WO1979001068A1 - 2'-substituted arabinofuranosyl nucleosides and nucleotides intermediates,preparation and use thereof - Google Patents
2'-substituted arabinofuranosyl nucleosides and nucleotides intermediates,preparation and use thereof Download PDFInfo
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- WO1979001068A1 WO1979001068A1 PCT/US1979/000325 US7900325W WO7901068A1 WO 1979001068 A1 WO1979001068 A1 WO 1979001068A1 US 7900325 W US7900325 W US 7900325W WO 7901068 A1 WO7901068 A1 WO 7901068A1
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- 0 CC1C*CC1 Chemical compound CC1C*CC1 0.000 description 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
- C07H9/02—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing only oxygen as ring hetero atoms
- C07H9/04—Cyclic acetals
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
Definitions
- This invention concerns novel arabinofuranosyl nucleosides and nucleotides which have useful antitumor, antiviral, and antimicrobial activities, processes of preparing these nucleosides and nucleotides, and pharmaceutical compositions containing them. More particularly, the invention is concerned with 2' -deoxyarabinofuranosyl nucleosides and nucleotides having an azido, amino, or hydrocarbylamino group on the 2' carbon atom.
- nucleic acid derivatives have been found to possess antitumor activity. Frequently, however, they are susceptible to deamination (and, therefore, deactivation) by deaminase enzymes found in mammals. This limits their effectiveness in antitumor therapy, for example requiring frequent, repeated administrations by .injection, e.g., intravenous infusion, and/or administration in combination with a compatible inhibitor which is active against deaminase enzymes. The need for an effective, deaminase resistant antitumor agent is generally recognized.
- Z is a pyrimidinyl-1, purinyl-9, or l,3-oxazinyl-3 moiety and X is selected from the group consisting of amino, azido, hydrocarbylamino (e.g., alkylamino) of 1 to 7 carbon
- each of R 2 and R 3 is hydrocarbylcarbonyl of 2 to 12 or 20 carbon atoms and Y is chloro, bromo, alkanoyl, or acyloxy, to obtain a nucleoside of the formula
- Z is a pyrimidinyl-1, purinyl-9, or l,3-oxazinyl-3 moiety.
- the pyrimidine, purine, or 1,3-oxazine base can be substituted or unsubstituted and may be acylated with hydrolyzable acyl groups.
- a preferred group of pyrimidine bases are those corresponding to the formula
- R 4 is amino, hydroxy, thio, hydroxylamino, alkylammo, arylamino, or aralkylamino, and R is hydrogen, fluoro, bromo, chloro, iodo, mercapto, nitro, nitrilo, thiocyanato, alkyl, alkenyl, or alkynyl.
- a preferred group of purine bases are those corresponding to the formula
- R 6 is amino, hydrogen, hydroxylamino, thio, chloro, alkylamino, arylamino, or aralkylammo
- R 7 is hydrogen, oxo, chloro, fluoro, amino, nitro, thio, or hydroxyalkyl.
- pyrimidine bases include cytosine, uracil, thymine, 5-flourouracil, 5-azauracil, 5-azacy- tosine, dihydro-5-azauracil, dihydro-5-azacytosine, 6-azauracil 6-azacytosine, 3-deazauracil, and 3-deazacytosine.
- suitable purine bases include adenine, guanine, 6-chloropuri hypoxanthine, and xanthine, as well as the 1-deaza, 2-aza, 3- deaza, 7-deaza, 8-aza, 2,8-diaza, 7-deaza-8-aza, and 9-deaza derivatives of those compounds.
- Hydrolyzable acyl groups which may be present on the heterocyclic base include acetyl, propionyl, butyryl, valeryl isovaleryl, hexanoyl, heptanoyl, octanoyl, nonanoyl, undecano lauroyl, benzoyl, phenylacetyl, phenylpropionyl, o- , m- , an p-methylbenzoyl, ⁇ -cyclopentylpropionyl, dihydrocinnamoyl, an the like.
- Silylation or alkoxylation of the labile hydrogen sites on the heterocyclic base can be accomplished by known methods. Silylation, for example, can be accomplished by the method described in British Patent Specification No. 1,070,41 The latter procedure generally involves reacting the labile hydrogen-containing base at about room temperature with a tri(lower )alkyl-chlorosilane in the presence of a tertiary amine in an anhydrous organic solvent such as benzene, toluene xylene, and dioxane. Suitable tertiary amines include tri( lower )alkyl amines such as trimethylamine, triethylamine, and tripropylamine. Alternatively, silylation can be effecte by suspending the base in anhydrous hexa( lower )alkyldisilazane and heating to reflux.
- Preparation of the 2-azido-2-deoxy-arabinofuranosyl halide can be by a multi-step synthesis involving
- acylating e.g. benzoylating
- 1,2-O-isopropyli dene-3-azido-3-deoxy-oc -D-glucofuranose (described by Meyer zu Reckendorf in Chemische Berichte, vol. 101, p. 3802 (1968)) to obtain 1 ,2-o-isopropylidene-6-o-acyl-3-azido-3-deoxy- ⁇ -D-gluc furanose of the formula Of ⁇ CH
- R 2 is hydrocarbylcarbonyl of 2 to 12 carbon atoms
- step (b) hydrolyzing the product of step (a) to obtain
- step ( c ) oxidizing and hydrolyzing the product of step (b) to obtain 5-o-acyl-2-azido-2-deoxy-D-arabinofuranose of the formula
- step (d) acylating (e.g. acetylating) the product of step (c) to obtain l,3-di-o-a.cyl-5-o-acyl-2-azido-2-deoxyara- binofuranose of the formula
- R 3 is hydrocarbylcarbonyl of 2 to 12 carbon atoms, and (e) halogenating the product of step (d) to obtain the 2-azido-2-deoxyarabinofuranosyl halide.
- hydrolysis can be performed by contacting an aqueous solution of the compound with a cation exchange resin.
- Oxidation and hydrolysis can be achieved by reaction with conventional oxidizing agents such as sodium or potassium metaperiodate, followed by treatment with an alkali metal bicarbonate.
- the step (d) halogenation can be effected by contacting the compound with a metallic halide halogenating agent such as titanium tetrachloride, or stannic chloride, preferably at lower than room temperature, e.g., about 0 to 4 degrees C.
- a metallic halide halogenating agent such as titanium tetrachloride, or stannic chloride
- the condensation reaction of the silylated or alkoxy lated heterocyclic base with the 2-azido-2-deoxy-arabinofura- nosyl halide can be conducted in a conventional manner for con densing such bases with saccharide halides, for example as disclosed in British Patent Specification No. 1,070,413. Gener ly, the reaction is performed by simply mixing the two reactants in an aprotic solvent such as tetrahydrofuran, methylene chloride, 1,2-dichloroethane, benzene, and toluene.
- an aprotic solvent such as tetrahydrofuran, methylene chloride, 1,2-dichloroethane, benzene, and toluene.
- a catalyst such as tin tetrachloride, titanium tetrachloride, and mercury salts, is optional.
- reaction temperature can be varied between about 10 degrees and 80 degrees C. for 1 hr. to several days or weeks, with the longer times being used at the lower temperatures and with the less reactive heterocyclic bases.
- Conversion of the 2' -azido group to an amino group can be accomplished by catalytic hydrogenation, for example using a nobel metal, such as platinum or palladium, catalyst.
- a nobel metal such as platinum or palladium
- Conversion of the amino group to a hydrocarbylamino group can be accomplished by reacting the compound with a hydrocarbylhalide such as an alkylhalide, e.g., ethyl chloride, under conditions generally suitable for amine alkylation reactions. If monosubstitution is desired, it is preferred to first acylate the 2' -amino group.
- a hydrocarbylhalide such as an alkylhalide, e.g., ethyl chloride
- Separation of the ⁇ c and /3 anomers of the nucleosides and nucleotides of the present invention can be accomplished using conventional column chromatography and crystallization procedures.
- the nucleosides and nucleotides of the present invention form acid addition salts with both organic and inorganic acids.
- Preferred acid addition salts are those which are pharmaceutically acceptable, such as the addition salts of hydro- chloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, succinic acid, maleic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like.
- nucleosides and nucleotides of the present invention or their acid addition salts, as therapeutic agents for the treatment of mammals
- a dosage unit form comprising from about 1 to about 500 milligrams of the compound per kilogram of the average body weight of the mammal, per dosage unit.
- the formulation may often contain about 100 to 2000 milli grams of the compound per dosage unit.
- the active compound is preferably mixed or dissolved in a compatible pharmaceutical carrier such as, for example, water, gelatin, gum arabic, lactose, starches, magnesium stea rate, talc, vegetable oils, polyalkylene glycols, petroleum jelly, etc.
- a compatible pharmaceutical carrier such as, for example, water, gelatin, gum arabic, lactose, starches, magnesium stea rate, talc, vegetable oils, polyalkylene glycols, petroleum jelly, etc.
- Administration of the compounds can be enteral or parenteral. Accordingly, their pharmaceutical preparations can either be in solid form (e.g., as tablets, capsules, dragees, or suppositories) or in liquid form (i.e., as solutions, suspensions, or emulsions).
- the preparations may be sterilized and/or may contain adjuvants such as preserving, stabilizing, wetting, or emulsifying agents, salts for varying the osmotic pressure, buffers, or other therapeutic
- Crude 1 which contains a small amount of 5 ,6-di-O-benzoate and a trace of 5-O-benzoate derivatives, is hydrolyzed in dioxane-water (1:1) with Dowex 50 [H + ] ion exchange resin to give 6-O-benzoyl-3-azido-3-deoxy-D-glucofuranose (2).
- Compound 2 which gives a poorly resolved NMR spectrum, is oxidized with sodium metaperiodate at 22-28 degrees C. for 3 hr .
- the chloroform solution is applied to a silica-gel column and the ⁇ and ⁇ anomers are eluted with an acetyl mixture of chloroform and 2- ⁇ ropanpl (10:1).
- the ⁇ -anomer l-(2-azido-2-deoxy-3-0-acetyl-5-0-benzoyl-B-D-arabinofuranosyl) cytosine, is eluted from the col umn first, and is obtained after evaporation of the solvent in 37% yield.
- Theoc-anomer, l-(2-azido-2-deoxy-3-0-benzoyl- ⁇ -D- arabinofuranosyl), cytosine is obtained in 10% yield.
- ⁇ -anomer l-( 2-azido-2-deoxy-3-0-acetyl-5-O- benzoyl- ⁇ c-D-arabinofuranosyl) cytosine
- ⁇ max CH 3 OH 273 nm, m.p. 175-176(dec)
- NMR (DMSO-d 6 , TMS) 7.68 (C H), 7.23 (NH 2 ), 5.76 (C 1 , H), 5.82 (C 5 H) , 4.93 (0 5 .H).
- Cytarazid, the ⁇ -anomer of the nucleoside prepared in Example 3 herein, and cytaramin, the nucleoside prepared in Example 4 herein, are evaluated in vitro for growth inhibiting potency against mammalian cancer cells by a micro technique, using the culture conditions described by Bobek et al. in J. Med. Chem., vol. 20, p. 458 (1977), whereby 0.5 ml. aliquots of compound are introduced into 16 x 125 mm. screw cap culture tubes, followed by 0.5 ml. portions of the medium containing 1 x 10 5 mammalian cancer cells. The cultures are incubated at 37 degrees C. for 40 hr., after which time the viable cells are counted by Trypan Blue exclusion. During this time the cell number in the controls increases about four- to nine-fold with an average cell viability of 99%.
- the test results are as follows:
- Cytarazid and cytaramin are evaluated in vivo for growth inhibitory potency against leukemic cells by intra peritoneally inoculating DBA/2 HaDD mice with an IP-PBS saline suspension of 1 x 10 6 L-1210 leukemic cells, waiting 24 hrs., and then administering the test compound intraperitoneally in 0.2 ml. of saline-phospate buffer solution (pH 7.0).
- Partially purified CR-CdR deaminase is prepared from two different sources: 1) human liver, following the procedure of Wentworth and Wolfenden, Biochemistry, vol. 14, p. 5099 (1975), and 2) blast cells of patients with acute myelocytic leukemia, using ammonium sulfate fractionation and DEAE column chromatography.
- the assay procedure is described by Wentworth and Wolfenden, ibid. Under these conditions 50% of the commer cially available anti-tumor agent, cytarabine, is deaminated in 45 minutes, whereas no significant deamination of cytaramin or cytarazid is detected in 8 hrs.
- S. faecalis is grown in the medium of Flynn et al. (1951) from which uracil and the purines are omitted, and to which 1 m ⁇ g/ml of folic acid is added.
- E. coli is grown in the synthetic medium described by Gray and Tatum (1944).
- the assays are carried out by placing 1 ml. portions of the media into 13 x 100 mm Pyrex culture tubes and adding 1 ml of water or of the solution containing the test compound. Sterilization is carried out by autoclaving or filtration.
- the inocula are prepared from cultures of the test organisms grown in 5 ml of the basal medium for 20 hr. at 37 degrees C. Following centrifugation and washing twice with iso- tonic saline, the cells are resuspended in enough saline to yield an optical density of 0.30 at 470 m ⁇ as measured in a Beckman Model B spectrophotometer. A 1 ml. portion of this suspension containing approximately 1.5 x 10 7 cells is diluted tenfold in saline, and 1 drop of this final dilution is placed in each assay tube. Incubation proceeds for 20 hours at 37 degrees C. All E. coli assays are carried out by shaking the cultures during incubation. The extent of growth is determined by means of a Klett-Summerson photoelectric colorimeter using a red filter (640-700 nut ) .
- Cytarazid and cytaramin when tested _i ⁇ vitro against Herpes Simplex types I and II viruses, utilizing the plaque reduction technique described by Dulbecco, Proceedings National Academy of Sciences, vol. 38, p. 747, exhibit significant antiviral properties. Cytarazid, for example, when used at 50 ⁇ *M concentration against Herpes Simplex type I, inhibited in. excess of 99.9% (3 log) of the virus and when used against type II inhibited greater than 99% (2 log).
Abstract
Novel arabinofuranosyl nucleosides and nucleotides having 2"-azido, 2"-amino, or 2"-hydrocarbylamino substituents, which have antitumor, antiviral, and antimicrobial properties, are prepared by condensation of a pyrimidine, purine, or 1, 3-oxazine base with an acylated 2-azido-2-deoxyarabinofuranosyl halide, followed by deblocking and catalytic hydrogenation, where appropriate, to convert the 2"-azido group to a 2"-amino group and, if desired, alkylation or the like to convert the 2"-amino group to a 2"-hydrocarbylamino group.
Description
Description
2 ' Substituted Arabinofuranosyl Nucleosides And Nucleotides Intermediates, Preparation And Use Thereof;
Technical Field
This invention concerns novel arabinofuranosyl nucleosides and nucleotides which have useful antitumor, antiviral, and antimicrobial activities, processes of preparing these nucleosides and nucleotides, and pharmaceutical compositions containing them. More particularly, the invention is concerned with 2' -deoxyarabinofuranosyl nucleosides and nucleotides having an azido, amino, or hydrocarbylamino group on the 2' carbon atom.
Background Art
Various nucleic acid derivatives have been found to possess antitumor activity. Frequently, however, they are susceptible to deamination (and, therefore, deactivation) by deaminase enzymes found in mammals. This limits their effectiveness in antitumor therapy, for example requiring frequent, repeated administrations by .injection, e.g., intravenous infusion, and/or administration in combination with a compatible inhibitor which is active against deaminase enzymes. The need for an effective, deaminase resistant antitumor agent is generally recognized.
Disclosure of Invention
In searching for such an agent we have developed a new family of arabinofuranosyl nucleosides and nucleotides which exhibit useful antitumor, antiviral, and antimicrobial properties, and which come within the formula
wherein Z is a pyrimidinyl-1, purinyl-9, or l,3-oxazinyl-3 moiety and X is selected from the group consisting of amino, azido, hydrocarbylamino (e.g., alkylamino) of 1 to 7 carbon
atoms, In addition, some of the
member having antitumor potency exhibit the desired resistance to enzymatic deamination.
Preparation of the 2' -azido nucleosides of the present invention may be by
(a) blocking the labile hydrogen sites on a pyrimidine, purine, or 1,3-oxazine base by silylation or alkoxylation and
(b) condensing the blocked base with a 2-azido-2- deoxyarabinofuranosyl halide of the formula
wherein each of R 2 and R 3 is hydrocarbylcarbonyl of 2 to 12 or 20 carbon atoms and Y is chloro, bromo, alkanoyl, or acyloxy, to obtain a nucleoside of the formula
wherein Z is a pyrimidinyl-1, purinyl-9, or l,3-oxazinyl-3 moiety.
The pyrimidine, purine, or 1,3-oxazine base can be substituted or unsubstituted and may be acylated with hydrolyzable acyl groups.
A preferred group of pyrimidine bases are those corresponding to the formula
wherein R4is amino, hydroxy, thio, hydroxylamino, alkylammo, arylamino, or aralkylamino, and R is hydrogen, fluoro, bromo, chloro, iodo, mercapto, nitro, nitrilo, thiocyanato, alkyl, alkenyl, or alkynyl.
A preferred group of purine bases are those corresponding to the formula
wherein R6 is amino, hydrogen, hydroxylamino, thio, chloro, alkylamino, arylamino, or aralkylammo, and R7 is hydrogen, oxo, chloro, fluoro, amino, nitro, thio, or hydroxyalkyl.
Suitable examples of pyrimidine bases include cytosine, uracil, thymine, 5-flourouracil, 5-azauracil, 5-azacy- tosine, dihydro-5-azauracil, dihydro-5-azacytosine, 6-azauracil 6-azacytosine, 3-deazauracil, and 3-deazacytosine. Examples of suitable purine bases include adenine, guanine, 6-chloropuri hypoxanthine, and xanthine, as well as the 1-deaza, 2-aza, 3- deaza, 7-deaza, 8-aza, 2,8-diaza, 7-deaza-8-aza, and 9-deaza derivatives of those compounds.
Hydrolyzable acyl groups which may be present on the heterocyclic base include acetyl, propionyl, butyryl, valeryl isovaleryl, hexanoyl, heptanoyl, octanoyl, nonanoyl, undecano lauroyl, benzoyl, phenylacetyl, phenylpropionyl, o- , m- , an p-methylbenzoyl, β-cyclopentylpropionyl, dihydrocinnamoyl, an the like.
Silylation or alkoxylation of the labile hydrogen sites on the heterocyclic base can be accomplished by known methods. Silylation, for example, can be accomplished by the method described in British Patent Specification No. 1,070,41 The latter procedure generally involves reacting the labile hydrogen-containing base at about room temperature with a tri(lower )alkyl-chlorosilane in the presence of a tertiary amine in an anhydrous organic solvent such as benzene, toluene xylene, and dioxane. Suitable tertiary amines include tri( lower )alkyl amines such as trimethylamine, triethylamine, and tripropylamine. Alternatively, silylation can be effecte by suspending the base in anhydrous hexa( lower )alkyldisilazane and heating to reflux.
Preparation of the 2-azido-2-deoxy-arabinofuranosyl halide can be by a multi-step synthesis involving
(a) acylating (e.g. benzoylating) 1,2-O-isopropyli dene-3-azido-3-deoxy-oc -D-glucofuranose (described by Meyer zu Reckendorf in Chemische Berichte, vol. 101, p. 3802 (1968)) to obtain 1 ,2-o-isopropylidene-6-o-acyl-3-azido-3-deoxy-α-D-gluc furanose of the formula
OfθCH
wherein R2 is hydrocarbylcarbonyl of 2 to 12 carbon atoms,
(b) hydrolyzing the product of step (a) to obtain
6-o-acyl-3-azido-3-deoxy-D-glucofuranose of the formula
( c ) oxidizing and hydrolyzing the product of step (b) to obtain 5-o-acyl-2-azido-2-deoxy-D-arabinofuranose of the formula
(d) acylating (e.g. acetylating) the product of step (c) to obtain l,3-di-o-a.cyl-5-o-acyl-2-azido-2-deoxyara- binofuranose of the formula
wherein R3 is hydrocarbylcarbonyl of 2 to 12 carbon atoms, and (e) halogenating the product of step (d) to obtain the 2-azido-2-deoxyarabinofuranosyl halide.
The same hydrolyzable acyl groups described earlier herein can generally be used in the above synthesis of the 2- azido-2-deoxyarabinofuranosyl halide. Steps (a) and (d) of that synthesis can be accomplished by conventional acylation techniques. The step (b) hydrolysis can be performed by contacting an aqueous solution of the compound with a cation exchange resin. Oxidation and hydrolysis (step (c)) can be achieved by reaction with conventional oxidizing agents such as sodium or potassium metaperiodate, followed by treatment with an alkali metal bicarbonate. The step (d) halogenation can be effected by contacting the compound with a metallic halide halogenating agent such as titanium tetrachloride, or stannic chloride, preferably at lower than room temperature, e.g., about 0 to 4 degrees C.
The condensation reaction of the silylated or alkoxy lated heterocyclic base with the 2-azido-2-deoxy-arabinofura- nosyl halide can be conducted in a conventional manner for con densing such bases with saccharide halides, for example as disclosed in British Patent Specification No. 1,070,413. Gener ly, the reaction is performed by simply mixing the two reactants in an aprotic solvent such as tetrahydrofuran, methylene chloride, 1,2-dichloroethane, benzene, and toluene. Use of a catalyst, such as tin tetrachloride, titanium tetrachloride, and mercury salts, is optional. The precise temperature and duration of the reaction are not critical and may be varied widely depending upon the reactants and solvents employed. How
ever, high temperatures promote decomposition of the saccharide halide and are therefore not preferred. Generally, the reaction temperature can be varied between about 10 degrees and 80 degrees C. for 1 hr. to several days or weeks, with the longer times being used at the lower temperatures and with the less reactive heterocyclic bases.
To unblock the 3' and 5' oxygens of the 2-azido-2- deoxy arabinofuranosyl nucleosides described above requires a conventional saponification treatment, for example using methanolic sodium. Conversion of the resultant 3' and 5' hydroxyls to phosphate, sulfamate, phosphonate, or acyl groups can be accomplished by simply reacting the nucleoside with phosphoric, sulfamic, or phosphorous acids, or with hydrocarbon acids in the presence of condensing agents such as dicyclo-hexylcarbodiimide, or suitable derivatives of the acids such as halides or anhydrides thereof. Further, the 5'-hydroxyl group can be replaced by halogenation with fluoro, chloro, bromo, or iodo atoms, or by replacement of these with an amino group.
Conversion of the 2' -azido group to an amino group can be accomplished by catalytic hydrogenation, for example using a nobel metal, such as platinum or palladium, catalyst.
Conversion of the amino group to a hydrocarbylamino group, such as an alkylamino or dialkylamino group wherein the alkyl substituents are methyl, ethyl, or propyl, can be accomplished by reacting the compound with a hydrocarbylhalide such as an alkylhalide, e.g., ethyl chloride, under conditions generally suitable for amine alkylation reactions. If monosubstitution is desired, it is preferred to first acylate the 2' -amino group.
Separation of the ©c and /3 anomers of the nucleosides and nucleotides of the present invention can be accomplished using conventional column chromatography and crystallization procedures.
The nucleosides and nucleotides of the present invention form acid addition salts with both organic and inorganic acids. Preferred acid addition salts are those which are pharmaceutically acceptable, such as the addition salts of hydro-
chloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, succinic acid, maleic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like.
To use the nucleosides and nucleotides of the present invention, or their acid addition salts, as therapeutic agents for the treatment of mammals, it is preferred to formulate the particular compound in a dosage unit form comprising from about 1 to about 500 milligrams of the compound per kilogram of the average body weight of the mammal, per dosage unit. For example, the formulation may often contain about 100 to 2000 milli grams of the compound per dosage unit.
The active compound is preferably mixed or dissolved in a compatible pharmaceutical carrier such as, for example, water, gelatin, gum arabic, lactose, starches, magnesium stea rate, talc, vegetable oils, polyalkylene glycols, petroleum jelly, etc. Administration of the compounds can be enteral or parenteral. Accordingly, their pharmaceutical preparations can either be in solid form (e.g., as tablets, capsules, dragees, or suppositories) or in liquid form (i.e., as solutions, suspensions, or emulsions). The preparations may be sterilized and/or may contain adjuvants such as preserving, stabilizing, wetting, or emulsifying agents, salts for varying the osmotic pressure, buffers, or other therapeutic agents.
Best Mode for Carrying Out the Invention
The invention may be better understood by reference to the following, non-limiting examples.
EXAMPLE 1
Preparation of 5-O-Benzoyl-3-0-Acetyl-2 Azido-2-Deoxy-D-Arabinofuranosyl Chloride
Benzoylation of l,2-O-isopropylidene-3-azido-3- deoxy-σc-D-glucofuranose with 1.05 molar equivalent of benzoylchloride gives a greater than 90% yield of 1,2-O-isopropylidene- 6-O-benzoyl-3-azido-3-deoxy- -D-glucofuranose (1). .A sample of 1 is purified on silica gel (CHC13 -ether; 3:1), NMR ( CDC3, TMS internal standard)/7.36-8.18 (2m, 5, aromatic), 5.93 (d, 1, J1,2 = 3.5 Hz, H-l), 4.67 (d, 1, J1,2 = 3.5 Hz, H-2), 4.25 - 4.80 (m, 5, H-3,4,5,6), 1.50,. 1.33 (2s, 6, 2CH3 ) . Crude 1, which contains a small amount of 5 ,6-di-O-benzoate and a trace of 5-O-benzoate derivatives, is hydrolyzed in dioxane-water (1:1) with Dowex 50 [H+] ion exchange resin to give 6-O-benzoyl-3-azido-3-deoxy-D-glucofuranose (2). Compound 2, which gives a poorly resolved NMR spectrum, is oxidized with sodium metaperiodate at 22-28 degrees C. for 3 hr . , followed by treatment with NaHCOj (to hydrolyze the forrayl group) overnight to give 5-O-benzoyl-2-azido-2-deoxy-D-arabinofuranose (3), which is purified by silica gel chroraatography (CH2Cl2-ether; 3:1).
Compound 3 is acetylated with pyridine-acetic anhydride to give an anomeric mixture (αc:β= 4:1, determined by NMR spectroscopy) of l,3-di-O-acetyl-5-O-benzoyl-2-azido-2- deoxyarabinofuranose (4). For thecC-anomer of 4, NMR (CDCl3) 7.42-8.36 (2m, 5 aromatic), 6.20 (s,l, H-l), 5.14 (dd, 1,
J2,3 = 1.5Hz,J3,4 = Hz H-3), 4.20 (d,I,J2 ,3 = 1.5 Hz, H-2); for the β -anomer of 4, 7.42 - 8.36 (2m, 5, aromatic), 6.39 (d,l,Jf A = 4.5 Hz, H-l), 5.56 (dd,l,JA3 = 8.0 Hz, Jq_ 3 = 6.0 Hz, H-3), 4.09 (dd,l,J1,3 = 4.5 Hz, J2,3 = 8.0 Hz, H-2).
Starting from 109 g. of l,2-0-isoptopylidene-3-azido3-deoxy-cc-D-glucofuranose, 86.4 g. of 4 (53.3% yield) is obtained. Compound 4 is converted to a mixture of 1-chloro derivatives 5 and 6 (5:6 = 4:1) by treatment with TiCl4 at 0-4 degrees C. for 3 hr. Compounds 5 and 6 are separated by silica gel chromatography (toluene-ethyl acetate, 8:1). For compound 5, NMR (CDC13),
7.32 - 8.20 (2m, 5H, aromatic), 6.13 (s,l,H-l), 5.10(d,l,J= 4.5 Hz , H-3 ) , 2.16 ( S , 3H , Ac ) ; 6 NMR ( CDCl^ )
1 .22 - 8.20 (2m, 5, aromatic), 6.25 (d,l,JI A = 4.5 Hz, H-l), 5.65 (dd,l,J2,3 = 8.5,J3,4 = 6.0 Hz, H-3), 4.31 (dd,l,Jl,2 = 4.5 Hz, J2,3 = 8.5 Hz, H-2), 2.13 (s,3H, Ac).
EXAMPLE 2
Preparation of l-(2-Azido-2-Deoxy-3-O- Acetyl-5-O-Benzoyl-D-Arabinofuranosyl) Cytosine
To a stirred solution of 7.8 g. of 2-azido-2-deoxy-3-O-acetyl-5-O-benzoyl-D-arabinofuranosyl chloride in 300 ml. 1,2-dichloroethane is added 6 g. of bis(triraethylsilyl) cytosine dissolved in 200 ml. of 1-2-dichloroethane. The solution is stirred at 60-65 degrees C. for 3 days, cooled to room tem perature and washed successively with 100 ml. of a saturated NaHCO solution and 100 ml. of water. It is then dried and evaporated at reduced pressure at 45 degrees C, and the residue is dissolved in 50 ml. of chloroform. The chloroform solution is applied to a silica-gel column and the β and α anomers are eluted with an acetyl mixture of chloroform and 2-ρropanpl (10:1). The β -anomer, l-(2-azido-2-deoxy-3-0-acetyl-5-0-benzoyl-B-D-arabinofuranosyl) cytosine, is eluted from the col umn first, and is obtained after evaporation of the solvent in 37% yield. Theoc-anomer, l-(2-azido-2-deoxy-3-0-benzoyl- α-D- arabinofuranosyl), cytosine, is obtained in 10% yield.
Preparation of l-(2-Azido-2-Deoxy-,-S-D- Arabinofuranosyl) Cytosine ( "Cytarazid")
To a stirred solution of 14 g. of l-( 2-azido-2-deoxy-3-O-acetyl-5-0-benzoyl-β -D-arabinofuranosyl) cytosine in 500 ml. of methanol is added a catalytic amount of sodium methoxide and the solution is stirred at room temperature overnight. The solution is evaporated to a syrup which is extracted twice with 200 ml. of ether. The residue is dissolved in 100 ml. of methanol and passed through a short column of Dowex 50 [NH4 +] ion exchange resin. The column is washed with 500-1000 ml. of methanol and the methanol solution is evaporated to a syrup. The syrup is crystallized from ethanol to give 8.2 g. (85%) of l-( 2-azido-2-deoxy- β -D-arabinofuranosyl) cytosine, to which the trivial name cytarazid is assigned λmax CH3OH = 273 nm, m.p. 157-158 (dec), NMR ( DMSO-d6, TMS)
7.76 (CgH), 7.20 (NH2), 6.17 (C. H), 5.75 (C^H), 5.86 ( Cy H) , 5.07 (O5'H).
The α -anomer, l-( 2-azido-2-deoxy-3-0-acetyl-5-O- benzoyl- σc-D-arabinofuranosyl) cytosine, is deblocked in the same manner; λmax CH3OH = 273 nm, m.p. 175-176(dec), NMR (DMSO-d6, TMS)
7.68 (C H), 7.23 (NH2), 5.76 (C1, H), 5.82 (C5H) , 4.93 (05.H).
EXAMPLE 4
Preparation of l-( 2-Amino-2-Deoxy-/B-D- Arabinofuranosyl) Cytosine ( "Cytaramin" )
To a solution of 1 g. of l-( 2-azido-2-deoxy-β-D-ara- binofuranosyl) cytosine in 200 ml. of methanol is added a catalytic amount of PtOΛ and the mixture is hydrogenated at room temperature and atmospheric pressure for 1.5 hrs. The mixture is filtered through a Celite pad and the filtrate is evaporated to a syrup which is crystallized from methanol to give 820 mg. (91%) of l-(2-amino-2-deoxy--β-D-arabinofuranosyl) cytosine, to which the trivial name cytaramin is assigned; λ max NH2) = 276, m.p. 209, NMR (DMSO-d6, TMS) <$7.79 (CgH), 7.03 (NH2), 5.99 (C1, H) , 5.68 (C5H).
EXAMPLES 5 - 10
Following the general condensation and deblocking procedures set forth in Examples 2 and 3 herein, but using the below-listed heterocyclic bases as reactants, in place of the silylated cytosine, the indicated arabinofuranosyl nucleoside a-re obtained:
EXAMPLE 11
A portion of each of the anomers of the arabinofura nosyl nucleosides prepared in Examples 5-10 is converted to its 2' -amino counterpart by the catalytic hydrogenation procedure set forth in Example 4 herein.
EXAMPLE 12
In Vitro Cytotoxicity Testing
Cytarazid, the β -anomer of the nucleoside prepared in Example 3 herein, and cytaramin, the nucleoside prepared in Example 4 herein, are evaluated in vitro for growth inhibiting potency against mammalian cancer cells by a micro technique, using the culture conditions described by Bobek et al. in J. Med. Chem., vol. 20, p. 458 (1977), whereby 0.5 ml. aliquots of
compound are introduced into 16 x 125 mm. screw cap culture tubes, followed by 0.5 ml. portions of the medium containing 1 x 105 mammalian cancer cells. The cultures are incubated at 37 degrees C. for 40 hr., after which time the viable cells are counted by Trypan Blue exclusion. During this time the cell number in the controls increases about four- to nine-fold with an average cell viability of 99%. The test results are as follows:
Concentration (Molar) for 50% Inhibition of Growth
Cell Line Cytarazid Cytaramin
When subjected to this same cytotoxicity test, the uracil derivative counterparts of cytarazid and cytaramin exhibited no growth inhibiting potency.
EXAMPLE 13 In Vivo Cytotoxicity Testing
Cytarazid and cytaramin are evaluated in vivo for growth inhibitory potency against leukemic cells by intra peritoneally inoculating DBA/2 HaDD mice with an IP-PBS saline suspension of 1 x 106 L-1210 leukemic cells, waiting 24 hrs., and then administering the test compound intraperitoneally in 0.2 ml. of saline-phospate buffer solution (pH 7.0).
EXAMPLE 14 Enzymatic Deamination Resistance Testing
Partially purified CR-CdR deaminase is prepared from two different sources: 1) human liver, following the procedure of Wentworth and Wolfenden, Biochemistry, vol. 14, p. 5099 (1975), and 2) blast cells of patients with acute myelocytic leukemia, using ammonium sulfate fractionation and DEAE column chromatography. The assay procedure is described by Wentworth and Wolfenden, ibid. Under these conditions 50% of the commer cially available anti-tumor agent, cytarabine, is deaminated in 45 minutes, whereas no significant deamination of cytaramin or cytarazid is detected in 8 hrs.
EXAMPLE 15
In Vitro Antimicrobial Testing
Cytarazid and cytaramin both prove effective to pre vent the growth of E. coli and S. faecium at concentrations of about 0.08 to 1.5 yzM, when evaluated by the following assay procedure, which is described in greater detail by Bobek et al in J. Med. Chem. , vol. 13, p. 411 (1970):
S. faecalis is grown in the medium of Flynn et al. (1951) from which uracil and the purines are omitted, and to
which 1 mμg/ml of folic acid is added. E. coli is grown in the synthetic medium described by Gray and Tatum (1944). The assays are carried out by placing 1 ml. portions of the media into 13 x 100 mm Pyrex culture tubes and adding 1 ml of water or of the solution containing the test compound. Sterilization is carried out by autoclaving or filtration.
The inocula are prepared from cultures of the test organisms grown in 5 ml of the basal medium for 20 hr. at 37 degrees C. Following centrifugation and washing twice with iso- tonic saline, the cells are resuspended in enough saline to yield an optical density of 0.30 at 470 mμ as measured in a Beckman Model B spectrophotometer. A 1 ml. portion of this suspension containing approximately 1.5 x 107 cells is diluted tenfold in saline, and 1 drop of this final dilution is placed in each assay tube. Incubation proceeds for 20 hours at 37 degrees C. All E. coli assays are carried out by shaking the cultures during incubation. The extent of growth is determined by means of a Klett-Summerson photoelectric colorimeter using a red filter (640-700 nut ) .
EXAMPLE 16
In Vitro Antiviral Testing
Cytarazid and cytaramin, when tested _iιι vitro against Herpes Simplex types I and II viruses, utilizing the plaque reduction technique described by Dulbecco, Proceedings National Academy of Sciences, vol. 38, p. 747, exhibit significant antiviral properties. Cytarazid, for example, when used at 50^*M concentration against Herpes Simplex type I, inhibited in. excess of 99.9% (3 log) of the virus and when used against type II inhibited greater than 99% (2 log).
Claims
1. A compound selected from the group consisting of arabinofuranosyl nucleosides and nucleotides of the formula
wherein Z is a pyrimidinyl-1, purinyl-9, or l,3-oxazinyl-3 moiety, X is selected from the group consisting of amino, azido and hydrocarbylamino of 1 to 7 carbon atoms, and each of R and R1 is selected from the group consisting of hydrogen, hydrocarbyl
carbonyl of 2 to 12 carbon atoms
2. A compound selected from the group consisting of l-(2-amino-2-deoxy-/3 -D-arabinofuranosyl) cytosine of the formula:
and pharmaceutically acceptable acid addition salts thereof.
3. A compound selected from the group consisting of l-(2-azido-2-deoxy-β-D-arabinofuranosyl) cytosine of the formula:
ana pnarmaceutically acceptable acid addition salts thereof.
4. A 2-azido-2-deoxyarabinofuranosyl halide of the formula
wherein each of R2 and R3 is hydrocarbylcarbonyl of 2 to 12 carbon atoms and Y is chloro or bromo.
5. A process of preparing the compound of claim 4 comprising the steps of
wherein R2 is hydrocarbylcarbonyl of 2 to 12 carbon atoms , to obtain 6-O-3-azido-3-deoxy-D-glucofuranose of the formula
(b) oxidizing and hydrolyzing the product of step (a) to obtain 5-O-acyl-2-azido-2-deoxy-D-arabinofuranose of the formula
( c ) acylating the product of step ( b ) to obta in 1 ,3-di-0-acyl-5-0-benzoyl-2-azido-2-deoxyarabinofuranose of the formula
wherein R3 is hydrocarbylcarbonyl of 2 to 12 carbon atoms, and (d) halogenating the product of step (c) to obtain 2-azido-2-deoxyarabinofuranosyl halide of the formula
wherein Y is chloro or bromo.
6. A process of preparing an arabinofuranosyl nucleoside or nucieotide of the formula-
wherein Z is a pyrimidinyl-1, purinyl-9, or 1 ,3-oxazinyl-3moiety, comprising the steps of (a) condensing a pyrimidine, purine, or 1,3-oxazine base, said base being silylated or alkoxylated, with a 2-azido 2-deoxy-arabinofuranosyl halide of the formula
wherein each of R2 and R3 is hydrocarbylcarbonyl of 2 to 12 carbon atoms and Y is chloro or bromo, to obtain a nucleoside of the formula
wherein Z is a pyrimidinyl-1, purinyl-9, or l,3-oxazinyl-3moiety,
(b) saponifying the product of step (a) to obtain an arabinofuranosyl nucleoside of the formula
and (c) catalytiσally hydrogenating the product of step (b) to obtain an arabinofuranosyl nucleoside of the formula
wherein Z is as defined above.
7. A method of inducing regression and/or palliation of a cancer disease in a mammal, comprising administering enterally or parenterally to the mammal an effective amount of an arabinofuranosyl nucleoside or nucleotide'of the formula
wherein Z is a pyrimidinyl.-l, purinyl-9, or l,3-oxazinyl-3 moiety, X is selected from the group consisting of amino, azido, and hydrocarbylamino of 1 to 7 carbon atoms, and each of R and R1 is selected from the group consisting of hydrogen, hydrocar- bylcarbonyl of 2 to 12 carbon atoms, , and with the proviso that Z is other than uracil, said nucleoside or nucleotide being either in the free base form or in the form of a pharmaceutically acceptable acid addition salt.
8. A composition in dosage unit form useful for in ducing regression and/or palliation of cancer diseases in mam mals, comprising from about 1 milligram to about 500 milligrams per kilogram of the average body weight of the mammal, per dos age unit, of an arabinofuranosyl nucleoside or nucleotide of the formula
wherein Z is a pyrimidinyl-1, purinyl-9, or l,3-oxazinyl-3 moiety, X is selected from the group consisting of amino, azido and hydrocarbylamino of 1 to 7 carbon atoms, and each of R and
10. The composition of claim 8 wherein the arabinofuranosyl nucleoside or nucleotide is a compound selected from the group consisting of l-( 2-azido- 2-deoxγ- β-D-arabinofurano-syl) cytosine of the formula:
ana pnarmaceutically acceptable acid addition salts thereof.
Priority Applications (1)
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DE7979900566T DE2967128D1 (en) | 1978-05-12 | 1979-05-14 | 2'-substituted beta-arabinofuranosyl nucleosides and nucleotides, preparation and use thereof |
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US05/905,529 US4230698A (en) | 1978-05-12 | 1978-05-12 | 2-Substituted arabinofuranosyl nucleosides and nucleotides |
US905529 | 1997-08-04 |
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WO1979001068A1 true WO1979001068A1 (en) | 1979-12-13 |
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PCT/US1979/000325 WO1979001068A1 (en) | 1978-05-12 | 1979-05-14 | 2'-substituted arabinofuranosyl nucleosides and nucleotides intermediates,preparation and use thereof |
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US (1) | US4230698A (en) |
EP (1) | EP0016005B1 (en) |
JP (1) | JPS55500441A (en) |
DE (1) | DE2967128D1 (en) |
ES (1) | ES480436A1 (en) |
IT (1) | IT1120956B (en) |
WO (1) | WO1979001068A1 (en) |
Cited By (3)
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US4724232A (en) * | 1985-03-16 | 1988-02-09 | Burroughs Wellcome Co. | Treatment of human viral infections |
US5006646A (en) * | 1989-02-22 | 1991-04-09 | Yuki Gosei Kogyo Co., Ltd. | Process for preparing 2'-deoxy-5-trifluoromethyl-beta-uridine |
WO2022008528A1 (en) * | 2020-07-07 | 2022-01-13 | Diamidex | Methods for treating cancer using a modified monosaccharide compound |
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US4711955A (en) * | 1981-04-17 | 1987-12-08 | Yale University | Modified nucleotides and methods of preparing and using same |
JPS5896024A (en) * | 1981-10-16 | 1983-06-07 | リチヤ−ド・エフ・ストツケル | Platinum toxicity detoxicant |
JPS58225097A (en) * | 1982-06-23 | 1983-12-27 | Yamasa Shoyu Co Ltd | Nucleoside 5'-alkyl or alkenylphosphate |
AU7120987A (en) * | 1986-02-20 | 1987-09-09 | Sheldon B. Greer | Composition for and method of treating aids and certain related diseases |
US4841039A (en) * | 1986-05-01 | 1989-06-20 | Emory University | 2',3'-dideoxy-5-substituted uridines and related compounds as antiviral agents |
US5455339A (en) * | 1986-05-01 | 1995-10-03 | University Of Georgia Research Foundation, Inc. | Method for the preparation of 2',3'-dideoxy and 2',3'-dideoxydide-hydro nucleosides |
US4916122A (en) * | 1987-01-28 | 1990-04-10 | University Of Georgia Research Foundation, Inc. | 3'-Azido-2',3'-dideoxyuridine anti-retroviral composition |
US4681933A (en) * | 1986-05-01 | 1987-07-21 | University Of Georgia Research Foundation, Inc. | 2',3'-dideoxy-5-substituted uridines and related compounds as antiviral agents |
US5077279A (en) * | 1986-05-01 | 1991-12-31 | University Of Georgia Research Foundation, Inc. | 3'-azido-2',3'-dideoxy-5-methylcytidine anti-viral composition |
US5190926A (en) * | 1987-01-28 | 1993-03-02 | University Of Georgia Research Foundation, Inc. | 3'-azido-2',3'-dideoxypyrimidines and related compounds as antiviral agents |
US5159067A (en) * | 1987-01-28 | 1992-10-27 | University Of Georgia Research Foundation Inc. | 5'-Diphosphohexose nucleoside pharmaceutical compositions |
US5384396A (en) * | 1988-02-23 | 1995-01-24 | The University Of Georgia Research Foundation, Inc. | Process for the deoxygenation of nucleosides |
US5077280A (en) * | 1988-04-12 | 1991-12-31 | Brown University Research Foundation | Treatment of viral infections |
US5109124A (en) * | 1988-06-01 | 1992-04-28 | Biogen, Inc. | Nucleic acid probe linked to a label having a terminal cysteine |
US5118672A (en) * | 1989-07-10 | 1992-06-02 | University Of Georgia Research Foundation | 5'-diphosphohexose nucleoside pharmaceutical compositions |
US5681941A (en) * | 1990-01-11 | 1997-10-28 | Isis Pharmaceuticals, Inc. | Substituted purines and oligonucleotide cross-linking |
US5175267A (en) * | 1990-03-02 | 1992-12-29 | University Of Georgia Research Foundation, Inc. | Stereoselective glycosylation of hetercyclic bases |
US5141943A (en) * | 1990-04-12 | 1992-08-25 | Brown University Research Foundation | 5-benzyl barbiturate derivatives |
US5278167A (en) * | 1992-05-13 | 1994-01-11 | Brown University Research Foundation | 6-pyridyl substituted pyrimidine derivatives |
US6232463B1 (en) | 1997-10-09 | 2001-05-15 | Isis Pharmaceuticals, Inc. | Substituted purines and oligonucleotide cross-linking |
AUPP823099A0 (en) * | 1999-01-18 | 1999-02-11 | Alchemia Pty Ltd | Protecting groups for carbohydrate synthesis |
US6505948B2 (en) | 2001-03-28 | 2003-01-14 | Fusion Uv Systems, Inc. | Method of modifying the spectral distribution of high-intensity ultraviolet lamps |
WO2009114325A2 (en) | 2008-03-03 | 2009-09-17 | Tosk, Incorporated | Methotrexate adjuvants to reduce toxicity and methods for using the same |
MX356509B (en) | 2011-12-22 | 2018-05-30 | Alios Biopharma Inc | Substituted nucleosides, nucleotides and analogs thereof. |
USRE48171E1 (en) | 2012-03-21 | 2020-08-25 | Janssen Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
US9441007B2 (en) | 2012-03-21 | 2016-09-13 | Alios Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
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- 1979-05-11 IT IT68009/79A patent/IT1120956B/en active
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- 1979-05-14 WO PCT/US1979/000325 patent/WO1979001068A1/en unknown
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US5885957A (en) * | 1985-03-16 | 1999-03-23 | Glaxo Wellcome Inc. | Treatment of HTLV-I infections |
US5006646A (en) * | 1989-02-22 | 1991-04-09 | Yuki Gosei Kogyo Co., Ltd. | Process for preparing 2'-deoxy-5-trifluoromethyl-beta-uridine |
WO2022008528A1 (en) * | 2020-07-07 | 2022-01-13 | Diamidex | Methods for treating cancer using a modified monosaccharide compound |
Also Published As
Publication number | Publication date |
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EP0016005A1 (en) | 1980-10-01 |
JPS55500441A (en) | 1980-07-24 |
DE2967128D1 (en) | 1984-08-30 |
US4230698A (en) | 1980-10-28 |
IT7968009A0 (en) | 1979-05-11 |
ES480436A1 (en) | 1980-08-16 |
EP0016005B1 (en) | 1984-07-25 |
EP0016005A4 (en) | 1980-05-21 |
IT1120956B (en) | 1986-03-26 |
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