JPS6061592A - 2'-deoxy-5-trifluoromethylcytidine derivative, its preparation and antitumor agent containing the same - Google Patents

Abstract

NEW MATERIAL:The compound of formula (R is 1-15C alkyl, methylenedioxyphenyl, or phenyl which may have lower alkyl, lower alkoxy or halogen as substituent group). EXAMPLE:5'-O-Hexanoyl-2'-deoxy-5-trifluoromethylcytidine. USE:An antitumor agent. PREPARATION:2'-Deoxy-5-trifluoromethylcytidine is made to react with the carboxylic acid of formula RCOOH or its reactive derivative (e.g. carboxylic acid halide, anhydride, etc.), at room temperature -80 deg.C, if necessary in an aprotic solvent such as pyridine.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel 2/-, 5-trifluoromethylcytidine, 7 derivative, a method for producing the same, and an antitumor agent containing the same.

2'-Dio+C5-trifluoroD methyluri, ;shi (hereinafter [F3Td
F3TdR is a compound first synthesized by Heidelberger et al. [Journal of American Chemical Society, Vol. 84, No. 359]
7 pages (1962)].

The compound #'i has an antitumor effect and is effective against Adenocarcinoma 755.
It has been reported that the therapeutic coefficient for 2'-zuo-5-fluoro-uridine (hereinafter referred to as "FudRJ") is superior to that of 2'-zuo-5-fluoro-uridine (FudRJ) [Chu Yancer Research Vol. 24, p. 1979 (1964)].

Based on the above points, F3TdR has been studied in various ways for its usefulness as a drug, but no development as an antitumor agent capable of producing clinically expected effects has yet been found.

The present inventors have demonstrated that F37'dR acts as an anti-metabolite in nucleic acid biosynthesis, and has a mechanism of action that is different from that of other antagonistic antiretroactive agents, such as 5-fluorouracil and cytosialadinoside. From this point of view, the F3
In order to improve the anti-tumor properties of TdH and improve the drug's ability to reach tumors, we have conducted intensive studies on 2'-diox-5-tri, which is metabolized in vivo and produces the above-mentioned F3TdR. A novel compound in which the hydroxyl group of the sugar moiety of fluoromethyl cysteine is substituted with a specific chain acylo + cy group or be, 7-soylo deci group exhibits excellent anticancer activity and is useful as an antitumor agent. Conventionally, the above 2'-Deocy 5-
Sugar T1 of trifluoromethylcytidine]! IF the hydroxyl group
<The converted compound is slightly: 3',5'-diO
-A1! Del-2'-dio + C-5-trifluoro-methyl-Si has only been reported (T-Naruora The Chemical Society, p. 2755 (1980)). At the same time 3', 5'-G0
-Acetyl-2'-dioxy-5-trifluoromethyluri, although there have been no reports on its anticancer activity,
The anticancer activity of the compound was not substantially improved compared to the base F3TdH, and
It is a new fact discovered for the first time by the present inventors that a compound with improved anticancer activity can be produced by substituting the hydroxyl group of the sugar moiety of trifluoromethyl cytiji with some substituent. The present invention has been completed based on the above findings.

That is, the present invention is based on the general formula (wherein RFi is an alkyl group having 1 to 15 carbon atoms, a methylated group or a diphenyl group, or a lower alkyl group as a substituent,
[lower alk] 10 or 8 uJf: JJry.

The present invention relates to a 2'-deoxy-5-trifluoromethylcytyl derivative represented by the formula (2'-deoxy-5-trifluoromethylcytyl group), a method for producing the derivative, and an antitumor agent containing the derivative.

Examples of the alkyl group having a carbon number of t-tS represented by R in the above general formula (I) include linear alkyl groups such as ethyl, butyl, hexyl, nonyl, and becitadicyl groups. . Examples of the lower alkyl group as a substituent for the phenyl group include alkyl groups having 91 to 4 carbon atoms, such as methyl, ethyl, buttyl groups, and lower alkyl groups as substituents for the phenyl group. shi groups, such as meth-to-jushi,
Examples of the 7 atoms include fluorine atom, chlorine atom, etc., respectively.

The method for producing the compound of the present invention will be described in detail below.

The compound of the Ichiki invention represented by the above general formula (I) is, for example, 2'-deocy5-trifultO methylsithi;
is used as a starting material, and is produced by reacting it with carposiic acid represented by the general formula % (in which R is the same as above) or a reactive derivative thereof.

The reactive derivative of the carboxylic acid represented by the general formula (II) refers to the halide of carposi acid and the anhydride of carposi acid which are generally used in the a7acylation reaction.

The above reaction is basically carried out in the same manner as the usual esterification reaction between an acid and an alcohol. The specific method varies slightly depending on the type of carposiic acid and its reactive derivative used, and is, for example, as follows. That is, when using carposiic acid anhydride, the above reaction is carried out using the nucleic acid anhydride itself as a solvent or using another suitable solvent. As the solvent, conventional non-50% solvents can be used, such as ether, dioxic, diform, acetonitrile, pyridine, dimethylformamide, etc. The ratio of raw materials to be used is particularly limited, e.g. Since the acid anhydride also functions as a solvent, it can be used in large excess in this case.Also, when other solvents are used, the amount of acid anhydride that is It is preferable to use at least an equivalent amount of the acid anhydride, preferably from 1 to 5,7 to one hydroxyl group.
2 is approximately 50 to 80°C. During the above reaction,
For example, it is preferable to have an aromatic amine such as lysine or a strong base such as trial amine present in the reaction system.

In addition, when using a carboxylic acid halide, the acid halide may be any acid halide, acid mite, etc.
Normal market D ride is preferred. These acid halides are
Usually, the amount of hydroxyl J to be reacted with 2'-trifluor, 5-trifluor, 0 methyl, (1 to 3'
Preferably, f-L8 degrees is used. The reaction is carried out in a suitable non-toxic organic solvent similar to that described above, and it is also preferable to have an organic base present in the reaction system. The amount of the unattached base to be used is usually about 1 to 5 mol per 1 mol of acid halide, but since the organic base itself can also be used as a reaction solvent, it may be used in excess of the above ton number. Of course, it is also possible. The reaction temperature is not particularly limited, and the reaction proceeds well within the range of water cooling to the boiling temperature of the solvent. Generally, it is normal to set the room temperature to 1 month.

The compound of the present invention thus obtained is isolated and purified by conventional methods such as recrystallization and chromatography.

When the compound of the present invention is used as a medicine, it is usually combined with a suitable pharmacologically compatible phase and formulated into a formulation suitable for its administration route.

The carriers used include known and commonly used excipients, binders, lubricants,
Coloring agents, disintegrants, etc. can be used, and the dosage form is perfect! lu as r
4. Oral preparations suitable for oral administration, such as tablets, cassettes, granules, powders, liquid preparations, etc.; injections suitable for parenteral administration such as intravenous injection; May be made into a suitable suppository.The direct active ingredient (
Compound of the present invention) containing -11e may be appropriately determined depending on its form, and 11? It is not much different from those in ordinary pharmaceuticals. The preferred active ingredient content is generally about 25 to 500 ffW per unit.

The preparation method for each of the above formulations is as follows: t tar
good.

The dosage of each preparation obtained in this way will of course vary depending on the symptoms, weight, age, etc. of the patient to whom it is administered, and although it cannot be generally limited, it is usually an adult with an immobile component of about 100 mg per day. The amount may be administered for ~2000 my, and this can be administered in 1 to 4 divided doses on day -.

Examples of manufacturing the compounds of the present invention are listed below as examples.
1 5'-〇- to 11 neuro-2'-deocy-5-trifluoromethylcytidine C general formula (t), /('
=n-C5H
2.59 was suspended in HirijiJIOmlKIMi, 1.21% of ethnoyl chloride was added thereto, and the mixture was stirred overnight at room temperature. After concentrating the reaction solution, the residue was subjected to silica gel column chromatography (solvent: 00 form-ethanol (1
0:l)) and reconsolidated from ethanol to obtain the target product 1.
．． 7F (yield 51%) was obtained.

m p l 99-202°C Example 2 5'-〇-besidiyl-2'-dio + C 5-trifluoromethylcytidine C General formula (I), R = 0, Preparation of compound 3] 2'-dio 10C 5-trifluoromethylcididine 2.
Dissolve 52 in 13 ml of #, #-dimethylallacetamide 71nlK and add Besilyluc O to this.
Add Ride 1.32 and stir overnight at room temperature. After concentrating the reaction solution, the residue was subjected to silica gel column chromatography (
Solvent: P! with chloroform-ethanol (10:l).
1 LFL, 1 g from ethanol, target 1.2 F
(yield 35%). ns p 202°C Example 3 In the same manner as in Example 1 or Example 2, each of the following compounds in -1 was synthesized.

Compound 2 [general formula (I), not'=-(C1),)j,
, CU3] nr 7> I 98-200°C yn 7> 216-217°C 1 no rp223-224. 5° C. nt pl 9 4-196° C. The results of scientific tests of the antitumor effects and toxicity of the compounds of the present invention will be shown below, and the usefulness of the compounds of the present invention will be explained by comparing the therapeutic coefficients calculated from the values.

<Pharmacological test> Experimental method σ) Method for measuring antitumor activity value: Mouse transplantable tumor macaque]-Ma I 801 flll cells 5 x 10 cells were injected into male I CR//CL mice (27
~30f? ) was implanted subcutaneously on the back of the patient. Specimen #; to, I
Chitween 80--dissolved or suspended in 0.5% CMC solution, the solution was administered to a group of 7 mice at 1.0 ml/I.
1F was administered orally 11 times daily for 7 days starting from the day after the day of tumor transplantation at a volume ratio of 0.00 y body weight. In addition, the control group included t'1 and t'1 of the above solution containing no specimen. Oml/l
OOf vacation was similarly administered once a day for 7 consecutive days.

On the 10th day after transplantation, the average tumor weight at each dose was measured for each sample, and these were compared with the average tumor weight for the control group, and the tumor growth inhibition for each dose versus the control group was determined. The rates were calculated for each. From these experimental values, the dose at which the tumor growth inhibition rate was 501 was determined as the antitumor activity value of each compound.

b) Method of measuring toxicity values: Conventionally, most of the methods of measuring toxicity values of anti-malignant lung cancer drugs have been to calculate the number of deaths (LD, .) of Fi test animals. Experimental methods require measurements under severe conditions that are far removed from the clinical use of drugs, making it impossible to evaluate the true toxicity of the drug. As a method for measuring toxic activity, we took into account the cumulative toxicity trap that is typical of the toxicity of anti-malignant M1 tumor drugs, and as a more sensitive method for detecting the toxicity, we used suppression of weight gain in test animals as an indicator [measured]. . That is, when conducting an experiment to measure the antitumor activity value in item a) above, for each dose group of each compound, the weight of each animal was measured every day from the day of tumor implantation and just before administration.
.

On the day of tumor weight determination, the real average weight gain from the day of tumor implantation at each dose was measured for each sample, and these were compared with the real average weight gain in the control group. The actual weight gain rate was determined for each compound, and from these experimental values, the dose at which the weight gain inhibition rate was 50 cm was determined, and this was taken as the toxicity value of each compound.

C) 1'' calculation method for therapeutic coefficient: From the antitumor activity value (denoted as A) and toxicity value (determined as B) for each compound determined in sections a) and b) above,
The therapeutic coefficient (referred to as C) was calculated according to the following formula.

C=- The therapeutic index value of each compound obtained here is large, indicating that the efficacy and toxicity of the compound, such as Jj Regearu tl, have a good balance and are highly useful.

The compound of the present invention (the number of compound stores is the same as that shown in each example, and the same shall apply hereinafter) and the compound of the present invention (2)
The results of the above test are shown in the table below using 1-year-old 5-1, Rifle J Omesenrushichi, ;shi) as the specimen (test compound).

Table 1 As is clear from Table 1 above, the compound of the present invention ti.

Compared to the comparative compound, it is about the same or better in terms of % toxicity, and it is especially superior in terms of anti-R-cancer activity. Comparing this with the therapeutic index, it is clear that the compounds of the present invention are extremely useful.

Next, examples of formulations of the compounds of the present invention will be shown.

Formulation example 1 Force cell agent Compound 11 Lactose, crystalline cellulose and L.

Koshi starch is mixed in the following ratio, and magnesium stearicate is further added and mixed in the following ratio.

This mixture is filled using a suitable force cell filling machine to a weight of about 293W9 per force cell to obtain a product.

Force Cell Prescription i/ Force Cell Compound 1 200.0 Lactose 30.0 Crystalline Cellulose 50.0 Totsu 10 Kosi Starch 10,0 S〒Magnesium Alisinate 3.0 293.0 Formulation Example 2! Mix granule compound 3, lactose, crystalline cellulose, and starch in the following proportions. A 10% ethanol solution of Nishido U+Shizu De'le cellulose was added to the mixture and kneaded, and the mixture was made into granules using a suitable granulator. After drying this, granulate it into 12 to 42 meshes. Using an appropriate coating machine, apply a coating of human methylcellulose to 10 to 42 meshes in the following proportions. Give - no. After sizing to 12 to 42 meshes, the product is prepared.

Compound 3 200.0 Lactose 200.0 Crystallization 11.・Loin 311.0 1-': le D, T] Shitenpun 200.
0 Hydro + Shi''50 Pill Cellulose 10.0 Hydro+
Shizurohiru Mezuru Cellulose 70.0 Fatty Acid Seven Nojiri Cellulose 1 3.5 Titanium Dioxide 5.5 1000.0 Formulation Example 3 Tablet Compound 1. ) Mix Umo D Koshi starch and cellulose and calcium glycolate in the following proportions.

To this, add a 10% ethanol solution of Dorojushiro Hill Cellulose, knead it, granulate it with a suitable granulator, dry it, add magnesium stearate and silicic anhydride in the proportions shown below, and mix it. The tablets are compressed using a suitable tablet press, and the tablets are coated with hydrodecylmethylcellulose to form a product.

Compound 1 200.0 Corn starch 5.0 Calcium silicate 20.0 Calcium silicolate 2.0 Magnesium stearate 2.5 Silicic anhydride 2.5 ΣRumez Lucel D-S 19.99
9 Macrojol 6000' (1,001 titanium oxide 2.0 54 Formulation example 4 Suppository Uitezusol W-35 (commercial name J%, manufactured by Titezu Mite Nobel Co., Ltd.) was dissolved at about 60°C. Thereafter, the temperature is maintained at about 45° C. Compound 3 is mixed with the mixture in the proportion shown in H1 below, and then molded into a suppository I2 using an appropriate suppository manufacturing device.

Compound 3 40(+,0 ``°Noitezu Seal W-35600,010(10,0 Proceedings Amendment Committee (Voluntary) August 14, 1980 Manabu Shiga, Commissioner of the Patent Office, 1.+,', I1. 7 1 Indication of the case 1981 Special revised application No. 1701480 2 Name of the invention 2'-deoxy-5-1-lifluoromethylcytedine (
1 conductor, its 1Fj 3N method and antitumor agent containing the same♂
1 with the case of the person making the amendment! il Section Patent developer 1 Kuwahinko 2 Co., Ltd. 4 Agent 2-10 Hirano-cho, Higashi-ku, Osaka City Sawanotsuru Building Sponsored by 6 Amendment pair m 4 contents of the amendment under "Detailed description of the invention" 1) Akirat! 1ltl! ! 61st Fri6ty Ni [0 mechi],! ＝Iruwo corrected it to ``first time.''

2) In the 6th line of page 8 of Group 4, replace the word ``acedelization'' with ``
Acylation” is corrected.

3) On page 11, line 15 of Mingkuosho, replace the phrase “directly effective ingredient” with “
"Active ingredient".

(IJ, top)

Claims (1)

[Claims] ■ General formula (wherein R is an alkyl group having 1 to 15 carbon atoms, a diphenyl group in a methyledidio group, or a lower alkyl group, a lower alkoxy group, or a bald atom as a substituent) 2'-dioxy 5 (representing a certain phenyl group)
-Triful'JO Methyl Shichijishi Visiting Conductor. ■ 2'-deo + C 5-trifluoro methyl sulfate, general formula (in the formula, R is an alkyl group having 1 to 15 carbon atoms, a diphenyl group in methylene diode, a lower alkyl group as a Fi substituent,
A general formula (in which R has the same meaning as above) is reacted with carbodiic acid represented by a lower alkoxy group or a phenyl group that may have a bald atom, or a reactive derivative thereof. 2 expressed as
1. A method for producing a 5-trifluoro-methylcytyl derivative in '-polyfluoride. ] General formula 0H (in the formula, R is an alkyl group having 1 to 15 carbon atoms, a methyledidiodiphenyl group, or may have a lower alkyl group, a lower alkoxy group, or a diphenyl atom as a substituent) 2'-pogyushi5 represented by phenyl group)
- An antitumor agent characterized in that it contains triflu'A1 comethylcytidine, a 7-carboxylic conductor.