JPS60152419A - Antitumor agent - Google Patents

Abstract

PURPOSE:An antitumor agent showing a high level of antitumor effect with a small amount used, extremely high remedy index, and improved sustained release ability in organism, containing a 5-fluoro-2'-deoxyuridine derivative as an active ingredient. CONSTITUTION:An antitumor agent containing 0.1-180mg, preferably 0.2-80mg (dosage form such as tablet, capsule, injection, etc.) compound shown by the formula (R1 and R2 are 10-15C aliphatic acyl). In medication, it is administered orally (e.g., tablet, pill, etc.), or parenterally (hypodermic, intravenous, endermic, or rectal administration). A dose is 0.005-9mg/kg/day, preferably 0.01-4mg/kg/ day. When the compounds shown by the formula as an active ingredient are used, two or more of the compounds are properly selected and can be administered together.

Description

DETAILED DESCRIPTION OF THE INVENTION Technical Field The present invention relates to anti-tumor agents. The object of the present invention is to provide an antitumor agent that exhibits a significantly higher sustained release performance of 5-fluoroq-2'-thioxyuridine in vivo.

Prior Art 5-Fluoro-2'-thioxyuridine is a compound known to have side muscle activity as one of the metabolites of 5-fluorouracil. Its anticancer activity is i
The growth inhibitory activity of established mouse-derived cell lines of nvjtro was more than 100 times that of 5-fluorouracil at the same molar concentration, and 10-100 times more than that of 5-fluorouridine, which is also a metabolite of 5-fluor-17 uracil. It is reported that [CancerResearch+
Cancer+35, ] 121 (1975)
;Proc, Amer, Aso, Cancer Re5
search+ 71 (1976); Cancer Re
5earch, 18.730 (195B)).

However, 7'c in vjvo using tumor-bearing animals
In this experiment, the effect of 5-fluoro-2'-thioxyuridine was not sufficient, contrary to the in vitro results.
It has been reported that its anticancer effect is inferior to that of 5-fluorouracil and 5-fluorouridine (Ca
ncerResearch+19+494 (1959
) + Proe, Soc, Exp, Biol, N, Y
, +97 H470 (1958); Proc, soc
, Exp, Biol, +N, Y, , 104 , 12
7 (1960); Ann, N. Y., Acad.

Sci, +76. 575 (1958)).

The reason for this is that the anticancer effect of 5-fluoro-2'-thioxyuridine largely depends on the contact time between 5-fluoro-2'-thioxyuridine and lung cancer cells.
It is thought that the half-life of 5-fluoro-2'-deoxyuridine administered in vivo is extremely short and is due to insufficient contact time with cancer cells (Canc.
erRe5earch+32.1045(1972)
;C11n, Pharmacol, thef, + mutual,
581 (1964); Cancer Research
+ 38, 3479 (1978); Bull
, Cancer (Paris) + 66, 67 (s
979); Bull, Cancer (Paris)
+66.75 (1979); Europ, J, Canc.
er+ 16, log 7 (1980)).

In order to improve these drawbacks, various 5-fluoro-2'-deoxyuridine derivatives have been studied to date. For example, 3-7silu-5-fluoro-2'-
Deoxyuridine (q# Kaisho 54-163586)? 3rd place and 31st place. r, 5 with acylated both first and second positions
-Fluoro-2'-deoxyuridine (%Kasho 56-1
13795.56-113796. -56-11379
Publication No. 7), etc. are known. However, even in these derivatives, the antitumor effect and the safety factor are not sufficiently improved.

For 3',5'-diacyl-5-fluoro I:I-2'-deoxyuridines, BiochemicalPha
rmacoloshagy, 14, 1605 (196
5) K has been shown to have antitumor activity, but according to the above report, all 3F +' s+ -diacyl-5-fluoro-2'-thioxyuridines have antitumor activity. We have only attempted to measure the activity in the range of 10 to 4 OW/7 days, in which fluoro-2'-deoxyuridine exhibits an antitumor effect, and found that the activity was significantly higher than that of 5-fluoro-22-thioxyuridine. It has not yet been found that it has a standard antitumor effect and a commercial therapeutic coefficient.

Also, 31, s/-dihexanoyl-5-fluoro-21-deoxyuridine 31, 51-dipalmitoyl-5-fluoro-2'-deoxyuridine 31
,5/,,-dibenzoyl-5-fluoro-2'-deoxyuridine:/,3',5'-ditoluoyl-5-sulo1-ff-2'-deoxyuridine.

31,5F-dichlorobenzoyl-5-fluoro-
2'-Deoxyuri'lysine is disclosed in Japanese Patent Application Laid-Open No. 58-4931.
In Publication No. 5, "5-fluoro-2'-deoxy'/, :')
Anti-1i11 at a lower dose than lysine! Although it has been shown to have tumor activity, 5-fluoro-
This shows an improvement of only 2 to 3 times compared to 2'-deoxyuridine trap. In order to obtain a derivative of 5-fluoro-2'-deoxyuridine that exhibits high antitumor activity by releasing '-thioxyuridine and has few side effects, the 3' As a result of intensive searches for mask-type compounds in which the 5' site was esterified with various groups, we found that compounds esterified with an aliphatic acyl group having 10 to 15 carbon atoms showed the same level of antitumor effect at low doses. Not only that, but its therapeutic index is extremely large, with 5-
The inventors discovered the surprising fact that fluoro-2'-thioxyuridine has excellent sustained-release performance and completed the present invention.

Therefore, an object of the present invention is to provide an excellent anti-neoplastic agent that exhibits a high level of anti-tumor effect at a low dose and has a significantly large therapeutic index.

Structure and Effects of the Invention The present invention provides a 5-fluoro-2'-deoxyuridine derivative represented by the general formula CI).

Specific examples of the compounds of the present invention include, for example, 3', 5
'-ndecanoyl-5-fluoro-2'-thioxyuridine, 3r, s/-dilauroyl-5-fluoro-
2'-deoxyuridine.

3', 5'-cimyristoyl-5-fluoro-2'
- Thioxyuridine, etc.

Compounds of the invention may be used, for example, in Biochemical P
hermacology +14 +1605 (196
As shown in 5), all can be synthesized by known methods. That is, for example, 5-fluoro-2'
It can be synthesized by a conventional method in which -deoxyuridine and the corresponding acid halide or acid anhydride are reacted in the presence of an organic base such as pyridine or trialkylamine.

According to the present invention, the antitumor effect of the compound represented by general formula (1) was investigated by examining the survival effect of 5-fluoro-2' mice transplanted with murine leukemia cells L1210.
- Thioxyuridine showed a strong survival effect at an extremely low dose of 1/10 to 130 times the dose at which it exhibits an antitumor effect, and the therapeutic index was also found to be 5 to 22 times higher. In addition, the compound represented by the general formula CI) can be prepared in an fc in vitro system using pig liver esterase, etc.
The enzymatic reaction has been shown to gradually release 5-fluoro-2'-deoxyuridine, and the in-vivo half-life is extremely important. For example, the 3′ of the present invention,
5'-dilauroyl-5-fluoro-p-2'-deoxyuridine was administered at a dose (
ILS,. ) shows the same life-prolonging effect as 5-fluor-2'
- Approximately 1/130 of deoxyuridine (1,5 uno
1/kg/day), and the dose required to show the maximum survival effect (LSmax) is approximately 1/10 of that of 5-fluoro-2'-deoxyuridine (4
s μmol/kg/day). Furthermore, ILSm
aa/ILS. It is also highly safe, with a therapeutic index of 15 times that of the parent compound, 5-fluoro-2'-thioxyuridine.

Furthermore, in a hydrolysis experiment using an esterase, for example, the 3',5'-dibucamyl-5-fluoro-2'
-deoxyuridine and -31,5r-dilauroyl-5-fluoroq21-deoxyuridine are 3',
In comparison with 5'-dimxanoyl-5-fluoro-2'-thioxyuridine, the release rate of the parent compound 5-fluoro-2'-deoxyuridine through enzymatic reaction was 1/100 and 1/1000000, respectively. Extremely slow.

This means that by gradually releasing 5-fluoro-2'-deoxyuridine, which has an extremely short half-life in the body, 5-fluoro-2'-thioxyuridine is brought into contact with tumor cells over a long period of time. This supports the high antitumor efficacy of the compounds of the present invention.

The 5-fluoro-2'-thioxyuridine derivative of the present invention has an excellent antitumor effect as described in -F σ), and therefore, according to the present invention, the 5-fluoro-2'-thioxyuridine derivative represented by the general formula CI) has an excellent antitumor effect. An antitumor agent containing a 2'-deoxyuridine derivative as an active ingredient is provided.

The 5-fluoro-2'-deoxyuridine derivative of the present invention is administered orally or parenterally, such as subcutaneously, intramuscularly, intravenously, transdermally, or rectally. Among these, oral and intravenous administration are preferred. Dosage forms for oral administration include, for example, tablets, pills, granules, powders, liquid + rr&turbid formulations, and capsules.

For example, excipients such as lactose, starch, crystalline cellulose, hydroxybrobyl cellulose; carboxymethyl cellulose, fumethyl cellulose,
It can be molded by a conventional method using a binder such as polyvinylpyrrolidone or sodium alginate, or a disintegrant such as carboxymethylcellulose calcium phthalate. Pills, powders, and granules can also be formed by conventional methods using the above-mentioned excipients and the like.

The liquid 71 and suspension agent are formed by a conventional method using, for example, glycerin esters such as tricabrilin, triacetin, and trilaurin; vegetable oils such as coconut oil; and alcohols such as ethanol. Capsules are formed by filling heart gelatin capsules with granules, powders, etc., or by filling soft gelatin capsules with liquid preparations.

Dosage forms for subcutaneous, intramuscular, and intravenous administration include injections in the form of aqueous or nonaqueous solutions, 9-layer suspensions, and the like. Examples of non-aqueous solutions and suspensions used include propylene glycol, polyethylene glycol, olive oil, and ethyl oleate, to which preservatives, stabilizers, and the like may be added as necessary. Injectables are usually sterilized by appropriate treatments such as filtration through a bacteria-retaining filter and addition of a sterilizing agent.

Examples of dosage forms for transdermal administration include ointments.

Examples include creams, ointments are formed by conventional methods using fatty oils such as castor oil and olive oil, petrolatum, etc., and creams are made using fatty oils or diethylene glycol.

It is molded by a conventional method using an emulsifier such as sorbitan monofatty acid ester.

For rectal administration, gelatin soft capsules or suppositories using cocoa butter or the like are used.

The dosage of the 5-fluoro-2'-deoxyuridine derivative of the present invention depends on the age and sex of the patient.

Although it varies depending on the severity of the disease and the dosage form, it is usually o, o.
o s~9 da/day, preferably 0.01~4~/day
9/day.

The amount of 5-fluoro-2'-deoxyuridine derivative to be contained in the drug of the present invention is determined from this dosage. For example, in dosage forms such as tablets, capsules, and injections, it is usually 0.1 to 180Ii, preferably 0.2 to 801n.
It contains 9 5-fluoro-2'-deoxyuridine derivatives.

Two or more 5-fluoro-2'-deoxyuridine derivatives of Kippatsu '131 can be appropriately selected and administered in combination.

The present invention will be explained in more detail below with reference to Examples.

Practical luster example 1 Compound of the present invention 3/, 5/-didecanoyl-5-fluoro-2'-deoxyuridine, 3', 5'-
For dilauroyl-5-fluoro-2'-deoxyuridine and a/, S/-cimyristoyl-5-fluoro-2'-deoxyuridine, murine leukemia L1
The antitumor effect against 210 was compared to the parent compound 5-fluoro-
2'-thioxyuridine and 3',5'-dihexanoyl-5-fluoro-27-thioxyuridine, 31
, , r, 1-dipalmitoyl-5-fluoro I:I-
2'-deoxyuridine (JP 111j58-4931
7t compared to the compound described in No. 5 common axis).

Mouse leukemia L1210 ascites lung tumor cells 10 days after transplantation
' BDF mice (female 6 weeks + Ca24.9.1 group =
It was transplanted intraperitoneally into 5 mice) and used for experiments.

Starting 24 hours after the transplantation of the lung tumor, the drug was continuously administered intrathecally once a day for 5 days.

The antitumor effect of a drug is determined by comparing the survival period of the drug administration group with that of the control group (
It is expressed as an increase percentage compared to that of (no drug administration).

In other words, the drug dose required to extend survival time by 30 cm compared to the control group is defined as ILS, 0, and the maximum survival rate (Ma
y, the dose required to show ILS (H)) is I
Expressed as LSmax. Also, ILSmas, /
ILSS. The therapeutic coefficient was used as an indicator of the safety of the drug.

The results are shown in Table 1 and Figure 1.

As can be seen from Table 1 and FIG.
'-Deoxyuridine showed strong antitumor effects at doses as low as 1/10 to s/tao of 5-fluoro-2'-demexuridine, and also had a therapeutic index 22 times higher.

In addition, 3,5-repalmitoyl-5-fluoroP-2'-
The therapeutic index was also nine times higher than deoxyuridine.

Male side 2, compound of the invention 3', 5'-ditechanoyl 5-
fluoro-2'-deoxyuridine and a7. s'-
For dilauroyl-5-fluoroc+-2'-thioxyuridine, the release rate of the parent drug by # elementary hydrolysis was determined by 3/3 using esterase extracted from pig liver.
, 5/-nhexanoyl-5-fluorop-22-thioxyuridine and 3',5'-dioctanoyl-5-
It was compared with fluoro-2'-deoxyuridine.

The drug was dissolved in isotonic phosphate buffer (pH 7, OO) K at a concentration of 10 μm 17 II LI, and esterase (manufactured by Sigma) extracted from the liver at 37°C was added to an enzyme concentration of 0.0.
3 units/+ff/~1s o unHs/m#
After adding 5-fluor I:I-2'-thioxyuridine, 10μ7 of Sanflu was injected into an HPLC column over time to measure the amount of 5-fluor I:I-2'-thioxyuridine released by the enzymatic reaction.

At each enzyme concentration, the KIF' time (tl/2) for converting ]/2 amount of the added 5-fluoro-21-thioxyuridine derivative into the parent drug was shown as an index of the rate of hydrolysis by the enzyme. .

The results are shown in Table 2.

Table 2 Hydrolysis wF rate of 5-fluoro-2'-thioxyuridine derivatives by esterase As seen from Table 2, the compounds of the present invention have 3', 5'-
dihexanoyl-5-fluoro-2'-thioxyuridine and 3',5'-dioctanoyl-5-fluoro-
Compared to 2'-deoxyuridine, the rate of release of the parent drug through enzymatic reaction is 1/100 to 1/1,000,000
It is clear that 5-fluoro-2'-deoxyuridine is a light substance that gradually releases 5-fluoro-2'-deoxyuridine by the enzyme system in the body after administration to the body.

Example 3 Manufacture of tablets Compound of the present invention
- Laratoyac uridine → Lactose 50 Dacorn starch 40 Instant carboxydimethyl cellulose calcium 57 - Magnesium stearate 3 - Example 4 1# production of capsules Compound of the present invention 10110 1R', sl-cimilistoyl-5-fur Low 2'-
] Lactose 97 Da Crystal Cell P-S 50 ~ Magnesium Stearate 3 ~ Example 5 Production of Granules Compound of the Invention 5orp c 31. s L dilauroyl-5-7-7-ol-2
2-Thioquicouridine) Lactose 587■ Cornstarch 260~ Carboxymethylcellulose Calcium 1009 Magnesium Stearate 3~ Example 6 The compound of the present invention (3,5-cimyristoyl-5-fluoro-2'-thioxyuridine) was dissolved in an aqueous solution (pH 6) ,00
-7,50) dissolved in l- medium Ko, am9~! An injection containing 1 to 1 was obtained.

[Brief explanation of drawings]

Figure 1 shows 5-fluoro-2'-deoxyuridine derivatives (5-fluoro-2'-deoxyuridine 31 ,
5/-dipalmitoyl-5-fluoro-2'-deoxyuridine, 3',5'-dimxamethyl-5-fluoroI7-2'-deoxyuridine. 3F, 51-ditechanoyl-5-fluoro-2'-
Deoxyuridine 31 , 5/- dilau ρ yl 5-
Fluoro-2'-thioxyuridine 3/, 5/-
This figure shows the antitumor activity (change in ILS value compared to before administration) of cimyristoyl-5-fluoro-2'-deoxyuridine.

Claims (1)

[Claims] 1. An anti-11 compound characterized by containing a 5-fluoro-2'-deoxyuridine derivative represented by the following formula 812 CI) 0J, t, H as an active ingredient.
ili kalpa. 2 In the above formula [I], R,, R, is a decanoyl group. The antitumor agent according to claim 1, which is a lauroyl group or myristoyl group. 3 Claim 1 in oral or intravenous dosage form
The anti-IIIa tumor agent according to item 1 or 2. 4. The drug according to claim 3, which is a tablet, capsule or injection. 0.55-fluoro-2'-deoxyuridine derivative.
1 to 13 QIl+9) Anti-inflammatory agent according to claim 3 or 4.