JPS6236321A - Antitumor agent - Google Patents

Abstract

PURPOSE:To obtain an antitumor agent containing 5-fluoro-2'-deoxyuridine in a state resistant to decomosition and having improved utility, by adding an acylated derivative of a specific uracil to an acylated derivative of 5- fluoro-2'-deoxyuridine. CONSTITUTION:The objective agent contains, as active components, the compound of formula I (R<1> and R<2> are H or acyl provided that both groups are not H at the same time) and an acylated derivative of 1-[(2-hydroxyethoxy) methyl]-uracil of formula II (X is H, halogen, CH3, etc.; R<3> is acyl). Each compound includes novel substance. The molar ratio of the compound of formula I to formula II is preferably 1:(0.5-5). Although the compound of formula II has no antitumor activity, it inhibits the enzymatic decomposition of the compound of formula I in the body and improves the utility and the antitumor activity of the compound.

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to an anti-11IJ tumor agent rc. More specifically, the present invention provides an antitumor composition containing as active ingredients an acylated derivative of 5-fluoro-2'-deoxyuridine and an acylated derivative of 1-((2-hydroxyethoxy)methyl)-uranyl. Regarding drugs. Anti-M of the present invention
In IJI agents, the combined use of acylated derivatives of 1-((2-hydroxyethoxy)methyl]uracils prevents the decomposition of acylated derivatives of 5-fluoro-2'-deoxyuridine in vivo. L9 to do
．． The in vivo availability of 5-fluoro-2'-deoxyuridine is increased by mV, and it exhibits a high level of antitumor effect at low doses.

Prior Art 5-Fluoro-2'-deoxyuridine is a compound known to have anticancer activity as one of the metabolites of 5-fluorouracil. Its anticancer activity is in
In vitro, the growth inhibitory activity of established mouse-derived cell lines was more than 100 times that of 5-fluorouracil at the same molar concentration, and 10 times more than that of 5-fluorouracil, a metabolite of 5-y fluorouracil. -10
It is reported that 0x (Cancer Φ Research (Cancer Φ Research)
cer Res, L35s11201975); Cancer Res, ), 19,4
94 (1959)).

However, the table shows that in vitro studies using tumor-bearing animals
In the ivo experiment, the effect of 5-fluoro-2'-deoxyuridine was not sufficient, and contrary to the results of the 1nyi tro experiment, the anticancer effect of 5-fluoro, uracil, L, and 5-fluorouridine was not significant. [Cancer Res,
) slL494 (1959); Proceeding from the Society for Experimental Biology and Medicine (Proc.

Soc, Exp, Bjol, Med, :1,97,47
0 (1958); Proc, 8oc, E
XT), B%ol.

Med, ), 104.27 (1960);
Op the New York Academy of Op-Science (Ann, N. Y., Acad, Sci.), 76.
575 (1958)).

The reason for this is that 5-fluoro-2
'-Deoxyuridine is rapidly degraded by uridine phosphorylase or thymidine phosphorylase [Experimental Cell Research (Exp, C.
e 11 Res,).

8upp1.9, 462 (1963); Biochemical Pharmacology (Biochern, Pharm
ac, ), L 328 (1959)), and furthermore, 5-fluoro-2'-deoxyuridine has a short blood half-life after in vivo administration due to its physicochemical properties.
Insufficient contact time with ffl cells [Cancer Rea, 32° 1045 (1972); Clinical Pharmacology and Therabutius (C11n.

Pharmacol, Thpr, ) + 5,581 (19
64); :i-ovian Journal of Cancer (Europ.

J. Caucer), 16.1087 (1980)).

In order to improve these drawbacks, various 5-fluoro-27-dioxyuridine derivatives have been studied to date. For example, 3-a/-5-fluoro-2'-deoxyuridine (Japanese Unexamined Patent Publication No. 163586/1986),
5-fluoro-2'-deoxyuridine acylated at both the 3-position, 3/, and S7-position (JP-A-Sho SS-11)
3795, 56-113796, 56-113797), etc. are known. However, these derivatives do not sufficiently improve the enhancement of antitumor effects.

Regarding 3/, S/-diacyl-5-fluoro-2'-deoxyuridine acylated at the 3' and 5' positions [
Biochemical Fist Pharmacology
al Pharmacology), 14.1605
(1965)) showed that 5-5-
Anti-1 at lower doses than fluoro-2'-deoxyuridine
It has been shown to have an activity of 1.11 g.

However, 3',5'-diacyl-5-fluoro-2'-deoxyuridine has low water solubility, making it difficult to apply to conventional injection dosage forms; Phosphorylase and thymidine phosphorylase activity is significantly higher in the intestinal tract than in other organs? It is reported that its antitumor effect (ke) is low because most of it is degraded [Chem, Pharm.
, Bull, 33.1652 (1985)).

On the other hand, 1-((2-hydroxyethoxy)methyl]
It has been reported that uranides act as inhibitors of uridine phosphorylase in B'Ji, yJjiluU cells and the side sill compartment of mouse liver [Biochemical.
Pharmacology (Biochem, Pharmac
, )+30+2097 (1981): 1b1d.

31.1857 (1982)).

Therefore, 1-((2-hydroxyethoxy)methyl)
It is conceivable that the anti-inflammatory properties of 5-fluoro-2'-deoxyuridine may be enhanced by the combination of uracils and 5-fluoro2/-deoxyuridine; The in vivo behavior of each drug may differ, making it difficult to obtain a combined effect.

<Problems to be solved by the invention> If 5-fluoro-2-deoxyuridine can be completely improved in its in vivo behavior and administered in a form that can prevent its decomposition by uridine phosphorylase or thymidine phosphorylase in vivo, it will be an excellent anti-inflammatory drug. Expected to be effective against tumors. However, it has been difficult to develop such compounds and dosage forms using conventional techniques.

Means for Solving Problems〉 The present inventors have discovered that the in vivo behavior of 5-fluoro-2'-deoxyuridine is improved at the 3' position and/or at the t-j 5' position.
The in vivo behavior of both the acylated derivatives of 5-fluoro-2'-deoxyuridine and the acylated derivatives of 1-((2/'% idroxyethoxy)methyl]-uracils is almost the same, and therefore 5-fluoro-2'-deoxyuridine Acylated derivatives of and 1-[(
The in vivo behavior of 5-fluoro-2'-deoxyuridine is improved by blending it with acylated derivatives of 2-hedrooxoethquine)methyl]-uracils, and furthermore, the in vivo behavior of 5-fluoro-2'-deoxyuridine is improved. The present inventors have discovered that it is possible to obtain an antitumor agent that is protected from degradation by phosphorylase, leading to the completion of the present invention.

That is, the present invention provides an acylation of 5-fluoro-27-zooxyuIJdine represented by the general formula
An anti-II! II tumor agent characterized by containing as an active ingredient at least one acylated derivative of 1-((2-hydrookyneethoxy7)methyl) disyl group represented by [1] as an active ingredient. It is.

According to the present invention, an acylated derivative of 5-fluoro-2'-thioquicouridine represented by the general formula (1) and 1-((2-hydrookyneethquine)methyl) represented by the general formula (II)] When 7-mylated derivatives of uracils are administered simultaneously to living organisms, their in vivo behavior is almost the same, and
The rates at which 5-fluoro-2'-deoxyuridine and 1-φ [(28hydrooxyethoxy)methyl]uracils are released by in vivo enzymes are also approximately the same.

Therefore, when both are administered simultaneously, 1-(
(,2-hydroxyethoxy)methyl]uracils do not have antitumor activity by themselves, but they strongly inhibit the activity of uridine phosphorylase or thymidine phosphorylase, which exists in the body, resulting in the release of 5-fluoride. It inhibits the degradation of -2'-deoxyuridine, increases its utilization and enhances its antitumor activity.

-ffi In the acylated derivative of 5-fluoro-2'-thioquicouridine of formula (1), R1 and Hm represent the same or different silium hydrogen atoms or acyl groups (provided that
R1 and R* are not hydrogen atoms at the same time. Butyryl is an acyl group.

Preferred examples include aliphatic acyl groups having 4 to 24 carbon atoms such as hexanoyl, tetradecanoyl, hexadecanoyl, 6 or 7 carbon atoms such as benzoyl and toluoyl, and those having an oral dosage form.

In the acylated derivatives of 1-((2-hydroxyethoxy)methyl]-u2-sils of general formula (II),
X represents a hydrogen atom, a halogen atom, a methyl group, a benzyl group or a vinyl group. Preferred examples of the halogen atom include a fluorine atom, an iodine atom, a chlorine atom, and a bromine atom. Hs represents an acyl group, and such acyl groups include acetyl and heΦnanoyl. octanoyl,
Octadecanoyl.

Preferred examples include aliphatic acyl groups having 2 to 24 carbon atoms such as decanoyl, arachitonoyl, and docosanoyl, and 7 carbon atoms such as benzoyl and toluoyl.

The acylated derivative of 5-fluoro-2'-deoxyuridine represented by the general formula [1] is a known or new compound, and these compounds can be used in a known manner [Bioch*m1cal Pharm
aeology Li2, 1605 (1965”)
Manufactured in accordance with or in accordance with.

That is, for example, it can be produced by reacting 5-fluoro-2'-deoxyuridine with the corresponding acid halide or acid anhydride of a carboxylic acid in the presence of a base such as trimethylamine or pyridine.

The acylated derivatives of 1=((2hydroxyethoxy)methyl)uracils represented by the general formula (fl) are known or new compounds, and these can be prepared by known methods [Journal Φ of Fist of Medicinal Chemistry ( J
.

Med, Chem, ) 24, 753 (1981)).

That is, for example, the following formula [■'] [X is the same as the above definition. ] The so-called Hilbert-Johnson <8% 1 ber reaction in which the 5-substituted uracil represented by the formula and 2-acyloxyethoxymethyl chloride are reacted in the presence of hexamethyldisilazane and trimethylsilyl chloride.
It can be produced by a modified method of the reaction of T-Johnson).

5-fluoro-27 of general formula [1] used in the present invention
Specific examples of acylated derivatives of -deoxyuridine include the following:
Fluoro-2'-deoxyuridine +31 3',5'-tatetradecanoyl-5-fluoro-27-deoxyuridine (413',5'-dimxadecanoyl-5-fluoro-2'-deoxyuridine (513 '-dodecanoyl-5'-toluoyl-5-fluoro-2'-deoxyuridine + 61 3', 5'-cytodecanoyl-5-fluoro-2'-deoxyuridine + 71 3', 5'-dibenzoyl-5-fluoro-2
7-Deoxyuridine Specific examples of the derivatives of 1-((2-hydroxyethquin)methyl)uracil of general formula (II) used in the present invention include the following 〇(811-((2 −(octanoyloxy)ethoxy]
Methyl]-5-methyluracil+91 1-C(2-
(octadecanoyloxy)ethoxy]methyl]-5-
Methyluracil Ql 1- ((2-(hexadecanoyloxy)ethoxy)methyl]-5-iodouracil tJυ 1-[:(2-(hexadecanoyloxy)ethoxy]methyl]-5-benzyluracil <12 1- ((2-(acetyloxy)ethoxy)
Methylcou-5-vinyluracil (1311-((2-1benzoyloxy)ethoxy)
Methyl]-5-methyluracil In the antitumor agent of the present invention, 5-methyluracil represented by the general formula (Ii)
- Preferred specific examples of combinations of acylated derivatives of fluoro-2'-deoxyuridine and acylated derivatives of 1-C(2-hydroxyethoxy)methyl]uracils represented by general formula [11] are as follows. There are things that can be mentioned.

(a) 3′,5′-ditetradecanoyl-5-fluoro-2′-deoxyuridine 1-((2-
(octadecanoyloxy)ethoxy]methyl]-5-
Methyluracil Φ) 3',5'-cytodecanoyl-5-fluoro-2'
-Deoxyuridine and 1-([2-(hexadecanoyloxy\)ethoxy]methyl]-5-methyluracil (c) 3'+5'-ndecanoyl-5-2fluoro-27
-deoxyuridine and 1-((2-(dodecanoyloquino)ethquine)ethquine]methyl]-5-bromouracil In the anti-Mi agent of the present invention, 5-fluoro-2'- The ratio of the acylated derivative of deoxyuridine and the acylated derivative of 1-((2-hydroxyethoxy)methyl)uracil represented by the general formula [11] varies depending on the type of compound selected, so it cannot be generalized. However, it is generally preferable to use 0.1 to 20 moles of the latter per 1 mole of the former.

Preferably it is 0.5 to 5 mol.

In the present invention, 5-fluoro-2 represented by general formula (1)
Acylated derivative of '-deoxyuridine and general formula 1:1
It is preferable that both of the 1-((2-hydroxyethoxy)methyl]uracil acylated!li! conductor represented by 1) be blended in advance and administered by containing them in the first preparation.

In the present invention, the acylated derivative of 5-fluoro-2'-deoxyuridine represented by the general formula [■] and the general formula C
1-((2-hydroxyethoxy) represented by U]
The following embodiment is also included in the present invention, in which the acylated derivatives of methyl]uracils are contained in separate preparations, and these preparations are considered as one set.

The dosage forms of the antitumor agent of the present invention include, for example, tablets, capsules, granules, pills, and powders.

Examples include oral preparations such as liquid preparations, aqueous injection preparations, non-aqueous injection preparations, non-light administration preparations such as bandages, and transdermal preparations. Among these, oral preparations and tablets are preferred; these preparations contain conventional carriers and excipients.

5-fluoro-2'-deoxy to be incorporated into the dosage form of the antitumor agent according to the present invention, which can be manufactured according to conventional methods using adjuvants, binders, lubricants, disintegrants, etc. Although the amount of the uridine acylated derivative varies depending on the species of the derivative and cannot be particularly limited, the clinical dose is generally 5 to 50 q/kg per day, more preferably 1.0 to 10 ff1g/kg. I'll go. 1-
The th of the acylated derivatives of ((2-hydroxyethoxy)methyl]uracils is determined from the above blending ratio.

<Effects of the Invention> The thus obtained acylated derivative of 5-fluoro-2'-thioxyuridine and the phosphorylase inhibitor 1-
The anti-W!! tumor agent containing acylated derivatives of ((2-hydroxyethoxy)methyl) uracils as all active ingredients exhibits high antitumor properties, such as liver cancer, gallbladder cancer, and curvature cancer.

It is used as a drug that exhibits superior pharmacological effects on lung cancer, esophageal cancer, colon cancer, stomach cancer, and skin cancer.

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

Test Example 1 Reversed phase high performance liquid chromatography of the compound of the present invention (Llchrosorb RP-18 column)
The retention time in K was measured in a 2 s solvent system.゛Retention times of compounds and solvent-based compounds are shown in Table 1 〇 Table 1 Waiting time [Column: Licrosolp RP-I R4, OX 130
aa+ Flow rate 1.2ml/min] From Table 1
For example, 3',5'-cytodecanoyl-5-fluorouridine (one of the compounds represented by general formula (1)) 61-(
(2-(hexadecanoyl oxine)ethoxy/]methyl)
Since the retention time is almost the same as that of the compound (one of the two compounds), it is thought that the fat solubility of these two compounds is also the same, and that the in vivo behavior based on the fat solubility of the compounds is also similar.

Test Example 2 Measurement of hydrophilicity of the body Normal phase high performance liquid chromatography of the compound of the present invention (Nucleo-7k (NucleolIil) 5CN column) K
The retention time was measured.

The compounds, solvent systems and retention times of the compounds are shown in Table 2.

Table 2 Retention time [Column: NucleosH 5CN,
5μm, 4.6 icl x 300mm solvent system n-
Hexane: Ethanol = 88212 1.2rnl/min] From Table 2, for example, 3/, S/-
ditetradecanoyl-5'-fluoro-2'-deoxy, 7+7dine (one of the compounds represented by the general formula [1]) Hl-((2-(arachitonoyloki/)ethoxy)
Since the retention time is almost the same as that of the compound represented by the formula (Il), the hydrophilicity of both compounds is also the same, and the in vivo behavior based on the hydrophilicity of the compound is also similar. It is thought that they are similar.

Test Example 3 Rat duodenal epithelial homogenate (1
%, w/v; Hydrolysis rate in Pl(7,0) was measured at 37°C. Compound and hydrolysis reaction constant as the third
Shown in the table below.

3rd Decomposition rate As seen from Table 3, 1 e.g. 3/, s/-
Tetradecanoyl-5-fluoro-2'-deoxyuridine (one of the compounds represented by general formula (1)) Hl-
((2-(arachitonoyloki/)ethoxycomethyl)
-5-Methyluracil (one of the compounds represented by the general formula (n)) has the same enzymatic hydrolysis reactivity, and when both compounds are administered to a living body at the same time, they are not easily hydrolyzed by the living enzyme system. , 5-fluoro-27-thioxyuridine and 1-((2-hydroxyethoxy), respectively
It is believed that the rate of release of methylcous-5-methyluracil is the same.

Test Example 4 Simultaneous oral administration of the compound of the present invention 3',5'-cytodecanoyl-5-fluoro-2'-deoxyuridine and 1-((2-(octadecanoyloxy)ethoxy]methyl]-5-methyluracil) Regarding murine leukemia L12
The anti-S oxidation effect on 10 was evaluated by ■5-fluoro2'-deoxyuridine alone, ■3/, S/-cytodecanoyl-5-fluoro-27-thioxyuridine alone, and ■3.
, 5'-cytodecanoyl-5-fluoro-2'-thioxyuridine and 1-((2-hydroxyethoxy)methyl]-5-methyluracil were compared orally.

Mouse leukemia Ll 210 ascites 11 if 70th transplant!
Tumor cell 10'fJ't BDF, ff7. (68
25-26 g of Ca per week.

Group 1: 5 animals) were transplanted by intraperitoneal pressure and used for the experiment.

1st and 3rd day after 424 hours of MA tumor cell transfer.

The drug was orally administered three times on the fifth day.

The anti-pD tumor effect of the drug was expressed as the percentage increase in survival time (survival prolongation %) of the drug-administered group compared to that of the control group (no drug administered). The results are shown in Table 4.

Claims (1)

[Claims] 1. General formula [I] ▲ Numerical formulas, chemical formulas, tables, etc.▼... [I] In the formula, R^1 and R^2 are the same or different and represent a hydrogen atom or an acyl represents a group. However, the case where R^1 and R^2 are both hydrogen atoms is excluded. At least one acylated derivative of 5-fluoro-2'-deoxyuridine represented by the formula [II] ▲ Numerical formulas, chemical formulas, tables, etc. are available▼...[II] [In the formula, X is a hydrogen atom , represents a halogen atom, methyl group, benzyl group or vinyl group, and R^3 represents an acyl group. An antitumor agent comprising at least one acylated derivative of 1-[(2-hydroxyethoxy)methyl]-uracil represented by the following as an active ingredient. 2. The antitumor agent according to claim 1, wherein in the general formula [II], X is a methyl group. 3. In general formula [II], R^3 has 2 to 24 carbon atoms
The antitumor agent according to claim 1 or 2, which is an aliphatic acyl group or an aromatic acyl group having 7 to 12 carbon atoms. 4. In general formula [I], R^1 and R^2 are aliphatic acyl groups having 4 to 24 carbon atoms or 7 to 24 carbon atoms;
Claims 1 to 12 aromatic acyl groups
The antitumor agent according to any one of item 3. The blending ratio of the acylated derivative of 5,5-fluoro-2'-deoxyuridine and the acylated derivative of 1-[(2-hydroxyethoxy)methyl]-uracils was set at a molar ratio of 1.
:0.1 to 1:20 Claims 1 to 4
1. The antitumor agent according to any one of the above items. The blending ratio of the acylated derivative of 6,5-fluoro-2'-deoxyuridine and the acylated derivative of 1-[(2-hydroxyethoxy)methyl]-uracils was set at a molar ratio of 1.
:0.5 to 1:5. The antitumor agent according to any one of claims 1 to 5. 7. The antitumor agent according to any one of claims 1 to 6, whose dosage form is an orally administered drug. 8. The antitumor agent according to claim 7, wherein the orally administered agent is a powder, capsule, tablet, liquid, granule, or pill. 9. The antitumor agent according to any one of claims 1 to 6, wherein the dosage form is a suppository.