WO1992017487A1 - 5'-phosphatidyl-5-fluorouridine derivative - Google Patents

5'-phosphatidyl-5-fluorouridine derivative

Info

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
Authority
WO
Grant status
Application
Patent type
Prior art keywords
group
phosphatidyl
derivative
ml
toxic
Prior art date
Application number
PCT/JP1991/001744
Other languages
French (fr)
Japanese (ja)
Inventor
Satoshi Shuto
Hiromichi Ito
Takumi Obara
Atsushi Sakai
Nobuhiro Mori
Original Assignee
Toyo Jozo Kabushiki Kaisha
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

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Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07HSUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06Pyrimidine radicals
    • C07H19/10Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids

Abstract

A 5'-phosphatidyl-5-fluorouridine derivative represented by general formula (I) and a non-toxic salt thereof, wherein R1 represents long-chain saturated acyl and R2 represents long-chain unsaturated acyl.

Description

Specification

5 'over phosphatidyl over 5 Furuorourijin derivatives

Technical field

The present invention, 5 '- phosphatidyl - regarding 5- Furuorourijin derivative or a nontoxic salt thereof, and an antitumor agent for them as an active ingredient. More particularly, the present invention is,

(However Shikichu, R, is a long chain saturated Ashiru group, R 2 is a long chain to an unsaturated Ashiru group) relates an antitumor agent or their active ingredients. Description of the Related Art

Nucleoside antitumor agents have been widely applied to clinical conventionally as usefulness drug chemotherapy of various types of tumor cells. However - in applications as chemotherapeutic agents, some problems have been pointed out. That is, these nucleoside anti Namagusa 蕩剤 as its action mechanism 5 '- are those expressing phosphorylated by activity and potash phosphate decomposition, rapidly undergo inactivation such as de-Amino reduction not active that the substance susceptible to degradation in, the tumor cells become resistant to these anti-tumor agents, various disadvantages has been made such that also represent the toxic to normal cells a rapidly dividing.

On the other hand, various compounds as a purpose prodrugs to improve the drawbacks of toxicity of the nucleoside antitumor agents have been chemically synthesized. From this course, an attempt to synthesize phospholipid * nucleoside derivatives having antitumor activity (cytotoxicity) is made, cytosine § Rapi waves * de (ara - C) · Li phospholipids derivatives are synthesized, some effect Chikaraku認 'has been fit [B iochimicaet B io ¾p hysica A cta, 6 1 9 (1 9 8 0) 6 1 9 -.. 6 3 1, J. M e d C he m, 1 9 8 2 , 2 5, 1 3 2 2 1 3 2 9.

Furthermore, in the treatment of malignant tumors, metastasis by lymphoid tumor cells is a major problem. However, in conventional anti-tumor agents, it has not been known in which excellent transferability of the lymphatic system. Therefore, Emarujiyo emissions reduction, using the formulation techniques ribosome, etc., but an attempt to selectively migrate antitumor agent Li Nba system is variously made and reached the practical, no.

Problems that the Invention is to you'll solve

For although Li phospholipid-nucleoside derivatives as described above are synthesized by chemical synthesis, a multistage reaction process for its synthesis, essential city, thus the yield was also low addition step is also complicated. Also, there is only an example of a cytosine Narabinoshido as nucleoside residue component of Li phospholipids' nucleoside derivative for its ©, hence its effect on the antitumor agent is also the ultimately cytosine § Rabbi Bruno Sid (ara - C: 1 - beta-Arabino furanosyl cytosine) effects only without as, disadvantages such as toxicity associated with cytosine Rabinoshi de did not improve. Means for Solving the Problems

As a means for solving such drawbacks, but it should I use nucleoside compound other than shea 'Toshinara Pinoshido, to synthesize their phospholipid ♦ nucleoside derivatives chemically multistep synthesis step requires, reaction conditions also difficult to set, synthesis was substantially difficult. The present inventors have found that, to improve the synthesis having such a drawback, to synthesize a new re phospholipid-nucleoside derivative, and repeated studies in an attempt to obtain the known superior material than antitumor agents , by reacting the presence of a Guriserori phospholipids and nucleosides earlier phospholipase D, it found that the primary alcohol groups and Darisero re phospholipids nucleosides conveniently reacted to give the novel Li phospholipid-nucleoside derivative ( JP 6 1 - 2 3 6 7 9 7). The new Li phospholipid-nucleoside derivatives as described above, various drawbacks associated with conventional nucleoside anti-tumor agents is the improved Chikaraku, however, it is specifically disclosed in the above patent publication Una, 5 'have the same long chain Ashiru groups 1, 2 position of the glycerol part - phosphatidyl nucleosides, poor solubility in water, as a medicament as Note Ysaÿe still have undesirable disadvantages It was those who are. In the case of using as an injection, it was not sufficient even migration to lymph system.

The present inventors have found that in order to obtain a re phospholipids' nucleoside derivative having superior properties useful re Nba migration and water-soluble as an injection, the results of extensive seed s study, unexpectedly, glycerol 1 of the long 鎮飽 sum Ashiru residue parts, Li phospholipid-nucleoside derivative with a 2-position to the long 鎮不 saturated Ashiru residues, in which and intramuscular administration excellent water solubility, excellent limber migration have sex, we found that it is a useful as an injection of anti-tumor agents. The present invention has been completed based on the above findings, the following general formula (I)

Is an antitumor agent 5 Furuorourijin derivative or non-toxic salts of the active ingredients thereof in Rabbi - (wherein Shikichu, R,, R 2 is the same group indicating) the 5 'single phosphatidyl represented by. First, 5 of the present invention represented by the formula [I] '- The Guriserori phospholipids that are used to obtain the phosphatidyl over 5 Furuorourijin derivatives, for example, phosphatidyl Rukorin system represented by the following general formula [Π] glycerin opening phospholipids, and the like. CH2 one 0- Ri

ίπ - 0 - R2 [H]

0

, II

CH2 one 0- Ρ- 0 ~ R 3

10

(Wherein and R 2 represents a same group as the, R 3 DOO shows a trimethyl § emissions monitor O E methyl group) in phosphatidylcholine systems glycerin port phospholipid represented by the more general formula [Π] , groups are those showing a long 鎮飽 sum Ashiru group, for example, long-chain saturated Ashiru group having a carbon number of 1 6 to 1 8, the length 鎮飽 sum Ashiru group is palmitic toyl or stearoyl for example in detail < the R 2 is a long chain unsaturated Ashiru groups, such as unsaturated bonds in a carbon number of 1 6 to 2 0 is long chain Ashiru group with four 1, for example in detail, Oreoiru, Arakidonoiru, Reno Reoiru or long chain unsaturated Ashiru group which is one or r one Reno Renoiru is 举 up. Specifically, the Palmi toyl group, 1-R 2 is Ru indicated by Oreoiru radical 1 Barumi Tiru one 2-O Les oil phosphatidyl choline, R, but Palmi Tiru group, R 2 is represented by Reno Reoiru 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 Sutearoiru one 2- Reno Reoiruho scan choline represented by group, R, but Palmi toyl group, 1 one palmitic Toiru 2 § Lucky de Noi Le phosphine histidinol Rukori emissions which R z is indicated by Arakidonoi Le group, R, but stearoyl group, R 2 is Arakidonoiru group 1 - steer port Iru 2 § Lucky de Noi phosphatidylcholine, R, but Palmi Toys Group, R 2 is a Rino Renoiru radical 1 Palmi preparative Iru 2-o - linolenoyl I le phosphatidyl choline, R, but steer Royle group, 1 Sutearoiru 2 one or- linolenoyl R z is an Rinorenoiru group phosphatidylcholine with both saturated and unsaturated long Zhen Ashiru group such as I Le phosphatidylcholine. Phosphatidylcholine with Matako these of R, and R 2 groups may be those obtained by combining with the saturated and unsaturated fatty acids corresponding to Ashiru groups described above may be used commercially. As nucleosides used in the present invention is also 5-Furuorou lysine L 5- F luorouridine; 5- F luoro- 1 ~ β ~ Ό- τ ibofuranosyl - 2, 4 one (1 H, 3 H) - pyrimidinedione; less is referred to as FUR]. Further in obtaining the phospholipid 'nucleoside derivative represented by the general formula [I], the presence of said Guriserori phospholipids and FUR and the metal ion, and more obtained by reacting in a solvent with phospholipase D. Used as the Hosuhoriba one peptidase D, for example, scan Trebes Tomisesu belonging to the genus scan Torebutomisesu 'es' Bee · ΑΑ 5 8 6 (S treptomycessp - AA 5 8 6; FE RM P - 6 1 0 0) derived from Hosuhoripa Ichize D - P (JP 5 8 1 5 2 4 8 1 JP, Toyo Jozo Co. catalog No. P- 3 9) is preferred. The amount thereof is, phosphatidyl choline per mmol phosphonic Horipaze D 1 00~ 1 0 0, 000 units, preferably 5 0 0-1 0, 000 units. Still solvent used, for example acetic Echiru, Jechirue one ether, buffer of an organic solvent and PH. 3 to 1 0, such as non-professional tons solvent or the black hole Holm such as benzene, is rather preferably 1 0 0 mMC a Cl 2 1 0 0 mM acetate buffer舍有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 solvent and the like. The amount of click every mouth Holm used, to the phosphatidyl co Li down 1 Mi remote Le,. 1 to 1 0 0 ml, preferably from. 5 to 30 ml. As still yet water-soluble salts for the metal ions forming, usually calcium © beam chloride is used, other metal as the Ion Sho 5 8 - inhibiting 1 5 2 4 8 No. 1 activity described in Japanese those that do not are used. 1-1 0 0 equivalents relative FUR phosphatidyl choline to be used is preferably 5 to 20 equivalents. The reaction temperature is usually 1 0-7 0 hands, preferably at 2 0 to 5 0 'C, the reaction time is 3 0 minutes to 5 days, usually in thoroughly with 3 0 minutes to 5 hours is there. Such 'a nucleoside derivative 5' Li phospholipids obtained in the - phosphatidyl one 5- Furuorourijin is leaving in be conveniently purified by liquid method Contact and Shirikageruku port Ma Togurafi scratch. Stage floor step synthesis of Li phospholipids' nucleoside derivative of the present invention as described above is shown as follows.

+ / CH3 +,

0 CHa-C OH OH

CHa

Phospholipase one D

Thus 5 obtained '- phosphatidyl over 5 Furuorou lysine, a portion of the re-phospho groups of Li phospholipids, 5 F UR using' be those in which position part of the primary hydroxyl group of the bound the 5 '- Hosufachi Giroux 5 Furuorourijin derivatives can be also be made with non-toxic salts such as Na Toriumu salts, generally by addition of distilled water for injection is administered as a uniform transparent solution. The dosage per day, and an injection 1 5 to 3 OmgZ humans, the oral dosage Ru 30-2 00 Nohi Todea. Effect of the invention

The 5 'of the way the present invention obtained - phosphatidyl one 5- off Ruorourijin derivatives, long reservoir (hence activity persists in the body for fat-soluble is large compared with the FUR used as original starting material it becomes), Hosuhori Resho emissions, have difficulty receiving the inactivation of reduction such as increased affinity for biological membranes, 5 'single monophosphate of FUR without kinases involved is produced intracellularly, There are advantages such antitumor activity persists, enhanced and, moreover, has the advantage of such toxicity is low. Also, it has excellent especially color as Yo antitumor agents by conducting selective migration to the lymph system. Further it has the advantage of using as an injection that water-soluble is excellent. 5 of the present invention '- phosphatidyl over 5 Furuorourijin derivatives prominent antitumor effect in vivo (vivo) will be shown later is observed. Also, further, anti-metastatic effect of the tumor generated in a living body to inhibit the spread to other sites also observed. 5 'of the present invention - phosphine Achijiru 5 Furuorouri gin shown below the results of examining the anti-tumor activity and lymphotropic for M eth- A fibrous sarcoma (Me th- A fibrosarcoma) for derivatives. Animal Experiment 1 (anti-tumor activity)

Ingredients Animals>

BALBZc mouse, a male, was used to buy than the 6-week-old Japan Chiya one Rusuriba one company. One group of the number of mice control group - 7, was administered group = 5 mice.

<Use cells and inoculation method>

M eth- A fibrosarcoma cells 1 X 1 0 6 Z0. The 2 ml, were inoculated into BALB / c mice flank subcutaneously, immediately drug>

Table 1

Ingredients drug concentration and administration>

Each compound to a predetermined concentration, was dissolved in distilled water by sonication. Both compounds were administered 0. 1 ml per weight 1 0 g mouse continuously tumor cell inoculation 5 days from 24 hours after intraperitoneally.

<Determination method>

Tumor volume of each mouse, a short diameter and long diameter of a tumor after 1 4 days implantation was measured using a vernier caliper, were San岀 using the following equation.

Tumor volume (mm 3) = (short diameter (mm)) 2 X major axis (mm) / 2 determination, the untreated group of mean tumor volume (C) the mean tumor volume of the treated group (T) from T / C ( %) was determined.

Ingredients result, consideration>

National Cancer Institute (NC I) of the TZC 4 0% criteria antitumor effect against an antitumor agent response criteria to 瘍 tumor reference, M eth- A fiber T Bruno C 4 0% or less for sarcomas There is an anti-tumor effect for the case of, it is determined that the. Table 1, the compounds of the present invention from the results shown in Table 2

(Compound 1-5) was significantly inhibited with both TZC 4 0% less growth of M eth- A line 維肉 tumors by the administration of more than 1 Omg / kg. Especially of compounds 1-4 in the administration of 3 Omg Roh kg showed TZC 9, 5- 1 5. 5 and the large variations stronger antitumor effect.

Table 2

M eth- A quantity antitumor effect compound administration on fibrosarcoma total dose T / C () 1 4 Day

(1) 1 0 5 0 2 6.5 *

3 0 1 5 0 9.5 *

(2) 1 0 5 0 3 1.8 *

3 0 1 5 0 1 5.5 *

(3) 1 0 5 0 2 2.6 *

3 0 1 5 0 1 1. 4 *

(4) 1 0 5 0 3 3.4 *

3 0 1 5 0 1 3.5 *

(5) 1 0 5 0 2 8.9 *

3 0 1 5 0 2 6.1 氺

N = 5

Significance was calculated using S tudent 'st one test, * P <0. 0 1 Animal experiment 2 (migration of the drug to rats intramuscularly in lymph fluid when administered and blood) ingredients experiments materials and methods> -

1. Using animal

Rats were used in Japan Esuerushi W were purchased from one (Ltd.) istar male rats (1 0-1 1-week-old).

2. compound

Shown in Table 1 (2), (4) and using the compound (5), as is or control compound 1, 2-di-saturated Ashiru type compound 5 '- (1, 2- Jisutearoiru sn- glycerin opening one 3-phospho) using an 5-Furuorouri gin.

3. The dosage and method of administration

This animal experiment, all were carried out in a non-fasting. After the addition of distilled water to give a homogeneous clear liquid for each compound, they were administered intramuscularly at a dose of 3 OmgZmlZkg in rats (body weight 2 60 to 270 g). Also after the rats are anesthetized awakening which has been subjected to cannulation one Reshiyo on to the thoracic duct limber, it was given investment in the same manner as described above.

4. collection of blood -

After the test drug administration, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, blood was collected from the rat jugular vein using a syringe which is valine process to 2 4 hours. The blood was immediately added EDTA (final concentration 1 O mM), 3, 0 00 rpm, 1 0 minutes, after centrifugation at 4 hands, resulting plasma was used as a sample. 5. collection of Li Nba solution

B 0 conforming to the 1 1 man's method 1>. That laparotomy in the rat Nenbu tar anesthesia (p 3 5 m g / kg , in), the Bruno re down process catheter into the thoracic duct limber to force two Jure one sucrose down, 0 after test drug administration 1, 1-2, 2-3, 3-4, 4-5, 5-6, was collected limber solution at intervals of 6-2 4 hours.

° B ollman, JL, C ain, JC and G rindlay, JHJ L a b. C li n. M e d. 3 3, 1 3 4 9~ 1 3 5 2, 1 9 4 8.

6. pre-treatment of the sample

Plasma and limber solution 1 0 0/1 methanol 5 0 0 mu \ and the mixture was shaken to remove proteins vibration, centrifugation (3, 0 0 0 rpm, 1 0 minutes, 4 Te) was. This operation was performed twice, was solidified and the supernatant concentrated to dryness. This HPLC mobile phase (1 5 mM KH 2 P 0 4 (p H 6. 5) / M e OH; 1 0 Bruno 9 0) was dissolved in I 0 0 mu \, compound (2), (4), (5) it was and contrast of the sample solution.

7. quantification by HPLC

The apparatus Shimadzu HPLC system (pump: LC- 9 A, the ultraviolet part variable wavelength detector: SPD 6 A, the data processing device: CR- 4 AX, detection wavelength 2 7 onm) used, the amount folding column YM CC 8 a ty P e (Yamamura chemical, 4. 6 X 1 5 0 Jour, 5 ^ m) was used. Mobile phase 1 5 mM K Hz P O4 (PH 6. 5) / M e OH; and 1 0/9 0, was quantified with a flow rate of 1. 5 ml Bruno min. Ingredients result>

1. plasma Φ concentration changes over time

Each compound was administered intramuscularly at a dose of 3 OmgZkg in rats (3 rats), it was measured over time in plasma concentration of the compound. Table 3 shows the mean and standard deviation of the plasma concentration (gZml).

Table 3 at the time

Compound

Things 0.5 24 Control 0.17 0.26 0.41 0.54 0.42 0.41

Sat 0.16 ± 0.01 ± 0.16 ± 0.10 ± 0.17 ± 0.13

(2) 0.79 0.74 0.69 0.78 1.09 0.21

Sat 0.43 ± 0.20 ± 0.31 mechanic 0.12 ± 0.13 ± 0.30

(4) 0.40 0.63 0.90 1.04 1.45 0.26

Sat 0.16 ± 0.23 ± 0.13 ± 0.11 ± 0.08 ± 0.10

(5) 0.65 0.74 1.11 1.05 1.21 0.61

Sat 0.25 ± 0.11 ± 0.21 ± 0.045 ± 0.17 ± 0.21

(Μ g / ml, M ean soil SD)

2. limber solution concentration changes over time

Each compound was administered intramuscularly at a dose of 3 OmgZkg in rats (3 rats) subjected to forces nu one, single Deployment in Munekan lymph was measured over time limber solution concentration of compound. Table 4 shows the mean density and the standard deviation (/ g Bruno ml).

Table 4

+1 +1 ^

i

Time between the compounds

Things 0 1 1 2 2 3 3 4 4 5 5 ο 6 24

Contrast 0.38 1.91 2.47 1.86

± 0.28 Sat 0.68 ± 0.93 ± 0.62

(2) 12.19 15.20 18.36 16.76 9.79 3.08

± 10.53 ± 10.49 Sat 8.83 ± 12.68 Sat 5.69 ± 1.97

(4) 10.36 12.91 16.10 17.21 16.38

Sat 1.57 mechanic 0.81 Sat 4.16 Sat 4.24 Sat 5.92

^ Bok -

(5) 10.57 9.12 7.58 6.14 4.84 2.89

Sat 3.73 ± 3.06 Sat 2.21 Sat 1.09 ± 0.84 ± 0 · 95

(Μ g / ml, M ean earth SD) by the above experimental results, the compound (2) (4) and (5) to exhibit high limber directivity by intramuscular administration compared to paired irradiation compound was observed. Example

Described in detail by way of Examples of the present invention are shown below, but the present invention is not limited to these.

Example 1

5-Furuorourijin (FUR) 5. 2 4 g (2 0 Mi Rimoru) and phospholipase D- P (. Scan Torebuto Mrs. derived from the genus, Toyo Jozo Co., Ltd.) 2 Omg: a (specific activity 1 Ί 4 unit Roh mg) 1 0 0 mM calcium chloride Complex Yes 1 0 0 mM acetate buffer (PH 5. 7) was dissolved in 1 0 ml, various phosphatidyl choline 1 m M a 2 0 ml black port Hol arm shown in the fifth Omotehara fee column after addition of a solution at 4 CTC, and stirred for 4 hours.

The reaction solution was refluxed for 5 minutes, the reaction was cooled (ice). Black hole Holm to this reaction solution, to recover the organic layer (lower layer) and the addition of methanol each 1 OML separated. Water 1 0 ml to the organic layer, add methanol 1 0 ml was separated, was the lower layer to dryness under reduced pressure. And melt-residue in a small amount of black port Holm, silica force gel flash column charged to (M ERCK Inc., silica gel A rt 9 3 8 5, diameter 2. 5 cmX 1 6 cm), click D port Hol beam ( from 2 0 0 ml), black hole Holm: methano Ichiru mixture (5 0 0 ml) (1 5: 1), the (5 0 0 ml) (5: 1), the (5 0 0ml) (3: developed eluted with order of 2): 1), the (5 0 0 ml) (5.

The desired product was evaporated under reduced pressure eluate Complex free fractions, the residue chloroform: methanol Ichiru mixture (2: 1) was dissolved in (6 0ml), 0. 5 NH C1 8ml was added for liquid separation after went water 8 ml, to liquid separation by adding methanol 8 ml 2 times the organic layer. Separated into an organic layer and 3 ml of water and the methanolate Ichiru 1 5 ml was added, through a column of Diaion (D iaion) WK- 2 0 tree butter (N a + -type) (2. 5 X 3cm), and eluted the solvent was distilled under reduced pressure. Residue, acetone was added, after ice cooling, was filtered off precipitated sediment resulting, to give the desired compound [I] as Natoriumu salt. The yield of the obtained compound, the physical properties are shown in Table 5. ¾ a 锌

s illustrates these fifth (6) to the table (8) compounds are also (1) to (5) of the compound as well as excellent anti-tumor activity. Reference Example 1 -

1- Palmi Tiru 2- one linolenoyl Iru sn- glyceryl opening one 3

- synthesis of Hosuhoko Li down

- dissolved Reno Ren acid 4 5 7 mg of (1.6, 4 mm Rimoru) to black port Holm 1 OML, chloride Chioniru 1 OML added, under an argon atmosphere at room temperature and stirred for 3 hours. The solvent was evaporated under reduced pressure, dissolved by adding a black hole Holm 1 OML to the residue, 1-palmitic toyl one sn- glyceryl port one 3- Ho Suhoko Li down 8 1 5 mg (1. 6 4 Mi Rimoru) and N , N- dimethylaminopyridine Roh Pyridine 6 0 Omg a (4.9 2 Mi Rimoru) was added, under argon, was 攬拌 overnight at room temperature.

The solvent was evaporated under reduced pressure, the residue black port Holm: methanol (2: 1) was dissolved in 3 5 ml, was separated with 1 NH C1 7 ml, further organic layer (lower layer) was washed with water two surfaces, vacuum drying It was solidified. The residue was purified by silica gel flash force ram (A rt 9 3 8 5 silica force gel, 3 X 1 5 cm, chloroform → click every mouth Holm: methanol Ichiru = 2 0: 1, 1 5 0 ml → the 1 0: 1, 1 5 0 ml → the 5: 2, 1: 1) to give the desired product 4 8 Omg. Yield 3 8%

R f values ​​(Merck A rt 5 7 1 5 plate, black hole Holm: methanol

- le: water = 6 5: 2 5: 3) = 0.2 1

FAB- MS (positive), m Roh e 7 5 6 (MH +) Reference Example 2

1 - Sutearo Iru 2- one linolenoyl Iru sn- glycero-3 - Hosuhokori down 1 one palmitic toyl in Reference Example 1 - sn- glyceryl port - 1 instead of 3-phosphocholine Sutearoiru one sn- glyceryl opening one using 3-phosphocholine 8 6 1 mg (1. 6 4 Mi Rimoru), using the same method as in above to give a 3 6 2 mg desired product. Yield 2 7%

R f value = 0.2 3

F AB-MS (positive), m / e 7 8 4 (MH +)

Claims

The scope of the claims
1.5 represented by the following formula '- phosphatidyl one 5 Furuorouriji down derivative or its non-toxic salts.
(However Shikichu, R, represents a long-chain saturated Ashiru group, R z is the length鎮不saturated Ashiru group)
2. radicals R, but long chain saturated Ashiru group having 1 6 to 1 8 carbon atoms, 5 radicals R 2 are claims claim 1 wherein a long-chain unsaturated Ashiru group having 1 6 to 2 0 carbon ' - phosphatidyl one 5- Furuorourijin derivative or its non-toxic salts.
3. groups Palmi toyl group, 5 groups R z is claimed claim 1, wherein a Oreoiru group '- phosphatidyl over 5 Furuoro lysine derivative conductor or a non-toxic salts.
4. group Ri is Palmi toyl group, 5 groups R z is claimed claim 1, wherein in Reno Reoiru group '- phosphatidyl over 5 Furuo "Urijin derivative or its non-toxic salts.
5. group R, but 5 'of the stearoyl group, group R 2 is wherein claim 1, wherein a Oreoiru group - phosphatidyl one 5- Furuorouri Jin derivative conductor or a non-toxic salts.
6. group R 1 is steer port I group, 5 of the radical R 2 is wherein claim 1, wherein a Reno Reoiru group '- phosphatidyl - 5 Furuorouri derivative or its non-toxic salts.
7. group Palmi toyl group, 5 of the radical R 2 is wherein the first term range billed a Arakidonoiru group '- phosphatidyl over 5 Furuorouriji down derivative or its non-toxic salts.
8. group R, but Palmi Tiru group, 5 'single phosphatidyl range described first of claims radical R 2 is α- Reno Renoiru group - 5 Furuorouri derivative or its non-toxic salts.
9. group R, but 5 'of the stearoyl group, group R 2 is wherein the first term range billed a Arakidonoiru group - phosphatidyl over 5 Furuorouriji down derivative or its non-toxic salts.
1 0. groups R, but stearoyl group, 5 'as set forth in claim 1, wherein claims radical R 2 is Ru or- Reno Renoiru group Der - phosphatidyl over 5 Furuorou lysine derivative or its non-toxic salts.
1 1.5 represented by the following formula '- phosphatidyl over 5 Furuorouri derivative or other anti-tumor 塲剤 as an active ingredient a non-toxic salt thereof,
(However Shikichu, R, represents a long-chain saturated Ashiru group, R 2 is a long chain unsaturated Ashiru group)
1 2. group R, but loading range first 1 Kouki according long鎮飽sum Ashiru group, the group R 2 is a long鎮不saturated Ashiru group having a carbon number of 1 6 to 2 0 of 1 6 to 1 8 carbon atoms antitumor agent comprising as an active ingredient toxic salts of phosphatidyl one 5- Furuorourijin derivative or its - 5 '.
1 3. radicals R, but Barumi toyl group, 5 of the radical R 2 is described first 1 wherein according a Oreoiru group '- anti-tumor and phosphatidyl over 5 Furuorouriji down derivative or active ingredient a non-toxic salt thereof agent.
1 4. group R, but 5 'of Palmi toyl group, group R 2 is billed ranging first 1 wherein a Reno Reoiru group - and phosphatidyl over 5 Furuorouri derivative or active ingredient a non-toxic salt thereof anti-tumor 塲剤.
1 5. group is stearoyl group, 5 of the radical R 2 is described first 1 wherein according a Oreoiru group '- phosphatidyl over 5 Furuorouriji down derivative or antitumor agent comprising as an active ingredient a non-toxic salt thereof.
1 6. group is stearoyl group, 5 of the radical R 2 is billed ranging first 1 wherein a Reno Reoiru group '- phosphatidyl - 5 Furuorouri derivative or antitumor agent comprising as an active ingredient a non-toxic salt thereof .
1 7. group R, but Palmi toyl group, 5 in the range first 1 claim of claim is a group R 2 is Araki Donoiru group '- phosphatidyl - and 5 _ Furuorou lysine derivative or active ingredient a non-toxic salt anti tumor agent.
1 8. group R, but Palmi toyl group, group R 2 is or- Reno Renoiru 5 groups der Ru Claims first 1 wherein '- phosphatidyl - 5 Furuoro Urijin derivative or active ingredient a non-toxic salt thereof an antitumor agent.
1 9. group is stearoyl group, 5 of the radical R 2 is Araki Donoiru a is described first 1 wherein according radicals' - phosphatidyl - 5 Furuorou lysine derivative or antitumor agent comprising as an active ingredient a non-toxic salt thereof.
2 0. groups R, but stearoyl group, 5 of the radical R 2 is one Reno Renoiru groups der Ru Claims first 1 wherein '- and 5-Furuoro Urijin derivative or active ingredient a non-toxic salts - phosphatidyl anti-tumor agents.
PCT/JP1991/001744 1991-04-04 1991-12-20 5'-phosphatidyl-5-fluorouridine derivative WO1992017487A1 (en)

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JP3/99579 1991-04-04
JP9957991 1991-04-04
JP3/190790 1991-07-04
JP19079091A JPH04364198A (en) 1991-04-04 1991-07-04 5'-phosphatidyl-5-fluorouridine derivative

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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)

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