Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
  • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
  • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
  • C07H19/06—Pyrimidine radicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• the present invention relates to 5'-deoxy-N-(substituted oxycarbonyl)-5-fluorocytosine, derivatives thereof, a method of preparing the same, and an anticancer composition comprising the same as active ingredients. More particularly, the present invention relates to 5'-deoxy-N-(substituted oxycarbonyl)-5-fluorocytosine and derivatives thereof, exhibiting good anticancer activity, a method of preparing the same and an anticancer composition comprising the same as active ingredients.
• Cancer is one of the incurable diseases that are a problem to be solved in modern medical science, together with acquired immune deficiency syndrome (AIDS).
• AIDS acquired immune deficiency syndrome
• the different types and number of cancer cases are increasing year by year domestically and its low cure rate causes the demise of many people.
• suitable drugs have not yet been developed.
• the development of an anticancer drug with good efficacy and without side effects to more efficiently and effectively cure cancer is required.
• 5-FU is a material to cure cancer by preventing synthesis of pyrimidine and neucleotide, but it is toxic to the stomach and intestine, and it has severe side effects.
• 5-FU derivatives with reduced side effects has been active, but new 5-FU derivatives still have a side effect causing diarrhea by activating the 5-FU derivatives in an intestinal wall after oral administration.
• N 4 -alkyloxycarbonyl-5-fluorocytosine derivatives of Formula 1 which activate by enzymes in the lung rather than in the intestine and can reduce side effects, have been developed (European Patent No. 6,025,454, Japanese Patent Laid-open No. 94-211891 and U. S. Patent No. 5,472,949).
• R a is saturated or unsaturated hydrogen carbonate; and R > b D is hydrogen, an easily hydrolysable radical or a protecting group easily removable under physiological conditions.
• the derivatives have shortcomings in that anticancer activity is somewhat low. Therefore, development of new anticancer drugs exhibiting good anticancer activity is required.
• oxycarbonyl-5-fluorocytosine and derivatives thereof It is still another to provide an anticancer composition including 5'-deoxy-N-substituted oxycarbonyl-5-fluorocytocine, or derivatives thereof, as an active ingredient.
• R 2 is an easily hydrolysable radical or a protecting group easily removable under physiological conditions
• R 3 is a C ⁇ -C 7 alkyl group, alkenyl group or alkynyl group
• R 4 is a hydroxymethyl group or a hydroxymethyl group with a protecting group.
• the present invention relates to a novel compound that has good anticancer activity and is usable for an anticancer drug, and provides 5'-deoxy-N-(substituted oxycarbonyl)-5-fluorocytosine and derivatives thereof, having Formula 2 or 3 and derivatives thereof, and pharmaceutically acceptable salts or solvating materials.
• R 2 is an easily hydrolysable radical or a protecting group easily removable under physiological conditions, preferably hydrogen or an acetyl group
• R 3 is a C- 1 -C7 alkyl group, alkenyl group or alkynyl group
• R 4 is a hydroxymethyl group or a hydroxymethyl group with a protecting group.
• R 1 is hydrogen, a C 1 -C 7 alkyl group or a C 1 -C 7 alkenyl group
• R 3 is a C 1 -C 7 alkyl group, alkenyl group or alkynyl group.
• trimethylsilylated 5-fluorocytosine of Formula 7 are mixed in the presence of a solvent such as acetonitrile with the addition of suitable additives, e.g. titanium (IV) chloride, iodotrimethylsilane or chlorotrimethylsilane/sodium iodide, to prepare a compound of Formula 4.
• suitable additives e.g. titanium (IV) chloride, iodotrimethylsilane or chlorotrimethylsilane/sodium iodide
• the compound of Formula 4 (Korean application No. 2000-461 79) is mixed with a compound of Formula 5 in the presence of a solvent such as methylene chloride or pyridine with the addition of a suitable base, e.g. pyridine, triethylamine, or diisopropylethylamine, to prepare a compound of Formula 3b.
• a solvent such as methylene chloride or pyridine
• a suitable base e.g. pyridine, triethylamine, or diisopropylethylamine
• the compound of Formula 3b is reduced in the presence of an alcohol such as methanol or ethanol using a C- ⁇ -C 2 sodium alkoxide or sodium hydroxide, to obtain a compound of Formula 3a.
• an alcohol such as methanol or ethanol using a C- ⁇ -C 2 sodium alkoxide or sodium hydroxide
• the compound of Formula 3a reacts with oxygen gas using a suitable
• alkyl alcohol or alkenyl alcohol and thionyl chloride is dropped in at -30 ° C to
• the present invention relates to an anticancer composition including 5'-deoxy-N-(substituted oxycarbonyl)-5-fluorocytosine derivatives as an active ingredient.
• the composition of the present invention may be variously orally or non-orally administered to patients, and the composition may include a compound of Formula 2 or 3, pharmaceutically acceptable salts, or solvating materials.
• the anticancer composition of the present invention may also include a physiologically acceptable liquid or solid carrier.
• the solid preparation form may include powder, tablets, dispensable particles, or capsule; and a suitable solid medication type for oral administration may be a tablet, powder, or a capsule.
• a suitable vehicle may be a diluent, a flavor agent, a solubilizer, a lubricant, a suspension agent, a binder and/or a purification-swelling agent. If a powder or capsule preparation form is used, the carrier may include granule active components of 5 to 70%, preferably 10 to 70%.
• a suitable solid carrier or vehicle may be corn starch, magnesium stearate, a film, polyethylene glycol, talc, sugar, lactose, pectin, dextrin, starch, gelatin, hydroxypropylmethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, dioxide titanium, wax with low melting point, cocoa, or butter.
• the liquid preparation may be a solution, a suspension, or an emulsion.
• a non-oral injection solution includes water or mixed water-propylene glycol, and the injection has suitable isotonic properties and pH for the body system.
• the liquid preparation may also be polyethylene glycol aqueous solution.
• the suitable aqueous solution for oral administration may be prepared by dissolving active ingredients in water, and adding a flavor agent, a coloring agent, a stabilizer and a concentration-aid to the resulting material.
• the suitable aqueous suspension agent for oral administration may be prepared by adding particle active ingredients to a viscosity material such as natural or synthetic gum, resin, methyl cellulose, sodium carboxymethyl cellulose or conventional suspension agent.
• a preferable pharmaceutical preparation is a unit administration type.
• the preparation includes separating a suitable amount of active ingredient into units for administration, wherein each unit of administration may be packaged as a separated amount of the preparation, for example, in a vial or ample, a tablet, a capsule, or as powder.
• each unit of administration may be packaged as a separated amount of the preparation, for example, in a vial or ample, a tablet, a capsule, or as powder.
• the cancer cells were incubated in an incubator with a constant
• fetal bovine serum was used for a basic medium.
• the cancer cells in a logarithmic phase were inoculated at 2-5 X 10 4 cells per well of a 96-well plate, and incubated for 24 hours.
• mice used were 5-week-old BDF1 male mice (19 to 20 g) that were purchased from Charles River Japan, and adapted for 1 week.
• the breeding condition of the mice was set to a temperature of
• mice supplied to the mice twice a week, and straws and cages were changed once a week.
• the experiment was performed using two mice per group.
• the tumor cell line an L1210 mouse blood tumor cell line was used, and the cell line was sub-cultured in a Falcon culture flask twice or three times, washed with a phosphorous buffer solution (pH 7.2), and quantified under a microscope to produce a cell suspension of 1 x 10 7 /ml, and 100 (1 x 10 6 ) ml of the cell suspension was abdominally administered to the mouse using 1 ml of a disposable sterilized injector. The drug was orally administered 24 hours after the cellular transplantation. The concentration of the administered
• capecitabine was 1 .2, 5.7, 28.8, 144, and 720 mg/kg/100 ⁇ for
• present invention was 1 .2, 5.8, and 28.8 mg/kg/100 il for respective
• mice The capecitabine was dissolved in dimethylsulfoxide and suspended in 0.5% carboxymethyl cellulose, and the compound of Formula 2a was dissolved in distilled water. The samples were administered to the mice five times a week for 3 weeks, for a total of 15 times, starting 24 hours after the tumor cell administration. The anticancer activity was determined as increased life span to control. The results are presented in Table 2. ⁇ Table 2>
• Example 3 As shown in Table 2, the compound of Example 3 exhibits good anticancer activity in vivo, through the animal experiment.
• N 4 -alkynyloxycarbonyl-5-fluorocytosine and derivatives can be used for an anticancer drug.
• Example 9 A compound was prepared by the same procedure in Example 8 except that a compound of Formula 5 with R 3 of ethyl, butyl, pentyl, hexyl, heptyl, allyl, and propargyl was used, respectively, instead of propyl chloroformate.
• Example 9 A compound was prepared by the same procedure in Example 8 except that a compound of Formula 5 with R 3 of ethyl, butyl, pentyl, hexyl, heptyl, allyl, and propargyl was used, respectively, instead of propyl chloroformate.
• R 3 pentyl, compound of Formula 3b)
• oxygen gas was injected into the resulting material at 90 ° C for 12
• a compound was prepared by the same procedure in Example 24 except that a compound of Formula 3a with R 3 of ethyl, propyl, butyl, pentyl, heptyl, allyl and propargyl was used, respectively, instead of 5-fluoro-N 4 -(hexyloxycarbonyl)-cytosine.
• 5'-deoxy-N-alkyloxycarbonyl-5-fluorocytosine-5'-carboxylic acid (compound of Formula 2a) of the present invention using 5-FU as a control the cell toxicity to human cancer cells was measured.
• the human cancer cells used were A549 (lung cancer), HCT15 (colon cancer), SK-OV-3 (ovarian cancer), and SK-MEL-2 (melanoma cancer).
• the cancer cells were cultured in an incubator with a constant
• the cancer cells in a logarithmic phase were inoculated into 2 to 5 x10 4 cells per well of a 96-well plate, incubated for 24 hours, and a sample solution of a stepwise dilution of 5-FU and
• the compound of Formula 2 according to the present invention exhibits about 0.005 to 0.5 g/ml anticancer activity to each
• Example 34
• mice used were 5-week-old BDF1 male mice (19 to 20 g) that were purchased from Charles River Japan, and adapted for 1 week.
• the breeding condition of the mouse was set to a temperature of
• the tumor cell line an L1210 mouse blood tumor cell line was used, the cell line was sub-cultured in a Falcon culture flask twice or three times, washed with a phosphorous buffer solution (pH 7.2), quantified under a microscope to produce a cell suspension of 1 x 1 0 7 /ml, and 100 (1 x 10 6 ) ml of the cell suspension was abdominally administered to the mouse using 1 ml of a disposable sterilized injector. The drug was orally administered 24 hours after the cellular transplantation. The concentration of the administered capecitabine
• mice was 1 .2, 5.7, 28.8, 144, and 720 mg/kg/100 ⁇ l for respective mice, and
• mice dimethylsulfoxide and suspended in 0.5% carboxymethyl cellulose, and the compound of 2a was dissolved in distilled water.
• the samples were administered to the mice five times a week for 3 weeks, for a total of 15 times, starting 24 hours after the tumor cell administration.
• the anticancer activity was determined as increased life span to control. The results are presented in Table 4.
• mice used were 5-week-old BDF1 male mice (19 to 20 g) that were purchased from Charles River Japan, and adapted for 1 week.
• the breeding condition of the mice was set to a temperature of
• mice As the tumor cell line, an L1210 mouse blood tumor cell line was used, the cell line was sub-cultured in a Falcon culture flask twice or three times, washed with a phosphorous buffer solution (pH 7.2), quantified under a microscope to produce a cell suspension of 1 x 10 7 /ml, and 100 (1 x 10 6 ) ml of the cell suspension was abdominally administered to the mouse using 1 ml of a disposable sterilized injector. The drug was orally administered 24 hours after the cellular transplantation. The concentration of the injected
• capecitabine was 1.2, 5.7, 28.8, 144, and 720 mg/kg/100 z for
• present invention was 1 .2, 5.8, 28.8 mg/kg/100 ⁇ for respective mice.
• the capecitabine was dissolved in dimethylsulfoxide and suspended in 0.5% carboxymethyl cellulose, and the compound of 2a was dissolved in distilled water.
• the samples were administered to the mice five times a week for 3 weeks, for a total of 15 times, starting 24 hours after the tumor cell administration.
• the anticancer activity was determined as increased life span. The results are presented in Table 5. ⁇ Table 5>
• the compound of Formula 2 according to the present invention exhibits excellent anticancer activity through animal tests.

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• 2001
  • 2001-08-08 WO PCT/KR2001/001351 patent/WO2002011668A2/en not_active Application Discontinuation
  • 2001-08-08 EP EP01957021A patent/EP1311524A2/en not_active Withdrawn
  • 2001-08-08 JP JP2002517006A patent/JP2004505899A/ja active Pending
  • 2001-08-08 CN CN01813741A patent/CN1446225A/zh active Pending
  • 2001-08-08 AU AU2001278804A patent/AU2001278804A1/en not_active Abandoned

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