JPH07101954A - Benzimidazole derivative and use thereof - Google Patents

Abstract

PURPOSE:To provide a new derivative having activity to potentiate the sensitivity of myocardial contraction protein to Ca, thus useful as a therapeutic agent for congestive heart failure. CONSTITUTION:The objective derivative of formula I or II (X is S or methylene; R1 is H or methyl; R2 to R5 are each H, halogen, etc.) or a salt thereof, e.g. 5,6-difluoro-2-(3,6-dihydro-2-oxo-2H-1,3,4-thiadiazine-5-yl)benzimidazole hydrochloride. The compound of the formula I or II can be obtained by reaction of (A) a diamine compound of formula III such as 4,5-difluoro-1,2-phenylenediamine with (B) a carboxylic acid of formula IV such as (3,6-dihydro-2-oxo-2H-1,3,4- thiadiazin-5-yl) carboxylic acid in the presence of a solvent such as THF at -10 to 150 deg.C followed by making a dehydrating agent such as acetic acid act on the resultant reaction mixture.

Description

Detailed Description of the Invention

BACKGROUND OF THE INVENTION

FIELD OF THE INVENTION The present invention relates to a novel benzimidazole compound, more specifically, a compound having an action of increasing the sensitivity of myocardial contractile protein to calcium, and a compound effective for heart diseases such as congestive heart failure and the like. The present invention relates to contained therapeutic agents.

[0002]

2. Description of the Related Art Phosphodiesterase inhibitors, calcium channel activators, agents for increasing the sensitivity of myocardial contractile proteins to calcium, etc. have recently been developed as drugs for enhancing the contractile force of myocardium for the treatment of congestive heart failure. There is. A compound having an action of increasing the sensitivity of myocardial contractile protein to calcium is disclosed in JP-A-55-33479.
JP-A-63-310886, JP-A-2-
142787, Japanese Patent Publication No. 57-48556,
It is disclosed in Japanese Patent Publication No. 1-34969.

[Outline of Invention]

At present, many drugs for enhancing the contractile force of myocardium have been developed, but most of them have an increased heart rate as the contractile force increases. Therefore, it is known that an increase in heart rate may increase myocardial oxygen consumption and may rather accelerate the progression of myocardial damage. So without causing a significant increase in heart rate,
The development of a therapeutic drug that selectively enhances myocardial contractility and is sufficiently effective in terms of improving exercise tolerance or long-term prognosis of patients is desired.

[0004]

DISCLOSURE OF THE INVENTION The inventors of the present invention have conducted extensive studies aiming at solving the above-mentioned problems, and as a result, a specific benzimidazole compound increased the sensitivity of myocardial contractile protein to calcium, The present inventors have found that the myocardial contractility is selectively increased without causing a significant increase in heart rate, and have completed the present invention. That is, the compound according to the present invention has the following formula (1) or (1
The benzimidazole derivative represented by a) or a pharmaceutically acceptable acid addition salt thereof.

[Chemical 2] [In the formula, X is a sulfur atom or a methylene group, R ₁ is a hydrogen atom or a methyl group, R _{2 to} R ₅ are hydrogen atoms, halogen atoms, lower alkyl groups, lower alkoxy groups, di-lower alkylamino groups, hydroxyl groups, tri groups. It shows a fluoromethyl group, a cyano group, a carboxy group, or a carboxy group esterified with a lower alkyl group. The present invention also relates to a therapeutic agent for congestive heart failure using this compound. That is, the therapeutic agent for congestive heart failure according to the present invention contains the above-mentioned benzimidazole derivative or a pharmaceutically acceptable acid addition salt thereof as an active ingredient.

DETAILED DESCRIPTION OF THE INVENTION Benzimidazole Derivatives Benzimidazole derivatives according to the present invention are represented by formula (1) or (1a) (wherein X and R _{1 to} R ₅ are defined as above). As described above, it is a mutant. Here, the halogen atom means fluorine, chlorine,
Means bromine and iodine. The lower alkyl means a linear or branched alkyl having 1 to 4 carbon atoms, specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, ter.
Examples include t-butyl and the like. The lower alkoxy means an alkoxy having 1 to 4 carbon atoms, and specific examples thereof include methoxy, ethoxy, propoxy, butoxy and the like. The di-lower alkylamino group means an amino group substituted with an alkyl group having 1 to 4 carbon atoms, and specific examples thereof include a dimethylamino group, a diethylamino group and a dipropylamino group. The compounds of formulas (1) and (1a) may be in the form of acid addition salts at the basic nitrogen atom position. The compound of the present invention also includes pharmaceutically acceptable acid addition salts. The pharmaceutically acceptable acid addition salts include inorganic acid salts such as salts with hydrochloric acid, sulfuric acid, phosphoric acid, etc., and organic acid salts such as acetic acid, formic acid,
Examples thereof include salts with propionic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, oxalic acid, toluenesulfonic acid, methanesulfonic acid and the like.

It is generally recognized that formula (1) or formula (1a) has a tautomeric structure, and an imidazo compound having a hydrogen atom on one of the imidazo nitrogen atoms (for example, a compound of formula (1)) has the other structure. There are corresponding tautomers (compounds of formula (1a)) having a hydrogen atom on the imidazo nitrogen atom.
These tautomeric forms exist in equilibrium with each other as N-unsubstituted compounds. In the present specification, the two types may be represented by the formulas (1) and (1a) or may be represented without specifying which nitrogen atom of the imidazole group the hydrogen atom is attached to. Formula (1) or (1
The tautomeric mixture of the compounds represented by a) may be able to separate each isomer by a method such as silica gel column, thin layer chromatography, etc., but usually coexist in the final equilibrium state. Like Representative preferred examples of benzimidazole compounds according to the present invention are shown in the examples below (compounds of examples 1-48).

Production of Benzimidazole Compounds The compounds represented by the above formulas (1) and (1a) can be produced by various purposeful methods. For example, a diamine compound represented by the following formula (2) can be prepared by It can be obtained by condensation with the carboxylic acid compound represented by (3) or a reactive derivative thereof (see, for example, Shin Jikken Kagaku Koza, 3rd edition, Vol. 14, pp. 2135 to 2252, Maruzen).

[Chemical 3] [Wherein R _{2 to} R ₅ are esterified with a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a di-lower alkylamino group, a hydroxyl group, a trifluoromethyl group, a cyano group, a carboxy group, or a lower alkyl group. Represents a carboxy group. ]

[Chemical 4] [In the formula, X represents a sulfur atom or a methylene group, and R ₁ represents a hydrogen atom or a methyl group. Examples of reactive derivatives of carboxylic acid compounds include acid halides, active esters, mixed acid anhydrides, acid amides, acid anhydrides, acid azides and nitriles. The condensation reaction between the diamine compound of formula (2) and the carboxylic acid compound of formula (3) or its reactive derivative is carried out in the presence or absence of a solvent in the range of about -20 to about 25.
It is carried out at a temperature of 0 ° C, preferably -10 to 150 ° C. Suitable solvents include, for example, benzene, nitrobenzene, toluene, xylene, dichloromethane, trichloroethylene, chloroform, methanol, acetone, diethylene glycol, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, dioxane and the like. Two or more kinds of these solvents may be appropriately mixed and used as necessary. Further, depending on the kind of the reactive derivative of the carboxylic acid used, for example, an acid halide,
In the case of an acid anhydride or the like, it may be preferable to react in the presence of a base in order to allow the reaction to proceed smoothly.
Examples of such a base include inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate and potassium carbonate, and organic bases such as trimethylamine, triethylamine, dimethylaniline and pyridine. Also,
These organic bases can also be used as a solvent. In some cases, the addition of dehydrating agents such as acetic acid, acetic anhydride, phosphorus oxychloride, polyphosphoric acid or thionyl chloride is recommended. These dehydrating agents can also be used as a solvent. When the carboxylic acid compound represented by the formula (3) is used in a free carboxylic acid state, N, N′-dicyclohexylcarbodiimide,
After condensation with a diamine compound represented by the formula (2) in the presence of a condensing agent such as N, N′-diethylcarbodiimide, N, N′-carbonyldiimidazole, ethyl chlorocarbonate, isobutyl chlorocarbonate, etc. Immediately without isolating the intermediate compound of the desired compound from the reaction mixture, acetic acid, phosphorus oxychloride, polyphosphoric acid, using a dehydrating agent such as thionyl chloride, or after isolating the intermediate compound, acetic acid, Using a dehydrating agent such as phosphorus oxychloride, polyphosphoric acid, and thionyl chloride, the desired formula (1) and formula (1
It is also possible to obtain the compound represented by a).

Further, by reacting the aldehyde compound represented by the following formula (4) with the diamine compound represented by the above formula (2) in the presence of an appropriate oxidizing agent, the compound represented by the formula (1) And a compound represented by the formula (1a) can be obtained.

[Chemical 5] [In the formula, X represents a sulfur atom or a methylene group, and R ₁ represents a hydrogen atom or a methyl group. The oxidizing agent used in the reaction is sulfur (in an organic solvent such as benzene, toluene, xylene), sodium disulfite (in an organic solvent such as dimethylacetamide), nitrobenzene, or the like. Nitrobenzene is used as an oxidizing agent, but it can also be used as a solvent by itself (Synthetic C
ommunications), 20 (7), 95
See pages 5 to 963, 1990). When using these oxidizing agents, the reaction temperature is preferably 80 to 200 ° C.

The diamine compound represented by the formula (2) is a known compound or a compound which can be produced by a known method starting from a commercially available aniline compound (Organic Synthesis Collective). Volume IV (Org. Synth., Col. Vol. IV),
42, 1963, etc.). Among the carboxylic acid compounds represented by the formula (3), compounds in which X is a methylene group and R ₁ is a hydrogen atom are known, and for example, α-ketoglutaric acid and hydrazine are appropriately mixed with acetic acid, water, acetonitrile or the like. It can be obtained by reacting with a simple solvent at a temperature of −10 to 150 ° C. (Journal of Organic Chemistry) (J. Org. Che.
m. ), 26, pp. 1854-6, 1961, etc.). Also, a compound in which X is a methylene group and R ₁ is a methyl group can be prepared by a known method (for example, Experimental Chemistry Lecture, 4th edition, 22.
Vol., Pp. 54-71, Maruzen), and can be similarly obtained from β-methyl-α-ketoglutaric acid.
In the formula (3), a compound in which X is a sulfur atom and R ₁ is a hydrogen atom or a methyl group is, for example, a known hydrazinothiocarboxylic acid ethyl ester (Journal of the Chemical Society Perkin Transactions I (J. Chem. Soc. Perkin Tran
s. I), 2011-5, 1983, etc.) and commercially available bromopyruvic acid or known β-bromo-α-ketobutyric acid (Biochemistry (Biochemistr).
y), Vol. 10, No. 14, 2669-77, 1971, etc.) with an appropriate solvent such as acetonitrile, tetrahydrofuran, dimethylformamide, methanol and the like.
It can be obtained by reacting at a temperature of 10 to 150 ° C. The aldehyde compound represented by the formula (4) can be obtained by a general method for converting a carboxylic acid into an aldehyde. That is, whether a carboxylic acid compound represented by formula (3) or one of its reactive derivatives is directly reduced to an aldehyde compound represented by formula (4) (for example, Experimental Chemistry Lecture, 4th Edition, Volume 21, 72-96 pages,
Maruzen) or a carboxylic acid represented by the formula (3) or one of its reactive derivatives is once reduced to a hydroxymethyl compound represented by the formula (5) and then represented by the formula (4). It can be obtained by re-oxidizing to an aldehyde compound.

[Chemical 6] [In the formula, X represents a sulfur atom or a methylene group, and R ₁ represents a hydrogen atom or a methyl group. ] In the latter method,
For example, an ester, an acid amide, an acid anhydride, an acid halide, an acid azide, which is a carboxylic acid compound represented by the formula (3) or a reactive derivative thereof, can be prepared by using a suitable solvent such as tetrahydrofuran, diethyl ether, dioxane and the like. In some cases, in the presence of aluminum chloride, lithium bromide, trifluoroborane, etc., a suitable reducing agent such as sodium borohydride, lithium borohydride, diborane, etc. is used to react at a temperature of -30 to 100 ° C. After obtaining the hydroxymethyl compound represented by the formula (5), manganese dioxide, chromium oxide (VI) can be obtained by using a suitable solvent such as acetonitrile, acetone, benzene, chloroform, dichloromethane, diethyl ether, dimethylformamide, pyridine. ) Pyridine complex, pyridinium chlorochromate, pyridinium dichromate A compound of formula (4) can be obtained by reacting at a temperature of -30 to 100 ° C with an appropriate oxidizing agent such as um, lead tetraacetate, dimethylsulfoxide in the presence of oxalyl chloride (Laboratory of Experimental Chemistry) , 4th edition, Volume 20, pages 1-30, Maruzen, and 2
Vol. 1, pp. 22-22).

Use of the Compound of the Present Invention The benzimidazole compound of the present invention is useful in that it has an action of increasing the sensitivity of myocardial contractile protein to calcium, as will be shown in the test examples described below, and thereby, it is effective in treating congestive heart failure. It can be used as a therapeutic agent. The compound of the present invention as a therapeutic agent may be administered by any desired route of administration, specifically intraperitoneal administration in the case of animals,
Methods such as subcutaneous administration, intravascular administration to veins or arteries and local administration by injection, and for humans, intravenous administration, intraarterial administration, local administration by injection, abdominal cavity, thoracic administration, oral administration, subcutaneous administration It can be administered by administration, intramuscular administration, sublingual administration, transdermal absorption or rectal administration. When the compound of the present invention is administered as a drug, a suitable dosage form depending on the administration method and the purpose of administration, specifically, injections, suspensions, tablets, granules, powders, capsule ointments,
It can be administered in the form of suppositories and the like. In order to produce these preparations, additives such as usual pharmaceutically acceptable carriers or diluents, specifically solvents (eg distilled water for injection), solubilizers (eg polysorbate, polyoxyethylene hydrogenated castor) Oils), tonicity agents (eg sodium chloride), preservatives (eg benzethonium chloride, pendyl alcohol), antioxidants (eg ascorbic acid), excipients (eg lactose, corn starch), binders (eg HPC ( Hydroxypropyl cellulose), PVP (polyvinylpyrrolidone)), lubricants (eg magnesium stearate, talc), stabilizers (eg propylene glycol) and the like can be added. The dose of the compound of the present invention is determined in consideration of the results of animal experiments and various situations so that the total dose does not exceed a certain amount when administered continuously or intermittently. The specific dose may vary depending on the administration method, the condition of the patient or the animal to be treated, such as age, weight, sex, sensitivity, meal (diet) administration time, drugs used in combination, the patient or the degree of the disease. Needless to say, the appropriate number of doses under certain conditions should be determined by a specialist's titration test based on the above guidelines. Specifically, it is about 10 to 100 mg, preferably about 30 to 60 mg per day for an adult.

[0011]

The following examples serve to explain the present invention in more detail, and the present invention is not limited to these examples. Example 1 5,6-Difluoro-2- (3,6-dihydro-2-oxo-2H-1,3,4-thiadiazin-5-yl) benzimidazole hydrochloride 34.8 g of bromopyruvic acid was added to 200 m of acetonitrile.
25 g of hydrazinothiocarboxylic acid ethyl ester was added dropwise under ice cooling, and the mixture was stirred overnight at room temperature. The precipitated crystals were separated by filtration, (3,6-dihydro-2-oxo-2H
-1,3,4-thiadiazin-5-yl) carboxylic acid 2
3.65 g was obtained. NMR (DMSO-d6): δ (ppm) 4.03 (s, 2H), 11.82
(s, 1H) mass spectrum: m / e 160 (M ⁺ ) 7.87 g of the above carboxylic acid was added to tetrahydrofuran 100
It was dissolved in ml, and 6.4 ml of isobutyl chlorocarbonate and 6.9 ml of triethylamine were added dropwise at -10 ° C. The reaction mixture was heated to 0 ° C. and stirred for 1 hour.
A solution of 7.87 g of difluoro-1,2-phenylenediamine in 100 ml of tetrahydrofuran was added dropwise at -10 ° C. After stirring overnight at room temperature, 300 ml of saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted twice with 500 ml of ethyl acetate. The extract was dried over sodium sulfate, concentrated, and crystallized from chloroform to obtain 8.91 g of the carboxylic acid monoamide. 8.91 g of the above monoamide compound was dissolved in 100 ml of acetic acid,
Refluxed for 4 hours. The mixture was cooled to room temperature, and the precipitated crystals were separated by filtration to give 5,6-difluoro-2- (3,6-dihydro-2.
6.89 g of -oxo-2H-1,3,4-thiadiazin-5-yl) benzimidazole was obtained. This compound (6.0 g) was dissolved in methanol (60 ml), and hydrogen chloride-
A methanol solution (10% (w / w), 10 ml) was added to make the solution acidic. Ether was added and the precipitated crystals were collected by filtration to give the title compound (3.42 g). NMR (DMSO-d6): δ (ppm) 4.42 (s, 2H), 7.64
(t, J = 9.2Hz, 2H), 12.04 (s, 1H) Mass spectrum: m / e 268 (M ⁺ ) Infrared absorption spectrum (KBr tablet method :) 3400,3050,285
0,1650,1610,1465,1440, ^{(free body)} 1410,1360,1
305,1270,1250,1200,1145,850,595,470cm ^-1

Example 2 4,5,6-trifluoro-2- (3,6-dihydro-
2-oxo-2H-1,3,4-thiadiazin-5-yl) benzimidazole hydrochloride Using the method of Example 1, 3,4,5-trifluoro-
1,2-phenylenediamine and 5- (3, 3 of Example 1
The title compound was obtained from 6-dihydro-2-oxo-2H-1,3,4-thiadiazinyl) carboxylic acid in a yield of 9.3%. NMR (DMSO-d6): δ (ppm) 4.43 (s, 2H), 7.35
~ 7.45 (m, 1H), 12.02 (s, 1H) mass spectrum: m / e 286 (M ⁺ ).

Example 3 4,5-Difluoro-2- (3,6-dihydro-2-oxo-2H-1,3,4-thiadiazin-5-yl) benzimidazole hydrochloride The method of Example 1 is used. , 3,4-difluoro-1,2-
The title compound was obtained from phenylenediamine and 5- (3,6-dihydro-2-oxo-2H-1,3,4-thiadiazinyl) carboxylic acid of Example 1 in a yield of 8.9%. NMR (DMSO-d6): δ (ppm) 4.44 (s, 2H), 7.30
~ 7.40 (m, 2H), 12.01 (s, 1H) Mass spectrum: m / e 268 (M ⁺ ).

Example 4 5-Chloro-6-fluoro-2- (3,6-dihydro-
2-oxo-2H-1,3,4-thiadiazin-5-yl) benzimidazole Using the method of Example 1, 4-chloro-5-fluoro-
1,2-phenylenediamine and 5- (3, 3 of Example 1
The title compound was obtained from 6-dihydro-2-oxo-2H-1,3,4-thiadiazinyl) carboxylic acid in a yield of 14%. NMR (DMSO-d6): δ (ppm) 4.41 (s, 2H), 7.40
~ 8.10 (m, 2H), 12.00 (s, 1H), 13.20 (br.s, 1H) Mass spectrum: m / e 284 (M ⁺ )

Example 5 4-Fluoro-2- (3,6-dihydro-2-oxo-
2H-1,3,4-thiadiazin-5-yl) -6-methylbenzimidazole hydrochloride Using the method of Example 1, 3-fluoro-5-methyl-
1,2-phenylenediamine and 5- (3, 3 of Example 1
The title compound was obtained from 6-dihydro-2-oxo-2H-1,3,4-thiadiazinyl) carboxylic acid in a yield of 9.6%. NMR (DMSO-d6): δ (ppm) 2.42 (s, 3H), 4.42
(s, 2H), 6.90 (d, J = 12.2Hz, 1H) 7.14 (s, 1H), 11.96 (s, 1H) Mass spectrum: m / e 264 (M ⁺ )

Example 6 5-Fluoro-2- (3,6-dihydro-2-oxo-
2H-1,3,4-thiadiazin-5-yl) -6-dimethylaminobenzimidazole hydrochloride Using the method of Example 1, 4-fluoro-5-dimethylamino-1,2-phenylenediamine and 5-of 1
(3,6-dihydro-2-oxo-2H-1,3,4-
The title compound was obtained from thiadiadinyl) carboxylic acid in a yield of 3.9%. NMR (DMSO-d6): δ (ppm) 2.98 (s, 6H), 4.41
(s, 2H), 7.40 to 7.70 (m, 2H), 12.01 (s, 1H) Mass spectrum: m / e 293 (M ⁺ )

Example 7 2- (3,6-dihydro-2-oxo-2H-1,3
4-Thiadiazin-5-yl) benzimidazole Hydrochloride Synthesized by the method of Example 1 (3,6-dihydro-2-
Oxo-2H-1,3,4-thiadiazin-5-yl)
1.2 g of carboxylic acid was dissolved in 5 ml of dimethylformamide, 1.2 g of N, N-carbonyldiimidazole was added, and the solution stirred at room temperature for 30 minutes was added to a solution of 1 g of 1,2-phenylenediamine in 20 ml of dimethylformamide, Stir at room temperature for 3 hours. The solvent was distilled off, and the residue was purified by silica gel chromatography eluting with chloroform / methanol (20/1) to obtain 1.2 g of the carboxylic acid monoamide. 1.2 g of the above monoamide compound was dissolved in 20 ml of acetic acid and refluxed for 4 hours. Cool to room temperature,
The precipitated crystals were filtered off, and 2- (3,6-dihydro-2-
Oxo-2H-1,3,4-thiadiazin-5-yl)
0.58 g of benzimidazole was obtained. 0.58 g of the above-mentioned benzimidazole compound was dissolved in 5 ml of methanol, and hydrogen chloride-methanol solution (10% (w / w), 1
ml) was added to make the solution acidic. Ether was added and the precipitated crystals were collected by filtration to give the title compound (0.48 g). NMR (DMSO-d6): δ (ppm) 4.47 (s, 2H), 7.20
~ 7.55 (m, 2H), 7.55 ~ 7.90 (m, 2H) 12.02 (br.s, 1H) Mass spectrum: m / e 232 (M ⁺ )

Example 8 4,6-Difluoro-2- (3,6-dihydro-2-oxo-2H-1,3,4-thiadiazin-5-yl) benzimidazole hydrochloride As in Example 7, 3 , 5-Difluoro-1,2-phenylenediamine was used to give 5- (3,6-dihydro-2-
The title compound was obtained from oxo-2H-1,3,4-thiadiazinyl) carboxylic acid in a yield of 13%. NMR (DMSO-d6): δ (ppm) 4.41 (s, 2H), 6.95
〜7.25 (m, 3H), 11.98 (s, 1H) Mass spectrum: m / e 268 (M ⁺ ).

Example 9 4-Fluoro-2- (3,6-dihydro-2-oxo-
2H-1,3,4-thiadiazin-5-yl) benzimidazole hydrochloride Using 3-fluoro-1,2-phenylenediamine as in Example 7, 5- (3,6-dihydro-2-oxo From -2H-1,3,4-thiadiazinyl) carboxylic acid, the title compound was obtained with a yield of 17%. NMR (DMSO-d6): δ (ppm) 4.46 (s, 2H), 6.90
~ 7.50 (m, 3H), 12.3 (br.s, 1H) Mass spectrum: m / e 250 (M ⁺ )

Example 10 5-Ethoxy-6-fluoro-2- (3,6-dihydro-2-oxo-2H-1,3,4-thiadiazine-5-
Yl) benzimidazole hydrochloride 4-ethoxy-5-fluoro-1,2 as in Example 7.
-With phenylenediamine, 5- (3,6-dihydro-2-oxo-2H-1,3,4-thiadiazinyl)
The title compound was obtained from the carboxylic acid in 18% yield. NMR (DMSO-d6): δ (ppm) 1.37 (t, J = 7.0Hz, 3
H), 4.12 (q, J = 7.0Hz, 2H), 4.39 (s, 2H), 7.22 (d, J = 7.7Hz, 1
H), 7.47 (d, J = 11.3Hz, 1H) 11.6 (s, 1H) Mass spectrum: m / e 294 (M ⁺ )

Example 11 5-Fluoro-2- (3,6-dihydro-2-oxo-
2H-1,3,4-thiadiazin-5-yl) -6-methylbenzimidazole hydrochloride 4-fluoro-5-methyl-1,2-similar to Example 7.
Using phenylenediamine, the title compound was obtained from 5- (3,6-dihydro-2-oxo-2H-1,3,4-thiadiazinyl) carboxylic acid in a yield of 18%. NMR (DMSO-d6): δ (ppm) 2.34 (s, 3H), 4.41
(s, 2H), 7.35 (d, J = 9.8Hz, 1H), 7.48 (d, J = 6.7Hz, 1H), 11.9
8 (s, 1H)

Example 12 5-chloro-2- (3,6-dihydro-2-oxo-2)
H-1,3,4-thiadiazin-5-yl) benzimidazole hydrochloride Using 4-chloro-1,2-phenylenediamine as in Example 7, 5- (3,6-dihydro-2-oxo −
From 2H-1,3,4-thiadiazinyl) carboxylic acid,
The title compound was obtained with a yield of 19%. NMR (DMSO-d6): δ (ppm) 4.43 (s, 2H), 7.30
(dd, J = 1.8Hz, 9.2Hz, 1H), 7.63 d, J = 9.2Hz, 1H), 7.65 (d, J =
1.8Hz, 1H), 12.03 (s, 1H) Mass spectrum: m / e 266 (M ⁺ )

Example 13 5,6-Dichloro-2- (3,6-dihydro-2-oxo-2H-1,3,4-thiadiazin-5-yl) benzimidazole hydrochloride 4 as in Example 7 , 5-Dichloro-1,2-phenylenediamine to give the title compound from 5- (3,6-dihydro-2-oxo-2H-1,3,4-thiadiazinyl) carboxylic acid in 19% yield. Got NMR (DMSO-d6): δ (ppm) 4.41 (s, 2H), 7.88
(s, 2H), 12.03 (s, 1H) Mass spectrum: m / e 300 (M ⁺ )

Example 14 4,6-Dichloro-2- (3,6-dihydro-2-oxo-2H-1,3,4-thiadiazin-5-yl) benzimidazole hydrochloride As in Example 7, 3 , 5-Dichloro-1,2-phenylenediamine was used to give the title in 7.6% yield from 5- (3,6-dihydro-2-oxo-2H-1,3,4-thiadiadinyl) carboxylic acid. Was obtained. NMR (DMSO-d6): δ (ppm) 4.42 (s, 2H), 7.41
(d, J = 2.6Hz, 1H), 7.48 (d, J = 2.6Hz, 1H), 12.03 (s, 1H) Mass spectrum: m / e 300 (M ⁺ )

Example 15 5-Chloro-6-ethoxy-2- (3,6-dihydro-
2-Oxo-2H-1,3,4-thiadiazin-5-yl) benzimidazole hydrochloride 4-chloro-5-ethoxy-1,2-as in Example 7.
The title compound was obtained from 5- (3,6-dihydro-2-oxo-2H-1,3,4-thiadiazinyl) carboxylic acid using phenylenediamine in a yield of 8.7%. NMR (DMSO-d6): δ (ppm) 1.40 (t, J = 7.0Hz, 3
H), 4.14 (q, J = 7.0Hz, 2H), 4.41 (s, 2H), 7.20 (s, 1H), 7.70
(s, 1H), 11.98 (s, 1H) mass spectrum: m / e 310 (M ⁺ )

Example 16 5-Bromo-2- (3,6-dihydro-2-oxo-2)
H-1,3,4-thiadiazin-5-yl) benzimidazole hydrochloride Using 4-bromo-1,2-phenylenediamine as in Example 7, 5- (3,6-dihydro-2-oxo −
From 2H-1,3,4-thiadiazinyl) carboxylic acid,
The title compound was obtained with a yield of 12%. NMR (DMSO-d6): δ (ppm) 4.43 (s, 2H), 7.39 (d
d, J = 1.8Hz, 8.5Hz, 1H), 7.58 (d, J = 8.5Hz, 1H), 7.79 (d, J = 1.
(8Hz, 1H)

Example 17 2- (3,6-dihydro-2-oxo-2H-1,3
4-Thiadiazin-5-yl) -5-propoxybenzimidazole hydrochloride Using 4-propoxy-1,2-phenylenediamine as in Example 7, 5- (3,6-dihydro-2-oxo-2H The title compound was obtained from -1,3,4-thiadiazinyl) carboxylic acid in a yield of 28%. NMR (DMSO-d6): δ (ppm) 0.98 (t, J = 7.3Hz, 3
H), 1.50 ~ 2.00 (m, 2H), 3.80 ~ 4.10 (m, 2H), 4.54 (s, 2H),
7.00 to 7.20 (m, 2H), 7.70 (d, J = 9.7Hz, 1H), 12.30 (s, 1H) Mass spectrum: m / e 290 (M ⁺ )

Example 18 2- (3,6-dihydro-2-oxo-2H-1,3
4-Thiadiazin-5-yl) -5-methylbenzimidazole hydrochloride Using 4-methyl-1,2-phenylenediamine as in Example 7, 5- (3,6-dihydro-2-oxo-
From 2H-1,3,4-thiadiazinyl) carboxylic acid,
The title compound was obtained with a yield of 7.4%. NMR (DMSO-d6): δ (ppm) 2.44 (s, 3H), 4.43
(s, 2H), 7.16 (d, J = 8.5Hz, 1H), 7.42 (s, 1H), 7.54 (d, J = 8.5
Hz, 1H), 12.05 (br.s, 1H)

Example 19 2- (3,6-dihydro-2-oxo-2H-1,3
4-Thiadiazin-5-yl) -5-methoxycarbonylbenzimidazole Using 4-methoxycarbonyl-1,2-phenylenediamine as in Example 7, 5- (3,6-dihydro-
The title compound was obtained from 2-oxo-2H-1,3,4-thiadiazinyl) carboxylic acid in a yield of 37%. NMR (DMSO-d6): δ (ppm) 3.88 (s, 3H), 4.46
(s, 2H), 7.67 (d, J = 8.6Hz, 1H), 7.89 (dd, J = 1.5Hz, 8.6Hz, 1
H), 8.22 (s, 1H), 12.34 (br, 1H) mass spectrum: m / e 290 (M ⁺ )

Example 20 5-Cyano-2- (3,6-dihydro-2-oxo-2
H-1,3,4-thiadiazin-5-yl) benzimidazole hydrochloride Using 4-cyano-1,2-phenylenediamine as in Example 7, 5- (3,6-dihydro-2-oxo −
From 2H-1,3,4-thiadiazinyl) carboxylic acid,
The title compound was obtained with a yield of 29%. NMR (DMSO-d6): δ (ppm) 4.45 (s, 2H), 7.60
~ 7.80 (m, 2H), 8.22 (br.s, 1H), 12.06 (br.s, 1H) Mass spectrum: m / e 257 (M ⁺ )

Example 21 5-Trifluoromethyl-2- (3,6-dihydro-2)
-Oxo-2H-1,3,4-thiadiazin-5-yl) benzimidazole Using 4-trifluoromethyl-1,2-phenylenediamine as in Example 7, 5- (3,6-dihydro-
The title compound was obtained from 2-oxo-2H-1,3,4-thiadiazinyl) carboxylic acid in 34% yield. NMR (DMSO-d6): δ (ppm) 4.46 (s, 2H), 7.40
~ 8.20 (m, 3H), 12.08 (s, 1H), 13.37 (br.s, 1H) Mass spectrum: m / e 300 (M ⁺ ).

Example 22 5-Fluoro-2- (3,6-dihydro-2-oxo-
2H-1,3,4-thiadiazin-5-yl) benzimidazole hydrochloride 5- (3,6-dihydro-2-oxo-2H-1,3
4-thiadiazinyl) carboxylic acid 6.0 g was added to acetone 1
After dissolving in 80 ml, 5.76 ml of triethylamine was added dropwise, and a solution of 3.94 ml of ethyl chlorocarbonate in 8 ml of acetone was added dropwise at -10 ° C. After 15 minutes, a solution of 4.86 g of sodium azide in 12 ml of water was added dropwise, and the mixture was stirred at -10 ° C for 1 hour and 30 minutes. 300 ml of water was added, extracted twice with 400 ml of ethyl acetate, and the organic layer was saturated saline solution 500
It was washed with ml and dried over sodium sulfate. 3.8 g of the residue obtained by concentration was dissolved in 190 ml of tetrahydrofuran, 4 ml of water was added, and sodium borohydride 1.94 was added.
g was added, and the mixture was stirred at room temperature for 1 hour. Evaporate the solvent and purify by silica gel chromatography eluting with chloroform / acetone (2/1) to give 3,6-dihydro-5-.
0.64 g of hydroxymethyl-2-oxo-2H-1,3,4-thiadiazine was obtained. 0.41 g of the above thiadiazine compound is dissolved in 20.5 ml of acetonitrile,
After adding 2.1 g of manganese dioxide and stirring at room temperature for 1 hour,
Further, 2.1 g of manganese dioxide was added. After stirring for 30 minutes,
After filtration through Celite, the filtrate was concentrated to obtain 0.3 g of 5- (3,6-dihydro-2-oxo-2H-1,3,4-thiadiazinyl) carbaldehyde. 0.3 g of the above carbaldehyde compound was dissolved in 20 ml of nitrobenzene, 0.26 g of 4-fluoro-1,2-phenylenediamine was added, and the mixture was stirred at 150 ° C. for 3 hours and 30 minutes. The solvent was distilled off, crystallization with chloroform and filtration were carried out, and 5-fluoro-2-
(3,6-dihydro-2-oxo-2H-1,3,4-
Thiadiazin-5-yl) benzimidazole 0.4
4 g was obtained. 0.44 g of this compound was added to 5 ml of methanol
Dissolved in hydrogen chloride-methanol solution (10% (w /
w), 1 ml) was added to acidify. Ether was added and the precipitated crystals were collected by filtration to give the title compound (0.34 g). NMR (DMSO-d6): δ (ppm) 4.46 (s, 2H), 7.20 (d
t, J = 1.8Hz, 9.2Hz, 1H), 7.42 (dd, J = 1.8Hz, 9.2Hz, 1H), 7.6
8 (dd, J = 4.9Hz, 9.2Hz, 1H), 12.12 (s, 1H) Mass spectrum: m / e 250 (M ⁺ )

Example 23 4,6-dibromo-2- (3,6-dihydro-2-oxo-2H-1,3,4-thiadiazin-5-yl) benzimidazole hydrochloride As in Example 22, 3 , 5-Dibromo-1,2-phenylenediamine was used to give 5- (3,6-dihydro-2-
The title compound was obtained from oxo-2H-1,3,4-thiadiazinyl) carbaldehyde in 75% yield. NMR (DMSO-d6): δ (ppm) 4.43 (s, 2H), 7.62
(d, J = 1.2Hz, 1H), 7.68 (d, J = 1.2Hz, 1H), 12.06 (s, 1H)

Example 24 2- (3,6-dihydro-2-oxo-2H-1,3
4-Thiadiazin-5-yl) -5-methoxybenzimidazole Using 4-methoxy-1,2-phenylenediamine as in Example 22, 5- (3,6-dihydro-2-oxo-2H-1) , 3,4-thiadiazinyl) carbaldehyde to give the title compound in a yield of 73%. NMR (DMSO-d6): δ (ppm) 3.88 (s, 3H), 4.35,
4.36 (each s, 2H), 6.90 ~ 7.75 (m, 3H), 8.80 (s, 1H), 9.72
(br, 1H) Mass spectrum: m / e 262 (M ⁺ )

Example 25 2- (3,6-dihydro-2-oxo-2H-1,3
4-Thiadiazin-5-yl) -5,6-dimethoxybenzimidazole Using 4,5-dimethoxy-1,2-phenylenediamine as in Example 22, 5- (3,6-dihydro-2)
The title compound was obtained from -oxo-2H-1,3,4-thiadiazinyl) carbaldehyde in 36% yield. NMR (CDCl ₃ ): δ (ppm) 3.95 (s, 6H), 4.35 (s, 2
H), 6.94 (s, 1H), 7.25 (s, 1H), 9.15 (s, 1H), 10.01 (br, 1H) Mass spectrum: m / e 292 (M ⁺ )

Example 26 2- (3,6-dihydro-2-oxo-2H-1,3
4-thiadiazin-5-yl) -4,5,6-trimethoxybenzimidazole 3,4,5-trimethoxy-1,2 as in Example 22
-With phenylenediamine, 5- (3,6-dihydro-2-oxo-2H-1,3,4-thiadiazinyl)
The title compound was obtained from carbaldehyde in 60% yield. NMR (CDCl ₃ ): δ (ppm) 3.88,3.91,3.92,3.94,
4.09 (each s, 9H), 4.34,4.37 (each s, 2H), 6.64,7.02 (ea
ch s, 1H), 9.14 (S, 1H), 9.94,10.00 (each s, 1H) mass spectrum: m / e 322 (M ⁺ )

Example 27 5-Ethoxy-2- (3,6-dihydro-2-oxo-
2H-1,3,4-thiadiazin-5-yl) benzimidazole hydrochloride Using 4-ethoxy-1,2-phenylenediamine as in Example 22, 5- (3,6-dihydro-2-oxo -2H-1,3,4-thiadiazinyl) carbaldehyde gave the title compound in 45% yield. NMR (DMSO-d6): δ (ppm) 1.37 (t, J = 6.7Hz, 3
H), 4.09 (q, J = 6.7Hz, 2H), 4.51 (s, 2H), 7.06 (dd, J = 2.5H
z, 9.2Hz, 1H), 7.10 (d, J = 2.5 Hz, 1H), 7.63 (d, J = 9.2Hz, 1
H), 12.24 (s, 1H) mass spectrum: m / e 276 (M ⁺ ).

Example 28 5,6-diethoxy-2- (3,6-dihydro-2-oxo-2H-1,3,4-thiadiazin-5-yl) benzimidazole hydrochloride 4 as in Example 22 , 5-Diethoxy-1,2-phenylenediamine was used to give 5- (3,6-dihydro-2
The title compound was obtained from -oxo-2H-1,3,4-thiadiazinyl) carbaldehyde in 51% yield. NMR (DMSO-d6): δ (ppm) 1.39 (t, J = 6.7Hz, 6
H), 4.10 (q, J = 6.7Hz, 4H), 4.52 (s, 2H), 7.13 (s, 2H), 12.24
(s, 1H) mass spectrum: m / e 320 (M ⁺ )

Example 29 2- (3,6-dihydro-2-oxo-2H-1,3
4-thiadiazin-5-yl) -5-methoxy-6-methylbenzimidazole As in Example 22, 4-methoxy-5-methyl-1,2.
-With phenylenediamine, 5- (3,6-dihydro-2-oxo-2H-1,3,4-thiadiazinyl)
The title compound was obtained from carbaldehyde in 73% yield. NMR (CDCl ₃ ): δ (ppm) 2.32,2.35 (each s, 3
H), 3.89 (s, 3H), 4.34,4.35 (each s, 2H), 6.85,7.19,7.23,
7.52 (each s, 2H), 8.83, 8.85 (each s, 1H), 9.73 (br, 1H) Mass spectrum: m / e 276 (M ⁺ )

Example 30 2- (3,6-dihydro-2-oxo-2H-1,3
4-Thiadiazin-5-yl) -4-hydroxybenzimidazole hydrochloride Using 3-hydroxy-1,2-phenylenediamine as in Example 22, 5- (3,6-dihydro-2-oxo-2H The title compound was obtained from -1,3,4-thiadiazinyl) carbaldehyde in a yield of 9%. NMR (DMSO-d6): δ (ppm) 4.49 (s, 2H), 6.87
(d, J = 7.3Hz, 1H), 7.11 (d, J = 8.5Hz, 1H), 7.27 (dd, J = 7.3HZ,
8.5Hz, 1H), 12.29 (s, 1H) Mass spectrum: m / e 248 (M ⁺ )

Example 31 2- (3,6-dihydro-2-oxo-2H-1,3
4-Thiadiazin-5-yl) -5,6-dimethylbenzimidazole hydrochloride Using 4,5-dimethyl-1,2-phenylenediamine as in Example 22, 5- (3,6-dihydro-2) −
The title compound was obtained from oxo-2H-1,3,4-thiadiazinyl) carbaldehyde in a yield of 12%. NMR (DMSO-d6): δ (ppm) 2.38 (s, 6H), 4.57
(s, 2H), 7.52 (s, 2H), 12.38 (s, 1H) Mass spectrum: m / e 260 (M ⁺ )

Example 32 5,6-difluoro-2- (3,6-dihydro-6-methyl-2-oxo-2H-1,3,4-thiadiazine-
5-yl) benzimidazole hydrochloride [beta] -bromo- [alpha] -ketobutyric acid (27 g) in acetonitrile 20
After dissolving in 0 ml and adding 17.45 g of hydrazinothiocarboxylic acid ethyl ester under ice cooling, the mixture was stirred overnight at room temperature. The solvent was distilled off, and chloroform / methanol (5 /
Purify by silica gel chromatography eluting with 1) to give (3,6-dihydro-6-methyl-2-oxo-2
13.65 g of H-1,3,4-thiadiazin-5-yl) carboxylic acid was obtained. 0.71 g of the above carboxylic acid was dissolved in 3 ml of dimethylformamide, 0.69 g of N, N-carbonyldiimidazole was added, and the solution was stirred at room temperature for 30 minutes to prepare a solution of 4,5-difluoro-1,2-phenylenediamine 1. It was added to a solution of dimethylformamide (100 g) in 07 g and the mixture was stirred at 80 ° C. for 4 hours. Evaporate the solvent,
Purification by silica gel chromatography eluting with chloroform / methanol (100/1) gave 0.27 g of the carboxylic acid monoamide. 0.27 g of the above monoamide compound was dissolved in 10 ml of acetic acid and refluxed for 4 hours. After cooling, the solvent was evaporated and purified by silica gel chromatography eluting with chloroform / methanol (20/1) to give 5,6-difluoro-2- (3,6-dihydro-6-methyl-2-oxo-2H). -1,3,4-thiadiazin-5-yl) benzimidazole 0.21
g was obtained. 0.21 g of this compound was dissolved in 5 ml of methanol, and a hydrogen chloride-methanol solution (10% (w / w
w), 1 ml) was added to acidify. Ether was added and the precipitated crystals were collected by filtration to give the title compound (0.20 g). NMR (DMSO-d6): δ (ppm) 1.54 (d, J = 7.3Hz, 3
H), 4.94 (q, J = 7.3Hz, 1H), 7.64 (t, J = 9.0Hz, 2H) 12.08 (br.
s, 1H) Mass spectrum: m / e 282 (M ⁺ )

Example 33 5-Fluoro-2- (3,6-dihydro-6-methyl-
2-oxo-2H-1,3,4-thiadiazin-5-yl) benzimidazole hydrochloride Using 4-fluoro-1,2-phenylenediamine as in Example 32, 5- (3,6-dihydro) -6-methyl-2-oxo-2H-1,3,4-thiadiazinyl)
The title compound was obtained from the carboxylic acid in a yield of 5%. NMR (DMSO-d6): δ (ppm) 1.55 (d, J = 7.3Hz, 3
H), 4.96 (q, J = 7.3Hz, 1H), 7.00 ~ 7.80 (m, 3H), 12.06 (s, 1
H) Mass spectrum: m / e 264 (M ⁺ )

Example 34 5-Chloro-2- (3,6-dihydro-6-methyl-2)
-Oxo-2H-1,3,4-thiadiazin-5-yl) benzimidazole hydrochloride Using 4-chloro-1,2-phenylenediamine as in Example 32, 5- (3,6-dihydro- The title compound was obtained from 6-methyl-2-oxo-2H-1,3,4-thiadiazinyl) carboxylic acid in a yield of 8%. NMR (DMSO-d6): δ (ppm) 1.53 (d, J = 7.3Hz, 3
H), 4.95 (q, J = 7.3Hz, 1H), 7.29 (dd, J = 2.0Hz, 8.5Hz, 1H), 7.
63 (d, J = 8.5Hz, 1H), 7.65 (d, J = 2.0Hz, 1H), 12.11 (s, 1H) Mass spectrum: m / e 280 (M ⁺ )

Example 35 5-Ethoxy-2- (3,6-dihydro-6-methyl-
2-Oxo-2H-1,3,4-thiadiazin-5-yl) benzimidazole hydrochloride Using 4-ethoxy-1,2-phenylenediamine as in Example 32, 5- (3,6-dihydro) -6-methyl-2-oxo-2H-1,3,4-thiadiazinyl)
The title compound was obtained from the carboxylic acid in 3% yield. NMR (DMSO-d6): δ (ppm) 1.35 (t, J = 6.8Hz, 3
H), 1.56 (d, J = 7.3Hz, 3H), 4.08 (q, J = 6.8Hz, 2H), 5.02 (q, J =
7.3Hz, 1H), 6.90 ~ 7.20 (m, 2H), 7.61 (d, J = 9.2Hz, 1H), 12.3
0 (s, 1H) mass spectrum: m / e 290 (M ⁺ )

Example 36 2- (3,6-dihydro-6-methyl-2-oxo-2
H-1,3,4-thiadiazin-5-yl) -5,6-
Dimethylbenzimidazole Hydrochloride Using 4,5-dimethyl-1,2-phenylenediamine as in Example 32, 5- (3,6-dihydro-6-
The title compound was obtained with a yield of 12% from methyl-2-oxo-2H-1,3,4-thiadiazinyl) carboxylic acid. NMR (DMSO-d6): δ (ppm) 1.59 (d, J = 7.0Hz, 3
H), 2.38 (s, 6H), 5.03 (q, J = 7.0Hz, 1H), 7.50 (s, 2H), 12.32
(s, 1H) mass spectrum: m / e 274 (M ⁺ )

Example 37 5-chloro-2- (4,5-dihydro-3-oxo-2
H-pyridazin-6-yl) benzimidazole hydrochloride 25 g α-ketoglutarate was dissolved in 150 ml acetic acid,
Add 8.7 ml of hydrazine monohydrate dropwise, and add 7 at 90 ° C.
Stir for hours. The mixture was cooled to room temperature, ether was added, and the precipitated crystals were collected by filtration, (4,5-dihydro-3-oxo-2).
19.55 g of H-pyridazin-6-yl) carboxylic acid was obtained. 1.75 g of the above carboxylic acid was dissolved in 5 ml of dimethylformamide, 2.45 g of N, N-carbonyldiimidazole was added, and the solution was stirred at room temperature for 30 minutes.
Chloro-1,2-phenylenediamine (3.5 g) was added to a dimethylformamide (50 ml) solution, and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off, and chloroform / methanol (2
Purification by silica gel chromatography eluting with 0/1) gave 1.2 g of the above carboxylic acid monoamide.
1.0 g of the above monoamide compound was dissolved in 15 ml of acetic acid and refluxed for 30 minutes. After cooling, the solvent was distilled off and purified by silica gel chromatography eluting with chloroform / methanol (20/1) to give 5-chloro-2- (4,4
0.42 g of 5-dihydro-3-oxo-2H-pyridazin-6-yl) benzimidazole was obtained. 0.42 g of this compound is dissolved in 5 ml of methanol, and hydrogen chloride-
Methanol solution (10% (w / w), 1 ml) was added to acidify. Ether was added and the precipitated crystals were collected by filtration to give the title compound (0.37 g). NMR (DMSO-d6): δ (ppm) 2.40 to 2.80 (m, 2)
H), 3.00 ~ 3.40 (m, 2H), 7.20 ~ 7.80 (m, 3H), 9.8 (br.s, 1
H), 11.6 (br.s, 1H) Mass spectrum: m / e 248 (M ⁺ )

Example 38 2- (4,5-Dihydro-3-oxo-2H-pyridazin-6-yl) benzimidazole Using 1,2-phenylenediamine as in Example 37, (4,5- The title compound was obtained from dihydro-3-oxo-2H-pyridazin-6-yl) carboxylic acid in a yield of 23%. NMR (DMSO-d6): δ (ppm) 2.40 to 2.80 (m, 2)
H), 3.00 to 3.40 (m, 2H), 7.40 to 7.65 (m, 2H), 7.65 to 8.00
(m, 2H), 11.8 (br.s, 1H) Mass spectrum: m / e 214 (M ⁺ )

Example 39 2- (4,5-Dihydro-3-oxo-2H-pyridazin-6-yl) -5-methoxybenzimidazole As in Example 37, 4-methoxy-1,2-phenylenediamine was added. Using (4,5-dihydro-3-oxo-
The title compound was obtained from 2H-pyridazin-6-yl) carboxylic acid in a yield of 3.1%. NMR (DMSO-d6): δ (ppm) 2.40 to 2.80 (m, 2)
H), 3.00 ~ 3.40 (m, 2H), 3.70,3.78 (each s, 3H), 6.40 ~ 7.
60 (m, 3H) mass spectrum: m / e 244 (M ⁺ )

Example 40 5-Ethoxy-2- (4,5-dihydro-3-oxo-
2H-pyridazin-6-yl) benzimidazole hydrochloride Using 4-ethoxy-1,2-phenylenediamine as in Example 37, (4,5-dihydro-3-oxo-
2H-pyridazin-6-yl) carboxylic acid yield 1
8% gave the title compound. NMR (DMSO-d6): δ (ppm) 1.38 (t, J = 6.7Hz, 3
H), 2.40 ~ 2.80 (m, 2H), 3.00 ~ 3.30 (m, 2H), 4.10 (q, J = 6.
7Hz, 2H), 7.00 to 7.80 (m, 3H), 11.61 (s, 1H) Mass spectrum: m / e 258 (M ⁺ )

Example 41 2- (4,5-Dihydro-3-oxo-2H-pyridazin-6-yl) -5,6-dimethoxybenzimidazole hydrochloride 4,5-dimethoxy-1 as in Example 37 , 2-phenylenediamine, from (4,5-dihydro-3-oxo-2H-pyridazin-6-yl) carboxylic acid,
The title compound was obtained with a yield of 9%. NMR (DMSO-d6): δ (ppm) 2.40 to 2.80 (m, 2)
H), 3.00 ~ 3.40 (m, 2H), 3.87 (s, 6H) 7.14 (s, 2H), 11.61
(s, 1H) mass spectrum: m / e 274 (M ⁺ )

Example 42 5-Ethoxy-2- (4,5-dihydro-3-oxo-
2H-pyridazin-6-yl) -6-methoxybenzimidazole 4-ethoxy-5-methoxy-1, as in Example 37
Using 2-phenylenediamine, the title compound was obtained from (4,5-dihydro-3-oxo-2H-pyridazin-6-yl) carboxylic acid in 18% yield. NMR (DMSO-d6): δ (ppm) 1.49 (t, J = 7.1Hz, 3
H), 2.50 ~ 2.80 (m, 2H), 3.20 ~ 3.50 (m, 2H), 3.90 (s, 3H),
4.05 (q, J = 7.1Hz, 2H), 6.91 (s, 1H), 7.25 (s, 1H), 9.55 (br.
s, 1H) 10.4 (br.s, 1H) Mass spectrum: m / e 258 (M ⁺ )

Example 43 5,6-difluoro-2- (4,5-dihydro-3-oxo-2H-pyridazin-6-yl) benzimidazole hydrochloride (4,5-dihydro-3-oxo-2H- Pyridazine-
6.0 g of 6-yl) carboxylic acid was dissolved in 50 ml of acetone, and 6.48 ml of triethylamine was added dropwise, and -10
At 4 ℃, 4.4 ml of ethyl chlorocarbonate, 9 ml of acetone
The solution was added dropwise. After 15 minutes 5.50 g of sodium azide
17 ml of water solution was added dropwise, and the mixture was stirred at -10 ° C for 1 hour and 30 minutes. 200 ml of water was added, and 200 ml of ethyl acetate
3 times, the organic layer was washed with 300 ml of saturated saline and dried over sodium sulfate. 5.85 g of the residue obtained by concentration was dissolved in 250 ml of tetrahydrofuran,
5 ml of water was added, 3.30 g of sodium borohydride was added, and the mixture was stirred at room temperature for 1 hour and 30 minutes. Evaporate the solvent and purify by silica gel chromatography eluting with chloroform / methanol (5/1) to give 4,5-dihydro-
1.09 g of 6-hydroxymethyl-3-oxo-2H-pyridazine was obtained. 1.09 g of the above pyridazine compound was dissolved in 55 ml of acetonitrile, and manganese dioxide 5.
After adding 45 g and stirring at room temperature for 1 hour, 5.45 g of manganese dioxide was further added. After stirring for 30 minutes, the mixture was filtered through Celite, and the filtrate was concentrated (4,5-dihydro-3-oxo-2).
H-pyridazin-6-yl) carbaldehyde 0.56 g
Got 0.56 g of the above carbaldehyde compound was dissolved in 45 ml of nitrobenzene, and 4,5-difluoro-1,
0.58 g of 2-phenylenediamine was added and stirred at 150 ° C. for 4 hours. The solvent was distilled off, and the residue was crystallized from chloroform and collected by filtration to obtain 0.35 g of 5,6-difluoro-2- (4,5-dihydro-3-oxo-2H-pyridazin-6-yl) benzimidazole. Obtained. This compound 0.3
5 g was dissolved in 5 ml of methanol, and a hydrogen chloride-methanol solution (10% (w / w), 1 ml) was added to make the solution acidic. Ether was added and the precipitated crystals were collected by filtration to give the title compound (0.28 g). NMR (DMSO-d6): δ (ppm) 2.50 to 2.80 (m, 2)
H), 3.00 ~ 3.40 (m, 2H), 7.67 (t, J = 9.2Hz, 2H), 11.48 (s, 1
H) Mass spectrum: m / e 250 (M ⁺ )

Example 44 5-Fluoro-2- (4,5-dihydro-3-oxo-
2H-pyridazin-6-yl) benzimidazole Using 4-fluoro-1,2-phenylenediamine as in Example 43, (4,5-dihydro-3-oxo-
The title compound was obtained from 2H-pyridazin-6-yl) carbaldehyde in 15% yield. NMR (DMSO-d6): δ (ppm) 2.40 to 2.80 (m, 2H)
3.00-3.40 (m, 2H) 7.10-7.90 (m, 3H) 11.67 (s, 1H) Mass spectrum: m / e 232 (M ⁺ )

Example 45 2- (4,5-Dihydro-3-oxo-2H-pyridazin-6-yl) -4,5,6-trimethoxybenzimidazole hydrochloride 3,4,4 as in Example 43 5-trimethoxy-1,2
-With phenylenediamine (4,5-dihydro-
The title compound was obtained from 3-oxo-2H-pyridazin-6-yl) carbaldehyde in 54% yield. NMR (CDCl ₃ : CD ₃ OD (5: 1)): δ (pp
m) 2.60 ~ 2.90 (m, 2H), 3.20 ~ 3.50 (m, 2H), 3.94 (s, 6H),
3.99 (s, 3H), 7.12 (s, 1H) Mass spectrum: m / e 304 (M ⁺ )

Example 46 2- (4,5-Dihydro-3-oxo-2H-pyridazin-6-yl) -5-methoxy-6-methylbenzimidazole hydrochloride 4-Methoxy-5 as in Example 43 -Methyl-1,2
-With phenylenediamine (4,5-dihydro-
The title compound was obtained from 3-oxo-2H-pyridazin-6-yl) carbaldehyde in 46% yield. NMR (DMSO-d6): δ (ppm) 2.29 (s, 3H), 2.40
~ 2.80 (m, 2H), 3.00 ~ 3.40 (m, 2H) 3.89 (s, 3H), 7.09 (s, 1
H), 7.52 (s, 1H), 11.64 (s, 1H) mass spectrum: m / e 258 (M ⁺ ).

Example 47 2- (4,5-Dihydro-3-oxo-2H-pyridazin-6-yl) -5,6-dimethylbenzimidazole hydrochloride 4,5-Dimethyl-1 as in Example 43 , 2-Phenylenediamine was used to obtain the title compound from (4,5-dihydro-3-oxo-2H-pyridazin-6-yl) carbaldehyde in a yield of 4.7%. NMR (DMSO-d6): δ (ppm) 2.38 (s, 6H), 2.40
~ 2.80 (m, 2H), 3.00 ~ 3.40 (m, 2H) 7.54 (s, 2H), 11.76 (s, 1
H) Mass spectrum: m / e 242 (M ⁺ )

Example 48 5-Chloro-2- (4,5-dihydro-5-methyl-3)
-Oxo-2H-pyridazin-6-yl) benzimidazole hydrochloride 5 g β-methyl-α-ketoglutarate was dissolved in 30 ml acetic acid and 1.7 ml hydrazine monohydrate was added dropwise.
The mixture was stirred at 0 ° C for 7 hours. After cooling to room temperature, the solvent was evaporated and the residue was purified by silica gel chromatography eluting with chloroform / methanol (5/1) to give (4,5-dihydro-5-methyl-3-oxo-2H-pyridazine-
6-yl) carboxylic acid 1.2 g was obtained, 4-chloro-1,
The title compound was obtained in a yield of 13% as in Example 37, using 2-phenylenediamine. NMR (DMSO-d6): δ (ppm) 1.17 (d, J = 7.3Hz, 3
H), 2.20 ~ 3.10 (m, 2H), 3.40 ~ 3.90 (m, 1H), 7.20 ~ 7.80
(m, 3H), 11.53 (s, 1H) Mass spectrum: m / e 262 (M ⁺ )

[Biological Evaluation] The present invention provides a compound having an action of increasing myocardial contractility and useful for treating congestive heart failure. The pharmacological effects of typical compounds of the present invention are shown below. Test Example 1 Langendorff Specimen 2000 units of heparin were intraperitoneally administered to guinea pigs (Hartley system, male 250-350 g), and 20 minutes later, they were lightly anesthetized with ether, the head was beaten, and the heart and surrounding tissues were extracted. The excised tissue was placed in a Krebs-Henseleit solution to separate the heart and surrounding tissue. The aorta of the heart was cannulated and retrogradely perfused with Krebs-Henseleit solution at 37 ° C, 75 cm water column. The Krebs-Henseleit solution was saturated with a mixed gas of 95% oxygen and 5% carbon dioxide. An incision was made under the left atrium and a balloon connected to a transducer was inserted. The transducer was connected to a polygraph and the heart rate and the first derivative of left ventricular pressure were measured. Each test compound was allowed to stabilize the heart for 30 to 40 minutes and then continuously infused from the junction of the cannula. The final concentration of the compound was determined by the following formula. The experimental results are shown in Table 1. Table 1 Compound concentration (M) Left ventricular pressure Heart rate First derivative increase rate Increase rate dp / dt (%) HR (%) Example 1 10 ^-4 93.4 0.1 Example 2 10 ^-5 31.2 6.8 Example 5 10 ^-5 41.2 6.7 Example 6 10 ^-4 64.1 2.2 Example 8 10 ^-4 57.1 17.9 Example 10 10 ^-4 54.6 -5.8 Example Example 22 10 ^-4 63.2 8.0 Example 27 10 ^-4 71.7 6.2 Example 31 10 ^-4 46.6 9.4 Example 32 10 ^-4 57.7 1.7 Example 33 10 ^-4 169.5 5.1 Example 37 10 ^-4 58.9 15.1 Example 38 10 ^-4 27.7 6.8 Example 48 10 ^-4 53.0 3.6 MCI-154 10 ^-4 57.7 -16.9 OPC8212 10 ^-4 20.0 7.2

Test Example 2 Effect of Contractile Protein System on Ca Sensitivity (Tension Measurement in Skinned Fiber Specimen) Guinea pigs (Hartley system, 240 to 400 g) were beaten on their heads, the hearts were excised, and the atrial papillary muscles of the hearts were raked. The contraction tension of the calskined fiber was measured isometrically and recorded. A uniform muscle bundle having a diameter of 200 μm and a length of 1 to 5 mm was cut out under a stereoscopic microscope and treated with a relaxing solution containing 1% Triton X-100 for 30 minutes to destroy the cell membrane in the specimen, and then used in the experiment. The composition of the relaxing fluid is as follows: 1
29 mM potassium methanesulfonate, 5.1 mM magnesium methanesulfonate, 4.2 mM ATP disodium salt, 2 mM EGTA, 20 mM piperazine-N, N ′
-Bis (potassium 2-ethanesulfonate (adjusted to pH 7.0 with potassium hydroxide). The contraction liquid is E of the above relaxation liquid.
A GTA concentration of 10 mM was used. The calcium concentration of this contraction liquid was adjusted to 10 ⁻⁶ M by adding an appropriate amount of calcium methanesulfonate to the contraction liquid. The ionic strength of the contraction fluid was adjusted to 0.2 M by changing the concentration of potassium methanesulfonate.
The skinned fiber specimen in the relaxing solution was transferred to a contracting solution having a Ca ion concentration of 10 ⁻⁶ M. After confirming that the generated tension of the skinned fiber sample was stable, various concentrations of the compound were treated without changing the Ca ion concentration, and the presence or absence of the Ca sensitivity enhancing effect of the compound was examined using the increase in tension as an index. The experimental result is the increase rate (%) after the compound treatment when the generated tension due to the Ca ion concentration of 10 ⁻⁶ M is 100%.
(Table 2). Table 1 (Test Example 1) and Table 2
In Test Example 2 and Table 3 (Test Example 3), MCI-154 (6- [4-
(4'-Pyridylamino) phenyl] -4,5-dihydropyridazi-3 (2H) -one hydrochloride) (Japanese Patent Publication No. 1-3)
4969) and OPC-8212 (3,4).
-Dihydro-6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -2 (1H) -quinolinone)
The experimental results (see Japanese Patent Publication No. 1-43747) are also shown. Table 2 Compound concentration (M) Increasing rate of generated tension (%) Example 1 10 ^-5 23.7 10 ^-4 186.7 Example 22 10 ^-5 41.7 10 ^-4 400.0 MCI-154 10 ^-5 17.3 10 ^-4 17.9 10 ^-3 89.9 OPC-8212 10 ^-4 14.2 10 ^-3 53.4

Test Example 3 Male and female Beagle dogs (8.5 to 11.5 kg) were anesthetized by intravenous administration of pentobarbital (30 mg / kg). Mean blood pressure (MBP) was measured via a pressure transducer from a cannula inserted in the femoral artery. Heart rate (HR) was measured from the blood pressure pulse wave by a heart rate meter. The primary differential value (dp / dt) of the pressure in the left ventricle was measured by inserting a catheter with a pressure sensor from the carotid artery and placing the tip of the pressure sensor in the left ventricle. The compound was administered via a catheter inserted into the femoral vein. The test results are shown in Table 3. Table 3 Compound Dose Mean blood pressure Left ventricular pressure Heart rate mg / kg Increase rate First derivative increase rate Increase rate MBP (%) dp / dt (%) HR (%) Example 1 11 4.3 14.6 -1.5 35 .8 22.4 -0.4 10 12.2 46.3 -4.2 MCI- 0.003 -4.5 11.8 3.9 154 0.01 -8.3 36.7 10.1 0 .03-16.0 38.4 10.3 OPC-1 -6.5 20.4 5.8 8212 3 -11.3 33.3 6.6

Formulation Example 1 5,6-Difluoro-2- (3,6-dihydro-2-oxo-2H-1,3,4-thiadiazin-5-yl) benzimidazole hydrochloride 5 mg Starch 132 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg A tablet of the above composition was produced in one tablet by a conventional method.

Formulation Example 2 5,6-Difluoro-2- (3,6-dihydro-2-oxo-2H-1,3,4-thiadiazin-5-yl) benzimidazole hydrochloride 10 mg Starch 132 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg A tablet of the above composition was produced in one tablet by a conventional method.

[0064]

INDUSTRIAL APPLICABILITY The compound according to the present invention has an action of increasing the sensitivity of myocardial contractile proteins to calcium, and thereby can increase myocardial contractility without causing a marked increase in heart rate. Therefore, according to the present invention, a therapeutic agent effective for diseases such as congestive heart failure is provided.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical display area // (C07D 403/04 235: 00 237: 00) (C07D 417/04 235: 00 285: 00) ) (72) Inventor Muro Oka Hideko, Kirin Brewery Co., Ltd. Pharmaceutical Research Center

Claims (2)

[Claims] 1. A benzimidazole derivative represented by the following formula (1) or (1a) or a pharmaceutically acceptable acid addition salt thereof. [Chemical 1] [In the formula, X is a sulfur atom or a methylene group, R ₁ is a hydrogen atom or a methyl group, R _{2 to} R ₅ are hydrogen atoms, halogen atoms, lower alkyl groups, lower alkoxy groups, di-lower alkylamino groups, hydroxyl groups, tri groups. It represents a carboxy group esterified with a fluoromethyl group, a cyano group, a carboxy group, or a lower alkyl group. ] 2. A therapeutic agent for congestive heart failure, which comprises the benzimidazole derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.