JPH0340037B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel 2'-deoxy-5-trifluoromethyluridine derivative and an antitumor agent containing the same. 2'-deoxy-5-trifluoromethyluridine (hereinafter referred to as "F ₃ TdR") is a compound first synthesized by Heiderberger et al. [Journal of the American Chemical Society, Vol. 84, No.
3597 pages (1962)]. The compound has antitumor activity and its adenocarcinoma (Adenocarcinoma)
The therapeutic index for 2′-deoxy-5-
There is a report that it is superior to fluorouridine (hereinafter referred to as "FuTdR") [Cancer Research, Vol. 24, p. 1979 (1964)]. Based on the above points, F ₃ TdR has been studied in various ways for its usefulness as a drug, but clinically the compound has not shown the expected effects, and its development as an antitumor agent is still not yet discovered. Not yet. The present inventors have demonstrated that the above F ₃ TdR can be used as an antimetabolite in nucleic acid biosynthesis, including other antimetabolite tumor agents,
For example, focusing on the fact that it has a different mechanism of action from that of 5-fluorouracil, cytosine arabinoside, etc., from this point of view, it is possible to enhance the antitumor properties of the F ₃ TdR.
We have conducted extensive research to improve the ability of drugs to reach tumors. As a result, it was discovered that a new compound in which the hydroxyl group of the sugar moiety or the NH- group at the 3-position of the base moiety of F ₃ TdR is benzoyl or tetrahydrofurylated exhibits excellent anticancer activity and is useful as an antitumor agent. Ta. The present invention has been completed based on the above findings. That is, the present invention is based on the general formula [In the formula, R ₁ represents a hydrogen atom, a tetrahydrofuryl group, or a benzoyl group that may have a lower alkyl group, a lower alkoxy group, or a halogen atom as a substituent. When R ₁ is a hydrogen atom, R ₂ and R ₃ represent a lower alkylcarbamoyl group and a lower alkoxycarbonyl group, respectively. Also R ₂ and R ₃
represents a hydrogen atom or a lower acyl group, respectively, when R ₁ is a group other than a hydrogen atom. ] The present invention relates to a 2'-deoxy-5-trifluoromethyluridine derivative represented by the following and an antitumor agent containing the derivative. In the above general formula [], the lower alkylcarbamoyl group defined by R ₂ and R ₃ has 2 carbon atoms.
-7 alkylcarbamoyl groups, such as methylcarbamoyl, ethylcarbamoyl, butylcarbamoyl, pentylcarbamoyl, hexylcarbamoyl groups, etc.; lower alkoxycarbonyl groups include alkoxycarbonyl groups having 2 to 7 carbon atoms;
For example, ethoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl groups, etc., and as lower acyl groups,
Examples include aliphatic acyl groups having 2 to 7 carbon atoms, such as acetyl, propionyl, butyryl, and valeryl groups. Examples of the lower alkyl group as a substituent for the benzoyl group defined by R ₁ include alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, and hexyl groups; examples of the lower alkoxy group include: Examples of alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propyloxy, butoxy, pentyloxy, and hexyloxy groups, and halogen atoms include fluorine, chlorine, bromine, and iodine atoms, respectively. The compound of the present invention represented by the above general formula [] can be produced, for example, by the following production method. That is, the general formula [In the formula, R ₄ represents a hydrogen atom or a benzoyl group that may have a lower alkyl group, a lower alkoxy group, or a halogen atom as a substituent. ] R ₅ COOH [] [In the formula, R ₅ represents a lower alkoxy group or a phenyl group which may have a lower alkyl group, a lower alkoxy group, or a halogen atom as a substituent. ] A carboxylic acid derivative or a reactive derivative thereof represented by (b) the general formula R ₆ -N=C=0 [] [wherein R ₆ represents a lower alkyl group]. ] An isocyanate compound represented by the above and (c) a compound selected from halogentetrahydrofuran are reacted. In the above general formulas [], [] and [], R ₄ ,
The lower alkyl group, lower alkoxy group, and halogen atom defined in R ₅ and R ₆ have the same meaning as each group defined in the general formula [].
In addition, the reactive derivative of the carboxylic acid derivative represented by the general formula [] refers to acid halides and acid anhydrides commonly used in general acylation reactions. The reaction for producing the above-mentioned compound of the present invention is basically as follows:
It is carried out in the same manner as a normal esterification reaction between an acid and an alcohol. The specific method is the general formula []
Reagents to be reacted with the compound represented by (carboxylic acid derivatives of general formula [] and reactive derivatives thereof,
They differ slightly depending on the type of isocyanate compound of general formula [] and tetrahydrofuran), and are as follows. That is, when an anhydride of a carboxylic acid derivative [] is used, the above reaction is carried out using the acid anhydride itself as a solvent or using another suitable solvent. As solvents, customary aprotic solvents such as ether, dioxane, chloroform, acetonitrile, pyridine, dimethylformamide and the like can be used. The molar ratio of the raw materials used is not particularly limited, and for example, one of the raw materials, acid anhydride, also functions as a solvent, so in this case it can be used in large excess. When using other solvents, the general formula []
The acid anhydride is preferably used in an amount of at least equivalent to the hydroxyl group to be reacted in the compound, preferably 1 to 5 moles per hydroxyl group. The reaction temperature is usually from room temperature to the boiling temperature of the acid anhydride, preferably about 50 to 80°C. In the above reaction, when a halide of reaction derivative [] of an aromatic amine such as pyridine or an organic base such as a trialkylamine is used, the acid halide may be either acid chloride or acid bromide, but usually Acid chlorides are preferred. The isoacid halide is preferably used in an amount of about 1 to 3 moles per hydroxyl group to be reacted in the compound of general formula [].
The reaction is carried out in a suitable aprotic organic solvent similar to that described above, and an organic base may also be present in the reaction system. The amount of the organic base to be used is usually preferably about 1 to 5 moles per mole of acid halide, but since the organic base itself can also be used as a reaction solvent, it is of course possible to use more than the above mole amount. It is. The reaction temperature is not particularly limited, and the reaction proceeds well within the range of ice cooling to the boiling temperature of the solvent. Generally, room temperature is used. In the reaction using a halide of the above carboxylic acid derivative [] and the reaction using halogenotetrahydrofuran, when a strong organic base such as trialkylamine is present in the reaction system, R ₁ in the compound [] of the present invention is hydrogen. Compounds that are groups other than atoms can be obtained. The reaction conditions are the same as above. The reaction using the isocyanate compound of the general formula [] is also carried out using the same solvent as above and under the same reaction conditions, but in this case it is not necessary to have a base present in the reaction system. The compound of the present invention thus obtained can be isolated by conventional methods such as recrystallization, chromatography, etc.
Refined. As mentioned above, the compound of the present invention has an antitumor effect and is useful as an antitumor agent, and also has an antiviral effect and is useful as an antiviral agent. When the compound of the present invention is used as a medicine utilizing the above-mentioned pharmacological action, it is usually combined with an appropriate pharmacologically acceptable carrier and prepared into a dosage form suitable for its administration route. The carriers used may be known and commonly used excipients, binders, lubricants, coloring agents, disintegrants, etc., and the formulation forms include oral preparations suitable for oral administration, such as tablets, capsules, granules, etc. Examples include powders, liquids, and injections suitable for parenteral administration such as intravenous injection, and suppositories suitable for rectal administration. The content of the active ingredient (the compound of the present invention) per unit form of each preparation may be appropriately determined depending on the form, and is not particularly different from that in ordinary pharmaceuticals. The preferred active ingredient content is generally about 25 to 500 mg per unit. Each of the above formulations may be prepared according to a conventional method. 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 cannot be absolutely limited, but it is usually about 100 to 2000 mg of the active ingredient per day for adults. The amount can be divided into 1 to 4 doses per day. Examples of the production of the compounds of the present invention are listed below as examples. Example 1 3-benzoyl-2'-deoxy-5-trifluoromethyluridine (general formula [],

[Formula] R ₂ = R ₃ = H, production of compound 1) 2.4 g of F ₃ TdR was dissolved in 6 ml of N,N-dimethylacetamide, and 11.2 g of benzoyl acrylide was added thereto in the presence of 1.6 ml of triethylamine. Stir overnight at room temperature. After removing the precipitate,
Concentrate the liquid and dissolve the residue in about 15 ml of chloroform. Add 1/5 to 1/10 amount of water while stirring, collect the precipitate, dry it, and recrystallize from ether-petroleum ether to obtain 1.8 g of the desired product (yield 56%).
get. Melting point: 155-156°C Compounds 2-4 below are obtained in the same manner as above. Compound 2 (general formula [],

[Formula] R ₂ = R ₃ = H) Compound 3 (General formula [],

[Formula] R ₂ = R ₃ = H) Compound 4 (General formula [],

[Formula] R ₂ = R ₃ = H) Example 2 3-(O-methoxybenzoyl)-3',5'-di-O-acetyl-2'-deoxy-5-trifluoromethyluridine (general formula [ ],

【formula】

[Formula] Production of compound 5) 3',5'-di-O-acetyl-2'-deoxy-5
-1.5g of trifluoromethyluridine N,N-
Dissolve in 10 ml of dimethylacetamide, add 0.83 g of O-methoxybenzoyl chloride in the presence of 0.7 ml of triethylamine, and stir overnight at room temperature. After collecting the precipitate, the liquid was concentrated and the residue was subjected to silica gel column chromatography (solvent:
Separate and purify with chloroform) to obtain 1.4g of the target product.
(yield 62%). The following compounds 6 to 8 are obtained in the same manner as above. Compound 6 (general formula [],

【formula】

[Formula]) Compound 7 (General formula [],

【formula】

【formula】) Compound 8 (general formula [],

【formula】

[Formula]) Example 3 3<,5'-di-O-butylcarbamoyl-2'-
Deoxy-5-trifluoromethyluridine (general formula [], R ₁ = H,

[Formula] Production of compound 9) Dissolve 1.5 g of F ₃ TdR in 6 ml of N,N-dimethylformamide and add 2.4 g of butyl isocyanate.
and stir at 60°C for 2 hours. After concentrating the reaction solution, the residue was separated by silica gel column chromatography (solvent: chloroform-ethanol (20:1)) and reconsolidated from ethanol-ether to obtain 1.1 g (yield: 44%) of the desired product. Melting point 184-185℃. Example 4 3′,5′-di-O-ethoxycarbonyl-2′-deoxy-5-trifluoromethyluridine (general formula [], R ₁ =H,

[Formula] Preparation of Compound 10) F ₃ Dissolve 1.5 g of TdR in 4.5 ml of pyridine, and add 1.2 g of ethyl chromium carbonate while cooling with ice water.
After stirring overnight, the reaction solution was poured into 50 ml of ice water and extracted with chloroform. After concentrating the chloroform extract, the residue was subjected to silica gel chromatography (solvent:
Purify with chloroform-ethanol (10:1) to obtain 0.42 g (yield 18.5%) of the desired product. The nuclear magnetic resonance spectroscopy (NMR) results (δppm) of each compound obtained above are shown in Table 1 below. As for the measurement solvent, for compounds 5 to 8,
CDCl ₃ was used and DMSO-d ₆ was used for the others.

【table】

【table】

[Table] <Pharmacological tests> Next, the results of pharmacological tests of the antitumor effects and toxicity of the compounds of the present invention are shown, and the usefulness of the compounds of the present invention will be explained by comparing the therapeutic coefficients calculated from the values. Experimental method a) Method for measuring antitumor activity value: Mouse transplantable tumor sarcoma 180 cells 5x
10 ⁶ mice were subcutaneously transplanted into the back of male ICR/JCL mice (27-30 g). The sample is 0.1% Tween 80
-The solution was dissolved or suspended in a 0.5% CMC solution, and the solution was orally administered to a group of 7 mice at a volume ratio of 1.0 ml/100 g body weight, once a day for 7 consecutive days, starting the day after the day of tumor implantation. . In addition, to the control group, 1.0 ml/100 g body weight of the above solution containing no specimen was similarly orally 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 in the control group to determine the tumor growth inhibition rate at each dose relative to the control group. . Based on these experimental values, the tumor growth inhibition rate is 50%.
The dose showing this was determined and used as the antitumor activity value for each compound. b) Method for measuring toxicity values: Traditionally, most methods for measuring the toxicity values of anti-cancer drugs have been to calculate them using the number of deaths ( _LD50 ) of test animals, but this experimental method In this case, measurements were taken under severe conditions that are far removed from the conditions in which the drug is used in clinical practice, and it is impossible to evaluate the true toxicity of the drug.
In this experiment, as a method for measuring the toxic activity of a compound, we took into account cumulative toxicity, which is a typical toxicity of antineoplastic agents, and used suppression of weight gain in test animals as an indicator for a more sensitive detection method of the toxicity. It was measured as That is, when conducting the experiment for measuring the antitumor activity value in the above section a), the body weight of each animal was measured for each dose group of each compound every day from the day of tumor implantation immediately 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% was determined, and this was used as the toxicity value of each compound. c) Calculation method of therapeutic coefficient: From the antitumor activity value (denoted as A) and toxicity value (determined as B) for each compound obtained in the above sections a) and b), the therapeutic coefficient is calculated according to the following formula. (C
) was calculated. C=B/A The larger the value of the therapeutic index of each compound obtained here, the better the balance between efficacy and toxicity of the compound and the higher the usefulness. The results obtained using the compound of the present invention and the comparative compound (F ₃ TdR) as samples are shown in Table 2 below.

[Table] As is clear from Table 2 above, the compounds of the present invention are approximately equivalent to or superior to the comparative compounds in terms of toxicity, and are particularly superior in terms of antitumor 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 Capsule Compound 2, lactose, crystalline cellulose, and corn starch are mixed in the following proportions, and magnesium stearate is further added and mixed in the following proportions. This mixture is filled using a suitable capsule filling machine so that each capsule is approximately 293 mg.
make Capsule formulation mg/Capsule compound 2 200.0 Lactose 30.0 Crystalline cellulose 50.0 Corn starch 10.0 Magnesium stearate 3.0 293.0 Formulation example 2 Granules Compound 3, lactose, crystalline cellulose, and corn starch are mixed in the following proportions. After adding a 10% ethanol solution of hydroxypropyl cellulose and kneading the mixture, it is made into granules using a suitable granulation device. After drying, it is sized into 12 to 42 mesh pieces. The sized particles are coated with hydroxypropyl methyl cellulose in the proportions shown below using an appropriate coating device. It is made into a product after grading into 12 to 42 mesh pieces. Granule formulation mg/packet Compound 3 200.0 Lactose 200.0 Crystalline cellulose 311.0 Corn starch 200.0 Hydroxypropyl cellulose 10.0 Hydroxypropyl methyl cellulose 70.0 Fatty acid monoglyceride 3.5 Titanium dioxide 5.5 1000.0 Formulation example 3 Tablet Compound 2, corn starch and cellulose glycolic acid Mix calcium in the following proportions.
A 10% ethanol solution of hydroxypropyl cellulose is added to this, kneaded, granulated using an appropriate granulation device, dried, and mixed with magnesium stearate and silicic acid anhydride in the proportions shown below, and then compressed into appropriate tablets. The tablets are compressed using a machine and coated with hydroxypropyl methylcellulose to produce a product. Tablet formulation mg/tablet compound 2 200.0 Corn starch 5.0 Cellulose calcium glycolate 20.0 Hydroxypropyl cellulose 2.0 Magnesium stearate 2.5 Silicic anhydride 2.5 Hydroxypropyl methylcellulose 19.999 Macrogol 6000 0.001 Titanium oxide 2.0 254 Formulation example 4 Suppository Witepsol W-35 (manufactured by Dynamite Nobel) at about 60℃ and then kept at about 45℃.
After mixing compound 3 with this in the following ratio,
Form into 1 g suppositories using a suitable suppository manufacturing device. Suppository prescription mg/Suppository compound 3 400.0 Witepsol W-35 600.0 1000.0

Claims (1)

[Claims] 1. General formula [In the formula, R ₁ represents a hydrogen atom, a tetrahydrofuryl group, or a benzoyl group that may have a lower alkyl group, a lower alkoxy group, or a halogen atom as a substituent. When R ₁ is a hydrogen atom, R ₂ and R ₃ represent a lower alkylcarbamoyl group and a lower alkoxycarbonyl group, respectively. Also R ₂ and R ₃
represents a hydrogen atom or a lower acyl group, respectively, when R ₁ is a group other than a hydrogen atom. ] A 2'-deoxy-5-trifluoromethyluridine derivative represented by: 2 General formula [In the formula, R ₁ represents a hydrogen atom, a tetrahydrofuryl group, or a benzoyl group that may have a lower alkyl group, a lower alkoxy group, or a halogen atom as a substituent. When R ₁ is a hydrogen atom, R ₂ and R ₃ represent a lower alkylcarbamoyl group and a lower alkoxycarbonyl group, respectively. Also R ₂ and R ₃
represents a hydrogen atom or a lower acyl group, respectively, when R ₁ is a group other than a hydrogen atom. ] An antitumor agent characterized by containing a 2'-deoxy-5-trifluoromethyluridine derivative represented by the following.