JPH05112559A - 4-amino-5-pyrimidinecarboxylic acid derivative - Google Patents

Abstract

PURPOSE:To obtain a 4-amino-5-pyrimidinecarboxylic acid derivative useful as an antipeptic ulcer having inhibitory action on secretion of acid in the stomach, protecting action on gastroinstestinal mucosa and excellent inhibitory action on H<+>/K<+>ATPase. CONSTITUTION:A 4-amino-5-pyrimidinecarboxyic acid derivative of formula I [R<1> and R<2> are H, (halogenated) alkyl, alkoxy or halogen; R<3> is amino of R<5>NR<6> (R<5> and R<6> are H, alkyl, cycloalkyl, phenyl, etc.); R<4> is H or alkyl; X is NR<7> (R<7> is H or alkyl), O or S; (n) is 0-2 with the proviso that a case wherein R<1> and R<2> are H, X is NH, (n) is 1 and R<3> is N, N-dimethylamino, N-ethyl-N- methylamino or morpholino is omitted] or its pharmaceutically acceptable salt such as 2-[(1H-benzimidazol-2-yl)thiomethy]-4-methylamino-5- pyrimidinecarboxylic acid ethyl ester. A compound of formula Ia among the compounds of formula I is obtained by reacting a compound of formula II with a compound of the formula R3H.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a 4-amino-5-pyrimidinecarboxylic acid derivative useful as an anti-peptic ulcer drug.

[0002]

2. Description of the Related Art Compounds having an anti-peptic ulcer action and having both a benzimidazole ring and a pyrimidine ring are disclosed in JP-A-61-85384 and JP-A-61-20527.
The compounds described in Japanese Patent Laid-Open No. 6-132821 and Japanese Patent Laid-Open No. 1-132581 are known.

[0003]

The conventional anti-peptic ulcer drugs mainly suppress the attack factors such as gastric acid and pepsin, and enhance the defense factors such as mucosal resistance, cell protection, blood flow and mucus. Can be broadly divided into different categories, each being used according to the condition. However, an attack factor inhibitor represented by cimetidine has a problem of rebound, which is a rebound phenomenon, and various protective factor enhancers have been used, but it is not always sufficient in terms of effects. Therefore, an object of the present invention is to provide a more effective and safer anti-peptic ulcer drug.

[0004]

Means for Solving the Problems As a result of intensive studies for solving the above problems, the present inventors have found that a novel 4-amino-5-pyrimidinecarboxylic acid derivative different from conventional pyrimidine derivatives and pharmacologically An acceptable salt thereof has a gastric acid secretion inhibitory action and a gastrointestinal mucosa protective action, and has excellent H
^The present invention has been completed by discovering that it has an inhibitory action on ⁺ / K ⁺ ATPase (proton pump inhibitory action).

That is, the present invention relates to a 4-amino-5-pyrimidinecarboxylic acid derivative represented by the following general formula [I] and a pharmacologically acceptable salt thereof.

[0006]

[Chemical 2]

[Wherein R ¹ and R ² are the same or different and each represents a hydrogen atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group or a halogen atom. R ³ is an amino group represented by R ⁵ NR ⁶ (R ⁵ and R ⁶ are the same or different and are a hydrogen atom, a lower alkyl group, a cycloalkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxyalkyl group, a hydroxyalkyl group. Group, a phenyl group, a substituted phenyl group, a benzyl group, or a substituted benzyl group) or a saturated or unsaturated heterocyclic group containing at least one nitrogen atom, which is a substituted or unsubstituted heterocyclic group (provided that , The bonding position with the pyrimidine nucleus means the nitrogen atom in the heterocycle). R ⁴ means a hydrogen atom or a lower alkyl group. X means NR ⁷ (R ⁷ represents a hydrogen atom or a lower alkyl group), an oxygen atom or a sulfur atom. n means 0, 1 or 2. However, R ¹
And R ² are each a hydrogen atom, X is NH and n is 1
Except when R ³ is an N, N-dimethylamino group, an N-ethyl-N-methylamino group or a morpholino group. ]

R ¹ , R ² , R in the above general formula [I]
Specific examples of ³ , R ⁴ , X and pharmacologically acceptable salts can be shown as follows. R ¹ and R ² are hydrogen atom, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, pentyl group, hexyl group, trifluoromethyl group, methoxy group, ethoxy group,
A propoxy group, a butoxy group, an isobutoxy group, a pentyloxy group, a hexyloxy group, fluorine, chlorine, bromine, iodine and the like are preferable, and it is preferable to substitute at the 5th to 6th positions of the benzene nucleus.

When R ³ is an amino group represented by R ⁵ NR ⁶ , R ⁵ and R ⁶ are a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group,
Butyl group, isobutyl group, tertiary butyl group, pentyl group, cyclopentyl group, hexyl group, cyclohexyl group, allyl group, 2-propynyl group, 2-hydroxyethyl group, 2-methoxyethyl group, 2-ethoxyethyl group,
A 3-methoxypropyl group, a phenyl group, a benzyl group and the like are preferable. Further, when R ³ is a heterocycle, an example is 1
-Pyrrolidinyl group, piperidino group, 3,5-dimethylpiperidino group, morpholino group, 2,6-dimethylmorpholino group, thiomorpholino group, 1-piperazinyl group, 4-methyl-1-piperazinyl group, 4-phenyl- 1-piperazinyl group, 4-benzyl-1-piperazinyl group, imidazo-1-yl group, 1,2,4-triazo-1-yl group,
Examples thereof include a tetrazo-1-yl group and a 1-pyrrolyl group.

R ⁴ is preferably a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tertiary butyl group, a pentyl group or a hexyl group.

When X is NR ⁷ , R ⁷ is preferably a hydrogen atom, methyl group, ethyl group, propyl group, butyl group, isobutyl group, pentyl group, hexyl group or the like.

The pharmacologically acceptable salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate and phosphate, acetate, citrate, maleate, tartrate and methane. Organic salts such as sulfonates, benzene sulfonates, toluene sulfonates, salts with L-arginine, L-aspartic acid, L-glutamic acid, etc., and, depending on the compound, sodium, potassium, calcium, magnesium, etc. Can be mentioned.

Some of the compounds included in the present invention may be hydrates or have stereoisomers.

The compound [I] of the present invention can be produced by various methods. Typical methods are as follows.

[0015]

[Chemical 3]

[Wherein R ¹ , R ² , R ³ and X are the same as defined above, and R ⁴ represents a lower alkyl group. In addition,
The compound [Ia] is an ester compound contained in the compound [I] of the present invention, and means the case where n is 0. The compound [Ia] of the present invention can be usually produced by reacting the compound [II] with an amine represented by the formula R ³ —H or an alkali metal salt thereof in a solvent. The solvent used in the reaction can be used as a solvent by using excess amines to be reacted, but diethyl ether, tetrahydrofuran, dioxane, toluene, acetone, methylene chloride,
Organic solvents such as chloroform, acetonitrile, N, N-dimethylformamide, dimethylsulfoxide and the like, or a mixed solvent thereof with water are preferable. In order to capture the hydrochloric acid generated in this reaction, a base such as triethylamine, pyridine, 1,8-diazabicyclo [5.6.0] -7-undecene, sodium hydrogen carbonate, sodium carbonate, potassium carbonate may be present. .. Reaction temperature is 0 ℃
To the boiling point of the solvent is preferable, and the reaction time is usually within the range of 30 minutes to 48 hours.

Further, the compound [I
The compound [Ib] included in the present invention can be produced by oxidizing a] according to a conventional method.

[0018]

[Chemical 4]

[Wherein R ¹ , R ² , R ³ and X are the same as defined above, R ⁴ is a lower alkyl group, and n is 1 or 2. ]

Examples of the oxidizing agent that can be used in this reaction include hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, sodium hypochlorite, sodium bromate and sodium metaperiodate. The amount used is preferably 1 to 5 equivalents. Further usable solvents include, for example, methylene chloride, chloroform, toluene,
Examples thereof include organic solvents such as methanol, ethanol, N, N-dimethylformamide, tetrahydrofuran and dioxane, water, and mixed solvents thereof. Reaction temperature is -10 ° C to 30 ° C, reaction time is 10 minutes to 24
Time is preferable.

The compound [Ib] can also be produced by reacting the compound [III] with an amine represented by the formula R ³ —H as shown in the following chemical formula 5 in the same manner as in the chemical formula ³ .

[0022]

[Chemical 5] [Wherein R ¹ , R ² , R ³ and X are the same as defined above,
R ⁴ means a lower alkyl group, and n means 1 or 2. ]

In the compound [I] of the present invention, R ⁴ is a hydrogen atom, that is, the compound [I]
c] can be produced by hydrolyzing compound [Ia] or compound [Ib] according to a conventional method.

[0024]

[Chemical 6]

[Wherein R ¹ , R ² , R ³ and X are the same as defined above, R ⁴ represents a lower alkyl group, n is 0,
It means 1 or 2. ]

The compound of the present invention [I obtained as described above
The pharmacologically acceptable salts of a], [Ib] and [Ic] can be easily produced according to a conventional method.

The compounds [II] and [III] used as starting materials in the above reaction can be produced by the following method.

[0028]

[Chemical 7]

[Wherein R ¹ , R ² and X are the same as defined above, R ⁴ represents a lower alkyl group, and R ⁸ represents a hydrogen atom or a lower alkyl group. ]

First, the raw material compound [IV] was prepared as follows from the Journal of Organic Chemistry.
Organic Chemistry), 26, 41
2 (1961).

Step A The compound [VI] can be produced by reacting the starting compound [IV] with the compound [V] in the presence of a base, without solvent or in a solvent. Examples of the base that can be used in this reaction include sodium hydrogen carbonate, sodium carbonate, potassium carbonate, potassium hydride, sodium hydride, sodium methoxide, sodium ethoxide and the like. The use ratio thereof is usually 1 to 4 times mol of the compound [IV]. Further, as the solvent, methanol, ethanol, propanol, dioxane, tetrahydrofuran,
An organic solvent such as toluene, N, N-dimethylformamide, dimethylsulfoxide, water, or a mixed solvent thereof can be preferably used. The reaction temperature may be from 0 ° C. to the boiling point of the solvent, and the reaction time is usually 2 to 24 hours.

Step B Compound [VIII] can be produced by reacting compound [VI] with compound [VII] in the same manner as above.

Step C Compound [II] can be obtained by reacting compound [VIII] with phosphorus oxychloride. The reaction is usually carried out in an organic solvent such as tetrahydrofuran, dioxane, acetonitrile, toluene, methylene chloride, chloroform, carbon tetrachloride, etc., and an organic base such as triethylamine, N-methylpiperidine, pyridine, N, N-dimethylaniline is added. May be. The reaction temperature is preferably room temperature to the boiling point of the solvent, and the reaction time is usually 0.5 to 24 hours.

Step D The compound [III] can be produced by oxidizing the compound [II] in the same manner as in the above chemical formula 4.

The compound [I] of the present invention and a pharmacologically acceptable salt thereof have excellent gastric acid secretion inhibitory action, gastrointestinal mucosa protective action, H ⁺ / K ⁺ ATPase inhibitory action, and are highly safe. It is useful as a therapeutic or preventive agent for peptic ulcer in humans or animals. The peptic ulcer includes a gastric ulcer,
Includes duodenal ulcer, Zolinger-Ellison syndrome, anastomotic ulcer, reflux esophagitis and the like. When the compound [I] of the present invention or a pharmaceutically acceptable salt thereof is used as the above-mentioned medicine, it is orally or non-orally administered in the form of tablets, powders, granules, capsules, syrups, suppositories, injections and the like. It can be administered orally. The dosage depends on the patient's condition, age, weight,
Depending on the compound used, administration route, etc., it is usually 5 to 1500 mg, preferably 20 to 800 mg per day for an adult.
The dose can be appropriately adjusted within the range of 1 to be administered once or divided into several times a day.

There is no particular difficulty in formulating the compound [I] of the present invention or a pharmacologically acceptable salt thereof, and any known method may be used. That is, the oral solid agents as exemplified above can be produced according to a conventional method using, if necessary, an excipient, a binder, a disintegrating agent, a lubricant, a coloring agent, a flavoring agent and the like. Excipients include lactose, corn starch,
Sucrose, glucose, crystalline cellulose, silicon dioxide, sorbit, non-pareil and the like can be used. As a binder,
Polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl cellulose, hydroxypropyl starch, polyvinylpyrrolidone and the like can be used. As the disintegrant, starch, agar, gelatin, crystalline cellulose, calcium carbonate, sodium hydrogen carbonate, calcium citrate, carboxymethyl cellulose calcium, dextrin and the like can be used. As the lubricant, magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oil and the like can be used. Any other coloring agent or flavoring agent permitted as a pharmaceutical additive can be used. Tablets, granules and the like may be coated with sugar coating, gelatin coating and the like. Injectables are also distilled water, pH adjuster,
It can be easily produced by appropriately using a buffer, a stabilizer, a solubilizer, and the like.

Reference Example 1 83 g of chloroacetamidine hydrochloride and diethyl ethoxymethylenemalonate 1
39.2 g was dissolved in 1300 ml of ethanol, cooled in an ice-water bath, and with stirring, a 40% aqueous solution of sodium hydroxide 13
0 ml was added dropwise in 1 hour. After continuously stirring at room temperature for 4 hours, 70 ml of concentrated hydrochloric acid was added dropwise over 10 minutes. Next, the solvent was distilled off under reduced pressure, 1000 ml of water was added to the residue, and the mixture was stirred at room temperature for 10 minutes. The precipitated crystals were collected by filtration, washed with water, and recrystallized from ethanol to give 2-chloromethyl-1,6-dihydro-
104 g (yield 75%) of 6-oxo-5-pyrimidinecarboxylic acid ethyl ester was obtained.

Melting point: 169 to 170 ° C. IR (nujol method) ν max cm ⁻¹ : 2300 to 2700 (NH),
1740, 1640 (C = O) Mass m / z: 216 (M
⁺ ). NMR (DMSO-d6) δ: 1.27 (3H, t, J = 7Hz, -OCH ₂ C H
₃ ), 4.23 (2H, q, J = 7Hz, -OC H ₂ CH ₃ ), 4.52 (2H, s, -CH
₂ Cl), 8.50 (1H, s, pyrimidine-H), 12.5 ~ 13.5 (1H, bs,
NH). Elemental analysis (C ₈ H ₉ ClN ₂ O ₃ ) Theoretical value (%): C, 44.36; H, 4.19; N, 12.93 Actual value (%): C, 44.30; H, 4.19; N, 12.73

Reference Example 2 To 200 ml of ethanol was added 6.6 ml of a 40% aqueous solution of sodium hydroxide, and then 2-
9.83 g of mercaptobenzimidazole was added and dissolved. To this solution, 11.81 g of 2-chloromethyl-1,6-dihydro-6-oxo-5-pyrimidinecarboxylic acid ethyl ester was added and stirred for 15 hours. Continue 60
After stirring at 0 ° C for 2 hours, the mixture was cooled to room temperature, 200 ml of water was added, and the mixture was stirred for 10 minutes. The precipitated crystals were collected by filtration, washed with water, and recrystallized from a mixed solution of N, N-dimethylformamide and ethanol to give 2-[(1H-benzimidazole-2-
Il) thiomethyl] -1,6-dihydro-6-oxo-
5-pyrimidinecarboxylic acid ethyl ester 16.8 g
(Yield 93%) was obtained.

Melting point: 205 to 206 ° C. IR (nujol method) ν max cm ⁻¹ : 3250, 2500 to 2700
(NH), 1740, 1660 (C = O) Mass m / z: 330 (M ⁺ ). NMR (DMSO-d6) δ: 1.24 (3H, t, J = 7Hz, -OCH ₂ C
H ₃ ), 4.20 (2H, q, J = 7Hz, -O CH ₂ CH ₃ ), 4.50 (2H, s, -SCH
_2- ), 7.10 ~ 7.18 (2H, m, benzene-H), 7.40 ~ 7.48 (2H, m,
benzene-H), 8.43 (1H, s, pyrimidine-H), 12.0 ~ 14.0
(2H, bs, NH, NH). Elemental analysis (C ₁₅ H ₁₄ N ₄ O ₃ S) Theoretical value (%): C, 54.53; H, 4.27; N, 16.96 Measured value (%): C, 54.70; H, 4.41; N, 16.64

Reference Examples 3 to 10 The compounds obtained in the same manner as in Reference Example 2 are shown together in Table 1.

[Table 1]

Reference Example 11 2-[(Benzoxazol-2-yl) thiomethyl] in 100 ml of acetonitrile
17.3 g of -1,6-dihydro-6-oxo-5-pyrimidinecarboxylic acid ethyl ester was suspended, 9.7 g of N, N-dimethylaniline and 11.7 ml of phosphorus oxychloride were added, and the mixture was stirred at 60 ° C for 2 hours. .. Next, acetonitrile was distilled off under reduced pressure, the residue was dissolved in methylene chloride, and ice water was added. After stirring for 10 minutes, the organic layer was separated, washed with 5% hydrochloric acid, washed with water, and dried over anhydrous sodium sulfate. Then, methylene chloride was distilled off under reduced pressure, and the residue was recrystallized from a mixed solution of ethyl acetate and isopropyl ether to give 2-[(benzoxazol-2-yl) thiomethyl] -4-chloro-
5-pyrimidinecarboxylic acid ethyl ester 15.4 g
(Yield 84%) was obtained.

Melting point: 105 to 106 ° C. IR (nujol method) ν max cm ⁻¹ : 1740 (C═O) Mass m / z: 349 (M ⁺ ) NMR (DMSO-d6) δ: 1.33 (3H, t, J) = 7Hz, -OCH ₂ C
H ₃ ), 4.35 (2H, q, J = 7Hz, -O CH ₂ CH ₃ ), 4.95 (2H, s, -SCH
_2- ), 7.25 ~ 7.40 (2H, m, benzene-H), 7.55 ~ 7.70 (2H,
m, benzene-H), 9.18 (1H, s, pyrimidine-H). Elemental analysis (C ₁₅ H ₁₂ ClN ₃ O ₃ S) theoretical value (%): C, 51.51; H, 3.46; N, 12.01 actual value (%): C, 51.62; H, 3.41; N, 11.93

[Reference Example 12] In the same manner as in Reference Example 11,
2-[(benzthiazol-2-yl) thiomethyl]-
4-Chloro-5-pyrimidinecarboxylic acid ethyl ester was obtained in a yield of 76%. Melting point: 93-94 ° C.

Reference Example 13 2 to 200 ml of acetonitrile
26 g of [[(1H-benzimidazol-2-yl) thiomethyl] -1,6-dihydro-6-oxo-5-pyrimidinecarboxylic acid ethyl ester was suspended, 14.4 ml of phosphorus oxychloride was added, and the mixture was heated under reflux for 30 minutes. did. Next, acetonitrile was distilled off under reduced pressure, methylene chloride and ice water were added to the residue, and the mixture was neutralized with a 40% aqueous solution of sodium hydroxide. The organic layer was separated, methylene chloride was distilled off under reduced pressure, and the residue was recrystallized from a mixed solution of tetrahydrofuran and isopropyl ether to give 2-[(1H-benzimidazole-2-
24.5 g (yield 89%) of ethyl ester of (yl) thiomethyl] -4-chloro-5-pyrimidinecarboxylic acid was obtained.

Melting point: 133-135 ° C. IR (nujol method) ν max cm ⁻¹ : 3350 (NH), 1720
(C = O) Mass m / z: 348 (M ⁺ ) NMR (DMSO-d6) δ: 1.32 (3H, t, J = 7Hz, -OCH ₂ C
H ₃ ), 4.35 (2H, q, J = 7Hz, -O CH ₂ CH ₃ ), 4.85 (2H, s, -SCH ₂
-), 7.10 ~ 7.15 (2H, m, benzene-H), 7.40 ~ 7.45 (2H, m,
benzene-H), 9.14 (1H, s, pyrimidine-H), 12.0 ~ 13.5 (2
H, bs, NH). Elemental analysis (C ₁₅ H ₁₃ ClN ₄ O ₂ S) Theoretical value (%): C, 51.65; H, 3.76; N, 16.06 Actual value (%): C, 51.40; H, 3.83 ; N, 15.87

Reference Examples 14 to 19 The compounds obtained in the same manner as in Reference Example 13 are collectively shown in Table 2.

[0048]

[Table 2]

[Reference Example 20] 2-N was added to a mixed solvent of 5 ml of N, N-dimethylformamide and 100 ml of methylene chloride.
[(1H-Benzimidazol-2-yl) thiomethyl] -4-chloro-5-pyrimidinecarboxylic acid ethyl ester (10.5 g) was dissolved, and 80% m-chloroperbenzoic acid (6.80 g) was salified under ice-cooling stirring. A solution dissolved in 80 ml of methylene was added dropwise over 1 hour. Then, 10 ml of a 5% aqueous solution of sodium thiosulfate and 30 ml of a saturated aqueous solution of sodium hydrogen carbonate were added and stirred, and the organic layer was separated. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solution of methylene chloride and ethyl acetate to give 2-[(1H-benzimidazol-2-yl).
Sulfinylmethyl] -4-chloro-5-pyrimidinecarboxylic acid ethyl ester (9.3 g, yield 85%) was obtained.

Melting point: 155 to 157 ° C. IR (nujol method) ν max cm ⁻¹ : 3260 (NH), 1730
(C = O) Mass m / z: 364 (M ⁺ ) NMR (DMSO-d6) δ: 1.33 (3H, t, J = 7Hz, -OCH ₂ C
H ₃ ), 4.36 (2H, q, J = 7Hz, -O CH ₂ CH ₃ ), 4.95 and 5.10
(2H, d and d, J = 13.3Hz, -SOCH _2- ), 7.25 ~ 7.35 (2H,
m, benzene-H), 7.55 ~ 7.75 (2H, m, benzene-H), 9.13
(1H, s, pyrimidine-H), 13.59 (1H, s, NH). Elemental analysis (C ₁₅ H ₁₃ ClN ₄ O ₃ S) Theoretical value (%): C, 49.39; H, 3.59; N, 15.36 Actual measurement Value (%): C, 49.47; H, 3.47; N, 15.29

Example 1 2.5 g of 2-[(1H-benzimidazol-2-yl) thiomethyl] -4-chloro-5-pyrimidinecarboxylic acid ethyl ester was dissolved in 50 ml of tetrahydrofuran and cooled in an ice-water bath. , Under stirring,
2 ml of a 40% aqueous solution of methylamine was added. Next, after stirring at room temperature for 1 hour, the reaction solution was dried under reduced pressure, and water was added to the residue for washing. The crystals were collected by filtration and recrystallized from a mixed solution of ethanol and isopropyl ether to give 2-[(1H-benzimidazol-2-yl) thiomethyl] -4-methylamino-5-pyrimidinecarboxylic acid ethyl ester.2.
2 g (yield 89%) was obtained.

Melting point: 105 to 107 ° C. IR (nujol method) νmax cm ⁻¹ : 3360, 2700 to 3300 (N
H), 1690 (C = O) Mass m / z: 343 (M ⁺ ) NMR (DMSO-d6) δ: 1.30 (3H, t, J = 7Hz, -OCH ₂ C
H ₃ ), 2.87 (3H, d, J ＝ 4.8Hz, -NH CH ₃ ), 4.39 (2H, q, J ＝
7Hz, -O CH ₂ CH ₃ ), 4.60 (2H, s, -SCH _2- ), 7.10 ~ 7.15 (2H, m,
benzene-H), 7.40 ~ 7.48 (2H, m, benzene-H), 8.21 (1H,
q, J = 4.8Hz, -N H CH ₃ ), 8.68 (1H, s, pyrimidine-H), 11.5
~13.5 (1H, bs, NH) Elemental analysis _{(C 16 H 17 N 5 O} 2 S · H 2 O) theory (%):. C, 53.17 ; H, 5.30; N, 19.38 Found (%): C, 53.17; H, 5.43; N, 19.66

[Examples 2 to 5] Table 3 collectively shows the compounds obtained in the same manner as in Example 1.

[0054]

[Table 3]

Example 6 3 g of 2-[(1H-benzimidazol-2-yl) thiomethyl] -4-chloro-5-pyrimidinecarboxylic acid ethyl ester was dissolved in 50 ml of tetrahydrofuran, cooled in an ice-water bath and stirred. Bottom, n-
2 ml of propylamine was added. Next, after stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure, and water was added to the residue for crystallization. The crystals collected by filtration were recrystallized from a mixed solution of ethyl acetate and diethyl ether to give 2-[(1H-benzimidazol-2-yl) thiomethyl] -4- (n-propylamino) -5-pyrimidinecarboxylic acid ethyl ester 3 .0
g (84% yield) was obtained.

Melting point: 113 to 115 ° C. IR (nujol method) ν max cm ⁻¹ : 3350,3300 (NH), 17
00 (C = O) Mass m / z: 371 (m ⁺ ) NMR (DMSO-d6) δ: 0.77 (3H, t, J = 7.5Hz, -NHCH ₂ C
H ₂ CH ₃ ), 1.30 (3H, t, J = 7Hz, -OCH ₂ CH ₃ ), 1.43 (2H, m,
-NHCH CH ₂ CH ₃ ), 3.29 (2H, m, -NH CH ₂ CH ₂ CH ₃ ), 4.28 (2H,
q, J = 7Hz, -O CH ₂ CH ₃ ), 4.59 (2H, s, -SCH _2- ), 7.05 to 7.15
(2H, m, benzene-H), 7.35 ~ 7.50 (2H, m, benzene-H), 8.2
5 (1H, t, J = 5.5Hz, -N H CH ₂ CH ₂ CH ₃ ), 8.69 (1H, s, pyrimidin
eH), 12.61 (1H, bs, NH). Elemental analysis (C ₁₈ H ₂₁ N ₅ O ₂ S) Theoretical value (%): C, 58.20; H, 5.70; N, 18.85 Measured value (%): C, 58.01; H, 5.89; N, 18.74

[Examples 7 to 10] The compounds obtained in the same manner as in Example 6 are collectively shown in Table 4.

[0058]

[Table 4]

Example 11 Tetrahydrofuran 50 ml
2-[(1H-benzimidazol-2-yl) thiomethyl] -4-chloro-5-pyrimidinecarboxylic acid ethyl ester (3.49 g) was dissolved in the solution, and n-butylamine (3 ml) was added under cooling and stirring in an ice-water bath. It was Then, after stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure, and methylene chloride and water were added to the residue to dissolve it. The organic layer was separated, washed with water, and dried over anhydrous sodium sulfate. Methylene chloride was distilled off under reduced pressure, and the residue was recrystallized from a mixed solution of ethyl acetate and diethyl ether to give 2-[(1H-benzimidazol-2-yl) thiomethyl] -4- (n-butylamino] -5-pyrimidine. Carboxylic acid ethyl ester 2.5 g (yield 65
%) Was obtained.

Melting point: 88 to 89 ° C. IR (nujol method) νmax cm ⁻¹ : 3450, 2600 to 3200 (N
H), 1720 (C = O) Mass m / z: 385 (M ⁺ ) NMR (DMSO-d6) δ: 0.81 (3H, t, J = 7.3Hz, -NHCH ₂ CH
₂ CH ₂ C H ₃ ), 1.06 to 1.47 (4H, m, -NHCH ₂ CH ₂ CH ₂ CH ₃ ), 1.30
(3H, t, J = 7Hz, -OCH ₂ C H ₃ ), 3.36 (2H, m, -NH CH ₂ CH ₂ CH ₂
CH ₃ ), 4.29 (2H, q, J = 7Hz, -O CH ₂ CH ₃ ), 4.59 (2H, s, -SC
H _2- ), 7.05 ~ 7.15 (2H, m, benzene-H), 7.30 ~ 7.60 (2
H, m, benzene-H), 8.23 (1H, t, J = 5.7Hz, -N H -CH ₂ CH ₂ CH ₂ CH
₃ ), 8.69 (1H, s, pyrimidine-H), 12.62 (1H, s, NH). Elemental analysis (C ₁₉ H ₂₃ N ₅ O ₂ S) Theoretical value (%): C, 59.20; H, 6.01; N, 18.17 Found (%): C, 59.12; H, 6.27; N, 18.13

[Examples 12 to 19] The compounds obtained in the same manner as in Example 11 are collectively shown in Table 5.

[0062]

[Table 5]

[Example 20] 50 ml of tetrahydrofuran
2-[(1H-benzimidazol-2-yl) thiomethyl] -4-chloro-5-pyrimidinecarboxylic acid ethyl ester (3.49 g) was dissolved in tert-butylamine 3
ml was added. Then, the mixture was stirred at 50 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and methylene chloride and water were added to the residue to dissolve it. The organic layer was separated, washed with water, and dried over anhydrous sodium sulfate. After evaporating methylene chloride under reduced pressure, the residue was purified by silica gel column chromatography (eluted with an equal volume mixture of ethyl acetate and n-hexane) to give 2-[(1
H-benzimidazol-2-yl] thiomethyl) -4
3.1 g (yield 80%) of-(tert-butylamino) -5-pyrimidinecarboxylic acid ethyl ester was obtained.

Melting point: 85 to 89 ° C. IR (nujol method) νmax cm ⁻¹ : 3330, 2600 to 2800 (N
H), 1700 (C = O) Mass m / z: 385 (M ⁺ ) NMR (DMSO-d6) δ: 1.30 (3H, t, J = 7Hz, -OCH ₂ C H ₃ ),
1.36 [9H, s, C (CH ₃ ) ₃ ], 4.28 (2H, q, J = 7Hz, -O CH ₂ CH ₃ ),
4.66 (2H, s, -SCH _2- ), 7.05 ~ 7.15 (2H, m, benzene-H),
7.25 ~ 7.55 (2H, m, benzene-H), 8.23 (1H, s, NH), 8.72
(1H, s, pyrimidine-H), 12.62 (1H, bs, NH). Elemental analysis (C ₁₉ H ₂₃ N ₅ O ₂ S) theoretical value (%): C, 59.20; H, 6.01; N, 18.17 actual measurement Value (%): C, 59.30; H, 6.22; N, 17.85

Example 21 Tetrahydrofuran 30 ml
2-[(1H-benzimidazol-2-yl) thiomethyl] -4-chloro-5-pyrimidinecarboxylic acid ethyl ester 2.79 g was dissolved in triethylamine 1 g.
And aniline 0.84 g were added, and the mixture was stirred at 50 ° C. for 3 hours. Then, the reaction solution was dried under reduced pressure, and water was added to the residue for washing. The solid substance was collected by filtration and recrystallized from ethanol to give 4-anilino-2-[(1H-benzimidazole-
2.7 g (yield 84%) of 2-yl) thiomethyl] -5-pyrimidinecarboxylic acid ethyl ester was obtained.

Melting point: 179 to 180 ° C. IR (nujol method) ν max cm ⁻¹ : 2500 to 3100 (NH),
1700 (C = O) Mass m / z: 405 (M ⁺ ) NMR (DMSO-d6) δ: 1.35 (3H, t, J = 7Hz, -OCH ₂ C H ₃ ),
4.37 (2H, q, J = 7Hz, -O CH ₂ CH ₃ ), 4.70 (2H, s, -SCH _2- ),
7.00 ~ 7.65 (9H, m, benzene-H), 8.90 (1H, s, pyrimidi
ne-H), 10.18 (1H, s, NH), 12.66 (1H, s, NH). Elemental analysis (C ₂₁ H ₁₉ N ₅ O ₂ S) Theoretical value (%): C, 62.21; H, 4.72; N, 17.27 Found (%): C, 62.19; H, 4.85; N, 17.60

Example 22 Tetrahydrofuran 30 ml
2-[(1H-benzimidazol-2-yl) thiomethyl] -4-chloro-5-pyrimidinecarboxylic acid ethyl ester (2.48 g) was dissolved in the solution, and 3% of a 50% aqueous solution of dimethylamine was added thereto while stirring with ice cooling. .. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure, and methylene chloride and water were added to the residue to dissolve it. The organic layer was separated, washed with water, and dried over anhydrous sodium sulfate. After distilling methylene chloride under reduced pressure, the residue was recrystallized from ethyl acetate and diethyl ether to give 2-
2.0 g (79%) of [(1H-benzimidazol-2-yl) thiomethyl] -4-dimethylamino-5-pyrimidinecarboxylic acid ethyl ester was obtained.

Melting point: 128 to 130 ° C. IR (nujol method) ν max cm ⁻¹ : 3180 (NH), 1720 (C
= O) Mass m / z: 357 (M ⁺ ) NMR (DMSO-d6) δ: 1.29 (3H, t, J = 7Hz, -OCH ₂ C H ₃ ),
2.95 [6H, s, -N (CH ₃ ) ₂ ], 4.27 (2H, q, J ＝ 7Hz, -OC H ₂ CH
₃ ), 4.60 (2H, s, -SCH _2- ), 7.10 ~ 7.14 (2H, m, benzene-
H), 7.42 ~ 7.46 (2H, m, benzene-H), 8.49 (1H, s, pyrim
idine-H), 12.0 to 13.5 (1H, bs, NH). Elemental analysis (C ₁₇ H ₁₉ N ₅ O ₂ S) Theoretical value (%): C, 57.13; H, 5.36; N, 19.59 Measured value (%) ): C, 57.00; H, 5.50; N, 19.50

[Examples 23 to 30] Table 6 collectively shows the compounds obtained in the same manner as in Example 22.

[0070]

[Table 6]

[Example 31] 50 ml of tetrahydrofuran
3.0 g of 4-chloro-2-[(5,6-dimethyl-1H-benzimidazol-2-yl) thiomethyl] -5-pyrimidinecarboxylic acid ethyl ester was dissolved in 2.1 g of morpholine under stirring with ice cooling. Was added. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure, and methylene chloride and water were added to the residue to dissolve it. The organic layer was separated, washed with water, and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was recrystallized from ethyl acetate and isopropyl ether to give 2-
[(5,6-Dimethyl-1H-benzimidazole-2
2.7 g (yield 80%) of ethyl ester of -yl) thiomethyl] -4-morpholino-5-pyrimidinecarboxylic acid were obtained.

Melting point: 133-134 ° C. IR (nujol method) ν max cm ⁻¹ : 3250 (NH), 1710 (C
= O) Mass m / z: 427 (M ⁺ ) NMR (DMSO-d6) δ: 1.28 (3H, t, J = 7Hz, -OCH ₂ C H ₃ ),
2.27 (3H, s, CH ₃ ), 2.28 (3H, s, CH ₃ ), 3.40 ~ 3.50 (8H, m,
morpholine-H), 4.26 (2H, q, J = 7Hz, -O CH ₂ CH ₃ ), 4.55
(2H, s, -SCH _2- ), 7.15 (1H, s, benzene-H), 7.27 (1H, s, be
nzene-H), 8.55 (1H, s, pyrimidine-H), 12.37 (1H, s, N
H). Elemental analysis (C ₂₁ H ₂₅ N ₅ O ₃ S) Theoretical value (%): C, 59.00; H, 5.89; N, 16.38 Actual value (%): C, 58.96; H, 5.90; N, 16.26

[Examples 32-49] Table 7 shows compounds obtained in the same manner as in Example 31.

[0074]

[Table 7]

Example 50 Tetrahydrofuran 50 ml
2.49 g of 2-[(1H-benzimidazol-2-yl) thiomethyl) -4-chloro-5-pyrimidinecarboxylic acid ethyl ester was dissolved in the solution, 4 ml of di-n-butylamine was added, and the mixture was stirred at room temperature for 3 hours. .. The reaction solution was concentrated under reduced pressure, and methylene chloride was added to the residue to dissolve it. This solution was washed with water and dried, and then methylene chloride was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted with an equal mixture of ethyl acetate and n-hexane) to give oily 2-[(1H-benzimidazol-2-yl) thiomethyl] -4- (di-n. -Butylamino] -5-pyrimidinecarboxylic acid ethyl ester 4.0 g (yield 91
%) Was obtained.

IR (film method) ν max cm ^-1 : 3150 (N
H), 1720 (C = O) Mass m / z: 441 (M ⁺ ) NMR (DMSO-d6) δ: 0.80 [6H, t, J = 6.5Hz, -N (CH ₂ CH
₂ CH ₂ CH ₃ ) ₂ ], 1.31 (3H, t, J = 7Hz, -OCH ₂ C H ₃ ), 1.00 to 1.
60 (8H, m, -N (CH ₂ C H ₂ CH ₂ CH ₃ ) ₂ ), 3.34 [4H, t, J = 6.5Hz,
-N (C H ₂ CH ₂ CH ₂ CH ₃ ) ₂ ], 4.26 (2H, q, J = 7Hz, -O CH ₂ CH ₃ ),
4.60 (2H, s, -SCH _2- ), 7.05 ~ 7.15 (2H, m, benzene-H), 7.
34 ~ 7.51 (2H, m, benzene-H), 8.41 (1H, s, pyrimidine-
H), 12.60 (1H, s, NH). Elemental analysis (C ₂₃ H ₃₁ N ₅ O ₂ S) Theoretical value (%): C, 62.56; H, 7.08; N, 15.86 Measured value (%): C, 62.72; H, 7.29; N, 15.65

[Examples 51 to 53] Table 8 shows compounds obtained in the same manner as in Example 50.

[0078]

[Table 8]

[Example 54] 50 ml of tetrahydrofuran
2.49 g of 2-[(1H-benzimidazol-2-yl) thiomethyl] -4-chloro-5-pyrimidinecarboxylic acid ethyl ester was dissolved in the solution, 5 ml of diisopropylamine was added and the mixture was refluxed for 48 hours. Next, the solvent was distilled off, and methylene chloride was added to the residue to dissolve it. This solution was washed with water and dried, and then methylene chloride was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate and n-
Elution with an equal volume mixture of hexane)
1.6 g (yield 39%) of ethyl ester of [(1H-benzimidazol-2-yl) thiomethyl] -4-diisopropylamino-5-pyrimidinecaponic acid was obtained.

Melting point: 131 to 132 ° C. IR (nujol method) νmax cm ⁻¹ : 3180 (NH), 1720 (C
= O) Mass m / z: 413 (M ⁺ ) NMR (DMSO-d6) δ: 1.28 (3H, t, J = 7Hz, -OCH ₂ C H ₃ ),
1.29 [12H, d, J = 7Hz, -N [CH (C H _{3) 2] 2],} 3.50 to 3.70
[2H, m, -N [ CH (CH ₃ ) ₂ ] ₂ ], 4.25 (2H, q, J = 7Hz, -O CH
₂ CH ₃ ), 4.62 (2H, s, -SCH _2- ), 7.05 ~ 7.15 (2H, m, benze
ne-H), 7.25 ~ 7.50 (2H, m, benzene-H), 8.34 (1H, s, py
rimidine-H), 12.61 (1H, s, NH). Elemental analysis (C ₂₁ H ₂₇ N ₅ O ₂ S) Theoretical value (%): C, 60.99; H, 6.58; N, 16.94 Measured value (%): C, 61.07; H, 6.99; N, 16.83

[Example 55] 50 ml of tetrahydrofuran
3.31 g of 2-[(1H-benzimidazol-2-yl) thiomethyl] -4-chloro-5-pyrimidinecarboxylic acid ethyl ester was dissolved in 3.0 g of imidazole
g was added, and the mixture was stirred at 60 ° C. for 3 hours. After cooling, 50 ml of water was added and the precipitated crystals were collected by filtration and washed with water. Recrystallization from a mixture of N, N-dimethylformamide and water
3.2 g of [(1H-benzimidazol-2-yl) thiomethyl] -4- (1H-imidazol-1-yl) -5-pyrimidinecarboxylic acid ethyl ester (yield 89
%) Was obtained.

Melting point: 196 to 198 ° C. IR (nujol method) νmax cm ⁻¹ : 1720 (C═O) Mass m / z: 380 (M ⁺ ) NMR (DMSO-d6) δ: 1.23 (3H, t, J) = 7Hz, -OCH ₂ C
H ₃ ), 4.30 (2H, q, J = 7Hz, -O CH ₂ CH ₃ ), 4.87 (2H, s, -SCH
_2- ), 7.07 (1H, s, imidazole-H), 7.10 ~ 7.20 (2H, m, ben
zene-H), 7.25 ~ 7.55 (2H, m, benzene-H), 7.52 (1H, s,
imidazole-H), 8.12 (1H, s, pyrimidine-H), 9.22 (1H, s,
imidazole-H), 12.66 (1H, s, NH). Elemental analysis (C ₁₈ H ₁₆ N ₆ O ₂ S) Theoretical value (%): C, 56.83; H, 4.24; N, 22.09 Actual value (%): C, 56.75; H, 4.06; N, 22.13

Example 56 2-to 20 ml of ethanol
[(1H-Benzimidazol-2-yl) thiomethyl] -4-dimethylamino-5-pyrimidinecarboxylic acid ethyl ester (3.57 g) was dissolved, 1N aqueous sodium hydroxide solution (20 ml) was added, and the mixture was stirred at 60 ° C for 1 hr. did. Then, ethanol was distilled off under reduced pressure, 10 ml of a 10% aqueous solution of sodium chloride was added to the residue, and the mixture was neutralized with 10% hydrochloric acid and ice-cooled, and the precipitated crystals were collected by filtration to give 2-[(1H-benzimidazole- 2.1 g (yield 64%) of 2-yl) thiomethyl] -4-dimethylamino-5-pyrimidinecarboxylic acid was obtained.

Melting point: 142-144 ° C. IR (nujol method) νmax cm ⁻¹ : 3150 (NH), 1700 (C
= O) Mass m / z: 329 (M +) NMR (DMSO-d6) δ: 2.97 _{[6H, s, -N (CH 3} ) 2 ], 4.60
(2H, s, -SCH _2- ), 7.00 ~ 7.20 (2H, m, benzene-H), 7.40
~ 7.50 (2H, m, benzene-H), 8.50 (1H, s, pyrimidine-H),
12.0 to 14.00 (2H, bs, NH and COOH). Elemental analysis (C ₁₅ H ₁₅ N ₅ O ₂ S) Theoretical value (%): C, 54.70; H, 4.59; N, 21.26 Actual value (%): C , 54.40; H, 4.74; N, 21.00

Example 57 1.98 g of 4-amino-2-[(1H-benzimidazol-2-yl) thiomethyl] -5-pyrimidinecarboxylic acid ethyl ester was dissolved in 30 ml of N, N-dimethylformamide, A solution prepared by dissolving 1.36 g of 80% m-chloroperbenzoic acid in 20 ml of methylene chloride was added dropwise over 30 minutes while stirring with ice cooling. Next, 5 ml of a 5% aqueous solution of sodium thiosulfate, 10 ml of a saturated aqueous solution of sodium hydrogen carbonate and 50 ml of water were added and stirred, and the precipitated crystals were collected by filtration. After washing with water, recrystallize from a mixture of ethanol and chloroform to give 4-amino-2-
1.6 g (yield 78%) of ethyl ester of [(1H-benzimidazol-2-yl) sulfinylmethyl] -5-pyrimidinecarboxylic acid was obtained.

Melting point: 181 to 183 ° C. IR (nujol method) νmax cm ⁻¹ : 3380, 3300, 3200 (N
H), 1720 (C = O) Mass m / z: 345 (M ⁺ ) NMR (DMSO-d6) δ: 1.31 (3H, t, J = 7Hz, -OCH ₂ C
H ₃ ), 4.30 (2H, q, J = 7Hz, -O CH ₂ CH ₃ ), 4.63 and 4.69
(2H, d and d, J = 13.7Hz, -SOCH _2- ), 7.25 ~ 7.40 (2H,
m, benzene-H), 7.50 ~ 7.80 (2H, m, benzene-H), 7.71
(1H, bs, NH), 8.21 (1H, bs, NH), 8.70 (1H, s, pyrimidine
-H), 13.66 (1H, bs, NH). Elemental analysis (C ₁₅ H ₁₅ N ₅ O ₃ S) Theoretical value (%): C, 52.16; H, 4.38; N, 20.28 Actual value (%): C , 51.92; H, 4.16; N, 20.38

[Examples 58 to 59] Table 9 shows compounds obtained in the same manner as in Example 57.

[0088]

[Table 9]

Example 60 In 30 ml of N, N-dimethylformamide, 2-[(1H-benzimidazole-2-
Iyl) thiomethyl] -4- (1H-imidazole-1-
Yl) -5-pyrimidinecarboxylic acid ethyl ester 2.
28 g was dissolved, and while stirring under ice-cooling, a solution prepared by dissolving 1.36 g of 80% m-chloroperbenzoic acid in 20 ml of methylene chloride was added.
It was dripped in 0 minutes. Then, 5 ml of a 5% aqueous solution of sodium thiosulfate, 10 ml of a saturated aqueous solution of sodium hydrogen carbonate and 30 ml of methylene chloride were added and stirred. The organic layer was separated, washed with water and dried, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixture of ethyl acetate and chloroform to give 2-[(1H
1.8 g of ethyl benzimidazole-2-yl) sulfinylmethyl] -4- (1H-imidazol-1-yl) -5-pyrimidinecarboxylic acid (yield 76
%) Was obtained.

Melting point: 161 to 163 ° C. IR (nujol method) ν max cm ⁻¹ : 1730 (C═O) Mass m / z: 396 (M ⁺ ) NMR (DMSO-d6) δ: 1.23 (3H, t, J) = 7Hz, -OCH ₂ C H ₃ ),
4.30 (2H, q, J = 7Hz, -O CH ₂ CH ₃ ), 4.97 and 5.06 (2H,
d and d, J = 13.7Hz, -SOCH _2- ), 7.00 (1H, s, imidazole-
H), 7.27 (1H, s, imidazole-H), 7.20 ~ 7.30 (2H, m, benze
ne-H), 7.50 ~ 7.80 (2H, m, benzene-H), 7.95 (1H, s, py
rimidine-H), 9.22 (1H, s, imidazole-H), 13.60 (1H, bs, N
H). Elemental analysis (C ₁₈ H ₁₆ N ₆ O ₃ S) Theoretical value (%): C, 54.54; H, 4.07; N, 21.20 Actual value (%): C, 54.32; H, 3.88; N, 21.25

Example 61 A mixture of 20 ml of N, N-dimethylformamide and 20 ml of methylene chloride was added with 2-[(1H
-Benzimidazol-2-yl) thiomethyl] -4-
[N- (2-hydroxyethyl) -N-methylamino]
2.5 g of -5-pyrimidinecarboxylic acid ethyl ester was dissolved, and while stirring at -10 ° C, 1.53 g of 80% m-chloroperbenzoic acid was dissolved in 20 ml of methylene chloride to prepare a solution.
Dropped over time. Then, 5 ml of a 5% aqueous solution of sodium thiosulfate and 10 ml of a saturated aqueous solution of sodium hydrogen carbonate were added and stirred. The organic layer was separated, washed with water and dried, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solution of ethyl acetate and chloroform to give 2-[(1H-benzimidazole-2-
Yield) sulfinylmethyl] -4- [N- (2-hydroxyethyl) -N-methylamino] -5-pyrimidinecarboxylic acid ethyl ester (1.5 g, yield 58%) was obtained.

Melting point: 119 to 121 ° C. IR (nujol method) νmax cm ⁻¹ : 3230 (NH), 1720 (C
= O) Mass m / z: 403 (M ⁺ ) NMR (DMSO-d6) δ: 1.29 (3H, t, J = 7Hz, -OCH ₂ C
H ₃ ), 2.90 (3H, s, NCH ₃ ), 3.40 to 3.65 (4H, m, N CH ₂ CH ₂ OH),
4.27 (2H, q, J = 7Hz, -O CH ₂ CH ₃ ), 4.63 and 4.74 (2H, d
And d, J = 13.8Hz, -SOCH _2- ), 4.72 (1H, t, J = 5.6Hz, NC
H ₂ CH ₂ O H ), 7.20 ~ 7.40 (2H, m, benzene-H), 7.50 ~ 7.85
(2H, m, benzene-H), 8.45 (1H, s, pyrimidine-H), 13.64
(1H, bs, NH). Elemental analysis (C ₁₈ H ₂₁ N ₅ O ₄ S) Theoretical value (%): C, 53.59; H, 5.25; N, 17.36 Actual value (%): C, 53.39; H, 4.98; N, 17.34

Example 62 2-to 30 ml of methylene chloride
2.0 g of [(1H-benzimidazol-2-yl) thiomethyl] -4- (2-methoxyethylamino) -5-pyrimidinecarboxylic acid ethyl ester was dissolved, -1
80% m-chloroperbenzoic acid 1.22 under stirring at 0 ° C.
A solution prepared by dissolving g in 20 ml of methylene chloride was added dropwise over 1 hour. Then, 10 ml of a 5% aqueous solution of sodium thiosulfate and 30 ml of a saturated aqueous solution of sodium hydrogen carbonate were added and stirred. The organic layer was separated, washed with water and dried, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixture of ethyl acetate and isopropyl ether to give 2-[(1H-benzimidazole-2-
Yield) sulfinylmethyl] -4- (2-methoxyethylamino) -5-pyrimidinecarboxylic acid ethyl ester (1.7 g, yield 82%) was obtained.

Melting point: 121 to 122 ° C. IR (nujol method) νmax cm ⁻¹ : 3330 (NH), 1700 (C
= O) Mass m / z: 403 (M ⁺ ) NMR (DMSO-d6) δ: 1.30 (3H, t, J = 7Hz, -OCH ₂ C H ₃ ),
3.22 (3H, s, -OCH ₃ ), 3.20 to 3.45 (4H, m, -NH CH ₂ CH _2- ),
4.29 (2H, q, J = 7Hz, -O CH ₂ CH ₃ ), 4.67 and 4.77 (2H, d
And d, J = 13.5Hz, -SOCH _2- ), 7.20 ~ 7.45 (2H, m, benze
ne-H), 7.50 ~ 7.80 (2H, m, benzene-H), 8.29 (1H, bs, N
H), 8.70 (1H, s, pyrimidine-H), 13.6 (1H, bs, NH). Elemental analysis (C ₁₈ H ₂₁ N ₅ O ₄ S) Theoretical value (%): C, 53.59; H, 5.25; N, 17.36 Found (%): C, 53.65; H, 5.59; N, 17.16

Examples 63 to 79 The compounds obtained in the same manner as in Example 62 are collectively shown in Table 10.

[0096]

[Table 10]

Example 80 2-to 50 ml of methylene chloride
[(5-Methyl-1H-benzimidazol-2-yl) thiomethyl] -4-dimethylamino-5-pyrimidinecarboxylic acid ethyl ester (1.7 g) was dissolved, and -10
A solution prepared by dissolving 1.1 g of 80% m-chloroperbenzoic acid in 20 ml of methylene chloride was added dropwise over 1 hour with stirring at ℃.
Then, 5 ml of a 5% aqueous solution of sodium thiosulfate and 25 ml of a saturated aqueous solution of sodium hydrogen carbonate were added and stirred. The organic layer was separated, washed with water and dried, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solution of ethyl acetate and diethyl ether to give 2-[(5-methyl-1H-benzimidazole-2-
Il) sulfinylmethyl] -4-dimethylamino-5
-1.1 g (62% yield) of pyrimidinecarboxylic acid ethyl ester was obtained.

Melting point: 148 to 149 ° C. IR (nujol method) νmax cm ⁻¹ : 3160 (NH), 1720 (C
= O) Mass m / z: 387 (M ⁺ ) NMR (DMSO-d6) δ: 1.29 (3H, t, J = 7Hz, -OCH ₂ C H ₃ ),
2.44 (3H, s, CH ₃ ), 2.87 [6H, s, N (CH ₃ ) ₂ ], 4.28 (2H, q,
J = 7Hz, -O CH ₂ CH ₃ ), 4.60 and 4.75 (2H, d and d, J = 1
3.5Hz, -SOCH _2- ), 7.13 (1H, m, benzene-H), 7.40 ~ 7.60
(2H, m, benzene-H), 8.47 (1H, s, pyrimidine-H), 13.48
(1H, bs, NH). Elemental analysis (C ₁₈ H ₂₁ N ₅ O ₃ S) Theoretical value (%): C, 55.80; H, 5.46; N, 18.08 Actual value (%): C, 55.70; H, 5.66; N, 18.19

[Examples 81 to 97] Table 11 collectively shows the compounds obtained in the same manner as in Example 80.

[0100]

[Table 11]

Example 98 2-into 50 ml of methylene chloride
5.0 g of [(1H-benzimidazol-2-yl) thiomethyl] -4- (1-pyrrolidinyl) -5-pyrimidinecarboxylic acid ethyl ester was dissolved and stirred at -10 ° C to give 80% m-chloroperoxide. A solution of 3.09 g of benzoic acid dissolved in 60 ml of methylene chloride was added dropwise over 1 hour. Then, 20 ml of a 5% aqueous solution of sodium thiosulfate and 50 ml of a saturated aqueous solution of sodium hydrogen carbonate were added and stirred. The organic layer was separated, washed with water and dried, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixture of ethyl acetate and diethyl ether to give 2
-[(1H-benzimidazol-2-yl) sulfinylmethyl] -4- (1-pyrrolidinyl) -5-pyrimidinecarboxylic acid ethyl ester 4.4 g (yield 85%)
Got

Melting point: 160 to 161 ° C. IR (nujol method) νmax cm ⁻¹ : 1715 (C═O) Mass m / z: 399 (M ⁺ ) NMR (DMSO-d6) δ: 1.29 (3H, t, J) = 7Hz, -OCH ₂ C H ₃ ),
1.75 (4H, m, pyrrolidine-H), 3.15 (4H, m, pyrrolidine
-H), 4.27 (2H, q, J = 7Hz, -O CH ₂ CH ₃ ), 4.61 and 4.75 (2
H, d and d, J = 13.5Hz, -SOCH _2- ), 7.20 ~ 7.40 (2H, m, be
nzene-H), 7.50 ~ 7.80 (2H, m, ben zene-H), 8.46 (1H,
s, pyrimidine-H), 13.61 (1H, s, NH). Elemental analysis (C ₁₉ H ₂₁ N ₅ O ₃ S) Theoretical value (%): C, 57.13; H, 5.30; N, 17.53 Actual value (%) ): C, 56.94; H, 5.60; N, 17.58

[Examples 99 to 102] Table 12 collectively shows the compounds obtained in the same manner as in Example 98.

[0104]

[Table 12]

Example 103 In a manner similar to Example 80, 4-dimethylamino-2-[(1-methyl-1H-
Benzimidazol-2-yl) thiomethyl] -5-pyrimidinecarboxylic acid ethyl ester is oxidized to give 4-dimethylamino-2-[(1-methyl-1H-benzimidazol-2-yl) sulfinylmethyl] -5-pyrimidine. Obtained carboxylic acid ethyl ester.

Melting point: 106 to 108 ° C. IR (nujol method) νmax cm ⁻¹ : 1720 (C═O) Mass m / z: 387 (M ⁺ ) NMR (DMSO-d6) δ: 1.28 (3H, t, J) = 7Hz, -OCH ₂ C H ₃ ),
2.87 [6H, s, -N (CH ₃ ) ₂ ], 4.04 (3H, s, CH ₃ ), 4.27 (2H,
q, J = 7Hz, -O CH ₂ CH ₃ ), 4.83 and 4.89 (2H, d and d, J
= 13.5Hz, -SOCH _2- ), 7.30 ~ 7.50 (2H, m, benzene-H),
7.60 ~ 7.80 (2H, m, benzene-H), 8.45 (1H, s, pyrimidin
eH). Elemental analysis (C ₁₈ H ₂₁ N ₅ O ₃ S) Theoretical value (%): C, 55.80; H, 5.46; N, 18.08 Actual value (%): C, 56.10; H, 5.75; N, 17.98

Example 104 2 to 30 ml of methylene chloride
1.5 g of-[(1H-benzimidazol-2-yl) sulfonylmethyl] -4-chloro-5-pyrimidinecarboxylic acid ethyl ester was dissolved, and 0.9 ml of thiomorpholine was added under stirring with ice cooling. After stirring at room temperature for 30 minutes,
Washed with water. Then, it was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solution of ethyl acetate and diethyl ether to give 2-[(1H-benzimidazole-
2-yl) sulfinylmethyl] -4-thiomorpholino-5-pyrimidinecarboxylic acid ethyl ester 1.4 g
(Yield 79%) was obtained.

Melting point: 144 to 146 ° C. IR (nujol method) νmax cm ⁻¹ : 3250 (NH), 1720 (C
= O) Mass m / z: 431 (M ⁺ ) NMR (DMSO-d6) δ: 1.29 (3H, t, J = 7Hz, -OCH ₂ C H ₃ ),
2.40 ~ 2.60 (4H, m, thiomorpholine-H), 3.40 ~ 3.60
(4H, m, thiomorpholine-H), 4.28 (2H, q, J ＝ 7Hz, -O CH ₂ CH
₃ ), 4.68 and 4.78 (2H, d and d, J = 13.4Hz, -SOC
H ₂ ), 7.20 ~ 7.40 (2H, m, benzene-H), 7.50 ~ 7.80 (2H,
m, benzene-H), 8.54 (1H, s, pyrimidine-H), 13.60 (1H,
elemental analysis (C ₁₉ H ₂₁ N ₅ O ₃ S ₂ ) theoretical value (%): C, 52.88; H, 4.90; N, 16.23 measured value (%): C, 52.87; H, 4.85; N, 16.27

[Examples 105 to 106] Table 13 shows compounds obtained in the same manner as in Example 104.

[0110]

[Table 13]

Example 107 2 to 20 ml of methylene chloride
2.0 g of [[(1H-benzimidazol-2-yl) thiomethyl] -4- (2-methoxyethylamino) -5-pyrimidinecarboxylic acid ethyl ester was dissolved, 10 ml of a saturated aqueous solution of sodium hydrogencarbonate was added, and ice was added. Under cold stirring, a solution of 5.57 g of 80% m-chloroperbenzoic acid in 60 ml of methylene chloride was added dropwise over 40 minutes. Then, 20 ml of a 5% aqueous solution of sodium thiosulfate was added and stirred. The organic layer was separated, washed with water and dried, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solution of ethyl acetate and diethyl ether to give 2-[(1H-benzimidazol-2-yl) sulfonylmethyl] -4- (2-methoxyethylamino) -5-pyrimidinecarboxylic acid ethyl ester.
7 g (yield 32%) was obtained.

Melting point: 174 to 176 ° C. IR (nujol method) νmax cm ⁻¹ : 3340 (NH), 1700 (C
= O) Mass m / z: 419 (M ⁺ ) NMR (DMSO-d6) δ: 1.29 (3H, t, J = 7Hz, -OCH ₂ C H ₃ ),
2.70 ~ 3.10 (4H, m, -NHC H ₂ CH _2- ), 3.12 (3H, s, -OCH ₃ ),
4.28 (2H, q, J = 7Hz, -O CH ₂ CH ₃ ), 5.00 (2H, s, -SO ₂ CH _2- ),
7.30 ~ 7.50 (2H, m, benzene-H), 7.50 ~ 7.90 (2H, m, b
enzene-H), 8.17 (1H, bs, NH), 8.65 (1H, s, pyrimidine
. -H), 13.85 (1H, bs, NH) Elemental analysis _{(C 18 H 21 N 5 O} 5 S) theory (%): C, 51.54; H, 5.05; N, 16.70 Found (%): C , 51.44; H, 4.81; N, 16.43

Example 108 2 to 50 ml of methylene chloride
1.7 g of [-((1H-benzimidazol-2-yl) thiomethyl] -4-dimethylamino-5-pyrimidinecarboxylic acid ethyl ester was dissolved, 17 ml of a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was stirred under ice-cooling to give 80%. 4.3 g of% m-chloroperbenzoic acid was added. After stirring at room temperature for 4 hours, 20 ml of a 5% aqueous solution of sodium thiosulfate was added and the mixture was stirred. The organic layer was separated, washed with water and dried, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solution of ethyl acetate and diethyl ether to give 2-[(1H-benzimidazole-
2-yl) sulfonylmethyl] -4-dimethylamino-
0.9 g (yield 49%) of 5-pyrimidinecarboxylic acid ethyl ester was obtained.

Melting point: 176 to 178 ° C. IR (nujol method) ν max cm ⁻¹ : 1720 (C═O) Mass m / z: 389 (M ⁺ ) NMR (DMSO-d6) δ: 1.27 (3H, t, J) = 7Hz, -OCH ₂ C H ₃ ),
2.56 [6H, s, -N (CH ₃ ) ₂ ], 4.25 (2H, q, J ＝ 7Hz, -O CH ₂ C
H ₃ ), 4.98 (2H, s, -SO ₂ CH _2- ), 7.35 ~ 7.50 (2H, m, benze
ne-H), 7.50 ~ 7.90 (2H, m, benzene-H), 8.41 (1H, s, py
rimidine-H), 13.85 (1H, s, NH). Elemental analysis (C ₁₇ H ₁₉ N ₅ O ₄ S) Theoretical value (%): C, 52.43; H, 4.92; N, 17.98 Measured value (%): C, 52.58; H, 4.73; N, 18.19

Next, formulation examples of the compound of the present invention will be described. [Formulation Example 1] The compound of Example 80, lactose, corn starch, microcrystalline cellulose and hydroxypropyl cellulose were mixed with a universal stirrer (Shinagawa Industry Co., Ltd.), and then a wetting liquid (30% ethanol) was added for granulation. .. The granulated product was dried and sieved (20 mesh), then carboxymethyl cellulose calcium, magnesium stearate and talc were added and mixed, and 200 mg of each tablet was obtained with a rotary tablet machine (Kikusui Seisakusho). Composition in 1 tablet (200 mg) Compound of Example 80 50 mg Lactose 60 mg Corn starch 40 mg Microcrystalline cellulose 30 mg Hydroxypropyl cellulose 8 mg Carboxymethyl cellulose calcium 10 mg Magnesium stearate 1 mg Talc 1 mg

[Formulation Example 2] Tablet temperature: 45 ° C., air supply temperature: 5
Under the condition of 5 ° C., the tablets obtained in Formulation Example 1 were coated with an enteric solution having the following composition to prepare 230 mg enteric-coated tablets per tablet. Composition of enteric solution Eudragit L-30D 69.0 mg (solid component 20.7 mg) Polyethylene glycol 6000 6.2 mg Talc 2.1 mg Tween 80 1.0 mg Water 0.28 ml

Formulation Example 3 After thoroughly mixing the following compositions, a wetting liquid (30% ethanol) was added and kneaded, and the mixture was granulated by an extrusion granulator (manufactured by Fuji Paudal, screen diameter 0.9 mm). The granules were granulated and immediately sized with a Marumerizer (manufactured by Fuji Paudal), dried and sieved to produce 12-42 mesh columnar granules. Composition of columnar granules 200 mg Compound of Example 80 50 mg Lactose 50 mg Corn starch 40 mg Microcrystalline cellulose 30 mg Hydroxypropyl cellulose 10 mg Carboxymethyl cellulose calcium 20 mg

[Formulation Example 4] In the same manner as in Formulation Example 2, the columnar granules obtained in Formulation Example 3 were coated with an enteric solution having the following composition to obtain enteric-coated columnar granules. This granule 260
No. 1 gelatin hard capsule was filled with mg. Composition of enteric solution Eudragit L-30D 138.0 mg (solid component 41.4 mg) Polyethylene glycol 6000 12.4 mg Talc 4.1 mg Tween 80 2.1 mg Water 0.28 ml Enteric coated granules 260〓 Composition Example 3 Columnar granules 200 mg Enteric film 60 mg Capsule formulation composition Enteric columnar granules 260 mg No. 1 gelatin hard capsule 76 mg

[Formulation Example 5] The compound of Example 80, lactose and corn starch were mixed to give a spray. Further, the above-mentioned spraying agent and non-pareil were put into a centrifugal fluidized coating granulator (manufactured by Freund Sangyo), and coating was performed while spraying a 4% aqueous solution of hydroxypropyl cellulose to obtain spherical granules. After drying the spherical granules, they are sieved to 12 to 3
A 2 mesh granule was obtained. Composition of spherical granules in 190 mg Compound of Example 80 50 mg Nonpareil 100 mg Lactose 20 mg Corn starch 18 mg Hydroxypropylcellulose 2 mg

Formulation Example 6 In the same manner as in Formulation Example 2, the spherical granules obtained in Formulation Example 5 were coated with an enteric solution having the following composition to obtain enteric coated spherical granules. This granule 240
No. 2 gelatin hard capsules were filled with mg. Composition of enteric solution Eudragit L-30D 104.7 mg (solid component 31.4 mg) Polyethylene glycol 6000 5.4 mg Talc 11.6 mg Tween 80 1.6 mg Water 0.22 ml Composition of enteric coated granules 240 Granules 190 mg Enteric coating 50 mg Capsule formulation composition Enteric coated spherical granules 240 mg No. 2 gelatin hard capsule 65 mg

[Formulation Example 7] 6 g of the compound of Example 80 was dispersed in distilled water for injection to prepare a 1N sodium hydroxide aqueous solution 1
After 6 ml was added and dissolved, distilled water for injection was added so that the total amount became 300 ml, and sterilized and filtered by a conventional method. Each 1 ml of the obtained filtrate was dispensed into a sterilized bottle, freeze-dried, and sealed. As described above, the lyophilized powder in a bottle containing 20 mg of the compound of Example 80 was dissolved in an appropriate amount of physiological saline at the time of administration and used as an injection solution.

Next, the pharmacological test and acute toxicity test of the compound of the present invention will be described. [Test Example 1] Inhibitory effect on acute gastric mucosal damage by ethanol SD male rats (7 weeks old, 1 group 5) fasted for 24 hours
30 mg / kg of the test compound suspended in a 0.5% aqueous solution of sodium carboxymethylcellulose was orally administered to 7 animals). The control group received only a 0.5% aqueous solution of sodium carboxymethyl cellulose. After 30 minutes, 0.5 ml of ethanol per 100 g of body weight was orally administered to cause gastric mucosal damage. After 1 hour, the rat was exsanguinated to death, and the stomach was removed and fixed with 1% formalin. After fixation, an incision was made along the greater curvature, the length of gastric mucosal damage was measured under a stereoscopic microscope, and the total sum per animal was taken as the ulcer index (mm). The inhibition rate (%) was calculated from the ulcer index of the control group and the ulcer index of the test compound group, and the results are shown in Table 14.

[0123]

[Table 14]

[Test Example 2] Gastric acid secretion inhibitory action Male SD rats (7-week-old, 1 group 5 to 5 hours) fasted for 24 hours
100 mg / test compound suspended in 0.5% aqueous solution of sodium carboxymethylcellulose immediately after laparotomy under anesthesia with diethyl ether to ligate the pylorus
kg was administered intraduodenally. The control group was administered only a 0.5% aqueous solution of sodium carboxymethyl cellulose. Then, the abdomen was sutured, left for 4 hours under fasting and dewatering, and then the rat was killed with an excessive amount of diethyl ether,
The gastric juice stored in the stomach was collected. After measuring the gastric juice volume,
The acid concentration was measured by the neutralization titration method, and the gastric acid secretion amount was calculated. Then, the inhibition rate (%) was determined from the gastric acid secretion amount of the control group and the gastric acid secretion amount of the test compound group, and the results are shown in Table 15.

[0125]

[Table 15]

Test Example 3 H ⁺ / K ⁺ -ATPase
Activity Inhibitory Action (1) Preparation of H ⁺ / K ⁺ -ATPase Saccoma (Saccoma) was prepared from fresh dog fundic glands.
ni) et al. [Biochem. and Bioph
ys. Acta, 464 , 313 (1977)]. (2) Measurement of H ⁺ / K ⁺ -ATPase activity Various concentrations of test compound dissolved in dimethyl sulfoxide, H ⁺ / K ⁺ -ATPase, 20 μg protein / m
l, 70 mM Tris.HCl (pH 8.6), 10 mM
KCl and 5 mM MgCl ₂ were incubated for 60 minutes at 37 ° C. Next, the ATPase reaction was started with ATP, and after 20 minutes, the reaction was stopped, and the released phosphoric acid was treated with Fiske and Sbbaro.
w) method [J. Biol. Chem., 66 , 375.
(1925)]. The inhibitory effect was determined as a percentage of the difference between the measured value of the control group containing no test compound and the measured value of the test compound group, relative to the measured value of the control group. From the results, H ⁺ / K ⁺ -ATPa of each test compound
The 50% inhibitory concentration (IC50) for se was determined and is shown in Table 16.

[0127]

[Table 16]

Test Example 4 Acute Toxicity Test Male ddY strain mice weighing 25 to 30 g (5 mice per group) and male SD strain rats weighing 220 to 250 g (5 rats per group)
5% of sodium carboxymethylcellulose
The compounds of Examples 87, 91, 98 and 99 suspended in an aqueous solution, 500 mg / kg each, were intraperitoneally administered, and observed for 7 days. As a result, no deaths were observed in any of the groups.

[Effects of the Invention] According to the above-mentioned test examples, the compound [I] of the present invention and a pharmacologically acceptable salt thereof have an excellent gastric mucosal protective action, gastric acid secretion inhibitory action and H ⁺ / K ⁺ -A.
It was revealed that it has a TPase activity inhibitory action and has low toxicity. Therefore, according to the present invention, it is possible to provide an anti-peptic ulcer agent having both an inhibitory action on an attacking factor and an enhancing action on a protective factor, which is useful for treating or preventing gastric ulcer or duodenal ulcer.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁵ Identification code Office reference number FI technical display location C07D 209: 00 239: 00) (C07D 405/12 239: 00 307: 00) (C07D 409/12 239: 00 333: 00) (72) Inventor Isami Kimura, No. 334, Yamanoyama, Ryuo-cho, Gamo-gun, Shiga Prefecture (72) Akemi Kamiya, Otsunohara, Yasu-cho, Yasu-cho, Shiga Prefecture 1823 No. 1 (72) Inventor Mikiko Kataoka 1060-6-403, Babacho, Kusatsu City, Shiga Prefecture (72) Makoto Sato 166-40 Harimatacho, Moriyama City, Shiga Prefecture

Claims (1)

[Claims] 1. A compound represented by the general formula [I]: [In the formula, R ¹ and R ² are the same or different and each represents a hydrogen atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group or a halogen atom. R ³ is R ⁵
An amino group represented by NR ⁶ (R ⁵ and R ⁶ are the same or different and are a hydrogen atom, a lower alkyl group, a cycloalkyl group,
A lower alkenyl group, a lower alkynyl group, a lower alkoxyalkyl group, a hydroxyalkyl group, a phenyl group, a substituted phenyl group, a benzyl group, or a substituted benzyl group is shown. ) Or a saturated or unsaturated heterocyclic group containing at least one nitrogen atom, which is a substituted or unsubstituted heterocyclic group (where the bonding position to the pyrimidine nucleus is a nitrogen atom in the heterocycle). R ⁴ means a hydrogen atom or a lower alkyl group. X means NR ⁷ (R ⁷ represents a hydrogen atom or a lower alkyl group), an oxygen atom or a sulfur atom.
n means 0, 1 or 2. Provided that R ¹ and R ² are each a hydrogen atom, X is NH and n is 1,
Except when ³ is an N, N-dimethylamino group, N-ethyl-N-methylamino group or morpholino group. ] A 4-amino-5-pyrimidinecarboxylic acid derivative represented by
Or a pharmaceutically acceptable salt thereof.