WO2023228177A1 - Compositions comprenant de l'aspacytarabine et des composés supplémentaires, et leur utilisation - Google Patents

Compositions comprenant de l'aspacytarabine et des composés supplémentaires, et leur utilisation Download PDF

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Publication number
WO2023228177A1
WO2023228177A1 PCT/IL2023/050522 IL2023050522W WO2023228177A1 WO 2023228177 A1 WO2023228177 A1 WO 2023228177A1 IL 2023050522 W IL2023050522 W IL 2023050522W WO 2023228177 A1 WO2023228177 A1 WO 2023228177A1
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compound
acceptable salt
pharmaceutically acceptable
present
composition
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PCT/IL2023/050522
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English (en)
Inventor
Ramy Lidor-Hadas
Margarita Shumilov
Shoshanna Tessler
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Biosight Ltd.
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Publication of WO2023228177A1 publication Critical patent/WO2023228177A1/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
    • C07H19/09—Pyrimidine radicals with arabinosyl as the saccharide radical
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/12—Acyclic radicals, not substituted by cyclic structures attached to a nitrogen atom of the saccharide radical

Definitions

  • the present invention relates to novel compositions comprising (l-((2R,3S,4S,5R)-3,4- dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-l,2-dihydropyrimidin-4-yl)-L-asparagine (also known as BST-236, Astarabine® or Aspacytarabine) or pharmaceutically acceptable salt thereof and additional compounds, and uses thereof for the treatment of neoplastic diseases.
  • Aspacytarabine is manufactured according to strict Good Manufacturing Practices (GMP) processes, and the product composition is carefully monitored.
  • Composition of the final Active Pharmaceutical Ingredient (API) is crucial and affects the efficacy and safety of the final product. According to regulatory requirement, it is mandatory to identify qualitatively and quantitatively the final API composition including all related compounds (ICH Q7).
  • Related compounds are defined as any components present in the intermediate or API that are not the desired entity and the final profile is a description of the identified and unidentified related compounds present in an API. The profile is normally dependent upon the production process and origin of the API.
  • the present disclosure provides a composition comprising the final product identified as aspacytarabine and identified compounds within the final product.
  • the present disclosure relates to a composition
  • a composition comprising aspacytarabine or pharmaceutically acceptable salt thereof and at least one compound, selected from: a. at least one cytarabine-di-aspartic acid-compound, ,
  • the present disclosure relates to a method of treating a neoplastic disease comprising administering to a subject in need thereof a pharmaceutical composition comprising aspacytarabine and at least one compound, selected from at least one cytarabine-di-aspartic acidcompound, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of Compound (6a) and Compound (6b).
  • the neoplastic disease is selected from the group consisting of hematological cancers and non-hematological cancers.
  • the hematological cancer is selected from the group consisting of leukemias, lymphomas, myelomas and Myelodysplastic Syndromes (MDS).
  • the pharmaceutical composition is administered parenterally, orally or by inhalation. In some further aspects, pharmaceutical composition is administered by intravenous, intraarterial, intramuscular, subcutaneous, intraperitoneal, intracerebral, intracerebroventricular, intrathecal or intradermal administration route.
  • the pharmaceutical composition is administered by intravenous infusion for a period ranging from 15 minutes to 24 hours.
  • the present disclosure relates to a compound defined by the following structure: Compound (1) or pharmaceutically acceptable salt thereof.
  • the present disclosure relates to a compound defined by the following Compound (4) or pharmaceutically acceptable salt thereof.
  • the present disclosure relates to a compound defined by the following structure:
  • the present disclosure relates to a compound defined by the following structure: Compound (6b) or pharmaceutically acceptable salt thereof.
  • the present disclosure relates to a compound defined by the following structure: Compound (12) or pharmaceutically acceptable salt thereof.
  • the present disclosure relates to a composition
  • a composition comprising aspacytarabine and at least one compound, selected from: a. at least one cytarabine-di-aspartic acid-compound, ,
  • the weight ratio of aspacytarabine relating to the weight of the compound in the composition is from 99.99:0.01 to 60:40.
  • the at least one cytarabine-di-aspartic acid-compound is selected from Compounds 8-11 and any combination thereof; represented by the following structures: , p , p .
  • Aspacytarabine also known as BST-236 and Astarabine®, is a conjugate of cytarabine and aspartic acid wherein cytarabine is covalently attached to the carboxyl group of the side chain of aspartic acid, with the following IUPAC nomenclature: N 4 -(l-((2R,3S,4S,5R)-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-l,2-dihydropyrimidin-4-yl)-L-asparagine.
  • the molecular formula of the free base is C 13 H 18 N 4 O 8 and the molecular weight is 358.31 g/Mol.
  • Aspacytarabine is represented by the structure below:
  • the aspacytarabine acceptable salt is of an organic or inorganic acid selected from the group consisting of acetic acid, hydrochloric acid, methanesulfonic acid, phosphoric acid, cirtic acid, lactic acid, succinic acid, tartaric acid, boric acid, benzoic acid, toluenesulfonic acid, benzenesulfonic acid, ascorbic acid, sulfuric acid, maleic acid, formic acid, malonic acid, nicotinic acid and oxalic acid.
  • the aspacytarabine acceptable salt is acetic acid. In another embodiment, the aspacytarabine acceptable salt is hydrochloric acid. In another embodiment, the aspacytarabine acceptable salt is methanesulfonic acid. In another embodiment, the aspacytarabine acceptable salt is phosphoric acid. In another embodiment, the aspacytarabine acceptable salt is cirtic acid. In another embodiment, the aspacytarabine acceptable salt is lactic acid. In another embodiment, the aspacytarabine acceptable salt is succinic acid. In another embodiment, the aspacytarabine acceptable salt is tartaric acid. In another embodiment, the aspacytarabine acceptable salt is boric acid.
  • the aspacytarabine acceptable salt is benzoic acid. In another embodiment, the aspacytarabine acceptable salt is toluenesulfonic acid. In another embodiment, the aspacytarabine acceptable salt is benzenesulfonic acid. In another embodiment, the aspacytarabine acceptable salt is ascorbic acid. In another embodiment, the aspacytarabine acceptable salt is sulfuric acid. In another embodiment, the aspacytarabine acceptable salt is maleic acid. In another embodiment, the aspacytarabine acceptable salt is formic acid. In another embodiment, the aspacytarabine acceptable salt is malonic acid. In another embodiment, the aspacytarabine acceptable salt is nicotinic acid. In another embodiment, the aspacytarabine acceptable salt is oxalic acid.
  • the present invention relates to a composition
  • a composition comprising (l-((2R,3S,4S,5R)-3,4-dihydroxy- 5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo- 1 ,2-dihydropyrimidin-4-yl)-L-asparagine (also known as BST-236, Astarabine® or Aspacytarabine) or pharmaceutically acceptable salt thereof and at least one additional compound.
  • the additional compound is cytarabine-di-aspartic acid-compound.
  • the cytarabine-di-aspartic acid-compounds are to be understood as active prodrugs of conjugates comprising cytarabine and two aspartic acids, substituted on both the sugar and the cytosine moieties of the drug or two aspartic acids on the cytosine moiety.
  • the cytarabine-di-aspartic acid-compound is presented by the structure below of Formula (1)-
  • R 1 , R 2 , R 3 and R 5 are each independently H or an aspartic acid, wherein when one of R 1 , R 2 , R 3 and R 5 is aspartic acid, the others are H.
  • composition comprising (l-((2R,3S,4S,5R)-3,4- dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-l,2-dihydropyrimidin-4-yl)-L-asparagine (also known as BST-236, Astarabine® or Aspacytarabine) or pharmaceutically acceptable salt thereof and at least one additional compound.
  • the additional compound is selected from at least one of the compounds listed in Table 1 below: Table 1
  • the additional compound is a cytarabine-di-aspartic acid-compound comprising compound (8), compound (9), compound (10), compound (11) or any combination thereof.
  • the cytarabine-di-aspartic acid-compound comprises compound (8).
  • the cytarabine-di-aspartic acid-compound comprises compound (9).
  • the cytarabine-di-aspartic acid-compound comprises compound (10).
  • the cytarabine-di-aspartic acid-compound comprises compound (11).
  • the additional compound is a mixture of compound (6a) and compound
  • the mixture of compound (6a) and Compound (6b) is a mixture comprising 50% of compound (6a) and 50% of compound (6b). In another embodiment, the mixture comprises 55% of compound (6a) and 45% of compound (6b). In another embodiment, the mixture comprises 60% of compound (6a) and 40% of compound (6b). In another embodiment, the mixture comprises 65% of compound (6a) and 35% of compound (6b). In another embodiment, the mixture comprises 70% of compound (6a) and 30% of compound (6b). In another embodiment, the mixture comprises 75% of compound (6a) and 25% of compound (6b). In another embodiment, the mixture comprises 80% of compound (6a) and 20% of compound (6b). In another embodiment, the mixture comprises 85% of compound (6a) and 15% of compound (6b).
  • the mixture comprises 90% of compound (6a) and 10% of compound (6b). In another embodiment, the mixture comprises 95% of compound (6a) and 5% of compound (6b). In another embodiment, the mixture comprises 98% of compound (6a) and 2% of compound (6b). In another embodiment, the mixture comprises 99% of compound (6a) and 1% of compound (6b). In another embodiment, the mixture comprises 99.5% of compound (6a) and 0.5% of compound (6b). In another embodiment, the mixture comprises 99.9% of compound (6a) and 0.1% of compound (6b).
  • the present disclosure relates to a compound defined by the following structure: ound (1) or pharmaceutically acceptable salt thereof.
  • the present disclosure relates to a compound defined by the following structure: Compound (4) or pharmaceutically acceptable salt thereof. [0037] In one embodiment, the present disclosure relates to a compound defined by the following structure:
  • the present disclosure relates to a compound defined by the following structure:
  • the present disclosure relates to a compound defined by the following structure - Compound (12).
  • the present disclosure relates to a composition
  • a composition comprising aspacytarabine or pharmaceutically acceptable salt thereof and at least one additiona compound, selected from at least one cytarabine-di-aspartic acid-compound, compound (1), compound (2), compound (3), compound (4), compound (5), compound (6a), compound (6b), a mixture of Compound (6a) and Compound (6b), compound (7), and compound (12) or pharmaceutically acceptable salt thereof, wherein the weight ratio of aspacytarabine relating to the weight of the compound in the composition is from 99.99:0.01 to 60:40.
  • the ratio of aspacytarabine relating to the weight of the additional compound in the composition is 99.99:0.01. In another embodiment, the ratio of aspacytarabine relating to the weight of the additional compound in the composition is 99: 1. In another embodiment, the ratio of aspacytarabine relating to the weight of the additional compound in the composition is 90:10. In another embodiment, the ratio of aspacytarabine relating to the weight of the additional compound in the composition is 85:15. In another embodiment, the ratio of aspacytarabine relating to the weight of the additional compound in the composition is 80:20. In another embodiment, the ratio of aspacytarabine relating to the weight of the additional compound in the composition is 75:25.
  • the ratio of aspacytarabine relating to the weight of the additional compound in the composition is 70:30. In another embodiment, the ratio of aspacytarabine relating to the weight of the additional compound in the composition is 65:35. In another embodiment, the ratio of aspacytarabine relating to the weight of the additional compound in the composition is 60:40.
  • the composition comprises aspacytarabine or pharmaceutically acceptable salt thereof and at least one cytarabine-di-aspartic acid-compound or pharmaceutically acceptable salt thereof.
  • the composition comprises aspacytarabine or pharmaceutically acceptable salt thereof and compound (2) or pharmaceutically acceptable salt thereof.
  • the composition comprises aspacytarabine or pharmaceutically acceptable salt thereof and compound (3) or pharmaceutically acceptable salt thereof.
  • the composition comprises aspacytarabine or pharmaceutically acceptable salt thereof and compound (4) or pharmaceutically acceptable salt thereof.
  • the composition comprises aspacytarabine or pharmaceutically acceptable salt thereof and compound (5) or pharmaceutically acceptable salt thereof.
  • the composition comprises aspacytarabine or pharmaceutically acceptable salt thereof and compound (6a) or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises aspacytarabine or pharmaceutically acceptable salt thereof and compound (6b) or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises aspacytarabine or pharmaceutically acceptable salt thereof and a mixture of compound (6a) and compound (6b) or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises aspacytarabine or pharmaceutically acceptable salt thereof and compound (7) or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises aspacytarabine or pharmaceutically acceptable salt thereof and compound (8) or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises aspacytarabine or pharmaceutically acceptable salt thereof and compound (9) or pharmaceutically acceptable salt thereof.
  • the composition comprises aspacytarabine or pharmaceutically acceptable salt thereof and compound (10) or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises aspacytarabine or pharmaceutically acceptable salt thereof and compound (11) or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises aspacytarabine or pharmaceutically acceptable salt thereof and compound (12) or pharmaceutically acceptable salt thereof.
  • the present disclosure relates to a composition
  • a composition comprising aspacytarabine or pharmaceutically acceptable salt thereof and at least one additional compound, selected from at least one cytarabine-di-aspartic acid-compound, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of Compound (6a) and Compound (6b), Compound (7), and Compound (12) or pharmaceutically acceptable salt thereof, wherein a. at least one cytarabine-di-aspartic acid-compound or pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.01- 40% w/w, or b.
  • Compound (1) or pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.01- 40% w/w, 0.01-0.1 % w/w, 0.1-1% w/w, 1-5% w/w, 5-10% w/w, 10-15% w/w, 15-20% w/w, 20-25% w/w, 25-30% w/w, 30-35% w/w, 35-40% w/w, 0.01-20%w/w, or 0.01-30%, or c.
  • Compound (2) or pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.01- 40% w/w, 0.01-0.1 % w/w, 0.1-1% w/w, 1-5% w/w, 5-10% w/w, 10-15% w/w, 15-20% w/w, 20-25% w/w, 25-30% w/w, 30-35% w/w, 35-40% w/w, 0.01-20%w/w, or 0.01-30%, or d.
  • Compound (3) or pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.01- 40% w/w, 0.01-0.1 % w/w, 0.1-1% w/w, 1-5% w/w, 5-10% w/w, 10-15% w/w, 15-20% w/w, 20-25% w/w, 25-30% w/w, 30-35% w/w, 35-40% w/w, 0.01-20%w/w, or 0.01-30%, or e.
  • Compound (4) or pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.01- 40% w/w, 0.01-0.1 % w/w, 0.1-1% w/w, 1-5% w/w, 5-10% w/w, 10-15% w/w, 15-20% w/w, 20-25% w/w, 25-30% w/w, 30-35% w/w, 35-40% w/w, 0.01-20%w/w, or 0.01-30%, or f.
  • Compound (5) or pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.01- 40% w/w, 0.01-0.1 % w/w, 0.1-1% w/w, 1-5% w/w, 5-10% w/w, 10-15% w/w, 15-20% w/w, 20-25% w/w, 25-30% w/w, 30-35% w/w, 35-40% w/w, 0.01-20%w/w, or 0.01-30% or g.
  • Compound (6a) or pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.01- 40% w/w, 0.01-0.1 % w/w, 0.1-1% w/w, 1-5% w/w, 5-10% w/w, 10-15% w/w, 15-20% w/w, 20-25% w/w, 25-30% w/w, 30-35% w/w, 35-40% w/w, 0.01-20%w/w, or 0.01-30% or h.
  • Compound (6b) or pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.01- 40% w/w, 0.01-0.1 % w/w, 0.1-1% w/w, 1-5% w/w, 5-10% w/w, 10-15% w/w, 15-20% w/w, 20-25% w/w, 25-30% w/w, 30-35% w/w, 35-40% w/w, 0.01-20%w/w, or 0.01-30%, or i.
  • a mixture of Compound (6a) and Compound (6b) or pharmaceutically acceptable salt thereof are present in the composition in an amount of 0.01- 40% w/w, 0.01-0.1 % w/w, 0.1-1% w/w, 1-5% w/w, 5-10% w/w, 10-15% w/w, 15-20% w/w, 20-25% w/w, 25-30% w/w, 30-35% w/w, 35-40% w/w, 0.01-20%w/w, or 0.01-30%. or j.
  • Compound (7) or pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.01- 40% w/w, 0.01-0.1 % w/w, 0.1-1% w/w, 1-5% w/w, 5-10% w/w, 10-15% w/w, 15-20% w/w, 20-25% w/w, 25-30% w/w, 30-35% w/w, 35-40% w/w, 0.01-20%w/w, or 0.01-30%, or k.
  • Compound (12) or pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.01- 40% w/w, 0.01-0.1 % w/w, 0.1-1% w/w, 1-5% w/w, 5-10% w/w, 10-15% w/w, 15-20% w/w, 20-25% w/w, 25-30% w/w, 30-35% w/w, 35-40% w/w, 0.01-20%w/w, or 0.01- 30%, or any combination thereof.
  • At least one cytarabine-di-aspartic acid-compound is present in the composition in an amount of about 0.01% w/w. In one embodiment, at least one cytarabine-di-aspartic acid-compound is present in the composition in an amount of about 0.05% w/w. In another embodiment, at least one cytarabine-di-aspartic acid-compound is present in the composition in an amount of about 0.1% w/w. In one embodiment, at least one cytarabine-di-aspartic acid-compound is present in the composition in an amount of about 0.5% w/w.
  • At least one cytarabine-di-aspartic acid-compound is present in the composition in an amount of about 1% w/w. In one embodiment, at least one cytarabine-di-aspartic acid-compound is present in the composition in an amount of about 5% w/w. In another embodiment, at least one cytarabine-di-aspartic acidcompound is present in the composition in an amount of about 10% w/w. In one embodiment, at least one cytarabine-di-aspartic acid-compound is present in the composition in an amount of about 15% w/w.
  • At least one cytarabine-di-aspartic acid-compound is present in the composition in an amount of about 20% w/w. In one embodiment, at least one cytarabine-di-aspartic acid-compound is present in the composition in an amount of about 25% w/w. In another embodiment, at least one cytarabine-di-aspartic acid-compound is present in the composition in an amount of about 30% w/w. In one embodiment, at least one cytarabine-di-aspartic acid-compound is present in the composition in an amount of about 35% w/w.
  • At least one cytarabine-di-aspartic acid-compound is present in the composition in an amount of about 40% w/w.
  • compound (1) is present in the composition in an amount of about 0.01% w/w. In another embodiment, compound (1) is present in the composition in an amount of about 0.05% w/w. In another embodiment, compound (1) is present in the composition in an amount of about 0.1% w/w. In another embodiment, compound (1) is present in the composition in an amount of about 0.5% w/w. In another embodiment, compound (1) is present in the composition in an amount of about 1% w/w. In another embodiment, compound (1) is present in the composition in an amount of about 5% w/w.
  • compound (1) is present in the composition in an amount of about 10% w/w. In another embodiment, compound (1) is present in the composition in an amount of about 15% w/w. In another embodiment, compound (1) is present in the composition in an amount of about 20% w/w. In another embodiment, compound (1) is present in the composition in an amount of about 25% w/w. In another embodiment, compound (1) is present in the composition in an amount of about 30% w/w. In another embodiment, compound (1) is present in the composition in an amount of about 35% w/w. In another embodiment, compound (1) is present in the composition in an amount of about 40% w/w.
  • compound (2) is present in the composition in an amount of about 0.01% w/w. In another embodiment, compound (2) is present in the composition in an amount of about 0.05% w/w. In another embodiment, compound (2) is present in the composition in an amount of about 0.1% w/w. In another embodiment, compound (2) is present in the composition in an amount of about 0.5% w/w. In another embodiment, compound (2) is present in the composition in an amount of about 1% w/w. In another embodiment, compound (2) is present in the composition in an amount of about 5% w/w. In another embodiment, compound (2) is present in the composition in an amount of about 10% w/w. In another embodiment, compound (2) is present in the composition in an amount of about 15% w/w.
  • compound (2) is present in the composition in an amount of about 20% w/w. In another embodiment, compound (2) is present in the composition in an amount of about 25% w/w. In another embodiment, compound (2) is present in the composition in an amount of about 30% w/w. In another embodiment, compound (2) is present in the composition in an amount of about 35% w/w. In another embodiment, compound (2) is present in the composition in an amount of about 40% w/w.
  • compound (3) is present in the composition in an amount of about 0.01% w/w. In another embodiment, compound (3) is present in the composition in an amount of about 0.05% w/w. In another embodiment, compound (3) is present in the composition in an amount of about 0.1% w/w. In one embodiment, compound (3) is present in the composition in an amount of about 0.5% w/w. In another embodiment, compound (3) is present in the composition in an amount of about 1% w/w. In another embodiment, compound (3) is present in the composition in an amount of about 5% w/w. In another embodiment, compound (3) is present in the composition in an amount of about 10% w/w. In another embodiment, compound (3) is present in the composition in an amount of about 15% w/w.
  • compound (3) is present in the composition in an amount of about 20% w/w. In another embodiment, compound (3) is present in the composition in an amount of about 25% w/w. In another embodiment, compound (3) is present in the composition in an amount of about 30% w/w. In another embodiment, compound (3) is present in the composition in an amount of about 35% w/w. In another embodiment, compound (3) is present in the composition in an amount of about 40% w/w.
  • compound (4) is present in the composition in an amount of about 0.01% w/w. In another embodiment, compound (4) is present in the composition in an amount of about 0.5% w/w. In another embodiment, compound (4) is present in the composition in an amount of about 0.1% w/w. In another embodiment, compound (4) is present in the composition in an amount of about 0.5% w/w. In another embodiment, compound (4) is present in the composition in an amount of about 1% w/w. In another embodiment, compound (4) is present in the composition in an amount of about 5% w/w. In another embodiment, compound (4) is present in the composition in an amount of about 10% w/w.
  • compound (4) is present in the composition in an amount of about 15% w/w. In another embodiment, compound (4) is present in the composition in an amount of about 20% w/w. In another embodiment, compound (4) is present in the composition in an amount of about 25% w/w. In another embodiment, compound (4) is present in the composition in an amount of about 30% w/w. In another embodiment, compound (4) is present in the composition in an amount of about 35% w/w. In another embodiment, compound (4) is present in the composition in an amount of about 40% w/w. [0049] In one embodiment, compound (5) is present in the composition in an amount of about 0.01% w/w. In another embodiment, compound (5) is present in the composition in an amount of about 0.5% w/w.
  • compound (5) is present in the composition in an amount of about 0.1% w/w. In another embodiment, compound (5) is present in the composition in an amount of about 0.5% w/w. In another embodiment, compound (5) is present in the composition in an amount of about 1% w/w. In another embodiment, compound (5) is present in the composition in an amount of about 5% w/w. In another embodiment, compound (5) is present in the composition in an amount of about 10% w/w. In another embodiment, compound (5) is present in the composition in an amount of about 15% w/w. In another embodiment, compound (5) is present in the composition in an amount of about 20% w/w. In another embodiment, compound (5) is present in the composition in an amount of about 25% w/w.
  • compound (5) is present in the composition in an amount of about 30% w/w. In another embodiment, compound (5) is present in the composition in an amount of about 35% w/w. In another embodiment, compound (5) is present in the composition in an amount of about 40% w/w.
  • compound (6a) is present in the composition in an amount of about 0.01% w/w. In another embodiment, compound (6a) is present in the composition in an amount of about 0.5% w/w. In another embodiment, compound (6a) is present in the composition in an amount of about 0.1% w/w. In another embodiment, compound (6a) is present in the composition in an amount of about 0.5% w/w. In another embodiment, compound (6a) is present in the composition in an amount of about 1% w/w. In another embodiment, compound (6a) is present in the composition in an amount of about 5% w/w. In another embodiment, compound (6a) is present in the composition in an amount of about 10% w/w.
  • compound (6a) is present in the composition in an amount of about 15% w/w. In another embodiment, compound (6a) is present in the composition in an amount of about 20% w/w. In another embodiment, compound (6a) is present in the composition in an amount of about 25% w/w. In another embodiment, compound (6a) is present in the composition in an amount of about 30% w/w. In another embodiment, compound (6a) is present in the composition in an amount of about 35% w/w. In another embodiment, compound (6a) is present in the composition in an amount of about 40% w/w.
  • compound (6b) is present in the composition in an amount of about 0.01% w/w. In another embodiment, compound (6b) is present in the composition in an amount of about 0.5% w/w. In another embodiment, compound (6b) is present in the composition in an amount of about 0.1% w/w. In another embodiment, compound (6b) is present in the composition in an amount of about 0.5% w/w. In another embodiment, compound (6b) is present in the composition in an amount of about 1% w/w. In another embodiment, compound (6b) is present in the composition in an amount of about 5% w/w. In another embodiment, compound (6b) is present in the composition in an amount of about 10% w/w.
  • compound (6b) is present in the composition in an amount of about 15% w/w. In another embodiment, compound (6b) is present in the composition in an amount of about 20% w/w. In another embodiment, compound (6b) is present in the composition in an amount of about 25% w/w. In another embodiment, compound (6b) is present in the composition in an amount of about 30% w/w. In another embodiment, compound (6b) is present in the composition in an amount of about 35% w/w. In another embodiment, compound (6b) is present in the composition in an amount of about 40% w/w.
  • a mixture of compound (6a) and compound (6b) is present in the composition in an amount of about 0.01% w/w. In another embodiment, a mixture of compound (6a) and compound (6b) is present in the composition in an amount of about 0.05% w/w. In another embodiment, a mixture of compound (6a) and compound (6b) is present in the composition in an amount of about 0.1% w/w. In another embodiment, a mixture of compound (6a) and compound (6b) is present in the composition in an amount of about 0.5% w/w. In another embodiment, a mixture of compound (6a) and compound (6b) is present in the composition in an amount of about 1% w/w.
  • a mixture of compound (6a) and compound (6b) is present in the composition in an amount of about 5% w/w. In another embodiment, a mixture of compound (6a) and compound (6b) is present in the composition in an amount of about 10% w/w. In another embodiment, a mixture of compound (6a) and compound (6b) is present in the composition in an amount of about 15% w/w. In another embodiment, a mixture of compound (6a) and compound (6b) is present in the composition in an amount of about 20% w/w. In another embodiment, a mixture of compound (6a) and compound (6b) is present in the composition in an amount of about 25% w/w.
  • a mixture of compound (6a) and compound (6b) is present in the composition in an amount of about 30% w/w. In another embodiment, a mixture of compound (6a) and compound (6b) is present in the composition in an amount of about 35% w/w. In another embodiment, a mixture of compound (6a) and compound (6b) is present in the composition in an amount of about 40% w/w.
  • compound (7) is present in the composition in an amount of about 0.01% w/w. In another embodiment, compound (7) is present in the composition in an amount of about 0.05% w/w. In another embodiment, compound (7) is present in the composition in an amount of about 0.1% w/w. In another embodiment, compound (7) is present in the composition in an amount of about 0.5% w/w. In another embodiment, compound (7) is present in the composition in an amount of about 1% w/w. In another embodiment, compound (7) is present in the composition in an amount of about 5% w/w. In another embodiment, compound (7) is present in the composition in an amount of about 10% w/w.
  • compound (7) is present in the composition in an amount of about 15% w/w. In another embodiment, compound (7) is present in the composition in an amount of about 20% w/w. In another embodiment, compound (7) is present in the composition in an amount of about 25% w/w. In another embodiment, compound (7) is present in the composition in an amount of about 30% w/w. In another embodiment, compound (7) is present in the composition in an amount of about 35% w/w. In another embodiment, compound (7) is present in the composition in an amount of about 40% w/w.
  • compound (8) is present in the composition in an amount of about 0.01% w/w. In another embodiment, compound (8) is present in the composition in an amount of about 0.05% w/w. In another embodiment, compound (8) is present in the composition in an amount of about 0.1% w/w. In another embodiment, compound (8) is present in the composition in an amount of about 0.5% w/w. In another embodiment, compound (8) is present in the composition in an amount of about 1% w/w. In another embodiment, compound (8) is present in the composition in an amount of about 5% w/w. In another embodiment, compound (8) is present in the composition in an amount of about 10% w/w.
  • compound (8) is present in the composition in an amount of about 15% w/w. In another embodiment, compound (8) is present in the composition in an amount of about 20% w/w. In another embodiment, compound (8) is present in the composition in an amount of about 25% w/w. In another embodiment, compound (8) is present in the composition in an amount of about 30% w/w. In another embodiment, compound (8) is present in the composition in an amount of about 35% w/w. In another embodiment, compound (8) is present in the composition in an amount of about 40% w/w.
  • compound (9) is present in the composition in an amount of about 0.01% w/w. In another embodiment, compound (9) is present in the composition in an amount of about 0.05% w/w. In another embodiment, compound (9) is present in the composition in an amount of about 0.1% w/w. In another embodiment, compound (9) is present in the composition in an amount of about 0.5% w/w. In another embodiment, compound (9) is present in the composition in an amount of about 1% w/w. In another embodiment, compound (9) is present in the composition in an amount of about 5% w/w. In another embodiment, compound (9) is present in the composition in an amount of about 10% w/w.
  • compound (9) is present in the composition in an amount of about 15% w/w. In another embodiment, compound (9) is present in the composition in an amount of about 20% w/w. In another embodiment, compound (9) is present in the composition in an amount of about 25% w/w. In another embodiment, compound (9) is present in the composition in an amount of about 30% w/w. In another embodiment, compound (9) is present in the composition in an amount of about 35% w/w. In another embodiment, compound (9) is present in the composition in an amount of about 40% w/w. [0056] In one embodiment, compound (10) is present in the composition in an amount of about 0.01% w/w.
  • compound (10) is present in the composition in an amount of about 0.05% w/w. In another embodiment, compound (10) is present in the composition in an amount of about 0.1% w/w. In another embodiment, compound (10) is present in the composition in an amount of about 0.5% w/w. In another embodiment, compound (10) is present in the composition in an amount of about 1% w/w. In another embodiment, compound (10) is present in the composition in an amount of about 5% w/w. In another embodiment, compound (10) is present in the composition in an amount of about 10% w/w. In another embodiment, compound ( 10) is present in the composition in an amount of about 15% w/w. In another embodiment, compound (10) is present in the composition in an amount of about 20% w/w.
  • compound ( 10) is present in the composition in an amount of about 25% w/w. In another embodiment, compound (10) is present in the composition in an amount of about 30% w/w. In another embodiment, compound ( 10) is present in the composition in an amount of about 35% w/w. In another embodiment, compound (10) is present in the composition in an amount of about 40% w/w.
  • compound (11) is present in the composition in an amount of about 0.01% w/w. In another embodiment, compound (11) is present in the composition in an amount of about 0.05% w/w. In another embodiment, compound (11) is present in the composition in an amount of about 0.1% w/w. In another embodiment, compound (11) is present in the composition in an amount of about 0.5% w/w. In another embodiment, compound (11) is present in the composition in an amount of about 1% w/w. In another embodiment, compound (11) is present in the composition in an amount of about 5% w/w. In another embodiment, compound (11) is present in the composition in an amount of about 10% w/w.
  • compound (11) is present in the composition in an amount of about 15% w/w. In another embodiment, compound (11) is present in the composition in an amount of about 20% w/w. In another embodiment, compound (11) is present in the composition in an amount of about 25% w/w. In another embodiment, compound (11) is present in the composition in an amount of about 30% w/w. In another embodiment, compound (11) is present in the composition in an amount of about 35% w/w. In another embodiment, compound (11) is present in the composition in an amount of about 40% w/w.
  • compound (12) is present in the composition in an amount of about 0.01% w/w. In another embodiment, compound (12) is present in the composition in an amount of about 0.05% w/w. In another embodiment, compound (12) is present in the composition in an amount of about 0.1% w/w. In another embodiment, compound (12) is present in the composition in an amount of about 0.5% w/w. In another embodiment, compound (12) is present in the composition in an amount of about 1% w/w. In another embodiment, compound (12) is present in the composition in an amount of about 5% w/w. In another embodiment, compound (12) is present in the composition in an amount of about 10% w/w.
  • compound ( 12) is present in the composition in an amount of about 15% w/w. In another embodiment, compound (12) is present in the composition in an amount of about 20% w/w. In another embodiment, compound ( 12) is present in the composition in an amount of about 25% w/w. In another embodiment, compound (12) is present in the composition in an amount of about 30% w/w. In another embodiment, compound ( 12) is present in the composition in an amount of about 35% w/w. In another embodiment, compound (12) is present in the composition in an amount of about 40% w/w.
  • composition comprising aspacytarabine or pharmaceutically acceptable salt thereof and a. at least one compound, selected from at least one cytarabine-di-aspartic acid-compound, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof, or b.
  • At least two compounds selected from at least one cytarabine-di-aspartic acid-compound, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12);or pharmaceutically acceptable salt thereof, or c.
  • at least three compounds selected from at least one cytarabine-di-aspartic acid-compound, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof, or d.
  • At least four compounds selected from at least one cytarabine-di-aspartic acid-compound, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof, or e. at least five compounds, selected from at least one cytarabine-di-aspartic acid-compound, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof, or f.
  • At least six compounds selected from at least one cytarabine-di-aspartic acid-compound, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof, or g. at least seven compounds, selected from at least one cytarabine-di-aspartic acid-compound, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof, or h.
  • At least eight compounds selected from at least one cytarabine-di-aspartic acid-compound, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof, or i. at least nine compounds, selected from at least one cytarabine-di-aspartic acid-compounds, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof, or j.
  • At least ten compounds selected from at least onecytarabine-di-aspartic acid-compounds, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof, or k.
  • at least eleven compounds selected from two cytarabine-di-aspartic acid-compounds, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof, or l.
  • At least twelve compounds selected from three cytarabine-di-aspartic acid-compounds, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof, or m. at least thirteen compounds, selected from four cytarabine-di-aspartic acid-compounds, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof.
  • composition comprising aspacytarabine or pharmaceutically acceptable salt thereof and a. at least one compound, selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or b.
  • At least two compounds selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or c.
  • at least three compounds selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or d.
  • At least four compounds selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or e. at least five compounds, selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or f.
  • At least six compounds selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or g. at least seven compounds, selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or h.
  • At least eight compounds selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or i. at least nine compounds, selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or j.
  • At least ten compounds selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or k.
  • at least eleven compounds selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or l.
  • At least twelve compounds selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or m.
  • at least thirteen compounds selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof.
  • the composition is a pharmaceutical composition.
  • the pharmaceutical composition comprises an excipient.
  • excipients are selected according to the delivery mode of the pharmaceutical composition.
  • the pharmaceutical composition further comprises at least one stabilizer and/or solubilizer.
  • the at least one stabilizer and/or solubilizer is a water-soluble linear polymer.
  • the linear polymer is ionic or non-ionic.
  • non-ionic water soluble linear polymer comprise poly(vinyl alcohol), polyacrylamide, polyethylene glycol (polyethylene oxide) (PEG), polyethylene oxide (PEG) or polyoxyethylene (POE), triblock copolymers comprising polyoxypropylene (polypropylene oxide)) two polyoxyethylene (poly(ethylene oxide)) (Poloxamer), polyvinyl pyrrolidone (PVP), derivative thereof or any combination thereof.
  • ionic water soluble linear polymer comprise ionic derivatives of poly(vinyl alcohol), polyacrylamide, polyethylene glycol (polyethylene oxide) (PEG), polyethylene oxide (PEO) or polyoxyethylene (POE), triblock copolymers comprising polyoxypropylene (polypropylene oxide)) and two polyoxyethylene (polypthylene oxide)) (Poloxamer), polyvinyl pyrrolidone (PVP), polystyrene sulfonic acid, polystyrene sulfonates derivatives thereof or any combination thereof.
  • PEG polyethylene glycol
  • PEO polyethylene oxide
  • POE polyoxyethylene
  • triblock copolymers comprising polyoxypropylene (polypropylene oxide)) and two polyoxyethylene (polypthylene oxide)) (Poloxamer), polyvinyl pyrrolidone (PVP), polystyrene sulfonic acid, polystyrene sulfonates
  • the at least one linear polymer is poloxamer.
  • the at least one water soluble linear polymer is combination of poloxamer and polyvinyl pyrrolidone (PVP).
  • PVP polyvinyl pyrrolidone
  • the at least one water soluble linear polymer is cyclodextrin.
  • non-limiting examples of cyclodextrin (CD) include a-CD, P- CD, y-CD, HP-P-CD (hydroxypropylated), SBE-P-CD (sulfobutyl-ether - modified), RM-P-CD (randomly methylated) and any combination thereof. Each possibility represents a separate embodiment of the present invention.
  • compositions as described herein further comprises a poloxamer.
  • compositions further comprise a combination of poloxamer and polyvinyl pyrrolidone (PVP).
  • PVP polyvinyl pyrrolidone
  • compositions further comprise cyclodextrin.
  • water-soluble stabilizer refers to a chemical ingredient that stabilizes the aspacytarabine or pharmaceutically acceptable salt thereof and prevents its decomposition.
  • the water-soluble stabilizer is also a solubilizer.
  • the water- soluble stabilizer is selected from a water-soluble linear polymer, a cyclodextrin or combination thereof.
  • the composition as described herein is formulated as a parenteral, oral, intranasal or inhalation composition.
  • the parenteral composition is selected from a solution, a suspension, an emulsion for injection or infusion, particles for injection or infusion, liposomes as injectable delivery system, a powder for injection or infusion, and a gel for injection.
  • the parenteral composition is administered by intravenous, intraarterial, intramuscular, subcutaneous, intraperitoneal, intracerebral, intracerebroventricular, intrathecal or intradermal administration route.
  • the oral composition is selected from a tablet, a pill, a capsule, a drage, a gel, a syrup, a slurry, a suspension, a powder, or a liquid form.
  • a tablet a pill, a capsule, a drage, a gel, a syrup, a slurry, a suspension, a powder, or a liquid form.
  • the composition as described herein further comprises a pharmaceutically acceptable carrier.
  • the carrier is water, saline solution, isotonic solution, aqueous dextrose, multiple electrolyte injection or aqueous glycerol solution. Each possibility represents a separate embodiment of the present invention.
  • the composition as described herein is formulated for infusion or injection in a pharmaceutically acceptable carrier, wherein the carrier is selected from water, saline solution, isotonic solution, solutions accepted for infusion, aqueous dextrose or aqueous glycerol solution, wherein the composition having a pH range of between 2.2 and 8.
  • the pH range is between 4 and 8.
  • the pH range is between 7 and 8.
  • the pH range is between 4-5.
  • the pH is physiological.
  • a buffer is used in order to maintain and/or adjust the required pH range.
  • the buffer can be a pharmaceutically acceptable mono-ionic buffer system or a poly- ionic buffer system having an ionization pK in the range of 2.2 - 8.
  • various buffers can be used, for example, ACES (N-(acetamido)-2-aminoethansulfonic acid); Acetate; N-(2- acetamido)-2 -iminodiacetic acid; BES (N,N-bis[2-hydroxyethyl]-2-aminoethansulfonic acid); Bicine (2-(Bis(2-hydroxyethyl)amino)acetic acid); Bis-Tris methane (2-[Bis(2 -hydroxy ethyl)amino] -2- (hydroxymethyl)propane- 1,3 -diol); Bis-Tris propane (1,3- bis(tris(hydroxymethyl)methylamino)propane); Carbonate; Citrate; 3,3-dimethyl glutarate; DIPSO (3
  • compositions for parenteral administration include aqueous solutions of the active ingredients in water-soluble form.
  • suspensions of the active compound may be prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acids esters such as ethyl oleate, triglycerides or liposomes.
  • compositions as described herein may be formulated as a liquid formulation.
  • compositions can be formulated as solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like.
  • the composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides, microcrystalline cellulose, gum tragacanth or gelatin. Each possibility represents a separate embodiment of the present invention.
  • the compositions can further comprise excipients including, but not limited to, sodium chloride, potassium chloride, magnesium chloride, sodium gluconate, sodium acetate, calcium chloride, sodium lactate, and the like.
  • the compositions if desired, can also contain minor amounts of sugar alcohols, wetting or emulsifying agents, and pH adjusting agents.
  • Antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; and agents for the adjustment of tonicity such as sodium chloride or dextrose are also envisioned. Each possibility represents a separate embodiment of the present invention.
  • compositions as described herein can be formulated readily by combining aspacytarabine and at least one stabilizer and/or solubilizer selected from a linear polymer, cyclodextrin or combination thereof with additional components as known in the art.
  • additional components as known in the art.
  • Such components enable the composition as described herein to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a subject.
  • Pharmacological preparations for oral use can be made using a solid component, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores.
  • Suitable components are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carbomethylcellulose.
  • disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate.
  • enteric coating can be useful if it is desirable to prevent exposure of the compounds of the invention to the gastric environment.
  • compositions which can be used orally include push-fit capsules made of gelatin as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules may contain the active ingredients in admixture with filler such as lactose, binders such as starches, lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added.
  • suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • the compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the active compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or a nebulizer with the use of a suitable propellant, e. g., dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide.
  • a suitable propellant e. g., dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, e. g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the peptide and a suitable powder base such as lactose or starch.
  • An intranasal composition may be formulated as a powder, an aqueous solution or a nonaqueous solution.
  • a preferred method of administering the solutions of the invention is using a spray device.
  • Spray devices can be single (“unit”) dose or multiple dose systems.
  • the powder formulation is preferably administered to the patient in aerosolized form whereby energy from patient inhalation (sniffing) is used to aerosolize the powder into the nasal cavity or where the device itself provides the aerosolization energy, such as via compressed air.
  • a "pharmaceutical composition” refers to a preparation of one or more of the compounds described herein, or physiologically acceptable salts or solvents thereof, with other chemical components such as physiologically suitable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound to a subject.
  • pharmaceutically acceptable salt of a drug refers to a salt according to IUPAC conventions.
  • Pharmaceutically acceptable salt is an inactive ingredient in a salt form combined with a drug.
  • Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral, base, acid or salt. Acid salts are also known as acid addition salts (see herein below).
  • Pharmaceutically acceptable salts are known in the art (Stahl and Wermuth, 2011, Handbook of pharmaceutical salts, Second edition).
  • the acid is a strong acid and is selected from the group consisting of acetic acid, hydrochloric acid, hydrobromide acid, methanesulfonic acid, phosphoric acid, toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, sulfuric acid, bisulfuric acid, and trifluoroacetic acid.
  • the salt is a hydrochloride salt. Each possibility represents a separate embodiment of the invention.
  • pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U. S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • carrier refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic compound is administered.
  • Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents.
  • the present disclosure relates to a method of treating a neoplastic disease comprising administering to a subject in need thereof a pharmaceutical composition comprising aspacytarabine or pharmaceutically acceptable salt thereof and at least one additional compound, selected from at least one cytarabine-di-aspartic acid-compound, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of Compound 6a and Compound 6b, Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof, wherein the weight ratio of aspacytarabine relating to the weight of the additional compound in the composition is from 99.99:0.01 to 60:40.
  • the present disclosure relates to a method of treating a neoplastic disease comprising administering to a subject in need thereof a pharmaceutical composition comprising aspacytarabine or pharmaceutically acceptable salt thereof and at least one compound, selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of Compound (6a) and Compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12), or pharmaceutically acceptable salt thereof, wherein the weight ratio of aspacytarabine relating to the weight of the compound in the composition is from 99.99:0.01 to 60:40.
  • the present disclosure relates to a method of treating a neoplastic disease comprising administering to a subject in need thereof a pharmaceutical composition comprising aspacytarabine or pharmaceutically acceptable salt thereof, and a. at least one compound, selected from at least one cytarabine-di-aspartic acid-compound, Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), and Compound (12); or pharmaceutically acceptable salt thereof, or b.
  • the present disclosure relates to a method of treating a neoplastic disease comprising administering to a subject in need thereof a pharmaceutical composition comprising aspacytarabine or pharmaceutically acceptable salt thereof and a. at least one compound, selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12) or pharmaceutically acceptable salt thereof; or b.
  • At least two compounds selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or c.
  • at least three compounds selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or d.
  • At least four compounds selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or e. at least five compounds, selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or f.
  • At least six compounds selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or g. at least seven compounds, selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or h.
  • At least eight compounds selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or i. at least nine compounds, selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or j.
  • At least ten compounds selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or k.
  • at least eleven compounds selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or l.
  • At least twelve compounds selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof, or m.
  • at least thirteen compounds selected from Compound (1), Compound (2), Compound (3), Compound (4), Compound (5), Compound (6a), Compound (6b), a mixture of compound (6a) and compound (6b), Compound (7), Compound (8), Compound (9), Compound (10), Compound (11), and Compound (12); or pharmaceutically acceptable salt thereof.
  • the term “treatment” refers to any process, action, application, therapy, or the like, wherein a subject, including a human being, is subjected to medical aid with the object of improving the subject's condition, directly or indirectly.
  • the term “treating” refers to reducing incidence, alleviating symptoms, eliminating recurrence, preventing recurrence, preventing incidence, improving symptoms, improving prognosis or combinations thereof in other embodiments.
  • Treating embraces in another embodiment, the amelioration of an existing condition.
  • treatment does not necessarily result in the complete absence or removal of symptoms.
  • Treatment also embraces palliative effects: that is, those that reduce the likelihood of a subsequent medical condition.
  • the alleviation of a condition that results in a more serious condition is encompassed by this term.
  • the neoplastic disease is selected from the group consisting of hematological cancers and non-hematological cancers. In another embodiment, the neoplastic disease is hematological cancer. In another embodiment, the neoplastic disease is non-hematological cancer. [0091] In one embodiment, the hematological cancer is selected from the group consisting of leukemias, lymphomas, myelomas and Myelodysplastic Syndromes (MDS). In another embodiment, the hematological cancer is leukemia. In another embodiment, the hematological cancer is lymphoma. In another embodiment, the hematological cancer is myeloma. In another embodiment, the hematological cancer is Myelodysplastic Syndrome (MDS).
  • MDS Myelodysplastic Syndrome
  • MDS Myelodysplastic Syndromes
  • AML acute myeloid leukemia
  • Non-hematological cancers also known as solid tumors include, but are not limited to, sarcoma, carcinoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endothelio sarcoma, mesothelioma, Ewing's tumor leiomyd sarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder
  • Non-hematological cancers include cancers of organs, wherein the cancer of an organ includes, but is not limited to, breast cancer, bladder cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, lung cancer, cervical cancer, pancreatic cancer, prostate cancer, testicular cancer, thyroid cancer, ovarian cancer, brain cancer including ependymoma, glioma, glioblastoma, medulloblastoma, craneopharyngioma, pinealoma, acustic neuroma, hemangioblastoma, oligodendroglioma, menangioma, neuroblastoma, retinoblastoma, and their metastasis.
  • the cancer of an organ includes, but is not limited to, breast cancer, bladder cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, lung cancer, cervical cancer, pancreatic cancer, prostate cancer, testicular cancer, thyroid cancer, ovarian cancer, brain cancer including epen
  • the leukemia is selected from the group consisting of Acute Myeloid Leukemia (AML), Acute Lymphoblastic Leukemia (ALL), Chronic Myeloid Leukemia (CML), and Chronic Lymphoblastic Leukemia (CLL).
  • AML Acute Myeloid Leukemia
  • ALL Acute Lymphoblastic Leukemia
  • ALL Acute Lymphoblastic Leukemia
  • CML Chronic Myeloid Leukemia
  • the leukemia is Chronic Lymphoblastic Leukemia (CLL).
  • the AML is selected from the group consisting of newly diagnosed AML, secondary AML, and relap sed/refractory AML.
  • the AML is newly diagnosed AML.
  • the AML is secondary AML.
  • the AML is relap sed/refractory AML.
  • the lymphoma is selected from the group consisting of Hodgkin’s lymphoma and non-Hodgkin’ s lymphoma. In another embodiment, the lymphoma is Hodgkin’s lymphoma. In another embodiment, the lymphoma is non-Hodgkin’ s lymphoma.
  • the pharmaceutical composition is administered parenterally, orally or by inhalation. In another embodiment, the pharmaceutical composition is administered parenterally. In another embodiment, the pharmaceutical composition is administered orally. In another embodiment, the pharmaceutical composition is administered by inhalation.
  • the pharmaceutical composition is administered by intravenous, intraarterial, intramuscular, subcutaneous, intraperitoneal, intracerebral, intracerebroventricular, intrathecal or intradermal administration route.
  • the pharmaceutical composition is administered by intravenous administration route.
  • the pharmaceutical composition is administered by intraarterial administration route.
  • the pharmaceutical composition is administered by intramuscular administration route.
  • the pharmaceutical composition is administered by subcutaneous administration route.
  • the pharmaceutical composition is administered by intraperitoneal administration route.
  • the pharmaceutical composition is administered by intracerebral administration route.
  • the pharmaceutical composition is administered by intracerebroventricular administration route.
  • the pharmaceutical composition is administered by intrathecal administration route.
  • the pharmaceutical composition is administered by intradermal administration route.
  • the pharmaceutical composition is administered by intravenous infusion for a period ranging from 15 minutes to 24 hours. In another embodiment, the pharmaceutical composition is administered by intravenous infusion for a period of 15 minutes. In another embodiment, the pharmaceutical composition is administered by intravenous infusion for a period of 30 minutes. In another embodiment, the pharmaceutical composition is administered by intravenous infusion for a period of 45 minutes. In another embodiment, the pharmaceutical composition is administered by intravenous infusion for a period of 60 minutes. In another embodiment, the pharmaceutical composition is administered by intravenous infusion for a period of 4 hours. In another embodiment, the pharmaceutical composition is administered by intravenous infusion for a period of 8 hours.
  • the pharmaceutical composition is administered by intravenous infusion for a period of 12 hours. In another embodiment, the pharmaceutical composition is administered by intravenous infusion for a period of 16 hours. In another embodiment, the pharmaceutical composition is administered by intravenous infusion for a period of 20 hours. In another embodiment, the pharmaceutical composition is administered by intravenous infusion for a period of 24 hours.
  • LCMS and HPLC were taken on a quadrupole Mass Spectrometer on Agilent 1290 system equipped with DAD detector or equivalent (Column: Sielc Prime 100 (3.2 x 150 mm, 3.0 pm).
  • Compound 1 N 4 -( l-(( 2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-l,2- dihydropyrimidin-4-yl)-D-asparagine
  • step 1 a mixture of tert-butyldimethylsilyl chloride (TBDMS-C1, 13.3 g) and toluene (15.4 mL) was added to a mixture of 4-amino-l- ((2S,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(lH)-one (cytarabine, 10.0 g), imidazole (7.00 g.) and anhydrous dimethylformamide (DMF, lOOmL) .
  • TDMS-C1 tert-butyldimethylsilyl chloride
  • step 2 a mixture of tert-butyldimethylsilyl chloride
  • toluene (15.4 mL) was added to a mixture of 4-amino-l- ((2S,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydr
  • step 2 the silylated cytarabine from step 1 in ethyl acetate was added to a solution prepared from (S)-4-(benzyloxy)-3- (((benzyloxy)carbonyl)amino)-4-oxobutanoic acid (Boc-Asp-OBzl), 1 -hydroxybenzotriazole
  • step 4 the solid product of step 3 was added to a hydrogenator and dissolved with a mixture of N-Methyl-2- pyrrolidone (NMP, 30 mL) and water (30 mL). Palladium on carbon (10% Pd/C, 50% wet, 1.5%,) was charged, and hydrogenolysis was accomplished after 4 hours stirring at 25°C with 20 psi of hydrogen. Pd/C was removed by filtration and washed with water from the reactor rinsing.
  • NMP N-Methyl-2- pyrrolidone
  • Compound 4 was synthetized by the following method: 10g of benzyl N 2 - ((benzyloxy)carbonyl)-N 4 -(l-((2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2- yl)-2-oxo-l,2-dihydropyrimidin-4-yl)-L-asparaginate (BC-BST-236) was added to 250 ml Fisher- Porter bottle with magnetic stirrer bar, followed by 1g Pd/C (type 91, Sigma-Aldrich), 116ml ethyl acetate and 70ml water.
  • the biphasic mixture was degassed with N 2 .
  • the bottle was charged and purged with H 2 four times and filled with H 2 to 20 psi for 4 days.
  • the reaction mixture was filtered through a prepacked celite funnel to remove the catalyst and the filter cake was rinsed with 2ml water, the phases were separated, and the water phase was lyophilized to give 5.7g of white solid (88% yield) with chemical purity of 100%.
  • Step 1 A solution of benzyl chloroformate (3.52 g,) in dioxane (21.0 mL) was added to a solution of N-(tert-butoxycarbonyl)-L-aspartic acid (Boc-Asp-OH, 3.00 g), dioxane (17.0 mL), water (34.0 mL) and NaHCO 3 (4.00 g). After stirring for 16 hours the reaction mixture was quenched with water and the aqueous phase was washed with ethyl acetate.
  • Boc-Asp-OH N-(tert-butoxycarbonyl)-L-aspartic acid
  • step 1 To a solution of uracil arabinoside (10.0 g) in dichloromethane (70.0 mL) was added tert-Butyldimethylsilyl chloride (TBSC1,, 30.8g ), 4- dimethylaminopyridine (DMAP, 500 mg) and imidazole (11.1 g). After stirring (16 hours) the mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried, filtered and concentrated under pressure. The residue was purified by prep- HPLC (Column: DAC-150 luna).
  • step 2 to the solution of step 1 (6.40 g) in DCM (112 mL) was added DMAP (133 mg).
  • the reaction mixture was cooled to 0 °C, and N,N-diisopropylethylamine (DIPEA, 7.05 g) and 2,4,6-triisopropylbenzenesulfonyl chloride (6.60 g) were added.
  • DIPEA N,N-diisopropylethylamine
  • 2,4,6-triisopropylbenzenesulfonyl chloride (6.60 g) were added.
  • the reaction mixture was stirred (4 hours) and washed by NaHCO 3 (80 mL x 3) at 0 °C.
  • step 3 to a solution of step 2 (2.50 g,) in 1-propanol (25.0 mL) were added tert-butyl L-asparaginate, (827 mg,) and N,N- diisopropylethylamine (DIPEA, 1.14 g). The mixture was stirred (14 hours), quenched by addition NaHCO 3 25 mL and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue that was purified by prep-HPLC.
  • DIPEA N,N- diisopropylethylamine
  • step 4 to a solution of step 3 (500 mg) in EtOAc (10.0 mL) was added HCl/EtOAc (4 M, 10.0 mL). The mixture was stirred at 40 °C (4 hours) and concentrated. The residue was purified by prep-HPLC. The fractions with the product were concentrated and lyophilized to give Compound 6a (100 mg, 99.5% purity) as a white solid. The structure was confirmed by MS, 1 H-NMR and 13 C-NMR.
  • step 1 To a solution of uracil arabinoside (10.0 g) in dichloromethane (70.0 mL) was added tert-Butyldimethylsilyl chloride (TBSC1,, 30.8g ), 4-dimethylaminopyridine (DMAP, 500 mg) and imidazole (11.1 g). After stirring (16 hours) the mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried, filtered and concentrated under pressure. The residue was purified by prep-HPLC (Column: DAC-150 luna).
  • step 2 to the solution of step 1 (6.40 g) in DCM (112 mL) was added DMAP (133 mg).
  • the reaction mixture was cooled to 0 °C, and N,N-diisopropylethylamine (DIPEA, 7.05 g) and 2,4,6-triisopropylbenzenesulfonyl chloride (6.60 g) were added.
  • DIPEA N,N-diisopropylethylamine
  • 2,4,6-triisopropylbenzenesulfonyl chloride (6.60 g) were added.
  • the reaction mixture was stirred (4 hours) and washed by NaHCO3 (80 mL x 3) at 0 °C.
  • step 3 to a solution of step 2 (1.0 g,) in 1-propanol (10 mL) were added tert-butyl (S)-3,4-diamino-4-oxobutanoate (331mg) and N,N-diisopropylethylamine (DIPEA, 303 mg). The mixture was stirred at 100 °C for 14 hours, quenched by addition NaHCO 3 (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • DIPEA N,N-diisopropylethylamine

Abstract

La présente invention concerne de nouvelles compositions comprenant de la (l-((2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxyméthyl) tétrahydrofuran-2-yl)-2-oxo-l, 2-dihydropyrimidin-4-yl)-l-asparagine (également connue sous le nom de BST-236, Astarabine® ou Aspacytarabine) ou un sel pharmaceutiquement acceptable de celle-ci et des composés supplémentaires, et leurs utilisations pour le traitement de maladies néoplasiques.
PCT/IL2023/050522 2022-05-22 2023-05-22 Compositions comprenant de l'aspacytarabine et des composés supplémentaires, et leur utilisation WO2023228177A1 (fr)

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Citations (4)

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Publication number Priority date Publication date Assignee Title
WO2017093993A1 (fr) * 2015-12-03 2017-06-08 Biosight Ltd. Conjugués de cytarabine pour le traitement du cancer
WO2019012328A1 (fr) * 2017-07-09 2019-01-17 Biosight Pharma Polythérapie anticancéreuse
US20210395285A1 (en) * 2015-12-03 2021-12-23 Biosight Ltd. Salts of conjugates for cancer therapy
WO2023089617A1 (fr) * 2021-11-21 2023-05-25 Biosight Ltd. Promédicament à base d'acide aminé-cytarabine pour le traitement du cancer

Patent Citations (4)

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Publication number Priority date Publication date Assignee Title
WO2017093993A1 (fr) * 2015-12-03 2017-06-08 Biosight Ltd. Conjugués de cytarabine pour le traitement du cancer
US20210395285A1 (en) * 2015-12-03 2021-12-23 Biosight Ltd. Salts of conjugates for cancer therapy
WO2019012328A1 (fr) * 2017-07-09 2019-01-17 Biosight Pharma Polythérapie anticancéreuse
WO2023089617A1 (fr) * 2021-11-21 2023-05-25 Biosight Ltd. Promédicament à base d'acide aminé-cytarabine pour le traitement du cancer

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Cytarabine. The American Society of Health-System Pharmacists. Archived from the original on 11 June 2016. URL: https://web.archive.org/web/20160611124414/http://www.drugs.com/monograph/cytarabine.html>. Retrieved 13 June 2023. (2016/06/11) *

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