JPS60126221A - Antitumor composition - Google Patents

Abstract

PURPOSE:To provide an antitumor composition composed of 5-fluoro-2'-deoxy-beta- uridines and a thymidine compound, having a reduced side effects keeping the antitumor effect of the uridine compound. CONSTITUTION:The objective antitumor composition is produced by compounding the 5-fluoro-2'-deoxy-beta-uridines of formula I [R' is acyl; R2-3 are (protected) OH] with thymidine compound of formula II [R<4> is H or acyl; R<5-7> is (protected) OH]. The amount of the thymidine of formula II is 0.3-8mol, preferably 0.5-5mol per 1mol of the compound of formula I . The side effect of the compound of formula I , e.g. the disorder of digestive organs, etc. can be mitigated while keeping the antitumor activity of the compound of formula I , by using the thymidine compound of formula II together with the compound of formula I . Furthermore, the toxicity of the compound of formula I can be mitigated.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides antitumor compositions, more specifically, antitumor compositions containing 5-fluoro-2'-deoxy-β-uridines represented by the general formula and thymidines represented by the general formula. Relating to tumor compositions.

5-Fluoro-τ-deoxy-β of the general formula [I] already known in JP-A-54-163586 etc.
-Uridines exhibit excellent antitumor effects, but have the disadvantage of having side effects such as gastrointestinal disorders. Therefore, as a result of intensive research to solve the above drawbacks, the present inventors succeeded in incorporating general formula [II] into 5-fluoro-2'-deoxy-β-uridines of general formula [I], The present invention has now been completed.

Next, the present invention will be explained in detail.

In the compounds of general formulas CI] and [I], R1 is an acyl group such as tyrefudioxybenzoyl or natutoyl; an alkanoyl group such as acetyl, propionyl, butyryl, valeryl, isobutyryl, isovaleryl, pivatetrayl, balmitoyl, or stearoyl; tenoil, 70
Heterocyclic carbonyl groups such as yl, thiazolylcarbonyl, oxasilylcarbonyl, isoxasilylcarbonyl, nicotinoyl; alkenoyl groups such as acryloyl, crotonoyl, and these include, for example, fluorine, chlorine, bromine, iodine, Halogen atom; hydroxyl group; nitro group; cyano group; amino group; carboxyl group; acyl group such as formyl, acetyl, propionyl, butyryl, acryloyl, crotonoyl, benzoyl, naphthoyl, furoyl, thenoyl, etc. or its no-rogen substituted product; acetyl Acyloxy groups such as oxy, propionyloxy, butyryloxy, acryloyloxy, benzoyloxy, naphthoyloxy, furoyloxy, thenoyloxy, or halogen-substituted products thereof;
Acylamino groups such as acetylamino and propionylamino, or their halogen-substituted products; alkyl groups, such as methyl, ethyl, propyl, butyl, or their halogen-substituted products; alkoxy groups, such as methoxy, ethoxy, propoxy, butoxy, pentoxy, octyloxy, etc.; It may be substituted with one or more substituents such as a halogen-substituted product; an aryl group such as phenyl or naphthyl, or a halogen-substituted product thereof; a heterocyclic group such as 7lyl or chenyl, or a halogen-substituted product thereof.

In addition, as the protecting group for the optionally protected hydroxyl group of it", R", R' and R6, for example, groups that are usually used as a protecting group for a hydroxyl group, such as a group having a substituent or Acyl groups that do not have acyl groups, specifically alkanoyl groups such as acetyl, propionyl, isopropionyl, butyryl, isobutyryl, 5ec-butyryl, and tert-butyryl; Luponyl group; acetyloxymethylcarbonyl, propionyloxymethylcarbonyl, acetyloxyethylcarbonyl, α-(acetyloxy)propionyl, β-
Acyloxyacyl groups such as (propionyloxy)propionyl; p-chlorobenzoyl, p-methylbenzoyl, p-nitrobenzoyl, m.

Aroyl group having a substituent such as p-dinitrobenzoyl; chloroacetyl, dichloroacetyl, trichloroacetyl, fluoroacetyl, difluoroacetyl, trifluoroacetyl, bromoacetyl, dibromoacetyl, tribromoacetyl, iodoacetyl, short acetyl, triiodo Examples include mono-, di- or trihalogenoalkanoyl groups such as acetyl.

The compound of the general formula [■] explained above is produced, for example, by the method described in JP-A-54-163586. Moreover, the compound of general formula [■] is, for example, JAC82, 736-738 (1955).

It is manufactured by the method described in JAC881, 178-187 (1959) and Japanese Patent Application Laid-Open No. 163586/1986.

Next, embodiments of the present invention will be described.

The antitumor composition of the present invention is a 5-fluoro-
2'-deoxy-β-uridines and general formula [II]
The ratio of the two used is generally 0.3 to 8 moles, preferably 0.3 to 8 moles of thymidine per mole of 5-fluoro-2'-deoxy-β-uridine. It is 5 to 5 moles.

In the present invention, 5-fluoro-21-deoxy-β-uridines and thymidines can also be administered individually and simultaneously.

The antitumor composition of the present invention can be administered in various forms depending on the therapeutic purpose, such as daily preparations such as tablets, capsules, tablets, and granules, injections, and suppositories. Examples include parenteral preparations such as drugs. Generally known methods are applied to formulate these oral or parenteral preparations, such as various excipients, lubricants, binders, disintegrants, suspending agents, isotonic A curing agent, an emulsifying agent, etc. may be added. The dose is 5-fluoro-! -deoxy-β
- As a crizine, generally 30 to 1 per day for adults
500q, but the administration group and frequency of administration may be changed as appropriate depending on the symptoms.

Next, the pharmacological effects of typical antitumor compositions of the present invention will be explained.

Experimental method Ehritzch ascites carcinoma cells s x io' were transplanted subcutaneously into the right inguinal region of ddY mice (5 weeks old, 10 mice in 3.1 groups), and 3 days later, 0.25 CMC/CMC/cells were transplanted into the control group. Physiological saline alone was orally administered continuously for 14 days, and 0,251 CMC/physiological saline in which single or two drugs were dissolved or partially suspended in the drug administration group was orally administered for 14 days. The mice were killed in layers. During this time, the short axis and long axis of the solid tumor were actually measured using calipers, and the tumor volume i was determined from these measured values.
By calculating (, X (major axis) x (minor axis) 2),
The tumor growth inhibition rate (1-T/c) was completely calculated (Table 1), the weight of the mice was measured, and death by drug poisoning was observed (20 days after transplantation) Table 2).

On the other hand, each part of the intestinal tract was removed from the sacrificed mouse, fixed in formalin, tissue sections were prepared, hematoxin-eosin staining was performed, and tissue lesions (abnormal bacterial count/number of surviving mice) were observed under a microscope. Table C-3).

Below margin 7 Weight change and drug poisoning death , &-2 *Same as Table-1.

It's tin 11.

As is clear from the above results, the 5-fluoro-2'-deoxy-β-uridines of the general formula CI] retain excellent anticancer effects when used in the antitumor composition of the present invention, and It can be understood that side effects such as disorders can be reduced, and toxicity can also be reduced by reducing drug fatalities.

Next, the present invention will be further explained by giving reference examples and formulation examples.

Reference Example 1 3-(4-Methylbenzoyl)thymidine (Compound A) Thymidine 2.4 F (0.01 mol) was suspended in 10-chloroform, and this was suspended in ζ-triethylamine 5,5
(0.04 mol) and trimethylsilyl chloride 2
．． 8d (0,022 mol) are added one after another and the reaction is allowed to proceed under reflux for 1 hour. Next, 1.8 f (0,012 mol) of 4-methylbenzoyl chloride was added thereto, and after refluxing for an additional 30 minutes, 10 mm of ice-cold FIN-hydrogen chloride methanol solution was added to the reaction mixture.

After stirring at the same temperature for 30 minutes, the mixture was neutralized with triethylamine. The reaction mixture was concentrated to dryness, the resulting residue was dissolved in ethyl acetate, diluted hydrochloric acid, and saturated hydrogen carbonate).
After sequentially washing with an aqueous Jumium solution and water, it is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Add 40% of a chloroform-methanol (211) mixture to the resulting residue and scrape off the insoluble matter to obtain a melting point of 161~
Crystalline 3-(4-methylbenzoyl) exhibiting a temperature of 162°C
3.2 t of thymidine (yield: 90 t) is obtained.

IR(KBr)cm-” νc=0 1740.16
90.1640UVλmax (nm) (CHmCH*0
H) Compounds shown in Table 4 were obtained in the same manner as 205,262.

Below is the blank Formulation Example 1 3- (3,4-methylenedioxybenzoyl)-5-
Fluo-4-2'-tetanyl-β-uridine 50 Chithymidine 35 W Lactose 355 Misaki Cornstarch 50 W Human xypropyl cellulose 1041 packets 500
MisakiPrepare granules at the above mixing ratio.

Formulation Example 2 315'-Diacetylthymidine 130 caps Lactose 55 ■ Crystalline cellulose soq Magnesium stearate 2w9 Talc 3q Hydroxyglobil methylcellulose l0W 300 caps per tablet Tablets are prepared at the above blending ratio.

Formulation example 3 3-(4-methylbenzoyl)thymidine 145■Lactose 80119 Cornstarch 22Misaki talc 3IIF 6 per 1 capsule 300y Formulation example 4 for preparing capsules at the above blending ratio 3-(4-methylbenzoyl)thymidine 145W9Lactose 70011P Corn starch 95 x Hydroxypropyl methyl cellulose 10191 packets 1000 kg Granules are prepared at the above blending ratio.

Formulation Example 5 3-(3,4-methylenedioxybenzoyl)-5-
Fluoro-2'-deoxy-β-uridine 50F3te57-diacetyltimidine 7 200 l vial per fi
225011F An injection is prepared at the above mixing ratio.

Formulation Example 6 3-(3,4-methylenedioxybenzoyl)-5-
Fluoro-2'-deoxy-β-uridine 1001v
3 57-Diacetyl chikidine 265 1 piece 15
00 MisakiPatent applicant Toyama Chemical Industry Co., Ltd., which features crude drugs with the above blending ratio

Claims (1)

Claims: (1) An antitumor composition containing 5-fluoro-2'-thioxy-β-uridine represented by the general formula and thymidine represented by the general formula. The antitumor composition according to claim (1), wherein f21 R1 is an aroyl group with or without a substituent. (31R' and R1 are hydroxyl groups, the antitumor composition according to claim 1) or (2). (41R' is 3,4-methylenedioxybenzoyl group,
The antitumor composition according to claim (3), wherein R2 and Rs are hydroxyl groups. (5) Claims Nos. (1) to 4, wherein R4 is a hydrogen atom or an aroyl group with or without a substituent.
(4) The antitumor composition according to any one of the items. (6) The antireactive agent according to any one of claims (2) to (5), wherein R' and R@ are a hydroxyl group optionally protected by an acyl group with or without a substituent. Tumor composition. (η The antitumor composition according to claim (6), wherein the acyl group is an aroyl group or an alkanoyl group. (8) 5-fluoro-2' represented by the general formula [1]
-deoxy-β-uridine per mole of general formula [■
] The antitumor composition according to any one of claims (1) to (7), comprising 0.3 to 8 moles of thymidine represented by the following formula.