JPH0848671A - Benzimidazole derivative - Google Patents

Abstract

PURPOSE:To obtain a new derivative having sufficient improving actions on renopathy in spite of no or weak antagonistic actions on angiotensin II receptor type 1 concerned in vasodepressor activities. CONSTITUTION:This derivative (salt) is expressed by formula I [R<1> is H or a 1-6C (halo)alkyl; R<2> is COOH, CON(R<11>) (R<11> is a 1-6C alkyl), etc.; R<3> is H, a 1-6C (halo)alkyl, etc.; R<5> is COOH, NH2, etc.], e.g. 1-{[2-butyl-1-(4- carboxyphenyl)methylbenzimidazol-6-yl]carbonyl}morpholine. The derivative is obtained by hydrolyzing, e.g. a compound of formula II (R<6> is a 1-6C alkyl) with an alkali, providing a compound of formula III, then reacting the resultant compound of formula III with morpholine, etc., in the presence of a condensing agent such as N,N'-dicyclohexylcarbodiimide, converting the COOH group into the group R<2>, subsequently reacting the resultant compound with a compound of formula IV (Y is an iminative group; R<4> is nitro, etc.), affording a compound of formula V and converting the group R<4> in the prepared compound of formula V into the group R<5>.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a benzimidazole derivative or a salt thereof and a pharmaceutical composition containing the benzimidazole derivative or a salt thereof as an active ingredient, particularly an anti-kidney disease agent. The benzimidazole derivative according to the present invention has a sufficient ameliorating effect on renal damage, although the angiotensin II receptor type 1 antagonism associated with the blood pressure lowering effect is not substantially observed or is very weak. .

[0002]

2. Description of the Related Art The number of patients with impaired renal function has been increasing in recent years. This may be because the population is aging, the living environment is changing, and the development of appropriate drugs for renal diseases is delayed. Therefore, there has been a strong demand for the therapeutic drug. That is,
In renal diseases such as nephritis, diabetic nephropathy, and renal failure, symptomatic treatment for treating lesions associated with the diseases is still the main subject.
That is, antihypertensive agents, diuretics, anti-inflammatory agents, diet therapy, exercise therapy, etc. In particular, renal diseases are often accompanied by hypertension, and since hypertension is considered to be one of the factors that exacerbate renal diseases, antihypertensive agents are often used. Among them, many attempts have been made on drugs that suppress the production and action of angiotensin II. That is, it is considered that angiotensin II has a function of increasing blood pressure and is a cause of exacerbating renal disease by promoting proliferation of stromal cells of the kidney, and therefore it is important to eliminate that factor as much as possible in renal disease. This is because it is considered to bring about improvement.

Specifically, a substance that inhibits an enzyme that converts angiotensin I to angiotensin II having a pressor action (that is, angiotensin converting enzyme: ACE), that is, an angiotensin converting enzyme inhibitor (ACE)
It has been reported that the use of an antihypertensive agent (I) such as enalapril and captolyl reduces blood pressure and improves progression of renal damage (J. Clin. Ph.
armacol. , 30: 155-158,199
0). Further, according to the description of US Pat. No. 5,071,867, it was found that administration of a dose higher than the usual amount used for the purpose of reducing blood pressure to rats with renal impairment resulted in improvement of renal impairment. It is said that even in humans (patients), if the dose is carefully and gradually increased, they can withstand high doses, and the benefits of the treatment of renal disorders can be brought about. On the other hand, however, it has been pointed out that careful administration is necessary due to side effects such as dry cough as a characteristic of this type of drug and the risk of causing acute renal failure with blood pressure reduction (Latest Medicine, 48: 1404- 1409, 1993).

Since then, an angiotensin II receptor antagonist (AGIIRA) has been developed as an antihypertensive agent. Currently, two types of receptors, type 1 and type 2, are known as receptors for angiotensin II. Of these, the action involved in type 2 has not been sufficiently clarified, but it is known that type 1 is involved in blood pressure, and therefore a type 1 receptor antagonist has been the goal of the development of antihypertensive agents. A compound which is a hypotensive agent having a strong antagonistic effect on the angiotensin II receptor and whose effect on renal diseases has also been investigated is 2-imidazole which is an imidazole derivative.
-Chloro-5- (hydroxymethyl) -1-[[2'-
(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] imidazole (DuP753 or MK95
4) is known. Administration of this imidazole derivative to renal-injured rats had an effect on proteinuria and glomerulosclerosis, but was accompanied by a clear blood pressure decrease (J. Clinical Invest., 90:76).
6-771, 1992). In addition, when this imidazole derivative was administered to hyperlipidemic rats, there was little effect on blood pressure at low doses, and renal lesions were improved, but a more effective high dose at renal lesions had a clear hypotensive effect. (Nephron, 65: 426-432, 1
993).

Further, a compound having a structure similar to that of the above-mentioned imidazole derivative is disclosed in, for example, JP-A-63-2386.
No. 8 and US Pat. Nos. 5,153,197 and 5,128.
No. 355 and No. 5155118. That is, those compounds are disclosed in JP-A-63-2386.
No. 8 is effective against hypertension and congestive heart failure, US Pat. No. 5,153,197 is effective against hypertension, and US Pat. No. 5,128,355 is effective against heart failure. And US Pat. No. 5,155,118 describes being effective against renal failure due to non-steroidal anti-inflammatory drugs. However, all of these imidazole derivatives are characterized by strong angiotensin II receptor antagonism and have a hypotensive action.

On the other hand, as a compound having a benzimidazole skeleton, for example, JP-A-4-364171 discloses a compound which is useful for hypertension, heart disease, stroke and nephritis. In addition, JP-A-4-3469
No. 78 and US Pat. No. 4,880,804 also disclose angiotensin II receptor antagonists having a benzimidazole skeleton. However, all of these compounds also show a strong angiotensin II receptor antagonistic action and are characterized by a hypotensive action. That is, since the above-mentioned benzimidazole compound has a hypotensive action based on a strong type 1 receptor antagonistic action, when applied to renal diseases, there is a risk of causing acute renal failure.

[0007]

As described above, in the conventional treatment of renal diseases with antihypertensive agents, a drug having a strong antihypertensive action is basically desired. However, in renal diseases, hypertension is an important pathological condition to be corrected, but it is important not to simply reduce it but to maintain proper blood pressure. For that purpose, it is necessary to control the blood pressure by combining the type and dose of antihypertensive agent depending on the condition. On the other hand, since renal disease itself is desired to be continuously treated with a sufficient dose, as long as a conventional drug is used, it is basically necessary to combine both blood pressure control and effective renal disease treatment with one drug. It was impossible. The problem of acute renal failure when using the above-mentioned antihypertensive agent is one example. The present inventor has conducted extensive studies to find a compound having a previously unknown property of having no effect on blood pressure and showing a sufficient improving effect on renal damage, Although the angiotensin II antagonistic activity against the type 1 receptor is 1/100 to 1/1000 or less than that of an antagonist having a standard effect as an antihypertensive agent, there is no substantial antagonistic effect, and On the other hand, a new benzimidazole derivative having a sufficient improvement effect was found. The present invention is based on these findings.

[0008]

Accordingly, the present invention is directed to the general formula (I)

Embedded image Wherein, R ¹ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or a haloalkyl group having 1 to 6 carbon atoms; R ² is ^{-COOH, -COOR 11, -COR 12,} -CON (R
¹³ ) ₂ , -CONHR ¹⁴ , -CONH ₂ , -SO ₂ NH
^{_{2, -SO 2 N (R 15}} ) 2, -SO 2 NHR 16, or -
SO ₂ R ¹⁷ ; R ³ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, —OR ¹⁸ , —O (CH ₂ ) _m C ₆ H ₅ , —
_{(CH 2) n C 6 H} 5, -NH 2, -NHR 19, -NH
^{C (= O) R 20,} -N (R 21) 2, -NHC (= O)
_{(CH 2) p C 6 H} 5, -NHC (= O) CH (C 6 H
₅ ) ₂ or a haloalkyl group having 1 to 6 carbon atoms; R
^{5 _{-COOH, -COOR 22, -NH 2,}} -N
_{^{(R 23) 2, -NHR 24}} , -OH, azole group, -SO
₃ H, or —OR ²⁵ ; R ¹¹ , R ¹³ , R ¹⁴ , R ¹⁵ ,
R ¹⁶ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ and R ²⁵ are each independently an alkyl group having 1 to 6 carbon atoms; R ¹² and R ¹⁷ are each independently And a nitrogen atom, an oxygen atom or a sulfur atom may intervene, and is a 3 to 7 membered saturated aliphatic cyclic amino group; m is 0 or an integer of 1 to 6; n is 0 or 1 to 4; It is an integer; p is 0 or an integer of 1 to 4] and a benzimidazole derivative (hereinafter sometimes referred to as the present substance) or a salt thereof.

In the present specification, the alkyl group includes a linear or branched alkyl group, and examples of the alkyl group having 1 to 4 carbon atoms include, for example, methyl group, ethyl group, n-propyl group and i- Propyl group, n-butyl group, i-butyl group,
The s-butyl group or t-butyl group is an alkyl group having 1 to 5 carbon atoms, in addition to the above groups, for example, n-
Pentyl group, i-pentyl group, neopentyl group, t-pentyl group, 1-methylbutyl group, 2-methylbutyl group,
A 1,2-dimethylpropyl group or a 1-ethylpropyl group can be mentioned, and examples of the alkyl group having 1 to 6 carbon atoms include, in addition to the groups described above, for example, an n-hexyl group and an i-hexyl group. Alternatively, a 2-ethylbutyl group can be mentioned.

The haloalkyl group having 1 to 6 carbon atoms is
A halogen atom of 1 to 1 is added to the alkyl group having 1 to 6 carbon atoms.
A group in which three are substituted, and the halogen atom is, for example, a chlorine atom, a bromine atom, a fluorine atom or an iodine atom.
Examples of preferable haloalkyl groups include a trifluoromethyl group, a pentafluoroethyl group, and a 4,4,4-trifluorobutyl group. The azole group is a 5-membered ring containing 2 to 4 hetero atoms (for example, nitrogen atom, oxygen atom or sulfur atom), and examples thereof include imidazole group, oxazole group, thiazole group, pyrazole group, isoxazole group and isothiazole. Group, triazole group, oxadiazole group, thiadiazole group, tetrazole group, oxatriazole group or thiatriazole group. Examples of preferable azole groups include a tetrazole group. Three
~ 7-membered saturated aliphatic cyclic amino group is optionally a heteroatom (eg, nitrogen atom, oxygen atom or sulfur atom) 1
An alkyleneamino group which may be intercalated with one another, and examples thereof include a 1-azetidinyl group, a 1-pyrrolidinyl group, a piperidino group, a morpholino group, a thiomorpholino group and a 1-piperazinyl group.

In the above general formula (I), R ¹ is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, or a haloalkyl group having 1 to 5 carbon atoms; R ² is -COOH or -COO.
^{R 11, -COR 12, -CON (} R 13) 2, -CONHR
_{^{14, -CONH 2, -SO 2 NH}} 2, -SO 2 N
_{^{(R 15) 2, -SO 2}} NHR 16, or be a -SO ₂ R ^17; R ³ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, -O
_{^{R 18, -O (CH 2)}} m C 6 H 5, - (CH 2) n C 6
^{_{H 5, -NH 2, -NHR 19}} , -NHC (= O) R 20,
_{^{-N (R 21) 2, -NHC}} (= O) (CH 2) p C 6 H
_{5, -NHC (= O) CH} (C 6 H 5) 2, or a haloalkyl group having 1 to 4 carbon atoms; R ⁵ is -COOH, -
_{^{COOR 22, -NH 2, -N (}} R 23) 2, -NHR 24,
-OH, azole group, a -SO ₃ H, or ^{-OR 25; R 11, R 13} , R 14, R 15, R 16, R 18, R 19,
R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ and R ²⁵ are each independently an alkyl group having 1 to 4 carbon atoms; R ¹² and R ¹⁷ are each independently, optionally a nitrogen atom, oxygen An atom or a sulfur atom, which may intervene, is a 3- to 6-membered saturated aliphatic cyclic amino group; m is 0 or an integer of 1 to 4; n is an integer of 0 or 1 to 4; 0 or 1-4
The compound represented by the general formula (I) or a salt thereof, which is an integer of, is preferable.

In the above general formula (I), a compound or a salt thereof in which R ² is at the 5-position or 6-position of the benzimidazole ring and R ⁵ is at the 4-position of the phenyl ring is more preferred, and R ^{2 is}
Is more preferably at the 6-position of the benzimidazole ring and R ⁵ is at the 4-position of the phenyl ring.

The salt of this substance includes a salt with an inorganic acid or an organic acid and a salt with an inorganic base or an organic base, and a pharmaceutically acceptable salt is preferable. Examples of the acid addition salt include a hydrochloride, a sulfate, a methanesulfonate or a p-toluenesulfonate, and a salt with a dicarboxylic acid such as oxalic acid, malonic acid, succinic acid, maleic acid or fumaric acid. Further, a salt with a monocarboxylic acid such as acetic acid, propionic acid or butyric acid can be exemplified. Inorganic bases suitable for forming the salt of this substance are, for example, hydroxides, carbonates and bicarbonates of ammonia, sodium, lithium, calcium, magnesium, aluminum and the like.
Examples of the salt with an organic base include mono-, di-, such as methylamine, dimethylamine and triethylamine,
And tri-alkylamine salts, mono-, di-, and tri-hydroxyalkylamine salts, guanidine salts, N-methylglucosamine salts, amino acid salts and the like.

As a typical example of this substance, Compound No. 1 to
No. The structure of 71 is shown in Tables 1 to 3 below, and the results of elemental analysis and mass spectrometry of the respective compounds are shown in Tables 4 to 6. In addition, each compound shown in Tables 1 to 3 below is referred to as a compound No. in the following description of the present specification. May be indicated by. In each table below, Me is a methyl group, Et is an ethyl group, Pr is a propyl group, Bu is a butyl group, and cyc.
NC ₄ H ₈ O is a morpholino group, cycNC ₄ H ₈ S is a thiomorpholino group, cycNC ₅ H ₁₀ is a piperidino group, and c
ycNC ₄ H ₈ is a 1-pyrrolidinyl group, cycNC ₃ H
₆ represents a 1-azetidinyl group, cycN ₂ C ₄ H ₉ represents a 1-piperazinyl group, and CN ₄ H represents a 1H-tetrazol-5-yl group.

[0015]

[Table 1] No. R ¹ R ² R ³ R ⁵ Chemical formula ─────────────────────────────── 1 nBu 6- COcycNC ₄ H ₈ OH 4-COOH C ₂₄ H ₂₇ N ₃ O ₄ 2 nBu 6-COcycNC ₅ H ₁₀ H 4-COOH C ₂₅ H ₂₉ N ₃ O ₃ 3 nBu 6-COcycNC ₃ H ₆ H 4-COOH C _{23 H 25 N 3 O 3 4 nBu} 6-COcycNC 4 H 8 O Me 4-COOH C 25 H 29 N 3 O 4 5 nBu 6-COcycNC 4 H 8 H 4-COOH C 24 H 27 N 3 O 3 6 nBu 6 _{-CON (Et) 2 Me 4-} COOH C 25 H 31 N 3 O 3 7 nBu 6-CON (Et) 2 H 4-COOH C 24 H 29 N 3 O 3 8 nBu 5-COOMe H 4-COOMe C 22 H ₂₄ N ₂ O ₄ 9 nBu 6-COOMe H 4-COOMe C ₂₂ H ₂₄ N ₂ O ₄ 10 nBu 5-COOH H 4-COOH C ₂₀ H ₂₀ N ₂ O ₄ 11 nBu 6-COOH H 4-COOH C ₂₀ H ₂₀ N ₂ O ₄ 12 nBu 6-COOMe H 4-NH ₂ C ₂₀ H ₂₃ N ₃ O ₂ 13 nBu 6-COcycNC ₄ H ₈ SH 4-NH ₂ C ₂₃ H ₂₈ N ₄ OS 14 nBu 6-COcycN ₂ C ₄ H ₉ H 4-COOH C ₂₄ H ₂₈ N ₄ O ₃ 15 nBu 6-SO ₂ cycNC ₄ H ₈ OH 4-COOH C ₂₃ H ₂₇ N ₃ O ₅ S 16 nBu 6-SO ₂ cycNC ₄ H ₈ O Me 4-COOH C ₂₄ H ₂₉ N ₃ O ₅ S 17 nBu 6-SO ₂ cycNC ₄ H ₈ OH 4-NH ₂ C ₂₂ H ₂₈ N ₄ O ₃ S 18 nBu 6-SO ₂ cycNC ₄ H ₈ OH 4-OH C ₂₂ H ₂₇ N ₃ O ₄ S 19 nBu 6-SO ₂ cycNC ₄ H ₈ OH 4-OMe C ₂₃ H ₂₉ N ₃ O ₄ S 20 nBu 6-SO ₂ cycNC ₄ H ₈ OH 4-NHMe C ₂₃ H ₃₀ N ₄ O ₃ S 21 nBu 6-SO ₂ cycNC ₄ H ₈ OH 4-N (Me) ₂ C ₂₄ H ₃₂ N ₄ O ₃ S 22 nBu 6-SO ₂ cycNC ₄ H ₈ O Me 4-COOMe C ₂₅ H ₃₁ N ₃ O ₅ S 23 nBu 6-SO ₂ cycNC ₄ H ₈ SH 4-COOH C ₂₃ H ₂₇ N ₃ O ₄ S ₂ 24 nBu 6-SO ₂ cycN ₂ C ₄ H ₉ H 4-COOMe C ₂₄ H ₃₀ N _{40 4} S 25 nBu 6-SO ₂ cycN ₃ H ₆ H 4-COOH C ₂₂ H ₂₅ N ₃ O ₄ S

[0016]

[Table 2] No. R ¹ R ² R ³ R ⁵ Chemical formula ─────────────────────────────── 26 nBu 6- SO ₂ N (Et) ₂ H 4-COOH C ₂₃ H ₂₉ N ₃ O ₄ S 27 nBu 6-SO ₂ N (nPr) ₂ H 4-COOMe C ₂₆ H ₃₅ N ₃ O ₄ S 28 nPr 6-SO ₂ cycNC ₄ H ₈ OH 4-COOH C ₂₂ H ₂₅ N ₃ O ₅ S 29 Et 6-SO ₂ cycNC ₄ H ₈ OH 4-COOH C ₂₁ H ₂₃ N ₃ O ₅ S 30 nBu 6-CON (nPr) ₂ H 4-COOH C ₂₆ H ₃₃ N ₃ O ₃ 31 nPr 6-COcycNC ₄ H ₈ OH 4-COOH C ₂₃ H ₂₅ N ₃ O ₄ 32 Et 6-COcycNC ₄ H ₈ OH 4-COOH C ₂₂ H ₂₃ N ₃ O ₄ 33 nBu 6-COcycNC ₄ H ₈ O CF ₃ 4-COOH C ₂₅ H ₂₆ N ₃ O ₄ F ₃ 34 nBu 6-COcycNC ₄ H ₈ O CF ₃ 4-COOMe C ₂₆ H ₂₈ N ₃ O ₄ F ₃ 35 nBu 6-COcycNC ₄ H ₈ O CH ₂ Ph 4-COOH C ₃₁ H ₃₃ N ₃ O ₄ 36 nBu 6-COcycNC ₄ H ₈ O NH ₂ 4-COOH C ₂₄ H ₂₈ N ₄ O ₄ 37 nBu 6-COcycNC ₄ H ₈ O NHMe 4-COOH C ₂₅ H ₃₀ N ₄ O ₄ 38 nBu 6-COcycNC ₄ H ₈ O NHEt 4-COOH C ₂₆ H ₃₂ N ₄ O ₄ 39 nBu 6-COcycNC ₄ H ₈ O NHCOMe 4-COOH C ₂₆ H ₃₀ N ₄ O ₅ 40 nBu 6-COcycNC ₄ H ₈ O NHCOCH ₂ Ph 4-COOH C ₃₂ H ₃₄ N ₄ O ₅ 41 nBu 6-COcycNC ₄ H ₈ O NHCOCH (Ph) ₂ 4- COOH C ₃₈ H ₃₈ N ₄ O ₅ 42 nBu 6-COcycNC ₄ H ₈ O NHMe 4-COOMe C ₂₆ H ₃₂ N ₄ O ₄ 43 nBu 6-COcycNC ₄ H ₈ O NHEt 4-COOMe C ₂₇ H ₃₄ N ₄ O ₄ 44 nBu 6-COcycNC ₄ H ₈ O NHCOMe 4-COOEt C ₂₈ H ₃₄ N ₄ O ₅ 45 nBu 6-COcycNC ₄ H ₈ O NHCOCH ₂ Ph 4-COOMe C ₃₃ H ₃₆ N ₄ O ₅ 46 nBu 6-COcycNC ₄ H ₈ O NHCOCH (Ph) ₂ 4-COOMe C ₃₉ H ₄₀ N ₄ O ₅ 47 nBu 6-COcycNC ₄ H ₈ O CF ₂ CF ₃ 4-COOH C ₂₆ H ₂₆ N ₃ O ₄ F ₅ 48 nBu 6- COcycNC ₄ H ₈ SH 4-COOH C ₂₄ H ₂₇ N ₃ O ₃ S 49 nBu 5-COcycN ₂ C ₄ H ₉ H 4-COOH C ₂₄ H ₂₈ N ₄ O ₃ 50 nBu 5-COcycNC ₃ H ₆ H 4- COOH C ₂₃ H ₂₅ N ₃ O ₃

[0017]

[Table 3] No. R ¹ R ² R ³ R ⁵ Chemical formula ─────────────────────────────── 51 nBu 6- COcycNC ₄ H ₈ OH 4-NH ₂ C ₂₃ H ₂₈ N ₄ O ₂ 52 nBu 6-COcycNC ₄ H ₈ OH 4-OH C ₂₃ H ₂₇ N ₃ O ₃ 53 nBu 6-COcycNC ₄ H ₈ OH 4-OMe C ₂₄ H ₂₉ N ₃ O ₃ 54 nBu 6-COcycNC ₄ H ₈ OH 4-OEt C ₂₅ H ₃₁ N ₃ O ₃ 55 nBu 6-COcycNC ₄ H ₈ OH 4-NHMe C ₂₄ H ₃₀ N ₄ O ₂ 56 nBu 6 -COcycNC ₄ H ₈ OH 4-N (Me) ₂ C ₂₅ H ₃₂ N ₄ O ₂ 57 nBu 6-COcycNC ₄ H ₈ SH 4-NH ₂ C ₂₃ H ₂₈ N ₄ OS 58 nBu 6-COcycN ₂ C ₄ H ₉ H 4-NHMe C ₂₄ H ₃₁ N ₅ O 59 nBu 5-COcycNC ₃ H ₆ H 4-N (Me) ₂ C ₂₄ H ₃₀ N ₄ O 60 nBu 6-COcycNC ₄ H ₈ H 4-NH ₂ C ₂₃ H ₂₈ N ₄ O 61 nBu 6-COcycNC ₃ H ₆ H 4-NH ₂ C ₂₂ H ₂₆ N ₄ O 62 nBu 6-COcycN ₂ C ₄ H ₉ H 4-NH ₂ C ₂₃ H ₂₉ N ₅ O 63 nBu 6 -COcycNC ₅ H ₁₀ H 4-NH ₂ C ₂₄ H ₃₀ N ₄ O 64 nBu 6-SO ₂ cycNC ₃ H ₆ H 4-NH ₂ C ₂₁ H ₂₆ N ₄ O ₂ S 65 nBu 6-SO ₂ cycN ₂ C ₄ H ₉ H 4-NH ₂ C ₂₂ H ₂₉ N ₅ O ₂ S 66 nBu 6-SO ₂ cycNC ₅ H ₁₀ H 4-NH ₂ C ₂₃ H ₃₀ N ₄ O ₂ S 67 nBu 6-COOH H 4-NH ₂ C ₁₉ H ₂₁ N ₃ O ₂ 6 8 nBu 6-COcycNC ₄ H ₈ O Ph 4-COOH C ₃₀ H ₃₁ N ₃ O ₄ 69 nBu 6-COcycNC ₄ H ₈ O OMe 4-COOH C ₂₅ H ₂₉ N ₃ O ₅ 70 nBu 6-COcycNC ₄ H ₈ OH 4-CN ₄ HC ₂₄ H ₂₇ N ₇ O ₂ 71 nBu 6-COcycNC ₄ H ₈ OH 4-SO ₃ HC ₂₃ H ₂₇ N ₃ O ₅ S

[0018]

[Table 4] No. Molecular weight Elemental analysis Mass spectrometry Calculated value Measured value C (%) H (%) N (%) C (%) H (%) N (%) 1 421.50 68.39 6.46 9.97 68.75 6.32 10.33 421 (EI ) 2 419.53 71.57 6.97 10.02 71.46 7.10 9.91 419 (EI) 3 391.47 70.57 6.44 10.73 70.44 6.11 10.60 391 (EI) 4 435.52 68.95 6.71 9.65 68.76 6.68 9.46 435 (EI) 5 405.50 71.09 6.71 10.36 71.36 6.61 10.63 405 ( 421.54 71.23 7.41 9.97 71.37 7.80 10.11 421 (EI) 7 407.51 70.74 7.17 10.31 70.51 7.34 10.08 407 (EI) 8 380.45 69.46 6.36 7.36 69.77 6.22 7.67 380 (EI) 9 380.45 69.46 6.36 7.36 69.50 6.68 7.40.380 (EI) 10 5.72 7.95 68.18 5.54 7.96 352 (EI) 11 352.39 68.17 5.72 7.95 67.99 5.49 7.77 352 (EI) 12 337.42 71.19 6.87 12.45 71.12 6.65 12.38 337 (EI) 13 408.56 67.62 6.91 13.71 67.78 6.95 13.87 408 (EI) 14 420.51 68.55 6.71 13.32 68.83 6.46 13.60 420 (EI) 15 457.55 60.38 5.95 9.18 60.31 6.30 9.11 457 (EI) 16 471.57 61.13 6.20 8.91 61.27 6.04 9.05 471 (EI) 17 428.55 61.66 6.59 13.07 61.54 6.59 12 .95 428 (EI) 18 429.54 61.52 6.34 9.78 61.54 6.28 9.80 429 (EI) 19 443.56 62.28 6.59 9.47 62.23 6.80 9.42 443 (EI) 20 442.58 62.42 6.83 12.66 62.23 6.95 12.47 442 (EI) 21 456.61 63.13 7.06 12.27 63.01 6.70 12.15 456 (EI) 22 485.60 61.84 6.43 8.65 61.75 6.29 8.56 485 (EI) 23 473.61 58.33 5.75 8.87 58.36 5.76 8.90 473 (EI) 24 470.59 61.26 6.43 11.91 60.88 6.60 11.53 470 (EI)

[0019]

[Table 5] No. Molecular weight Elemental analysis Mass spectrometry Calculated value Measured value C (%) H (%) N (%) C (%) H (%) N (%) 25 427.52 61.81 5.89 9.83 61.70 5.99 9.72 427 (EI ) 26 443.56 62.28 6.59 9.47 62.13 6.27 9.32 443 (EI) 27 485.64 64.30 7.26 8.65 64.38 6.91 8.73 485 (EI) 28 443.52 59.58 5.68 9.47 59.78 5.59 9.67 443 (EI) 29 429.49 58.73 5.40 9.78 58.42 5.26 9.47 429 (EI) 30 435.57 71.70 7.64 9.65 71.62 7.90 9.57 435 (EI) 31 407.47 67.80 6.18 10.31 67.99 6.20 10.50 407 (EI) 32 393.44 67.16 5.89 10.68 67.37 5.57 10.89 393 (EI) 33 489.50 61.34 5.35 8.58 61.28 5.04 8.52 489 (62) 02 503.5 5.61 8.35 61.99 5.45 8.32 503 (EI) 35 511.62 72.78 6.50 8.21 72.85 6.30 8.28 511 (EI) 36 436.51 66.04 6.47 12.84 66.35 6.58 13.15 436 (EI) 37 450.54 66.65 6.71 12.44 66.55 6.72 12.34 450 (EI) 38 464.57 67.22 6.94 12.06 67.17 6.95 12.01 464 (EI) 39 478.55 65.26 6.32 11.71 65.28 6.34 11.73 478 (EI) 40 554.65 69.30 6.18 10.10 69.45 6.35 10.25 554 (EI) 41 630.75 72.36 6.07 8.88 72.48 6.07 9.00 630 (EI) 42 464.57 67.22 6.94 12.06 67 .31 6.49 12.15 464 (EI) 43 478.59 67.76 7.16 11.71 68.09 6.80 12.04 478 (EI) 44 506.60 66.39 6.77 11.06 66.80 6.62 11.47 506 (EI) 45 568.67 69.70 6.38 9.85 69.30 6.61 9.45 568 (EI) 46 644.77 72.65 6.25 8.69 72.50 5.99 8.54 644 (EI) 47 539.50 57.88 4.86 7.79 57.50 4.61 7.41 539 (EI) 48 437.56 65.88 6.22 9.60 65.86 6.24 9.58 437 (EI)

[0020]

[Table 6] No. Molecular weight Elemental analysis Mass analysis Calculated value Actual value C (%) H (%) N (%) C (%) H (%) N (%) 49 420.51 68.55 6.71 13.32 68.27 6.60 13.04 420 (EI ) 50 391.47 70.57 6.44 10.73 70.60 6.04 10.76 391 (EI) 51 392.50 70.38 7.19 14.27 70.37 7.52 14.26 392 (EI) 52 393.49 70.21 6.92 10.68 70.49 7.11 10.96 393 (EI) 53 407.51 70.74 7.17 10.31 70.36 7.04 9.93 407 (EI) 421.54 71.23 7.41 9.97 71.23 7.13 9.97 421 (EI) 55 406.53 70.91 7.44 13.78 70.56 7.63 13.43 406 (EI) 56 420.56 71.40 7.67 13.32 71.82 7.54 13.74 420 (EI) 57 408.56 67.62 6.91 13.71 67.82 7.02 13.91 408 (EI) 58 405.54 71.08 7.71 17.27 71.13 7.67 17.32 405 (EI) 59 390.53 73.81 7.74 14.35 73.78 7.81 14.32 390 (EI) 60 376.50 73.37 7.50 14.88 73.28 7.44 14.79 376 (EI) 61 362.48 72.90 7.23 15.46 72.79 7.64 15.35 362 (EI) 62 391.52 70.56 7.47 17.47. 70.77 7.09 18.10 391 (EI) 63 390.53 73.81 7.74 14.35 73.83 7.65 14.37 390 (EI) 64 398.52 63.29 6.58 14.06 63.19 6.58 13.96 398 (EI) 65 427.57 61.80 6.84 16.38 61.76 7.05 16.34 427 (EI) 66 426.58 64.76 7.09 13.13 64.96 7.09 13.33 426 (EI) 67 323.40 70.57 6.55 12.99 70.27 6.57 12.69 323 (EI) 68 497.60 72.41 6.28 8.44 72.34 6.56 8.37 497 (EI) 69 451.52 66.50 6.47 9.31 66.29 6.74 9.10 451 (EI) 70 445.53 64.70 6.11 64.85 5.73 22.16 445 (FAB) 71 457.55 60.38 5.95 9.18 60.23 6.08 9.03 457 (EI)

This substance can be prepared by a method known per se. The following are representative examples of synthetic routes that can be used to prepare this material. Synthetic route [1]:

(Equation 1)

[1]-(a) Step Methanol is added to a compound of the general formula (11) (wherein R ¹ and R ³ have the same meanings as described above, and R ⁶ represents an alkyl group having 1 to ⁶ carbon atoms). Lower alcohols such as ethanol and butanol, diethyl ether, tetrahydrofuran (T
HF), ethers such as dioxane, or a mixed solvent thereof, and the mixture is treated with an alkaline aqueous solution at 10 ° C. to the boiling point of the solvent, cooled, and acid-precipitated to give a compound represented by the general formula (1)
2) (wherein R ¹ and R ³ have the same meanings as described above). The compound of the general formula (11) can be prepared according to, for example, J.
Med. Chem. , 36: 1772-1784 (19
It can be obtained according to the method described in the literature of 93).

[1]-(b) step In the compound of the general formula (12), a --COOH group is added to an R ² group (R
² has the same meaning as described above), for example, a condensing agent such as N, N′-dicyclohexylcarbodiimide (DCCI), a solvent such as N, N-dimethylformamide (DMF), acetonitrile or chloroform, 1-hydroxybenzotriazole (H
Add auxiliaries such as OBt) at 5 to 48 at 10 to 40 ° C.
After reacting for a time, a compound of the general formula (13) (wherein R ¹ , R ² and R ³ have the same meanings as described above) is obtained. -CO
Examples of the compound capable of converting the OH group into the R ² group include morpholine when the R ² group is carbonylmorpholine. In the case of other R ² groups, those skilled in the art can appropriately select them depending on the intended R ² group.

[1]-(c) step The compound of the general formula (13) is added to the compound of the general formula (14) (wherein Y is a removable group, for example, OH, OSO ₂ CH ₃ and OSO).
_{2 C 6 H 4 -4-CH} 3, OSO 2 CF 3, or Cl,
Is a halogen such as I or Br, and R ⁴ is R ^{5 which} may be protected or a nitro group).
The compound of general formula (15) is obtained by reacting at -60 ° C for 5-75 hours.

[1]-(d) Step If necessary, the compound of the general formula (15) is converted from R ⁴ into R ⁵ by a suitable method, and a lower alcohol such as methanol, ethanol or butanol, diethyl ether or tetrahydrofuran. , ethers such as dioxane, or dissolved in a mixture of these solvents, by adding an alkali aqueous solution, and treated with 10 ° C. to the boiling point of the solvent, compounds of general formula (I) by acid precipitation after cooling (R ¹ , R ² , R ³ , and R ⁵
Is the same as above). Salts of compounds of general formula (I), especially pharmaceutically acceptable salts thereof, are prepared by the synthetic route [1]
In step (d), the compound of the general formula (15) and an equivalent amount of an acid or a base or the like are used to evaporate the solvent or concentrate the solution, dry it, and purify it. In the step of obtaining the compound of general formula (I) in this synthetic route [1], the compound of general formula (11) is reacted with the compound of general formula (14), and then the steps (a) and (b) are performed. Steps corresponding to step and step (d) can also be performed.

Synthesis route [2]:

(Equation 2)

[2]-(a) Step The compound of the general formula (21) is dissolved in a solvent such as dichloromethane and the —SO ₂ Cl group is converted to the R ² group (R ² has the same meaning as described above). An organic solution of a compound capable of being reacted (a solvent such as tetrahydrofuran, acetone, DMF, chloroform or dichloromethane) is added and reacted to obtain a compound of the general formula (22) (R ² and R ³ are the same as above). Examples of the compound capable of converting the —SO ₂ Cl group to the R ² group include morpholine when the R ² group is a sulfonylmorpholine.
In the case of other R ² groups, those skilled in the art can appropriately select them depending on the intended R ² group. The compound represented by the general formula (21) can be prepared according to, for example, Chem. Ber. , 24: 319
0 (1891).

[2]-(b) Step The compound of the general formula (22) is dissolved in a solvent such as dioxane, aqueous ammonia is added and the mixture is treated at 50 to 120 ° C. to obtain the compound of the general formula (23).

[2]-(c) step The compound of the general formula (23) is dissolved in a solvent such as DMF, dichloromethane, tetrahydrofuran, acetone, chloroform or pyridine, and the amino group is converted to R ¹ -CONH group (R
¹ has the same meaning as described above) and the reaction is carried out at 0 to 80 ° C. for 5 to 40 hours to obtain the compound of the general formula (24). The amino group is represented by R ¹ -CON
Examples of the compound that can be converted into the H group include valeric acid chloride when the R ¹ group is n-butyl. In the case of other R ¹ groups, those skilled in the art can appropriately select them depending on the intended R ¹ group.

[2]-(d) Step A Pd / C alcohol suspension is added to an alcohol solution of the compound of the general formula (24), and hydrazine monohydrate is added to the solution to treat the compound of the general formula (25). Obtain the compound.

[2]-(e) Step The compound of the general formula (25) is dissolved in a solvent such as benzene or chloroform, and N-ethyldiisopropylamine and the compound of the general formula (26) (Y and R ⁴ are as described above). The same meaning) is added and reacted at 20 to 80 ° C. for 10 to 40 hours to obtain a compound of the general formula (27) (R ⁴ has the same meaning as described above).

[2]-(f) step If necessary, the compound of the general formula (27) is converted into R ⁵ by converting R ⁴ into a suitable method, added to a solvent such as tetrahydrofuran or chloroform, and added with an aqueous hydrochloric acid solution. 3-10 at room temperature
Stir for hours, then remove solvent. Further, if necessary, alcohol, tetrahydrofuran or sodium hydroxide aqueous solution is added to the residue, the mixture is treated for 1 to 20 hours, cooled and acid-deposited to give a compound of the general formula (I) (R ¹ , R ² ,
R ³ and R ⁵ have the same meanings as described above.

Synthetic route [3]

(Equation 3)

[3]-(a) Step A compound of the general formula (31) (wherein R ¹ , R ³ and Me have the same meanings as described above) is added to a lower alcohol such as methanol, ethanol or butanol, diethyl ether, tetrahydrofuran. , An ether such as dioxane, or a mixed solvent thereof is added, and the mixture is treated with an alkaline aqueous solution at 10 ° C. to the boiling point of the solvent, cooled, and then acid-deposited to give a compound represented by the general formula (32) (wherein R ¹ and R ³ are as described above). Of the same meaning). The compound of the general formula (31) can be synthesized according to, for example, J. Med. Chem. , 36: 1772-17
84 (1993).

[3]-(b) Step The compound of the general formula (32) is replaced with a —COOH group and an R ² group (R ²
Has the same meaning as described above), for example, a condensing agent such as DCCI, a solvent such as DMF, acetonitrile, chloroform and the like, and optionally an auxiliary agent such as HOBt, at 10 to 40 ° C. The reaction is carried out for ~ 48 hours to obtain the compound of the general formula (33) (wherein R ¹ , R ² and R ³ have the same meanings as described above). -COOH group is R
Examples of the compound that can be converted into ^two groups include morpholine when the R ² group is carbonylmorpholine. In the case of other R ² groups,
It can be appropriately selected by those skilled in the art depending on the intended R ² group.

[3]-(c) Step A Pd / C alcohol suspension is added to an alcohol solution of a compound of the general formula (33), and hydrazine monohydrate is added to the solution to treat the compound of the general formula (34). Obtain the compound.

[3]-(d) Step The compound of the general formula (34) is dissolved in a solvent such as benzene or chloroform, and N-ethyldiisopropylamine and the compound of the general formula (35) (Y and R ⁴ are as described above). The same meaning) is added and reacted at 20 to 80 ° C. for 10 to 40 hours to obtain a compound of the general formula (36) (R ⁴ has the same meaning as described above).

Step [3]-(e) The compound of the general formula (36) is converted, if necessary, from R ⁴ to R ⁵ by a suitable method, added to a solvent such as tetrahydrofuran or chloroform, and an aqueous hydrochloric acid solution is added. 3-10 at room temperature
Stir for hours, then remove solvent. Further, if necessary, alcohol, tetrahydrofuran, or sodium hydroxide aqueous solution is added to the residue, and the mixture is treated for 1 to 20 hours, and after cooling, acid precipitation is carried out to obtain the compound of the general formula (I) (R ¹ , R ² , R ³ , and R ⁵ Has the same meaning as above).

The benzimidazole derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to the present invention has no effect on blood pressure and has a sufficient improving effect on renal damage. Indicates. Therefore, the present invention also relates to a pharmaceutical composition characterized by containing a benzimidazole derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, particularly an anti-kidney disease agent. Concerned. This substance is useful as an anti-renal disease drug. Nephritis, nephropathy, renal failure, nephrotic syndrome, asymptomatic proteinuria, hematuria, diabetic nephropathy, drug-induced nephropathy, urinary tract infection,
It is useful for prostatitis and the like. This substance is orally or parenterally (eg, transdermally, intravenously, intraperitoneally) administered to mammals including human. 500 mg of this substance in mice
Orally administered in an amount of 1 kg / kg and observed for one week, but no death was observed.

This substance can be added to one or more pharmaceutically acceptable additives to prepare a preparation such as powder, tablets, granules, capsules, suppositories, injections, or oral liquids. it can. Examples of the additive include magnesium stearate, talc, lactose, dextrin, starches, methyl cellulose, fatty acid glycerides, water, propylene glycol, macrogols, alcohol, crystalline cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose. , Carmellose, povidone, polyvinyl alcohol, calcium stearate and the like. Further, if necessary, a colorant, a stabilizer, an antioxidant, an antiseptic, a pH adjusting agent, an isotonicity agent, a solubilizing agent and / or a soothing agent can be added. Granules, tablets or capsules may be coated with a base such as hydroxypropylmethyl cellulose,
It can also be coated with hydroxypropylmethyl cellulose phthalate or the like.

0.1 to 500 m of this substance in a unit dose
g, preferably 1-100 mg. The amount of this substance used is 0 per 1 kg of body weight per day.
The amount is 1 to 150 mg, preferably 1 to 100 mg. This is administered once a day or divided into 2 to 3 times. However, the dose can be appropriately selected depending on the medical condition of the patient.

[0042]

[Function] The present inventors have developed angiotensin by a unique method.
The three-dimensional structural analysis of II was carried out, and the properties of various compounds were studied while considering the degree of affinity with II. That is, when an antagonistic activity against angiotensin II type 1 receptor, which is known to be related to antihypertensive effect, an effect of improving renal damage in animals with renal damage, an effect on blood pressure, etc. were investigated in detail, The salt
It has been found that it possesses the desired properties which are quite different from the hitherto known antihypertensive compounds. As mentioned above, this substance or a salt thereof is 1/100 to 1/1000 or less of the conventionally known antagonist having a standard effect as an antihypertensive agent with respect to the angiotensin II type 1 receptor antagonistic activity,
Despite no substantial antagonism, it shows an improving effect on renal damage. The existence of compounds with these properties is surprising, which cannot be predicted from existing knowledge. The clear reason for how this substance exhibits the above-mentioned effects is not yet known at present, and the present invention is not bound by the following reasoning, but it causes, for example, exacerbation of renal damage. A specific antagonism of angiotensin II receptors (new receptors other than the already known type 1 and type 2) involved in actions such as renal stromal cell proliferation and accumulation in the kidney is estimated. It may also be due to an action of a completely different mechanism that is not angiotensin II receptor antagonism. Even if the substance is classified as an angiotensin II receptor antagonist, and if not, in any case,
Angiotensin, which has a strong anti-hypertensive effect and has a well-known receptor antagonistic effect, which has been conventionally developed as a hypotensive agent
II receptor antagonists are compounds with completely different properties. That is, this substance has a chemical structure, an action effect,
In addition, it is a novel compound that has not existed in the past in terms of its practicality as a medicine.

[0043]

The present invention will be described in detail below with reference to examples, but these do not limit the scope of the present invention. Example 1: 2-Butyl-5-benzimidazole carbo
Preparation of acid ([1]-(12) -1): [1]-(a)
Step Methyl 2-butyl-5-benzimidazolecarboxylate ([1]-(11) -1) (15.01 g) was added to methanol (75.5 ml) and 1N NaOH aqueous solution (75.
5 ml) and left in an oil bath at 70 ° C. for 2.5 hours. The reaction solution was cooled and then concentrated, and 1N HCl aqueous solution (80 ml) was added for acid precipitation (pH 4). The precipitated dark green viscous substance was separated from the aqueous layer, washed with water, and dried to obtain the title compound (12.11 g) as a dark green solid. ¹ H-NMR (500 MHz, d ₆ -DMSO) δ: 0.0.
92 (t, 3H), 1.37 (sext, 2H), 1.
77 (quint, 2H), 2.90 (t, 2H),
7.58 (d, 1H), 7.82 (d, 1H), 8.0
9 (s, 1H), 12.72 (bs, 1H)

Example 2: 1-[(2-butylbenzimi
Dazol-5-yl) carbonyl] morpholine ([1]
-(13) -1) Preparation: [1]-(b) Step The compound prepared in Example 1 ([1]-(12)-
1) (10.23 g) in acetonitrile solution (100 m
l) DCCI (12.5 8g), HOBt (8.24)
g) and morpholine (5.3 ml) were added, and the mixture was mixed at room temperature for 1
Stir for 9 hours. The reaction solution was filtered to remove insoluble matter. The residue was concentrated to give a dark green oil (24.15g). This oily substance was subjected to silica gel column chromatography (Kieselgel 60, 280 g, CHCl ₃ /
Purify with CH ₃ OH = 30/1) to give the title compound (1
2.36 g) was obtained as a white foam. ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 0.8
7 (t, 3H), 1.32 (sext, 2H), 1.7
4 (quint, 2H), 2.78 (t, 2H), 3.
72 (bs, 6H), 7.18 (d, 1H), 7.54
(Bs, 2H)

Example 3: 1-[[2-butyl-1- (4
-Methoxycarbonylphenyl) methylbenzimidazo
Rol-6-yl] carbonyl] morpholine ([1]-
Preparation of (15) -1): Step [1]-(c) The compound prepared in Example 2 ([1]-(13)-
1) To a solution of (0.25 g) in dry DMF (2.5 ml) was added methyl 4-bromomethylbenzoate (0.30).
g) and anhydrous K ₂ CO ₃ (0.18 g) were added and stirred at room temperature for 13 hours. The reaction solution was poured into water and CHCl was added.
_{It was} extracted with ₃ and washed with saturated aqueous NaCl solution. The extract was dried over Na ₂ SO ₄ and concentrated to give a pale yellow oil (0.58 g). This oily substance was subjected to silica gel column chromatography (Lobar column gr).
oβe C; benzene / acetone = 3/1 to 1/1)
The title compound (0.16 g) was obtained as a white foam. ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 0.9
2 (t, 3H), 1.42 (sext, 2H), 1.9
9 (quint, 2H), 2.84 (t, 2H), 3.
65 (bs, 6H), 3.88 (s, 3H), 5.40
(S, 2H), 7.09 (d, 2H), 7.28 (d,
1H), 7.30 (s, 1H), 7.76 (d, 1
H), 7.98 (d, 2H) The isomer 1-[[2-butyl-1- (4-methoxycarbonylphenyl) methylbenzimidazol-5-yl] carbonyl] morpholine (0.21 g) was white foamed. Obtained as a substance. The structures of both regioisomers were determined by NOE difference spectroscopy.

Example 4: 1-[[2-butyl-1- (4
-Carboxyphenyl) methylbenzimidazole-6
-Yl] carbonyl] morpholine ([1]-(I)-
1) (Compound No. 1): [1]-(d) step
The compound prepared in Example 3 ([1]-(15)-
1) (0.15 g) was dissolved in methanol (0.75 ml) and 1N aqueous NaOH solution (0.75 ml), and the mixture was allowed to stand at room temperature for 15 hours. The reaction solution is concentrated, and 1N HCl is added.
An aqueous solution (0.8 ml) was added for acid precipitation. The precipitated crystals were filtered, washed with water and dried to give the title compound (0.10%).
g) was obtained as pale yellow crystals. Melting point: 227.0-229.5 ° C. ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 0.8
8 (t, 3H), 1.38 (sext, 2H), 1.7
7 (quint, 2H), 2.79 (t, 2H), 3.
69 (bs, 6H), 5.43 (s, 2H), 6.98
(D, 2H), 7.29 (d, 1H), 7.68 (s,
1H), 7.81 (d, 1H), 7.83 (d, 2H) The compound prepared in Example 3 ([1]-(15)-
In step [1]-(d) of step 1), the reaction solution was concentrated without acid precipitation, and the evaporation residue was purified to obtain the sodium salt of this substance.

Example 5: 1-[(2-butylbenzimi
Dazol-5-yl) carbonyl] piperidine ([1]
Preparation of-(13) -2): Step [1]-(b) The compound prepared in Example 1 ([1]-(12)-
1) (0.31 g) in acetonitrile (3.1 ml), DCCI (0.38 g), HOBt (0.25
g) and piperidine (0.18 ml) were added, and 1 was added at room temperature.
Stir for 5 hours. The reaction solution was filtered to remove insolubles and concentrated to give a yellow-green oily substance. This was subjected to silica gel column chromatography (Kieselgel 60, 15).
g, CHCl ₃ / acetone = 1/1) to give the title compound ([1]-(13) -2) (0.33 g) as a white foam. ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 0.9
0 (t, 3H), 1.35 (sext, 2H), 1.4
5-1.85 (b, 6H), 1.76 (quint, 2
H), 2.79 (t, 2H), 3.43, 3.74 (b
s, each 2H), 7.17 (d, 1H), 7.3
5-7.80 (b, 2H), 10.94-11.32.
(B, 1H)

Example 6: 1-[[2-butyl-1- (4
-Methoxycarbonylphenyl) methylbenzimidazo
Ol-6-yl] carbonyl] piperidine ([1]-
Preparation of (15) -2): Step [1]-(c) The compound prepared in Example 5 ([1]-(13)-
2) (0.32 g) in dry DMF (3.2 ml) was added with methyl 4-bromomethylbenzoate (0.38 g).
g) and anhydrous K ₂ CO ₃ (0.23 g) were added, and the mixture was stirred at room temperature for 19.5 hours. The reaction solution was poured into water and CHC was added.
It was extracted with l ₃ . The extract was washed with saturated aqueous NaCl solution, dried over Na ₂ SO ₄ and concentrated to a yellow oil (0.
72 g) was obtained. This was purified by silica gel column chromatography (LiChropprep Si60, 70 g, benzene / acetone / methanol = 80/20/3) to obtain the title compound (0.076 g) as a white foamy substance. ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 0.9
2 (t, 3H), 1.43 (sext, 2H), 1.5
0-1.75 (b, 6H), 1.82 (quint, 2
H), 2.82 (t, 2H), 3.20-3.75.
(B, 4H), 3.90 (s, 3H), 5.39 (s,
2H), 7.10 (d, 2H), 7.26 (d, 1
H), 7.29 (s, 1H), 7.75 (d, 1H),
7.98 (d, 2H)

Example 7: 1-[[2-butyl-1- (4
-Carboxyphenyl) methylbenzimidazole-6
-Yl] carbonyl] piperidine ([1]-(I)-
2) Preparation of (Compound No. 2): [1]-(d) step
The compound prepared in Example 6 ([1]-(15)-
2) (0.061 g) was dissolved in methanol (0.30 ml) and 1N NaOH aqueous solution (0.30 ml), and the mixture was allowed to stand at room temperature for 21 hours. The reaction solution is concentrated, and 1N HCl is added.
An aqueous solution (0.8 ml) was added for acid precipitation. The precipitated crystals were filtered, washed with water and dried to give the title compound (0.014).
g) was obtained as white crystals. Melting point: 137.0-139.0 ° C. ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 0.8
6 (t, 3H), 1.36 (sext, 2H), 1.4
5-1.75 (b, 6H) 1.77 (quint, 2
H), 2.87 (t, 2H), 3.40, 3.73 (b
s, each 2H), 5.46 (s, 2H), 6.9
5 (d, 2H), 7.37 (d, 1H), 7.75
(D, 2H), 7.82 (s, 1H), 7.89 (d,
1H)

Example 8: 1-[(2-butylbenzimid
Dazol-5-yl) carbonyl] azetidine ([1]
Preparation of (13) -3): Step [1]-(b) Compound ([1]-(12) -prepared in Example 1 above
1) (1.33 g) of acetonitrile (11.2 ml)
To the solution, DCCI (1.39 g), HOBt (0.91
g) and azetidine (0.45 ml) were added, and 1 was added at room temperature.
Stir for 5 hours. The reaction solution was filtered to remove insolubles and concentrated to give a yellow-green oily substance. This is subjected to silica gel column chromatography (Kieselgel 60, 55).
g, CHCl ₃ / acetone = 2/1) to give the title compound (1.42 g) as a pale yellow foam. ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 0.8
2 (t, 3H), 1.28 (sext, 2H), 1.7
3 (quint, 2H), 2.34 (dt, 2H),
2.88 (t, 2H), 4.23, 4.31 (bs, e
ach 2H), 7.30-7.85 (m, 3H)

Example 9: 1-[[2-butyl-1- (4
-Methoxycarbonylphenyl) methylbenzimidazo
Ol-6-yl] carbonyl] azetidine ([1]-
Preparation of (15) -3): Step [1]-(c) The compound prepared in Example 8 ([1]-(13)-
3) (1.42 g) in dry DMF (14.1 ml) was added with methyl 4-bromomethylbenzoate (1.89).
g) and anhydrous K ₂ CO ₃ (1.15 g) were added, and the mixture was stirred at room temperature for 19.5 hours. The reaction solution was poured into water and CHC was added.
It was extracted with l ₃ . The extract was washed with saturated aqueous NaCl solution, dried over Na ₂ SO ₄ and concentrated to give a yellow oil. This is subjected to silica gel column chromatography (Li
Purified with Chroprep Si60, 200 g, benzene / acetone = 1/1) to give the title compound ([1]-
(15) -3) (0.41 g), compound ([1]-(1
5) -4) (0.11 g) and a mixture (1.17 g) were obtained as a white foamy substance. Compound ([1]-(15)-
The structures of 3) and the compound ([1]-(15) -4) are NO.
Determined by E difference spectrum. Compound ([1]-
(15) -4) is 1-[[2-butyl-1- (4-methoxycarbonylphenyl) methylbenzimidazole-
5-yl] carbonyl] azetidine. ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 0.9
2 (t, 3H), 1.42 (sext, 2H), 1.8
2 (quint, 2H), 2.31 (dt, 2H),
2.83 (t, 2H), 3.90 (s, 3H), 4.2
6 (b, 4H), 5.41 (s, 2H), 7.09
(D, 2H), 7.48 (d, 1H), 7.61 (s,
1H), 7.74 (d, 1H), 7.98 (d. 2H)

Example 10: 1-[[2-butyl-1-
(4-Carboxyphenyl) methylbenzimidazole
-6-yl] carbonyl] azetidine ([1]-(I)
-3) (Compound No. 3): [1]-(d) Step
The compound prepared in Example 9 ([1]-(15)-
3) (0.39 g) with methanol (2.0 ml) and 1
Dissolve in normal NaOH aqueous solution (2.0 ml), and add 2 at room temperature.
It was left for 1 hour. The reaction solution was concentrated, and 1N HCl aqueous solution was added for acid precipitation. The precipitated crystals were filtered, washed with water and dried to give the title compound (0.15 g) as white crystals. Melting point: 120.0-122.0 ° C. ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 0.8
6 (t, 3H), 1.36 (sext, 2H), 1.7
7 (quint, 2H), 2.37 (dt, 2H),
2.85 (t, 2H), 4.28, 4.37 (bs, e
ach 2H), 5.49 (s, 2H), 6.92
(D, 2H), 7.50 (d, 1H), 7.73 (d,
2H), 7.85 (d, 1H), 8.18 (s, 1H)

Example 11: 1-[(2-butylbenzii
Midazol-5-yl) carbonyl] pyrrolidine
Preparation of ([1]-(13) -5): [1]-(b) Step
The compound prepared in Example 1 ([1]-(12)-
1) (0.92 g) in acetonitrile (9.2 ml) solution, DCCI (1.13 g), HOBt (0.74)
g) and pyrrolidine (0.46 ml) were added, and 1 was added at room temperature.
Stir for 5 hours. The reaction solution was filtered to remove insolubles and concentrated to give a yellow-green oily substance. This is subjected to silica gel column chromatography (Kieselgel 60, 50).
g, CHCl ₃ / acetone = 1/1) to give the title compound (1.04 g) as a pale yellow foam. ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 0.8
5 (t, 3H), 1.29 (sext, 2H), 1.7
2 (quint, 2H), 1.88 (dt, 2H),
1.99 (dt, 2H), 2.82 (t, 2H), 3.
45 (t, 2H), 3.67 (t, 2H), 7.30
(D, 1H), 7.37 (d, 1H), 7.66 (s,
1H)

Example 12: 1-[[2-butyl-1-
(4-Methoxycarbonylphenyl) methylbenzimi
Dazol-6-yl] carbonyl] pyrrolidine ([1]
-(15) -5) Preparation: [1]-(c) Step The compound ([1]-(13)-prepared in Example 11 above.
5) (1.04 g) in dry DMF (10.4 ml) was added with methyl 4-bromomethylbenzoate (1.31).
g) and anhydrous K ₂ CO ₃ (0.79 g) were added, and the mixture was stirred at room temperature for 19.5 hours. The reaction solution was poured into water and CHC was added.
It was extracted with l ₃ . The extract was washed with saturated aqueous NaCl solution, dried over Na ₂ SO ₄ and concentrated to give a yellow oil. This is subjected to silica gel column chromatography (Li
Chroprep Si60, 180 g, benzene / acetone = 2/3) and the title compound ([1]-
(15) -5) (0.30 g), compound ([1]-(1
5) -6) (0.38 g), a mixture of both (0.41)
g) was obtained as a white foam. Compound ([1]-(1
The structures of 5) -5) and the compound ([1]-(15) -6) were determined by the NOE difference spectrum. The compound ([1]-(15) -6) is 1-[[2-butyl-1-
(4-methoxycarbonylphenyl) methylbenzimidazol-5-yl] carbonyl] pyrrolidine. ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 0.9
2 (t, 3H), 1.42 (sext, 2H), 1.7
9-1.85 (m, 6H), 1.92-1.95 (m,
6H), 2.83 (t, 2H), 3.38 (t, 2)
H), 3.63 (t, 2H), 3.90 (s, 3H),
5.40 (s, 2H), 7.09 (d, 2H), 7.4
2 (d, 1H), 7.43 (s, 1H), 7.75
(D, 1H), 8.00 (d, 2H)

Example 13: 1-[[2-butyl-1-
(4-Carboxyphenyl) methylbenzimidazole
-6-yl] carbonyl] pyrrolidine ([1]-(I)
-5) (Compound No. 5): [1]-(d)
The compound prepared in Example 12 ([1]-(15)-
5) (0.30 g) in methanol (1.5 ml) and 1
Dissolve in normal NaOH aqueous solution (1.5 ml), and add 2 at room temperature.
It was left for 1 hour. The reaction solution was concentrated, and 1N HCl aqueous solution was added for acid precipitation. The precipitated crystals were filtered, washed with water and dried to give the title compound No. 5 (0.088 g) was obtained as white crystals. Melting point: 206.0-207.0 ° C. ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 0.8
5 (t, 3H), 1.33 (sext, 2H), 1.7
4 (quint, 2H), 1.87 (dt, 2H),
1.97 (dt, 2H), 2.73 (t, 2H), 3.
52, 3.69 (t, each 2H), 5.43
(S, 2H), 6.88 (d, 2H), 7.44 (d,
1H), 7.69 (d, 2H), 7.78 (d, 1
H), 8.01 (s, 1H)

Example 14: N, N-diethyl-5- (2
-Butylbenzimidazole) carboxamide ([1]
-(13) -7) Preparation: [1]-(b) Step The compound prepared in Example 1 ([1]-(12)-
1) (1.23 g) of acetonitrile (12.2 ml)
To the solution, DCCI (1.51 g), HOBt (0.99
g) and diethylamine (0.76 ml) were added, and the mixture was stirred at room temperature for 15 hours. The reaction solution is filtered to remove insoluble matter,
Concentration gave a yellow-green oil. This is subjected to silica gel column chromatography (Kieselgel 60,5).
Purification with 5 g, CHCl ₃ / acetone = 3/2) gave the title compound (1.75 g) as a pale yellow foam. ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 0.7
9 (t, 3H), 1.10, 1.26 (bs, each)
3H), 1.22 (sext, 2H), 1.65 (q
uint, 2H), 2.75 (t, 2H), 3.27,
3.57 (bs, each 2H), 7.09 (d, 1)
H), 7, 29 (d, 1H), 7.46 (s, 1H)

Example 15: N, N-diethyl-6- [2
-Butyl-1- (4-methoxycarbonylphenyl) me
Cylbenzimidazole] carboxamide ([1]-
Preparation of (15) -7): Step [1]-(c) The compound prepared in Example 14 ([1]-(13)-
7) (1.75 g) in dry DMF (17.5 ml) was added with methyl 4-bromomethylbenzoate (2.19).
g) and anhydrous K ₂ CO ₃ (1.33 g) were added, and the mixture was stirred at room temperature for 19.5 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution, dried over Na ₂ SO ₄ and concentrated to give a yellow oil. This is subjected to silica gel column chromatography (Li
Purify with Chroprep Si60, 200 g, benzene / acetone = 1/1) to give the title compound ([1]-
(15) -7) (0.65 g), compound ([1]-(1
5) -8) (0.84 g), a mixture of both (0.26)
g) was obtained as a white foam. Compound ([1]-(1
The structures of 5) -7) and the compound ([1]-(15) -8) were determined by the NOE difference spectrum. The compound ([1]-(15) -8) is N, N-diethyl-5-
[2-butyl-1- (4-methoxycarbonylphenyl) methylbenzimidazole] carboxamide. ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 0.9
2 (t, 3H), 0.95-1.30 (b, 6H),
1.42 (sext, 2H), 1.82 (quint,
2H), 2.82 (t, 2H), 3.15-3.60.
(B, 4H), 3.90 (s, 3H), 5.39 (s,
2H), 7.09 (d, 2H), 7.24 (s, 1
H), 7.27 (d, 1H), 7.75 (d, 1H),
7.98 (d, 2H)

Example 16: N, N-diethyl-6- [2
-Butyl-1- (4-carboxyphenyl) methylben
Zimidazole] carboxamide ([1]-(I)-
7) (Compound No. 7): [1]-(d) step
The compound prepared in Example 15 ([1]-(15)-
7) (0.59 g) with methanol (3.0 ml) and 1
Dissolve in normal NaOH aqueous solution (3.0 ml), and add 2 at room temperature.
It was left for 1 hour. The reaction solution was concentrated, and 1N HCl aqueous solution was added for acid precipitation. The precipitated crystals were filtered, washed with water and dried to give the title compound (Compound No. 7) (0.36 g)
Was obtained as white crystals. Melting point: 195.0-197.0 ° C. ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 0.8
6 (t, 3H), 1.10, 1.24 (bs, each)
3H), 1.36 (sext, 2H), 1.76 (q
uint, 2H), 2.81 (t, 2H), 3.31,
3.55 (bs, each 2H), 5.43 (s, 2
H), 6.94 (d, 2H), 7.31 (d, 1H),
7.72 (s, 2H), 7.77 (d, 2H), 7.8
4 (d, 1H)

Example 17: [2-Butyl-1- (4-me
Toxycarbonylphenyl) methylbenzimidazo
] -5-carboxylic acid methyl ester (Compound No.
8) and [2-butyl-1- (4-methoxycarbonylphenyl)
Phenyl) methylbenzimidazole] -6-carboxylic acid
Preparation of methyl ester (Compound No. 9) To a solution of 2-butyl-5-benzimidazolecarboxylic acid methyl ester (3.02 g) in dry dimethyl sulfoxide (DMSO) (60 ml), methyl 4-bromomethylbenzoate (4.21 g) was added. ) And anhydrous K ₂ CO ₃
(1.80 g) was added, and the mixture was stirred at room temperature for 4 days and nights. The reaction solution was poured into ice water, and ethyl acetate (EtOAc) (150 m
It was extracted with l), dried over anhydrous MgSO ₄ and concentrated to give a pale yellow-green viscous material (6.20 g). EtOA
c (10 ml) and benzene (30 ml) were added, and the mixture was heated and dissolved, and then allowed to cool. 9 (1.76 g) was obtained as colorless crystals. On the other hand, the residue obtained by concentrating the filtrate was subjected to silica gel column chromatography (Kiese).
lgel 60, 200 g, benzene / EtOAc = 4
/ 1) and recrystallized from EtOAc / hexane to give compound No. 8 (1.27 g) was obtained as colorless crystals. Compound No. 8 Melting point: 98.0-100.0 ° C. ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 0.9
2 (t, 3H), 1.42 (sext, 2H), 1.8
2 (quint, 2H), 2.83 (t, 2H), 3.
90 (s, 3H), 3.94 (s, 3H), 5.41
(S, 2H), 7.08 (d, 2H), 7.17 (d,
1H), 7.93 (d, 1H), 7.98 (d, 2)
H), 8.48 (s, 1H) Compound No. 9 Melting point: 134.0-137.5 ° C. ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 0.9
1 (t, 3H), 1.41 (sext, 2H), 1.8
2 (quint, 2H), 2.82 (t, 2H), 3.
90 (s, 6H), 5.44 (s, 2H), 7.08
(D, 2H), 7.77 (d, 1H), 7.95 (s,
1H), 7.96 (d, 1H), 7.98 (d, 2H)

Example 18: [2-Butyl-1- (4-carbohydrate)
Ruboxiphenyl) methylbenzimidazole] -5-
Preparation of carboxylic acid (Compound No. 10) Compound No. prepared in Example 17 above. 8 (0.60
g) was dissolved in methanol (15 ml) and 1N NaOH aqueous solution (2.5 ml), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated, water (30 ml) was added to the residue, and the mixture was mixed with 1
Acid precipitation was performed with a normal HCl aqueous solution. The precipitated solid was filtered off to obtain a colorless solid (0.54g). This is CH ₃ CN /
The compound No. was recrystallized from THF. 10 ([1]-
(I) -10) (0.27 g) was obtained as colorless crystals. Melting point: 255.0-257.0 ° C. ¹ H-NMR (500 MHz, d ₆ -DMSO) δ: 0.0.
85 (t, 3H), 1.34 (sext, 2H), 1.
69 (quint, 2H), 2.84 (t, 2H),
5.64 (s, 2H), 7.17 (d, 2H), 7.5
3 (d, 1H), 7.80 (d, 1H), 7.89
(D, 2H), 8.18 (s, 1H), 12.79 (b
s, 2H)

Example 19: [2-Butyl-1- (4-carbohydrate)
Ruboxiphenyl) methylbenzimidazole] -6-
Preparation of carboxylic acid (Compound No. 11) Compound No. prepared in Example 17 above. 9 (0.91
g) to methanol (4 ml), THF (4 ml), 1
Normal NaOH aqueous solution (3.6 ml), and water (3.6 m)
1) at 80 ° C., cooled to room temperature and stirred for 16 hours. The solvent was distilled off under reduced pressure, and 1N HCl aqueous solution (3.
It was acidified with 6 ml) to obtain a precipitated solid (0.71 g). This was recrystallized from CH ₃ CN / THF to obtain compound No. 11 (0.32 g) was obtained as colorless crystals. Melting point: 285.0-289.0 ° C. ¹ H-NMR (500 MHz, d ₆ -DMSO) δ: 0.0.
85 (t, 3H), 1.35 (sext, 2H), 1.
71 (quint, 2H), 2.86 (t, 2H),
5.69 (s, 2H), 7.15 (d, 2H), 7.6
6 (d, 1H), 7.80 (d, 1H), 7.90
(D, 2H), 8.04 (s, 1H), 12.84 (b
s, 2H)

Example 20: 4-[(4-chloro-3-ni
Trobenzene) sulfonyl] morpholine ([2]-(2
2) -15) Preparation: [2]-(a) Step 4-chloro-3-nitrobenzenesulfonyl chloride ([2]-(21) -15) (50.0 g) in CH ₂ C.
l was dissolved in ₂ (500ml), it was cooled with ice. A CH ₂ Cl ₂ solution (30 ml) of morpholine (33.1 g) was added dropwise over 1 hour. The mixture was stirred under ice cooling for 1 hour and at room temperature for 1 hour. The reaction solution was washed with distilled water and a saturated NaCl aqueous solution, and the organic layer was dried over Na ₂ SO ₄ . Evaporate the solvent,
Silica gel column chromatography (Kieselg)
el 60, 1.5 kg, CHCl ₃ ) to give the title compound (56.6 g) as pale yellow needle crystals. Melting point: 145.5-148.0 ° C. ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 3.0
8 (t, 4H), 3.78 (t, 4H), 7.77
(D, 1H), 7.88 (d, 1H), 8.23 (s,
1H)

Example 21: 4-[(4-amino-3-ni
Trobenzene) sulfonyl] morpholine ([2]-(2
Preparation of 3) -15): [2]-(b) step The compound ([2]-(22)-prepared in Example 20 above.
15) (5.00 g) was dissolved in dioxane (70 ml), 28% aqueous ammonia (50 ml) was added, and the mixture was reacted at 95 ° C for 12 hours in a pressure resistant glass container. CHCl ₃
(100 ml) extracted 3 times, and the organic layer was dried over Na ₂ SO ₄ . The solvent was distilled off, and the title compound (4.51 g)
I got Melting point: 199.0-200.0 ° C ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 3.0
3 (t, 4H), 3.76 (t, 4H), 6.51 (b
s, 2H), 6.93 (d, 1H), 7.68 (d, 1)
H), 8.55 (d, 1H)

Example 22: 4-[(3-Nitro-4-va
Leramidebenzene) sulfonyl] morpholine ([2]-
Preparation of (24) -15): [2]-(c) step The compound ([2]-(23)-prepared in Example 21 above.
15) (22.8 g) was dissolved in anhydrous pyridine (150 ml), and dimethylaminopyridine (DMAP) (11.
6 g) was added and ice-cooled. Valeric acid chloride (28.3 ml) was added dropwise to this solution over 30 minutes, and the mixture was stirred at room temperature for 30 minutes and at 60 ° C. for 27 hours. CH the reaction solution
Extracted 3 times with Cl ₃ (200 ml). The organic layer is Na ₂
After drying with SO ₄ , the solvent was distilled off, toluene was added, and pyridine was removed azeotropically. The crude product was subjected to silica gel column chromatography (Kieselgel 60, 2.0).
kg, CHCl ₃ to CHCl ₃ / MeOH = 40 /
Purification in 1) gave the title compound (24.9 g) as a solid. The solid was recrystallized from CH ₂ Cl ₂ / hexane = 2/1 to obtain the title compound (20.1 g) as pale yellow needle crystals. Melting point: 129.0-130.0 ° C ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 0.
98 (t, 3H), 1.45 (sext, 2H), 1.
77 (quint, 2H), 2, 55 (t, 2H),
3.05 (t, 4H), 3.76 (t, 4H), 7.9
6 (d, 1H), 8.61 (d, 1H), 9.08
(D, 1H), 10.57 (bs, 1H)

Example 23: 4-[(3-amino-Varella
[Midobenzene) sulfonyl] morpholine ([2]-(2
Preparation of 5) -15): [2]-(d) step The compound ([2]-(24)-prepared in Example 22 above.
15) (10.1 g) was dissolved in EtOH (750 ml) and heated at 55 ° C. After stopping foaming, 10% Pd / C
A suspension of (1.50 g) in EtOH (20 ml) was added. Hydrazine monohydrate (10 ml) was added, heating was stopped after 5 minutes, and the catalyst was removed with Celite. The filtrate was concentrated to give the title compound (8.49 g) as a white foam. ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 0.9
7 (t, 3H), 1.44 (b, 2H), 1.75
(B, 2H), 2.45 (t, 2H), 3.00 (t,
4H), 3.74 (t, 4H), 3.98 (bs, 2)
H), 7.16 (bs, 1H), 7.18 (s, 1
H), 7.52 (d, 1H)

Example 24: 4-[[3-[(4'-meth
Xycarbonylphenyl) methylamino] -4-valera
[Midobenzene] sulfonyl] morpholine ([2]-(2
7) -15) Preparation: [2]-(e) Step The compound ([2]-(25)-prepared in Example 23 above.
15) (5.49 g) with anhydrous CHCl ₃ (150 ml)
Was dissolved in ethyl acetate, methyl 4-bromomethylbenzoate (4.39 g) was added, and N-ethyldiisopropylamine (5.90 ml) was further added. This solution was stirred at 60 ° C. for 23 hours under a nitrogen atmosphere. After washing the reaction solution with distilled water, the organic layer was dried over Na ₂ SO ₄ . The solvent was distilled off, and the crude product was purified by silica gel column chromatography (Kieselgel 60, 300 g, CHCl ₃ to CHCl ₃ / MeOH = 50/1) to give the title compound (2.73 g) as a white foamy substance. Got as. ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 0.9
7 (t, 3H), 1.44 (bsext, 2H), 1.
75 (bquint, 2H), 2.47 (bt, 2
H), 2.63 (bs, 4H), 3.57 (t, 4)
H), 3.90 (s, 3H), 4.48 (d, 2H),
4.91 (bs, 1H), 6.86 (d, 1H), 7.
08 (d, 1H), 7.24 (bd, 1H), 7.37
(D, 1H), 7.45 (d, 2H), 7.99 (d,
2H)

Example 25: 4-[[2-butyl-1-
(4-Carboxyphenyl) methylbenzimidazole
-6-yl] sulfonyl] morpholine ([2]-(I)
-15) (Compound No. 15): [2]-(f)
Step The compound prepared in Example 24 ([2]-(27)-
15) (4.53 g) was dissolved in THF (30 ml),
12% HCl aqueous solution (15 ml) was added, and the mixture was stirred at room temperature for 5 hours. The solvent was removed, MeOH (250 ml), T
HF (80 ml) and 1N NaOH aqueous solution (100
ml) was added and stirred for 15 hours. The reaction solution was adjusted to pH 4 with a 1N HCl aqueous solution and concentrated. The precipitated solid was collected by filtration, washed with distilled water and dried to give the title compound N
o. 15 (3.36 g) was obtained as an off-white solid. Melting point: 202.0-205.0 ° C ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 0.9
3 (t, 3H), 1.44 (sext, 2H), 1.8
5 (quint, 2H), 2.84 (bs, 4H),
2.91 (t, 2H), 3.67 (t, 4H), 5.4
8 (s, 2H), 7.11 (d, 2H), 7.57
(S, 1H), 7.63 (d, 1H), 7.91 (d,
1H), 8.05 (d, 2H)

Example 26: 4-[(2-butylbenzii
Midazol-5-yl) carbonyl] thiomorpholine
Preparation of ([1]-(13) -48): [1]-(b)
Tep 2-butylbenzimidazole-5-carboxylic acid (2.
56 g) is dissolved in acetonitrile (30 ml) and DC
CI (3.18 g), HOBt (2.08 g) and thiomorpholine (1.56 g) were added, and the mixture was stirred overnight. The precipitated insoluble matter was filtered and then concentrated. The pale yellow foam obtained was subjected to silica gel column chromatography (Kiese).
lgel 60, 200 g, CHCl ₃ / MeOH = 4
(0/1) to give the title compound (1.86 g) as a white foam. ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 0.9
3 (t, 3H), 1.38 (bsext, 2H), 1.
79 (bquint, 2H), 2.66 (bs, 4
H), 2.84 (bt, 2H), 3.89 (bs, 4)
H), 7.17-7.22 (m, 2H), 7.65-
7.68 (m, 1H), 10.15-10.62 (b,
1H)

Example 27: 4-[[2-butyl-1-
(4-Methoxycarbonylphenyl) methylbenzimi
Dazol-6-yl] carbonyl] thiomorpholine
Preparation of ([1]-(15) -48): [1]-(c)
The compound prepared in Example 26 ([1]-(13)-
48) (1.54 g) was dissolved in DMF (10 ml). Anhydrous K ₂ CO ₃ a (0.84 g) and methyl 4-bromomethyl benzoate (1.42 g) was added, 19.5
Stir for hours. The reaction solution was extracted twice with EtOAc (30 ml), and the organic layer was washed with saturated aqueous NaCl solution. The organic layer was dried over Na ₂ SO ₄ and then concentrated. The obtained yellow oily substance was subjected to silica gel column chromatography (Kie).
selgel 60, 250 g, benzene / acetone =
(3/1) to give a colorless oil (2.43 g).
Furthermore, silica gel column chromatography (Kiese
lgel 60,250 g, CHCl ₃ / acetone = 5
/ 1) to give the title compound (0.20 g). N
The isomer structure was determined by OE difference spectrum. The isomer is 4-[[2-butyl-1- (4-methoxycarbonylphenyl) methylbenzimidazol-5-yl] carbonyl] thiomorpholine. ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 0.9
2 (t, 3H), 1.42 (sext, 2H), 2.8
2 (quint, 2H), 2.63 (bs, 4H),
3.86 (bs, 4H), 3.92 (s, 3H), 5.
40 (s, 2H), 7.09 (d, 2H), 7.23
(D, 1H), 7.25 (s, 1H), 7, 77 (d,
1H), 7.98 (d, 2H)

Example 28: 4-[[2-butyl-1-
(4-Carboxyphenyl) methylbenzimidazole
-6-yl] carbonyl] thiomorpholine ([1]-
Preparation of (I) -48) (Compound No. 48): [1]-
Step (d) The compound prepared in Example 27 ([1]-(15)-
48) (0.22 g) was dissolved in methanol (5 ml), 1N NaOH aqueous solution (1.0 ml) was added, and the mixture was stirred for 12 hours. The solvent was evaporated, and 1N HCl aqueous solution was added to adjust the pH to 7. The precipitated crystals were filtered, washed with water, and dried under reduced pressure to give the title compound (0.11 g) as a white solid. Melting point: 223.5-225.5 ° C. ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 0.8
8 (t, 3H), 1.38 (sext, 2H), 1.7
8 (quint, 2H), 2.45-2.90 (b, 4
H), 2.79 (t, 3H), 3.65-4.15.
(B, 4H), 5.43 (s, 2H), 6.98 (d,
2H), 7.27 (d, 2H), 7.60 (s, 1
H), 7.76 (d, 1H), 7.98 (d, 2H)

Example 29: N-[(2-butylbenzii
Midazol-5-yl) carbonyl] -N'-triphe
Nylmethylpiperazine ([1]-(13) -14) tone
Production: [1]-(b) Step 2-Butylbenzimidazole-5-carboxylic acid (2.
35 g) was dissolved in CH ₃ CN (40 ml), and DCCI was added.
(2.89 g), HOBt (1.89 g), and N-triphenylmethylpiperazine (4.59 g) were added 17
Stir for hours. The precipitated insoluble material was filtered, and the filtrate was concentrated. The obtained crude product was subjected to silica gel column chromatography (Kieselgel 60, 250 g, CHC).
l ₃ / MeOH = 30/1 to CHCl ₃ / MeOH =
15/1) and the title compound (1.
47 g) was obtained.

Example 30: N-[[2-butyl-1-
(4-Methoxycarbonylphenyl) methylbenzimi
Dazol-6-yl] carbonyl] -N'-tripheni
Lumethylpiperazine ([1]-(15) -14) tone
Production: [1]-(c) step The compound prepared in Example 29 ([1]-(13)-
14) (1.40 g) was dissolved in DMF (10 ml). Anhydrous K ₂ CO ₃ a (0.44 g) and methyl 4-bromomethyl benzoate (0.75 g) was added, 17.5
Stir for hours. The reaction mixture was diluted with CH ₂ Cl ₂ (30 ml) to 2
It was extracted twice and the organic layer was washed with saturated aqueous NaCl solution. The organic layer was dried over Na ₂ SO ₄ and then concentrated. The obtained yellow oily substance was subjected to silica gel column chromatography (Ki
Eselgel 60,150 g, benzene / acetone = 4/1) was applied to obtain the title compound (0.54 g). ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 0.9
0 (t, 3H), 1.40 (sext, 2H), 1.8
0 (quint, 2H), 1.90-2.60 (b, 4
H), 2.80 (t, 3H), 3.50-3.90.
(B, 4H), 3.89 (s, 3H), 5.35 (s,
2H), 7.05 (d, 2H), 7.10-7.30.
(M, 11H), 7.45 (bs, 6H), 7.68
(D, 1H), 7.98 (d, 2H)

Example 31: N-[[2-butyl-1-
(4-Carboxyphenyl) methylbenzimidazole
-6-yl] carbonyl] -N'-triphenylmethyl
Preparation of piperazine ([1]-(I) -14 '): [1]
-(D) Step The compound prepared in Example 30 ([1]-(15)-
14) (0.20 g) was dissolved in MeOH (5 ml),
1N NaOH aqueous solution (0.6 ml) was added, and the mixture was stirred for 18 hours. Furthermore, dioxane (0.5 ml) and 1N
An aqueous aOH solution (0.5 ml) was added and the mixture was stirred for 18 hours. Furthermore, 1N HCl aqueous solution is added to cause acid precipitation (pH 4).
The precipitated crystals were filtered, washed with water, and dried under reduced pressure to give the title compound (0.18 g) as white crystals. Melting point: 170.0-172.5 ° C ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 0.8
4 (t, 3H), 1.34 (sext, 2H), 1.7
3 (quint, 2H), 2.10-3.10 (b, 4
H), 2.72 (t, 2H), 3.30-4.10.
(B, 4H), 5.37 (s, 2H), 6.90 (d,
2H), 7.10-7.35 (m, 14H), 7.45.
(Bs, 3H), 7.66 (s, 1H), 7.71
(D, 1H), 7.74 (d, 1H)

Example 32: N-[[2-butyl-1-
(4-Carboxyphenyl) methylbenzimidazole
-6-yl] carbonyl] piperazine ([1]-(I)
-14) Preparation of (Compound No. 14) The compound ([1]-(I) -1 prepared in Example 31 above.
4 ′) (0.079 g) was dissolved in dioxane (1 ml), 1N HCl aqueous solution (0.12 ml) was added, and the mixture was stirred at room temperature for 16 hr. Since a white solid was deposited, distilled water (1 ml) was added and the mixture was further stirred for 24 hours. The reaction solution was concentrated, distilled water was added, the precipitated crystals were collected by filtration, dissolved in distilled water, adjusted to pH 6 with a 1N NaOH aqueous solution, and the precipitated crystals were collected by filtration. This is dried to give the title compound (0.
012 g) was obtained as a white solid. Melting point: 170.0-172.0 ° C

Example 33: [2-Butyl-1- (4-d
Trophenyl) methylbenzimidazole] -6-car
Preparation of boric acid methyl ester ([1]-(15) -12)
2-butylbenzimidazole-5-carboxylic acid methyl ester (23.20 g) manufactured by DSO (500 m)
l) and dissolved in 4-nitrobenzyl bromide (32.4
1 g) and anhydrous K ₂ CO ₃ (13.82 g) were added to obtain a suspension, which was stirred at room temperature for 3 days and nights. This suspension was cooled with ice water, water (900 ml) was added, and CHCl ₃ (1000 ml) was added.
ml), dried over anhydrous MgSO ₄ , and then concentrated to obtain a light brown viscous substance. Add CHCl ₃ (10
0 ml) was added, insoluble matter was filtered off, and the filtrate was subjected to silica gel column chromatography (Kieselgel 60,
After purification with 250 g, CHCl ₃ ) and collecting 8.32 g of the product, further EtOAc (100 ml) was added, heated and filtered to obtain the title compound (4.79 g) as a colorless solid. Melting point: 199.0-201.0 ° C ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 0.9
3 (t, 3H), 1.43 (sext, 2H), 1.8
4 (quint, 2H), 2.82 (t, 2H), 3.
90 (s, 3H), 5.49 (s, 2H), 7.18
(D, 2H), 7.79 (d, 1H), 7.91 (s,
1H), 7.99 (d, 1H), 8.19 (d, 2H)

Example 34: [2-Butyl-1- (4-a
Minophenyl) methylbenzimidazole] -6-cal
Boronic acid methyl ester ([1]-(I) -12) (compound
Item No. Preparation of 12) The compound prepared in the above Example 33 ([1]-(15)-
12) (3.38 g) with CHCl ₃ (150 ml),
And dissolved in methanol (30 ml), stannous chloride 2
A hydrate (11.45 g) was added to obtain a suspension. The suspension was heated to reflux temperature over 5 minutes, stirred for 3.5 hours, allowed to cool, and then aqueous Na ₂ CO ₃ solution (5 g / 100 m 2
1) was added to adjust the pH to 7, and the mixture was concentrated under reduced pressure at a bath temperature of 60 ° C. The obtained solid was extracted with CHCl ₃ (250 ml), dried over anhydrous MgSO ₄ , and the solvent was distilled off to obtain a solid (2.90 g). This is EtOAc / CHCl ₃
Recrystallized from (3/2) to give the titled compound No. 12
(2.34 g) was obtained as colorless crystals. Melting point: 168.0-171.0 ° C ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 0.9
3 (t, 3H), 1.42 (sext, 2H), 1.8
2 (quint, 2H), 2.84 (t, 2H), 3.
68 (bs, 2H), 3.91 (s, 3H), 5.26
(S, 2H), 6.59 (d, 2H), 6.84 (d,
2H), 7.73 (d, 1H), 7.94 (d, 1
H), 8.02 (d, 1H)

Example 35: Acute toxicity Five-week-old ICR mice (female) were divided into 5 groups, and each group was bred for 1 week. Oral administration (dose 500m
g / kg), and the number of deaths after 6 days was examined. The results are shown in Table 7.

[0078]

Table 7 Compound No. Number of deaths / Number of survivors ──────────────────── 1 0/5 2 0/5 3 0/5 5 0/5 7 0/5 8 0/5 9 0/5 10 0/5 11 0/5 12 0/5 14 0/5 15 0/5 48 0/5

Example 36: Receptor binding In this example, the affinity of angiotensin II for type 1 and type 2 receptors was determined in the literature (Biochem. Pha).
rmacol. , 33: 4057-4062, 198.
4) Obtained by the binding assay method according to the method described. Specifically, the measurement of total binding in the presence of each drug was performed as follows. A drug of a predetermined concentration (dissolved in DMSO, diluted 2-fold with the buffer attached to the drug discovery system and used for the assay; 0.025 ml), tracer (0.025 ml), and receptor (0.2
ml) was added to make a total of 0.25 ml, and the mixture was incubated [for angiotensin II receptor type 1 (AT ₁ ) at room temperature for 3 hours, and for type 2 (AT ₂ ) at 37 ° C. for 1 hour], and the reaction solution was suction filtered. (AT _{1 used} GF / C filter paper and AT ₂ used GF / B filter paper). The filter paper (tracer and receptor conjugate) after suction filtration was measured with a γ-well counter (ARC-500, Aloka). Non-specific binding was determined by adding a large excess of displacer and operating in the same manner. Specific binding at a given concentration of drug was determined by subtracting nonspecific binding from total binding, respectively. In AT ₁ and AT ₂ , using a predetermined concentration of the test drug and the control drug, the ratio of the test drug inhibiting the binding between the radioligand (tracer) and the receptor (IC ₅₀ value at a concentration that inhibits 50%, or binding at 100 μM) % Inhibition) was determined. Table 8 shows the results.

[0080]

Table 8 Compound IC ₅₀ % inhibition of binding at 100 μM No. AT ₁ (nM) AT ₁ AT ₂ ───────────────────────────────── 1 6900 0 2 9700 0 3 5800 0 5 14000 0 7 5200 0 8 0 0 9 18 0 10 79000 0 11 16000 0 12 28 28 0 14 17000 0 15 38000 0 48 9900 0 DuP753 20 0

In AT ₁ Receptor: Rabbit adrenal derived tracer: ³ H-Angiotensin II Control drug: DuP753 (Displacer): DuP753 In AT ₂ Receptor: Bovine cerebellar cortex derived tracer: ¹²⁵ I-Tyr ⁴ -Angiotensin II control drug: Angiotensin II (human) (Displacer): Angiotensin II (human)

As is clear from the results in Table 8 above, the IC ₅₀ value of the angiotensin II type 1 receptor for this substance was 5000 nM or more. DuP753 used as a comparative substance has an IC ₅₀ value of 20 nM, whereas this substance having a concentration of 5000 nM or more has no inhibitory effect on the type 1 receptor. This type 1
The fact that this substance has no ability to bind to the receptor indicates that this substance is a compound having a completely different mechanism of action from conventionally known ACE inhibitors and angiotensin II antagonists.

Example 37: Antihypertensive effect This substance and a comparative substance were orally administered by gavage to rats with renal disease to examine the antihypertensive effect. Rats with renal disease were prepared by ligation of a branch of a renal artery according to a conventional method. That is, Sprag
Using a ue-Dawley female rat, the left renal hilum was exposed under anesthesia, leaving only one of the four second branches of the renal artery,
The remaining three were ligated respectively. One week later, the hilum of the right kidney (artery, vein, ureter) was ligated to prepare a rat having a renal function lowered to about 1/8 of normal. There were 8 rats in each group, and each group was administered with the specimen (20 mg / kg) and water as a control, and after 2 days, systolic blood pressure was measured using a blood pressure measurement device (UR5000, Ueda Seisakusho) by the tail cuff method. . Table 9 shows the average values of blood pressure.

[0084]

Table 9 Compound No. Blood pressure (mmHg) ──────────────────── 1 208 2 211 312 212 5 207 7 202 202 8 203 9 200 10 10 201 11 212 212 209 14 205 15 206 48 207 Control 210 DuP753 130

Comparative substance (DuP753) compared to the control group
Had a clear hypotensive effect, whereas this substance had virtually no effect on blood pressure.

Example 38: Renal function index value (for renal diseases
Action) Rats with renal disease were prepared in the same manner as in Example 37. Serum creatinine level, which is an index of renal function, with 8 animals per group,
Fifteen groups were prepared so that there was no difference in the urea nitrogen value. Rats were allowed to freely ingest food and water, and this group and comparative substance (DuP753) were administered to each group at a dose of 20 mg / kg · day, and to the control group, water alone was orally administered daily. Two weeks later, 0.2 ml of blood was collected from the carotid artery of the rat under anesthesia and centrifuged to obtain 25 μm of serum.
Serum creatinine (Scr) was measured by using a creatinine analyzer (manufactured by Beckman) using 1. Urea nitrogen (BU
N) was measured with a BUN analyzer (manufactured by Beckman) using 10 μl of serum obtained in the same manner. For creatinine clearance, after measuring serum creatinine, the rat was placed in a urine metabolism cage for 24 hours to collect urine, and then urinary creatinine concentration (Ucr) was measured by a creatinine analyzer, and total urine output (Uvol) was measured. Creatinine clearance (CCr) was calculated by the following formula. The results are shown in Table 10.

[0087]

Table 10 Compound No. Creatinine Urea Nitrogen Creatinine Clearance mg / dl mg / dl ml / min ─────────────────────────────────── 1 1 .5 75 0.38 2 1.6 80 0.32 3 1.6 79 0.33 5 1.6 80 0.32 7 1.6 80 0.32 8 1.6 81 0.30 9 1.7 82 0.30 10 1.7 84 0.29 11 1.6 77 0.34 12 1.6 80 0.30 14 1.5 78 78 0.35 15 1.5 77 77 0.35 48 1.6 760 .35 Control 2.0 100 0.22 DuP753 1.6 80 0.32 Serum creatinine and urea nitrogen levels, which increase with deterioration of renal failure, are clearly lower than those of the control by administration of this substance. , Creatinine clearance, which indicates renal function, is clearer than controls Improved. The effect is similar to that of the comparative substance, and this substance is known to have angiotensin II.
It was shown that there is substantially no receptor antagonism and blood pressure lowering action, and there is a renal disease improving action.

Example 39: Survival of renal disease animals
Action Renal disease rats were prepared in the same manner as in Example 37. Serum creatinine level, which is an index of renal function, with 8 animals per group,
Fifteen groups were prepared so that there was no difference in the urea nitrogen value. Rats were allowed to freely ingest food and water, and this group and comparative substance (DuP753) were administered to each group at a dose of 20 mg / kg · day, and to the control group, water alone was orally administered daily. Rats die of uremia as renal disease progresses, so the survival time of rats was examined as a comprehensive index of the improving effect on renal disease. The results are shown in Table 11.
The test period was 8 weeks. Therefore, when all the rats survived, the average survival time was 8 weeks, which is the upper limit.

[0089]

Table 11 Compound No. Average survival date (week) ────────────────────── 1 7.5 2 7.0 7.0 3 7.0 5 6.9 7 7.0 7.0 8 2.2 9 7.3 10 7.0 11 11 7.3 12 6.9 14 7.3 15 6.9 48 7.3 Control 5.0 DuP753 6.9 This substance reveals the survival time of renal disease rats. Extended to. The effect is similar to or higher than that of the comparative substance, and this substance has been shown to prolong the survival of rats dying from renal disease, with substantially no known angiotensin II receptor antagonistic action and hypotensive action. It was

Example 40 Compound No. 1 (10 mg), lactose (36 m
g), corn starch (150 mg), microcrystalline cellulose (29 mg), and magnesium stearate (5 m
g) are mixed and compressed into tablets (230 mg / tablet)
I made it.

[0091]

INDUSTRIAL APPLICABILITY The benzimidazole derivative of the general formula (I) or a pharmaceutically acceptable salt thereof according to the present invention has a very small effect on blood pressure, but has a sufficient effect on renal damage. Indicates. Therefore, the treatment of renal diseases is sufficiently performed by using such a drug, while the blood pressure is adjusted to a desired level by using an appropriate antihypertensive agent as necessary to prevent acute renal failure and the like. Appropriate treatment without problems is possible.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number within the agency FI Technical indication location A61K 31/54 31/55 C07D 235/10 403/10 235 (72) Inventor Michihito Ise Saitama 41-2 Shinmeicho, Kawagoe City 101 Yutaka Heights

Claims (5)

[Claims] 1. A compound of the general formula (I) [In the formula, R ¹ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms,
Or a haloalkyl group having 1 to 6 carbon atoms; R ² is -C
OOH, -COOR ¹¹ , -COR ¹² , -CON (R ¹³ )
₂ , -CONHR ¹⁴ , -CONH ₂ , -SO ₂ NH ₂ ,
_{^{-SO 2 N (R 15) 2}} , -SO 2 NHR 16, or -SO
₂ R ¹⁷ ; R ³ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, —OR ¹⁸ , —O (CH ₂ ) _m C ₆ H ₅ , — (CH
_{2) n C 6 H 5,} -NH 2, -NHR 19, -NHC (=
^{O) R 20, -N (R} 21) 2, -NHC (= O) (CH
_{2) p C 6 H 5,} -NHC (= O) CH (C 6 H 5)
_2, or a haloalkyl group having 1 to 6 carbon atoms; R ⁵ is _{^{-COOH, -COOR 22, -NH 2,}} -N (R 23)
_2, -NHR ^24, -OH, azole group, a -SO ₃ H, or ^{-OR 25; R 11, R 13} , R 14, R 15, R 16, R
¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ and R ²⁵ are each independently an alkyl group having 1 to 6 carbon atoms; R ¹²
And R ¹⁷ are each independently a 3- to 7-membered saturated aliphatic cyclic amino group in which a nitrogen atom, an oxygen atom or a sulfur atom may intervene; m is 0 or an integer of 1 to 6; n is 0 or an integer of 1 to 4; p is 0 or 1 to
Which is an integer of 4] or a salt thereof. 2. R ¹ is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, or a haloalkyl group having 1 to 5 carbon atoms; R ²
Is -COOH, -COOR ¹¹ , -COR ¹² , -CON
_{^{(R 13) 2, -CONHR 14}} , -CONH 2, -SO 2
_{NH 2, -SO 2 N (R} 15) 2, -SO 2 NHR 16, or be a -SO ₂ R ^17; R ³ is a hydrogen atom, a carbon number from 1 to 4
Alkyl _{^{group, -OR 18, -O (CH 2}} ) m C 6 H 5,
_{- (CH 2) n C 6} H 5, -NH 2, -NHR 19, -N
^{HC (= O) R 20,} -N (R 21) 2, -NHC (= O)
_{(CH 2) p C 6 H} 5, -NHC (= O) CH (C 6 H
₅ ) ₂ or a haloalkyl group having 1 to 4 carbon atoms; R ⁵
There _{^{-COOH, -COOR 22, -NH 2,}} -N
_{^{(R 23) 2, -NHR 24}} , -OH, azole group, -SO
₃ H, or —OR ²⁵ ; R ¹¹ , R ¹³ , R ¹⁴ , R ¹⁵ ,
R ¹⁶ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ and R ²⁵ are each independently an alkyl group having 1 to 4 carbon atoms; R ¹² and R ¹⁷ are each independently And is a 3- to 6-membered saturated aliphatic cyclic amino group in which a nitrogen atom, an oxygen atom or a sulfur atom may intervene; m is 0 or an integer of 1 to 4; n is 0 or 1 to 4 The benzimidazole derivative or its salt according to claim 1, wherein p is 0 or an integer of 1 to 4. 3. The benzimidazole derivative or a salt thereof according to claim 1, wherein R ² is at the 5-position or 6-position of the benzimidazole ring and R ⁵ is at the 4-position of the phenyl ring. 4. The benzimidazole derivative or a salt thereof according to claim 1, wherein R ² is at the 6-position of the benzimidazole ring and R ⁵ is at the 4-position of the phenyl ring. 5. A pharmaceutical composition comprising the compound represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.