JP3269658B2 - Phenol derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a phenol derivative or a pharmacologically acceptable salt thereof having excellent action as a medicament. More specifically, the present invention relates to a phenol derivative or a pharmacologically acceptable salt thereof effective as an agent for preventing or treating hypertension or / and an agent for preventing or treating heart failure.

[0002]

2. Description of the Related Art Hypertension affects about 20% of all Japanese people, that is, about 20 million or more, and is an important risk factor for various brain diseases and heart diseases. Currently, thiazide antihypertensive diuretics, β
Blockers, Ca antagonists, ACE inhibitors and the like are actually used clinically.

[0003] However, the causes and pathologies of hypertension are extremely diverse, and it is difficult to significantly control all types of hypertension with at least one agent. Furthermore, in terms of safety, for example, β-blockers have cardiac suppression and bronchoconstriction, and diuretics have side effects such as hyperuricemia, abnormal glucose metabolism, abnormal lipid metabolism, and ACE inhibition. The drug has a dry cough as a side effect.

[0004] Under these circumstances, there is still a need for better antihypertensive agents of different types by various mechanisms.

[0005] Thus, the present inventors have intensively studied compounds having a non-peptidic angiotensin II antagonistic effect for many years, and have found that a phenol derivative has an excellent effect as described later.

Compounds having an angiotensin II antagonistic activity are disclosed, for example, in JP-A-3-5480 and JP-A-3-9.
No. 5181, JP-A-3-106879, JP-A-3-2
No. 36377, JP-A-3-188076, JP-A-3-18876
63264, JP-A-3-27362, JP-A-3-1
No. 84976, JP-A-4-9373, EP-A-434037, EP-A-458136 and U.S. Pat. No. 4,880,804. The compounds disclosed therein are biphenyl derivatives. In contrast, the compounds of the present invention are structurally different in that the biphenyl moiety is phenol.

[0007]

The compound of the present invention is a phenol derivative represented by the following general formula (I) and a pharmacologically acceptable salt thereof.

[0008]

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Wherein R ¹ represents an alkyl group, a cycloalkyl group, an alkoxy group, an alkylthio group, a cyanoalkyl group or an alkoxyalkyl group. R ² and R ³ represent the same or different hydrogen atoms, halogen atoms, lower alkyl groups or carboxyl groups which may be protected.
R ⁴ and R ⁵ are the same or different, a hydrogen atom, a halogen atom,
It means a lower alkyl group, a cyano group, a lower alkoxy group or a nitro group.

The group represented by the formula -A ¹ = A ² -A ³ = A ⁴ -is a group represented by the formula -CH = CH-CH = CH-, the formula -N = CH-CH = CH
A group represented by-, a group represented by the formula -CH = N-CH = CH-,
A group of formula -CH = CH-N = CH-, a formula of -CH = CH-CH = N
A group represented by-or a group represented by the formula -CH = N-CH = N-.

However, R ¹ is an alkyl group, and R ² and R ³ are each
R ⁴ and R ⁵ are each a hydrogen atom or a lower alkyl group
A hydrogen atom or a lower alkyl group and having the formula -A ¹ = A ² -A ³ = A ⁴
The group represented by-is represented by the formula -CH = CH-CH = CH-
A group represented by the formula -N = CH-CH = CH- or a formula -CH = CH
Excludes the case where -CH = N-. In the definition of the present invention, a lower alkyl group found in the definition of R ² , R ³ , R ⁴ , R ⁵ is a straight-chain or branched alkyl group having 1 to 6 carbon atoms, for example, a methyl group, ethyl Group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, s
ec-butyl group, tert-butyl group, n-pentyl group (amyl group), isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group,
1,2-dimethylpropyl group, n-hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl Group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group and the like. Among these, preferred groups include a methyl group, an ethyl group, a propyl group, and an isopropyl group, and among them, the most preferred groups include a methyl group and an ethyl group. Particularly, the lower alkyl group in the definitions of R ⁴ and R ⁵ is most preferably a methyl group.

The lower alkoxy group in the definition of R ⁴ and R ⁵ means a lower alkoxy group derived from the above lower alkyl group such as a methoxy group, an ethoxy group and an n-propoxy group. Examples of the group include a methoxy group and an ethoxy group. Furthermore, R ² , R
The halogen atom in the definition of ³ , R ⁴ and R ⁵ means a chlorine atom, a bromine atom, a fluorine atom, an iodine atom and the like.

The alkyl group in the definition of R ¹ is preferably a straight-chain or branched alkyl group having 1 to 10 carbon atoms. In addition to the above-mentioned alkyl group having 1 to 6 carbon atoms, in addition to an n-heptyl group, an n-octyl group, an n-nonyl group, an n-decyl group, a branched alkyl group is also included. Of these, preferred alkyl groups have 1 to 8 carbon atoms.
And a preferable group among them is, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an n-pentyl group and the like. be able to. Also,
The cycloalkyl group for R ¹ is, for example, a group having 3 to 6 carbon atoms.
And the most preferred are a cyclopropyl group and a cyclobutyl group.

In the definition of R ¹ , the alkoxy group means a group derived from a straight-chain or branched alkyl group having 1 to 10 carbon atoms defined as the above-mentioned alkyl group. Methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, n-pentoxy group and the like. In the definition of R ¹ , an alkylthio group refers to a group having 1 to 1 carbon atoms defined for the above alkyl group.
It means a group derived from 10 linear or branched alkyl groups, but preferred examples include a methylthio group,
Examples include an ethylthio group, an n-propylthio group, an isopropylthio group, an n-butylthio group, and an n-pentylthio group.

In the definition of R ¹ , a cyanoalkyl group means a group in which one or two cyano groups are bonded to any carbon atom of the above-defined alkyl group. In the definition of R ^1,
The alkoxyalkyl group means a lower alkoxy group defined above bonded to any carbon atom of the above alkyl group.

The group represented by the formula -A ¹ = A ² -A ³ = A ⁴ -is a group represented by the formula -CH = CH-CH = CH-, and the group represented by the formula -N = CH-CH = CH- A group represented by the formula -CH = N-CH = CH-; a group represented by the formula -CH = CH-N = CH-; a group represented by the formula -CH = CH-CH = N-; It means a group represented by -CH = N-CH = N-. That is, the portion fused to the imidazole ring in the compound of the present invention is specifically described as follows.

[0017]

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The pharmacologically acceptable salt is not particularly limited as long as it is possible in the compound of the present invention. Examples thereof include ammonium salt, sodium salt, potassium salt, hydrochloride, hydrobromide and methane. Sulfonate, sulfate and the like can be mentioned. In addition, depending on the compound, when the compound becomes a hydrate, an optically active substance may further exist. Needless to say, these compounds fall within the scope of the present invention.

Next, a typical method for producing the compound of the present invention will be described. Production Method 1 The compound represented by the general formula (I) can be produced by the following method.

[0020]

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(In the series of equations, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , equation −A ¹ =
The group represented by A ² -A ³ = A ⁴ -has the above-mentioned meaning. X represents a leaving group such as a halogen atom, a methanesulfonyloxy group, and a p-toluenesulfonyloxy group. That is, the compound represented by the general formula (II) and the compound represented by the general formula (III)
This is a method for obtaining the target compound (I) by condensing the compound represented by the general formula (1) in the presence of a base.

Examples of the base used include inorganic bases such as sodium hydride, lithium hydride, sodium hydroxide, potassium hydroxide, potassium carbonate and sodium carbonate, and sodium alcoholate, potassium tert-butoxy, triethylamine, diisopropylethylamine and the like. Organic bases and the like can be mentioned. As the reaction solvent, dimethylformamide, dimethylsulfoxide,
Preferred are N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, dioxane, alcohols such as methanol and ethanol, and acetone.

Production method 2 In the case where R ⁴ and R ⁵ are the same or different halogen atoms or nitro groups in the general formula (I), they can also be produced by the following method.

[0024]

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(In the series of formulas, R ¹ , R ² , R ³ , X, formula −A ¹ = A ² −
A ³ = A ⁴ - group represented by are as defined above. Z represents a hydroxyl-protecting group such as a lower alkyl group, an alkoxyalkyl group, a trimethylsilyl group, and a tetrahydropyran-2-yl group. R ⁶ represents a hydrogen atom or a lower alkyl group. That is, this is a step of condensing the compound represented by the general formula (II) and the compound represented by the general formula (IV) in the same manner as in the production method 1.

[0026]

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(In the series of formulas, R ¹ , R ² , R ³ , formula −A ¹ = A ² −A ³
= A ⁴ - group represented by, Z, R ⁶ are as defined above. That is, a step of deprotecting a hydroxyl group by a usual method. For example, when Z is a lower alkyl group, a compound represented by the general formula (VI) is obtained by a method such as acting boron tribromide in hydrogen bromide-acetic acid or pyridine hydrochloride or a halogen-based solvent. Is the way. When Z is another protecting group, any method can be used as long as the protecting group Z can be eliminated.

[0028]

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(In the series of formulas, R ¹ , R ² , R ³ , formula −A ¹ = A ² −A ³
= A ⁴ - group represented by are as defined above. R ⁴ _a, R ⁵ _a represents a halogen atom or a nitro group. That is, this is a step of obtaining the target compound (VII) by halogenating or nitrating the compound (VI) obtained in the second step by an ordinary method. Examples of the halogenating agent include chlorine, bromine, iodine, iodine monochloride, iodine monobromide and the like. As the nitrating agent, nitric acid and the like can be mentioned. As the reaction solvent, any solvent that does not participate in the reaction can be used, but acetic acid and the like are preferable.

Production Method 3 The compound represented by the general formula (I) can also be produced by the following method.

[0031]

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(In the series of formulas, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and the formula -A ^{1
= A 2 -A 3 = A 4} - group represented by are as defined above. That is, a reaction in which the compound represented by the general formula (II) is added to the compound represented by the general formula (VIII) in the presence of a base to obtain the target compound (I).

Although any base can be used,
Examples include inorganic bases such as sodium hydride, lithium hydride, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium alcoholate,
Preferred are potassium tert-butoxy, triethylamine, diisopropylethylamine and the like. As the reaction solvent, any solvent that does not participate in the reaction can be used. For example, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, 1,3-dimethyl-2-
Preferred are alcohols such as imidazolidinone, dioxane, methanol and ethanol, and acetone.

[0034]

Next, pharmacological experiments will be described in order to explain the effects of the compounds of the present invention in detail. Pharmacological experiment example 1. Experimental method (1) Angiotensin II contracture using rabbit aortic strip
Antagonistic male New Zealand white rabbits weighing 2-3 kg were anesthetized with pentobarbital sodium and the thoracic aorta was removed. Aorta 1.5-2mm wide, 15-20mm long
Helical specimen, and a krebe bicarbonate solution (Krebs Bicarbonate (mM): NaCl 118.4, KCl 4.7, Ca
_{Cl 2 2.0, MgSO 4 · 7H} 2 O 1.2, NaHCO 3 25.0, KH 2 PO 4
1.2, glucose 11.1) was suspended in a 10 ml Magnus bath. Indomethacin 10 ^-5 M was added to exclude the effect of prostaglandin. Keep Krebs solution at 37 ° C, 95
Bubble with% O ₂ -5% CO ₂ . Strips have initial tension of 1g
, And allowed to stand for about 1 hour, and then 50 mM KCl was added to induce contracture. After the contracture was stabilized, washing was performed. This operation was repeated twice, and the second time was set to 100% contracture.

Thereafter, angiotensin II was cumulatively added from 10 ⁻¹⁰ to 3 × 10 ⁻⁶ , and a dose-response curve was obtained. When the antagonism of an angiotensin II antagonist is to be examined, the test compound is added to a concentration of 10 ^-6 to 10 ^-9 M 40 minutes before the addition of 10 ^-10 M of angiotensin, and the dose-
A rightward shift of the response curve was observed. The contraction was drawn on a multi-pen recorder (R-10, Rika Denki) via a carrier amplifier (AP620G or AP621G, Nihon Kohden) using an isometric pressure transducer (TB611T, Nihon Kohden). Potency of angiotensin II antagonist is calculated using Schild's formula,
It was determined and calculated pA ₂ value Negative logarithm rhythm of the concentration of [the dose ratio of the active agent concentration of competing antagonist, such as a 2] (-log).

(2) Angio in anesthetized node-blocked rats (Wistar Kyoto)
Inhibition of Tensin II hypertension Male 9-25 week old Wistar Kyoto rats (Charles River Japan) were treated with sodium pentobarbital 50 mg / kg, i.
Anesthesia was performed by p., and the jugular vein was cannulated. The arterial cannula is connected to a pressure transducer (TP-200T), and a polygraph system (RM-6000, RM-6000, Nihon Kohden). Venous cannula from pentolinium
iv) 10mg / kg iv, blockade of nodes, blood pressure stabilized, angiotensin II 0.003-0.1 or 0.3μg / k
g and iv were cumulatively administered at time intervals (2 to 3 minutes) at which the pressor response at each dose almost recovered, and a dose-response curve was obtained. Then, 0.1-10 mg / kg, iv of the test compound was administered, and 3 minutes later, 0.03-mg of angiotensin II was again administered.
1 μg / kg, iv was administered, the rightward shift of the dose-pressure response curve was determined, and the dose of the antagonist (A, mg / kg, iv)
The dose (C, ΔED ₅₀ , mg / kg, i, v.) That produces a two-fold rightward movement was determined from the following formula and the above-mentioned transfer magnification (B).

[0037]

(Equation 1)

2. Experimental Results Tables 1 and 2 show the results of pharmacological experiments (1) and (2) for the compound of the present invention (test compound). In the table, Me represents a methyl group, n-Pr represents an n-propyl group, and n-Bu represents an n-butyl group.

[0039]

[Table 1]

[0040]

[Table 2]

From the above pharmacological experimental examples, it is clear that the compounds of the present invention have remarkably excellent angiotensin II antagonistic activity. Therefore, the compound of the present invention is effective for the treatment and prevention of hypertension, and is also effective for the treatment and prevention of heart failure based on angiotensin II antagonism, and for the treatment of other diseases in which angiotensin II antagonism is effective.・ It is also effective for prevention. Specifically, it is useful as a therapeutic / prophylactic agent for hypertension such as instinct hypertension, renal hypertension, renal vascular hypertension, and malignant hypertension, and as a therapeutic / prophylactic agent for heart failure. In addition, since the compounds of the present invention have low toxicity and high safety, the value of the present invention is high also in this sense.

When the compounds of the present invention are used as these medicaments, they are administered orally or parenterally. The dosage depends on the severity of the condition; the age, sex, weight,
Sensitivity difference; administration method; timing and interval of administration; nature, preparation, type of pharmaceutical preparation;
There is no particular limitation. In the case of oral administration, it is usually about 1 to 2,000 mg, preferably about 5 to 1,000 mg per day for an adult, which is usually administered in 1 to 3 times a day. In the case of injection, the amount is usually about 1 μg / kg to 10,000 μg / kg, preferably about 3 μg / kg to 3,000 μg / kg.

That is, when an oral solid preparation is prepared, an excipient, a binder, a disintegrant,
After adding lubricants, coloring agents, flavoring agents and the like, tablets, coated tablets, granules, powders, capsules and the like are prepared in a usual manner. As excipients, for example, lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose, silicon dioxide, etc., as binders, for example, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, Hydroxypropylcellulose, hydroxypropylmethylcellulose, calcium citrate, dextrin, pectin, etc., as lubricants, for example, magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oils, etc. Is approved, but as flavoring agents, cocoa powder, peppermint brain, aromatic acid, peppermint oil, dragon brain,
For example, cinnamon powder is used. Of course, these tablets and granules may be sugar-coated, gelatin-coated and optionally coated as needed.

When preparing an injection, a pH adjuster, a buffer, a suspending agent, a solubilizing agent, a stabilizing agent, an isotonic agent, a preservative, etc. are added to the main drug, if necessary, and a conventional method is used. By vein,
Subcutaneous or intramuscular injection. At that time, if necessary, it is necessary to prepare a freeze-dried product by a conventional method.

Examples of suspending agents include, for example, methylcellulose, polysorbate 80, hydroxyethylcellulose, gum arabic, tragacanth powder, sodium carboxymethylcellulose, polyoxyethylene sorbitan monolaurate and the like. Examples of the solubilizer include polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, magrogol, and castor oil fatty acid ethyl ester. As the stabilizer, for example, sodium sulfite,
Examples of the preservative include sodium metasulfite and ether. Examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, sorbic acid, phenol, cresol, and chlorocresol.

[0046]

EXAMPLES Next, examples are given for typical compounds of the present invention, but it goes without saying that the present invention is not limited to these. An example given as a production example separately from the examples is a method for producing a starting material (raw material) used for the final compound of the present invention (the compound of the present invention).
In the chemical structural formulas, Me represents a methyl group, Et represents an ethyl group, n-Pr represents an n-propyl group, and n-Bu represents an n-butyl group.

Production Example 1 2-n-butyl-1- (4-methoxyphenylmethyl)
Benzimidazole

[0048]

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In a nitrogen stream, 1.2 g of sodium hydride (60%, oily) was added to 5.22 of 2-n-butylbenzimidazole.
g was dissolved in 60 ml of dimethylformamide and added dropwise. After stirring at room temperature for 20 minutes, the mixture was ice-cooled, 4.9 g of 4-methoxyphenylmethyl chloride was dissolved in 20 ml of dimethylformamide, and added dropwise. The ice bath was removed, the temperature was returned to room temperature, and an aqueous ammonium chloride solution was added. Add ethyl acetate and water,
The organic layer was separated, washed with water three times, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel chromatography (eluted with 1% ethanol-99% chloroform). Yield 8.7g.

¹ H-NMR (400 MHz, CDCl ₃ , δ value); 7.75 (d, 1H, J = 8 Hz), 7.25 to 7.15 (m, 3H), 6.98 (d, 2H, J = 8H)
z), 6.82 (d, 2H, J = 8Hz), 5.27 (s, 2H), 3.76 (s, 3H), 2.84 (t, 2
H, J = 8 Hz), 1.82 (m, 2H), 1.42 (m, 2H), 0.93 (t, 3H, J = 8 Hz) Production Example 2 2-n-butyl-1- (4-hydroxyphenylmethyl)
Le) Benzimidazole

[0051]

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2-n-butyl-1- obtained in Production Example 1
(4-methoxyphenylmethyl) benzimidazole
42 ml of 25% hydrogen bromide acetic acid was added to 4.7 g, and the mixture was heated under reflux for 5 hours. The mixture was poured into an aqueous sodium hydroxide solution under ice-cooling, acidified with acetic acid, and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate and concentration, the residue was subjected to silica gel chromatography (eluted with 2% ethanol-98% chloroform). Yield 1.5 g. It was recrystallized from a mixed solvent of tetrahydrofuran-isopropyl ether. Yield 1.
28g.

Melting point: 209 to 212 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ , δ value); 9.42 (bs, 1 H), 7.56 (m, 1 H), 7.45 (m, 1 H), 7.17 to 7.12 (m,
2H), 6.94 (d, 2H, J = 8Hz), 6.70 (d, 2H, J = 8Hz), 5.33 (s, 2H), 2.
83 (t, 2H, J = 8Hz), 1.69 (m, 2H), 1.36 (m, 2H), 0.87 (t, 3H, J = 8Hz) ・ Elemental analysis value; As C ₁₈ H ₂₀ N ₂ O Example 1 2-n-butyl-1- (3,5-diiodo-4-hydro
Hydroxyphenyl methyl) Baie lens imidazole

[0054]

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2-n-butyl-1- obtained in Production Example 2
(4-hydroxyphenylmethyl) benzimidazole
715 mg of iodine monochloride was dissolved in 2 ml of acetic acid and added dropwise to a solution of 560 mg of acetic acid in 5 ml of ice under ice cooling. After stirring at room temperature for 1 hour, the mixture was ice-cooled, poured into an aqueous sodium hydroxide solution, acidified with acetic acid, and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate and concentration, the residue was subjected to silica gel chromatography (1% ethanol-99% chloroform). It was recrystallized from a mixed solvent of tetrahydrofuran-isopropyl ether. Yield 700mg.

Melting point: 207 to 209 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ , δ value): 9.60 (bs, 1H), 7.57 (m, 1H), 7.48 (m, 1H), 7.47 ( s, 2H),
7.20 to 7.14 (m, 2H), 5.37 (s, 2H), 2.82 (t, 2H, J = 8 Hz), 1.66 (m, 2H), 1.35 (m, 2
H), 0.87 (t, 3H, J = 8Hz) ・ Elemental analysis value; as C ₁₈ H ₁₈ I ₂ N ₂ O Example 2 2-n-butyl-1- (3,5-dichloro-4-hydro
(Xyphenylmethyl) -4-methylbenzimidazole

[0057]

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In a nitrogen stream, 570 mg of 2-n-butyl-4-methylbenzimidazole was dissolved in 135 mg of sodium hydride (60%, oily) in 10 ml of dimethylformamide and added dropwise. After stirring at room temperature for 10 minutes, the mixture was cooled on ice, 634 mg of 4-chloromethyl-2,6-dichlorophenol was dissolved in 6 ml of dimethylformamide, and the mixture was added dropwise. After stirring for 10 minutes, an aqueous ammonium chloride solution was added. Ethyl acetate and water were added, the organic layer was separated, washed three times with water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel chromatography (1% ethanol-99%
(Eluted with chloroform). Recrystallization from tetrahydrofuran-isopropyl ether gave 600 mg of the title compound.

Decomposition point: 199 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ , δ value); 7.27 (d, 1 H, J = 8 Hz), 7.06 (s, 2 H), 7.05 (dd, 2 H, J = 8Hz, 8H
z), 6.97 (d, 1H, J = 8Hz), 5.37 (s, 2H), 2.83 (t, 2H, J = 8Hz), 2.
51 (s, 2H), 1.65 (m, 2H), 1.36 (m, 2H), 0.87 (t, 3H, J = 8Hz) ・ Elemental analysis value; as C ₁₉ H ₂₀ Cl ₂ N ₂ O Example 3 2-n-butyl-3- (3,5-dichloro-4-hydro
(Xyphenylmethyl) -3H-imidazo [4,5-b]
Pyridine and 2-n-butyl-1- (3,5-dichloro
2-Hydroxyphenylmethyl) -1H-imidazo
[4,5-b] pyridine (1) 2-n-butyl-3- (3,5-dichloro-4-h
(Droxyphenylmethyl) -3H-imidazo [4,5-
b) pyridine

[0060]

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Under a nitrogen stream, 880 mg of 2-n-butylimidazo [4,5-b] pyridine was dissolved in 15 ml of dimethylformamide in 210 mg of sodium hydride (60%, oily) and added dropwise. After stirring at room temperature for 10 minutes, the mixture was cooled on ice, and 1.06 g of 4-chloromethyl-2,6-dichlorophenol was dissolved in 10 ml of dimethylformamide and added dropwise. After stirring for 10 minutes, an aqueous ammonium chloride solution was added. Ethyl acetate and water were added, the organic layer was separated, washed three times with water, dried over anhydrous magnesium sulfate, concentrated, and subjected to silica gel chromatography (eluted with 1% ethanol-99% chloroform). . The fraction eluted first is 2-n-butyl-3- (3,5-dichloro-4-hydroxyphenylmethyl) -3H-imidazo [4,5-b].
Pyridine. It was recrystallized from a mixed solvent of tetrahydrofuran-isopropyl ether. Yield 140mg.

Melting point: 157 to 159 ° C. ¹ H-NMR (400 MHz, CDCl ₃ , δ value): 8.36 (dd, 1 H, J = 1 Hz, 5 Hz), 8.04 (dd, 1 H, J = 1 Hz, 8 Hz) , 7.25
(dd, 1H, J = 5Hz, 8Hz), 7.01 (s, 2H), 5.39 (s, 2H), 2.80 (t, 2H, J = 8Hz), 1.80 (m, 2
H), 1.43 (m, 2H), 0.93 (t, 3H, J = 8Hz) ・ Elemental analysis: C ₁₇ H ₁₇ Cl ₂ N ₃ O (2) 2-n-butyl-1- (3,5-dichloro-4-
(Hydroxyphenylmethyl) -1H-imidazo [4,5
-B] pyridine

[0063]

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The reaction was carried out in the same manner as in (1), and the second fraction eluted by silica gel chromatography was 2-n-butyl-1- (3,5-dichloro-4-hydroxyphenylmethyl) -1H- Imidazo [4,5-
b) pyridine. It was recrystallized from a mixed solvent of tetrahydrofuran-isopropyl ether. Yield 450mg.

Melting point: 169 to 171 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ , δ value): 8.35 (dd, 1 H, J = 1 Hz, 5 Hz), 7.94 (dd, 1 H, J = 1 Hz, 8Hz), 7.20
(dd, 1H, J = 5Hz, 8Hz), 7.12 (s, 2H), 5.44 (s, 2H), 2.89 (t, 2H, J = 8Hz), 1.69 (m, 2
H), 1.37 (m, 2H ), 0.88 (t, 3H, J = 8Hz) · Elemental analysis: as _{C 17 H 17 Cl 2 N 3} O Examples 4 to 16 The following compounds were synthesized according to the methods described in Examples 1 to 3 .

Example 4 2-cyanomethyl-1- (3,5-dichloro-4-hydrid)
Roxyphenylmethyl) benzimidazole

[0067]

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¹ H-NMR (90 MHz, DMSO-d ₆ , δ value): 7.00 to 7.72 (m, 7H), 5.36 (s, 2H), 4.54 (s, 2H) Example 5 2-n-butyl -1- (3,5-dibromo-4-hydro
(Xiphenylmethyl) benzimidazole / hydrobromic acid
salt

[0069]

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¹ H-NMR (90 MHz, DMSO-d ₆ , δ value); 7.95 to 7.68 (m, 2H), 7.67 to 7.40 (m, 2H), 7.55 (s, 2H), 5.
68 (s, 2H), 3.24 (t, 2H, J = 8Hz), 1.93 ~ 1.07 (m, 4H), 0.92 (t, 3H, J = 8H
z) Example 6 (1) 2-n-butyl-1- (3,5-dichloro-4-hi
(Droxyphenylmethyl ) -5-fluorobenzimidida
Zol (2) 2-n-butyl-3- (3,5-dichloro-4-h
Droxyphenylmethyl -)-5-fluorobenziimi
Dazol

[0071]

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¹ H-NMR (90 MHz, DMSO-d ₆ , δ value); 7.20 to 7.68 (m, 2H), 6.80 to 7.20 (m, 3H), 5.36 (s, 2H), 2.
60 to 3.00 (m, 2H), 1.10 to 1.90 (m, 4H), 0.88 (t, 3H, J = 8 Hz) Example 7 2-n-butyl-1- (4-hydroxy-5-methyl-
3-nitrophenylmethyl) benzimidazole

[0073]

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¹ H-NMR (90 MHz, DMSO-d ₆ , δ value); 7.00 to 7.70 (m, 6H), 5.45 (s, 2H), 2.90 (t, 2H, J = 8 Hz), 2.
20 (s, 3H), 1.10 to 1.90 (m, 4H), 0.88 (t, 3H, J = 8 Hz) Example 8 2-n-butyl-1- (4-hydroxy-3-iodo-
5-methylphenylmethyl) benzimidazole

[0075]

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¹ H-NMR (90 MHz, DMSO-d ₆ , δ value); 9.06 (s, 1H), 6.94 to 7.66 (m, 5H), 6.80 (s, 1H), 5.28 (s, 2)
H), 2.82 (t, 2H, J = 8Hz), 2.14 (s, 3H), 1.10 to 1.90 (m, 4H), 0.
98 (t, 3H, J = 8 Hz) Example 9 2-n-butyl-1- (3,5-dichloro-4-hydro
(Xyphenylmethyl) benzimidazole

[0077]

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Decomposition point: 190 ° C. ¹ H-NMR (90 MHz, DMSO-d ₆ , δ value); 7.60 to 7.30 (m, 2H), 7.22 to 6.94 (m, 2H), 7.03 (s, 2H) , Five.
36 (s, 2H), 2.82 (t, 2H, J = 8Hz), 1.85 ~ 1.05 (m, 4H), 0.86 (t, 3H, J = 8H
z) ・ Elemental analysis value; as C ₁₈ H ₁₈ Cl ₂ N ₂ O Example 10 3- (3,5-dichloro-4-hydroxyphenylmethyl)
Ru) -2-n-propyl-3H-imidazo [4,5-
b) pyridine

[0079]

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Decomposition point: 195 ° C. ¹ H-NMR (400 MHz, CDCl ₃ , δ value): 8.36 (dd, 1 H, J = 1 Hz, 5 Hz), 8.04 (dd, 1 H, J = 1 Hz, 8 Hz), 7.20
(dd, 1H, J = 5Hz, 8Hz), 7.01 (s, 2H), 5.39 (s, 2H), 2.78 (t, 2H, J = 8Hz), 1.67 (m, 2
H), 1.02 (t, 3H, J = 8Hz) ・ Elemental analysis value; as C ₁₆ H ₁₅ Cl ₂ N ₃ O Example 11 1- (3,5-dichloro-4-hydroxyphenylmethyl)
Ru) -2-n-propyl-3H-imidazo [4,5-
b) pyridine

[0081]

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Decomposition point: 203 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ , δ value); 8.36 (dd, 1 H, J = 1 Hz, 5 Hz), 7.93 (dd, 1 H, J = 1 Hz, 8 Hz) ), 7.20
(dd, 1H, J = 5Hz, 8Hz), 7.13 (s, 2H), 5.44 (s, 2H), 2.88 (t, 2H, J = 8Hz), 1.76 (m, 2
H), 0.96 (t, 3H, J = 8Hz) ・ Elemental analysis value; as C ₁₆ H ₁₅ Cl ₂ N ₃ O Example 12 2-cyclopropyl-3- (3,5-dichloro-4-h)
(Droxyphenylmethyl) -3H-imidazo [4,5-
b) pyridine

[0083]

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Decomposition point: 208 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ , δ value); 8.28 (dd, 1 H, J = 1 Hz, 5 Hz), 7.91 (dd, 1 H, J = 1 Hz, 8 Hz) ), 7.30
(s, 2H), 7.23 (dd, 1H, J = 5Hz, 8Hz), 5.53 (s, 3H), 2.35 (m, 1H), 1.0
6 (m, 4H) ・ Elemental analysis value; as C ₁₆ H ₁₃ Cl ₂ N ₃ O Example 13 2-cyclopropyl-1- (3,5-dichloro-4-h)
(Droxyphenylmethyl) -3H-imidazo [4,5-
b) pyridine

[0085]

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Decomposition point: 190 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ , δ value); 8.31 (dd, 1 H, J = 1 Hz, 5 Hz), 7.96 (dd, 1 H, J = 1 Hz, 8 Hz) ), 7.24
(s, 2H), 7.17 (dd, 1H, J = 5Hz, 8Hz), 5.55 (s, 3H), 2.38 (m, 1H), 1.1
1 (m, 4H) ・ Elemental analysis value; as C ₁₆ H ₁₃ Cl ₂ N ₃ O ・ H ₂ O Example 14 2-n-butyl-3- (3,5-dichloro-4-hydro
(Xyphenylmethyl) -7-methyl-3H-imidazo
[4,5-b] pyridine

[0087]

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Melting point: 205 to 207 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ , δ value): 8.17 (d, 1 H, J = 5 Hz), 7.28 (s, 2 H), 7.09 (d, 1 H) , J = 5Hz), 5.
40 (s, 2H), 2.84 (t, 2H, J = 8Hz), 2.55 (s, 2H), 1.62 (m, 2H), 1.35 (m, 2
H), 0.86 (t, 3H , J = 8Hz) · Elemental analysis: as _{C 18 H 19 Cl 2 N 3} O Example 15 3- (3,5-dichloro-4-hydroxyphenylmethyl)
) -7-Methyl-2-n-propyl-3H-imidazo
[4,5-b] pyridine

[0089]

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Decomposition point: 210 ° C. (decomposition) ¹ H-NMR (400 MHz, CDCl ₃ , δ value): 8.24 (d, 1H, J = 5 Hz), 7.07 (d, 1H, J = 5 Hz), 6.91 (s, 2H), 5.
38 (s, 2H), 2.77 (t, 2H, J = 8Hz), 2.70 (s, 3H), 1.78 (m, 2H), 0.99 (t, 3
H) ・ Elemental analysis value; as C ₁₇ H ₁₇ Cl ₂ N ₃ O Example 16 2-cyclopropyl-3- (3,5-dichloro-4-h)
(Droxyphenylmethyl) -7-methyl-3H-imida
Zo [4,5-b] pyridine

[0091]

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Decomposition point: 220 ° C. (decomposition) ¹ H-NMR (400 MHz, DMSO-d ₆ , δ value); 8.14 (d, 1 H, J = 5 Hz), 7.28 (s, 2 H), 7.06 (d , 1H, J = 5Hz), 5.
50 (s, 2H), 2.49 (s, 2H), 2.32 (m, 1H), 1.05 (m, 4H) ・ Elemental analysis: C ₁₇ H ₁₅ Cl ₂ N ₃ O

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61P 43/00 A61P 43/00 C07D 235/26 C07D 235/26 235/28 235/28 471/04 471/04 (72) Invention Nobuyuki Mori 410-9 Shimohirooka, Tsukuba City, Ibaraki Prefecture (72) Inventor Hiroki Ishihara 42-10 Midorigaoka, Oji, Tsukuba City, Ibaraki Prefecture (72) Inventor Takashi Musha 3-5-1 Kasuga Tsukuba, Tsukuba City, Ibaraki Prefecture 303 72) Inventor Toshiyuki Matsuoka 4-19-13, Kasuga, Tsukuba-shi, Ibaraki 305 Eisai Shizan Dormitory 305 (72) Inventor, Yuyuki Hamano 3-27-A14-4, Nakadai, Itabashi-ku, Tokyo 702-59 Shimohirooka, Tsukuba-shi, Japan (56) References JP-A-4-186879 (JP, A) International Publication No. 91/11999 (WO, A1) Herdan Jean, Rev. R oum. Chim, 28 (2), 129-37, 1983 (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 235/08 C07D 235/26 C07D 235/28 C07D 471/04 CA (STN) CAOLD ( STN) REGISTRY (STN)

Claims (4)

(57) [Claims] 1. A compound of the general formula (I) [In the formula, R ¹ represents an alkyl group, a cycloalkyl group, an alkoxy group, an alkylthio group, a cyanoalkyl group or an alkoxyalkyl group. R ² and R ³ represent the same or different hydrogen atoms, halogen atoms, lower alkyl groups or carboxyl groups which may be protected. R ⁴ and R ⁵ represent the same or different hydrogen atoms, halogen atoms, lower alkyl groups, cyano groups, lower alkoxy groups or nitro groups. A group represented by the formula -A ¹ = A ² -A ³ = A ⁴ -is represented by the formula -CH = CH
A group represented by the formula -CH = CH-, a group represented by the formula -N = CH-CH = CH-, a group represented by the formula -CH = N-CH = CH-, a formula -CH = C
It means a group represented by HN = CH-, a group represented by the formula -CH = CH-CH = N- or a group represented by the formula -CH = N-CH = N-. However, R ¹ is an alkyl group, and R ² and R ³ are each a hydrogen atom.
R ⁴ and R ⁵ are each a hydrogen atom or a lower alkyl group.
Is a lower alkyl group, and the formula ^{-A 1 = A 2 -A 3 =} A 4 - in shown
Is a group represented by the formula -CH = CH-CH = CH-,
= CH-CH = CH- or a group represented by the formula -CH = CH-CH = N-
Except when it is a group represented by Or a pharmaceutically acceptable salt thereof. 2. An angiotensin II antagonist comprising the phenol derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 3. An agent for treating or preventing hypertension, comprising the phenol derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 4. A therapeutic or prophylactic agent for heart failure comprising the phenol derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.