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WO2011153374A1 - Promédicaments de 5'-phosphate d'azacitidine - Google Patents

Promédicaments de 5'-phosphate d'azacitidine Download PDF

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Publication number
WO2011153374A1
WO2011153374A1 PCT/US2011/038961 US2011038961W WO2011153374A1 WO 2011153374 A1 WO2011153374 A1 WO 2011153374A1 US 2011038961 W US2011038961 W US 2011038961W WO 2011153374 A1 WO2011153374 A1 WO 2011153374A1
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Prior art keywords
compound
alkyl
formula
administration
pharmaceutically acceptable
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PCT/US2011/038961
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English (en)
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John F.W. Keana
Peter Ordentlich
Robert Goodenow
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Syndax Pharmaceuticals Inc.
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Publication of WO2011153374A1 publication Critical patent/WO2011153374A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C07H19/11—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids containing cyclic phosphate

Definitions

  • the present disclosure relates to analogs or derivatives of azacitidine with improved pharmaceutical properties.
  • prodrugs of azacitidine 5 ' -phosphate are provided herein.
  • One embodiment provides a compound of Formula I, or pharmaceutically acceptable salt, solvate or polymorph thereof,
  • R is H or C0 2 (C1 -C6 alkyl).
  • R 1 is H or C0 2 (C1-C6 alkyl).
  • Another embodiment provides the compound of Formula I wherein R is H and R 1 is H. Another embodiment provides the compound of Formula I wherein R is C0 2 (C1 -C6 alkyl) and R 1 is H. Another embodiment provides the compound of Formula I wherein R is H and R 1 is C0 2 (0-C6 alkyl). Another embodiment provides the compound of Formula I wherein R is C0 2 (C1 -C6 alkyl) and R 1 is C0 2 (C1 -C6 alkyl).
  • One embodiment provides a compound having the Formula la:
  • One embodiment provides a compound having the Formula lb:
  • compositions comprising a compound of Formula I or a pharmaceutically acceptable salt, solvate or polymorph thereof, and a pharmaceutically acceptable excipeint, wherein the compound of Formula I has the structure:
  • Another embodiment provides the pharmaceutical composition comprising a compound of Formula la and a pharmaceutically acceptable excipeint, wherein the compound of Formula la has the structure:
  • Another embodiment provides the pharmaceutical composition comprising a compound of Formula lb and a pharmaceutically acceptable excipeint, wherein the compound of Formula lb has the structure:
  • One embodiment provides a method for the treatment of proliferative disease in a patient comprising administration of a composition comprising a compound of Formula I, or pharmaceutically acceptable salt, solvate or polymorph thereof,
  • R 1 is H or C0 2 (C1-C6 alkyl).
  • Another embodiment provides a method for the treatment of proliferative disease wherein the proliferative disease is myelodysplastic syndrome.
  • Another embodiment provides a method for the treatment of proliferative disease wherein the proliferative disease is selected from colon cancer, lung cancer, pancreatic cancer, gastric cancer, prostate cancer, and hepatocellular carcinoma.
  • Figure 1 shows the LC trace for the purification of Example 1 ;
  • Figure 2 shows the MS analysis of Example 1 ;
  • Figure 3 shows the 400 MHz : H NMR spectrum of Example 1 ;
  • Figure 4 shows the expanded 400 MHz : H NMR spectrum of Example 1 ;
  • Figure 5 shows the D 2 0 exchange 400 MHz : H NMR spectrum of Example 1 ;
  • Figure 6 shows the effect of Example 1 on the gene expression in Calu-6 cell lines as described in Example 6.
  • Azacitidine (chemical name: 4-amino-l-beta-D-ribofuranosyl-l,3,5-triazin-2(lH)-one, also known as 5-azacytidine, azacytidine, ladakamycin or 5-AC; PubChem CID 9444) is a pyrrolidine nucleoside analogue of cytidine with antineoplastic activity. Azacitidine is incorporated into DNA, where it reversibly inhibits DNA methyltransferase, thereby blocking DNA methylation. Hypomethylation of DNA by azacitidine may activate tumor suppressor genes silenced by hypermethylation, resulting in an antitumor effect. This agent is also incorporated into RNA, thereby disrupting normal RNA function and impairing tRNA cytosine-5- methyltransferase activity.
  • azacitidine marketed as Vidaza
  • FAB French-American-British myelodysplastic syndrome subtypes: refractory anemia (RA) or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL).
  • the recommended starting dose for the first treatment cycle is 75 mg/m 2 subcutaneously or intravenously, daily for 7 days. Patients should be premedicated for nausea and vomiting.
  • Prodrugs are generally drug precursors that, following administration to an individual and subsequent absorption, are converted to an active, or a more active species via some process, such as conversion by a metabolic pathway. Some prodrugs have a chemical group present on the prodrug that renders it less active and/or confers solubility or some other property to the drug. Once the chemical group has been cleaved and/or modified from the prodrug the active drug is generated. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They are, for instance, bioavailable by oral administration whereas the parent is not. In certain instances, the prodrug also has improved solubility in pharmaceutical compositions over the parent drug.
  • a prodrug would be a compound as described herein which is administered orally, subsequrntly subjected to a biotransformation in vivo and thus provides a therapeutically effective concentration of an active agent.
  • a prodrug would be a compound as described herein which is administered orally, subsequrntly subjected to a biotransformation in vivo and thus provides a therapeutically effective concentration of an active agent.
  • Bundgaard Design and Application of Prodrugs in A Textbook of Drug Design and Development, Krosgaard- Larsen and Bundgaard, Ed., 1991, Chapter 5, 113-191, which is incorporated herein by reference.
  • Azacitidine once it is in the body, must first be activated by conversion into the 5 '-monophosphate and then into the 5 '-diphosphate and finally into the 5 '-triphosphate, which is then a substrate for the DNA replication machinery.
  • Azacitidine 5 '-triphosphate incorporated into DNA is the active DNA methylation inhibitor form of the drug.
  • the first rate limiting step in this cascade is the ATP-dependent phosphorylation of azacitidine to the monophosphorylated nucleotide (see Stressmann, C; Lyko, F. "Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine" Int. J. Cancer 2008, 123, 8-13).
  • prodrugs of azacitidine 5 ' -phosphate are provided herein.
  • One embodiment provides a compound of Formula I, or pharmaceutically acceptable salt, solvate or polymorph thereof,
  • R is H or C0 2 (C1 -C6 alkyl).
  • R 1 is H or C0 2 (C1-C6 alkyl).
  • Another embodiment provides the compound of Formula I wherein R is H and R 1 is H. Another embodiment provides the compound of Formula I wherein R is C0 2 (C1 -C6 alkyl) and R 1 is H. Another embodiment provides the compound of Formula I wherein R is H and R 1 is C0 2 (C1-C6 alkyl). Another embodiment provides the compound of Formula I wherein R is C0 2 (C1 -C6 alkyl) and R 1 is C0 2 (C1 -C6 alkyl).
  • One embodiment provides a compound having the Formula la:
  • One embodiment provides a compound having the Formula lb:
  • the term "patient”, “subject” or “individual” are used interchangeably. As used herein, they refer to individuals suffering from a disorder, and the like, encompasses mammals and non-mammals. None of the terms require that the individual be under the care and/or supervision of a medical professional. Mammals are any member of the Mammalian class, including but not limited to humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish and the like.
  • the individual is a mammal. In preferred embodiments, the individual is a human.
  • treat include alleviating, abating or ameliorating a disease or condition or one or more symptoms thereof, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition, and are intended to include prophylaxis.
  • the terms further include achieving a therapeutic benefit and/or a prophylactic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
  • compositions are administered to an individual at risk of developing a particular disease, or to an individual reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.
  • administer refers to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In preferred embodiments, the compounds and compositions described herein are administered orally.
  • an “effective amount”, “therapeutically effective amount” or “pharmaceutically effective amount” as used herein, refer to a sufficient amount of at least one agent or compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in a disease.
  • An appropriate “effective” amount may differ from one individual to another.
  • An appropriate “effective” amount in any individual case may be determined using techniques, such as a dose escalation study.
  • pharmaceutically acceptable refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compounds described herein, and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • prodrug refers to a drug precursor that, following administration to an individual and subsequent absorption, is converted to an active, or a more active species via some process, such as conversion by a metabolic pathway.
  • the term encompasses any derivative of a drug compound, which, upon administration to a recipient, is capable of providing, either directly or indirectly, said drug compound.
  • Some prodrugs have a chemical group present on the prodrug that renders it less active and/or confers solubility or some other property to the drug. Once the chemical group has been cleaved and/or modified from the prodrug the active drug compound is generated. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug.
  • Particularly favored derivatives or prodrugs are those that increase the bioavailability of the parent compounds when such prodrugs are administered to an individual (e.g. by allowing an orally administered prodrug to be more readily absorbed into the blood than the parent compound) or which enhance delivery of the parent compound to a biological compartment (e.g. the brain or lymphatic system).
  • salts refers to salts that retain the biological effectiveness of the free acids and bases of the specified compound and that are not biologically or otherwise undesirable.
  • Compounds described herein may possess acidic or basic groups and therefore may react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
  • composition refers to a active pharmaceutical ingredient, optionally mixed with at least one pharmaceutically acceptable chemical component, such as, though not limited to carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, excipients and the like.
  • carrier refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of a compound into cells or tissues.
  • pharmaceutical combination refers to a pharmaceutical therapy resulting from the mixing or combining of more than one active ingredient or prodrug and includes both fixed and non- fixed combinations of the active ingredients or prodrugs.
  • fixed combination means that at least one of the compounds described herein, and at least one co-agent, are both administered to an individual simultaneously in the form of a single entity or dosage.
  • non- fixed combination means that at least one of the compounds described herein, and at least one co-agent, are administered to an individual as separate entities either simultaneously, concurrently or sequentially with variable intervening time limits, wherein such administration provides effective levels of the two or more compounds in the body of the individual.
  • cocktail therapies e.g. the administration of three or more active ingredients.
  • co-administration are meant to encompass administration of the selected therapeutic agents to a single individual, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different times.
  • the compounds described herein will be co-administered with other agents.
  • These terms encompass administration of two or more agents to an animal so that both agents and/or their metabolites are present in the animal at the same time. They include simultaneous administration in separate compositions, administration at different times in separate compositions, and/or administration in a composition in which both agents are present.
  • the compounds of the invention and the other agent(s) are administered in a single composition.
  • compounds of the invention and the other agent(s) are admixed in the composition.
  • metabolite refers to a derivative of a compound which is formed when the compound is metabolized.
  • active metabolite refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
  • the term "metabolized,” as used herein, refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism.
  • enzymes may produce specific structural alterations to a compound.
  • cytochrome P450 catalyzes a variety of oxidative and reductive reactions
  • uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulphydryl groups. Further information on metabolism may be obtained from The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996).
  • alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to six carbon atoms (e.g., Ci-Ce alkyl).
  • an alkyl may comprise one to five carbon atoms (e.g., C 1 -C5 alkyl).
  • an alkyl may comprise one to four carbon atoms (e.g., C 1 -C4 alkyl).
  • an alkyl may comprise one to three carbon atoms (e.g., Q-C3 alkyl).
  • the alkyl is attached to the rest of the molecule by a single bond, for example, methyl (Me), ethyl (Et), «-propyl, 1-methylethyl (iso -propyl), «-butyl, «-pentyl, 1 , 1 -dimethylethyl (i-butyl), and the like.
  • an alkyl group may be optionally substituted by one or more of the following substituents: halo, cyano, nitro, thioxo, trimethylsilanyl, -OR 3 , -OC(0)-R a , -N(R a ) 2 , -C(0)R a , -C(0)OR a , -C(0)N(R a ) 2 , -N(R a )C(0)OR a , -N(R a )C(0)R a , -N(R a )S(0) t R a (where t is 1 or 2), -S(0) t OR a (where t is 1 or 2) and -S(0) t N(R a ) 2 (where t is 1 or 2) where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl carbocyclylalkyl, aryl, aralkyl
  • the compounds described herein exist as stereoisomers.
  • the phosphorous atom is chiral, all possible stereoisomers are contemplated.
  • the compounds described herein exist as solvates.
  • the invention provides for methods of treating diseases by administering such solvates.
  • the invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, insome embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol.
  • the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • the compounds described herein exist as polymorphs.
  • the invention provides for methods of treating diseases by administering such polymorphs.
  • the invention further provides for methods of treating diseases by administering such polymorphs as pharmaceutical compositions.
  • the compounds described herein include all their crystalline forms, known as polymorphs.
  • Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound.
  • polymorphs have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility.
  • various factors such as the recrystallization solvent, rate of crystallization, and storage temperature cause a single crystal form to dominate.
  • compositions comprising a compound of Formula I or a pharmaceutically acceptable salt, solvate or polymorph thereof, and a pharmaceutically acceptable excipeint, wherein the compound of Formula I has the structure:
  • Another embodiment provides the pharmaceutical composition comprising a compound of Formula la and a pharmaceutically acceptable excipeint, wherein the compound of Formula la has the structure:
  • Another embodiment provides the pharmaceutical composition comprising a compound of Formula lb and a pharmaceutically acceptable excipeint, wherein the compound of Formula lb has the structure:
  • the pharmaceutical composition comprises a pharmaceutically acceptable vehicle, carrier, diluent, or excipient, or a mixture thereof.
  • compositions in film-coated dosage forms which comprise a combination of an active ingredient, and one or more tabletting excipients to form a tablet core using conventional tabletting processes and subsequently coating the core.
  • the tablet cores can be produced using conventional granulation methods, for example wet or dry granulation, with optional comminution of the granules and with subsequent compression and coating.
  • the pharmaceutical compositions provided herein may be provided in unit-dosage forms or multiple- dosage forms.
  • Unit-dosage forms refer to physically discrete units suitable for administration to human and animal subjects and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of the active ingredient sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carriers or excipients. Examples of unit-dosage forms include ampules, syringes, and individually packaged tablets and capsules. Unit-dosage forms may be administered in fractions or multiples thereof.
  • a multiple -dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dosage form. Examples of multiple-dosage forms include vials or bottles of tablets or capsules.
  • compositions provided herein may be administered at once, or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations.
  • the administration of the combinations may be administered chronically, that is, for an extended period of time, including throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.
  • the administration of the combinations may be given continuously or temporarily suspended for a certain length of time ⁇ i.e., a "drug holiday").
  • a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained.
  • Treatment dosages generally may be titrated to optimize safety and efficacy.
  • dosage -effect relationships from in vitro studies initially can provide useful guidance on the proper doses for patient administration.
  • Studies in animal models also generally may be used for guidance regarding effective dosages for treatment in accordance with the present disclosure.
  • the dosage to be administered will depend on several factors, including the particular agent that is administered, the route administered, the condition of the particular patient, etc. Determination of these parameters are well within the skill of the art. These considerations, as well as effective formulations and administration procedures are well known in the art and are described in standard textbooks.
  • compositions provided herein may be administered alone, or in combination with one or more other active ingredients.
  • compositions provided herein may be formulated in various dosage forms for oral, parenteral, buccal, intranasal, epidural, sublingual, pulmonary, local, rectal, transdermal, or topical administration.
  • the pharmaceutical compositions may also be formulated as a modified release dosage form, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms.
  • dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see, Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Deliver Technology, athbone et al, Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, NY, 2002; Vol. 126).
  • compositions provided herein may be provided in solid, semisolid, or liquid dosage forms for oral administration
  • oral administration also include buccal, lingual, and sublingual administration.
  • Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs, and syrups.
  • the pharmaceutical compositions may contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye -migration inhibitors, sweetening agents, and flavoring agents.
  • pharmaceutically acceptable carriers or excipients including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye -migration inhibitors, sweetening agents, and flavoring agents.
  • the pharmaceutical compositions provided herein may be provided as compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coating tablets, sugar-coated, or film-coated tablets.
  • Enteric-coated tablets are compressed tablets coated with substances that resist the action of stomach acid but dissolve or disintegrate in the intestine, thus protecting the active ingredients from the acidic environment of the stomach.
  • the tablet dosage forms may be prepared from the active ingredient in powdered, crystalline, or granular forms, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and/or colorants. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.
  • the pharmaceutical compositions provided herein may be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate.
  • the hard gelatin capsule also known as the dry- filled capsule (DFC)
  • DFC dry- filled capsule
  • the soft elastic capsule is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol.
  • the liquid, semisolid, and solid dosage forms provided herein may be encapsulated in a capsule. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides.
  • the pharmaceutical compositions provided herein may be provided as non- effervescent or effervescent, granules and powders, to be reconstituted into a liquid dosage form.
  • Pharmaceutically acceptable carriers and excipients used in the non-effervescent granules or powders may include diluents, sweeteners, and wetting agents.
  • Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide.
  • the pharmaceutical compositions provided herein may be formulated as a modified release dosage form.
  • modified release refers to a dosage form in which the rate or place of release of the active ingredient(s) is different from that of an immediate dosage form when administered by the same route.
  • Modified release dosage forms include delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms.
  • modified release dosage forms can be prepared using a variety of modified release devices and methods known to those skilled in the art, including, but not limited to, matrix controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion-exchange resins, enteric coatings, multilayered coatings, microspheres, liposomes, and combinations thereof.
  • the release rate of the active ingredient can also be modified by varying the particle size of the active ingredient(s). Examples of modified release include, but are not limited to, those described in U.S. Pat.
  • the pharmaceutical compositions provided herein in an immediate release dosage form are capable of releasing not less than 75 % of the therapeutically active ingredient or combination and/or meet the disintegration or dissolution requirements for immediate release tablets of the particular therapeutic agents or combination included in the tablet core, as set forth in USP XXII, 1990 (The United States Pharmacopeia.).
  • One embodiment provides a method for the treatment of proliferative disease in a patient comprising administration of a composition comprising a compound of Formula I, or pharmaceutically acceptable salt, solvate or polymorph thereof,
  • R 1 is H or C0 2 (C1-C6 alkyl).
  • Another embodiment provides a method for the treatment of proliferative disease wherein the proliferative disease is myelodysplasia syndrome.
  • Another embodiment provides a method for the treatment of proliferative disease wherein the proliferative disease is selected from colon cancer, lung cancer, pancreatic cancer, gastric cancer, prostate cancer, and hepatocellular carcinoma.
  • Test compound (at various concentrations from 0.05 ⁇ to 10 ⁇ ) is added to human whole blood. At various time points ranging from 1 min to 6 hours, an aliquot is removed and partitioned between
  • dichloromethane and water Analysis by LC/MS of the dichloromethane phase for test compound and azacitidine will allow for the determination of rate of release of azacitidine.
  • Formulations of test compound and azacitidine suitable for oral dosing to rodents are prepared. After dosing by gavage, blood samples are obtained at various time points ranging from 1 min post-dose to 6 hours post-dose, and the aliquot placed into acetonitrile or dichloromethane to quech all biotransformations prior to analysis. Analysis by LC/MS of the organic phase for test compound and azacitidine will allow for the determination of bioavailability.
  • the Calu-6 cell line was selected for study. Test compound was dissolved in PBS and stored as frozen aliquots in dark tubes between dosing. The test solution was sonicated in a water bath for 15 min prior to addition to the cells. Cells were treated with either vehicle control (sham), 1 ⁇ Example 1 (prodrug), 3 ⁇ Example 1 (prodrug), 1 ⁇ azacitidine (aza), or 0.5 ⁇ decitabine (DAC) for four consecutive days. The levels of mPvNA expression for four genes (GATA5, IL20RA, Pak6, and TCF21) was determined by QPC . The results are provided in Figure 1.

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Abstract

La présente invention concerne des analogues ou dérivés d'azacitidine qui présentent des propriétés pharmaceutiques améliorées, ainsi que des méthodes de traitement d'une maladie proliférative à l'aide desdits analogues ou dérivés.
PCT/US2011/038961 2010-06-04 2011-06-02 Promédicaments de 5'-phosphate d'azacitidine WO2011153374A1 (fr)

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WO2017090264A1 (fr) * 2015-11-27 2017-06-01 大原薬品工業株式会社 Ester d'acide dibenzylphosphorique en position 5' de la 5-azacytidine ou 2'-désoxy-5-azacytidine
WO2018199049A1 (fr) * 2017-04-25 2018-11-01 大原薬品工業株式会社 Nouvel inhibiteur de dnmt en tant que médicament thérapeutique pour tumeur solide
WO2021007316A1 (fr) 2019-07-08 2021-01-14 Sumitomo Dainippon Pharma Oncology, Inc. Traitement du cancer
WO2021113688A1 (fr) 2019-12-05 2021-06-10 Sumitomo Dainippon Pharma Oncology, Inc. Polythérapies pour le traitement du syndrome myélodysplasique
US11279694B2 (en) 2016-11-18 2022-03-22 Sumitomo Dainippon Pharma Oncology, Inc. Alvocidib prodrugs and their use as protein kinase inhibitors
US11497756B2 (en) 2017-09-12 2022-11-15 Sumitomo Pharma Oncology, Inc. Treatment regimen for cancers that are insensitive to BCL-2 inhibitors using the MCL-1 inhibitor alvocidib
US11530231B2 (en) 2018-12-04 2022-12-20 Sumitomo Pharma Oncology, Inc. CDK9 inhibitors and polymorphs thereof for use as agents for treatment of cancer
US11793802B2 (en) 2019-03-20 2023-10-24 Sumitomo Pharma Oncology, Inc. Treatment of acute myeloid leukemia (AML) with venetoclax failure

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060014800A1 (en) * 2003-08-01 2006-01-19 Bruno Tse Novel therapeutic agents for the treatment of cancer, metabolic diseases and skin disorders
US20060035912A1 (en) * 2004-05-27 2006-02-16 Pfizer Inc Pyrrolopyrimidine derivatives useful in cancer treatment
US20080145372A1 (en) * 2004-09-24 2008-06-19 Angiogene, Pharmaceuticals Limited Bioreductively-Activated Prodrugs
US20080182806A1 (en) * 2007-01-25 2008-07-31 Nevada Cancer Institute Use of acetylated or esterificated azacytidine, decitabine, or other nucleoside analogs as oral agents for the treatment of tumors or other dysplastic syndromes sensitive to hypomethylating agents

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060014800A1 (en) * 2003-08-01 2006-01-19 Bruno Tse Novel therapeutic agents for the treatment of cancer, metabolic diseases and skin disorders
US20060035912A1 (en) * 2004-05-27 2006-02-16 Pfizer Inc Pyrrolopyrimidine derivatives useful in cancer treatment
US20080145372A1 (en) * 2004-09-24 2008-06-19 Angiogene, Pharmaceuticals Limited Bioreductively-Activated Prodrugs
US20080182806A1 (en) * 2007-01-25 2008-07-31 Nevada Cancer Institute Use of acetylated or esterificated azacytidine, decitabine, or other nucleoside analogs as oral agents for the treatment of tumors or other dysplastic syndromes sensitive to hypomethylating agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SAVOSTINA ET AL.: "To The Problem Of The Reaction Mechanism Of 2-methoxybenzo[d]-1,3,2- dioxaphosphorin-4-one With Chloral On The Basis Of Quantum-chemical Calculations: II. The Perkov Reaction.", RUSSIAN JOURNAL OF GENERAL CHEMISTRY, vol. 76, no. 7, 2006, pages 1031 - 1040 *

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108290920B (zh) * 2015-11-27 2021-08-10 大原药品工业株式会社 5-氮杂胞苷或2’-脱氧-5-氮杂胞苷的5’-二苄基磷酸酯
WO2017090275A1 (fr) 2015-11-27 2017-06-01 大原薬品工業株式会社 Ester d'acide dibenzylphosphorique en position 5' de la 5-azacytidine ou 2'-désoxy-5-azacytidine
US20170152275A1 (en) * 2015-11-27 2017-06-01 Ohara Pharmaceutical Co., Ltd. 5'-dibenzyl phosphates of 5-azacytidine or 2'-deoxy-5-azacytidine
US9670238B1 (en) 2015-11-27 2017-06-06 Ohara Pharmaceutical Co., Ltd. 5′-dibenzyl phosphates of 5-azacytidine or 2′-deoxy-5-azacytidine
JP6142098B1 (ja) * 2015-11-27 2017-06-07 大原薬品工業株式会社 ５−アザシチジン又は其の２’−デオキシ体の５’位ジベンジル燐酸エステル
CN108290920A (zh) * 2015-11-27 2018-07-17 大原药品工业株式会社 5-氮杂胞苷或2’-脱氧-5-氮杂胞苷的5’-二苄基磷酸酯
WO2017090264A1 (fr) * 2015-11-27 2017-06-01 大原薬品工業株式会社 Ester d'acide dibenzylphosphorique en position 5' de la 5-azacytidine ou 2'-désoxy-5-azacytidine
US11279694B2 (en) 2016-11-18 2022-03-22 Sumitomo Dainippon Pharma Oncology, Inc. Alvocidib prodrugs and their use as protein kinase inhibitors
JPWO2018199049A1 (ja) * 2017-04-25 2020-03-12 大原薬品工業株式会社 固形がん治療薬としての新規ｄｎｍｔ阻害剤
US11173174B2 (en) 2017-04-25 2021-11-16 Ohara Pharmaceutical Co., Ltd. DNMT inhibitor as solid tumor therapeutic drug
WO2018199049A1 (fr) * 2017-04-25 2018-11-01 大原薬品工業株式会社 Nouvel inhibiteur de dnmt en tant que médicament thérapeutique pour tumeur solide
US11497756B2 (en) 2017-09-12 2022-11-15 Sumitomo Pharma Oncology, Inc. Treatment regimen for cancers that are insensitive to BCL-2 inhibitors using the MCL-1 inhibitor alvocidib
US11530231B2 (en) 2018-12-04 2022-12-20 Sumitomo Pharma Oncology, Inc. CDK9 inhibitors and polymorphs thereof for use as agents for treatment of cancer
US12077554B2 (en) 2018-12-04 2024-09-03 Sumitomo Pharma Oncology, Inc. CDK9 inhibitors and polymorphs thereof for use as agents for treatment of cancer
US11793802B2 (en) 2019-03-20 2023-10-24 Sumitomo Pharma Oncology, Inc. Treatment of acute myeloid leukemia (AML) with venetoclax failure
WO2021007316A1 (fr) 2019-07-08 2021-01-14 Sumitomo Dainippon Pharma Oncology, Inc. Traitement du cancer
WO2021113688A1 (fr) 2019-12-05 2021-06-10 Sumitomo Dainippon Pharma Oncology, Inc. Polythérapies pour le traitement du syndrome myélodysplasique

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