JP3295277B2 - Antinephrotic agent and benzimidazole derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION This invention is, anti-renal disease agents, and new
It relates to benzimidazole derivatives or salts thereof. The anti-renal disease agent according to the present invention has a sufficient ameliorating effect on renal impairment despite substantially no or very weak antagonistic effect on angiotensin II receptor type 1 relating to blood pressure lowering effect. Have.

[0002]

2. Description of the Related Art In recent years, patients with impaired renal function have shown an increasing tendency. It is considered that the reason for this is that the aging of the population and changes in the living environment have led to delays in the development of accurate drugs for renal diseases. Therefore, there has been a strong demand for such therapeutic agents. That is,
For renal diseases such as nephritis, diabetic nephropathy, and renal failure, symptomatic treatment for treating lesions associated with the disease is still mainly performed.
That is, antihypertensives, diuretics, anti-inflammatory drugs, diet, exercise and the like. In particular, hypertension is often accompanied by renal disease, and hypertension is considered to be one of the causes of exacerbation of renal disease, so antihypertensive drugs are often used. Among them, many attempts have been made on drugs that suppress the production and action of angiotensin II. In other words, angiotensin II has the effect of increasing blood pressure, and is considered to be a cause of exacerbation of renal disease by promoting the proliferation of stromal cells of the kidney. This is because it is considered to be an improvement.

[0003] Specifically, a substance that inhibits an enzyme that converts angiotensin I to angiotensin II having a pressor action (namely, angiotensin converting enzyme: ACE), that is, an angiotensin converting enzyme inhibitor (ACE)
It has been reported that the use of antihypertensive agents (I) (eg, enalapril and captoril) lowers blood pressure and improves the progression of renal damage (J. Clin. Ph.).
armacol. , 30: 155-158,199.
0). Also, according to the description of US Pat. No. 5,071,867, renal impairment was improved by administering to rats with renal impairment a dose higher than the usual dose used for hypotensive purposes. It is said that even if the dose is carefully and gradually increased even in humans (patients), it is possible to tolerate a high dose and bring the benefit of treating renal impairment. However, on the other hand, it has been pointed out that side effects such as dry cough as a characteristic of this kind of drug and that there is a risk of causing acute renal failure due to lowering of blood pressure requires careful administration (Latest Medicine, 48: 1404- 1409, 1993).

[0004] Subsequently, an angiotensin II receptor antagonist (AGIIRA) has been developed as an antihypertensive agent. At present, two types of angiotensin II receptors, type 1 and type 2, are known. Of these, the action involving type 2 has not yet been fully elucidated, but since type 1 is known to be involved in blood pressure, antagonists of type 1 receptors have been the target of antihypertensive drug development. An antihypertensive agent that exhibits a strong antagonistic effect on angiotensin II receptor and has also been investigated for its effect on renal disease, is an imidazole derivative, 2-butyl-4.
-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 rats with renal impairment was effective for proteinuria and glomerulosclerosis, but was accompanied by a clear decrease in blood pressure (J. Clinical Invest., 90:76).
6-771, 1992). In addition, when this imidazole derivative was administered to hyperlipidemic rats, low doses had little effect on blood pressure and improved renal lesions, but higher doses more effective against renal lesions had a clear hypotensive effect. (Nephron, 65: 426-432, 1).
993).

Further, compounds having a structure similar to the above-mentioned imidazole derivatives are disclosed in, for example, JP-A-63-2386.
No. 8 and US Pat. Nos. 5,153,197 and 5,128.
No. 355 and No. 5,155,118. 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 states that it is effective against non-steroidal anti-inflammatory drug renal failure. However, all of these imidazole derivatives are characterized by strong angiotensin II receptor antagonism and have antihypertensive action.

On the other hand, as a compound having a benzimidazole skeleton, for example, JP-A-4-364171 discloses a compound useful for hypertension, heart disease, stroke, nephritis and the like. Also, 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 exhibit potent angiotensin II receptor antagonism and are characterized by hypotensive action. That is, the benzimidazole compound has an antihypertensive effect based on a strong type 1 receptor antagonism, and thus may cause acute renal failure when applied to renal diseases.

[0007]

As described above, in the treatment of renal diseases with conventional antihypertensive agents, basically, a drug having as strong an antihypertensive effect as desired is desired. However, in renal diseases, hypertension is an important condition to be corrected, but it is important to maintain proper blood pressure, not just to reduce it. For that purpose, it is necessary to adjust the blood pressure by combining the types and doses of antihypertensive agents according to the disease state. On the other hand, continuous treatment with a sufficient dose is desirable for renal disease itself. Therefore, as long as conventional drugs are used, it is basically necessary to use one drug to control blood pressure and treat renal disease effectively. It was impossible. The problem of acute renal failure when using antihypertensive agents as described above is one example. The present inventor, without having an effect on blood pressure, shows a sufficient ameliorating effect on renal impairment, and conducted intensive research to find a compound having a conventionally completely unknown property. Angiotensin II antagonizes the type 1 receptor at 1/100 to 1/1000 that of a standard antihypertensive agent and has no substantial antagonism. A new benzimidazole derivative that shows a sufficient improvement
A group of benzimidazole derivatives containing conductors has been found. The present invention is based on these findings.

[0008]

SUMMARY OF THE INVENTION Accordingly, the present invention is 1-
[[2-butyl-1- (4-carboxyphenyl) methyl
Rubenzimidazol-6-yl] carbonyl] morpho
Phosphorus (i.e., as shown in Table 1 below and Examples 35-39)
Compound No. 1), 1-[[2-butyl-1- (4-
(Carboxyphenyl) methylbenzimidazole-6
Yl] carbonyl] piperidine (ie, Table 1 below)
And Compound Nos. Shown in Examples 35 to 39. 2), 1-
[[2-butyl-1- (4-carboxyphenyl) methyl
Rubenzimidazol-6-yl] carbonyl] azeti
Gin (ie, as shown in Table 1 below and Examples 35-39)
Compound No. 3), 1-[[2-butyl-1- (4-
(Carboxyphenyl) methylbenzimidazole-6
Yl] carbonyl] pyrrolidine (ie, Table 1 below)
And Compound Nos. Shown in Examples 35 to 39. 4), N, N
-Diethyl-6- [2-butyl-1- (4-carboxy)
Phenyl) methylbenzimidazole] carboxamide
(That is, the chemical composition shown in Table 1 and Examples 35 to 39 described below.
Compound No. 5), [2-butyl-1- (4-methoxyca)
Rubonylphenyl) methylbenzimidazole] -5-
Carboxylic acid methyl ester (that is, Table 1 and
Compound Nos. Shown in Examples 35 to 39. 6), [2-buty
1- (4-methoxycarbonylphenyl) methyl
Nsimidazole] -6-carboxylic acid methyl ester
(That is, the chemical composition shown in Table 1 and Examples 35 to 39 described below.
Compound No. 7), [2-butyl-1- (4-carboxy)
Phenyl) methylbenzimidazole] -5-carvone
Acids (i.e., as shown in Table 1 below and Examples 35-39)
Compound No. 8), [2-butyl-1- (4-carboxy)
Cyphenyl) methylbenzimidazole] -6-carbo
Acid (ie, as shown in Table 1 below and Examples 35-39)
Compound No. 9), [2-butyl-1- (4-amino
Phenyl) methylbenzimidazole] -6-carvone
Acid methyl ester (ie, Table 1 below and Example 3)
Compound Nos. 5 to 39. 10), N-[[2-buty
Ru-1- (4-carboxyphenyl) methylbenziimi
Dazol-6-yl] carbonyl] piperazine
The compound N shown in Table 1 and Examples 35 to 39 described below.
o. 11), and 4-[[2-butyl-1- (4-cal
Boxyphenyl) methylbenzimidazole-6-i
L] carbonyl] thiomorpholine (that is,
Compound No. 2 shown in Example 2 and Examples 35 to 39. It is selected benzimidazole derived body or from the group consisting of 27), characterized in that it contains a salt which can be acceptable pharmaceutically, about substantially no anti-renal disease agent effect on blood pressure. Hereinafter, each compound included in the group, and described later
And a compound represented by the general formula (I)
It may be called. Further, the present invention provides a compound represented by the general formula ( I):

Embedded image [ Wherein , 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 -S
O ₂ N ( R ¹⁵ ) ₂ or —SO ₂ R ¹⁷ ; R ³ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, —O R ¹⁸ , —O (CH
_{2) q C 6 H 5,} - (CH 2) r C 6 H 5, -NH 2, -NH R
^{19, -NHC (= O) R} 20, -N (R 21) 2, -NHC
_{(= O) (CH 2)} s 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, -COO R 22, -NH 2}} , -N
_{^{(R 23) 2, -NH R}} 24, -OH, azole group, -SO ₃
H, or be ^{-O R 25; R 15, R} 18, R 19, R 20, R
R ²¹ , R ²² , R ²³ , R ²⁴ and R ²⁵ are each independently an alkyl group having 1 to 6 carbon atoms; R ¹⁷ is an alkyl group having a nitrogen atom, an oxygen atom or a sulfur atom; 7
Membered saturated aliphatic cyclic amino group; q is 0 or 1-6
R is 0 or an integer of 1 to 4; s is 0
Or an integer from 1 to 4] or a salt thereof. The benzimidazole derivative represented by the general formula ( I) or a salt thereof is a novel compound per se, and therefore, a pharmaceutical composition characterized by containing it, especially an anti-renal agent is also novel. is there.

In the present specification, the alkyl group includes a linear or branched alkyl group. For example, an alkyl group having 1 to 4 carbon atoms is, for example, a methyl group, an ethyl group, an n-propyl group, an i- Propyl group, n-butyl group, i-butyl group,
It is an s-butyl group or a t-butyl group. As the 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,
Examples thereof include a 1,2-dimethylpropyl group and a 1-ethylpropyl group. Examples of the alkyl group having 1 to 6 carbon atoms include an n-hexyl group and an i-hexyl group in addition to the above groups. Or a 2-ethylbutyl group can be mentioned.

A haloalkyl group having 1 to 6 carbon atoms is
The alkyl group having 1 to 6 carbon atoms has a halogen atom of 1 to 1
Three of them are substituted groups, and the halogen atom is, for example, a chlorine atom, a bromine atom, a fluorine atom or an iodine atom.
Preferred haloalkyl groups include, for example, 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, a nitrogen atom, an oxygen atom or a sulfur atom), for example, an imidazole group, an oxazole group, a thiazole group, a pyrazole group, an isoxazole group, and an isothiazole. Group, triazole group, oxadiazole group, thiadiazole group, tetrazole group, oxatriazole group or thiatriazole group. Preferred azole groups include, for example, a tetrazole group. 3
The 7 to 7 membered saturated aliphatic cyclic amino group may optionally be a heteroatom (eg, a nitrogen, oxygen or sulfur atom).
It is an alkyleneamino group which may be interposed, 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 —SO ₂ N (R ¹⁵ ) ₂ also -
Be SO ₂ R ^17; R ³ is a hydrogen atom, an alkyl group having 1 to 4 carbon _{^{atoms, -OR 18, -O (CH 2}} ) q C 6 H 5, - (C
H ₂ ) _r C ₆ H ₅ , —NH ₂ , —NHR ¹⁹ , —NHC (=
^{O) R 20, -N (R} 21) 2, -NHC (= O) (CH 2)
_s 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, an azole group, —SO ₃ H, or —OR ²⁵ ; R ¹⁵ , 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 ¹⁷ is optionally a nitrogen atom, an oxygen atom or sulfur atom of the intervention, 3-6 membered saturated aliphatic cyclic amino Q is 0 or an integer of 1 to 4; r is 0 or an integer of 1 to 4; s is 0 or 1 to 4
The compound represented by the general formula (I) or a salt thereof, which is an integer of

[0012] In the general formula (I), there R ² is a 5- or 6-position of the benzimidazole ring, more preferably a compound or a salt thereof at the 4-position of R ⁵ is a phenyl ring, R ²
Is more preferably a compound or a salt thereof in which is at the 6-position of the benzimidazole ring and R ⁵ is at the 4-position of the phenyl ring.

[0013] Salts of the substance include salts with inorganic or organic acids and salts with inorganic or organic bases, and pharmaceutically acceptable salts are preferred. As the acid addition salt, for example, hydrochloride, sulfate, methanesulfonate or p-toluenesulfonate, and further, salts with dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, maleic acid or fumaric acid And a salt with a monocarboxylic acid such as acetic acid, propionic acid or butyric acid. Inorganic bases suitable for forming salts of this substance are, for example, hydroxides, carbonates and bicarbonates of ammonia, sodium, lithium, calcium, magnesium, aluminum and the like.
As salts with organic bases, for example, mono-, di-, such as methylamine, dimethylamine, 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 the present substance which is an active ingredient in the anti-renal disease agent of the present invention, Compound No. 1 to No. 30
Are shown in Tables 1 to 3 below, and the results of elemental analysis and mass analysis of those compounds are shown in Tables 4 to 6. In addition, each compound shown in the following Tables 1-3 is referred to as Compound No. in the following description of this specification. May be indicated by In each of the following tables, Me is a methyl group, Et is an ethyl group, P
r is a propyl group, Bu is a butyl group, cycNC 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, cycNC ₄ H ₈ is 1
- pyrrolidinyl group, cycNC ₃ H ₆ 1-azetidinyl group, cycN ₂ C ₄ H ₉ denotes a 1-piperazinyl group.

[0015]

TABLE 1 ^{No. R 1 R 2 R 3 R} 5 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 H 4-COOH C 24 H 27 N 3 O 3 5 nBu 6-CON _{(Et) 2 H 4-COOH} C 24 H 29 N 3 O 3 6 nBu 5-COOMe H 4-COOMe C 22 H 24 N 2 O 4 7 nBu 6-COOMe H 4-COOMe C 22 H 24 N 2 O 4 8 nBu 5-COOH H 4-COOH C ₂₀ H ₂₀ N ₂ O ₄ 9 nBu 6-COOH H 4-COOH C ₂₀ H ₂₀ N ₂ O ₄ 10 nBu 6-COOMe H 4-NH ₂ C ₂₀ H ₂₃ N _{3 O 2 11 nBu 6-COcycN 2} C 4 H 9 H 4-COOH C 24 H 28 N 4 O 3 12 nBu 6-SO 2 cycNC 4 H 8 OH 4-COOH C 23 H 27 N 3 O 5 S 13 nBu 6 _{-SO 2 cycNC 4 H 8 O Me} 4-COOH C 24 H 29 N 3 O 5 S 14 nBu 6-SO 2 cycNC 4 H 8 OH 4-NH 2 C 22 H 28 N 4 O 3 S 15 nBu 6-SO _{2 cycNC 4 H 8 OH 4-} OH C 22 H 27 N 3 O 4 S 16 nBu 6-SO 2 cycNC 4 H 8 OH 4-OMe C 23 H 29 N 3 O 4 S 17 nBu 6-SO 2 cycNC 4 H ₈ OH 4-NHMe C ₂₃ H ₃₀ N ₄ O ₃ S 18 nBu 6-SO ₂ cycNC ₄ H ₈ OH 4-N (Me) ₂ C ₂₄ H ₃₂ N ₄ O ₃ S 19 nBu 6-SO ₂ cycNC ₄ H ₈ O Me 4-COOMe C ₂₅ H ₃₁ N ₃ O ₅ S 20 nBu 6-SO ₂ cycNC ₄ H ₈ SH 4-COOH C ₂₃ H ₂₇ N ₃ O ₄ S ₂ 21 nBu 6-SO ₂ cycN ₂ C ₄ H ₉ H 4-COOMe C ₂₄ H ₃₀ N ₄ O ₄ S 22 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 23 nBu 6-SO ₂ N (Et) ₂ H 4-COOH C ₂₃ H ₂₉ N ₃ O ₄ S 24 nBu 6-SO ₂ N (nPr) _{2 H 4-COOMe C 26 H 35} N 3 O 4 S 25 nPr 6-SO 2 cycNC 4 H 8 OH 4-COOH C 22 H 25 N 3 O 5 S 26 Et 6-SO 2 cycNC 4 H 8 OH 4-COOH C ₂₁ H ₂₃ N ₃ O ₅ S 27 nBu 6-COcycNC ₄ H ₈ SH 4-COOH C ₂₄ H ₂₇ N ₃ O ₃ S

[0017]

[Table 3] No. R ¹ R ² R ³ R ⁵ Chemical formula 28 nBu 6-SO ₂ cycNC ₃ H ₆ H 4-NH ₂ C ₂₁ H ₂₆ N ₄ O ₂ S 29 nBu 6-SO ₂ cycN ₂ C ₄ H ₉ H 4-NH ₂ C ₂₂ H ₂₉ N ₅ O ₂ S 30 nBu 6-SO ₂ cycNC ₅ H ₁₀ H 4-NH ₂ C ₂₃ H ₃₀ N ₄ O ₂ S

[0018]

[Table 4] No. Molecular weight Elemental analysis Mass spectrometry Calculated value Actual 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) 4 405.50 71.09 6.71 10.36 71.36 6.61 10.63 405 (EI) 5 407.51 70.74 7.17 10.31 70.51 7.34 10.08 407 (EI) 6 380.45 69.46 6.36 7.36 69.77 6.22 7.67 380 (EI) 7 380.45 69.46 6.36 7.36 69.50 6.68 7.40 380 (EI) 8 352.39 68.17 5.72 7.95 68.18 5.54 7.96 352 (EI) 9 352.39 68.17 5.72 7.95 67.99 5.49 7.77 352 (EI) 10 337.42 71.19 6.87 12.45 71.12 6.65 12.38 337 (EI) 11 420.51 68.55 6.71 13.32 68.83 6.46 13.60 420 (EI) 12 457.55 60.38 5.95 9.18 60.31 6.30 9.11 457 (EI) 13 471.57 61.13 6.20 8.91 61.27 6.04 9.05 471 (EI) 14 428.55 61.66 6.59 13.07 61.54 6.59 12.95 428 (EI) 15 429.54 61.52 6.34 9.78 61.54 6.28 9.80 429 (EI) 16 443.56 62.28 6.59 9.47 62.23 6.80 9.42 443 (EI) 17 442.58 62.42 6.83 12.66 62.23 6.95 12.4 7 442 (EI) 18 456.61 63.13 7.06 12.27 63.01 6.70 12.15 456 (EI) 19 485.60 61.84 6.43 8.65 61.75 6.29 8.56 485 (EI) 20 473.61 58.33 5.75 8.87 58.36 5.76 8.90 473 (EI) 21 470.59 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 Actual value C (%) H (%) N (%) C (%) H (%) N (%) 22 427.52 61.81 5.89 9.83 61.70 5.99 9.72 427 (EI ) 23 443.56 62.28 6.59 9.47 62.13 6.27 9.32 443 (EI) 24 485.64 64.30 7.26 8.65 64.38 6.91 8.73 485 (EI) 25 443.52 59.58 5.68 9.47 59.78 5.59 9.67 443 (EI) 26 429.49 58.73 5.40 9.78 58.42 5.26 9.47 429 (EI) 27 437.56 65.88 6.22 9.60 65.86 6.24 9.58 437 (EI)

[0020]

[Table 6] No. Molecular weight Elemental analysis Mass spectrometry Calculated value Actual value C (%) H (%) N (%) C (%) H (%) N (%) 28 398.52 63.29 6.58 14.06 63.19 6.58 13.96 398 (EI ) 29 427.57 61.80 6.84 16.38 61.76 7.05 16.34 427 (EI) 30 426.58 64.76 7.09 13.13 64.96 7.09 13.33 426 (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. Synthesis route [1]:

(Equation 1)

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

[1]-(b) Step The compound of the general formula (12) is added to the R ² group (R
² is the same as defined above), for example, a condensing agent such as N, N′-dicyclohexylcarbodiimide (DCCI), a solvent such as N, N-dimethylformamide (DMF), acetonitrile, chloroform, Optionally, 1-hydroxybenzotriazole (H
OBt) and the like, and at 10 to 40 ° C, 5-48
The reaction is carried out for a time to obtain a compound of the general formula (13) (wherein R ¹ , R ² and R ³ have the same meaning as described above). -CO
Examples of the compound capable of converting an OH group into an R ² group include, for example, 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 according to the intended R ² group.

[1]-(c) Step A compound of the general formula (13) is added to the compound of the general formula (13) (where Y is a removable group, for example, OH, OSO ₂ CH ₃ , OSO
_{2 C 6 H 4 -4-CH} 3, OSO 2 CF 3, or Cl,
A halogen such as I or Br, and R ⁴ is optionally protected R ⁵ or a nitro group).
The reaction is performed at ６０60 ° C. for 5 to 75 hours to obtain a compound of the general formula (15).

[1]-(d) Step The compound of the general formula (15) is converted, if necessary, from R ⁴ to R ⁵ by a method suitable for lower alcohols such as methanol, ethanol and butanol, diethyl ether and tetrahydrofuran. , Dioxane or the like, or a mixed solvent thereof, an aqueous alkali solution is added thereto, the mixture is treated at a temperature of 10 ° C. to the boiling point of the solvent or lower, and after cooling, the compound of the formula (I) (R ¹ , R ² , R ³ , and R ⁵
Is the same as described above). Salts of the compounds of the general formula (I), especially pharmaceutically acceptable salts thereof, can be prepared by the synthesis route [1]
In step (d), the solvent can be evaporated or the solution can be concentrated to dryness by using an acid or a base and the like in an equivalent amount to the compound of the general formula (15) to obtain a purified product. In the step of obtaining the compound of the general formula (I) in this synthesis route [1], the compound of the general formula (11) is reacted with the compound of the general formula (14), and then the step (a) and the step (b) Steps and steps corresponding to step (d) can also be performed.

Synthesis route [2]:

(Equation 2)

[2] Step (a) The compound of the general formula (21) is dissolved in a solvent such as dichloromethane to convert a —SO ₂ Cl group into an R ² group (R ² has the same meaning as described above). An organic solution of a compound that can be used (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 described above). Examples of the compound capable of converting a —SO ₂ Cl group into an R ² group include, for example, 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 according to the intended R ² group. Compounds of general formula (21) are described, for example, in Chem. Ber. , 24: 319
0 (1891).

[2]-(b) Step The compound of the general formula (23) is obtained by dissolving the compound of the general formula (22) in a solvent such as dioxane, adding aqueous ammonia and treating at 50 to 120 ° C.

[2]-(c) Step The compound of the formula (23) is dissolved in a solvent such as DMF, dichloromethane, tetrahydrofuran, acetone, chloroform or pyridine, and the amino group is converted to a R ¹ -CONH group (R
⁽¹ is as defined above), and the mixture is reacted at 0 to 80 ° C. for 5 to 40 hours to obtain a compound of the general formula (24). Amino group is represented by R ¹ -CON
Compounds that can be converted to H groups include, for example, valerate 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 according to the intended R ¹ group.

[2]-(d) Step An alcoholic suspension of Pd / C is added to an alcohol solution of the compound of the general formula (24), and hydrazine monohydrate is added thereto for treatment. 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 defined above) Is added and reacted at 20-80 ° C. for 10-40 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 formula (27) is converted from R ⁴ to R ⁵ by an appropriate 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 and then remove the solvent. If necessary, an alcohol, tetrahydrofuran or sodium hydroxide aqueous solution is added to the residue, the mixture is treated for 1 to 20 hours, and after cooling, the compound of the general formula (I) (R ¹ , R ² ,
R ³ and R ⁵ are as defined above.

Synthesis 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 above) is added to a lower alcohol such as methanol, ethanol or butanol, diethyl ether, tetrahydrofuran. And an ether such as dioxane, or a mixed solvent thereof, is treated with an aqueous alkali solution at a temperature of 10 ° C. to the boiling point of the solvent or lower, cooled, and subjected to acid precipitation to obtain a compound represented by the general formula (32) (where R ¹ and R ³ are Has the same meaning as described above). The compound of the general formula (31) is described, for example, in J. Am. Med. Chem. , 36: 1772-17.
84 (1993).

[3]-(b) Step The compound of the general formula (32) is replaced with a -COOH group by an R ² group (R ²
Are the same as those described above), for example, a condensing agent such as DCCI, a solvent such as DMF, acetonitrile, chloroform and the like, and optionally an auxiliary such as HOBt, and the like. The reaction is carried out for up to 48 hours to obtain a 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
Compounds which can be converted into ² groups, for example, when the R ² group is a carbonyl morpholine, for example, a morpholine. In the case of other R ² groups,
Those skilled in the art can appropriately select them according to the desired R ² group.

[3]-(c) Step An alcoholic suspension of Pd / C is added to an alcohol solution of the compound of the general formula (33), and hydrazine monohydrate is added thereto for treatment. 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 defined above) Is added 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).

[3]-(e) Step The compound of the formula (36) is converted, if necessary, from R ⁴ to R ⁵ by an appropriate 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 and then remove the solvent. For an additional alcohol to the residue optionally added tetrahydrofuran or sodium hydroxide solution for 1 to 20 hours, the formula by acid precipitation after cooling ^{(I) (R 1, R} 2, R 3, and R ⁵ Has the same meaning as described above).

[0039] Salts real Shitsumata is capable of acceptable pharmaceutically which is an active ingredient in anti kidney disease agent of the present invention, without having an effect on blood pressure, a sufficient improvement effect on renal dysfunction Show. Therefore, the present substance is useful as an anti-renal disease agent having substantially no effect on blood pressure. Nephritis,
It is useful for nephropathy, renal failure, nephrotic syndrome, asymptomatic proteinuria, hematuria, diabetic nephropathy, drug-induced nephropathy, urinary tract infection, prostatitis and the like. The substance is administered orally or parenterally (eg, transdermally, intravenously, intraperitoneally, etc.) to mammals including humans. 500mg / kg of this substance in mice
The dose was orally administered and the amount was observed for one week, but no death was observed.

This substance can be made into a preparation, for example, powder, tablet, granule, capsule, suppository, injection, oral liquid, etc. by adding one or more pharmaceutically acceptable additives. it can. As additives, for example, magnesium stearate, talc, lactose, dextrin, starches, methylcellulose, fatty acid glycerides, water, propylene glycol, macrogol, alcohol, crystalline cellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose , Carmellose, povidone, polyvinyl alcohol, calcium stearate and the like. Further, a coloring agent, a stabilizing agent, an antioxidant, an antiseptic, a pH adjusting agent, a tonicity agent, a solubilizing agent, and / or a soothing agent may be added as necessary. Granules, tablets or capsules are coated bases, for example, hydroxypropyl methylcellulose,
It can also be coated with hydroxypropyl methylcellulose phthalate or the like.

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

[0042]

[Action] The present inventors have developed angiotensin using a unique method.
The structure of II was analyzed in solution, and the properties of various compounds were studied while considering the degree of affinity. That is, antagonistic force for the type 1 receptor of angiotensin II, which is known to be related to the hypotensive effect, renal disorder improving action in renal failure animals, was added a detailed study about such effects on blood pressure, genuine Shitsumata Is the salt
It has been found that it has desired properties completely different from those of the conventionally known antihypertensive compounds. As described above, the present substance or a salt thereof has an antagonistic effect on angiotensin II type 1 receptor that is 1/100 to 1/1000 or less of a conventionally known antagonist having a standard effect as an antihypertensive agent,
Despite no substantial antagonism, it shows an improving effect on renal impairment. The existence of a compound having such properties is surprising that cannot be predicted at all from existing knowledge. The exact reasons for how the substance exerts such effects are currently unknown, and the present invention is not limited by the following inferences, but may, for example, result in exacerbation of renal damage. It is presumed that the specific antagonistic effect on angiotensin II receptors (new known receptors other than type 1 and type 2) which are involved in the action such as renal stromal cell proliferation, accumulation in the kidney, and the like. It may also be due to an entirely different mechanism of action that is not angiotensin II receptor antagonism. Even if the substance is classified as an angiotensin II receptor antagonist, and if not, anyway,
Known angiotensin with strong receptor antagonism and antihypertensive action, as conventionally developed as an antihypertensive agent
II receptor antagonists are compounds with completely different properties. That is, real quality is a point of action and effect, and a novel in any of practicality point as a medicament. In addition, among the present substances, the benzimidazole derivative represented by the general formula ( I) has not existed conventionally in terms of chemical structure, action and effect, and practicality as a medicine. It is a new compound.

[0043]

EXAMPLES The present invention will be described below in more detail with reference to examples, but these examples do not limit the scope of the present invention. Example 1: 2-butyl-5-benzimidazole carb
Preparation of acid ([1]-(12) -1): [1]-(a)
Step 2-Methyl 2-butyl-5-benzimidazolecarboxylate ([1]-(11) -1) (15.0 g) was dissolved in methanol (75.5 ml) and a 1N aqueous NaOH solution (75.
5 ml) and left in a 70 ° C. oil bath for 2.5 hours. After cooling, the reaction solution was concentrated, and 1N HCl aqueous solution (80 ml) was added to perform 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: 0.1
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-butylbenziimi)
Dazol-5-yl) carbonyl] morpholine ([1]
Preparation of-(13) -1): Step [1]-(b) Step (1)-(12)-
1) A solution of (0.23 g) in acetonitrile (100 m
l) to DCCI (12.58 g), HOBt (8.24)
g) and morpholine (5.3 ml).
Stir for 9 hours. The reaction solution was filtered to remove insoluble components. The residue was concentrated to give a dark green oil (24.15 g). This oil was purified by silica gel column chromatography (Kieselgel 60, 280 g, CHCl ₃ /
Purification with CH ₃ OH = 30/1) afforded the title compound (1
2.36 g) were 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)

[0045]Example 3: 1-[[2-butyl-1- (4
-Methoxycarbonylphenyl) methylbenzimidazo
Yl-6-yl] carbonyl] morpholine ([1]-
Preparation of (15) -1): Step [1]-(c) Compound ([1]-(13)-) prepared in Example 2
1) A solution of (0.25 g) in dry DMF (2.5 ml)
In addition, methyl 4-bromomethylbenzoate (0.30)
g) and anhydrous K_Two CO_Three (0.18 g) and room temperature
For 13 hours. Pour the reaction into water and add CHCl
_Three , And washed with a saturated aqueous solution of NaCl. This extraction
Discharge the Na_Two SO_Four And concentrated to a pale yellow oil
(0.58 g). This oil is applied to a silica gel column.
Chromatography (Lobar column gr
oβe C; benzene / acetone = 3/1 to 1/1)
And purified the title compound (0.16 g) as a white foam.
As obtained.¹ H-NMR (500 MHz, CDCl_Three ) 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) isomer 1-[[2-butyl-1- (4-methoxyca)
Rubonylphenyl) methylbenzimidazole-5-i
[Carbonyl] morpholine (0.21 g) in the form of white foam
Obtained as material. The structure of both regioisomers is NOE difference spec.
It was decided in torr.

[0046]Example 4: 1-[[2-butyl-1- (4
-Carboxyphenyl) methylbenzimidazole-6
-Yl] carbonyl] morpholine ([1]-(I)-
1) Preparation of (Compound No. 1): [1]-(d) Step
Step Compound ([1]-(15)-) prepared in Example 3
1) (0.15 g) was added to methanol (0.75 ml) and
Dissolve in 1N NaOH aqueous solution (0.75 ml)
Leave for 15 hours at room temperature. The reaction solution was concentrated and 1N HCl was added.
An aqueous solution (0.8 ml) was added for acid precipitation. Precipitated crystals
Is 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 ° C¹ H-NMR (500 MHz, CDCl_Three ) 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) Compound ([1]-(15)-) prepared in Example 3 above.
1) is subjected to acid precipitation in step [1]-(d).
The reaction mixture was concentrated and the evaporation residue was purified.
Thorium salt was obtained.

Example 5 1-[(2-butylbenziimi)
Dazol-5-yl) carbonyl] piperidine ([1]
Preparation of-(13) -2): Step [1]-(b) The compound ([1]-(12)-) prepared in Example 1 above
1) To a solution of (0.31 g) in acetonitrile (3.1 ml) was added DCCI (0.38 g), HOBt (0.25 g).
g) and piperidine (0.18 ml).
Stir for 5 hours. The reaction solution was filtered to remove insolubles and concentrated to obtain a yellow-green oil. 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)

[0048]Example 6: 1-[[2-butyl-1- (4
-Methoxycarbonylphenyl) methylbenzimidazo
Yl-6-yl] carbonyl] piperidine ([1]-
Preparation of (15) -2): Step [1]-(c) Compound ([1]-(13)-) prepared in Example 5
2) A solution of (0.32 g) in dry DMF (3.2 ml)
In addition, methyl 4-bromomethylbenzoate (0.38
g) and anhydrous K_Two CO_Three (0.23 g) at room temperature
Stirred for 19.5 hours. The reaction solution was poured into water and CHC
l_Three Extracted. Wash extract with saturated aqueous NaCl
And Na_Two SO_Four And concentrated to a yellow oil (0.
72 g) were obtained. This is a silica gel column chromatograph.
Fee (LiChroprep Si60, 70g,
Nzen / acetone / methanol = 80/20/3)
To give the title compound (0.076 g) as a white foam.
As obtained.¹ H-NMR (500 MHz, CDCl_Three ) 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)

[0049]Example 7: 1-[[2-butyl-1- (4
-Carboxyphenyl) methylbenzimidazole-6
-Yl] carbonyl] piperidine ([1]-(I)-
2) Preparation of (Compound No. 2): [1]-(d) Step
Step The compound ([1]-(15)-) prepared in Example 6 above
2) (0.061 g) in methanol (0.30 ml)
And 1N NaOH aqueous solution (0.30 ml).
Leave for 21 hours at room temperature. The reaction solution was concentrated and 1N HCl was added.
An aqueous solution (0.8 ml) was added for acid precipitation. Precipitated crystals
Was 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 ° C¹ H-NMR (500 MHz, CDCl_Three ) 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-butylbenziimi
Dazol-5-yl) carbonyl] azetidine ([1]
Preparation of-(13) -3): [1]-(b) step The compound ([1]-(12)-) prepared in Example 1 above
1) (1.33 g) of acetonitrile (11.2 ml)
DCCI (1.39 g), HOBt (0.91 g) were added to the solution.
g) and azetidine (0.45 ml) were added at room temperature.
Stir for 5 hours. The reaction solution was filtered to remove insolubles and concentrated to obtain a yellow-green oil. This was 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)

[0051]Example 9: 1-[[2-butyl-1- (4
-Methoxycarbonylphenyl) methylbenzimidazo
Yl-6-yl] carbonyl] azetidine ([1]-
Preparation of (15) -3): Step [1]-(c) Compound ([1]-(13)-) prepared in Example 8 above
3) A solution of (1.42 g) in dry DMF (14.1 ml)
In addition, methyl 4-bromomethylbenzoate (1.89)
g) and anhydrous K_Two CO_Three (1.15 g) at room temperature
Stirred for 19.5 hours. The reaction solution was poured into water and CHC
l_Three Extracted. Wash extract with saturated aqueous NaCl
And Na_Two SO_Four And concentrated to give a yellow oil
Was. This was subjected to silica gel column chromatography (Li
Cropprep Si60, 200g, benzene / a
(Seton = 1/1) to give the title compound ([1]-
(15) -3) (0.41 g), compound ([1]-(1
5) -4) (0.11 g), the mixture (1.17 g)
Obtained as a colored foam. Compound ([1]-(15)-
The structure of 3) and the compound ([1]-(15) -4) is NO
Determined by E difference spectrum. Compound ([1]-
(15) -4) is 1-[[2-butyl-1- (4-methoxy)
(Xycarbonylphenyl) methylbenzimidazole-
5-yl] carbonyl] azetidine.¹ H-NMR (500 MHz, CDCl_Three ) 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)

[0052]Example 10: 1-[[2-butyl-1-
(4-carboxyphenyl) methylbenzimidazole
-6-yl] carbonyl] azetidine ([1]-(I)
-3) Preparation of (Compound No. 3): [1]-(d)
Up The compound prepared in Example 9 ([1]-(15)-
3) (0.39 g) was added to methanol (2.0 ml) and 1
Dissolve in normal NaOH aqueous solution (2.0 ml) and add
Left for 1 hour. Concentrate the reaction solution and add 1N HCl aqueous solution
Was added for acid precipitation. The precipitated crystals are filtered, washed with water, and dried.
Dry to give the title compound (0.15 g) as white crystals.
Was. Melting point: 120.0-122.0 ° C¹ H-NMR (500 MHz, CDCl_Three ) 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)

[0053]Example 11: 1-[(2-butylbenzi
Midazol-5-yl) carbonyl] pyrrolidine
Preparation of ([1]-(13) -5): [1]-(b) Step
Up Compound ([1]-(12)-) prepared in Example 1
1) Dissolve (0.92 g) in acetonitrile (9.2 ml)
DCCI (1.13 g), HOBt (0.74
g) and pyrrolidine (0.46 ml) were added.
Stir for 5 hours. Filter the reaction mixture to remove insolubles and concentrate
To give a yellow-green oil. This is a silica gel column
Chromatography (Kieselgel 60, 50)
g, CHCl_Three/ Acetone = 1/1)
The compound (1.04 g) was obtained as a pale yellow foam.¹ H-NMR (500 MHz, CDCl_Three ) 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)

[0054]Example 12: 1-[[2-butyl-1-
(4-methoxycarbonylphenyl) methylbenzimi
Dazol-6-yl] carbonyl] pyrrolidine ([1]
Preparation of-(15) -5): Step [1]-(c) Compound ([1]-(13)-) prepared in Example 11
5) A solution of (1.04 g) in dry DMF (10.4 ml)
In addition, methyl 4-bromomethylbenzoate (1.31)
g) and anhydrous K_Two CO_Three (0.79 g) at room temperature
Stirred for 19.5 hours. The reaction solution was poured into water and CHC
l_Three Extracted. Wash extract with saturated aqueous NaCl
And Na_Two SO_Four And concentrated to give a yellow oil
Was. This was subjected to silica gel column chromatography (Li
Cropprep Si60, 180g, benzene / a
(Seton = 2/3) to give 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
5) -5) and the structure of the compound ([1]-(15) -6)
Was determined based on the NOE difference spectrum. Compound
([1]-(15) -6) is 1-[[2-butyl-1-
(4-methoxycarbonylphenyl) methylbenzimi
Dazol-5-yl] carbonyl] pyrrolidine.¹ H-NMR (500 MHz, CDCl_Three ) Δ: 0.9
2 (t, 3H), 1.42 (sext, 2H), 1.7
9-1.85 (m, 6H), 1.92-1.95 (m, 6H)
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-carboxy)
(Ciphenyl) methylbenzimidazol-6-yl] ca
Rubonyl] pyrrolidine ([1]-(I) -5) (compound
No. Preparation of 4): [1]-(d) Step The compound ([1]-(15)-prepared in Example 12 above)
5) (0.30 g) was added to methanol (1.5 ml) and 1
Dissolve in normal aqueous NaOH (1.5 ml) and add
Left for 1 hour. The reaction solution was concentrated, and 1N HCl aqueous solution was added to perform acid precipitation. The precipitated crystals were filtered, washed with water, and dried to give the title compound No. 4 (0.088 g) was obtained as white crystals. Melting point: 206.0-207.0 ° C. ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 0.85
(T, 3H), 1.33 (sext, 2H), 1.74
(Quint, 2H), 1.87 (dt, 2H), 1.
97 (dt, 2H), 2.73 (t, 2H), 3.5
2, 3.69 (t, each 2H), 5.43 (s,
2H), 6.88 (d, 2H), 7.44 (d, 1
H), 7.69 (d, 2H), 7.78 (d, 1H),
8.01 (s, 1H)

Example 14: N, N-diethyl-5- (2
-Butylbenzimidazole) carboxamide ([1]
Preparation of-(13) -7): [1]-(b) Step The compound ([1]-(12)-) prepared in Example 1 above
1) (1.23 g) of acetonitrile (12.2 ml)
DCCI (1.51 g), HOBt (0.99) were added to the solution.
g) and diethylamine (0.76 ml) were added, and the mixture was stirred at room temperature for 15 hours. Filter the reaction solution to remove insolubles,
Concentration gave a yellow-green oil. This was 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)

[0057]Example 15: N, N-diethyl-6- [2
-Butyl-1- (4-methoxycarbonylphenyl) methyl
Tilbenzimidazole] carboxamide ([1]-
Preparation of (15) -7): Step [1]-(c) Compound ([1]-(13)-) prepared in Example 14
7) A solution of (1.75 g) in dry DMF (17.5 ml)
In addition, methyl 4-bromomethylbenzoate (2.19)
g) and anhydrous K_Two CO_Three (1.33 g) at room temperature
Stirred for 19.5 hours. Pour the reaction solution into water and add
Extracted with chill. Wash extract with saturated aqueous NaCl
And Na_Two SO_Four And concentrated to give a yellow oil
Was. This was subjected to silica gel column chromatography (Li
Cropprep Si60, 200g, benzene / a
(Seton = 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
5) -7) and the structure of the compound ([1]-(15) -8)
Was determined based on the NOE difference spectrum. Compound
([1]-(15) -8) is N, N-diethyl-5-
[2-butyl-1- (4-methoxycarbonylphenyl)
L) methylbenzimidazole] carboxamide
You.¹ H-NMR (500 MHz, CDCl_Three ) 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) methylbenzimidazo
L] carboxamide ([1]-(I) -7) (compound N
o. Preparation of 5): [1]-(d) Step The compound prepared in the above Example 15 ([1]-(15)-
7) (0.59 g) was added to methanol (3.0 ml) and 1
Dissolve in a specified aqueous NaOH solution (3.0 ml) and add
Left for 1 hour. The reaction solution was concentrated, and 1N HCl aqueous solution was added to perform acid precipitation. The precipitated crystals were filtered, washed with water, and dried to give the title compound (Compound No. 5 ) (0.36 g)
Was obtained as white crystals. Melting point: 195.0-197.0 ° C. ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 0.86
(T, 3H), 1.10, 1.24 (bs, each
3H), 1.36 (sext, 2H), 1.76 (qu
int, 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-methoxycarbo)
Nylphenyl) methylbenzimidazole] -5-car
Bonic acid methyl ester (Compound No. 6) and [2-butyric acid]
1- (4-methoxycarbonylphenyl) methyl
Nsimidazole] -6-carboxylic acid methyl ester
Preparation of (Compound No. 7) In 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) 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
1), dried over anhydrous MgSO ₄ and concentrated to give a pale yellow-green viscous material (6.20 g). This is EtOA
c (10 ml) and benzene (30 ml) were added, dissolved by heating, and then allowed to cool. 7 (1.76 g) was obtained as colorless crystals. On the other hand, the residue obtained by concentrating the filtrate is subjected to silica gel column chromatography (Kiese).
lgel 60,200 g, benzene / EtOAc = 4
/ 1) and recrystallized from EtOAc / hexane to give Compound No. 6 (1.27 g) was obtained as colorless crystals. Compound No. 6 melting point: 98.0-100.0 ° C. ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 0.92
(T, 3H), 1.42 (sext, 2H), 1.82
(Quint, 2H), 2.83 (t, 2H), 3.9
0 (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. 7 melting point: 134.0-137.5 ° C ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 0.91
(T, 3H), 1.41 (sext, 2H), 1.82
(Quint, 2H), 2.82 (t, 2H), 3.9
0 (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-carboxyphene)
Nyl) methylbenzimidazole] -5-carboxylic acid
Preparation of Compound No. 8 Compound No. 8 prepared in Example 17 above was prepared. 6 (0.60
g) was dissolved in methanol (15 ml) and a 1 N aqueous solution of NaOH (2.5 ml) and stirred at room temperature for 16 hours. The reaction mixture was concentrated, and water (30 ml) was added to the residue.
Acid precipitation was performed with a normal aqueous HCl solution. The precipitated solid was separated by filtration to obtain a colorless solid (0.54 g). This is called CH ₃ CN /
The compound was recrystallized from THF to give Compound No. 8 ([1]-(I)
-10) (0.27 g) as colorless crystals. Melting point: 255.0-257.0 ° C. ¹ H-NMR (500 MHz, d ₆ -DMSO) δ: 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-carboxyphenyl)
Nyl) methylbenzimidazole] -6-carboxylic acid
Preparation of (Compound No. 9) Compound No. 9 prepared in Example 17 above. 7 (0.91
g) with methanol (4 ml), THF (4 ml), 1
NaOH aqueous solution (3.6 ml) and water (3.6 m
l) at 80 ° C., cooled to room temperature and stirred for 16 hours. The solvent was distilled off under reduced pressure, and a 1N aqueous HCl solution (3.
6 ml) to give a precipitated solid (0.71 g). This was recrystallized from CH ₃ CN / THF to give Compound No. 9 (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.
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
Preparation of 2) -15): [2]-(a) Step 4-chloro-3-nitrobenzenesulfonyl chloride ([2]-(21) -15) (50.0 g) was converted to CH ₂ C.
This was dissolved in l ₂ (500 ml) and cooled with ice. A solution of morpholine (33.1 g) in CH ₂ Cl ₂ (30 ml) was added dropwise over 1 hour. The mixture was stirred for 1 hour under ice cooling and for 1 hour at room temperature. The reaction solution was washed with distilled water and a saturated aqueous solution of NaCl, 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 needles. 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
3) Preparation of -15): [2]-(b) Step The compound prepared in the above Example 20 ([2]-(22)-
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) three times, and the organic layer was dried over Na ₂ SO ₄ . The solvent was distilled off, and the title compound (4.51 g) was obtained.
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-ba
Relamidobenzene) sulfonyl] morpholine ([2]-
Preparation of (24) -15): [2]-(c) Step The compound prepared in the above Example 21 ([2]-(23)-
15) (22.8 g) was dissolved in anhydrous pyridine (150 ml), and dimethylaminopyridine (DMAP) (11.
6 g) was added and the mixture was ice-cooled. To this solution, valeric chloride (28.3 ml) was added dropwise over 30 minutes, stirred at room temperature for 30 minutes, and stirred at 60 ° C. for 27 hours. The reaction solution was CH
Extracted three times with Cl ₃ (200 ml). The organic layer Na ₂
After drying over SO ₄ , the solvent was distilled off, toluene was added, and pyridine was removed by azeotropic distillation. 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 give the title compound (20.1 g) as pale yellow needles. 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-valera
Midobenzene) sulfonyl] morpholine ([2]-(2
5) Preparation of 15): [2]-(d) Step The compound prepared in the above Example 22 ([2]-(24)-
15) (10.1 g) was dissolved in EtOH (750 ml) and heated at 55 ° C. After stopping foaming, 10% Pd / C
(1.50 g) of EtOH suspension (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
Xycarbonylcarbonyl) methylamino] -4-valera
Midobenzene] sulfonyl] morpholine ([2]-(2
7) Preparation of 15): Step [2]-(e) Compound prepared in the above Example 23 ([2]-(25)-
15) (5.49 g) in anhydrous CHCl ₃ (150 ml)
, And 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 the reaction solution was washed 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 foam. As obtained. ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 0.9
7 (t, 3H), 1.44 (bsext, 2H), 1.
75 (bquint, 2H), 2.47 (bt, 2H)
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-carboxy)
(Ciphenyl) methylbenzimidazol-6-yl] s
Ruphonyl] morpholine ([2]-(I) -15) (compound
Object No. Preparation of 12): [2]-(f) step The compound prepared in the above Example 24 ([2]-(27)-
15) Dissolve (4.53 g) in THF (30 ml)
A 12% aqueous HCl solution (15 ml) was added, and the mixture was stirred at room temperature for 5 hours. The solvent was removed and MeOH (250 ml), T
HF (80 ml) and 1 N NaOH aqueous solution (100
ml) and stirred for 15 hours. The reaction solution was adjusted to pH 4 using 1N HCl aqueous solution and concentrated. The precipitated solid was collected by filtration, washed with distilled water, dried, and treated with the title compound N
o. 12 (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: 0.93
(T, 3H), 1.44 (sext, 2H), 1.85
(Quint, 2H), 2.84 (bs, 4H), 2.
91 (t, 2H), 3.67 (t, 4H), 5.48
(S, 2H), 7.11 (d, 2H), 7.57 (s,
1H), 7.63 (d, 1H), 7.91 (d, 1
H), 8.05 (d, 2H).

[0068]Example 26: 4-[(2-butylbenzi
Midazol-5-yl) carbonyl] thiomorpholine
Preparation of ([1]-(13) -48): [1]-(b)
Tep 2-butylbenzimidazole-5-carboxylic acid (2.
56 g) in acetonitrile (30 ml) and DC
CI (3.18 g), HOBt (2.08 g) and thio
Morpholine (1.56 g) was added and stirred overnight. Precipitation
The insolubles thus obtained were filtered and then concentrated. The pale yellow foam obtained
The product was subjected to silica gel column chromatography (Kiese).
lgel 60,200g, CHCl_Three / MeOH = 4
0/1) and the title compound as a white foam
(1.86 g) was obtained.¹ H-NMR (500 MHz, CDCl_Three ) 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)

[0069]Example 27: 4-[[2-butyl-1-
(4-methoxycarbonylphenyl) methylbenzimi
Dazol-6-yl] carbonyl] thiomorpholine
Preparation of ([1]-(15) -48): [1]-(c)
Tep Compound ([1]-(13)-) prepared in Example 26
48) (1.54 g) was dissolved in DMF (10 ml)
Was. Anhydrous K_Two CO_Three (0.84 g) and methyl 4-bro
Addition of mmethyl benzoate (1.42 g), 19.5
Stirred for hours. The reaction was twice with EtOAc (30 ml)
Extract and wash the organic layer with saturated aqueous NaCl. Organic
Na layer_Two SO_Four And then concentrated. The resulting yellow
The oily substance was subjected to silica gel column chromatography (Kie
selgel 60,250g, benzene / acetone =
3/1) to give a colorless oil (2.43 g).
Furthermore, silica gel column chromatography (Kiese
lgel 60, 250 g, CHCl_Three / Acetone = 5
/ 1) to give the title compound (0.20 g). N
The isomeric structure was determined by the OE difference spectrum. Isomer
Is 4-[[2-butyl-1- (4-methoxycarbonyl)
Phenyl) methylbenzimidazol-5-yl] cal
Bonyl] thiomorpholine.¹ H-NMR (500 MHz, CDCl_Three ) 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-carboxy)
(Ciphenyl) methylbenzimidazol-6-yl] ca
Rubonyl] thiomorpholine ([1]-(I) -48)
Preparation of (Compound No. 27): [1]-(d) Step The compound ([1]-(15)-
48) (0.22 g) was dissolved in methanol (5 ml), 1N aqueous NaOH solution (1.0 ml) was added, and the mixture was stirred for 12 hours. The solvent was distilled off, and a 1N aqueous HCl solution was added to adjust the pH to 7. The precipitated crystals were filtered, washed with water, and dried under reduced pressure to obtain 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: 0.88
(T, 3H), 1.38 (sext, 2H), 1.78
(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-butylbenzi
Midazol-5-yl) carbonyl] -N'-triphe
Preparation of Nylmethylpiperazine ([1]-(13) -14)
Manufactured: [1]-(b) Step 2-butylbenzimidazole-5-carboxylic acid (2.
35 g) was dissolved in CH ₃ CN (40 ml) and DCCI
(2.89 g), HOBt (1.89 g), and N-triphenylmethylpiperazine (4.59 g) were added, and the mixture was added 17
Stirred for hours. After filtering the precipitated insoluble matter, 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) were obtained.

[0072]Example 30: N-[[2-butyl-1-
(4-methoxycarbonylphenyl) methylbenzimi
Dazol-6-yl] carbonyl] -N'-triphenyl
Toluene piperazine ([1]-(15) -14)
Made: [1]-(c) step Compound ([1]-(13)-) prepared in Example 29
14) Dissolve (1.40 g) in DMF (10 ml)
Was. Anhydrous K_Two CO_Three (0.44 g) and methyl 4-bro
Addition of momethyl benzoate (0.75 g), 17.5
Stirred for hours. The reaction solution was CH_Two Cl_Two (30ml) for 2
Extracted twice and the organic layer was washed with saturated aqueous NaCl. Yes
Na layer_Two SO_Four And then concentrated. The resulting yellow
The oily substance was purified by silica gel column chromatography (Ki
eselgel 60,150g, benzene / acetone
= 4/1) to give the title compound (0.54 g).
Was.¹ H-NMR (500 MHz, CDCl_Three ) 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)

[0073]Example 31: N-[[2-butyl-1-
(4-carboxyphenyl) methylbenzimidazole
-6-yl] carbonyl] -N'-triphenylmethyl
Preparation of piperazine ([1]-(I) -14 '): [1]
-(D) step Compound ([1]-(15)-) prepared in Example 30
14) Dissolve (0.20 g) in MeOH (5 ml),
1N NaOH aqueous solution (0.6 ml) was added, and 18 hours
Stirred. Further dioxane (0.5 ml) and 1N
An aqueous aOH solution (0.5 ml) was added and stirred for 18 hours.
Was. Further, 1N HCl aqueous solution is added for acid precipitation (pH 4).
The precipitated crystals were filtered, washed with water, dried under reduced pressure,
The title compound (0.18 g) was obtained as white crystals. Melting point: 170.0-172.5 ° C¹ H-NMR (500 MHz, CDCl_Three ) 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-carboxy)
(Ciphenyl) methylbenzimidazol-6-yl] ca
Rubonyl] piperazine ([1]-(I) -14) (compound
Object No. Preparation of 11) Compound ([1]-(I) -1 ) prepared in the above Example 31
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 hours. Since a white solid precipitated, distilled water (1 ml) was added, and the mixture was further stirred for 24 hours. The reaction solution was concentrated, distilled water was added, and the precipitated crystals were collected by filtration, dissolved in distilled water, adjusted to pH 6 with a 1N aqueous NaOH solution, and the precipitated crystals were collected by filtration. This was dried and 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-cal
Preparation of Bonic Acid Methyl Ester ([1]-(15) -12)
Ltd. 2-butyl-5-carboxylic acid methyl ester (23.20g) dry DMSO (500 meters
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. The suspension was cooled with ice water, water (900 ml) was added and CHCl ₃ (1000
ml), dried over anhydrous MgSO ₄ and concentrated to give a pale brown viscous substance. Add CHCl ₃ (10
0 ml), the insolubles were filtered, and the filtrate was subjected to silica gel column chromatography (Kieselgel 60,
250 g, CHCl ₃ ) and fractionation of the product (8.32 g), further addition of EtOAc (100 ml), heating and filtration gave 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-aminophenyl)
M) methylbenzimidazole] -6-carboxylate
Ester ([1]-(I) -12) (compound No. 1)
Preparation of 0) Compound ([1]-(15)- ) prepared in the above Example 33
12) (3.38 g) in CHCl ₃ (150 ml),
And stannous chloride 2 dissolved in methanol (30 ml)
Hydrate (11.45 g) was added to obtain a suspension. This suspension was heated to the reflux temperature over 5 minutes, stirred for 3.5 hours, allowed to cool, and then Na ₂ CO ₃ aqueous solution (5 g / 100 ml)
Was added to pH 7 and concentrated under reduced pressure at a bath temperature of 60 ° C.
The resulting solid was extracted with CHCl ₃ (250 ml),
After drying over anhydrous MgSO ₄ , the solvent was distilled off to give a solid (2.
90 g) were obtained. This was added to EtOAc / CHCl ₃ (3 /
Recrystallized from 2) to give the title compound No. 10 (2.34
g) was obtained as colorless crystals. Melting point: 168.0-171.0 ° C ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 0.93
(T, 3H), 1.42 (sext, 2H), 1.82
(Quint, 2H), 2.84 (t, 2H), 3.6
8 (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 5-week-old ICR mice (female) were divided into 5 mice in each group, bred for 1 week, and dissolved or dispersed in a 0.5% aqueous methylcellulose solution to disperse the substance. Oral administration (dose 500m
g / kg) and the number of deaths after 6 days was examined. Table 7 shows the results.

[0078]

[Table 7]

Example 36: Binding to Receptor In this example, the affinity of angiotensin II for type 1 and type 2 receptors was determined by the literature (Biochem. Pha).
rmacol. , 33: 4057-4062, 198.
4) Determined by binding assay according to the method described. Specifically, the measurement of total binding in the presence of each drug was performed as follows. A predetermined concentration of the drug (after dissolving in DMSO, diluted 2-fold with the buffer attached to the drug discovery system and subjected to the assay; 0.025 ml), tracer (0.025 ml), and receptor (0.25 ml)
ml), and the mixture was incubated (at room temperature for angiotensin II receptor type 1 (AT ₁ ) for 3 hours, at 37 ° C. for type 2 (AT ₂ ) for 1 hour), and the reaction solution was suction-filtered. (in AT ₁ GF / C filter paper, AT ₂ was 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 similarly. Specific binding at a given concentration of drug was determined by subtracting non-specific binding from total binding, respectively. In AT ₁ and AT _2, using the test drugs and control drugs in the given concentration, IC ₅₀ values of the concentration test drug to the ratio (50% inhibition to inhibit binding of the receptor with the radioligand (tracer), or binding at 100μM % Inhibition) was determined. Table 8 shows the results.

[0080]

Binding inhibition% in Table 8 Compound IC ₅₀ 100 [mu] M No. AT ₁ (nM) AT ₁ AT ₂ 1 6900 0 2 9700 0 3 5800 0 4 14000 0 5 5200 0 6 0 0 7 18 0 8 79000 0 9 16000 0 10 28 0 11 17000 0 12 38000 0 27 9900 0 DuP753 20 0

[0081] Receptor In AT _1: rabbit adrenal origin Tracer: ³ H- angiotensin II control drug: DuP753 (displacer): DuP753 receptor in AT _2: bovine cerebellar cortex-derived tracers: ¹²⁵ I-Tyr ⁴ - angiotensin II control drug: Angiotensin II (human) (Displacer): Angiotensin II (human)

As is evident from the results shown in Table 8 above, the angiotensin II type 1 receptor had an IC ₅₀ value of 5000 nM or more for this substance. The IC ₅₀ values of DuP753 used as comparative substance whereas a 20 nM, the substance which is more than 5000nM can be said that there is no inhibitory effect on receptor type 1. This type 1
The fact that the substance has no binding ability 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: Blood pressure lowering effect The substance and a comparative substance were administered orally by gavage to rats with renal disease, and the blood pressure lowering effect was examined. Rats with renal disease were prepared by branching and ligating renal arteries according to a conventional method. That is, Sprag
Using a ue-Dawley female rat, exposing the left renal hilum under anesthesia, leaving only one of the four second branches of the renal artery,
The remaining three were each ligated. One week later, the renal hilum (artery, vein, ureter) of the right kidney was ligated to produce a rat whose renal function was reduced to about １ ／ of normal renal function. Each group consisted of 8 rats, and each group was administered with only a sample (20 mg / kg) and water as a control. 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 the blood pressure.

[0084]

[Table 9]

A control substance (DuP753)
Showed a clear blood pressure lowering effect, whereas the substance had substantially no effect on blood pressure.

Example 38: Index value of renal function (for renal disease
In the same manner as in Example 37, a kidney disease rat was prepared. As a group of 8 animals, serum creatinine level as an indicator of renal function,
Fifteen groups were prepared so that there was no difference in the urea nitrogen value. Rats were allowed food and water ad libitum, and each group was dosed with this substance and a comparative substance (DuP753) at a dose of 20 mg / kg / day, and the control group was gavaged with water only daily. Two weeks later, under anesthesia, 0.2 ml of blood was collected from the carotid artery of the rat, and the blood was collected by centrifugation.
The serum creatinine (Scr) was measured with a creatinine analyzer (manufactured by Beckman) using l. Urea nitrogen (BU
N) was measured using a BUN analyzer (manufactured by Beckman) using 10 μl of the serum obtained in the same manner. For the creatinine clearance, after measuring serum creatinine, the rats were placed in a urine metabolic cage for 24 hours and urine was stored, then urine creatinine concentration (Ucr) was measured by a creatinine analyzer, and total excreted urine volume (Uvol) was measured. Creatinine clearance (CCr) was calculated by the following equation. Table 10 shows the results.

[0087]

[Table 10] Creatinine Urea nitrogen Creatinine clearance mg / dl mg / dl ml / min 1 1.5 75 0.38 2 1.6 80 0.32 3 1.679 0.33 4 1.6 80 0.32 5 1.6 80 0.32 6 1.6 81 0.30 7 1.7 82 82 0.30 8 1.7 84 0.29 9 1.6 77 0.34 10 1.6 80 0.30 11 1.5 780 .35 12 1.5 77 0.35 27 1.6 76 0.35 control 2.0 100 0.22 DuP753 1.6 80 0.32

Example 39: Survival time of animals with kidney disease
A renal disease rat was prepared in the same manner as in Example 37. As a group of 8 animals, serum creatinine level as an indicator of renal function,
Fifteen groups were prepared so that there was no difference in the urea nitrogen value. Rats were allowed food and water ad libitum, and each group was dosed with this substance and a comparative substance (DuP753) at a dose of 20 mg / kg / day, and the control group was gavaged with water only daily. Rats died from uremia as the renal disease progressed. Therefore, the survival time of the rats was examined as a comprehensive index of the improvement effect on the renal disease. Table 11 shows the results.
Here, the test period was 8 weeks. Therefore, when all the rats survive, the average survival time is 8 weeks, which is the upper limit.

[0089]

[Table 11]

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) was mixed and compressed into tablets (230 mg / tablet).
I made it.

[0091]

The substance or a pharmaceutically acceptable salt thereof, which is the active ingredient in the anti-renal disease agent of the present invention, comprises:
Despite having very little effect on blood pressure, it shows a sufficient effect on renal impairment. Therefore, the renal disease is sufficiently treated by using the anti-renal disease agent of the present invention, while the blood pressure is adjusted to a desired level by using an appropriate anti-hypertensive agent as needed, so that acute renal disease can be obtained. Appropriate treatment without problems such as insufficiency becomes possible.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61K 31/541 A61K 31/541 A61P 13/12 A61P 13/12 C07D 235/10 C07D 235/10 403/10 403/10 (72 Inventor Michihito Ise 41-2 Shinmeicho, Kawagoe-shi, Saitama 101 Yutaka Heights 101 (72) Inventor Hiroshi Takahashi 6-21-1-301, Honcho, Hoya-shi, Tokyo (56) (A) JP-A-4-235974 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 235/08 C07D 235/10 C07D 403/10 CA (STN) CAOLD (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] (1) 1-[[2-butyl-1- (4-carbo)
[Xyphenyl) methylbenzimidazol-6-yl]
Carbonyl] morpholine, 1-[[2-butyl-1- (4-carboxyphenyl)
Methylbenzimidazol-6-yl] carbonyl] pi
Peridine, 1-[[2-butyl-1- (4-carboxyphenyl)
Methylbenzimidazol-6-yl] carbonyl] a
Zetidine, 1-[[2-butyl-1- (4-carboxyphenyl)
Methylbenzimidazol-6-yl] carbonyl] pi
Loridine, N, N-diethyl-6- [2-butyl-1- (4-cal
Boxoxyphenyl) methylbenzimidazole] carbox
Samide, [2-butyl-1- (4-methoxycarbonylphenyl)
M) methylbenzimidazole] -5-carboxylate
Ester , [2-butyl-1- (4-methoxycarbonylphenyl)
M) methylbenzimidazole] -6-carboxylate
Ester, [2-butyl-1- (4-carboxyphenyl) methyl
[ Benzimidazole] -5-carboxylic acid, [2-butyl-1- (4-carboxyphenyl) methyl]
[ Benzimidazole] -6-carboxylic acid, [2-butyl-1- (4-aminophenyl) methylben
Zimidazole] -6-carboxylic acid methyl ester, N-[[2-butyl-1- (4-carboxyphenyl)
Methylbenzimidazol-6-yl] carbonyl] pi
Perazine, and 4-[[2-butyl-1- (4-carbo
[Xyphenyl) methylbenzimidazol-6-yl]
An anti-renal disease agent having substantially no effect on blood pressure, comprising a benzimidazole derivative selected from the group consisting of carbonyl] thiomorpholine or a pharmaceutically acceptable salt thereof. 2. A compound of the general formula ( I) [ Wherein , 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 -S
O ₂ N ( R ¹⁵ ) ₂ or —SO ₂ R ¹⁷ ; R ³ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, —O R ¹⁸ , —O (CH
_{2) q C 6 H 5,} - (CH 2) r C 6 H 5, -NH 2, -NH R
^{19, -NHC (= O) R} 20, -N (R 21) 2, -NHC
_{(= O) (CH 2)} s 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, -COO R 22, -NH 2}} , -N
_{^{(R 23) 2, -NH R}} 24, -OH, azole group, -SO ₃
H, or be ^{-O R 25; R 15, R} 18, R 19, R 20, R
R ²¹ , R ²² , R ²³ , R ²⁴ and R ²⁵ are each independently an alkyl group having 1 to 6 carbon atoms; R ¹⁷ is an alkyl group having a nitrogen atom, an oxygen atom or a sulfur atom; 7
Membered saturated aliphatic cyclic amino group; q is 0 or 1-6
R is 0 or an integer of 1 to 4; s is 0
Or an integer of 1 to 4], or a benzimidazole derivative or a salt thereof. 3. An anti-renal disease agent comprising the compound represented by the general formula ( I) according to claim 2 or a pharmaceutically acceptable salt thereof.