WO2011109012A1 - Utilisation de 2'-désoxy-4'-thiocytidine et de ses analogues comme agents anticancéreux à effet d'hypométhylation d'adn - Google Patents

Utilisation de 2'-désoxy-4'-thiocytidine et de ses analogues comme agents anticancéreux à effet d'hypométhylation d'adn Download PDF

Info

Publication number
WO2011109012A1
WO2011109012A1 PCT/US2010/025883 US2010025883W WO2011109012A1 WO 2011109012 A1 WO2011109012 A1 WO 2011109012A1 US 2010025883 W US2010025883 W US 2010025883W WO 2011109012 A1 WO2011109012 A1 WO 2011109012A1
Authority
WO
WIPO (PCT)
Prior art keywords
dcyd
dna
formula
compound represented
compound
Prior art date
Application number
PCT/US2010/025883
Other languages
English (en)
Inventor
Jaideep Thottassery
Kamal N. Tiwari
William B. Parker
John A. Secrist
Original Assignee
Southern Research Institute
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Southern Research Institute filed Critical Southern Research Institute
Priority to PCT/US2010/025883 priority Critical patent/WO2011109012A1/fr
Priority to PCT/US2011/026669 priority patent/WO2011109383A1/fr
Publication of WO2011109012A1 publication Critical patent/WO2011109012A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present disclosure relates to certain cytidine nucleosides that are useful as inhibitors of DNA methyltransferases (DNMTs).
  • DNMTs DNA methyltransferases
  • the present disclosure relates to methods of using these compounds to treat diseases in which inhibition of DNA methylation results in beneficial effects.
  • Cancer is considered to be a leading cause of death in the United States with one of every four Americans likely to be diagnosed with the disease. Even though significant advances have occurred in the treatment of cancer, it still remains a major health concern. A considerable amount of research over the years has led to the identification of many drug compounds that kill tumor cells and inhibit tumor progression. Some of this research has resulted in finding FDA- approved treatments for patients afflicted with various cancers although complete cures are rare. Furthermore compounds that are found to exhibit cytotoxicity are quite often not selective against tumor cells. Therefore, efforts continue at an ever increasing rate in view of the extreme difficulty in uncovering promising anticancer treatments and there still remains room for improved drugs that are effective for the desired treatment, while at the same time exhibiting reduced adverse side effects.
  • the present disclosure relates to a method for inhibiting DNA methylation in cells of patients by administering to the patient at least one compound represented by the formulae:
  • R is selected individually from the group consisting of H, aliphatic acyl, aromatic acyl, halo, alkoxy, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, amino, monoalkylamino, dialkylamino, cyano, aryl and nitro; a pharmaceutically acceptable salt thereof, a prodrug thereof, solvate thereof and mixtures thereof; in an amount effective for inhibiting DNA methylation.
  • a still further aspect of the present disclosure relates to a method for treating a patient suffering from aberrant DNA methylation related diseases which comprises administering to said patient an effective amount of at least one of the above disclosed compounds.
  • Another aspect of the present invention relates to a method for preventing or treating a mammalian host at risk of developing cancer, or one who has been diagnosed with cancer, which comprises administering to said host an effective amount of at least one compound represented by the formulae; a pharmaceutically acceptable salt thereof; a prodrug thereof or a solvate thereof.
  • Fig 1 illustrates the effect of 4'-thio-2'-deoxycytidine (T-dCyd) and 5- aza-4'-thio-2'-deoxycytidine (5-aza-T-dCyd) on DNMT1 protein levels in comparison with that of zebularine (ZEB), 5-aza-2'-deoxycytidine (5-azadCyd), 5-fluoro-2'- deoxycytidine (5F-dCyd) and ara-AC (Fazarabine, i.e. 5-aza-arabinofuranosylcytosine) in KG la myeloid leukemia cells.
  • ZEB zebularine
  • 5-aza-2'-deoxycytidine 5-azadCyd
  • 5-fluoro-2'- deoxycytidine 5F-dCyd
  • ara-AC Flurabine, i.e. 5-aza-arabinofuranosylcytosine
  • Fig 2 compares the incorporation of T-dCyd into DNA with that of the natural 2'- deoxycytidine, and also with that of araC (arabinofuranosylcytosine) and T-araC (4'-thio- arabmofuranosylcytosine).
  • Fig 3 compares the incorporation of T-dCyd into DNA versus that of 5-azadCyd.
  • Fig 4 illustrates the stability of 5-aza-T-dCyd in phosphate buffered saline in comparison with that of 5-azadCyd.
  • Fig 5 and Fig 6 show results of anti-tumor activity of T-dCyd and 5-aza-T-dCyd in in vivo tumor models, respectively. Best and Various Modes for Carrying Out the Invention
  • R is individually selected from the group consisting of H, aliphatic acyl, aromatic acyl, halo, alkoxy, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, amino, monoalkylamino, dialkylamino, cyano, aryl and nitro; a pharmaceutically acceptable salt thereof, a prodrug thereof, solvates and mixtures thereof.
  • Typical aliphatic acyl groups contain 1 to 6 carbon atoms and include formyl, acetyl and propionyl.
  • Typical aromatic acyl groups include unsubstituted and alkyl substituted aromatic groups containing 7 to 10 carbon atoms in the aromatic ring. When substituted the alkyl group typically contains 1-6 carbon atoms.
  • Typical aromatic acyl groups include benzoyl and para-toluoyl.
  • alkyl refers to straight or branched chain unsubstituted hydrocarbon groups of typically 1 to 22 carbon atoms, more typically 1 to 8 carbon atoms, and even more typically 1 to 4 carbon atoms.
  • alkyl groups examples include methyl, ethyl and propyl.
  • branched alkyl groups include isopropyl and t-butyl.
  • the alkoxy group typically contains 1 to 6 carbon atoms.
  • Suitable alkoxy groups typically contain 1-6 carbon atoms and include methoxy, ethoxy, propoxy and butoxy.
  • Suitable haloalkyl groups typically contain 1-6 carbon atoms and can be straight or branched chain and include CI, Br, F or I, substituted alkyl groups including the above specifically disclosed alkyl groups.
  • Suitable alkenyl groups typically contain 2-6 carbon atoms and include ethenyl and propenyl.
  • Suitable haloalkenyl groups typically contain 1-6 carbon atoms and include CI, Br, F or I, substituted alkenyl groups including the above specifically disclosed alkenyl groups.
  • Suitable alkynyl groups typically contain 1-6 carbon atoms and include ethynyl and propynyl.
  • Suitable monoalkylamino groups contain 1-6 carbon atoms and include
  • alkyl moiety can be straight or branched chain.
  • Suitable dialkylamino groups contain 1-6 carbon atoms in each alkyl group.
  • the alkyl groups can be the same or different and can be straight or branched chain. Examples of some suitable groups are dimethylamino, diethylamino, ethylmethylamino, dipropylamino, dibutylamino, dipentylamino, dihexylamino, methylpentylamino, ethylpropylamino and ethylhexy lamino .
  • halo groups are CI, F, Br and I.
  • aryl refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, biphenyl, and diphenyl groups, each of which may be substituted such as with a halo or alkyl group.
  • the compounds according to this disclosure may form prodrugs at hydroxyl or amino functionalities using alkoxy, amino acids, etc. groups as the prodrug forming moieties.
  • the hydroxymethyl position may form mono-, di- or triphosphates and again these phosphates can form prodrugs.
  • Preparations of such prodrug derivatives are discussed in various literature sources (examples are: Alexander et ah, J. Med. Chem. 1988, 31, 318; Aligas-Martin et al., PCT WO pp/41531, p.30).
  • the nitrogen function converted in preparing these derivatives is one (or more) of the nitrogen atoms of a compound of the disclosure.
  • “Pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • the compounds of this disclosure form acid and base addition salts with a wide variety of organic and inorganic acids and bases and includes the physiologically acceptable salts which are often used in pharmaceutical chemistry. Such salts are also part of this disclosure.
  • Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric and the like. Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenyl substituted alkonic acids, hydroxyalkanoic and
  • hydroxyalkandioic acids aromatic acids, aliphatic and aromatic sulfonic acids, may also be used.
  • Such pharmaceutically acceptable salts thus include acetate, phenylacetate,
  • Bases commonly used for formation of salts include ammonium hydroxide and alkali and alkaline earth metal hydroxides, carbonates, as well as aliphatic and primary, secondary and tertiary amines, aliphatic diamines.
  • Bases especially useful in the preparation of addition salts include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, memylamine, diethylamine, and ethylene diamine.
  • “Solvates” refers to the compound formed by the interaction of a solvent and a solute and includes hydrates. Solvates are usually crystalline solid adducts containing solvent molecules within the crystal structure, in either stoichiometric or nonstoichiometric proportions.
  • the present disclosure is concerned with inhibiting DNMTs and with treating patients afflicted with diseases related to or resulting from aberrant DNA methylation.
  • T-dCyd and 5-aza-T-dCyd can deplete human DNMT1 in cancer cells (Fig 1 A, 1C, ID and IE). It has also been observed according to the present disclosure that T-dCyd is inserted into replicating DNA (Fig 2 and Fig 3).
  • T-dCyd is readily activated to its triphosphate T-dCTP (4'-thio-2'- deoxycytidine triphosphate), which is a good substrate for DNA polymerase mediated incorporation, and DNA polymerases also readily extend the chain after incorporation. It has also been observed that the T-dCMP formed in T-dCyd treated cells will not be deaminated (Table 1), and therefore, intracellular levels of unwanted metabolites that could inhibit thymidylate synthase would be diminished. Structural studies have also shown that DNA bearing 4'-thio modifications are only subtly altered.
  • 4'-thionucleosides are bioisosteric with respect to the natural 4'-oxonucleosides and have other advantages such as a stable glycosyl bond and increased metabolic stability against cellular enzymes. Furthermore, it has been observed according to the present disclosure that T-dCyd and 5-aza-T-dCyd are efficacious in in vivo tumor models (Fig 5 and Fig 6). Studies suggest that the inhibition of DNA cytosine-5 methylation and the re-expression of silenced tumor suppressors contribute to the beneficial effects of these drugs. However inhibition of DNA synthesis and other toxicities of FDA approved DNA hypomethylators represent major drawbacks in the clinic.
  • T-dCyd exhibited very little toxicity at nanomolar doses although it is robustly incorporated into DNA and markedly depletes DNMT1.
  • Fig 1 A and IB depicts results from an experiment wherein KG la human myeloid leukemia cells were treated with T-dCyd or with ZEB, 5F-dCyd, 5-azadCyd or ara-AC. Cells were incubated with drugs for the indicated times and analyzed by western blot. (*ns indicates a non-specific band used as a loading control). The results clearly show that a 72 hour exposure at low non-toxic doses of T-dCyd was capable of reducing DNMT1, comparable to levels obtained with 5F-dCyd. Strikingly, 5-aza-T-dCyd completely depleted DNMT1 at similar exposures for as little as 48h (Fig 1C).
  • T-dCyd The metabolism of T-dCyd in human cells has also been evaluated, and it has been found that it is activated to the 5 '-triphosphate of T-dCyd (T-dCTP), which is readily used as a substrate for DNA synthesis.
  • T-dCTP T-dCyd
  • Fig 2 refers to an experiment where CEM leukemia cells were incubated with 100 nM of [5- 3 H]T-dCyd, [5- 3 H]dCyd, [5- 3 H]araC or [5- 3 H]T-araC and the incorporation of compound into the DNA was determined.
  • T-dCyd or araC concentration of T-dCyd or araC required to inhibit CEM cell growth by 50% after 72 hours of incubation was 2.2 or 0.006 ⁇ , respectively.
  • Fig 3 compares T-dCyd incorporation into DNA versus that of the currently clinically used 5- azadCyd in KGla human myeloid leukemia cells.
  • the data indicate that only a moderate amount of 5-azadCyd is incorporated into DNA after 4h of incubation at 300 nM in these cells.
  • T-dCyd at the same dose is rapidly incorporated to very high levels in these cells similar to our findings in CEM cells.
  • the metabolites that were produced in CEM cells treated with either [5- 3 H]dCyd or [5- 3 H]T-dCyd were also determined (Table 1). Cells were treated with 100 nM of each compound for 1 hour and the medium and cells were extracted to determine the major metabolites that were formed. The medium was analyzed by reverse phase HPLC to measure the parent compound, deaminated product, or [ H] -water. The acid-soluble extract was analyzed by strong anion exchange HPLC to measure the intracellular concentration of nucleotide metabolites. The radioactivity in the acid-insoluble fraction represents the amount of compound that was incorporated into DNA.
  • T-dCyd was tested against human lung NCI-H23 (Fig 5), and also in DLD-1 colon tumor xenografts (not shown).
  • MTD MTD was 2 mg/kg.
  • the 9-day treatment schedule is a classical schedule for a cytotoxic anticancer agent.
  • T-dCyd as a potential DNA hypomethylating agent has not been evaluated in tumor models.
  • the 0.9 mg/kg (MTD 045 ) and the 0.6 mg/kg (MTD 0.3 ) doses also suggested some encouraging in vivo activity in a 9 day treatment schedule (Fig 5).
  • the compounds of the present disclosure can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but generally are administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
  • the compounds can also be administered in conjunction with other therapeutic agents such as interferon (IFN), interferon a-2a, interferon a-2b, consensus interferon (CIFN), ribavirin, amantadine, remantadine, interleukine-12, ursodeoxycholic acid (UDCA), and glycyrrhizin or other agents
  • the pharmaceutically acceptable carrier is chemically inert to the active
  • the pharmaceutically acceptable carriers can include polymers and polymer matrices.
  • the compounds of this disclosure can be administered by any conventional method available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents.
  • the dosage administered will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; and the effect desired.
  • a daily dosage of active ingredient can be expected to be about 0.001 to 1000 milligrams (mg) per kilogram (kg) of body weight, with the preferred dose being 0.1 to about 30 mg/kg.
  • Dosage forms typically contain from about 1 mg to about 500 mg of active ingredient per unit.
  • the active ingredient will ordinarily be present in an amount of about 0.5-95% weight based on the total weight of the composition.
  • the active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups and suspensions. It can also be administered parenterally, in sterile liquid dosage forms. The active ingredient can also be administered intranasally (nose drops) or by inhalation of a drug powder mist. Other dosage forms are potentially possible such as administration
  • transdermally via patch mechanism or ointment.
  • Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions.
  • Liquid formulations may include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, propylene glycol, glycerin, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • diluents such as water and alcohols, for example, ethanol, benzyl alcohol, propylene glycol, glycerin, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and corn starch.
  • Tablet forms can include one or more of the following: lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers.
  • Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acadia, emulsions, and gels containing, in addition to the active ingredient, such carriers as are known in the art.
  • a flavor usually sucrose and acacia or tragacanth
  • pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acadia, emulsions, and gels containing, in addition to the active ingredient, such carriers as are known in the art.
  • the compounds of the present disclosure can be made into aerosol formulations to be administered via inhalation.
  • aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, and nitrogen. They also may be formulated as
  • Formulations suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents,
  • solubilizers thickening agents, stabilizers, and preservatives.
  • the compound can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol, or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycols such as poly(ethyleneglycol) 400, glycerol ketals, such as 2,2-dimethyl-l,3-dioxolane-4-methanol, ethers, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxy
  • carboxymethylcellulose or emulsifying agents and other pharmaceutical adjuvants.
  • Oils which can be used in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.
  • Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts
  • suitable detergents include (a) cationic detergents such as, for example, dimethyldialkylammonium halides, and alkylpyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene polypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl ⁇ -aminopropionates, and 2- alkylimidazoline quaternary ammonium salts, and (e) mixtures thereof.
  • cationic detergents such as,
  • the parenteral formulations typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Suitable preservatives and buffers can be used in such formulations. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations ranges from about 5% to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • HLB hydrophile-lipophile balance
  • compositions of the present disclosure are also well-known to those who are skilled in the art. The choice of excipient will be determined in part by the particular compound, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the pharmaceutical composition of the present disclosure. The following methods and excipients are merely exemplary and are in no way limiting.
  • the pharmaceutically acceptable excipients preferably do not interfere with the action of the active ingredients and do not cause adverse side-effects.
  • Suitable carriers and excipients include solvents such as water, alcohol, and propylene glycol, solid absorbants and diluents, surface active agents, suspending agent, tableting binders, lubricants, flavors, and coloring agents.
  • the formulations can be presented in unit-dose or multi-dose sealed containers, such as ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use.
  • sterile liquid excipient for example, water
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets.
  • the requirements for effective pharmaceutical carriers for injectable compositions are well known to those of ordinary skill in the art. See Pharmaceutics and Pharmacy Practice, J.B. Lippincott Co., Philadelphia, PA, Banker and Chalmers, Eds., 238-250 (1982) and ASHP Handbook on Injectable Drugs, Toissel, 4th ed., 622-630 (1986). '
  • Formulations suitable for topical administration include lozenges comprising the active ingredient in a flavor, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier; as well as creams, emulsions, and gels containing, in addition to the active ingredient, such carriers as are known in the art.
  • formulations suitable for rectal administration may be presented as suppositories by mixing with a variety of bases such as emulsifying bases or water-soluble bases.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.
  • Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.
  • the dose administered to an animal, particularly a human, in the context of the present disclosure should be sufficient to affect a therapeutic response in the animal over a reasonable time frame.
  • dosage will depend upon a variety of factors including a condition of the animal, the body weight of the animal, as well as the severity and stage of the condition being treated.
  • a suitable dose is that which will result in a concentration of the active agent in a patient which is known to affect the desired response.
  • the preferred dosage is the amount which results in maximum inhibition of the condition being treated, without unmanageable side effects.
  • the size of the dose also will be determined by the route, timing and frequency of administration as well as the existence, nature, and extend of any adverse side effects that might accompany the administration of the compound and the desired physiological effect.
  • a large number of unit capsules are prepared by filling standard two-piece hard gelatine capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.
  • a mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient.
  • the capsules are washed and dried.
  • the active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.
  • a large number of tablets are prepared by conventional procedures so that the dosage unit was 100 mg of active ingredient, 0.2 mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg. of starch, and 98.8 mg of lactose.
  • aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption.
  • the active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques.
  • the drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.
  • the compounds of the present disclosure can be administered in the form of nose drops, or metered dose and a nasal or buccal inhaler.
  • the drug is delivered from a nasal solution as a fine mist or from a powder as an aerosol.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés représentés par les formules : dans lesquelles chaque R est individuellement choisi dans le groupe constitué par H et les groupes acyle aliphatique, acyle aromatique, fluoro, chloro, bromo, iodo, alcoxy, alkyle, haloalkyle, alcényle, halogénoalcényle, alcynyle, amino, monoalkylamino, dialkylamino, cyano, aryle et nitro ; des sels de qualité pharmaceutique de ceux-ci, des promédicaments, des solvates et des mélanges de ceux-ci. Lesdits composés sont utilisés comme inhibiteurs de l'ADN méthyltransférase et pour le traitement de patients souffrant de maladies résultant d'une méthylation aberrante de l'ADN ou liées à celle-ci telles que des syndromes myélodysplasiques et d'autres cancers.
PCT/US2010/025883 2010-03-02 2010-03-02 Utilisation de 2'-désoxy-4'-thiocytidine et de ses analogues comme agents anticancéreux à effet d'hypométhylation d'adn WO2011109012A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/US2010/025883 WO2011109012A1 (fr) 2010-03-02 2010-03-02 Utilisation de 2'-désoxy-4'-thiocytidine et de ses analogues comme agents anticancéreux à effet d'hypométhylation d'adn
PCT/US2011/026669 WO2011109383A1 (fr) 2010-03-02 2011-03-01 Utilisation de la 2-désoxy-4'-thiocytidine et de ses analogues en tant qu'agents anticancéreux d'hypométhylation de l'adn

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2010/025883 WO2011109012A1 (fr) 2010-03-02 2010-03-02 Utilisation de 2'-désoxy-4'-thiocytidine et de ses analogues comme agents anticancéreux à effet d'hypométhylation d'adn

Publications (1)

Publication Number Publication Date
WO2011109012A1 true WO2011109012A1 (fr) 2011-09-09

Family

ID=43063920

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2010/025883 WO2011109012A1 (fr) 2010-03-02 2010-03-02 Utilisation de 2'-désoxy-4'-thiocytidine et de ses analogues comme agents anticancéreux à effet d'hypométhylation d'adn

Country Status (1)

Country Link
WO (1) WO2011109012A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021216936A1 (fr) * 2020-04-23 2021-10-28 Southern Research Institute Composition destinée au traitement de cancer du sang à l'aide de 4'-thio-5-aza-2'-désoxycytidine et ses utilisations
US11447472B2 (en) 2020-07-23 2022-09-20 Pinotbio, Inc. Polymorophs of 5-aza-4′-thio-2′-deoxycytidine

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0421777A1 (fr) 1989-10-04 1991-04-10 The University Of Birmingham Nucléosides pyrimidiniques antiviraux
US5591722A (en) 1989-09-15 1997-01-07 Southern Research Institute 2'-deoxy-4'-thioribonucleosides and their antiviral activity

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5591722A (en) 1989-09-15 1997-01-07 Southern Research Institute 2'-deoxy-4'-thioribonucleosides and their antiviral activity
EP0421777A1 (fr) 1989-10-04 1991-04-10 The University Of Birmingham Nucléosides pyrimidiniques antiviraux

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
"Pharmaceutics and Pharmacy Practice", 1982, J.B. LIPPINCOTT CO., pages: 238 - 250
ALEXANDER ET AL., J. MED. CHEM., vol. 31, 1988, pages 318
CHRISTMAN JUDITH K: "5-Azacytidine and 5-aza-2'-deoxycytidine as inhibitors of DNA methylation: Mechanistic studies and their implications for cancer therapy", ONCOGENE, vol. 21, no. 35 Review Issue 3, 12 August 2002 (2002-08-12), pages 5483 - 5495, XP002610231, ISSN: 0950-9232 *
SECRIST J A ET AL: "SYNTHESIS AND BIOLOGICAL ACTIVITY OF 2'-DEOXY-4'-THIO PYRIMIDINE NECLEOSIDES", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, WASHINGTON, US, vol. 34, 1 January 1991 (1991-01-01), pages 2361 - 2366, XP000919405, ISSN: 0022-2623, DOI: DOI:10.1021/JM00112A007 *
SECRIST JA, III; TIWARI KN; RIORDAN JM; MONTGOMERY JA: "Synthesis and biological activity of 2'-deoxy-4'-thio pyrimidine nucleosides", J. MED. CHEM., vol. 34, 1991, pages 2361 - 2366
TIWARI KN; CAPPELLACCI L; MONTGOMERY JA; SECRIST JA: "III. Synthesis and anti-cancer activity of some novel 5-azacytosine nucleosides", NUCLEOSIDES NUCLEOTIDES NUCLEIC ACIDS, vol. 22, 2003, pages 2161 - 2170
TOISSEL: "ASHP Handbook on Injectable Drugs", 1986, pages: 622 - 630

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021216936A1 (fr) * 2020-04-23 2021-10-28 Southern Research Institute Composition destinée au traitement de cancer du sang à l'aide de 4'-thio-5-aza-2'-désoxycytidine et ses utilisations
US11447472B2 (en) 2020-07-23 2022-09-20 Pinotbio, Inc. Polymorophs of 5-aza-4′-thio-2′-deoxycytidine

Similar Documents

Publication Publication Date Title
US20110218170A1 (en) Use of 2'-deoxy-4'-thiocytidine and its analogues as dna hypomethylating anticancer agents
KR20100102092A (ko) 아자시티딘 유사체 및 이들의 용도
AU2016213880A1 (en) Combination of cytidine-based antineoplastic drugs with cytidine deaminase inhibitor and use thereof in the treatment of cancer
CA2718175C (fr) Utilisation de4'-thio-2'-desoxynucleosides comme agents anti-orthopoxvirus
AU2016213881A1 (en) (2’-deoxy-ribofuranosyl)-1,3,4,7-tetrahydro-(1,3)diazepin-2-one derivatives for treating cancer
WO2011109012A1 (fr) Utilisation de 2'-désoxy-4'-thiocytidine et de ses analogues comme agents anticancéreux à effet d'hypométhylation d'adn
CA2926909A1 (fr) Promedicament reciproque comportant des acides gras a chaine courte et de la zebularine ou de la 1'-cyano-cytarabine pour un traitement de cancer
KR101449579B1 (ko) 화학요법제 및 방사선을 결합한 종양 치료방법
EP2268287B1 (fr) Les schémas posologiques d'un agent anticancéreux comportant un dérivé de désoxycytidine
WO2011109383A1 (fr) Utilisation de la 2-désoxy-4'-thiocytidine et de ses analogues en tant qu'agents anticancéreux d'hypométhylation de l'adn
US20020183277A1 (en) Combination of vitamin D analogue and pyrimidine nucleoside analogue
CA2684938A1 (fr) Derive de dihydropyridine destine au traitement d'un cancer ou d'une affection precancereuse et d'autres affections
KR20190099500A (ko) 암 치료용 약물 조성물 및 그 응용
RU2471486C2 (ru) Противоопухолевое средство для непрерывного внутривенного введения, содержащее цитидиновое производное
EP2711008A1 (fr) N6,N6-dimethyladenosine destiné à être utilisé dans le traitement ou la prévention du cancer du sein primitif et métastatique
US8586561B2 (en) Anti-tumor agent comprising cytidine derivative and carboplatin
JP2024514024A (ja) ４’－チオ－５－アザ－２’－デオキシシチジンおよびベネトクラクスの併用療法
RU2487883C2 (ru) Аналоги азацитидина и их применение
EP2711009A1 (fr) Composés destinés à être utilisés dans le traitement ou la prévention du cancer primitif et métastatique du sein et de la prostate
Woessner et al. FMdC
WO2016195353A1 (fr) Utilisation de 1'-cyano-cytarabine permettant le traitement du cancer
MXPA98005083A (en) Method of treatment of disorders characterizopopor the over-expression of citidina deaminasa or deoxicitidina deamin

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10708454

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10708454

Country of ref document: EP

Kind code of ref document: A1