HK1086830B - Heterocyclic compounds and antitumor drugs containing the same as the active ingredient - Google Patents

Description

Heterocyclic compound and antitumor agent containing the same as active ingredient

Technical Field

The present invention relates to a heterocyclic compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, and an antitumor agent containing the heterocyclic compound as an active ingredient.

[ in the formula, X represents a nitrogen atom or CH, R₁Represents a halogen atom or a hydroxyl group, R₂Represents a hydrogen atom, a hydroxyl group or an amino group, R₃Represents a morpholino group (which may be substituted by 1 to 2C atoms)₁～C₆Alkyl-substituted), pyrrolidinyl (may also be substituted by hydroxy C)₁～C₆Alkyl substituted), NR₆R₇[R₆Is represented by C₁～C₆Alkyl radical, R₇Represents piperidinyl (which may also be substituted by C)₁～C₆Alkyl substituted)]，R₄、R₅Represents a hydrogen atom or C₁～C₆An alkyl group. Wherein R is₁When it is hydroxy, R₂Is a hydrogen atom, R₃Represents pyrrolidinyl (which may be substituted by hydroxy C)₁～C₆Alkyl substituted).]

Background

Heretofore, s-triazine [1, 3, 5-triazine ] derivatives and pyrimidine derivatives have been studied in various fields of synthetic resins, synthetic fibers, dyes and agricultural chemicals, and a large number of compounds have been synthesized. In addition, in the medical field, various fields such as antitumor, anti-inflammatory, analgesic, and anti-contracture have been studied, and Hexamethylmelamine (HMM) developed as an analog of Triethylenemelamine (TEM) as an antitumor agent is particularly widely known (see, for example, b.l. johnson et al cancer, 42: 2157 to 2161 (1978)).

TEM is known as an alkylating agent and is an s-triazine derivative having an antitumor effect based on a cell killing effect. In addition, HMM has been marketed in europe as a drug suitable for ovarian cancer and alveolar carcinoma, and its effect on solid cancer has been noted.

Among s-triazine derivatives, imidazolyl-s-triazine derivatives having both cell-killing activity and selective aromatase-inhibiting activity are disclosed for use as a therapeutic agent for estrogen-dependent diseases (e.g., endometrial diseases, polycystic ovarian diseases, benign breast diseases, endometrial cancer, and breast cancer) (see, for example, PCT international publication No. WO 93/17009).

The present inventors have previously studied the enhancement of the antitumor activity of HMM and the reduction of the aromatase-inhibiting activity of an imidazole-s-triazine derivative, and as a result, have obtained s-triazine and pyrimidine derivatives substituted with benzimidazole (see, for example, PCT International publication Nos. WO99/05138 and WO 00/43385).

However, b.l.johnson et al.cancer, 42: 2157-2161 (1978), HMM still leaves room for improvement in the antitumor spectrum or antitumor activity intensity of solid cancers. Further, the imidazolyl-s-triazine derivatives disclosed in PCT International publication No. WO93/17009 are far superior in aromatase inhibitory action to cell-killing action, and when used in cancer patients other than estrogen-dependent diseases, they have side effects such as menstrual disorder due to lack of estrogen, and thus, the application range is limited, and there is a demand for development of a drug which is effective for solid cancers without aromatase inhibitory action.

Further, it is difficult to satisfy the requirement for antitumor activity for the compounds disclosed in PCT International publication Nos. WO99/05138 and WO 00/43385.

Disclosure of Invention

The present inventors have further studied and found that a heterocyclic compound of the general formula (I) having a specific substituent at the 2-position of the benzimidazole ring has a significant activity-improving effect, and completed the present invention.

The heterocyclic compound of the present invention is represented by the above general formula (I), and specific examples of the meanings of the words and phrases used in the definitions of the symbols in the formula are described below.

“C₁～C₆"is a group having 1 to 6 carbon atoms, unless otherwise specified.

As "C₁～C₆Examples of the alkyl group "include a straight-chain or branched-chain alkyl group such as a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, a tert-butyl group, a n-pentyl group, and a n-hexyl group.

"hydroxy group C₁～C₆Alkyl "means" C "as defined above₁～C₆Alkyl "defines a group having a hydroxyl group bonded to any one of the carbon atoms of the group.

Examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

Examples of the compound of the present invention include the following compounds, but the present invention is not limited to the following compounds.

2- (6-amino-4-chloro-2-difluoromethylbenzimidazol-1-yl) -4- (2, 2-dimethylmorpholinyl) -6-morpholinyl-1, 3, 5-triazine

2- (6-amino-4-chloro-2-difluoromethylbenzimidazol-1-yl) -4- [ methyl (1-methylpiperidin-4-yl) amino ] -6-morpholinyl-1, 3, 5-triazine

2- (6-amino-4-chloro-2-difluoromethylbenzimidazol-1-yl) -4- (2-hydroxymethylpyrrolidin-1-yl) -6-morpholinyl-1, 3, 5-triazine

2- (4-chloro-2-difluoromethyl-5-hydroxybenzimidazol-1-yl) -4, 6-dimorpholinyl-1, 3, 5-triazine

2- (4-chloro-2-difluoromethyl-5-hydroxybenzimidazol-1-yl) -4- (2, 2-dimethylmorpholinyl) -6-morpholinyl-1, 3, 5-triazine

2- (2-difluoromethyl-4-hydroxybenzimidazol-1-yl) -4- (2-hydroxymethylpyrrolidin-1-yl) -6-morpholinyl-1, 3, 5-triazine

2- (2-difluoromethyl-4-hydroxybenzimidazol-1-yl) -4- (2-hydroxymethylpyrrolidin-1-yl) -6-morpholinopyrimidine

2- (6-amino-4-chloro-2-difluoromethylbenzimidazol-1-yl) -4- (2, 2-dimethylmorpholinyl) -6-morpholinylpyrimidine

2- (4-chloro-2-difluoromethyl-5-hydroxybenzimidazol-1-yl) -4, 6-dimorpholinopyrimidine

2- (4-chloro-2-difluoromethyl-5-hydroxybenzimidazol-1-yl) -4- (2, 2-dimethylmorpholinyl) -6-morpholinylpyrimidine

2- (4-bromo-2-difluoromethylbenzimidazol-1-yl) -4, 6-dimorpholinyl-1, 3, 5-triazine

2- (4-fluoro-2-difluoromethylbenzimidazol-1-yl) -4, 6-dimorpholinyl-1, 3, 5-triazine

When a chiral carbon atom is present in the structure of the compound of the present invention, isomers derived from the chiral carbon atom and mixtures thereof (racemates) are present and are also included in the scope of the compound of the present invention.

In addition, the compounds of the present invention may also be in the form of their pharmaceutically acceptable salt-forming acid salts. As suitable acid salts, for example, hydrochloride, sulfate, hydrobromide, nitrate, phosphate and the like; examples of the organic acid salt include acetate, oxalate, propionate, glycolate, lactate, pyruvate, malonate, succinate, maleate, fumarate, malate, tartrate, citrate, benzoate, cutinate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, salicylate and the like.

(production step)

The compound of the invention represented by the general formula (I) is shown in the following reaction formula, cyanuric chloride or 2, 4, 6-trichloropyrimidine (compound II) is used as a starting material, and a benzimidazole compound (compound V), a morpholine compound (compound VI) and R are sequentially mixed with the compound₃H (compound VII) is reacted to produce.

(reaction formula)

(in the formula, R₁、R₂、R₃、R₄、R₅And X is as defined above, and R' represents a hydrogen atom, an amino group or a tert-butyldimethylsiloxy group. )

Next, the respective manufacturing steps are explained.

1) Production step (i) of intermediate III

(in the formula, R₁R' and X are as defined above. )

Cyanuric chloride or 2, 4, 6-trichloropyrimidine (compound II) is reacted with a benzimidazole compound (compound V) in the presence of a hydrogen chloride scavenger in a solvent to give an intermediate III.

Examples of the hydrogen chloride trapping agent used in the reaction include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, triethylamine, pyridine, and the like; examples of the solvent include acetone, toluene, hexane, xylene, dioxane, tetrahydrofuran or dichloroethane, and N, N-Dimethylformamide (DMF).

In this reaction, 0.5 to 1.2 mol of the compound V is reacted at-15 to-5 ℃ for 0.5 to 2 hours in the presence of 0.5 to 2 mol of a hydrogen chloride trapping agent relative to 1 mol of the compound II, and then at room temperature for 5 to 50 hours.

Further, the compound V can be used as a hydrogen chloride trapping agent.

2) Production step (ii) of intermediate IV

(in the formula, R₁、R₄、R₅R' and X are as defined above. )

The intermediate III obtained in the above production step (i) is reacted with a morpholine compound (compound VI) in a solvent in the presence of a hydrogen chloride trapping agent to obtain an intermediate IV. Examples of the hydrogen chloride trapping agent used in the reaction include the same compounds as those used in the above-mentioned production process (i); examples of the solvent include DMF, acetone, toluene, xylene, dichloroethane, and methylene chloride.

In this reaction, 0.5 to 1.2 mol of compound VI is reacted at-5 to 0 ℃ for 0.5 to 3 hours in the presence of 0.5 to 3 mol of a hydrogen chloride scavenger relative to 1 mol of compound III, and then reacted at room temperature for 5 to 50 hours.

Further, the compound VI can also be used as a hydrogen chloride scavenger.

3) Production step (iii) of Compound (I)

(in the formula, R₁、R₂、R₃、R₄、R₅R' and X are as defined above. )

(iii) reacting the intermediate IV and R obtained in the above-mentioned production step (ii) in a solvent in the presence of a hydrogen chloride trapping agent₃H (compound VII) to obtain the compound (I) of the invention.

Examples of the hydrogen chloride trapping agent used in the reaction include the same compounds as those used in the above-mentioned production process (i); examples of the solvent include DMF, dimethyl sulfoxide (DMSO), xylene, and dichloroethane.

In this reaction, the intermediate IV is reacted with1 mol of 1 to 5 mol of R₃H (compound VII) reacts for 0.1 to 16 hours at the temperature of room temperature to 140 ℃. In addition, in the reaction in the presence of the hydrogen chloride scavenger, 1 to 5 moles of the hydrogen chloride scavenger relative to 1 mole of the intermediate IV is used. Further, the compound VII may be used as a hydrogen chloride scavenger.

However, when compound VI is the same as compound VII in the production of compound (I), production steps (ii) and (iii) may be completed in one step to obtain compound (I). In this case, the reaction conditions of the above production step (ii) are followed except that 2 to 10 moles of the compound VI or VII based on 1 mole of the compound III are used, the reaction is carried out at-10 to 5 ℃ for 0.1 to 5 hours, and the reaction is carried out at room temperature to 120 ℃ for 3 to 50 hours.

When the reactivity of compound V, VI or VII used in production steps (i), (ii), and (iii) is low, it is preferable to carry out the reaction in each step after treatment with sodium hydroxide. When sodium hydroxide is used, 1.0 to 1.2 moles of sodium hydroxide are used per 1 mole of the starting material (compound II, III or IV) in each step.

In addition, R₁、R₂In the case of a hydrogen atom, the target compound is obtained by a conventional method using a benzimidazole compound in which a hydroxyl group is protected with an alkylsilyl group such as t-butyldimethylsilyl group, and removing the protecting group in the final step. R₁Is a chlorine atom, R₂Compounds of the invention which are hydroxy groups use R which is obtained analogously as described above₁Is a hydrogen atom, R₂The compound (I) which is a hydroxyl group is obtained by halogenation according to a conventional method.

The order of the above-mentioned production steps (i), (ii) and (iii) may be changed, and the reaction conditions in this case may be changed within a known range by those skilled in the art.

The product obtained in each step may be isolated and purified by a conventional method such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography, or the like, if necessary.

The acid salts of the compounds of formula (I) of the present invention may be prepared by various methods known in the art. As the acid to be preferably used, for example, hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, phosphate, and the like; examples of the organic acid include acetic acid, oxalic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

The antitumor effect of the compound of the present invention represented by the general formula (I) is described below. The test compound numbers in tests 1 and 2 correspond to the compound numbers of the examples described below.

In addition, as a comparative compound, the following s-triazine antitumor agent or estrogen-dependent disease therapeutic agent was used.

A compound A: 2- (benzimidazol-1-yl) -4- (trans-2, 3-dimethylmorpholinyl) -6-morpholinylpyrimidine [ representative examples disclosed in International publication (WO99/05138) ]

Compound B: 2- (2-methylbenzimidazol-1-yl) -4, 6-dimorpholinyl-1, 3, 5-triazine [ representative examples disclosed in International publication (WO99/05138) ]

Compound C: 2- (imidazol-1-yl) -4, 6-dimorpholinyl-1, 3, 5-triazine [ representative examples disclosed in International publication (WO93/17009) ]

Compound D: hexamethylmelamine (HMM)

Test 1

A culture solution was prepared by adding 10% bovine embryo serum, 25mM HEPES and 0.1mg/ml kanamycin to MEM medium, and the MCF-7 human breast cancer cells that maintained the secondary transfer were tested in the culture solution at 37 ℃ under 5% carbonic acid gas. MCF-7 cells in logarithmic growth phase were treated with trypsin/EDTA to obtain monoplankton cells, which were cultured in MEM medium (supplemented with 10% bovine embryonic serum, 25mM HEPES, 0.1mg/ml kanamycin)Element) the concentration of the cell suspension was adjusted to 4X 10⁴Each 1 ml. The test compound was dissolved in DMSO, diluted with RPMI 1640 medium (supplemented with 10% bovine embryonic serum, 25mM HEPES, and 0.1mg/ml kanamycin) and adjusted to a concentration of 2.0X 10^-9～2.0×10^-4M。

0.1ml of the cell suspension was added to each well of a 96-well microplate, and the cells were cultured for 24 hours, and after the cells were seeded in the microplate, 0.1ml of the sample solution was added, and the cells were cultured for 72 hours at 37 ℃ in 5% carbonic acid gas.

The 50% proliferation inhibitory concentration (GI) was calculated from the proliferation inhibitory levels at various sample concentrations₅₀μ M), the results are shown in table 1 below.

TABLE 1

From the above test results, it is clear that the compound of the present invention has an antitumor effect on human breast cancer cells superior to that of the known comparative compound A, B, C, D.

In addition, the compounds of the present invention are also effective in vitro tests using human non-small cell lung cancer cells and human colon cancer cells, and thus are expected to be applied to the treatment of various human solid cancers.

Test 2

2mm square sections of secondary human colon cancer WiDr obtained from the mutation BALB/c nude mice are used as tumor transplantation slices, the tumor transplantation slices are transplanted under the left chest skin of the mutation BALB/c nude mice, and when the tumors reach an exponential proliferation stage, the tumor transplantation slices are divided into groups, and 5 mice in each group are used for experiments. The test substance was dissolved in a physiological saline solution or suspended in a 1% HPC solution in an agate mortar, and administered intraperitoneally 1 time a day and 6 times a week for 2 weeks at a dose of 200mg/kg, respectively. The long and short diameters of the tumor were measured daily and the tumor volume was calculated. The relative tumor growth rate was calculated by dividing the tumor volume on each measurement day by the tumor volume on the day of initiation of the test substance administration, and the T/C (%) was calculated from the relative tumor growth rate (T) in the test substance-administered group and the relative tumor growth rate (C) in the control group. The final day was judged to be effective (+) when T/C (%) was 50% or less and there was a significant difference in the risk of 1% on one side in the U-assay of Mann-Whitney. Results the compound of the invention used in test 1 was effective and the comparative compound a was not.

The method of administration, dosage form and dose of the compound of the present invention when used in mammals in humans will be described below.

The compound of the present invention may be administered orally or parenterally, and as a dosage form for oral administration, tablets, coating agents, powders, granules, capsules, microcapsules, syrups, and the like can be used; examples of the parenteral dosage form include injections (including lyophilized injections which are dissolved and reused at the time of use), suppositories, and the like. The above dosage forms can be prepared using pharmaceutically acceptable excipients, binders, lubricants, disintegrating agents, suspending agents, emulsifiers, preservatives, stabilizers and dispersing agents, such as lactose, white sugar, starch, dextrin, crystalline cellulose, kaolin, calcium carbonate, talc, magnesium stearate, distilled water or physiological saline.

The dosage varies according to the symptoms, age, weight, etc. of the patient, and the daily dosage of an adult is 100-1000 mg, and the dosage is divided into 2-3 times.

Detailed Description

Examples of the compounds of the present invention will be described below, more specifically, but the present invention is not limited thereto.

(example 1)

2- (2-difluoromethyl-4-hydroxybenzimidazol-1-yl) -4- (2-hydroxymethylpyrrolidin-1-yl) -6-morpholinopyrimidine

(Compound 1)

(1) 1.49g (5.0mmol) of 4-t-butyldimethylsilyloxy-2-difluoromethylbenzimidazole was dissolved in DMF (10ml), and 0.91g (5.0mmol) of 2, 4, 6-triaminopyrimidine was added at room temperature, and 0.55g of potassium carbonate was further added, followed by stirring for 5 hours. The reaction mixture was extracted several times with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate: 8: 1) to give 1.12g of 2- (4-tert-butyldimethylsilyloxy-2-difluoromethylbenzimidazol-1-yl) -4, 6-dichloropyrimidine (yield 50%).

(2) 386mg (0.87mmol) of the obtained 2- (4-tert-butyldimethylsilyloxy-2-difluoromethylbenzimidazol-1-yl) -4, 6-dichloropyrimidine was dissolved in DMF (6ml), and 0.13ml (1.3mmol) of 2-pyrrolidinemethanol and 179mg of potassium carbonate were added at room temperature. After stirring at room temperature for 30 minutes, the reaction mixture was added with water, extracted several times with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate: 1), whereby 291mg of 2- (4-tert-butyldimethylsilyloxy-2-difluoromethylbenzimidazol-1-yl) -4- (2-hydroxymethylpyrrolidin-1-yl) -6-chloropyrimidine (yield: 64%) was obtained.

(3) 281mg (0.54mmol) of the obtained 2- (4-tert-butyldimethylsilyloxy-2-difluoromethylbenzimidazol-1-yl) -4- (2-hydroxymethylpyrrolidin-1-yl) -6-chloropyrimidine was added with 4.4g (50mmol) of morpholine and stirred at room temperature for 9 hours. The reaction mixture was extracted several times with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate: 2: 3) to give 216mg (yield 72%) of 2- (4-tert-butyldimethylsilyloxy-2-difluoromethylbenzimidazol-1-yl) -4- (2-hydroxymethylpyrrolidin-1-yl) -6-morpholinopyrimidine.

213mg (0.38mmol) of 2- (4-tert-butyldimethylsilyloxy-2-difluoromethylbenzimidazol-1-yl) -4- (2-hydroxymethylpyrrolidin-1-yl) -6-morpholinopyrimidine was dissolved in anhydrous THF (7ml), and 0.4ml (1M THF solution) of tetra-n-butylammonium bromide was added thereto at room temperature, followed by stirring for 30 minutes. The reaction mixture was extracted several times with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate: 1: 4) to give 101mg (yield 60%) of the objective compound as colorless crystals.

Melting point: 195-198 deg.C

NMR(CDCl₃)δ：2.0-2.1(4H，m)，3.4-4.0(12H，m)，4.0-4.1(1H，m)，4.3-4.4(1H，m)，5.36(1H，s)，6.85(1H，d，J＝8Hz)，7.28(1H，t，J＝8Hz)，7.58(1H，brs)，7.58(1H，t，J＝54Hz)，7.73(1H，d，1＝8Hz)

MS m/z：446(M⁺)

(example 2)

2- (6-amino-4-chloro-2-difluoromethylbenzimidazol-1-yl) -4- (2, 2-dimethylmorpholinyl) -6-morpholinyl-1, 3, 5-triazine (Compound 2)

(1) 500mg (2.3mmol) of 6-amino-4-chloro-2-difluoromethylbenzimidazole was dissolved in acetone (50ml), and 542mg (2.3mmol) of 2, 4-dichloro-6-morpholinyl-1, 3, 5-triazine was added thereto at-15 ℃ to add 500mg of potassium carbonate. After slowly warming to room temperature, the mixture was stirred at room temperature for 5 hours. The solvent was removed by distillation under the reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate: 1: 4) to give 272mg of 2- (6-amino-4-chloro-2-difluoromethylbenzimidazol-1-yl) -4-chloro-6-morpholinyl-1, 3, 5-triazine (yield 28%).

(2) 150mg (0.36mmol) of the thus-obtained 2- (6-amino-4-chloro-2-difluoromethylbenzimidazol-1-yl) -4-chloro-6-morpholinyl-1, 3, 5-triazine is dissolved in DMF (6ml), 150mg (1.0mmol) of 2, 2-dimethylmorpholine hydrochloride is added at-15 ℃ and 500mg of potassium carbonate is added. After stirring at room temperature for 1 night, the reaction mixture was added with water, extracted several times with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate: 1: 2) to give 130mg of the objective compound as colorless crystals (yield 73%).

Melting point: 238 deg.C (decomposition)

NMR(CDCl₃)δ：1.27(6H，s)，3.68(2H，s)，3.7-3.9(12H，m)，6.82(1H，d，J＝2.3Hz)，7.42(1H，dt，J＝9.6Hz，J＝53Hz)，7.50(1H，d，J＝2.3Hz)

MS m/z：494(M⁺)

The following compounds were prepared from appropriate starting materials in the same manner as in example 2.

2- (6-amino-4-chloro-2-difluoromethylbenzimidazol-1-yl) -4- (2-hydroxymethylpyrrolidin-1-yl) -6-morpholinyl-1, 3, 5-triazine (Compound 3)

Melting point: 256 deg.C (decomposition)

NMR(CD₃OD-CDCl₃(1∶1))δ：1.9-2.2(4H，m)，3.68(2H，s)，3.5-4.0(11H，m)，4.39(1H，brs)，6.84(1H，d，J＝2.1Hz)，7.58(1H，t，J＝53Hz)，7.64(1H，d，J＝2.1Hz)

MS m/z：480(M⁺)

2- (6-amino-4-chloro-2-difluoromethylbenzimidazol-1-yl) -4- [ methyl (1-methylpiperidin-4-yl) amino ] -6-morpholinyl-1, 3, 5-triazine (Compound 4)

Melting point: 194 deg.C (decomposition)

NMR(CD₃OD-CDCl₃(1∶1))δ：1.3-1.5(2H，m)，1.8-2.1(4H，m)，2.35(3H，s)，2.9-3.2(3H，m)，3.21(3H，s)，3.5-3.8(8H，m)，6.84(1H，d，J＝2.2Hz)，7.49(1H，t，J＝53Hz)，7.80(1H，d，J＝2.2Hz)

MS m/z：507(M⁺)

2- (2-difluoromethyl-4-hydroxybenzimidazol-1-yl) -4- (2-hydroxymethylpyrrolidin-1-yl) -6-morpholinyl-1, 3, 5-triazine (Compound 5)

Melting point: 245 ℃ (decomposition)

NMR(CDCl₃)δ：1.9-2.1(4H，m)，3.5-4.0(12H，m)，4.7-4.8(1H，m)，5.1-5.3(1H，m)，6.89(1H，d，J＝9Hz)，7.30(1H，t，J＝9Hz)，7.50(1H，brs)，7.55(1H，t，J＝54Hz)，7.83(1H，d，J＝9Hz)

MS m/z：447(M⁺)

2- (2-difluoromethyl-5-hydroxybenzimidazol-1-yl) -4, 6-dimorpholinyl-1, 3, 5-triazine

Melting point: higher than 250 DEG C

NMR(CDCl₃)δ：3.8-4.0(16H，m)，7.01(1H，d，J＝9Hz)，7.30(1H，s)，7.54(1H，t，J＝53Hz)，8.19(1H，d，J＝9Hz)

MS m/z：433(M⁺)

(example 3)

2- (4-chloro-2-difluoromethyl-5-hydroxybenzimidazol-1-yl) -4, 6-dimorpholinyl-1, 3, 5-triazine (Compound 6)

433mg (1.00mmol) of 2- (2-difluoromethyl-5-hydroxybenzimidazol-1-yl) -4, 6-dimorpholinyl-1, 3, 5-triazine prepared by the method of (example 2) was dissolved in chloroform (10ml), and 400mg (3.0mmol) of N-chlorosuccinimide was added. After stirring at 60 ℃ for 1 hour, the reaction mixture was added with water, extracted several times with chloroform, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol 99: 1) to give 189mg (yield 44%) of the objective compound as colorless crystals.

Melting point: higher than 250 DEG C

NMR(CDCl₃)δ：3.7-3.9(16H，m)，5.63(1H，s)，7.15(1H，d，J＝9Hz)，7.51(1H，t，J＝53Hz)，8.14(1H，d，J＝9Hz)

MS m/z：467(M⁺)

Industrial applicability

The compound has no aromatase inhibition effect, has an anti-tumor effect obviously stronger than that of the existing s-triazine derivative and pyrimidine derivative, and can be used for treating solid cancer.

Claims (11)

1. A heterocyclic compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof,

wherein X represents a nitrogen atom or CH, R₁Represents a halogen atom or a hydroxyl group, R₂Represents a hydrogen atom, a hydroxyl group or an amino group, R₃Represents a morpholino group which may be substituted by 1 to 2C₁～C₆Alkyl substitution; a pyrrolidinyl group,it may also be substituted by hydroxy C₁～C₆Alkyl substitution; NR (nitrogen to noise ratio)₆R₇，R₆Is represented by C₁～C₆Alkyl radical, R₇The representation can also be C₁～C₆An alkyl-substituted piperidinyl group; r₄、R₅Represents a hydrogen atom or C₁～C₆Alkyl radical, wherein R₁When it is hydroxy, R₂Represents a hydrogen atom, R₃Represent optionally substituted by hydroxy groups C₁～C₆Alkyl-substituted pyrrolidinyl.

2. The compound of claim 1, wherein R₁Is chlorine.

3. The compound of claim 1, wherein R₁Is chlorine, R₂Is an amino group.

4. The compound of claim 1, wherein R₁Is chlorine, R₂Is amino, R₃Is dimethylmorpholinyl, R₄、R₅Is a hydrogen atom and X is a nitrogen atom.

5. The compound of claim 1, wherein R₁Is chlorine, R₂Is a hydroxyl group.

6. The compound of claim 1, wherein R₁Is chlorine, R₂Is hydroxy, R₃Is morpholinyl, R₄、R₅Is a hydrogen atom and X is a nitrogen atom.

7. The compound of claim 1, wherein R₁Is hydroxy, R₂Is a hydrogen atom, R₃Is pyrrolidinyl which may also be substituted with hydroxymethyl.

8. The compound according to claim 1, wherein the compound represented by the general formula (I) is 2- (2-difluoromethyl-4-hydroxybenzimidazol-1-yl) -4- (2-hydroxymethylpyrrolidin-1-yl) -6-morpholinopyrimidine, 2- (6-amino-4-chloro-2-difluoromethylbenzimidazol-1-yl) -4- (2, 2-dimethylmorpholinyl) -6-morpholino-1, 3, 5-triazine, 2- (6-amino-4-chloro-2-difluoromethylbenzimidazol-1-yl) -4- (2-hydroxymethylpyrrolidin-1-yl) -6-morpholino-1, 3, 5-triazine, 2- (6-amino-4-chloro-2-difluoromethylbenzimidazol-1-yl) -4- [ methyl (1-methylpiperidin-4-yl) amino ] -6-morpholinyl-1, 3, 5-triazine, 2- (2-difluoromethyl-4-hydroxybenzimidazol-1-yl) -4- (2-hydroxymethylpyrrolidin-1-yl) -6-morpholinyl-1, 3, 5-triazine or 2- (4-chloro-2-difluoromethyl-5-hydroxybenzimidazol-1-yl) -4, 6-dimorpholinyl-1, 3, 5-triazine.

9. The compound according to claim 1, wherein the compound represented by the general formula (I) is 2- (2-difluoromethyl-4-hydroxybenzimidazol-1-yl) -4- (2-hydroxymethylpyrrolidin-1-yl) -6-morpholinyl-1, 3, 5-triazine.

10. An antitumor agent comprising as an active ingredient at least one compound according to claim 1 to 9.

11. A pharmaceutical composition comprising a pharmaceutically acceptable diluent or carrier and, as an anti-tumour active ingredient, at least one compound according to claims 1 to 9.