WO2000049030A1 - Derives de 5-fluorouridine et anticancereux renfermant ces derives comme principe actif - Google Patents

Derives de 5-fluorouridine et anticancereux renfermant ces derives comme principe actif Download PDF

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Publication number
WO2000049030A1
WO2000049030A1 PCT/JP1999/000705 JP9900705W WO0049030A1 WO 2000049030 A1 WO2000049030 A1 WO 2000049030A1 JP 9900705 W JP9900705 W JP 9900705W WO 0049030 A1 WO0049030 A1 WO 0049030A1
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WO
WIPO (PCT)
Prior art keywords
formula
physiologically acceptable
medicament
derivative
medicament according
Prior art date
Application number
PCT/JP1999/000705
Other languages
English (en)
Japanese (ja)
Inventor
Hirotaka Endoh
Katsuyori Kumakura
Hiromasa Omori
Original Assignee
Nikken Chemicals Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to JP9269169A priority Critical patent/JPH1192386A/ja
Application filed by Nikken Chemicals Co., Ltd. filed Critical Nikken Chemicals Co., Ltd.
Priority to PCT/JP1999/000705 priority patent/WO2000049030A1/fr
Publication of WO2000049030A1 publication Critical patent/WO2000049030A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—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
    • A61K31/7072—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 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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

Definitions

  • the present invention relates to a 5-fluoroperidine derivative and an anticancer agent containing the derivative as an active ingredient.
  • the present invention relates to a novel 5-fluorouridine derivative and an anticancer agent containing the derivative as an active ingredient.
  • lymph nodes around the tumor are dissected during surgery to prevent metastasis. In this case, the burden on the patient is increased, but the operation is often not complete, and the cancer often recurs and spreads.
  • the prognosis of a surgical operation is largely determined by the presence or absence of cancer metastasis to the lymph and to other tissues via the lymphatic system. It is considered to be extremely effective as a therapeutic agent.
  • 5'-deoxy 5-fluorouridine is widely used orally in clinical settings as an anticancer drug.
  • This anticancer drug is a prodrug of 5-fluorouracil (5-FU), which has no effect, but is converted to 5-FU by pyrimidine nucleoside phosphorylase, which is specifically active at the cancer site after administration. It is evaluated as having high safety with few side effects compared to other fluorinated pyrimidine-based anticancer drugs. However, because this anticancer drug is highly water-soluble, drug transfer to the lymphatic system is small.
  • Japanese Patent Publication No. 63-2960 Although no specific example of the compound of the present invention is shown, a fatty acid ester derivative of 5'-deoxy-5-fluoroperidine is disclosed. Disclosure of the invention
  • the present inventors thought that if 5'-DFUR could be transferred to the lymphatic system at a high concentration by oral administration, a chemotherapeutic agent with less side effects for the purpose of preventing or treating cancer metastasis would be obtained.
  • Intensive research to solve the problem As a result, the 2H and 3H 0H groups of water-soluble 5'-DFUR were esterified with a specific fatty acid to form a highly fat-soluble diester derivative, and this derivative was mixed with oil and a surfactant. It was found that when administered orally as an oily preparation or as an emulsion containing water in the oily preparation, the drug was transferred to the lymphatic system at a high concentration. They have also found that this diester derivative is converted into 5'-DFUR in vivo by esterases widely distributed in the living body, and can achieve high anticancer activity and cancer metastasis preventing effect. The present invention has been completed based on these findings.
  • R 1 represents a C 3 -C 13 linear or branched alkyl group
  • a physiologically acceptable salt thereof or a hydrate or a hydrate thereof. It is intended to provide a medicine containing a solvate as an active ingredient.
  • This medicament can be used as an anticancer agent. According to a preferred embodiment of the present invention, there is provided the above medicament, which is a linear or branched alkyl group of R 4; C 4 to C 13 .
  • the above-mentioned medicament in the form of an oily preparation or an emulsion; the above-mentioned medicament which is an oral lymph-translocating anticancer agent having increased lymphatic translocation; and the above-mentioned medicament which is an agent for preventing lymph-mediated cancer metastasis.
  • a medicament is provided.
  • the present invention provides a compound represented by the following formula (II):
  • R 2 represents a C 4 -C 13 linear or branched alkyl group
  • a method for treating cancer which is selected from the group consisting of a 5-fluoroperidine derivative represented by the above formula (I), a physiologically acceptable salt thereof, and a hydrate and a solvate thereof.
  • a method comprising the step of administering a therapeutically effective amount of a substance to a patient; a method for preventing lymph-mediated cancer metastasis, which comprises a 5-fluorouridine derivative represented by the above formula (I) and a physiologically acceptable salt thereof.
  • a method comprising administering to a cancer patient a prophylactically effective amount of a substance selected from the group consisting of hydrates and solvates thereof.
  • the 5-fluoroperidine derivative represented by the formula (I) of the present invention can be produced according to the method described in JP-B-63-2960. For example, it can be synthesized by reacting 5′-DFUR with a fatty acid mouth ride or a fatty acid anhydride by a conventional method.
  • a 5-hydrate of a 5-fluorouridine derivative represented by the formula (I) or a physiologically acceptable salt thereof, a hydrate or a solvate thereof may be used.
  • R 1 is a linear alkyl group of C 5 to C U , particularly a linear alkyl group of C 7 to C 9. Compounds that are groups are preferred.
  • the medicament of the present invention can be used as an anticancer agent for the treatment of various solid or non-solid cancers.However, the medicament of the present invention is characterized by being particularly excellent in the ability to transfer to the lymphatic system. It is particularly useful for preventing lymph-mediated cancer metastasis.
  • the anticancer agent of the present invention is preferably used as an oily preparation or an emulsion.
  • the oil-based preparation has the ability to dissolve the active ingredient such as a 5-fluorouridine derivative represented by the formula (I) or a physiologically acceptable salt thereof in an oily base and a surfactant, or to dissolve the active ingredient. It can be manufactured by dispersing in
  • the emulsion can be produced by a usual method for producing an oil-in-water emulsion.
  • an active ingredient such as a 5-fluorouridine derivative represented by the formula (I) or a physiologically acceptable salt thereof is dissolved in a mixture of an oil base and a surfactant, and water is added to the obtained mixture. It is produced by homogenization.
  • oils and oils that can dissolve or uniformly disperse an active ingredient such as a 5-fluorouridine derivative represented by the formula (I) or a physiologically acceptable salt thereof, and are physiologically acceptable.
  • a solvent may be used together with fats and oils to help dissolve the drug. Examples of such a solvent include ethanol and medium-chain fatty acid triglycerides. Phosphate is a surfactant And phospholipids such as atidylcholine, phosphatidylserine and sphingomyelin.
  • sugars such as glucose, maltose and trehalose, glycerin, nonionic surfactants, and emulsifying aids such as gelatin can be added to the emulsion.
  • the medicament of the present invention can be produced using various pharmaceutical additives. For example, a flavoring agent, a flavor, and the like can be added.
  • the amount of the active ingredient contained in the medicament of the present invention can be appropriately increased or decreased.
  • the active ingredient content is preferably in the range of 0.01 to 60 (w / v)%, more preferably 1 to 50 (w / v)%.
  • the content is preferably in the range of 0.001 to 20 (w / v)%, more preferably in the range of 0.1 to 10 (w / v)%.
  • Oral administration is suitable as the method for administering the medicament of the present invention, but it is also possible to select a non-oral administration method such as rectal administration or intravascular administration.
  • the administration frequency, dosage, and administration period of the medicament of the present invention can be appropriately selected depending on the purpose of treatment or prevention, the age and weight of the patient, the type and severity of the disease, and the like. Specifically, desired treatment or prevention can be performed with reference to the dose and the number of times of administration of 5'-deoxy-5-fluorouridine (5'-DFUR).
  • 5'-DFUR 5'-deoxy-5-fluorouridine
  • the novel compound represented by the formula (II) provided by the present invention can be produced by the same method as in the formula (I).
  • the 5-fluorouridine derivative represented by the formula (II) or a salt thereof, or a hydrate or a solvate thereof, is included in the scope of the present invention.
  • the use of the compound of the present invention represented by the formula (II) is not particularly limited, but the above-mentioned use as a medicine is a preferable use.
  • Synthesis Example 1 Synthesis of 2 ', 3, -didecanol-5'-DFUR
  • 5'-DFUR (60.5 g, 232.4 ol) was added to pyridine (900 ml) and benzene (600 ml) At 0 ° C., a solution of n-decanoic acid chloride (110.8 g, 581.1 mmol) in benzene (750 ml) was added dropwise to the solution dissolved in the mixed solvent over 4 hours. The mixture was returned to room temperature and stirred for 20 hours. The reaction mixture was cooled to 0 ° C, methanol (50 ml) was added, and the mixture was stirred for 30 minutes to decompose excess acid chloride. Most of the solvent was distilled off under reduced pressure, and the residue was dispersed in a large amount of water.
  • the mixture was extracted with ethyl acetate, and the extract was washed with water, 10% hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated saline solution, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain an oil.
  • a lymph fluid sample was collected in the same manner as in Test Example 1.
  • the drug concentration in the sample was determined by subjecting the sample to esterase treatment and converting the unchanged 2,2'-didecanyl-5'-DFUR (10-57% of the total drug concentration) partially contained in the sample to 5'- After conversion to DFUR, the 5'-DFUR concentration was measured by HPLC. Table 1 shows the results. Table 1 Lymph drug concentration
  • the AUC ⁇ of lymph about 7 times compared to A formulation control drug, about 3.6 times and clearly large in B formulation, it was shown to migrate to lymph is increased. Furthermore, it was shown that MRT ⁇ ⁇ ⁇ ⁇ was clearly longer and the drug concentration in the lymph persisted. On the other hand, the AUC ⁇ in plasma, about 74% in A formulation as compared to the control drug, and about 63% in B formulation, that there is no migration is despite marked reduction increased to lymph It could be confirmed. Also, A formulation for MRT ⁇ , sustained long become plasma drug concentration than the control drug with B formulation were observed. Test Example 5: Release of 5-FU in the intestinal tract
  • 5'-DFUR is highly toxic to the intestinal tract, causing side effects such as nausea, vomiting, diarrhea, and anorexia. This is thought to be due to 5-FU produced by enzymes in the intestinal tract.
  • the release of 5-FU in the intestinal tract was examined.
  • Oral administration of 2 ', 3'-dibutyryl-5'-DFUR (pharmaceutical of the present invention) and 5'-DFUR (control) was performed in rats, and the AU of 5'-DFUR in plasma and intestinal membrane of small intestine were observed.
  • the AUC ⁇ of 5-FU was measured of, AU of 5'-DFUR in the pharmaceutical as compared to controls in the plasma of the present invention. Power: 1.
  • the medicament of the present invention can transfer to the lymph as a prodrug after oral administration, and is characterized by being retained in the lymph for a longer period of time at a higher concentration than conventional 5'-DFUR. Accordingly, the medicament of the present invention is useful for treating cancer of the lymph system such as malignant lymphoma, preventing cancer metastasis to the lymph system and preventing cancer metastasis to other tissues via the lymph, or treating cancer metastasized to the lymph system. Suitable for chemotherapy.

Abstract

L'invention concerne des anticancéreux ayant comme principe actif les dérivés de 5-fluorouridine représentés par la formule générale (I), y compris les sels physiologiquement acceptables ou les hydrates ou solvates correspondants, qui ont une excellente aptitude à la migration dans la lymphe. Dans ladite formule, R1 est alkyle C¿3-13? linéaire ou ramifié.
PCT/JP1999/000705 1997-09-17 1999-02-18 Derives de 5-fluorouridine et anticancereux renfermant ces derives comme principe actif WO2000049030A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP9269169A JPH1192386A (ja) 1997-09-17 1997-09-17 ５−フルオロウリジン誘導体を有効成分とする抗癌剤
PCT/JP1999/000705 WO2000049030A1 (fr) 1997-09-17 1999-02-18 Derives de 5-fluorouridine et anticancereux renfermant ces derives comme principe actif

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP9269169A JPH1192386A (ja) 1997-09-17 1997-09-17 ５−フルオロウリジン誘導体を有効成分とする抗癌剤
PCT/JP1999/000705 WO2000049030A1 (fr) 1997-09-17 1999-02-18 Derives de 5-fluorouridine et anticancereux renfermant ces derives comme principe actif

Publications (1)

Publication Number Publication Date
WO2000049030A1 true WO2000049030A1 (fr) 2000-08-24

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PCT/JP1999/000705 WO2000049030A1 (fr) 1997-09-17 1999-02-18 Derives de 5-fluorouridine et anticancereux renfermant ces derives comme principe actif

Country Status (2)

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JP (1) JPH1192386A (fr)
WO (1) WO2000049030A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA3027118C (fr) * 2016-06-28 2023-08-15 Cellix Bio Private Limited Compositions et methodes pour le traitement du cancer

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59144798A (ja) * 1979-06-15 1984-08-18 エフ・ホフマン・ラ・ロシユ・ウント・コンパニ−・アクチエンゲゼルシヤフト ５−フルオロウラシル誘導体
JPH0692987A (ja) * 1992-09-17 1994-04-05 Tanabe Seiyaku Co Ltd ウリジン誘導体およびその製法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59144798A (ja) * 1979-06-15 1984-08-18 エフ・ホフマン・ラ・ロシユ・ウント・コンパニ−・アクチエンゲゼルシヤフト ５−フルオロウラシル誘導体
JPH0692987A (ja) * 1992-09-17 1994-04-05 Tanabe Seiyaku Co Ltd ウリジン誘導体およびその製法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LADISLAV NOVOTNY ET AL: "The Effect of Structural Modifications of 5-Fluorouracil Derivatives on their Transport and Biodegradation by Isolated rat Jejunum", CANCER CHEMOTHER. AND PHARMACOL., vol. 24, 1989, pages 238 - 242, XP002929203 *

Also Published As

Publication number Publication date
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