JPH0441145B2 - - Google Patents

Description

[Detailed description of the invention]

TECHNICAL FIELD This invention relates to novel 5-pyrimidine-carboxamides and thiocarboxamides and their pharmaceutically acceptable addition salts and nucleosides. The invention particularly relates to novel 5-pyrimidine carboxamide derivatives. This new compound can be used as a treatment for leukemia and tumors. The present invention also relates to medicinal compositions containing the above derivatives as therapeutically active ingredients. BACKGROUND ART It is known that 5-pyrimidine carboxamides, particularly the 5-carboxamide of barbituric acid, have potential anticancer effects. For example, Tokko Akira
Publication No. 39-1445 [Takeda Pharmaceutical Co., Ltd.; 1964 2
(Announced on May 14th), the following formula The use of compounds such as 5-phenylcarbamoylbarbituric acid (R=H) and 1-substituted-phenylcarbamoylbarbituric acid (R=alkyl or phenyl group) for this purpose has been disclosed. . When in vivo experiments were conducted using mice with Ehrlich's carcinomatous ascites, the unsubstituted compounds mentioned above, their 1-methyl derivatives, and 1-phenyl derivatives did not show any anticancer activity [■Chem.&Pharm .Bull. (Tokyo),
8, 1021-1028 (1960)]. Barbiturate derivatives similar to the above-mentioned known compounds are also described in the literature. For example, (Here, R ¹ is an alkyl group, an alkenyl group,
Various substituted alkyl groups, substituted alkenyl groups, carbonyl groups, unsubstituted or substituted aryl groups or aralkyl groups. Each of R ² and R ³ is an alkyl group, alkenyl group, cycloalkyl group, aryl group, aralkyl group, or hydrogen, provided that R ² and R ³ do not jointly represent hydrogen, and X is oxygen or sulfur) is an N-substituted-2-amidocarbonylthiobarbituric acid having
DE 2405732 (Bayer AG) and US Pat. No. 3961061 (Kramer et al.;
(published June 1, 1976). The above publications describe that these thiobarbituric acid derivatives have insecticidal, acaricidal, bactericidal, and bactericidal properties. Another 5-carboxamide-substituted-thiobarbituric acid, such as _{( wherein} ^, and R ₄ is hydrogen, methyl or trihalomethyl and R ₅ is hydrogen, halogen, methyl or methoxy. These compounds are described in European Patent No. 74335 (Ciba-Geigy) and US Patent No. 4283444 (De Sousa et al.; 1981
(Published August 11, 2013) and disclose that they are useful as insect repellents for keratinous materials, such as wool. An object of the present invention is to provide novel 5-pyrimidine carboxamides and thiocarboxamides, particularly 5-carboxamide derivatives, and pharmaceutical compositions thereof useful as therapeutic agents for leukemia and tumors. Other objects and advantages of the invention will become more apparent from the following description of preferred embodiments of the invention. Structure of the invention The present invention is based on the following formula (Here, each of R ₁ and R ₂ is independently hydrogen, an alkyl group, an aryl group, an aralkyl group, an allyl group, an aralkenyl group, an aralkynyl group, and an alkyl group, an alkenyl group among these groups) The radical or alkynyl moiety has 1-6 carbon atoms; R ₃ is hydrogen, C ₁ -C ₄ alkyl or aryl; R ₄ is phenyl, naphthyl, benzine,
naphthylmethyl, thienyl, thienylmethyl or pyridyl; or substituted phenyl, naphthyl, benzyl, naphthylmethyl, thienyl, thienylmethyl or pyridyl; The groups are substituted with one or more of the following groups: hydroxyl; halogen; 1-
Alkyl, alkoxy, alkylthio, haloalkyl or haloalkoxy with 4 carbon atoms; carboxyl; alkoxycarbonyl with 2-5 carbon atoms; nitro; cyano; aryl; aryloxy Base;
arylthio group; benzyl group; benzyloxy group; naphthylmethyl group; naphthylmethyloxy group; thienyl group; or substituted with thienylmethyl group; W is oxygen or sulfur; X is sulfur or selenium; each of Y and Z is independently oxygen, sulfur or selenium) It concerns the addition salt obtained. The present invention is particularly applicable to the following formula: (wherein R ₄ is a phenyl group or a substituted phenyl group, and such a substituted phenyl group is one substituted with one or more of the following groups, i.e., halogen, or 1-4 is an alkyl group or alkoxy group having carbon atoms; each of R ₅ and R ₆ is independently hydrogen, or a furanosyl group, a pyranosyl group,
The present invention relates to 5-pyrimidine carboxamides having a carbohydrate residue selected from the group consisting of deoxy-derived groups thereof and aliphatic analogues thereof, and pharmaceutically acceptable addition salts thereof. These are useful compounds. Addition salts of the above compounds can be formed using a variety of pharmaceutically acceptable organic and salt-forming agents. For example, useful addition salts can be formed by mixing the compound, which is an organic acid, with one equivalent of base. Examples of this base include triethylamine or N
-Organic amines such as methylglucamine, and inorganic cations such as sodium and potassium ions. The organic acid addition salts of the present invention are generally crystalline solids, which are relatively sparingly soluble in both polar solvents such as water, methanol and ethanol, and non-polar solvents such as diethyl ether, benzene and toluene. It is. It is somewhat soluble in aprotic solvents such as dimethylformamide and dimethylsulfoxide. When R ₁ or R ₂ is a carbohydrate residue,
This includes furanosyl groups (e.g. arabinofuranosyl or ribofuranosyl groups), pyranosyl groups (e.g. glucofuranosyl groups), their deoxy derivatives or their aliphatic analogs [e.g. hydroxyalkoxyalkyl or polyhydroxyalkyl groups (such as alkoxy and alkyl groups in the group have 2-12 carbon atoms),
Specific examples thereof may be 2-hydroxyethoxymethyl group and 2,3-dihydroxypropyl group. As used herein, the term "carbohydrate residue" refers to cyclic and acyclic groups that constitute pyrimidine or pseudonucleosides, and examples of these nucleoside materials include the specific Examples include various substances containing cyclic groups and acyclic groups. The 5-carboxamide or thiocarboxamide 2-thio-barbituric acid derivatives mentioned above may exist in the form of formula () or in the form of its tautomers. For ease of description, the compounds of the invention are:
Although described herein as having the form shown in formula (), it is understood that this description also includes the tautomer or tautomeric mixture thereof. Should. Among the compounds mentioned above, each of R ₁ and R ₂ is hydrogen, or one of R ₁ and R ₂ is hydrogen and the other is a carbohydrate residue.
Pyrimidine carboxamides (i.e. 5-pyrimidine carboxamides of formula ()) and thiocarboxamide compounds are new compounds. Furthermore, 5-pyrimidine carboxamides and thiocarboxamides of 2-selenobarbituric acid are also new compounds. The 5-carboxamido-2-thiobarbituric acid derivative is prepared in the presence of a solvent or dispersion medium such as dimethylsulfoxide, pyridine, dimethylformamide, N-methylpyrrolidone, dimethylformamide, sulfolane, tetrahydrothiophene oxide or acetamide. It can be easily produced by reacting 2-thiobarbituric acid with phenyl isocyanate or a suitable organic isocyanate. It is known to add tertiary amines, such as triethylamine, or organic bases, such as pyridine, to promote reactions involving isocyanates or isothiocyanates. The molar ratio of 2-thiobarbituric acid to phenyl isocyanate reactant may be about 2:1 to 1:2, preferably about 1.1:1 to 1:1.1. Generally, stoichiometric ratios are sufficient. This reaction can be carried out at temperatures of about 0-200°C, generally 24-160°C. In most cases, the reaction proceeds very well at temperatures of about 80-100°C. The reaction for producing the 5-carboxamide derivative is substantially complete in a reaction time of about 1/2 to 6 hours, generally about 2 to 4 hours. Alternatively, it is also possible to produce the carboxamides and thiocarboxamides described above by other production methods. For example, by reacting thiourea with a suitable arylaminocarbonyl malonic acid diester (prepared by reacting a malonic acid diester with a suitable unsubstituted or substituted arylisocyanate according to known methods), The product can be produced by a method consisting of separating and recovering the product. If desired, instead of thiourea, the formula 2-thioxo - It is also possible to produce pyrimidine carboxamides or thiocarboxamides. The compounds of the present invention can also be prepared by the following process: reacting an unsubstituted pyrimidine with a dialkyl sulfate or other alkylating agent, and reacting the resulting 2-(alkylthio)pyrimidinedione with a suitable unsubstituted pyrimidine. or a substituted organic isocyanate to produce a product having the desired 5-carboxamide or thiocarboxamide group, and this product is reacted with hydrogen sulfide or its alkali metal or ammonium salt to produce the desired product. can get things. Alternatively, the desired product of the present invention, the carboxamide or It is also possible to produce thiocarboxamide compounds. The carboxamides and thiocarboxamides of 2-selenobarbituric acid described above can be produced by reacting selenourea with a suitable arylaminocarbonylpropane dioxic acid diester according to the method described above. The compounds of the present invention are useful cytotoxic drugs that induce regression of symptoms of hematological malignancies such as leukemia and inhibit the growth of solid and non-solid tumors. It can be used alone or in combination with other chemotherapeutic agents for the above purposes. The term “degeneracy” used here
(regression) and “inhibition” are
means to prevent or retard the growth of malignant tumors or the development of other symptoms in the above-mentioned diseases (i.e., the growth of tumors or the development of other symptoms in the above-mentioned diseases if left untreated) but,
(means that it has been prevented or delayed by drug administration, etc.). When administering the 5-pyrimidine carboxamides and thiocarboxamides of the present invention to mice, the dosage is about 12-200 mg/Kg (body weight), preferably about 25-200 mg/Kg (body weight).
A dose of 100 mg/Kg (body weight) was found to be an effective dose to induce regression of leukemia and to inhibit tumor growth. Regarding the relationship between dose and animal type and size (or body weight), see Freireich, EJ's article “Quantitative Comparison of Toxicity of Anticancer Drugs in Mice, Rats, Hamsters, Dogs, Monkeys, and Humans” [“Cancer
Chemotherapy”, Reg・50, No. 4, pp. 219-244,
published in May 1966]. The dosage can be adjusted accordingly to obtain the optimum therapeutic effect. For example, the drug can be administered several times every month, or if a dangerous condition arises during treatment, the dose and frequency of administration can be reduced as appropriate depending on the condition. Preferably, the active compound is administered parenterally, for example by intraperitoneal or intravenous injection, or by oral administration. Solutions or dispersions can be prepared by mixing the active compounds with water. In this case it is advantageous to incorporate surfactants such as hydroxy-propyl cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, mixtures thereof, or in oils. Preservatives are preferably added to these formulations to prevent the growth of microorganisms when stored and used under normal conditions. Examples of formulations suitable for injection include sterile aqueous solutions and dispersions. Sterile powder formulations are also conveniently prepared for the extemporaneous preparation of sterile injectable solutions or dispersions. Preparations used as injections must be sterile and fluid enough to be injectable. It must be stable under the conditions of manufacture and storage and must have preservative properties that resist the contaminating action of microorganisms such as bacteria and fungi. The carrier in the formulation may be a solvent or dispersion medium, including water, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. can give.
To maintain proper liquidity, the following operations can be performed:
That is, it can be coated with lecithin etc.
Alternatively, in the case of a dispersion, the particle size can be maintained at a predetermined size, or a surfactant can be added. Various types of disinfectants can be used to prevent the growth of microorganisms, examples of which include parabens, chlorobutanol, phenols, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, examples of which include sucrose and common salt in the form of dosage forms. By incorporating an absorption delaying agent such as aluminum monostearate or gelatin into an injectable preparation, the injectable preparation can be made to have long-term absorption. The manufacturing method of sterile injection solution will be explained. The active compound is mixed with a suitable solvent and, if necessary, various other ingredients mentioned above, followed by filtration and sterilization. For preparing dispersions, the sterile active ingredient is generally incorporated into a sterile vehicle that contains the dispersion medium and the required other ingredients. On the other hand, when making a sterile injection using a sterile powder, a solution of the prescribed ingredients is sterilized and filtered, and then this solution is vacuum-dried or freeze-dried to separate the active ingredients and desired auxiliary ingredients. It is preferable to prepare a powder containing the following and use this powder to make an injection. The term "pharmaceutically acceptable substantially non-toxic carrier or excipient" as used herein refers to
Solvents, dispersion media, coating agents, bactericides, isotonic agents,
This term includes absorption delaying agents and the like. The use of carriers or excipients as described above for the formulation of pharmaceutically active substances is well known in the art. Any conventional vehicle or excipient can be used in the present invention for the preparation of therapeutic agents, except those vehicles or excipients that are incompatible with the active ingredient or are toxic. It is also possible to incorporate supplementary active ingredients into the therapeutic agent. It is advantageous to formulate the compositions of the present invention into unit dose formulations to allow for accurate and easy administration of a given dose of medicament. As used herein, the term "unit-dose preparation" refers to a physically separate preparation suitable for administering a unit dose (e.g., a single dose) of a drug to the mammalian animal in which a therapeutic trial is to be conducted. means. Here, one unit of the preparation contains a predetermined amount of the active ingredient calculated to produce the desired therapeutic effect, together with a predetermined pharmaceutically acceptable carrier. The formulation and preparation method for this unit dose-containing preparation is subject to the following conditions:
It will vary depending directly on (a) and (b). (a) the unique properties of the active substance and the type of therapeutic effect to be achieved; (b) in formulating the therapeutic active substance to treat diseased organisms without undue cytotoxic side effects; Restrictive requirements imposed on the technical field. This formulation is administered daily, and this administration is
It has been found that by continuing the treatment for up to 10 days, or for up to 10 days, or longer, leukemia symptoms can be reduced and tumor growth can be inhibited. Repeated administration or administration over a period of time is also possible. Thus, this therapeutic active ingredient can be administered in a sufficient amount to exhibit the effect of reducing the symptoms of leukemia and inhibiting tumor growth, and in this case, no excessive side effects due to cytotoxicity are observed. do not have. Description of the best embodiment of the invention Among the 5-pyrimidine carboxamides and thiocarboxamides of the present invention, preferred ones are those in which R ₄ in formula () is a phenyl group, a 2- or 3-halophenyl group, a 2-methylphenyl group, 2, 4-difluorophenyl group, 4-fluorophenyl group,
2-methoxy-5-methylphenyl group, 4-(C ₁
-C ₆ ) alkoxyphenyl group, 2- or 4-
This is a compound that is a trifluoromethylphenyl group. Particularly preferred compounds include a _phenyl group (Example 1 below), a 2-chlorophenyl group (Example 2), a 2-
Methylphenyl group (Example 3), 3-fluorophenyl group (Example 4), 4-fluorophenyl group (Example 5),
4-methoxyphenyl group (Example 6), or 4-ethoxyphenyl group (Example 7), 2-fluorophenyl group (Example 8), 2,4-difluorophenyl group (Example 9), 2-methoxy -5-methylphenyl group (Example 10). The best results to date have been obtained using the compound of Example 1, 1,2,3,4-tetrahydro-6-hydroxy-4-oxo-N-phenyl-2-thioxo-5-pyrimidine carboxide. Obtained. The following examples are presented to specifically illustrate the preparation of the compounds of the invention and the results of pharmacological testing, ie to illustrate the invention. The temperature values given in these examples are in degrees Celsius.
and "parts" are "parts by weight." Abbreviations in the NMR data of the following examples have the following meanings. multi.: multiplet, integ.: area of peak, sing.: singlet, br.diff.p.: widely dispersed peak, overlap.br.sing.: overlapping broad singlet, comb.integ.: combined area of the peak, dovbl.: doublet, tripl.: triplet, quart.: quartet, br.diff.multi.: widely dispersed multiplet, br.singl.: broad singlet, br.diff.absorp.: broadly dispersed absorption, diff.br.p.: widely dispersed peaks, overlap.: overlapping, diff.p.: dispersed peaks, compl.multi.: complex multiplet. (I) Production example of the compound of the present invention 1 1,2,3,4-tetridro-6-hydroxy-4-oxo-N-phenyl-2-thioxo-5
-Production of pyrimidine carboxamide (A) Reaction of thiobarbituric acid and phenyl isocyanate 2-thiobarbituric acid [also known as dihydro-2
-thioxo-4,6-(1H,5H)-pyrimidine-
14.4 g of dione or 4,6-dihydroxy-2-mercaptopyrimidine] and 11.9 g of phenyl isocyanate were dissolved in 100 ml of dry pyridine. The solution was heated with stirring and kept at 75-85°C for about 4 hours. After cooling, an orange solid precipitates out and this precipitate is isolated and treated with dimethylformamide approx.
Washed with 25 ml and dried. Yield: 16.8g (64%). NMR (DMSO): 7.1−8.0δ (multi; integ.5);
11.4δ (sing., 1); 12.0−13.7δ (br.diff.p., 3
) The results of elemental analysis were as follows (C ₁₁ H ₉ N ₃
as _O3S ). Calculated value Measured value C 50.19(%) 50.30(%) H 3.45 4.02 N 15.96 15.75 The results of mass spectrometry analysis were as follows. Calculated Value Measured Value M/e=263 263 This compound decomposed at temperatures above 310°C. The structure of this compound was further confirmed by X-ray crystallographic studies on its triethylammonium salt. (B) Reaction between thiourea and carboxyanilide malonate 1.5 g of thiourea and the following formula and 3.6 g of carboxyanilide malonate were placed in a small flask and heated very gently on an oil bath. At about 115°C the reaction mixture became semi-liquid and solid residue settled to the bottom of the flask. At about 150°C the reaction mixture began to thicken and volatiles were lost. reaction mixture to 180
℃ and held at this temperature for 1/2 hour, then cooled. A khaki to ocher colored powder product was obtained. The product was washed with ethanol and dried (1.8g). Molecular weight: 263; molecular weight of pyrimidine carbonyl moiety: 171; molecular weight of aniline moiety: 93. Example 2 N-(2-chlorophenyl)-1,2,3,4-tetrahydro-6-hydroxy-4-oxo-2-
Preparation of thioxo-5-pyrimidinecarboxamide 14.4 g of 2-thiobarbituric acid were carefully dried, finely ground and suspended in 100 ml of dry toluene. This suspension was heated to about 50°C under stirring,
15.35 g of 2-chlorophenyl isocyanate was added. Most of this suspension became a solution.
The mixture was stirred at 75-85°C for 4 hours and left overnight at room temperature. Pyrimidine carboxamide was obtained as a purple powder. This was washed with a small amount of pyridine,
At this time, most of the color disappeared. Resuspended in 100% ethanol, triturated, and the product was collected and dried. Yield 23g (77%). The product was an off-white powder. No sharp melting point, 250
Decomposed at temperatures above °C. NMR (DMSO)7.1
−8.3δ (multi., integ.4); 11.8δ (sing.1); 11.7
−
13.0δ (br.diff.p.3) Mass spectrum: 299-297 (molecular ion, chlorine isotope); 171 (pyrimidine carbonyl moiety); 129-127 (o-chloroaniline moiety; chlorine isotope). Example 3 1,2,3,4-tetrahydro-6-hydroxy-N-(2-methylphenyl)-4-oxo-2-
Preparation of thioxo-5-pyrimidine-carboxamide 2-thiobarbituric acid and 2-methylphenyl isocyanate were reacted according to the procedure described in Example 2. The desired pyrimidine carboxamide was obtained in the form of a tan powder. Melting point >250℃ (decomposition); NMR (DMSO), 2.3δ (sing., integ.3);
7.15−8.00δ(multi., 4); 11.4δ(sing., 1); 1
2.0
−13.7δ (br.diff.p., 3). Mass spectrum: 277;
171; 107. Example 4 N-(3-fluorophenyl)-1,2,3,4-
Tetrahydro-6-hydroxy-4-oxo-2
Preparation of -thioxo-5-pyrimidinecarboxamide The reaction was carried out according to the procedure described in Example 2 using 3-fluorophenyl isocyanate. The desired pyrimidine carboxamide was obtained in the form of a red powder. Melting point >250°C (decomposition). NMR
(DMSO): 6.7−7.7δ (multi; integ.4); 11.4δ
(sing.1); 12−13δ (br.diff.p.3). Mass spectrum: 281; 171; 111. Example 5 N-(4-fluorophenyl)-1,2,3,4-
Tetrahydro-6-hydroxy-4-oxo-2
Preparation of -thioxo-5-pyrimidinecarboxamide 14.4 g of 2-thiobarbituric acid was suspended in pyridine, and 13.7 g of 4-fluorophenyl isocyanate was added thereto. The reaction mixture was kept at 90° C. for 1 hour and then left at room temperature overnight. The resulting solid was collected, washed with pyridine, resuspended in ethanol, collected again and dried. This gave a bluish-white powdered product. Melting point >250°C (decomposition). NMR (DMSO):
7.0−7.7δ (multi, integ.4); 10.7−11.4δ (overla
p.
br.sing.;comb.integ.4). MS (“mass spectrum”)
(abbreviation): M/e = 281 (calculated value 281). Example 6 1,2,3,4-tetrahydro-6-hydroxy-N-(4-methoxyphenyl)-4-oxo-2
Preparation of -thioxo-5-pyrimidinecarboxamide The reaction was carried out according to the procedure described in Example 2 using 4-methoxyphenyl isocyanate. The desired product was obtained as a yellow powder. Melting point >330°C (decomposition). MNR (DMSO): 3.81δ (singl,
integ.3); 6.9−7.6δ [two symmetrical doubles (the distance between them is short)]; 11.4δ (singl.1); 11.7−12.3
δ
(br.diff.p.3). MS: 293; 171; 123. Example 7 N-(4-ethoxyphenyl)-1,2,3,4-
Tetrahydro-6-hydroxy-4-oxo-2
Preparation of -thioxo-5-pyrimidinecarboxamide The reaction was carried out according to the procedure described in Example 2 using 4-ethoxyphenyl isocyanate. The desired pyrimidine was obtained as a yellow-red powder. Melting point >250°C (decomposition). NMR (DMSO):
1.35δ (tripl., integ.3); 4.1δ (quart., 2); 6.
9−
7.6δ (two symmetrical doubles with narrow mutual spacing, 4);
11.4δ (singl.1); 12−13δ (br.diff.p.). MS：307
;
171; 137. Example 8 N-(2-fluorophenyl)-1,2,3,4-
Tetrahydro-6-hydroxy-4-oxo-2
-Production of thioxo-5-pyrimidine-carboxamide The same procedure as in Example 2 was carried out, but this time 2
-The reaction was carried out using fluorophenyl isocyanate. The desired pyrimidine compound was obtained as a blue-white-reddish-purple powder. Melting point>250℃
(Disassembly). NMR (DMSO): 7.2−8.4δ (complex
multi.); 11.8δ (singl.). MS: 281; 171; 111. Example 9 N-(2,4-difluorophenyl)-1,2,
Preparation of 3,4-tetrahydro-6-hydroxy-4-oxo-2-thioxo-5-pyrimidinecarboxamide The same procedure as in Example 2 was carried out, but this time using 2,4-difluorophenyl isocyanate. The reaction was carried out. The desired pyrimidine compound was obtained as a blue-white-reddish-purple powder. Melting point >250°C (decomposition). NMR (DMSO) 7.0−8.3δ (complex multi.); 11.8δ (singl.); about 10.7−11.8δ (br.d
iff.
multi.). MS: 299; 171; 129. Example 10 1,2,3,4-tetrahydro-6-hydroxy-N-(2-methoxy-5-methylphenyl)-4
-Production of oxo-2-thioxo-5-pyrimidinecarboxamide The same operation as in Example 2 was carried out, but this time 2
The reaction was carried out using -methoxy-5-methylphenyl isocyanate. The desired pyrimidine compound was obtained as a red powder. Melting point >280°C (decomposition). NMR (DMSO): 2.3δ (singl., integ.3);
3.9δ (singl., integ., 3); 7.0δ (br.singl.,
integral2); 7.9δ (br.singl., integ.1); 11.6δ (
br.
singl., integ.1). MS: 307; 171; 137. Example 11 Production of 1,2,3,4-tetrahydro-6-hydroxy-1,3-dimethyl-4-oxo-N-phenyl-2-thioxo-5-pyrimidinecarboxamide (A) N,N-dimethylthiobarbi Reaction between toric acid and phenyl isocyanate (reaction in the presence of triethylamine) N,N-dimethyl-2-thiobarbituric acid
10g was suspended in 250ml toluene and 7.1g triethylamine was added followed by 8.26g phenyl isocyanate. These solids went into solution. The reaction mixture was heated under reflux for 12 hours,
Afterwards the solvent was removed in vacuo. Dilute the residue with dilute HCl
The mixture was then ground and recrystallized from glacial acetic acid. The desired pyrimidine carboxamide was obtained as red-yellow needles. Melting point 194-196℃.
Yield: 13.6g. NMR (CICl ₃ ): 3.78δ (singl,
integ.6);7.25−7.55δ(multi.integ.4);11.8−
18.3δ (br.singl.). (B) Reaction without using triethylamine 10 g of N,N'-dimethyl-2-thiobarbituric acid was prepared in the same manner as described in (A) above.
and 8.26 g of phenyl isocyanate were reacted in pyridine. However, this time I did not use triethylamine. The reaction mixture was heated gently for 2 hours, cooled and acidified with dilute HCl. The resulting red solid was collected, washed with water, suspended in ethanol, heated and filtered hot. The filter cake was recrystallized from glacial acetic acid. Previous item
A yellow solid product was obtained which was substantially identical to the product described in (A). Melting point: 193℃. Example 12 1,2,3,4-tetrahydro-6-hydroxy-4-oxo-N-1,3-triphenyl-2-
Production of thioxo-5-pyrimidinecarboxamide 1,3-diphenyl-2-thiobarbituric acid
10 g was dissolved in the minimum required amount of dimethyl sulfoxide (DMSO) and 3.5 g of triethylamine was added. 4.5 g of phenyl isocyanate were added to this solution with stirring, and the mixture was heated gently for 2 hours and then poured into water. The resulting solid was separated, dried and recrystallized from glacial acetic acid. Grayish white small needle crystals were obtained. Melting point 291.5-293℃.
NMR (DMSO): 7.2-7.5δ (multi.); several other peaks (diff. significant, impossible to accurately identify). Example 13 1,2,3,4-tetrahydro-6-hydroxy-3-methyl-4-oxo-N-phenyl-2-
Production of thioxo-5-pyrimidinecarboxamide 10 g of N-methyl-2-thiobarbituric acid
Dissolved in DMSO and added 9.7 g of triethylamine followed by 8.26 g of phenyl isocyanate.
This mixture was heated for several hours. After cooling, a cluster of white needles formed. This was collected and suspended in hot HCl, and the solids were collected and dried. Melting point 252−254
A grayish white powder was obtained. NMR
(DMSO): 3.53δ (singl.integr.3); 7.2−7.6δ
(multi.integr.4); 11.4δ (br.singl.integr.1);
Approximately 5.2
−6.7δ (br.diff.absorp.). Example 14 2-[[(1,2,3,4-tetrahydro-6-hydroxy-4-oxo-1,3-diphenyl-2
-thioxo-5-pyrimidinyl)carbonyl]amino]-benzoic acid methyl ester Dissolve 8 g of N,N'-diphenyl-2-thiobarbituric acid in a minimum amount of DMSO, add 4 g of triethylamine, and then A solution of 5.1 g of methoxyphenyl isocyanate (solvent: small amount of DMSO) was added. Heat this mixture and
It was then left overnight. The resulting group of yellow crystals was collected and triturated in dilute HCl. The product was collected, washed with water and dried. A yellow powder product was obtained, which did not have a clear melting point (began to decompose at 230° C.). NMR
(DMSO): 3.8δ (singl.integ.3); 7.2−8.3δ (complex
multi.;integ.14);12.5δ(br.singl.;imteg.1). Example 15 N-(4-chlorophenyl)-1,2,3,4-tetrahydro-6-hydroxy-4-oxo-2-
Preparation of Thioxo-5-pyrimidinecarboxamide Following the same procedure as in Example 14, N-phenyl-2-thiobarbituric acid and 4-chlorophenyl isocyanate were reacted. A red powder product was obtained with no distinct melting point. this is
Decomposed at 170-185°C. MNR (DMSO):
4.7−5.6δ (diff.br.p.); 7.2−7.7δ (multi); 8.8
δ(br.
singl.). Example 16 N-(3,4-dichlorophenyl)-1,2,3,
Preparation of 4-tetrahydro-6-hydroxy-4-oxo-2-thioxo-5-pyrimidinecarboxamide 7.2 g of 2-thiobarbituric acid were suspended in dry DMF and 6.9 g of triethylamine were added. To this was added a solution of 3,4-dichlorophenyl isocyanate in DMF. The reaction mixture was heated gently for several hours, cooled, and poured into dilute hydrochloric acid. A large amount of reddish-white solid formed. Collect this product,
This was resuspended in ethanol and collected again.
Dry. The product was obtained in the form of a red solid. Melting point >275°C (decomposition). NMR (DMSO): 7.5−7.75δ
(Two br.p. specific to chlorophenyl compounds);
The other peaks were extremely diff. and could not be identified. Example 17 N-(4-butylphenyl)-1,2,3,4-tetrahydro-6-hydroxy-3-methyl-4-
Preparation of oxo-2-thioxo-5-pyrimidinecarboxamide Following the same method as in Example 11, 7.7 g of N-methyl-2-thiobarbituric acid and 4-butylphenyl isocyanate were reacted. The product was obtained in the form of a bluish-red solid. melting point
190℃ (decomposition). NMR (DMSO): 0.6−1.7δ (tripl.
and muti., integ.7); 2.5δ (DMSO
D5 - peak overlapped with the signal, i.e. hidden by the signal); 3.5δ (singl., integ.3); 6.9 -
7.5δ (multi., integ., 4); 8.4δ and 11.4δ (di
ff.
p.). Example 18 1,2,3,4-tetrahydro-6-hydroxy-3-methyl-4-oxo-N-phenyl-2-
Preparation of thioxo-5-pyrimidinecarbothioamide 9.5 g of N-methyl-2-thiobarbituric acid is dissolved in the minimum required amount of DMSO, to which 8.4 g of triethylamine is added, and then a solution of 8.2 g of phenylisothiocyanate ( A solution dissolved in a small amount of DMSO) was added. The mixture was heated for several hours, cooled and poured into dilute hydrochloric acid. A large amount of red solid formed. The solid was collected, washed with water and ethanol, and dried. A gray amorphous powder product was obtained. Melting point: approximately 245°C (decomposition). NMR (DMSO):
3.6δ (singl., integ.3); 6.96δ (singl., integ.1
);
7.2−7.6δ(mult., integ.5); 13.6δ(br.singl.,
integ.1). MS: M/e=293 (calculated value 293). Example 19 Preparation of 1,2,3,4-tetrahydro-6-hydroxy-N-(1-naphthalenyl)-4-oxo-2-thioxo-5-pyrimidinecarboxamide 10 g of 2-thiobarbituric acid are suspended in pyridine. 11.1 g of 1-naphthalenyl isocyanate
was added. The reaction mixture was kept at 90° C. for 1 hour and then left at room temperature overnight. The resulting solid was collected, washed with a small amount of pyridine, then suspended in ethanol, collected again, and dried. A product was obtained in the form of a red-yellow powder. Melting point 305-310℃ (decomposition). NMR (DMSO): 7.3−8.3δ (multi.,
integ.7); 11−13δ (diff.p. and br.singl.
overlap., integ.4). Example 20 1,2,3,4-tetrahydro-6-hydroxy-4-oxo-2-thioxo-N-(3,4,5
Preparation of -trimethoxyphenyl)-5-pyrimidinecarboxamide The same procedure as in Example 19 was carried out. However, this time 2-thiobarbituric acid and 3,4,5-trimethoxyphenyl isocyanate were used.
A red powder product was obtained. Melting point >310°C (decomposition). NMR (DMSO): 3.66δ (singl., integ.3);
3.80δ (singl., integ.6); 6.95δ (singl., integ.2
);
11.4δ (singl., integ.1); 12−13δ (br.diff.p.)
. Example 21 1,2,3,4-tetrahydro-6-hydroxy-N-(2-methyl-5-nitrophenyl)-4-
Preparation of oxo-2-thioxo-5-pyrimidinecarboxamide The procedure was carried out analogously to Example 19. However, this time 2-methyl-5-nitrophenyl isocyanate was used. A bluish-yellow powder product was obtained. Melting point >300℃ (decomposition). NMR (DMSO): 2.35δ (singl., integ.3);
7.35−7.85δ(multi., integ.4); 11.4δ(singl.,
integ.1); 12−13δ (br.diff.p.). Example 22 Preparation of 1,2,3,4-tetrahydro-6-hydroxy-4-oxo-N-phenyl-3-(2-propenyl)-2-thioxo-5-pyrimidinecarboxamide N-allyl-2-thiobarbi Dissolve 20g of toric acid in 300ml of pyridine and add triethylamine to this.
15.2 ml and 13 g of phenyl isocyanate were added. The reaction mixture was stirred at 80-90° C. for 4 hours, cooled, and the solid product was collected, treated with dilute HCl, washed with water and ethanol, and dried. The resulting product was an off-white solid. Melting point 209-211℃. NMR (DMSO): 4.8−6.2δ
(compl.multi., integ.5); 7.2−7.7δ(multi.,
integ.5); 11.4δ (singl., integ.1); 10−11δ (br
.
diff.p.). Example 23 1,2,3,4-tetrahydro-6-hydroxy-4-oxo-N-phenyl-2-selenoxo-
Preparation of 5-pyrimidinecarboxamide 4 g of selenourea and 9 g of [phenylamino]carbonylpropanedioic acid diethyl ester were intimately mixed in a nitrogen atmosphere and gently heated on an oil bath. The reaction mixture liquefied at an oil bath temperature of about 120°C. At about 140°C, the clear liquid began to evaporate. As the distillation process progressed, the reaction mixture began to solidify. Bath at 145℃ for a few minutes
The reaction mixture was then cooled, triturated in hot ethanol, and filtered hot. The filter cake was resuspended in hot ethanol, then triethylamine was added until most of the solids went into solution, insoluble material was removed by filtration, and cooled. The pyrimidine derivative product crystallized out as a yellow solid in the form of the triethylamine salt. Melting point: 190℃ (decomposition).
NMR (DMSO): 1.1−1.3δ (tripl., integ.9); 2.9
−3.3δ (quart., integ.6); 6.8−7.7δ (multi.,
integ.5); 11.8δ (br.singl.integ.1); approximately 10−11δ
(br.
diff.aborp.). Mass spectrum: M/e=307;
308; 309; 311; 313 (calculated value 307; 308; 309;
311; 313; The abundance ratio of selenium isotopes measured here was very close to the natural abundance ratio). () Pharmacological Tests of Compounds of the Invention From the results of the in vivo tests described below, it was found that the compounds described in Examples 1-7 have therapeutic effects on leukemia and tumors. In Vivo Testing (A) Antitumor Activity of the Compound of Example 1 The antitumor activity spectrum of the compound described in Example 1 was investigated using the standard protocol of the NCI (National Cancer Institute). The antitumor activity was investigated by in vivo tests, ie, various experiments were carried out consisting of administering the drug to several types of tumors under various administration conditions and using various administration methods. The experimental results obtained were recorded as ILS (lifespan increase rate) (%) of the test animals. The results of this experiment are shown in the table below.

【table】

Table: In the case of L1210 ip and sc for leukemia, at least 50% of the test animals (rats) were cured when the test compound was administered ip at a rate of 100 mg/Kg daily for 9 days. This 100mg/
With Kg administration, some toxicity was occasionally observed when administered ip. In this experiment, it was found that a dose of 50 mg/Kg increased lifespan by up to 80-190%. Same dosing regimen as above (9 doses at a rate of 100 mg/Kg daily)
In the case of ip administration over several days), marginal activity (ILS = 28-34%) was observed in transplanted L1210 compared to ic administration; Rather, it was found that it has a systemic effect. In the case of B16 melanoma, the best results (ILS = 93-85%) were obtained when administered ip at a rate of 100 mg/Kg daily for 9 days. Activity (ILS
= 25%) was observed within at least 4 repeated administrations. We conducted three experiments on ip transplanted M5076 sarcoma.
i.e. 1 day, 5 days, 9 days and 13 days.
The highest ILS values for ip administration were 72%, 72% and 48%. The compound of Example 1 is also used in standard NCI lymphocytic leukemia
Excellent activity was also observed in preliminary drug assay tests using P388 samples, i.e. 50
The highest ILS values when administered at mg/Kg over 5 days were 101%, 94% and 62%. This test compound, under the experimental conditions described, was found to have a s.
c. Transplanted CD8F ₁ carcinoma of the breast and colon38,
iv transplanted lewis lung carcinoma, src human MX-1
There was no effect on xenograft for breast carcinoma. The data obtained from various tests are shown in the table. In this in-vivo test, drugs were administered to animals at various dosages, and in each case, the survival period of drug-treated animals T and the survival period of control animals C was compared, and the ratio was calculated. The results are shown in Table 1.

【table】

[Table] (B) Effect of administration conditions and route of administration on the activity of the compound of Example 1 on sc-transplanted L-1210 leukemia test animals The influence of route of administration was investigated. 50 mg of this compound and N-
A lyophilized preparation containing 100 mg of methylglucamine was prepared, and 5 ml of sterile water was added to it to reconstitute it into a liquid.
In other words, make a solution with a concentration of 10 mg/ml (PH approximately 9.5),
This was used for administration. The drugs were administered through various administration routes under various administration conditions, and the ILS values in these cases are shown in the graphs in the accompanying drawings. As shown in the graph, an increase in lifespan was observed in all administration experiments using various routes of administration (except for one injection for one day (see “Test A” and “Test G” in the graph). )]. The highest value of ILS is 471%
This is a daily IP injection of the active substance at a rate of 45 mg/Kg/dose for 5 days, with a total dose of 225 mg/dose.
Kg/total period"("TestC" described in the graph). Five cases were cured with this administration.1
Even when administered orally every day for 9 days at a dose of 124 mg/Kg/dose,
A high ILS value of 452% was obtained, and the total dose at this time was "1116 mg/Kg/total administration period"("TestI" shown in the graph). There were 4 cases of cure with this administration method. As is clear from the graph, toxicity was observed at the highest dose for each administration method. with the exception of ip administration every 3 hours on days 1, 5, and 9 of a 9-day study ("Study F"). As is clear from the results of this experiment, only once
Substantial increases in lifespan were observed in each of the dosing experiments under the above dosing conditions (i.e., 25% of ILS), except when ip or iv administration was performed.
). (B') Acute toxicity value of the compound of Example 1. Once a day for 29 days in mice.
When the compound of Example 1 was administered intravenously, the LD ₅₀ was determined as follows. LD ₅₀ = 55 mg/Kg - body weight or 165 mg/m ² - body surface (C) Comparison of antitumor activity, ie, symptom reduction effect, of various test compounds on ip-transplanted lymphocytic leukemia L1210 test animals Example 1-10 was used as a test compound. Using the compound and a somewhat similar reference compound, the NCI test protocol 3LE31 [“NCI Protocol 1.100,
Cancer Chemotherapy Reports”, Part 3,
vol.3, No.2 (September 1972)],
ip transplant L1210 leukemia [“J.Nat′l.Canc.Inst.13
(5): 1328 (1953)] were conducted to evaluate the effects of these compounds. In each study, the following procedure was performed: six DBA/s mice of each sex were implanted with the leukemic cells for one experiment. The minimum weight for male mice is 18g, and the minimum weight for female mice is
17 g, and the body weight of all test animals varied within 3 g. Test compound is diluted ascites 0.1ml
(The number of cells per administration was 10 ⁵ ) and ip administration was performed. Administration is 1 day after tumor transplantation.
2 days later and were administered daily for 9 days. During the 30-day test period, the number of surviving test animals and body weights were recorded at regular intervals. The survival time ratio (T/C; %) between drug-administered animals and control animals was calculated. Note that T/C and ILS have a relationship expressed by the following formula. ILS = T/C % - 100% This test was conducted at various doses and was repeated an appropriate number of times depending on the results for each test compound. Furthermore, in this 3LE31 test, the first T/C
The statistical study concluded that the T/C value should be 125% or higher, and if this T/C value (125% or higher) is reproducible, further research should be conducted. It was discovered. If a T/C value of 150% or more is reproducibly obtained, it is considered that there is a fairly high degree of activity. The number of cured mice, i.e. the number of mice that remained alive after the 30-day test period (per each test animal group), is included in and among the T/C value (%) data in the table. shown in numbers. “T/C value (%)〓” indicates the data of the reversal test. “Toxi” means “toxic.”

【table】

【table】

[Table] Amine salt)






100 143
114







50 108
112







25 108
112

Claims (1)

[Claims] Linear formula (Here, R ₄ is a phenyl group; or a halogen,
Alkyl groups having 1 to 4 carbon atoms and 1 to
a phenyl group substituted with one or more groups selected from the group consisting of alkoxy groups having 4 carbon atoms; R ₅ and R ₆ are hydrogen), and pharmaceuticals thereof Addition salts that are legally acceptable. 2 R ₄ is a phenyl group, a 2- or 3-halophenyl group, a 2-methylphenyl group, a 2,4-difluorophenyl group, a 4-fluorophenyl group,
2-methoxy-5-methylphenyl group, 4-(C _1
-C6 ) 5-pyrimidine carboxamide according to claim 1, which is an alkoxyphenyl group or a 2- or 4-trifluoromethylphenyl group. 3 R ₄ is a phenyl group, 2-chlorophenyl group,
2-methylphenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 4-methoxyphenyl group, 4-ethoxyphenyl group, 2-fluorophenyl group, 2,4-difluorophenyl group, or 5-pyrimidine carboxamide according to claim 1, which is a 2-methoxy-5-methylphenyl group. 4. 5-pyrimidine carboxamide according to claim 1, which is 1,2,3,4-tetrahydro-6-hydroxy-4-oxo-N-phenyl-2-thioxo-5-pyrimidine carboxamide. 5 N-(2-chlorophenyl)-1,2,3,4
-tetrahydro-6-hydroxy-4-oxo-
5-pyrimidine carboxamide according to claim 1, which is 2-thioxo-5-pyrimidine carboxamide. 6 1,2,3,4-tetrahydro-6-hydroxy-N-(2-methylphenyl)-4-oxo-
5-pyrimidine carboxamide according to claim 1, which is 2-thioxo-5-pyrimidine carboxamide. 7 N-(3-fluorophenyl)-1,2,3,
5-pyrimidine carboxamide according to claim 1, which is 4-tetrahydro-6-hydroxy-4-oxo-2-thioxo-5-pyrimidine carboxamide. 8 5 according to claim 1, which is 1,2,3,4-tetrahydro-6-hydroxy-N-(4-methoxyphenyl)-4-oxo-2-thioxo-5-pyrimidinecarboxamide -Pyrimidine carboxamide. 9 N-(4-ethoxyphenyl)-1,2,3,
5-pyrimidine carboxamide according to claim 1, which is 4-tetrahydro-6-hydroxy-4-oxo-2-thioxo-5-pyrimidine carboxamide. 10 N-(4-fluorophenyl)-1,2,
3,4-tetrahydro-6-hydroxy-4-
5- of claim 1, which is oxo-2-thioxo-5-pyrimidinecarboxamide.
Pyrimidine carboxamide. 11 N-(2-fluorophenyl)-1,2,
5-pyrimidine carboxamide according to claim 1, which is 3,4-tetrahydro-6-hydroxy-4-oxo-2-thioxo-5-pyrimidine carboxamide. 12 N-(2,4-difluorophenyl)-1,
2,3,4-tetrahydro-6-hydroxy-4
-oxo-2-thioxo-5-pyrimidinecarboxamide
-Pyrimidine carboxamide. 13 1,2,3,4-tetrahydro-6-hydroxy-N-(2-methoxy-5-methylphenyl)-4-oxo-2thioxo-5-pyrimidinecarboxamide according to claim 1 5-pyrimidinecarboxamide. 14th equation (Here, R ₄ is a phenyl group; or a halogen,
Alkyl groups having 1 to 4 carbon atoms and 1 to
a phenyl group substituted with one or more groups selected from the group consisting of alkoxy groups having 4 carbon atoms; R ₅ and R ₆ are hydrogen), and pharmaceuticals thereof 2-thiobarbituric acid and an isocyanate (R ₄ -N=C=O) are reacted in the presence of a solvent or a dispersion medium. Method. 15 2-thiobarbituric acid and isocyanate are reacted in a molar ratio of 2:1 to 1:2, and the reaction is carried out at a temperature of 0 to 200°C. The method for producing 5-pyrimidine carboxamide described above. 16 R ₄ is a phenyl group, 2- or 3-halophenyl group, 2-methylphenyl group, 2,4-
Difluorophenyl group, 4-fluorophenyl group, 2-methoxy-5-methylphenyl group, 4-
The method for producing 5-pyrimidine carboxamide according to claim 14 or 15, which is a ( _C1 - _C6 ) alkoxyphenyl group or a 2- or 4-trifluoromethylphenyl group. 17 R ₄ is a phenyl group, 2-chlorophenyl group, 2-methylphenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 4-methoxyphenyl group, 4-ethoxyphenyl group, 2-fluorophenyl group enyl group, 2,4-difluorophenyl group,
or 2-methoxy-5-methylphenyl group, the method for producing 5-pyrimidine carboxamide according to claim 14 or 15. 18 Any one of claims 14 to 17 for producing 1,2,3,4-tetrahydro-6-hydroxy-4-oxo-N-phenyl-2-thioxo-5-pyrimidinecarboxamide The method for producing 5-pyrimidine carboxamide as described in . 19 N-(2-chlorophenyl)-1,2,3,
The manufacturing method according to any one of claims 14 to 17, for manufacturing 4-tetrahydro-6-hydroxy-4-oxo-2-thioxo-5-pyrimidinecarboxamide. 20 Claims 14 to 17 for producing 1,2,3,4-tetrahydro-6-hydroxy-N-(2-methylphenyl)-4-oxo-2-thioxo-5-pyrimidinecarboxamide The manufacturing method according to any one of the items. 21 N-(3-fluorophenyl)1,2,3,
The manufacturing method according to any one of claims 14 to 17, for manufacturing 4-tetrahydro-6-hydroxy-4-oxo-2-thioxo-5-pyrimidinecarboxamide. 22 Claims 14 to 17 for producing 1,2,3,4-tetrahydro-6-hydroxy-N-(4-methoxyphenyl)-4oxo-2-thioxo-5-pyrimidinecarboxamide The manufacturing method according to any one of the above. 23 N-(4-ethoxyphenyl)-1,2,
Claims 14 to 17 for producing 3,4-tetrahydro-6-hydroxy-4-oxo-2-thioxo-5-pyrimidinecarboxamide
The manufacturing method according to any one of Items. 24 N-(4-fluorophenyl)-1,2,
Claims 14 to 17 for producing 3,4-tetrahydro-6-hydroxy-4-oxo-2-thioxo-5-pyrimidinecarboxamide
The manufacturing method according to any one of Items. 25 N-(2-fluorophenyl)-1,2,
Claims 14 to 17 for producing 3,4-tetrahydro-6-hydroxy-4-oxo-2-thioxo-5-pyrimidinecarboxamide
The manufacturing method according to any one of Items. 26 N-(2,4-difluorophenyl)-1,
2,3,4-tetrahydro-6-hydroxy-4
-The manufacturing method according to any one of claims 14 to 17, for manufacturing oxo-2-thioxo-5-pyrimidinecarboxamide. 27 Claim 1 for producing 1,2,3,4-tetrahydro-6-hydroxy-N-(2-methoxy-5-methylphenyl)-4-oxo-2-thioxo-5-pyrimidinecarboxamide
The manufacturing method according to any one of Items 4 to 17. 28th formula (Here, R ₄ is a phenyl group; or a halogen,
Alkyl groups having 1 to 4 carbon atoms and 1 to
a phenyl group substituted with one or more groups selected from the group consisting of alkoxy groups having 4 carbon atoms; R ₅ and R ₆ are hydrogen), and pharmaceuticals thereof 1. A method for producing a legally acceptable addition salt, which comprises reacting a thiourea with an arylaminocarbonyl malonic acid diester. 29 R ₄ is a phenyl group, 2- or 3-halophenyl group, 2-methylphenyl group, 2,4-
Difluorophenyl group, 4-fluorophenyl group, 2-methoxy-5-methylphenyl group, 4-
29. The method for producing 5-pyrimidine carboxamide according to claim 28, which is a ( _C1 - _C6 ) alkoxyphenyl group or a 2- or 4-trifluoromethylphenyl group. 30 R ₄ is a phenyl group, 2-chlorophenyl group, 2-methylphenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 4-methoxyphenyl group, 4-ethoxyphenyl group, 2-fluorophenyl group enyl group, 2,4-difluoropheyl group,
or 2-methoxy-5-methylphenyl group, the method for producing 5-pyrimidine carboxamide according to claim 28. 31 Any one of claims 28 to 30 for producing 1,2,3,4-tetrahydro-6-hydroxy-4-oxo-N-phenyl-2-thioxo-5-pyrimidinecarboxamide The method for producing 5-pyrimidine carboxamide as described in . 32 N-(2-chlorophenyl)-1,2,3,
The manufacturing method according to any one of claims 28 to 30, for manufacturing 4-tetrahydro-6-hydroxy-4-oxo-2-thioxo-5-pyrimidinecarboxamide. 33 Claims 28 to 30 for producing 1,2,3,4-tetrahydro-6-hydroxy-N-(2-methylphenyl)-4-oxo-2-thioxo-5-pyrimidinecarboxamide The manufacturing method according to any one of the items. 34N-(3-fluorophenyl)-1,2,3,
The manufacturing method according to any one of claims 28 to 30, for manufacturing 4-tetrahydro-6-hydroxy-4-oxo-2-thioxo-5-pyrimidinecarboxamide. 35 Claims 28 to 30 for producing 1,2,3,4-tetrahydro-6-hydroxy-N-(4-methoxyphenyl)-4-oxo-2-thioxo-5-pyrimidinecarboxamide The manufacturing method according to any one of Items. 36 N-(4-ethoxyphenyl)-1,2,
Claims 28 to 30 for producing 3,4-tetrahydro-6-hydroxy-4-oxo-2-thioxo-5-pyrimidine carboxamide
The manufacturing method according to any one of Items. 37 N-(40-fluorophenyl)-1,2,
Claims 28 to 30 for producing 3,4-tetrahydro-6-hydroxy-4-oxo-2-thioxo-5-pyrimidine carboxamide
The manufacturing method according to any one of Items. 38 N-(2-fluorophenyl)-1,2,
Claims 28 to 30 for producing 3,4-tetrahydro-6-hydroxy-4-oxo-2-thioxo-5-pyrimidine carboxamide
The manufacturing method according to any one of Items. 39 N-(2,4-difluorophenyl)-1,
2,3,4-tetrahydro-6-hydroxy-4
-Oxo-2-thioxo-5-pyrimidinecarboxamide is produced by the production method according to any one of claims 28 to 30. 40 Claim 2 for producing 1,2,3,4-tetrahydro-6-hydroxy-N-(2-methoxy-5-methylphenyl)-4-oxo-2-thioxo-5-pyrimidinecarboxamide
The manufacturing method according to any one of Items 8 to 30. 41st formula (Here, R ₄ is a phenyl group; or a halogen,
Alkyl groups having 1 to 4 carbon atoms and 1 to
5-pyrimidinecarboxamide, which is a phenyl group substituted with one or more groups selected from the group consisting of alkoxy groups having 4 carbon atoms; R ₅ and R ₆ are hydrogen, or pharmaceuticals thereof 1. A pharmaceutical composition for the treatment of leukemia and tumors, characterized in that it contains an effective amount of a legally acceptable addition salt. 42 R ₄ is a phenyl group, a 2- or 3-halophenyl group, a 2-methylphenyl group, a 2,4-difluorophenyl group, a 4-fluorophenyl group,
2-methoxy-5-methylphenyl group, 4-(C ₁
-C ₆ ) 5 which is an alkoxyphenyl group or a 2- or 4-trifluoromethylphenyl group
- Pharmaceutical composition according to claim 41, containing a pyrimidine carboxamide. 43 R ₄ is a phenyl group, 2-chlorophenyl group, 2-methylphenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 4-methoxyphenyl group, 4-ethoxyphenyl group, 2-fluorophenyl group enyl group, 2,4-difluorophenyl group,
or 2-methoxy-5-methylphenyl group, 5-pyrimidine carboxamide. 44. The pharmaceutical composition according to claim 41, containing 1,2,3,4-tetrahydro-6-hydroxy-4-oxo-N-phenyl-2-thioxo-5-pyrimidine carboxamide. 45 N-(2-chlorophenyl)-1,2,3,
42. A pharmaceutical composition according to claim 41 containing 4-tetrahydro-6-hydroxy-4-oxo-2-thioxo-5-pyrimidinecarboxamide. 46 The medicinal composition according to claim 41 containing 1,2,3,4-tetrahydro-6-hydroxy-N-(2-methylphenyl)-4-oxo-2-thioxo-5-pyrimidinecarboxamide thing. 47 N-(3-fluorophenyl)-1,2,
42. The pharmaceutical composition according to claim 41, containing 3,4-tetrahydro-6-hydroxy-4-oxo-2-thioxo-5-pyrimidinecarboxamide. 48 1,2,3,4-tetrahydro-6-hydroxy-N-(4-methoxyphenyl)-4-oxo-2-thioxo-5-pyrimidinecarboxamide according to claim 41 Medicinal composition. 49 N-(4-ethoxyphenyl)-1,2,
42. The pharmaceutical composition according to claim 41, containing 3,4-tetrahydro-6-hydroxy-4-oxo-2-thioxo-5-pyrimidinecarboxamide. 50 N-(4-fluorophenyl)-1,2,
42. The pharmaceutical composition according to claim 41, containing 3,4-tetrahydro-6-hydroxy-4-oxo-2-thioxo-5-pyrimidinecarboxamide. 51 N-(2-fluorophenyl)-1,2,
42. The pharmaceutical composition according to claim 41, containing 3,4-tetrahydro-6-hydroxy-4-oxo-2-thioxo-5-pyrimidinecarboxamide. 52 N-(2,4-difluorophenyl)-1,
2,3,4-tetrahydro-6-hydroxy-4
The pharmaceutical composition according to claim 41, containing -oxo-2-thioxo-5-pyrimidinecarboxamide. 53 Claim 4 containing 1,2,3,4-tetrahydro-6-hydroxy-N-(2-methoxy-5-methylphenyl)-4-oxo-2-thioxo-5-pyrimidinecarboxamide
Pharmaceutical composition according to item 1.