WO1992017487A1 - Derive de 5'-phosphatidyl-5-fluoro-uridine - Google Patents

Derive de 5'-phosphatidyl-5-fluoro-uridine Download PDF

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Publication number
WO1992017487A1
WO1992017487A1 PCT/JP1991/001744 JP9101744W WO9217487A1 WO 1992017487 A1 WO1992017487 A1 WO 1992017487A1 JP 9101744 W JP9101744 W JP 9101744W WO 9217487 A1 WO9217487 A1 WO 9217487A1
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WIPO (PCT)
Prior art keywords
group
phosphatidyl
derivative
toxic salt
active ingredient
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Ceased
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PCT/JP1991/001744
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English (en)
Japanese (ja)
Inventor
Satoshi Shuto
Hiromichi Ito
Takumi Obara
Atsushi Sakai
Nobuhiro Mori
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Toyo Jozo KK
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Toyo Jozo KK
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Publication of WO1992017487A1 publication Critical patent/WO1992017487A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • 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 a 5′-phosphatidyl-5-fluorouridine derivative or a non-toxic salt thereof, and an antitumor agent containing them as an active ingredient. More specifically, the present invention provides
  • R represents a long-chain saturated acyl group and R 2 represents a long-chain unsaturated acyl group
  • an antitumor agent containing them as an active ingredient.
  • nucleoside antitumor agents have been widely and clinically used as drugs useful for chemotherapy of various types of tumor cells.
  • some problems have been pointed out in its application as a chemotherapeutic agent.
  • these nucleoside anti-palutants are activated by 5′-phosphorylation as a mechanism of action and exhibit activity, and are rapidly inactivated due to inactivation such as phosphorylation and deamination. Breaks down into active substances There are various drawbacks, such as being easily susceptible to tumor cells, becoming resistant to these antitumor agents, and being toxic to rapidly dividing normal cells.
  • lymphatic metastasis of tumor cells is a major problem in the treatment of malignant tumors.
  • conventional antitumor agent that has excellent transferability to the lymphatic system. Therefore, various attempts have been made to selectively transfer an antitumor agent to a linker system by using a pharmaceutical technique such as emulation or ribosome formation, but it has not been put to practical use.
  • cytosine arabinoside as a nucleoside residue component of a phospholipid 'nucleoside derivative. Therefore, its effect as an antitumor agent is ultimately limited to cytosine arabinoside (ara-C: 1 — ⁇ -arabino furanosylcytosine) Defects such as toxicity associated with the drug were not improved.
  • nucleoside compounds other than cystocinarapinoside are used.However, in order to chemically synthesize those phospholipid nucleoside derivatives, multi-step synthesis is required. A process was required, the reaction conditions were difficult to set, and the synthesis was practically difficult. The present inventors have improved the synthetic method having such disadvantages, synthesized a new phospholipid / nucleoside derivative, and conducted repeated studies to obtain a substance superior to the known antitumor agent.
  • the 5'-phosphatidyl nucleoside which has the same long-chain acryl group at the 1- and 2-positions of the glycerol moiety, has poor water solubility and is still unfavorable as a pharmaceutical for injection. It was something. In addition, when used as an injection, transferability to a lymph system was not sufficient.
  • a phospholipid / nucleoside derivative having a long-chain unsaturated acyl residue at position 1 of the glycerol moiety and a long unsaturated unsaturated acyl residue at position 2 of the glycerol moiety has an unexpectedly high water solubility. It has been found that it is excellent and has excellent limber transferability in intramuscular administration, and is useful as an injection for an antitumor agent.
  • the present invention has been completed based on the above findings, and has the following general formula (I)
  • 5′-Phosphatidyl-5-fluorouridine derivatives or non-toxic salts and antitumor agents containing them as active ingredients are used as the glycerol lipid used to obtain the 5′-phosphatidyl 5-5-fluorouridine derivative represented by the general formula [I] of the present invention.
  • a phosphatidyl choline type represented by the following general formula [ ⁇ ] is used as the glycerol lipid used to obtain the 5′-phosphatidyl 5-5-fluorouridine derivative represented by the general formula [I] of the present invention.
  • R 2 represents the same group as described above, and R 3 represents a trimethylammonioethyl group.
  • R 3 represents a trimethylammonioethyl group.
  • R 2 is a long-chain unsaturated acryl group, for example, a long-chain acryl group having 16 to 20 carbon atoms and having 1 to 4 unsaturated bonds, and specifically, for example, oleoyl, arachidonyl, and lino Long-chain unsaturated acetyl groups that are leyl or mono- or rh-linolenoyl are included. Specifically, is a palmitoyl group, R 2 is represented by an oleoyl group, 1—valmityl-12-oleoylphosphatidylcholine, R, is a palmitoyl group, and R 2 is a linoleoyl group.
  • Palmi DOO Iru 2- linoleoyl phosphatidyl choline, Ri is Sutearoi le group, R 2 is represented by Oreoiru group 1- stearoyl 2 O Les oil phosphatidyl choline and R, but a stearoyl group, R 2 Chikaraku Reno Reoiru 1-stearoyl-1 2-linoleoyl Sphatidylcholine, R, is a palmitoyl group, R z is an arachidonyl group 1-palmitoyl 2-arachidonylphosphhtidylcholine, R, is a stearoyl group, R 2 is an arachidonyl group 1 —Stear mouth 2—Arachidonyl phosphatidylcholine, where R and R are palmitoyl groups, and R 2 is a linolenoyl group 1—Palmitolyl 2—o —Linolenoyl
  • the phosphatidylcholine having these R 1 and R 2 groups may be obtained by synthesizing using the saturated and unsaturated fatty acids corresponding to the above-mentioned acyl group, or may be a commercially available product.
  • the nucleoside used in the present invention includes 5-fluorolusin L 5—Fluorouridine; 5-Fluoro—1- ⁇ - ⁇ - ⁇ ibofuranosyl-2,41- (1H, 3H) -pyrimidinedione; FUR).
  • the phospholipid 'nucleoside derivative represented by the general formula [I] it can be obtained by reacting the glycerophospholipid with FUR in a solvent using phospholipase D in the presence of a metal ion.
  • the phospholipase D to be used include, for example, Phospholipase D derived from Streptomyces 'S' BB ⁇ ⁇ ⁇ belonging to the genus Streptomyces genus (Streptomycessp-AA5886; FERMP-610).
  • Phospholipase D derived from Streptomyces 'S' BB ⁇ ⁇ ⁇ belonging to the genus Streptomyces genus (Streptomycessp-AA5886; FERMP-610).
  • Phospholipase D derived from Streptomyces 'S' BB ⁇ ⁇ ⁇ belonging to the genus Streptomyces genus (Streptomycess
  • the amount of the phosphatidylcholine used is 100 to 100,000 units of phospholipase D per 1 mmol of phosphatidylcholine, preferably 500 to 10,000 units.
  • the solvent to be used for example, a non-protonic solvent such as ethyl acetate, dimethyl ether, benzene or the like, or an organic solvent such as chloroform, and a buffer solution having a pH of 3 to 10, preferably 100 mMC a Cl 2 1 0 0 mM acetate buffer ⁇ the (PH 5 6.) the organic solvent layer - more homogeneous mixed solvent of water layer solvent Ya dimethylformamidine de Ya dimethylcarbamoyl Rusuruhokishido and the buffer Solvents.
  • the amount of the oral form used is 1 to 100 ml, preferably 5 to 30 ml, per millimole of phosphatidylcholine.
  • the FUR used is 1 to 100 equivalents, preferably 5 to 20 equivalents, based on phosphatidyl choline.
  • the reaction temperature is usually from 10 to 70, preferably from 20 to 50'C, and the reaction time is from 30 minutes to 5 days, but usually from 30 minutes to 5 hours. is there.
  • the thus obtained phospholipid 'nucleoside derivative 5'-phosphatidyl-1-5-fluorouridine can be easily purified by a liquid separation method and silica gel chromatography.
  • the above-described one-step synthesis method of the phospholipid 'nucleoside derivative of the present invention as described above is shown as follows.
  • the thus obtained 5'-phosphatidyl 5-fluorofluorine is a product in which the phosphate group of the phospholipid is linked to the primary hydroxyl group at the 5 'position of the FUR used.
  • the 5'-phosphatidyl 5-5-fluoridine derivative can also be made into a non-toxic salt such as sodium salt, and can be generally administered as a uniform transparent liquid by adding distilled water for injection.
  • the daily dose is 15 to 3 mg OmgZ as an injection and 30 to 200 nm as an oral dose per day.
  • the 5′-phosphatidyl-5-fluorouridine derivative of the present invention obtained in this manner has a higher lipophilicity than FUR used as the original raw material, and therefore remains in the living body for a long time (therefore, the activity is maintained).
  • Is less susceptible to inactivation such as phosphorylation and reduction increases affinity for biological membranes, and generates 5 'monophosphate of FUR in cells without the involvement of kinases. It has such advantages as sustained and enhanced antitumor activity and reduced toxicity.
  • it selectively migrates to the lymphatic system. It has excellent characteristics as an antitumor agent. Further, it has an advantage of being excellent in water solubility when used as an injection.
  • the 5′-phosphatidyl 5-fluorofluorine derivative of the present invention has a remarkable antitumor effect in vivo (inv ivo) as shown below.
  • an anti-metastatic effect of inhibiting the metastasis of a tumor generated in a living body to another site was also observed.
  • the results obtained by examining the antitumor activity and lymphotropic property of the 5′-phosphatidyl 5-5-fluoridin derivative of the present invention against Meth-A fiber meat species (Meth-Afibrosarcoma) are shown below. Animal experiment 1 (antitumor activity)
  • mice Male, 6-week-old were purchased and used from Nippon Charlsriver, Inc. The number of mice in one group was -7 for the control group and five for the administration group.
  • M eth- A fibrosarcoma cells 1 X 1 0 6 Z0.
  • Each compound was dissolved in distilled water by sonication to a predetermined concentration. Each compound was intraperitoneally administered at 0.1 ml per 10 g of mouse body weight for 5 consecutive days from 24 hours after tumor cell inoculation.
  • the tumor volume of each mouse was measured using a caliper for the minor axis and major axis of the tumor 14 days after transplantation, and calculated using the following formula.
  • Tumor volume (mm 3 ) (minor axis (mm)) 2 X major axis (mm) / 2 Judgment was based on the average tumor volume (C) of the untreated group and the average tumor volume (T) of the administration group. %).
  • Compounds 1 to 5 significantly suppressed the growth of Meth-A line fibrosarcoma to TZC 40% or less by administration of 1 Omg / kg or more.
  • Compounds 1-4 showed a very strong antitumor effect of TZC 9,5-15.5 at a dose of 3 Omg.
  • the rat used was a Wistar male rat (10- to 11-week-old) purchased from Japan SLC Co., Ltd.
  • the compounds (2), (4) and (5) shown in Table 1 were used, and the control compound was a 1,2-disaturated acyl-type compound 5 ′ — (1,2-distearoyl-sn— Glyce-1-3-phospho) -5-fluorinidine was used.
  • the instrument used was a Shimadzu HPLC system (pump: LC-9A, UV variable wavelength detector: SPD-6A, data processor: CR-4AX, detection wavelength 27 Onm), and YM was used for the separation column.
  • CC 8 Aty Pe (Yamamura Chemical, 4.6 X 150 related, 5 ⁇ m) was used.
  • the mobile phase was 15 mM KHzPO4 (PH6.5) / MeOH; 10/90, and the quantification was performed at a flow rate of 1.5 ml / min. Results>
  • Each compound was intramuscularly administered to rats (3 animals) at a dose of 3 OmgZkg, and the plasma concentration of the compound was measured over time.
  • Table 3 shows the mean and standard deviation of the plasma concentration (gZml).
  • Each compound was intramuscularly administered at a dose of 3 OmgZkg to rats (3 rats) that had been subjected to thoracic lymph lymphatic administration. The degree was measured over time. Table 4 shows the average value and standard deviation of the concentration (/ g / ml).
  • reaction solution After refluxing the reaction solution for 5 minutes, the reaction solution was cooled (ice-cooled). To this reaction solution were added 1 mL of methanol and 1 Oml of methanol, and the layers were separated to collect the organic layer (lower layer). The organic layer was separated by adding 10 ml of water and 10 ml of methanol, and the lower layer was dried under reduced pressure.

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

Dérivé de 5'-phosphatidyl-5-fluoro-uridine répondant à la formule générale (I), et sel non-toxique dudit dérivé. Dans ladite formule, R1 représente un acyle saturé à chaîne longue, et R2 représente un acyle non saturé à chaîne longue.
PCT/JP1991/001744 1991-04-04 1991-12-20 Derive de 5'-phosphatidyl-5-fluoro-uridine Ceased WO1992017487A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP3/99579 1991-04-04
JP9957991 1991-04-04
JP3/190790 1991-07-04
JP3190790A JPH04364198A (ja) 1991-04-04 1991-07-04 ５’−ホスファチジル−５−フルオロウリジン誘導体

Publications (1)

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WO1992017487A1 true WO1992017487A1 (fr) 1992-10-15

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5563257A (en) * 1990-08-20 1996-10-08 Boehringer Mannheim Gmbh Phospholipid derivatives of nucleosides

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6191195A (ja) * 1984-10-12 1986-05-09 Toyama Chem Co Ltd 新規な５−フルオロ−２′−デオキシウリジン−５′−ホスフエ−ト誘導体およびその塩
DE3612636A1 (de) * 1985-04-15 1986-11-06 Toyo Jozo K.K., Tagata, Shizuoka Nucleosid-phospholipid-komplexe
EP0262876A2 (fr) * 1986-09-27 1988-04-06 Toyo Jozo Kabushiki Kaisha Conjugué nucléoside-phospholipide

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6191195A (ja) * 1984-10-12 1986-05-09 Toyama Chem Co Ltd 新規な５−フルオロ−２′−デオキシウリジン−５′−ホスフエ−ト誘導体およびその塩
DE3612636A1 (de) * 1985-04-15 1986-11-06 Toyo Jozo K.K., Tagata, Shizuoka Nucleosid-phospholipid-komplexe
EP0262876A2 (fr) * 1986-09-27 1988-04-06 Toyo Jozo Kabushiki Kaisha Conjugué nucléoside-phospholipide

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL & PHARMACEUTICAL BULLETIN, Vol. 36, No. 1, P. 209-17, (1988), SHUTO. S. et al., "A Facile Enzymatic Synthesis of 5'-(3-Sn-Phosphatidyl) nucleosides and their Antileu Kemic Activities". *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5563257A (en) * 1990-08-20 1996-10-08 Boehringer Mannheim Gmbh Phospholipid derivatives of nucleosides

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Publication number Publication date
JPH04364198A (ja) 1992-12-16

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