (trifluoromethanesulρhonyloxy)trimethylsilane (0.6 g) was strirred at room temperature for 3 days before the reaction was stopped by the addition of methanol. The solvent was evaporated and the residue subjected to flash chromatography on silica gel using light petroleum:CH2Cl2:EtOAc ( 10: 10: 1) and finally EtOAαhexane (7:3). The product was mainly the β-anomer with some of the cc-anomer. -1H-NMR (200 MHz, CDCI3): δ 0.1, 0.9 and 1.6 (2 x thexSiMe^, 1.92 (5-Me), 3.7-4.0 (CH2), 4.2 (H3'); 4.5 (H4'), 6.3 (HI'), 7.24 and 7.16 (H6), 9.05 and 9.1 (NH).
d) 2'.2'- Difluoro-3-pivaloyloxymethylthvmidine:
Potassium carbonate (7 mmol) was added to a solution of 3',5'-bis-O- (thexyldimethylsilyl)-2',2'-difluorothymidine (6 mmol) in dry DMF (20 ml), the mixture stirred at 60°C for 1 h, cooled to 0°C, chloromethyl pivalate (10 mmol) added and the mixture stirred at 60°C for 2 h. Water was added and the mixture freeze-dried and the residue subjected to flash chromatography on silica gel using EtOAc:hexane (5:7). The product, a colourless oily material, was dissolved in dry THF (20 ml) and a solution of anhydrous tetrabutylammonium fluoride in dry THF (0.2 g ml, 15 ml) added dropwise with stirring. The mixture was stirred at room temperature for 35 min, the solvent evaporated, water added, the mixture extracted with chloroform, the chloroform solution evaporated and the residue subjected to flash chromatography on silica gel using CHCI3 : MeOH (10:1). -1H-NMR (200 MHz, CDCI3): δ 1.2 (piv), 1.98 (5-Me), 3.8-4.1 (5'-
CH2), 4.3-4.6 (H3', H4'), 5.97 (OCH2N), 6.1-6.3 (HI'), 7.2-7.3 (H6).
Example 17 3-oc-(Ethyloxycarbonyloxy)ethyl-2',2'-diΩuorothymidine
Potassium carbonate (0.25 mmol) was added to a solution of 3',5'-bis-O- (thexyldimethylsilyI)-2',2'-difluorothymidine (0.2 mmol) in DMF (4 ml), the mixture was stirred at room temperature for 1.5 hours, cooled to 0°C, 1-chloroethyl ethyl carbonate (0.25 mmol) added and the mixture stirred at 40°C for 2 days before the solvent was removed at reduced pressure. The residue was dissolved in hexane: EtOAc (7:5) and the filtrate subjected to flash cromatography using the above eluant. The product thus obtained was dissolved in dry THF (5 ml) and a solution of anhydrous tetrabutylammoium fluoride (0.6 mmol) in THF ( 8 ml) added. The mixture was stirred at room temperature for 35 min and the solvent evaporated. The residue was extracted with chloroform (20 ml) washed and dried (MgSO4), the solvent evaporated and the product purified by flash chromatography on silica gel using CHCl3:MeOH (1:1) . -1H- NMR (200 MHz, CDCI3): δ 1.2 and 4.1 (OEt), 1.7 (d, MeCH), 7.0 (OCHN).
Example 18 N -Ethyloxycarbonyl-l-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)cytosine
Sodium hydride (60% in oil; 4.4 mg, 0.18 mmol) was added to a solution of l-(2- deoxy-2-fluoro-β-D-arabinofuranosyI)cytosine (17 mg, 0.07 mmol) i DMF (6 ml) at 0°C, and the mixture was stirred at room temperature under nitrogen for 1 h before α- chloroethyl ethyl carbonate (10 μl, 0.07 mmol) was added. The resultant mixture was stirred overnight before the reaction was stopped by the addition of saturated aqueous ammonium chloride (6 ml). The solvents were removed by reduced pressure and the residue subjected to flash chromatography on silica gel using ethyl acetate:ethanol (1:1); yield 10 mg (40 %). *H NMR (200 MHz; CDCI3): δ 1.26 and 4.19 (EtO), 3.6 (2H, m, H-5'), 3.9 (IH, m, H-4'), 4.28 (IH, m, H-2'), 5.2 and 4.95 (IH, m, H-2'), 5.92 (IH, s, NH), 6.12 (IH, dd, H-l'), 7.10 (IH, d, H-5), 8.16 (IH, d, H-6).

Claims

Claims
1. Nucleoside compounds of the general formula
Y10 - G - X (I)
(wherein G is the residue of the glycone moiety of the nucleoside, Y is a hydrogen atom or a physiologically acceptable group of the formula
where n is O or 1, m is 0 or 1 and
R 1 i.s an optionally substi.tuted alkyl or aryl group or an N-(C alkyl)-1,4-dihydropyridin- 3-yl group or, where n is 0, a hydrogen atom;
R 2 and R3 are independently hydrogen atoms or lower alkyl groups or R 2 and R3 together are an alkylidene group; and X is a group selected from
(where the groups Y' and Y are as defined for Y" and may be the same as or different from Y or each other, R 4 i.s a hydrogen atom or a group -NY3Y4, where Y '~ and Y 4 have the above meani.ngs and R5 is a hydrogen or halogen atom or a lower alkyl or trifluoromethyl group, with the following provisos (a) at least one of the groups Y , Y and Y is other than hydrogen,
(b) when all of those groups Y Y 3 and Y4 which are present are hydrogen or all of those groups Y , Y and R 5 which are present in formulae 1(C) , 1(F) and
1(G) are hydrogen and Y 4 is R1CO, then Y1 is a group R 1(O) .CO. (OCR2R3) i.n whi.ch n and/or m is 1,
(c) the glycone group - G - is not a 2 ' ,3 '- dideoxyribosyl group or such a group having 3 '- fluorine or 3'-azido substituent nor a 2 ',3'- dehydro-dideoxyribosyl group) and/or salts thereof.
2. Compounds of formula (I) as claimed in claim 1 wherein Rτ is selected from optionally substituted C,.^ alkyl groups and C6.20 aryl groups.
3. Compounds of formula (I) as claimed in claim 1 wherein m represents 1 in at least one of the groups Y1, Y2, Y3 and YA; R2 is a hydrogen atom; and R3 is a hydrogen atom or a methyl group.
4. Compounds of formula (I) as claimed in claim 1 wherein the glycone moiety is a 2,3-dideoxy-3-halo- pentofuranosyl group.
5. Compounds of formula (I) as claimed in claim 1 wherein the glycone moiety is a 2,2-difluoro-2-deoxy- pentofuranosyl group.
6. A pharmaceutical composition comprising as active ingredient one or more compounds of formula (I) as defined in any preceding claim and/or a non-toxic salt thereof, together with a pharmaceutical carrier or excipient.
7. A process for the preparation of a compound of formula (I) as defined in any of claims 1 to 5, which comprises reaction of a compound of formula (II)
Y-'Ό - G - XB (II)
1 B [wherein Y is as defined in claim 1 and X is as defined in claim 1 for X except that any of the groμps
Y 1, Y2, Y3 and Y4 may each additionally represent a protecting group, with the proviso that at least one of
1 2 3 4
Y , Y , Y and Y is a hydrogen atom] with a reagent serving to introduce a group Rl(0) CO. (OCR2R3) as defined in claim 1 followed where required by removal of any protecting groups and/or unwanted substituents so introduced.
8. Use of compounds of formula (I) as defined in any of claims 1 to 5, and/or salts thereof, in the manufacture of a medicament for the treatment or prophylaxis of virus infections.
EP91906957A 1990-04-04 1991-04-04 Nucleoside derivatives Withdrawn EP0523110A1 (en)

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Families Citing this family (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991006554A1 (en) * 1989-11-06 1991-05-16 Nycomed As Nucleoside derivatives
YU43193A (en) * 1992-06-22 1997-01-08 Eli Lilly And Company 2'-DEOXY-2 ', 2'-DIFLUORO (4-SUBSTITUTED) PYRIMIDINE NUCLEOSIDS OF ANTIVIRUS AND ANTICANCEROGENIC ACTIVITY AND INTERMEDIATES
UA41261C2 (en) * 1992-06-22 2001-09-17 Елі Ліллі Енд Компані METHOD OF OBTAINING BETA-ANOMER-ENRICHED NUCLEOSIDES
JPH0692987A (en) * 1992-09-17 1994-04-05 Tanabe Seiyaku Co Ltd Uridine derivative and its production
JPH11217396A (en) * 1998-01-30 1999-08-10 Ajinomoto Co Inc Production of nucleoside derivative
US6326507B1 (en) 1998-06-19 2001-12-04 Trustees Of Dartmouth College Therapeutic compounds and methods of use
US7435755B2 (en) 2000-11-28 2008-10-14 The Trustees Of Dartmouth College CDDO-compounds and combination therapies thereof
EP1465615B1 (en) 2002-01-15 2012-08-01 Trustees of Dartmouth College Tricyclic-bis-enone derivatives and methods of use thereof
AU2003291726A1 (en) 2002-11-04 2004-06-07 Xenoport, Inc. Gemcitabine prodrugs, pharmaceutical compositions and uses thereof
CN1693309A (en) * 2005-04-18 2005-11-09 成都正开生物科技发展有限公司 N4 (substituted oxycarbonyl) 2',2'-bifluoro-2'-deoxycytidine derivate and application thereof
US8921340B2 (en) 2006-11-17 2014-12-30 Trustees Of Dartmouth College Methods for using synthetic triterpenoids in the treatment of bone or cartilage diseases or conditions
CA2670099A1 (en) 2006-11-17 2008-05-29 Trustees Of Dartmouth College Synthesis and biological activities of new tricyclic-bis-enones (tbes)
WO2008064132A2 (en) 2006-11-17 2008-05-29 Trustees Of Dartmouth College Synthetic triterpenoids and tricyclic-bis-enones for use in stimulating bone and cartilage growth
ES2718047T3 (en) 2008-01-11 2019-06-27 Reata Pharmaceuticals Inc Synthetic triterpenoids and methods of use in the treatment of the disease
US7915402B2 (en) 2008-04-18 2011-03-29 Reata Pharmaceuticals, Inc. Antioxidant inflammation modulators: oleanolic acid derivatives with saturation in the C-ring
JP5564490B2 (en) 2008-04-18 2014-07-30 リアタ ファーマシューティカルズ インコーポレイテッド Compounds containing anti-inflammatory pharmacores and methods of use
WO2009146216A2 (en) 2008-04-18 2009-12-03 Reata Pharmaceuticals. Inc. Antioxidant inflammation modulators: novel derivatives of oleanolic acid
AU2009237579C1 (en) 2008-04-18 2016-05-12 Reata Pharmaceuticals Holdings, LLC Antioxidant inflammation modulators: oleanolic acid derivatives with amino and other modifications at C-17
RS55631B1 (en) 2008-04-18 2017-06-30 Reata Pharmaceuticals Inc Antioxidant inflammation modulators: c-17 homologated oleanolic acid derivatives
AU2013243873B2 (en) 2012-04-04 2016-08-25 Halozyme, Inc. Combination therapy with an anti - hyaluronan agent and a tumor - targeted taxane
US8921419B2 (en) 2012-05-08 2014-12-30 Trustees Of Dartmouth College Triterpenoids and compositions containing the same
WO2016078160A1 (en) * 2014-11-17 2016-05-26 常州方圆制药有限公司 Cytidine derivative and application thereof
WO2016078397A1 (en) * 2014-11-17 2016-05-26 常州方圆制药有限公司 New type of cytidine derivative and application thereof
WO2019222435A1 (en) 2018-05-16 2019-11-21 Halozyme, Inc. Methods of selecting subjects for combination cancer therapy with a polymer-conjugated soluble ph20
GR1009958B (en) * 2019-04-24 2021-03-18 ΕΝΟΡΑΣΙΣ ΑΝΩΝΥΜΗ ΕΜΠΟΡΙΚΗ ΕΤΑΙΡΕΙΑ ΦΑΡΜΑΚΕΥΤΙΚΩΝ ΚΑΙ ΙΑΤΡΙΚΩΝ ΥΛΙΚΩΝ ΚΑΙ ΜΗΧΑΝΗΜΑΤΩΝ με δ.τ. "ΕΝΟΡΑΣΙΣ Α.Ε." Gemcitabine derivatives and methods of forming gemcotabine derivatives

Family Cites Families (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3651045A (en) * 1968-10-21 1972-03-21 Parke Davis & Co 9-(beta-d-arabinofuranosyl)adenine esters and methods for their production
IE51332B1 (en) * 1980-06-23 1986-12-10 Univ Minnesota Novel adenine nucleoside derivatives,their preparation and pharmaceutical compositions containing them
DE3100478A1 (en) * 1981-01-09 1982-08-12 Dr. Thilo & Co GmbH, 8021 Sauerlach 5'ESTERS OF PYRIMIDINE NUCLEOSIDES WITH ANTIVIRAL EFFECTIVENESS, METHOD FOR THE PRODUCTION AND MEDICINAL PRODUCTS THEREOF
US4495180A (en) * 1982-06-21 1985-01-22 Merck & Co., Inc. Prodrugs of Ara-A an antiviral agent
EP0104857A1 (en) * 1982-09-28 1984-04-04 Beecham Group Plc Deoxyuridine compounds, methods for preparing them and their use in medicine
WO1985000608A1 (en) * 1983-07-20 1985-02-14 Teijin Limited Antineoplastic agent
ATE190064T1 (en) * 1985-09-17 2000-03-15 Wellcome Found COMBINATION THERAPEUTIC NUCLEOSIDES WITH OTHER THERAPEUTICALLY EFFECTIVE COMPONENTS.
US4751221A (en) * 1985-10-18 1988-06-14 Sloan-Kettering Institute For Cancer Research 2-fluoro-arabinofuranosyl purine nucleosides
US4780452A (en) * 1986-09-08 1988-10-25 Burroughs Wellcome Co. F-substituted-3-β-D-ribofuranosyl-3H-imidazo[4,5-b]pyridines and pharmaceutical compositions thereof
JPH02503312A (en) * 1987-03-24 1990-10-11 ニユコメド・アクシエセルカペト chemical compound
IL89258A0 (en) * 1988-02-16 1989-09-10 Lilly Co Eli 2',3'-dideoxy-2',2'-difluoro-nucleosides
JPH02152976A (en) * 1988-05-06 1990-06-12 Bristol Myers Co Prodrug of 2',3'-didehydro-2',3'-dideoxynucleoside
US4900828A (en) * 1988-05-12 1990-02-13 Hoffmann-Laroche Inc. Intermediate compounds and an improved procedure for the synthesis of 2',3'-dideoxycytidine
EP0346108A3 (en) * 1988-06-09 1991-04-24 The Wellcome Foundation Limited Anti-infective nucleosides
EP0355031A3 (en) * 1988-08-17 1990-12-27 MATTHES, Eckart, Dr. Substituted pyrimidine nucleosides, process for their preparation and pharmaceutical compounds containing them
GB8823320D0 (en) * 1988-10-05 1988-11-09 Nycomed As Chemical compounds
GB8823319D0 (en) * 1988-10-05 1988-11-09 Nycomed As Chemical compounds
GB8920534D0 (en) * 1989-09-11 1989-10-25 Wellcome Found Antiviral compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9115498A2 *

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