JPS6337766B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to antitumor agents. Recently, various excellent antitumor agents are being introduced into chemotherapy for malignant tumors. However, at present, no antitumor agent has been obtained that satisfies the objective of completely suppressing tumor growth and allowing patients to survive for a long period of time. Currently, 5-fluorouracils are the most commonly used and mainstream antitumor agents clinically, and it is thought that various 5-fluorouracils will be developed in the future. However, antitumor agents containing these 5-fluorouracil-based compounds as active ingredients,
Each has advantages and disadvantages. For example, 5-fluorouracil is highly effective but also has significant toxicity and side effects. Also 1-(2'-tetrahydrofuryl)-
Although 5-fluorouracil has relatively little toxicity and side effects, its antitumor effect is said to be inferior. Therefore, the development of even better 5-fluorouracils is expected. On the other hand, research is underway to enhance the antitumor effects of conventionally used antitumor agents by improving their administration methods and dosage forms. For example, (i) 5-fluorouracil is used as a water-in-oil emulsion with good lymphotropic properties; (ii) 1-(2'-tetrahydrofuryl)-5-fluorouracil is used as a suppository to enhance the antitumor effect. (iii) a multi-drug combination method in which the above-mentioned anti-tumor agent is combined with another anti-tumor agent, and the above-mentioned anti-tumor agent, for the purpose of enhancing the anti-tumor effect and reducing side effects; A method is being carried out in which the drug is used in combination with a drug that has no antitumor effect by itself. For example, J.Biol.Chem., 235 , 433 (1960).
-Although the relationship between fluorouracil and thymine has been reported, no antitumor effects have been described at all. Also, article 540 of the 36th general meeting of the Japanese Cancer Society
(1977) reported a combination therapy of 5-fluorouracil and orotic acid, but this did not involve simultaneous administration, but oral administration of orotic acid 2 hours before, followed by intraperitoneal administration of 5-fluorouracil. The administration method is difficult to use as a drug. Compounds with a skeleton of 5-fluorouracil are converted to 5-fluorouracil in vivo,
This is said to exert antitumor effects. Therefore, in this case, the concentration of 5-fluorouracil in tumor cells and its persistence are important. However, since 5-fluorouracil is metabolized very quickly and quickly becomes an inactive substance, it is necessary to take measures to prevent 5-fluorouracil from being inactivated. In such a treatment, the concentration ratio of 5-fluorouracil and the substance to prevent it from being inactivated and their persistence become important issues. In addition, it is desirable that such a substance inhibits the inactivation of 5-fluorouracil present in tumor tissues, but does not inhibit the inactivation of 5-fluorouracil present in other normal tissues. . Based on this idea, Japanese Unexamined Patent Publication No. 1973
No. 124624 reports the combined use of 5-fluorouracils and uracil. However, although uracil inhibits the metabolism of 5-fluorouracil,
-Also affects incorporation into fluorouridine monophosphate. Also, the concentration, duration and distribution of uracil are of concern. Therefore, the mixing ratio of 5-fluorouracil and uracil is 1 mole of the former to 4 to 5 moles of the latter. Furthermore, it is said that 5-fluorouracil is taken into living organisms and becomes 5-fluorouridine monophosphate, and the corresponding uridine monophosphate is biosynthesized not only from uracil but also from orotic acid. Cancer Research,
34, 3414 (1974) does not specify any combination therapy, but it does state that there is a difference in uptake between tumor tissue and normal tissue; The concentration ratio and its persistence in the medium are important issues. In view of the current situation, the present invention has carried out extensive research in order to obtain an antitumor agent that only enhances the antitumor effect of 5-fluorouracils without increasing its toxicity or side effects. As a result, 5-fluorouracils have no or almost no antitumor effect by themselves, and the general formulas [2], [3],
At least one compound represented by [4] or [5]
The present invention was completed by discovering that the object can be achieved when the seeds are mixed. That is, the present invention
general formula [In the formula, R ₁ and R ₂ may be the same or different, but each represents a hydrogen atom, an alkoxycarbonyl group,
It represents an alkoxymethyl group, a tetrahydrofuryl group, or an alkylcarbamoyl group. However, R ₁ and R ₂ are not hydrogen atoms at the same time. ] At least one 5-fluorouracil selected from the group of compounds represented by the formula [Formula] [Formula] and [Formula] [wherein R ₃ and R ₄ are the same or different] However, each hydrogen atom, bromine atom, carboxy group, nitro group, cyano group, alkylamido group,
It represents an alkylamino group, an amino group, a hydroxyl group, an alkyl group, a halogenated alkyl group, a mercapto group, or an alkoxycarbonyl group, and R ₅ and R ₆ may be the same or different, but each is a hydrogen atom or an alkyl group. , represents an alkenyl group, an alkoxycarbonyl group, an arylsulfonyl group or an alkoxymethyl group. However, in general formula [2]
Except when R ₃ is a hydrogen atom, a bromine atom, or a methyl group, and R ₄ , R ₅ and R ₆ are all hydrogen atoms. ] Compound and general formula shown by [In the formula, R ₃ and R ₄ represent the same meanings as above,
R ₇ and R ₈ may be the same or different, and each represents a hydrogen atom, an amino group, a hydroxyl group, or a mercapto group. However, R ₇ and R ₈ are not hydroxyl groups at the same time. ] An antitumor agent characterized by containing as an active ingredient at least one concomitant agent selected from the group consisting of the compounds shown below. However, general formula [In the formula, R ₉ and R ₁₀ are the same or different and represent a hydrogen atom, an alkoxymethyl group, a tetrahydrofuryl group, or an alkylcarbamoyl group. ] At least one 5-fluorouracil selected from the group of compounds represented by, and uridine, 2'-deoxyuridine, thymine, orotic acid, 5-bromouracil, 5-iodouracil, 5-bromo-
2'-deoxyuridine, 1-acetyluracil,
1-(2-tetrahydrofuryl)-uracil, 3-
Excludes antitumor agents containing as an active ingredient at least one uracil selected from benzoyluracil, 1-cyclohexylcarbamoyluracil, 1-n-hexylcarbamoyluracil, cytosine, cytidine, and 2'-deoxycytidine. All of the 5-fluorouracils used in the present invention are known compounds, and the compound represented by the general formula [1] is, for example, Japanese Patent Publication No. 49-10510, Japanese Patent Application Laid-open No. 50384-1984, Japanese Patent Application Publication No. 50-50- No. 148365, JP-A-Sho
No. 48-90135, Japanese Patent Application Publication No. 1983-88078, Japanese Patent Application Publication No. 1973-
No. 284, JP-A No. 51-86479, JP-A No. 53-31874,
It is described in JP-A-53-79880, JP-A-53-31676, JP-A-53-087371, etc. For example, as specific examples of the compound represented by the general formula [1], R ₂ is a hydrogen atom, and R ₁ is a tetrahydrofuryl group, an ethoxymethyl group, an isopropoxymethyl group, an n-hexylcarbamoyl group, an n-
Compounds such as octoxycarbonyl group, R ₁
and a compound in which R ₂ are both a tetrahydrofuryl group, an ethoxymethyl group, an n-hexylcarbonyl group, etc., and a compound in which R ₁ is an ethoxymethyl group,
Examples include compounds in which R ₂ is a tetrahydrofuryl group or the like. Compounds represented by general formulas [2], [3], [4] and [5] are also known and are generally commercially available or can be easily synthesized by known methods. These are, for example, Japanese Patent Application Laid-Open No. 52-148084
No., JP-A-49-127982, JP-A-53-40781,
Beilstein E, 24 , 170, Special Publication No. 42-12774,
US Patent No. 3322526 and British Patent No. 1035098,
It is described in issues such as No. 968661. To produce a compound in which R ₅ and R ₆ in the general formula [2], [3] or [4] are both substituted with a hydrogen atom or an organic group other than a halogen atom, the general formula [Formula] Y- R ₁₀ [7], Y-SO ₂ -R ₁₁ [8] or Y-CH ₂ -O-R ₉ [9] (wherein, Y represents a halogen atom, R ₉ is alkyl, R ₁₀ is alkyl or alkenyl, R ₁₁ represents an aryl group) [These compounds are known and generally commercially available, or can be easily synthesized by known methods. ] using a base in an aprotic organic solvent to obtain the general formula [Formula] [Formula] or [Formula] (wherein R ₃ and R ₄ have the same meanings as above).
Compounds represented by (these compounds are also known,
They are generally commercially available or can be easily synthesized by known methods. ) are condensed. As the aprotic solvent, it is advantageous to use chloroform, acetonitrile, nitromethane, etc., and as the base, organic bases such as pyridine, triethylamine, inorganic bases such as sodium hydride, sodium bicarbonate, potassium carbonate, sodium iodide, etc. A base is used. Reaction is -10℃~200℃
It can be carried out at a temperature of Although the reaction temperature varies depending on the substance used, it is preferable to carry out the reaction at room temperature to 100°C. Most reactions are completed within 1 to 24 hours. After distilling off the solvent from the reaction solution, water is added and extraction is performed using an organic solvent such as ethyl acetate. After drying the extract, it is concentrated to dryness and then recrystallized to obtain the general formula [2], [3] or [4]. ] The target compound can be obtained in high yield. To synthesize a compound of general formula [2], [3] or [4] in which R ₅ and R ₆ represent the same group, two or more equivalents of the halogen compound are used.
On the other hand, to synthesize a compound of general formula [2], [3] or [4] in which R ₅ and R ₆ represent different groups,
When either R ₅ or R ₆ represents hydrogen, it is preferred to use 1 to 1.2 equivalents of the halogen compound. Other compounds of general formula [2], [3] or [4] can be synthesized by once isolating the compound and then reacting the corresponding halogen compound in the same manner. In addition, to produce a compound represented by general formula [5], for example, a compound represented by general formula [10] and
By reacting with POCl ₃ in the presence of dimethylaniline, the general formula (In the formula, R ₃ and R ₄ have the same meanings as above.) A compound represented by the following was obtained (J.Chem.Soc., 1951 ,
1568), and a corresponding compound can be produced by reacting this with, for example, ammonia. In addition, the compound represented by the general formula [10] and P ₄ S ₁₀
When reacted with, R ₇ of general formula [5] or
_R8 is thiolated [J.Am.Chem.Soc., 78 ,
1938 (1956) and Chem.Pharm.Bull., 10 , 647
(1962)], corresponding compounds can be prepared. For example, compounds represented by the general formula [10] include thymine, 5-promouracil, 5-nitrouracil, 5-cyanouracil, 5-aminouracil, isoorotic acid, 5-dimethylaminouracil, 5-ethyluracil, isobarbituric acid,
5-dimethylamideuracil, 5-isopropyluracil, 5-chloromethyluracil, 5-mercaptouracil, 5-methoxycarbonyluracil, 5-methylcarbamoyluracil, 6-aminothymine, 6-carboxythymine, 6-cyanothymine, 6- Dimethylaminothymine, 6-nitrothymine, 6-mercaptothymine, 6-amino-5
-isopropyluracil, 6-bromothymine, 6
-Methylthymine, 6-hydroxythymine, 6-nitrothymine, 6-dimethylamidothymine, 6-n
-Hexyloxycarbonylthymine, 6-amino-5-nitrouracil, 6-carboxy-5-nitrothymine, 5,6-diaminouracil, 6-amino-5-bromouracil, 6-dimethylamino-5-nitrouracil, 6 -amino-uracil,
and 6-bromothymine. General formula [11]
Compounds represented by include 6-azauracil,
6-Azathymine, 6-aza-5-nitrouracil, 6-aza-5-isopropyluracil, 6-
Aza-5-ethyluracil, 6-aza-5-aminouracil, 6-aza-5-bromouracil, 6
-aza-isobarbituric acid, 6-aza-isoorotic acid, and 6-aza-5-mercaptouracil. Further, as the compound represented by the general formula [12], 5-azauracil, 5-aza-6-aminouracil, 5-aza-6-methyluracil,
5-Aza-6-dimethylaminouracil, 5-aza-orotic acid, 5-aza-barbituric acid, 5
-aza-6-bromouracil, 5-aza-6-dimethylamideuracil, 5-aza-6-cyanouracil, 5-aza-6-mercaptouracil, and 5-aza-6-nitrouracil. Shown in general formulas [2], [3] and [4]
Examples of R ₅ and R ₆ include the following atoms or organic groups. H, _-CH3 , -( _CH2 ) _2H , -( _CH2 ) _3H , -CH
( _CH3 ) ₂ , -( _CH2 ) _4H , -( _CH2 ) _6H , -C( _CH3 ) ₃ ,
−CH=CH ₂ , −COO(CH ₂ ) ₂ H, −COO(CH ₂ ) ₆ H,
−COOCH(CH ₃ ) ₂ , −COO(CH ₂ ) ₁₀ H, −CH ₂ CH
＝CH ₂ , [Formula] −CH ₂ OCH ₃ , −CH ₂ O(CH ₂ ) ₂ H, −CH(CH ₃ )OCH ₃ , −CH−
(OCH ₃ ) ₂ and -CH ₂ OCH (CH ₃ ) ₂ , etc.
Moreover, R ₃ , R ₄ , R ₇ shown in general formula [5]
and R ₈ include, for example, the following atoms or organic groups. -Br, _-NO2 , _-CH3 , _-NH2 , -OH, -CN, -
SH, −COOH, −COOCH ₃ , −COO(CH ₂ ) ₄ H, −
CONH(CH ₂ ) ₂ H, −CH ₂ CH ₃ , −CH(CH ₃ ) ₂ , −
Examples include CH=CH ₂ and -CH ₂ Cl. General formula [5]
Examples of the compounds include 4,6-dihydroxy-5-methylpyrimidine, 5-nitropyrimidine, 5-bromopyrimidine, 4,6-dihydroxy-5-nitro-pyrimidine, 5-methylpyrimidine, 4,6-dihydroxy- 5-aminopyrimidine, 2-mercapto-4-hydroxy-5-methylpyrimidine, cytosine, 5-methylcytosine, 5-nitrocytosine, 5-bromocytosine,
and 4-hydroxy-5-methyl-6-amino-
There are pyrimidines, etc. In the antitumor agent of the present invention, the proportion of 5-fluorouracil and a compound selected from the compounds represented by general formula [2], [3], [4], or [5] is 5-fluorouracil. and general formula [2],
Although it is difficult to make a general statement because it differs depending on the combination with the compound represented by [3], [4] or [5], generally the former (5-fluorouracils) 1
0.01 to 50 mol of the latter, preferably
It is preferable to use 0.01 mol to 10 mol. Furthermore, when two or more types of the latter are used, it is preferable to use each of them in the above-mentioned molar amounts. However, the amounts of each do not need to be the same. In the present invention, the 5-fluorouracils and the compounds represented by the general formulas [2], [3], [4] and [5] can be administered separately, but they can be administered by combining them in advance. Preferably, they are administered simultaneously. As the dosage unit form of the antitumor agent according to the present invention, various forms can be selected depending on the therapeutic purpose. For example, oral preparations include tablets, capsules, granules, etc., and parenteral preparations include injections, suppositories, etc. The amount of 5-fluorouracil compounded in these various dosage unit forms varies depending on the type of 5-fluorouracil compound, so it cannot be particularly limited, but it is based on the clinical value estimated from actual clinical and basic efficacy experiments. The recommended dose is 5 mg to 3000 mg per person per day. More specifically, it is desirable to use 50 mg to 1000 mg per day for oral preparations, and 5 mg to 500 mg per day for injection preparations. However, the dosage range varies depending on the patient's age, sex, and symptoms. Next, as a representative example of 5-fluorouracil,
^N1 -ethoxymethyl-5-fluorouracil,
FT-207, N1- ⁿ -octoxycarbonyl-5
-Fluorouracil, ^N1 , ^N3 -di(2'-tetrahydrofuryl)-5-fluorouracil, N1 ^- n
-Hexylcarbamoyl-5-fluorouracil was used to investigate the effects of combination with various concomitant drugs. Seven days after transplantation, Sarcoma-180 solid tumors were cut into pieces with a diameter of 2 to 4 mm with a scalpel, and placed subcutaneously in the left fossa of JCL-ICR mice (5 weeks old, 1 group: 6 to 8 mice). It was transplanted and used for experiments. 1 day after 24 hours after tumor implantation
The drug was orally administered every day for 7 days, and tumor weight and body weight were measured on the 10th day. Efficacy was evaluated by comparing the drug administration group and the control group based on the average tumor weight ratio (T/C) and body weight change rate (average body weight ratio between the first day of administration and the 10th day). Weight change rate is a barometer of drug toxicity. In addition, in the sense of comparison with the drugs of the present invention, the effects of each alone, the effects when used in combination with uracil, and the currently commercially available antitumor agent N ¹ -(2'-tetrahydrofuryl) are also shown. -5-
The effect of fluorouracil (FT-207) was also investigated. These results are shown in the table. [Table] [Table] [Table] [Table] [Table] [Table] As is clear from the table, the antitumor effect is more enhanced when used in combination than when used alone.
Moreover, the combination of uracil and 5-fluorouracils and FT-207 alone are superior in terms of antitumor efficacy, toxicity, and dosage. Next, a prescription example of the antitumor agent of the present invention will be given. Formulation Example 1 N ¹ -(2′-tetrahydrofuryl)-5-fluorouracil 200 mg N ¹ -methyluracil 100 mg Lactose 97 mg Crystalline cellulose 50 mg Magnesium stearate 3 mg Capsules containing 450 mg per capsule are prepared at the above blending ratio. Prescription example 2 N ¹ -ethoxymethyl-5-fluorouracil
200mg N1- ⁿ -butoxycarbonyluracil 200mg Lactose 240mg Corn starch 350mg Hydroxypropyl methylcellulose 10mg Granules of 1000mg per package are prepared at the above mixing ratio. Prescription example 3 N ¹ -ethoxymethyl-5-fluorouracil
250mg 6-Azathymine 500mg Trisaminomethane 800mg Distilled water for injection Appropriate amount Prepare 5ml of injection per ampoule using the above mixing ratio. Formulation example 4 N ¹ ,N ³ -bis(2'-tetrahydrofuryl)-5-
Fluorouracil 1000mg 5-nitrouracil 500mg Uitebuzol W-35 700mg Prepare 2200mg suppositories per suppository using the above mixing ratios. When the antitumor effect against Sarcoma-180 solid tumor was measured for the drugs prepared in Prescription Examples 1 to 4 according to the above test method, all T/C values were
It was 0.1-0.8.

Claims (1)

[Claims] 1. General formula [In the formula, R ₁ and R ₂ may be the same or different, but each represents a hydrogen atom, an alkoxycarbonyl group,
It represents an alkoxymethyl group, a tetrahydrofuryl group, or an alkylcarbamoyl group. However, R ₁ and R ₂ are not hydrogen atoms at the same time. ] At least one 5-fluorouracil selected from the group of compounds represented by the formula [Formula] [Formula] and [Formula] [wherein R ₃ and R ₄ are the same or different] However, each hydrogen atom, bromine atom, carboxy group, nitro group, cyano group, alkylamido group,
It represents an alkylamino group, an amino group, a hydroxyl group, an alkyl group, a halogenated alkyl group, a mercapto group, or an alkoxycarbonyl group, and R ₅ and R ₆ may be the same or different, but each is a hydrogen atom or an alkyl group. , represents an alkenyl group, an alkoxycarbonyl group, an arylsulfonyl group or an alkoxymethyl group. However, in general formula [2]
R ₃ is a hydrogen atom, a bromine atom or a methyl group,
The case where R ₄ , R ₅ and R ₆ are all hydrogen atoms is excluded. ] Compounds and general formula [In the formula, R ₃ and R ₄ represent the same meanings as above,
R ₇ and R ₈ may be the same or different, and each represents a hydrogen atom, an amino group, a hydroxyl group, or a mercapto group. However, R ₇ and R ₈ are not hydroxyl groups at the same time. ] An antitumor agent characterized by containing as an active ingredient at least one concomitant agent selected from the group consisting of the compounds shown below. However, general formula [In the formula, R ₉ and R ₁₀ are the same or different and represent a hydrogen atom, an alkoxymethyl group, a tetrahydrofuryl group, or an alkylcarbamoyl group. ] At least one 5-fluorouracil selected from the group of compounds represented by, and uridine, 2'-deoxyuridine, thymine, orotic acid, 5-bromouracil, 5-iodouracil, 5-bromo-
2'-deoxyuridine, 1-acetyluracil,
1-(2-tetrahydrofuryl)-uracil, 3-
Excludes antitumor agents containing as an active ingredient at least one uracil selected from benzoyluracil, 1-cyclohexylcarbamoyluracil, 1-n-hexylcarbamoyluracil, cytosine, cytidine, and 2'-deoxycytidine. . 2 The compound represented by the general formula [1] is N ¹ −(2′-
tetrahydrofuryl)-5-fluorouracil,
The antitumor agent according to claim ¹ , which is N1-ethoxymethyl-5-fluorouracil or ^N1 -n-hexylcarbamoyl-5-fluorouracil.