JPH06211853A - 4,5,6,7-tetrahydro-1h-imidazo(4,5-c)pyridine-6-carboxylic acid amide derivative - Google Patents

Abstract

PURPOSE:To obtain a new compound having the action of antagonistic agent for AT2 receptor of angiotensin II and useful for the treatment of hypertension, central nervous system diseases, etc. CONSTITUTION:The compound of formula I (R<1> is H, halogen, 1-6C alkyl, etc.; R<2> is carbamoyl, mono or dial-6C alkyl)carbamoyl, etc.; R<3> is CH2(phenyl), CH(phenyl)2, etc.; R<4>, R<7> and R<8> are H or 1-6C alkyl), e.g. (S)-1-(4-(2- carboxybenzoylamino)-3-methylphenyl)methyl-N,N-dimethyl-5- diphenylacetyl-4,5,6,7-tetrahydro-1H-imidazo-[4, 5-c] pyridine-6-carboxamide. The compound of formula I can be produced by using a compound of formula II (BOC is t-butoxycarbonyl) as a starting substance, converting the compound into a compound of formula III via 8 steps and reacting the compound of formula III with a benzoic acid derivative at 10-40 deg.C for 10-24hr.

Description

Detailed Description of the Invention

[0001]

This invention relates to 4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridine-
The present invention relates to a 6-carboxylic acid amide derivative (hereinafter, abbreviated as this substance), an intermediate for the production thereof, and an angiotensin II (AII) antagonist containing this substance.

[0002]

2. Description of the Related Art Angiotensin II is an octapeptide hormone associated with hypertension, central nervous system diseases and the like. Therefore, it is known that suppressing the action of angiotensin II is effective in treating hypertension, central nervous system diseases and the like. As an angiotensin II inhibitor, a renin inhibitor and an angiotensin converting enzyme (ACE) inhibitor that inhibit the synthesis of angiotensin II have been developed. However, with these inhibitors, renin and A
Angiotensin II produced by a group of enzymes different from CE
However, there is a problem that the action of is not able to be suppressed and that it adversely affects other metabolic systems.

Therefore, since angiotensin II exerts its action by interacting with a specific receptor existing in the cell membrane, it inhibits the action of all angiotensin II produced at the receptor level, and Angiotensin II receptor antagonists, which do not affect the metabolic system, are expected to be more specific and have fewer side effects. As an angiotensin II receptor antagonist, for example, a peptide analog such as salaracin has been reported, but its antagonistic activity is not sufficient and its application is limited due to its lack of oral absorption. There is.

As a means for overcoming these drawbacks, a non-peptide angiotensin II receptor antagonist has recently been reported. In these examples, the structural formulas are shown below,
Dup753 (1), PD123177 (2) (Bio-or
ganic & Medical Chemistry Letters, 1 (12), 711-716,
1991) and 4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridine-6-carboxylic acid derivative (3) described in U.S. Pat. No. 5,091,390. is there.

[0005]

[Chemical 11]

[0006]

[Problems to be Solved by the Invention] However, there is an ever-increasing demand for the provision of compounds having higher selectivity for angiotensin II receptors and higher angiotensin II antagonistic activity. In view of the above situation, the inventors of the present application have searched a compound over a wide range,
The specific 4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridine-6-carboxylic acid amide derivative has an extremely high angiotensin as compared with known compounds.
They found that they have II antagonistic activity and angiotensin II receptor selectivity, and completed the invention of this application.

[0007]

The first gist of the invention of this application is the general formula (I).

[Chemical 12] Or a stereoisomer thereof or a pharmaceutically acceptable salt thereof. [In the formula, R ¹ represents a hydrogen atom, a halogen atom, a C _{1 to} C ₆ alkyl group, a C _{3 to} C ₆ alkenyl group,
C ₃ -C ₆ alkynyl _{^{group, R 20 - (CH 2)}} n - ( wherein, R
^20, C ₃ -C ₈ cycloalkyl group, a naphthyl group, a phenyl group, or, C ₁ -C ₄ alkyl group, a halogen atom, a trifluoromethyl group, hydroxy group, C ₁ -C ₄ alkoxy group, C ₁ ~ C ₃ acyloxy group, amino group, N-mono-C
₁ -C ₄ alkylamino group, N- di -C ₁ -C ₄ alkylamino group, C ₁ -C ₄ thioalkyl radical, C ₁ -C ₃ alkylsulfonyl group, a nitro group, or -NHCOR ²¹ (wherein, R ^21, C ₁ -C ₃ alkyl group, a phenyl group, C ₁ ~
C ₃ alkylphenyl group, or amino or C ₁ -C ₄
Phenyl substituted with any 1 to 5 of alkylaminophenyl group), and n is an integer from 1 to 6. ^{), R 20 -C (O)} - ( wherein, R ²⁰ is as defined above), or ^{R 20 -CH (OH) -.} ( Wherein, R
²⁰ has the same meaning as above. And R ² is a carbamoyl group, a mono- or di-C ₁ -C ₆ alkylcarbamoyl group, or a 4- to 6-membered heterocyclic carbamoyl group, and R is an amino group, a carboxy group, (1H -Tetrazol-5-yl) phenyl group, carboxyphenyl group,
Carboxybenzamide group, (1H-tetrazole-5
- yl) benzamide group, carboxy phenyl carbamoyl group, or (a 1H- tetrazol-5-yl) phenylcarbamoyl group, R ³ is, -CH ₂ (phenyl), - CH (phenyl) _2, -CH (phenyl) C
H _3, -CH (phenyl) (cyclohexyl), - CH ₂
CH ₂ (phenyl), —CH ₂ (C ₁ -C ₆ alkoxyphenyl), or —CH ₂ (hydroxyphenyl),
R ⁴ , R ⁷ , and R ⁸ are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group. ]

A preferred substance of the present invention is that, in the general formula (I), R ¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ² _{is, -CONH 2, -CONHCH 3, -CON} (C
_{H 3) 2, -CONH (C} 2 H 5), - CON (C
₂ H ₅ ) ₂ ,

[0009]

[Chemical 13] And R is an amino group, a carboxy group, 2- (1H-
Tetrazol-5-yl) phenyl group, 2-carboxyphenyl group, carboxybenzamide group, 2- (1H-
A tetrazol-5-yl) benzamide group, a 2-carboxyphenylcarbamoyl group, or a 2- (1H-tetrazol-5-yl) phenylcarbamoyl group, and R
³ is —CH (phenyl) ₂ , —CH ₂ (phenyl), —
CH (phenyl) CH _3, -CH (phenyl) (cyclohexyl), - CH ₂ CH ₂ (phenyl), - CH ₂ (p
- methoxyphenyl), or a -CH ₂ (p-hydroxyphenyl), R ^4, R ^7, and R ⁸ are each independently a compound or a stereoisomer is hydrogen atom or a C ₁ -C ₂ alkyl group The body or a pharmaceutically acceptable salt thereof.

This substance has an asymmetric carbon atom at the 6-position of the fused imidazole ring. Therefore, this substance includes a single stereoisomer and a mixture of stereoisomers.
Preferably, the substance has 6-position of the fused imidazole ring,
It is a stereoisomer with S configuration. The pharmaceutically acceptable salts of the substances are obtained using acids or bases commonly used in the pharmaceutical field. Preferred acids include inorganic and organic acids such as hydrochloric acid, sulfuric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, maleic acid, tartaric acid. Preferred organic bases include mono-, di- and tri-amines such as mono-, di- and tri-alkylamines, such as methylamine, dimethylamine and triethylamine, mono-, di- and Examples thereof include tri-hydroxyalkylamine. Examples of the preferable inorganic base include hydroxides, carbonates and bicarbonates of ammonium, sodium, lithium, potassium, calcium, magnesium, aluminum, zinc and the like. In the invention of this application, the halogen atom means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

In the invention of the present application, the phenyl group having a substituent may have the substituent at any of the o-, m- and p-positions unless otherwise specified. Next, an example of a method for producing this substance (referred to as method A) is shown.

[0012]

[Chemical 14] The method A will be described by dividing it into steps (a) to (j). Step (a) The compound of the general formula (XI) (R ¹ is the same as described above;
BOC is tertiary-butoxycarbonyl) and a compound of the general formula (X) (Y is OH, Cl, Br, and OSO _2).
CF ₃ ; R ₄ is H, C ₁ -C ₆ alkyl; R ⁶ is NO ₂ , cyanophenyl, cyano, (1H-tetrazol-5-yl) phenyl, C ₁ -C ₃ alkoxycarbonyl; R ⁷ ,
R ⁸ independently represents H or C ₁ -C ₆ alkyl) 0 to
Reaction is carried out at 60 ° C. for 10 to 48 hours to obtain a compound of the general formula (IX) (R ¹ , R ⁴ , R ⁶ , R ⁷ , R ⁸ and Boc are the same as described above).

Step (b) The compound of the general formula (IX) is treated with an acid such as hydrochloric acid to give the compound of the general formula (VIII) (R ¹ , R ⁴ , R ⁶ , R ⁷ and R ⁸⁾ as described above. Is).

Step (c) Add acid and HCHO to the compound of general formula (VIII) and
After reacting at 0 to 150 ° C. for 0.5 to 4 hours, the compound of the general formula (V
II) compound (R ¹ , R ⁴ , R ⁶ , R ⁷ , and R ⁸ are the same as described above) is obtained.

Step (d): The compound of the general formula (VII) is suspended in alcohol and trimethyl orthoformate, blown with HCl, and 60
The compound of the general formula (VI) (R ¹ , R ⁴ , R ⁶ , R ⁷ , and R ⁸ are the same as above) is obtained by reacting at -100 ° C for 4-8 hours.

(E) Step Carbodiimide, 1-hydroxybenzotriazole,
Further, the compound of the general formula (VI) is added to a solution of acetonitrile, chloroform, dimethylformamide, or THF containing diphenylacetic acid or phenylcyclohexylacetic acid, and the mixture is reacted at 10 to 40 ° C. for 10 to 48 hours to give the general formula (V (R ¹ , R ⁴ , R ⁶ , R ⁷ , and R ⁸ are the same as described above, and R ³ is CH (phenyl) ₂ , CH (phenyl) (cyclohexyl), CH ₂ (phenyl), CH ₂ C
H ₂ (phenyl), CHCH ₃ (phenyl), CH ₂ (C ₁
-C ₆ alkoxyphenyl), or obtaining a compound of CH ₂ (hydroxyphenyl)).

Step (f) An alkali, for example, NaOH is added to the compound of the general formula (V) to obtain the compound (R ¹ , R ³ , R ⁴ , R ⁶ , R ^{6 of} the general formula (IV).
⁷ and R ⁸ are the same as described above).

Step (g) Add a nitrogen-containing compound to the compound of the general formula (IV)
0 reacted for 10 to 24 hours at ℃ compounds of general formula ^{(III) (R 1, R} 3, R 4 .R 6, R 7, and R ⁸ are the same as described above .R ^{2 'is} amino, mono Alternatively, di-C ₁ -C ₆ alkylamino or a 4- to 6-membered heterocyclic amino) is obtained. R
^{When 6} is (1H-tetrazol-5-yl) phenyl, compounds of general formula (I) (R ⁵ is tetrazole) can be obtained here.

Step (h) The compound of the general formula (II) is prepared by adding tin chloride dihydrate to the compound of the general formula (III) (R ⁶ is NO ₂ ) and reacting at 40 to 100 ° C. for 10 to 120 minutes. (R ¹ , R ^{2 ′} , R ³ , R ⁴ ,
R ⁷ and R ⁸ are the same as described above).

Step (i) Addition of 10 to 4 benzoic acid derivatives to the compound of the general formula (II)
The reaction is carried out at 0 ° C. for 10 to 24 hours to obtain the compound of the general formula (I) (R ¹ , R ^{2 ′} , R ³ , R ⁴ , R ⁷ and R ⁸ are the same as described above).

(J) When R ⁶ is cyanophenyl or the like, the compound of the general formula (I) (X is a C—C single bond) is obtained by hydrolysis of the general formula (III).

The compound of formula (XI) (raw material) is described in J. A
m. Chem. Soc. , 114 (5), 1906-1
908, 1992. The compound (raw material) represented by the general formula (X) can be prepared according to, for example, J. M
ed. Chem. , 33, 1312 to 1329 (199
0), J. Med. Chem. , 34, 2525-25
47 (1991), and J. Med. Chem. , 3
4, 3248-3260 (1991) and the like. Another manufacturing method (referred to as B method) is shown in formulas (2), (3), (4), and (5). The steps are shown separately.

[0023]

[Chemical 15]

[0024]

[Chemical 16]

The production examples of the method B of this substance are as follows (a) to
(S) Steps will be described separately. (A) Step The compound of the formula (XXIII) is combined with a tertiary amine such as Tr (triphenylmethyl) chloride and triethylamine in a solvent such as ether, tetrahydrofuran (THF), dioxane, methylene chloride, or chloroform to 10 to 6
By reacting at 0 ° C. for 2 to 24 hours, the compound of formula (XXI
The compound of I) is obtained. The compound of formula (XXIII) is commercially available.

(B) Step The compound of formula (XXII) is reacted with a reducing agent such as lithium aluminum hydride in a solvent such as ether, THF, or dioxane at 0 to 40 ° C. for 0.1 to 1 hour to obtain a compound of the formula The compound of (XXI) is obtained.

(C) Step The compound of formula (XXI) is treated with dimethylformamide (DM).
F) and the like in a solvent such as tert-butyldimethylsilyl (TBDMS) chloride and imidazole 0-40
The reaction of formula (XX)
To obtain the compound of

(D) Step The compound of the formula (XX) is dissolved in a solvent such as ether, THF, or dioxane in an atmosphere of an inert gas such as nitrogen or argon to obtain a solution of butyl lithium (normal, secondary, or tertiary). A compound of the general formula (XIX) by reacting with R ¹ halide (chloride, bromide, or iodide) in the presence of a base and hexamethylphosphoramide (HMPA) at 0 to 40 ° C. for 0.1 to 6 hours. To get

Step (e) An acid, for example, aqueous hydrochloric acid is added to the compound of the general formula (XIX),
The compound of general formula (XVIII) is obtained by reacting at 10 to 120 ° C. for 0.5 to 6 hours. Compound (XV
III) may or may not be isolated.
The compound of the general formula (XVII) is obtained by reacting for 5 to 6 hours.

(F) Step Carbodiimide, 1-hydroxybenztriazole,
The compound of the general formula (XVII) is added to a solution of acetonitrile, chloroform, THF or the like containing R ³ COOH and R ³ COOH and reacted at 10 to 60 ° C. for 1 to 48 hours to obtain the compound of the general formula (XVI).

Step (g) The compound of the general formula (XVI) and the compound of the general formula (X) are
The compound of general formula (XV) is obtained by reacting in a solvent such as acetone, DMF, ether, THF, or chloroform in the presence of a suitable base, for example, anhydrous potassium carbonate at 10 to 60 ° C. for 1 to 48 hours.

Step (h) The compound of the general formula (XV) is mixed with an oxidizing agent such as chromic acid in a solvent such as acetone, methylene chloride or chloroform for 10 to 10 times.
The compound of general formula (XIV) is obtained by reacting at 40 ° C. for 0.1 to 3 hours.

(I) Step Carbodiimide, 1-hydroxybenztriazole,
And a compound of the general formula (XIII) by adding the compound of the general formula (XIV) to a solution of acetonitrile, chloroform, THF or the like containing a chain or cyclic amine and reacting at 10 to 60 ° C. for 1 to 48 hours. To get

(J) Step When R ⁶ is a methoxycarbonyl group, the compound of the general formula (XII
Alkali, ether or THF of the compound of I) or a mixed solution thereof is added with an alkali, for example, an aqueous solution of sodium hydroxide, and the mixture is reacted at 10 to 40 ° C. for 1 to 24 hours to give a compound represented by the general formula (I ′) (R ¹⁰ is carboxy)
To obtain the compound of

(K) When R ⁶ is a nitro group or the like, tin chloride or tin chloride dihydrate is added to ethyl acetate or alcohol of the compound of the general formula (XIII) or a mixed solution thereof, and nitrogen is added. Or 10 to 100 ° C. in an inert gas atmosphere such as argon,
By reacting for 0.1 to 1 hour, the compound of the general formula (I ′)
(R ¹⁰ is an amino group) is obtained.

(L) Step When R ⁶ is a cyanophenyl group, trimethyltin azide or tributyltin azide is added to a solution of the compound of the general formula (XIII) in toluene or xylene, and an atmosphere of an inert gas such as nitrogen or argon is added. In 100-120 ℃, 12
After the reaction for 120 hours, the compound of the general formula (I) (R ¹⁰ is (1H-tetrazol-5-yl) phenyl group) is obtained by treating with an acid, for example, aqueous hydrochloric acid.

(M) Step When R ⁶ is a ((1-triphenylmethyl) -1H-tetrazol-5-yl) phenyl group, it has the general formula (XII
The compound of I) is dissolved in a solvent such as THF or dioxane, and an acid, for example, aqueous hydrochloric acid is added to the solution to obtain a temperature of 10 to 100 ° C.
By reacting for ~ 6 hours, the general formula (I) (R is (1
A compound of H-tetrazol-5-yl) phenyl group) is obtained.

(N) Step When R ¹⁰ is an amino group, a carboxylic acid or the like, the compound of the general formula (I ′) is treated with chloroform, acetonitrile, T
The compound of the general formula (I) is obtained by dissolving in a solvent such as HF or dioxane, adding a compound containing a necessary group and reacting at 10 to 60 ° C. for 1 to 24 hours.

Step (o) The compound of the general formula (XIX) is dissolved in a solvent such as THF and ether, tetra-n-butylammonium fluoride is added, and the mixture is reacted at 0 to 40 ° C. for 0.5 to 6 hours. Thus, the compound of the general formula (XXIV) is obtained.

(P) Step The compound of the general formula (XXIV) is dissolved in DMF, and PDC is added.
(Pyridinium dichromate) was added at 0-40 ° C,
By reacting for 0.5 to 24 hours, the general formula (XX
The compound of V) is obtained.

Step (q) An acid, for example, aqueous hydrochloric acid is added to the compound of the general formula (XXV),
The compound of general formula (XXV ′) is obtained by reacting at 10 to 120 ° C. for 0.5 to 6 hours. Compound (XX
V ′) may or may not be isolated, and when it is not added, an aqueous HCHO solution is added as it is, at 10 to 120 ° C.
The compound of general formula (XXVI) is obtained by reacting for ~ 6 hours.

Step (r) The compound of the general formula (XXVI) is added to a solution of carbodiimide, dimethylformamide, 1-hydroxybenztriazole and acetonitrile containing R ³ COOH, chloroform or THF at 10 to 60 ° C. , 1
By reacting for 48 hours, a compound of general formula (XXVII) is obtained.

Step (s) The compound of the general formula (XXVII) and the compound of the general formula (X) are treated in a solvent such as acetone, DMF, ether, THF, or chloroform in the presence of a suitable base such as anhydrous potassium carbonate. The compound of general formula (XIV) is obtained by reacting at 10 to 60 ° C. for 1 to 48 hours.

The compound of the general formula (X) can be prepared according to, for example, J. Me
d. Chem. , 34, 2525-2547 (199
1), and J. Med. Chem. , 35, 4027-
4038 (1992) and the like.

The second gist of the present invention resides in the following intermediate compound for the production of this substance. (A) General formula (VIII ')

[Chemical 17] Or a salt thereof. [In the formula, R ¹ represents a hydrogen atom, a halogen atom, a C _{1 to} C ₆ alkyl group, a C _{3 to} C ₆ alkenyl group, a C _{3 to} C ₆ alkynyl group, R ²⁰ — (CH ₂ ) _n — (in the formula, , R ²⁰ is a C ₃ -C ₈ cycloalkyl group, a naphthyl group,
Phenyl group, or, C ₁ -C ₄ alkyl group, a halogen atom, a trifluoromethyl group, hydroxy group, C ₁ -C ₄ alkoxy, C ₁ -C ₃ acyloxy group, an amino group, N-
Mono -C ₁ -C ₄ alkylamino group, N- di -C ₁ -C ₄ alkylamino group, C ₁ -C ₄ thioalkyl radical, C ₁ -C ₃ alkylsulfonyl group, a nitro group or a -NHCO,
1 to any one of R ²¹ (in the formula, R ²¹ is a C _{1 to} C ₃ alkyl group, a phenyl group, a C _{1 to} C ₃ alkylphenyl group, or an amino or a C _{1 to} C ₄ alkylaminophenyl group)
Is phenyl substituted with 5 and n is 1-6
Is an integer. ^{), R 20 -C (O)} -. ( Wherein, R ²⁰ is as defined above), or R ²⁰ -CH (OH) -
(Wherein R ²⁰ has the same meaning as described above), and R ⁴
Is a hydrogen atom or a C ₁ -C ₆ alkyl group, and R ⁶ is
A nitro group, a (1-triphenylmethyl-1H-tetrazol-5-yl) phenyl group, a cyano group, a C ₁ -C ₃ alkoxycarbonyl group, or a cyanophenyl group, and R
⁷ and R ⁸ are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group, R ⁹ is a hydrogen atom or a t-butoxycarbonyl group, and R ¹⁰ is a hydrogen atom or C ₁ -C ₆ It is an alkyl group. In the general formula (VIII ′), R ¹ is preferably a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ⁴ is a hydrogen atom or a C ₁ -C ₂ alkyl group, R 4
⁶ is a nitro group, 2- (1-triphenylmethyl-1H
-Tetrazol-5-yl) phenyl group or 2-cyanophenyl group, and R ⁷ and R ⁸ are each independently
It is a hydrogen atom or a C ₁ -C ₆ alkyl group, and R ¹⁰ is a hydrogen atom or a C ₁ -C ₆ alkyl group.

(B) General formula (XXVIII)

[Chemical 18] Or a salt thereof. [In the formula, R ¹ represents a hydrogen atom, a halogen atom, a C _{1 to} C ₆ alkyl group, a C _{3 to} C ₆ alkenyl group, a C _{3 to} C ₆ alkynyl group, R ²⁰ — (CH ₂ ) _n — (in the formula, , R ²⁰ is a C ₃ -C ₈ cycloalkyl group, a naphthyl group,
Phenyl group, or, C ₁ -C ₄ alkyl group, a halogen atom, a trifluoromethyl group, hydroxy group, C ₁ -C ₄ alkoxy, C ₁ -C ₃ acyloxy group, an amino group, N-
Mono -C ₁ -C ₄ alkylamino group, N- di -C ₁ -C ₄ alkylamino group, C ₁ -C ₄ thioalkyl radical, C ₁ -C ₃ alkylsulfonyl group, a nitro group or a -NHCO,
1 to any one of R ²¹ (in the formula, R ²¹ is a C _{1 to} C ₃ alkyl group, a phenyl group, a C _{1 to} C ₃ alkylphenyl group, or an amino or a C _{1 to} C ₄ alkylaminophenyl group)
Is phenyl substituted with 5 and n is 1-6
Is an integer. ^{), R 20 -C (O)} -. ( Wherein, R ²⁰ is as defined above), or R ²⁰ -CH (OH) -
(Wherein R ²⁰ has the same meaning as described above) and R ¹⁵
Is —CH ₂ —R ¹⁷ (wherein R ¹⁷ is a hydroxy group or a t-butyldimethylsilyloxy group), or —
C (O) -R ¹⁷ (in the formula, R ¹⁷ has the same meaning as described above), and R ¹⁶ is a hydrogen atom or a triphenylmethyl group. (However, when R ¹ and R ¹⁶ are hydrogen atoms, R ¹⁵ is not —CH ₂ —OH, and when R ¹ is a hydrogen atom or a methyl group and R ¹⁶ is a hydrogen atom. , R ¹⁵ is not —COOH.)]

(C) General formula (XXIX)

[Chemical 19] Or a salt thereof. [In the formula, R ¹ represents a hydrogen atom, a halogen atom, a C _{1 to} C ₆ alkyl group, a C _{3 to} C ₆ alkenyl group, a C _{3 to} C ₆ alkynyl group, R ²⁰ — (CH ₂ ) _n — (in the formula, , R ²⁰ is a C ₃ -C 8 cycloalkyl group, a naphthyl group,
Phenyl group, or, C ₁ -C ₄ alkyl group, a halogen atom, a trifluoromethyl group, hydroxy group, C ₁ -C ₄ alkoxy, C ₁ -C ₃ acyloxy group, an amino group, N-
Mono -C ₁ -C ₄ alkylamino group, N- di -C ₁ -C ₄ alkylamino group, C ₁ -C ₄ thioalkyl radical, C ₁ -C ₃ alkylsulfonyl group, a nitro group or a -NHCO,
1 to any one of R ²¹ (in the formula, R ²¹ is a C _{1 to} C ₃ alkyl group, a phenyl group, a C _{1 to} C ₃ alkylphenyl group, or an amino or a C _{1 to} C ₄ alkylaminophenyl group)
Is phenyl substituted with 5 and n is 1-6
Is an integer. ^{), R 20 -C (O)} -. ( Wherein, R ²⁰ is as defined above), or R ²⁰ -CH (OH) -
(Wherein R ²⁰ has the same meaning as described above) and R ¹⁵
Is —CH ₂ —R ¹⁷ (wherein R ¹⁷ is a hydroxy group or a t-butyldimethylsilyloxy group), or —
C (O) -R ¹⁷ (in the formula, R ¹⁷ has the same meaning as described above). R ^{3 'is} a hydrogen atom, -COCH ₂ (phenyl), - COCH (phenyl) _2, -COCH (phenyl) CH _3, -COCH (phenyl) (cyclohexyl), - COCH ₂ CH ₂ (phenyl), - COCH
₂ (C ₁ -C ₆ alkoxyphenyl), or -COCH
₂ (hydroxyphenyl). (However, R ¹ and R ^{3 '}
Is a hydrogen atom, R ¹⁵ is not —COOH. )] In the general formula (XXIX), preferably, R ¹ is
A hydrogen atom or a C ₁ -C ₆ alkyl group, and R ¹⁵ is —C
It is OOH and R ^{3 ′} is —COCH (phenyl) ₂ or —COCH (phenyl) (cyclohexyl).

(D) General formula (XXX)

[Chemical 20] Or a salt thereof. [In the formula, R ¹ represents a hydrogen atom, a halogen atom, a C _{1 to} C ₆ alkyl group, a C _{3 to} C ₆ alkenyl group, a C _{3 to} C ₆ alkynyl group, R ²⁰ — (CH ₂ ) _n — (in the formula, , R ²⁰ is a C ₃ -C ₈ cycloalkyl group, a naphthyl group,
Phenyl group, or, C ₁ -C ₄ alkyl group, a halogen atom, a trifluoromethyl group, hydroxy group, C ₁ -C ₄ alkoxy, C ₁ -C ₃ acyloxy group, an amino group, N-
Mono -C ₁ -C ₄ alkylamino group, N- di -C ₁ -C ₄ alkylamino group, C ₁ -C ₄ thioalkyl radical, C ₁ -C ₃ alkylsulfonyl group, a nitro group or a -NHCO,
1 to any one of R ²¹ (in the formula, R ²¹ is a C _{1 to} C ₃ alkyl group, a phenyl group, a C _{1 to} C ₃ alkylphenyl group, or an amino or a C _{1 to} C ₄ alkylaminophenyl group)
Is phenyl substituted with 5 and n is 1-6
Is an integer. ^{), R 20 -C (O)} -. ( Wherein, R ²⁰ is as defined above), or R ²⁰ -CH (OH) -
(Wherein R ²⁰ has the same meaning as described above) and R ^{3 ′}
Is a hydrogen atom, -COCH ₂ (phenyl), -COCH
(Phenyl) ₂ , -COCH (Phenyl) CH ₃ , -CO
CH (phenyl) (cyclohexyl), - COCH ₂ C
H ₂ (phenyl), - COCH ₂ (C ₁ -C ₆ alkoxyphenyl), or -COCH a ₂ (hydroxyphenyl), R ^4, R ^7, and R ⁸ each independently represent a hydrogen atom or a C ₁ To C ₆ alkyl group, R ⁶ is a nitro group,
(1-Triphenylmethyl-1H-tetrazole-5-
Yl) phenyl group, cyano group, C ₁ -C ₃ alkoxycarbonyl group, or cyanophenyl group, and R ^{15 ′} is —
CH ₂ -R ¹⁹ (wherein, R ¹⁹ is hydrogen atom or a C ₁ -C ₆ alkyl group.), Or -C (O) -R ¹⁹ (wherein, R
¹⁹ has the same meaning as above. ). ]

In the general formula (XXX), preferably R ¹
Is a hydrogen atom or a C ₁ -C ₆ alkyl group, and R ^{3 ′} is
-COCH (phenyl) ₂ or -COCH (phenyl) (cyclohexyl), R ⁶ is a nitro group, 2
-(1-Triphenylmethyl-1H-tetrazole-5
-Yl) a phenyl group, a cyano group, a methoxycarbonyl group, or a 2-cyanophenyl group, and R ⁴ , R ⁷ , and R ⁸ are each independently a hydrogen atom or a C ₁ -C ₂ alkyl group, R ¹⁹ is a hydrogen atom or a C ₁ -C ₂ alkyl group.

(E) General formula (XIII)

[Chemical 21] Or a salt thereof. [Wherein R ¹ is a halogen atom,
C ₁ -C ₆ alkyl group, C ₃ -C ₆ alkenyl group, C ₃ -C ₆
Alkynyl _{^{group, R 20 - (CH 2)}} n - ( wherein, R ²⁰ is, C
_{3 to} C ₈ cycloalkyl group, naphthyl group, phenyl group, or C _{1 to} C ₄ alkyl group, halogen atom, trifluoromethyl group, hydroxy group, C _{1 to} C ₄ alkoxy group, C ₁
To C ₃ acyloxy group, amino group, N-mono-C _{1 to} C ₄
Alkylamino group, N-di-C ₁ -C ₄ alkylamino group, C ₁ -C ₄ thioalkyl group, C ₁ -C ₃ alkylsulfonyl group, nitro group, or —NHCOR ²¹ (wherein,
R ²¹ is phenyl substituted with 1 to 5 C ₁ -C ₃ alkyl groups, phenyl groups, C ₁ -C ₃ alkylphenyl groups, or amino or C ₁ -C ₄ alkylaminophenyl groups). And n is an integer from 1 to 6. ), R ²⁰ —C (O) — (in the formula, R ²⁰ has the same meaning as described above), or R ²⁰ —CH (OH) — (in the formula, R ²⁰
Has the same meaning as above. ), R ^{2 ′} is an amino group, a mono- or di-C ₁ -C ₆ alkylamino group, or a 4- to 6-membered heterocyclic amino group, and R ³ is —CH ₂
(Phenyl), - CH (phenyl) _2, -CH (phenyl) CH _3, -CH (phenyl) (cyclohexyl),
-CH ₂ CH _{2 (phenyl), - CH 2 (C 1} ~C 6 alkoxyphenyl), or -CH ₂ (hydroxyphenyl)
And R ⁴ , R ⁷ , and R ⁸ are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group, R ⁶ is a nitro group, (1-triphenylmethyl-1H-tetrazole-
5-yl) phenyl group, C ₁ -C ₃ alkoxycarbonyl group, cyano group, or 2-cyanophenyl group. ]

In the general formula (XIII), preferably R
1 is a hydrogen atom or a C 1 -C 6 alkyl group, and R
2 ', -NH 2, -NHCH 3, -N (CH 3) 2, -NH
(C 2 H 5 ), N (C 2 H 5 ) 2 ,

[Chemical formula 22] And R ³ is —CH (phenyl) ₂ , —CH (phenyl) (cyclohexyl), R ⁴ , R ⁷ , and R
⁸ is each independently a hydrogen atom or a C ₁ -C ₂ alkyl group, R ⁶ is a nitro group, 2- (1-triphenylmethyl-1H-tetrazol-5-yl) phenyl group,
It is a methoxycarbonyl group, a cyano group, or a 2-cyanophenyl group.

Each of the above intermediate compounds has an asymmetric carbon atom at the 6-position of the fused imidazole ring or at a position corresponding to this position. Therefore, each of the above intermediate compounds includes a single stereoisomer and a mixture of stereoisomers. Preferably, each of the above intermediate compounds is a stereoisomer having the S configuration at the 6-position of the fused imidazole ring. The salts of the above intermediate compounds are obtained by using an acid or base which can form a salt chemically with each intermediate compound.

The compound of the general formula (VIII ') of the above (a) is a compound of the formulas (IX) and (VIII) in the above method A.
The compound of the general formula (XXVIII) of the above (b) corresponds to the compound of the formula (XVIII), (XIX),
Compounds of the general formula (XXIX) of (c) above corresponding to the compounds of (XXIV) and (XXV) have the formula (XVII), (XVI), (XXVI), and (XXVII) in the above-mentioned Method B.
Corresponding to the compound of the general formula (XXX) of the above (d), the compound of the formula (VII), (VI),
It corresponds to the compounds of (V) and (IV). Therefore, these intermediate compounds can be obtained according to the above Method A or Method B.

The third gist of the present invention resides in an angiotensin II antagonist characterized by containing a compound of general formula (I) or a pharmaceutically acceptable salt thereof. This substance antagonizes the receptor of angiotensin II,
By blocking the action of angiotensin II, it exerts its pharmacological effect. In particular, the AT ₁ receptor (when R ¹ is other than a hydrogen atom) and the AT ₂ receptor (where R ¹ is R ¹ are known to be receptors for angiotensin II due to the difference in R ¹ in the general formula (I) When it is a hydrogen atom), it specifically antagonizes each. In addition, this substance has remarkably high antagonistic activity as compared with known compounds, as will be apparent from the examples below.

Therefore, the present substance is useful as a therapeutic agent for circulatory system diseases such as hypertension, heart disease (cardiac hypertrophy, heart failure, myocardial infarction, etc.), and stroke and central nervous system diseases. It is also useful as a reagent or drug for studying the role of angiotensin II and its receptor in these diseases.

This substance can be made into a preparation by adding a pharmaceutically acceptable carrier. This substance is orally or parenterally administered to mammals including human. This substance is usually contained in a unit dose of 0.1 to 500 mg, preferably 1 to 100 mg. The dose of this substance is usually 0.1 to 150 mg, preferably 1 to 100 mg per 1 kg of body weight per day. This dose can be administered once a day or in 2 to 3 divided doses. However, the dose is appropriately selected depending on the medical condition of the patient. In addition,
The substance was orally administered to mice at a dose of 300 mg / kg and observed for 1 week. As a result, it was confirmed that there was no death and no acute toxicity.

Examples will be described below, but the invention of the present application is not limited to the following examples as long as the gist thereof is not exceeded.

【Example】

Example 1, Method A Step (a) 3- (3-Methyl-4-nitrophenyl) methyl-N-
t-Butoxycarbonyl-L-histidine methyl ester (IX-2) In a 500 ml separable flask thoroughly dried and replaced with nitrogen gas, trifluoromethanesulfonic anhydride (10.
00 g, 0.0354 mol) and dry methylene chloride (60 ml) were added, and the mixture was cooled to -70 ° C. To this 3-
Methyl-4-nitrobenzyl alcohol (5.43 g,
A solution of 0.0325 mol) and N, N-diisopropylethylamine (6.2 ml, 0.0356 mol) in dry methylene chloride (40 ml) was added dropwise over 15 minutes, followed by stirring for 30 minutes. Then, N, 1-bis-t-butoxycarbonyl-L-histidine methyl ester (X
A solution of I-2) (10.00 g, 0.0271 mol) in dry methylene chloride (40 ml) was added dropwise over 20 minutes, then the reaction flask was raised from the cooling bath and stirred at room temperature for 16 hours. At the time of rapid stirring, the reaction solution was poured into 0.2 M phosphate buffer (about 400 ml) to separate the methylene chloride layer,
After further washing with 0.2 M phosphate buffer (about 400 ml), it was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain an orange yellow oil (12.07 g). This crude oily substance was subjected to silica gel column chromatography (LiChr
Prep Si60, 300 g, chloroform / methanol (30: 1)) for purification to obtain the target compound (IX-2) (4.45 g, yield 39.3%) as a pale yellow oil. . Similarly, R ¹ is H, Et, i
The compounds of Pr, nBu and nHex with R ⁴ , R ⁶ , R ⁷ , R ⁸ and Y in Table 1 were also synthesized.

[0058]

[Table 1]

Example 2, Method A Step (b) 3- (3-Methyl-4-nitrophenyl) methyl-L-
Histidine dihydrochloride (VIII-2) 3- (3-methyl-4-nitrophenyl) methyl-N-
t-Butoxycarbonyl-L-histidine methyl ester (IX-2) (1.3626g, 0.00326mo)
6N hydrochloric acid aqueous solution (54.5 ml) was added to l), and 12
The mixture was heated under reflux in a 0 ° C. oil bath for 2.5 hours. The reaction solution was cooled and then concentrated to obtain the desired product (VIII-2) (1.1406 g, yield 92.9%) as a yellowish brown oily product.

Example 3, Method A Step (c) (S) -1- (3-Methyl-4-nitrophenyl) methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c ] Pyridine-6-carboxylic acid dihydrochloride (V
II-2) 3- (3-methyl-4-nitrophenyl) methyl-L-
Histidine dihydrochloride (VIII-2) (1.1406
g, 0.00302 mol) to 1N aqueous hydrochloric acid solution (1
3.7 ml) and 37% formaldehyde aqueous solution (0.7
4 ml, 0.00907 mol) and added at room temperature to 0.5
After stirring for 1.5 hours in a 120 ° C. oil bath, the mixture was cooled and concentrated to give the desired product (VII-2) (1.1538 g, yield 9
8.0%) was obtained as tan crystals (decomposed at 256.5-258 ° C.).

Example 4, Method A Step (d) (S) -1- (3-Methyl-4-nitrophenyl) methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c ] Pyridine-6-carboxylic acid methyl ester (VI-2) (S) -1- (3-methyl-4-nitrophenyl) methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5- c] Pyridine-6-carboxylic acid dihydrochloride (V
II-2) (1.1538 g, 0.00296 mol)
Was suspended in dry methanol (46 ml) and trimethyl orthoformate (4.6 ml), and hydrogen chloride was bubbled into the mixture under ice-cooling stirring until it was saturated. The reaction was then stirred in a 90 ° C. oil bath for 6 hours, cooled and concentrated. The obtained yellowish brown oily substance (0.7456 g) was subjected to silica gel column chromatography (Kiesegel 60, 60).
g, chloroform / methanol (15: 1)) for purification, and the desired product (VI-2) (0.7076 g, yield 7)
2.3%) as an orange-yellow oil. The compounds in Table 2 were synthesized in the same manner as in Examples 1 to 4.

[0062]

[Table 2]

Example 5, Method A Step (e) (S) -5-diphenylacetyl-1- (3-methyl-
4-Nitrophenyl) methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridine-6-
Carboxylic acid methyl ester (V-2) N, N'-dicyclohexylcarbodiimide (DCC
I) (2.1080 g, 0.01022 mol), 1-
Hydroxybenzotriazole (HBTA) (1.38
Acetonitrile (16 ml) was added to 06 g (0.01022 mol) and diphenylacetic acid (2.1685 g, 0.01022 mol), and the mixture was stirred at room temperature for 20 minutes.
(S) -1- (3-Methyl-4-nitrophenyl) methyl-4,5,6,7-tetrahydro-1H was added to this suspension.
-Imidazo [4,5-c] pyridine-6-carboxylic acid methyl ester (VI-2) (2.7000 g, 0.00
A solution of 817 mol) in acetonitrile (14 ml) was added, and the mixture was stirred at room temperature for 21 hours. Insoluble matter in the reaction solution is filtered off,
After washing with acetonitrile, the filtrate and washings were combined and concentrated, and the residue was dissolved by adding methylene chloride (40 ml), washed with 10% aqueous sodium carbonate solution and saturated saline solution, dried over sodium sulfate and concentrated to give a yellow oil. (4.5203
g) was obtained. This crude oily substance was subjected to silica gel column chromatography (Kieselgel 60, 270 g,
Chloroform / methanol (60:11)) was added for purification, and the desired product (V-2) (2.8250 g, yield 65.
9%) was obtained as colorless crystals (mp.174.5-177 ° C).

Example 6, Method A Step (f) (S) -5-diphenylacetyl-1- (3-methyl-
4-Nitrophenyl) methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridine-6-
Carboxylic acid (IV-2) (S) -5-diphenylacetyl-1- (3-methyl-
4-Nitrophenyl) methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridine-6-
Carboxylic acid methyl ester (V-2) (2.8250)
g, 0.00539 mol) in tetrahydrofuran / methanol (3/1, 17 ml) solution, 1N caustic soda aqueous solution (5.7 ml) was added, and the mixture was allowed to stand at room temperature for 6 hours. After the reaction solution was concentrated, the residue was treated with 1N hydrochloric acid aqueous solution (6.0
(ml) was added to weakly acidify and the mixture was extracted with methylene chloride. The methylene chloride layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the desired product (IV-
2) (2.5558 g, yield 93.0%) was obtained as a pale yellow viscous oil. MS (El) 492 (M-18) The compounds in Table 3 were synthesized in the same manner as in Examples 5-6.

[0065]

[Table 3]

Example 7, Method A Step (g) (S) -N, N-dimethyl-5-diphenylacetyl-
1- (3-methyl-4-nitrophenyl) methyl-4,
5,6,7-Tetrahydro-1H-imidazo- [4,5
-C] Pyridine-6-carboxamide (III-2) (S) -5-diphenylacetyl-1- (3-methyl-
4-Nitrophenyl) methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridine-6-
Carboxylic acid (IV-2) (2.5558 g, 0.005
01 mol), DCCI (1.2916 g, 0.006)
26 mol), HBTA (0.8456 g, 0.006)
Acetonitrile (40 ml) was added to 26 mol) and the mixture was stirred at room temperature for 20 minutes. Dimethylamine hydrochloride (0.4488 g, 0.00626 mol) was added to this suspension, and the mixture was stirred at room temperature for 18 hours. The insoluble matter in the reaction mixture was filtered off, washed with acetonitrile, and the filtrate and washings were combined and concentrated. Chloroform (40 ml) was added to the residue for dissolution, and the mixture was washed with 10% aqueous sodium carbonate solution and saturated brine solution, and then sulfuric acid Sodium dried and concentrated to a pale yellow oil (4.3025
g) was obtained. This crude oily substance was purified by subjecting it to silica gel column chromatography (Kieselgel 60, 220 g, chloroform / methanol (60: 1)) to obtain the desired product (III-2) (2.3636 g, yield 8).
7.8%) as a pale yellow viscous oil. MS (E
I) 538 (M + 1) Similarly, the compounds in Table 4 were synthesized.

[0067]

[Table 4]

Example 8, Method A Step (h) (S) -1- (4-amino-3-methylphenyl) methyl-N, N-dimethyl-5-diphenylacetyl-4,
5,6,7-Tetrahydro-1H-imidazo- [4,5
-C] Pyridine-6-carboxamide (II-2) (S) -N, N-dimethyl-5-diphenylacetyl-
1- (3-methyl-4-nitrophenyl) methyl-4,
5,6,7-Tetrahydro-1H-imidazo [4,5-
c] pyridine-carboxamide (III-2)
(2.3636 g, 0.00440 mol) was dissolved in 28 ml of ethyl acetate and 5 ml of methanol, and tin chloride 2 was added.
A hydrate (4.9580 g, 0.0220 mol) was added, and the mixture was stirred under a nitrogen stream in an 80 ° C. oil bath for 30 minutes.
After cooling the reaction solution, a 5% sodium carbonate aqueous solution was added to neutralize and concentrate, and the residue was extracted with chloroform. The chloroform layer was washed with water, dried over sodium sulfate, and concentrated to give a pale yellow foamy substance (2.2368 g). This was subjected to silica gel column chromatography (Kiselgel 60, 120).
g, chloroform / methanol = (50: 1) for purification, and the desired product (II-2; 2.0077 g, yield 9
0.0%) was obtained as a white foam. MS (EI) 5
08 (M + 1) Similarly, the compounds in Table 5 were synthesized.

[0069]

[Table 5]

Example 9, Method A Step (i) (S) -1- (4- (2-Carboxybenzoylamino) -3-methylphenyl) methyl-N, N-dimethyl-5-diphenylacetyl-4, 5,6,7-Tetrahydro-1H-imidazo- [4,5-c] pyridine-6-
Carboxamide (I-2) (S) -1- (4-amino-3-methylphenyl) methyl-N, N-dimethyl-5-diphenylacetyl-4,
5,6,7-Tetrahydro-1H-imidazo- [4,5
-C] Pyridine-6-carboxamide (II-2)
To a solution of (2.077 g, 0.00396 mol) in 30 ml of ethyl acetate was added phthalic acid (0.722) under stirring at room temperature.
3 g, 0.00435 ml) ethyl acetate (10 ml)
The solution was added. After stirring at room temperature for 23 hours, the reaction solution was filtered, and the obtained white solid was washed with ethyl acetate (about 20 ml) and dried to obtain the desired product (I-2, compound number 2) (2.41).
07 g, yield 93.0%) was obtained. MS637 (EI)
(M-18) A compound was synthesized in the same manner. The results are shown in Table 6 and the elemental analysis values of the compounds are shown in Table 7.

[0071]

[Table 6]

[0072]

[Table 7]

Example 10, Method A Step (j) (S) -1-((2'-Carboxybiphenyl-4-yl) methyl) -N, N-dimethyl-5-diphenylacetyl-4,5,6 , 7-Tetrahydro-1H-imidazo- [4,5c] pyridine-6-carboxamide (I-1
Synthesis of 5) (S) -1-((2'-cyanobiphenyl-4-yl)
Methyl) -N, N-dimethyl-5-diphenylacetyl-4,5,6,7-tetrahydro-1H-imidazo-
[4,5-c] Pyridine-6-carboxamide (III
-14) (1.9550 g, 0.00337 mol) in 10 ml of ethyl alcohol and 20 ml of 1N aqueous sodium hydroxide solution were added, and the mixture was heated under reflux for 3 hours, neutralized with 6N hydrochloric acid solution and concentrated. The residue was extracted with chloroform, washed with water, dried over sodium sulfate, and concentrated to give a pale yellow foamy substance (2.
1179 g) was obtained. This was purified from silica gel by chromatography (Kiselgel 60, 110 g, chloroform / methanol (50: 1)) to obtain the desired product (I-15; compound No. 15; 1.8756 g, yield 92.9%). Obtained as a white foam. MS (E
I) 580 (M-18) In the same manner, various compounds were synthesized, and the results are shown in Tables 8 and 9. A compound in which R ⁵ is tetrazole is also shown.

[0074]

[Table 8]

[0075]

[Table 9]

Example 11, Method B Step (a) (S) -2-Triphenylmethylamino-3- (1-triphenylmethylimidazol-5-yl) propanoic acid methyl ester (XXII) Compound (XXIII) ( 50.25g, 0.208mo
l), TrCl (138.90 g, 0.498 mol)
Solution in CH ₂ Cl ₂ (500 ml) under ice-cooled stirring.
Ethylamine (145ml, 1.038mo
l) was added dropwise over 30 minutes, and the mixture was stirred at room temperature for 6 hours. The reaction solution was poured into water, extracted with CH ₂ Cl ₂ , and the organic layer was washed with sat. NaCl _aq . Washing, drying with Na ₂ SO ₄ and concentration gave the crude product (168.87 g) as a yellow oil. This was purified by subjecting it to silica gel column chromatography (hexane / acetone = 3/1) to obtain the compound (XXII) (119.934 g, yield 88.4%) as a white foam. ¹ H-NMR (CDCl ₃ ): δ, 2.71 (d, 1H,
J = 10.5 Hz, NH), 2.78 (dd, 1H, J
= 6.9, 13.8 Hz), 2.96 (dd, 1H, J
= 6.9, 13.8 Hz), 3.05 (s, 3H),
3.66 (dt, 1H, J = 6.9, 10.5Hz),
6.62 (s, 1H), 7.11-7.15 (m, 9
H), 7.18-7.21 (m, 6H), 7.26-
7.32 (m, 9H), 7.36 (s, 1H), 7.4
3 (d-like, 6H, J = 7.3 Hz) IR (ν _max , KBr) 3480, 1748, 1509, 1455, 1163.
748,705 cm ^-1

Example 12, Method B Step (b) (S) -2-Triphenylmethylamino-3- (1-triphenylmethylimidazol-5-yl) propanol (XXI) LiAlH ₄ (6.839 g, 0) 180 mol) d
In a ry Et ₂ O (590 ml) suspension, while stirring with ice cooling,
Compound (XXII) (58.917g, 0.0901m)
ol) was added over 2.5 hours. After stirring with ice-cooling for 1 hour, Na ₂ SO ₄ · 10H ₂ O was added to the reaction solution to treat excess LiAlH ₄ , filtered through Celite 545, and the filtrate was concentrated. The residue was diluted with CHCl ₃ and washed with sat. NH ₄
Cl _aq . , Sat. NaCl _aq . The extract was washed, dried over Na ₂ SO ₄ , and concentrated to obtain compound (XXI) (56.390 g, yield 100%) as a white foamy substance. ¹ H-NMR (CDCl ₃ ): δ, 1.90 (b, 1H,
NH), 1.95 (dd, 1H, J = 6.4, 14.7)
Hz), 2.38 (dd, 1H, J = 3.2, 14.7)
Hz), 2.91 (b, 1H), 2.99 (dd, 1)
H, J = 6.4, 11.5 Hz), 3.47 (dd, 1
H, J = 3.2, 11.5 Hz), 4.95 (b, 1
H, OH), 6.29 (s, 1H), 7.09-7.2.
0 (m, 15H), 7.26-7.33 (m, 10
H), 7.48-7.49 (m, 6H) IR (ν _max , KBr): 3480, 1550, 145.
5,1036,746,702cm ^-1

Example 13, Method B Step (c) (S) -1-t-Butyldimethylsilyloxy-2-triphenylmethylamino-3- (1-triphenylmethylimidazol-5-yl) propane (XX ) Compound (XXI) (56.390 g, 0.0901 mo
l) in dry DMF (560 ml) solution, while stirring with ice cooling, imidazole (12.269 g, 0.180 m)
ol), tert-butyldimethylsil
ylchloride (TBDMSCl) (20.37
g, 0.135 mol) was added, and the mixture was stirred at room temperature for 3.5 hours. The reaction solution was poured into water, extracted with Et ₂ 0, H
₂ O, sat. NaCl _aq . Washing, drying with Na ₂ SO ₄ and concentration gave a pale yellow foam (67.602 g). This crude product was subjected to silica gel column chromatography (h
Exane / acetone = 5/1) for purification, and compound (XX) (58.770 g, yield 88.1).
%) As a white foam. ¹ H-NMR (CDCl ₃ ): δ, −0.13 (s, 6
H), 0.80 (s, 9H), 1.60 (b, 1H, N
H), 2.19 (dd, 1H, J = 7.6, 14.2H)
z), 2.57 (dd, 1H, J = 4.1, 14.2H
z), 2.73 (b, 1H), 2.89 (dd, 1H,
J = 6.0, 9.6 Hz), 3.27 (dd, 1H, J
= 4.1, 9.6 Hz), 5.35 (s, 2H), 6.
38 (s, 1H), 7.12-7.35 (m, 25
H), 7.56 (d-like, 6H, J = 7.3H)
z) IR (ν _max , KBr): 3100, 2990, 297.
0,2925,2890,1508,1480,145
5,1253,1132,1090,1072,103
5,900,830,770,742,700,65
8,636 cm ^-1

Example 14, Method B Step (d) (S) -1-t-butyldimethylsilyloxy-2-triphenylmethylamino-3- (2-n-butyl-1-)
Triphenylmethylimidazol-5-yl) propane (XIX-3) Compound (XX) (22.557g, 0.0305mo)
l) in a dry Et ₂ O (340 ml) solution under a nitrogen atmosphere with ice-cooling and stirring, 1.5 N nBuLi / hexane.
(61.0 ml, 0.0914 mol) with a syringe 15
It was added dropwise over a period of minutes. After 3 minutes, under the same conditions, nBuI
(5.2 ml, 0.0457 mol), HMPA (38
(ml) was added dropwise with a syringe and the mixture was stirred for 20 minutes, then warmed to room temperature and further stirred for 4 hours. The reaction solution was poured into water and EtOA was added.
After extraction with c, the organic layer was washed with sat. NaCl _aq . Wash, Na ₂
Dry with SO ₄ and concentrate to a yellow oil (25.830 g,
100% up) was obtained. This was subjected to silica gel column chromatography (hexane / acetone = 20 /
1) and purified to give compound (XIX-3) 10.71
0 g (yield 44.1%) was obtained as a pale yellow foam. ¹ H-NMR (CD ₂ Cl ₂ ): δ-0.136, −0.
144 (each s, each 3H), 0.58
(T, 3H, J = 7.3 Hz), 0.77 (s, 9
H), 0.89 (sext, 2H, J = 7.3 Hz),
1.01 (m, 1H), 1.12 (m, 1H), 1.7
8 (m, 2H), 1.98 (dd, 1H, J = 6.7,
14.0 Hz), 2.43 (dd, 1H, J = 4.8,
14.0 Hz), 2.57 (b, 1H, CH), 3.0
6 (dd, 1H, J = 6.9, 9.6 Hz), 3.10
(B, 1H, NH), 3.28 (dd, 1H, J = 4.
4, 9.6 Hz), 6.19 (s, 1H), 7.06-
7.54 (m, 30H) IR (ν _max , KBr): 3500, 3000, 297
5,2905,1510,1459,1408,126
0,1160,1093,1075,1038,83
The compound was synthesized in the same manner as in 4,775,746,702,640 cm ⁻¹ . Shown in the table.

[0080]

[Table 10] General formula (XIX) synthesis example

Example 15, Method B Step (e) (S) -2-Amino-3- (2-n-butyl-1H-imidazol-5-yl) propanol (XVIII-
3), and (S) -2-n-butyl-4,5,5,7-
Tetrahydro-1H-imidazo [4,5-c] pyridine-6-methanol, hydrochloride (XVII-3) Compound (XIX-3) (11.745 g, 0.0148)
mol) 1N HCl _aq (140 ml), 37% HCH
O _aq (3.6 ml) was added, and the mixture was stirred at room temperature for 40 minutes and in a 120 ° C. oil bath for 4 hours. After cooling the reaction solution, the insoluble matter was filtered off and washed with water, the aqueous layer was washed with Et ₂ O, and then concentrated and dried,
Compound (XVII-3) (4.0370 g, yield 97.
0%) as a yellow solid. ¹ H-NMR (D ₂ O): δ, 0.95 (t, 3H, J =
7.3 Hz), 1.40 (sext, 2H, J = 7.3)
Hz), 1.79 (quint, 2H, J = 7.3H)
z), 3.02 (t, 2H, J = 7.3 Hz), 3.1
2 (d-like, 1H, J = 4.6 Hz), 3.16
(Bs, 1H), 3.85-3.90 (m, 2H),
4.08 (d-like, 1H, J = 9.2 Hz),
4.48 (d, 1H, J = 15.4Hz), 4.52
(D, 1H, J = 15.4 Hz) IR (ν _max , KBr): 3410, 2950, 167
5, 1620, 1560, 1430, 1065 cm ^{−1 The} compounds were synthesized in the same manner. Shown in the table.

[0082]

Table 11 Synthesis example of general formula (XVII) No. R ₁ MASS (El) XVII-1 nPr 195 (M-2HCl) XVII-2 iPr 195 (M-2HCl) XVII-3 nBu 209 (M-2HCl) XVII-4 nHex 237 (M-2HCl) Compound (XIX- 3) (1.7750 g, 0.0022)
3 mol), 1N HCl _aq . (18 ml) using the same reaction procedure as in 37% HCHO _aq . Compound (XVIII-3) (0.7003 g, yield 99.6%) was obtained as a yellow viscous substance by performing the reaction without adding. ¹ H-NMR (D ₂ O) δ: 0.96 (t, 3H, J =
7.3 Hz), 1.39 (sext, 2H, J = 7.3)
Hz), 1.80 (quint, 2H, J = 7.3H)
z), 3.00 (t, 2H, J = 7.3 Hz), 2.8
-3.3 (m, 3H), 3.7-4.3 (m, 2H),
6.05 (bs, 1H) MASS (EI): 197 (M-2HCl) A compound was similarly synthesized. Shown in the table.

[0083]

Table 12 Synthesis example of general formula (XVIII) No. R ₁ MASS (El) XVIII-1 nPr 183 (M-2HCl) XVIII-2 iPr 183 (M-2HCl) XVIII-3 nBu 197 (M-2HCl) XVIII-4 nHex 225 (M-2HCl)

Example 16, Method B Step (f) (S) -2-n-butyl-5-diphenylacetyl-
4,5,6,7-Tetrahydro-1H-imidazo [4
5-c] Pyridine-6-methanol (XVI-4) Diphenylacetic acid (14.66)
17 g, 0.069 mol), N, N'-dicycl
hexyl carbodiimide (DCCl)
(14.2528 g, 0.069 mol), 1-hyd
roxybenzotriazole (HBTA)
(9.3345 g, 0.069 mol) in dry TH
It was dissolved in F (61 ml) and stirred at room temperature for 20 minutes. Compound (XVII-3) (6.0920 g, 0.0
216 mol) in dry THF (30 ml) and d
ry triethylamine (TEA) (6.
0 ml, 0.043 mol) was added, and the mixture was stirred at room temperature for 14 hours. The insoluble matter was filtered off, washed with THF, and the filtrate / washing solution was concentrated to give a crude oil (11.0015 g). This was dissolved in (THF / MeOH = 1 / 1,100 ml),
1N HCl _aq . (25 ml) was added and left for 8 hours,
(THF / MeOH = 1/1) (100 ml) and 1N
NaOH _aq . (50 ml) was added and the mixture was left for 10 hours. The reaction solution was concentrated and H ₂ O (50 ml) was added to precipitate white crystals. This is washed with water and then dried in vacuum to give 2.1518 g (mp.199-20) of compound (XVI-4).
2 ° C., yield 24.7%) was obtained. ¹ H-NMR (CDCl ₃ ): δ 0.90, 0.91
(Each t, 3H, J = 7.3 Hz), 1.30-
1.38 (m, 2H), 1.40-1.90 (b, 1
H, OH), 1.55-1.70 (m, 2H), 2.5
5-2.62 (m, 2H), 2.33, 2.81 (s-
like, dd, 2H), 3.43-3.58 (m, 2
H), 3.86, 4.08 (each d, 1H, J =
16.7, 15.4 Hz), 4.47, 4.70 (b
s, d, 2H, J = 16.7 Hz), 5.28, 5.3
2, 5.51 (d, s, s, 2H, J = 16.7H
z), 7.10-7.60 (m, 10H), 8.80.
(B, 1H, NH) IR (ν _max , KBr): 3425, 2970, 293
0,2860,1620,1450,1420,74
A compound was synthesized in the same manner as 0,695 cm ^-1 . Shown in the table.

[0085]

[Table 13]

Example 17, Method B Step (g) (S) -2-n-Butyl-1-[(4-methoxycarbonylphenyl) methyl] -5-diphenylacetyl-
4,5,6,7-Tetrahydro-1H-imidazo [4
5-c] pyridine-6-methanol (XV-8) compound (XVI-4) (0.0491 g, 0.0001)
2 mol) in dryDMF (0.49 ml),
ethyl 4- (bromomethyl) benz
oate (0.0334 g, 0.00015 mol),
K ₂ CO ₃ (0.0201 g, 0.00015 mol) was added, and the mixture was vigorously stirred at room temperature for 24 hours. The reaction mixture was poured into water, extracted with EtOAc, washed with water, dried over Na ₂ SO ₄ , and concentrated to give a pale yellow oily substance (0.0656 g). This crude oily substance was subjected to silica gel column chromatography (hex
ane / acetone = 1/2) for purification, and the compound (XV-8) (0.0211 g) and its 3-position isomer (0.0262 g), and a mixture of both (0.0035 g) are each obtained as white foam. Obtained as a substance. (Yield 75.7%)
The structures of both compounds were determined by NOE difference spectrum. ¹ H-NMR (CDCl ₃ ): δ 0.86, 0.87
(Each t, 3H, J = 7.3 Hz), 1.28-
1.36 (m, 2H), 1.58-1.65 (m, 3
_{H, CH 3 CH 2 CH 2} CH 2 -, CH 2 OH), 1.99
-2.63 (m, 2H), 2.52-2.63 (m, 2)
H), 3.31-3.57 (m, 2H , C H 2 OH),
3.92, 3.93 (each, 3H), 3.9
0, 4.13, 4.76, 5.42 (each d, 2
H, J = 15.4 Hz), 4.40-4.47, 5.2
6-5.30 (each m, 1H), 4.94, 5.
02 (each s, 2H) 5.35, 5.43 (ea
chs, 1H), 6.91-6.99 (m, 2H),
7.17-7.32 (m, 10H), 7.98-8.0
1 (m, 2H) IR (ν _max , KBr): 3460, 1725, 164
0,1453,1430,1415,1280,111
0.743,700 cm ^-1

Example 18, Method B Step (h) (S) -2-n-Butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] -5-diphenylacetyl-
4,5,6,7-Tetrahydro-1H-imidazo [4
5-c] pyridine-6-methanol (XV-10) compound (XVI-4) (2.8060 g, 0.0069)
5 mol) in dryDMF (28 ml) solution, 4'-
(Bromomethyl) -2-cyanobiph
enyl (2.3655 g, 0.0869 mol), K
₂ CO ₃ (1.9222 g, 0.0139 mol) was added, and the mixture was vigorously stirred at room temperature for 23 hours. The reaction solution was poured into water, extracted with EtOAc, washed with water, dried with Na ₂ SO ₄ , and concentrated to obtain a pale yellow foam substance (4.5301 g). This was purified by subjecting it to silica gel column chromatography to give compound (XV-10) (0.9288 g) and its 3-position isomer (1.4733 g), and a mixture of both (0.0207).
g, yield 58.6%) was obtained. The structures of both compounds are NOE
Determined by difference spectrum. ¹ H-NMR (CDCl ₃ ): δ 0.89, 0.90 (e
ach t, 3H, J = 7.3 Hz), 1.36 (Ss
ext, 2H, J = 7.3 Hz), 1.64-1.78
(M, 2H), 1.88 (bs, 1H, OH), 2.1
4, 2.72 (each dd, 1H, J = 6.0, 1
5.6 Hz), 2.21, 2.51 (each d, 1
H, J = 15.6 Hz), 2.60-2.67 (m, 2
H), 3.35-3.62 (m, 2H , CH 2 OH),
3.96, 4.93 (each d, 1H, J = 17.
0 Hz), 4.12, 4.78 (each d, 1H,
J = 15.6 Hz), 4.47-4.51, 5.35-
5.40 (each m, 1H), 5.06-5.13
(M, 2H), 5.36, 5.42 (each s, 1
H), 6.93-7.10 (m, 2H), 7.15-
7.39 (m, 10H), 7.40-7.58 (m, 4
H), 7.60-7.82 (m, 2H), IR (ν _max , KBr / disk): 3425, 296.
0,2925,2860,1637,1500,148
0, 1450, 1410, 1375, 760, 740,
A compound was synthesized in the same manner as 700 cm ⁻¹ . Shown in the table.

[0088]

[Table 14]

Example 19, Method B Step (i) (S) -2-n-butyl-1-[(4-methoxycarbonylphenyl) methyl] -5-diphenylacetyl-
4,5,6,7-tetrahydro-1H-imidazo [4,4
5-c] pyridine-6-carboxylic acid (XIV-8) CrO ₃ (0.33 g) was dissolved in H ₂ O (0.62 ml), and then conc. H ₂ SO ₄ (0.58 ml) was slowly added dropwise. The salt generated here was dissolved in H ₂ O (0.1 ml) to prepare an oxidizing reagent. Compound (XV-8) (0.29
1 g) was dissolved in acetone (4.4 ml), and the oxidizing reagent prepared above was added dropwise at room temperature until the orange red color disappeared. After stirring for 30 minutes, iPrOH was added until the reaction solution turned green and concentrated. The crude product was subjected to silica gel column chromatography (CHCl ₃ / MeOH = 8 /
1) and purified to give compound (XIV-8) (0.18
83 g, m, p. 177-180 ° C, yield 63.0%)
Got ¹ H-NMR (CDCl ₃ ): δ 0.79, 0.83
(Each t, 3H, J = 7.3 Hz), 1.18-
1.28 (m, 2H), 1.40-1.55 (m, 2
H), 1.77, 2.99, 3.24-3.44 (m,
d, m, 2H, J = 14.7 Hz), 2.45-2.7
0 (m, 2H), 3.89, 3.92 (each,
3H), 4.28, 4.57, 4.69, 5.07 (e
ach d, 2H, J = 14.7 Hz), 5.17-
5.27 (m, 2H), 5.51, 5.55 (each
s, 1H), 5.51-5.55, 5.70 (d, 1
H, J = 5.5 Hz), 7.09-7.45 (m, 12
H), 7.90-8.10 (m, 2H) IR (ν _max KBr): 3470, 2980, 172.
6,1640,1615,1506,1455,143
5,1417,1283,1190,1112,75
0,700 cm ^-1

Example 20, Method B Step (j) (S) -2-n-butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] -5-diphenylacetyl-
4,5,6,7-Tetrahydro-1H-imidazo [4
5-c] Pyridine-6-carboxylic acid (XIV-10) Oxidation reagent prepared in the same manner as in Example 19 (0.9 m
l) was dissolved in acetone (9.4 ml) to give compound (X
V-10) (0.6249 g, 0.00105 mol)
At room temperature. After stirring for 30 minutes, iPrOH was added until the reaction solution turned green, and then concentrated. The crude product was subjected to silica gel column chromatography (CHCl ₃ / M
eOH = 6/1) and purified to give compound (XIV-1
0) (0.3619 g, yield 56.6%) was obtained as a white foam. ¹ H-NMR (CDCl ₃ ): δ 0.75-1.06
(M, 3H), 1.15 to 1.40 (m, 2H), 1.
44-1.70 (m, 2H), 2.46-2.64
(M, 2H), 2.69, 2.93 (each dd,
1H, J = 6.0, 15.6 Hz), 3.08, 3.3
1 (each d, 1H, J = 15.6 Hz), 4.2
7, 4.67 (each, 1H, J = 15.6H)
z), 4.58, 4.99 (each d, 1H, J =
15.6 Hz), 4.94-5.25 (m, 2H),
5.32, 5.43 (each, 1H), 4.8
3,5.68 (each d, 1H, J = 6.0H
z), 7.02-7.85 (m, 18H) IR (ν _max , KBr / disk): 3425, 296.
0, 1620, 1500, 1408, 758, 742
A compound was synthesized in the same manner as 700,630,560 cm ⁻¹ . Shown in the table

[0091]

[Table 15]

Example 21, Method B Step (k) 4-[[(S) -2-Butyl-1-[(4-methoxycarbonylphenyl) -methyl] -5-diphenylacetyl-4,5,6,6. 7-Tetrahydro-1H-imidazo [4,5-c] pyridin-6-yl] carbonyl] morpholine (XIII-8) Compound (XIV-8) (0.1315 g, 0.0002
3 mol), DCCI (0.0624 g, 0.0003)
mol), HBTA (0.0377 g, 0.00028)
mol), morpholine (0.024 ml,
0.00028 mol) in dry THF (2.0 m
It was dissolved in 1) and stirred at room temperature for 19 hours. The insoluble matter was filtered off, washed with THF, and the filtrate / washing solution was concentrated to give a crude oil (0.3010 g). This is subjected to silica gel column chromatography (CHCl ₃ / MeOH = 60/1).
After purification by filtration, a white foamy substance (0.1204 g) was obtained. This is further sorted by a TLC plate (0.5 mm thick,
20 cm x 20 cm, developing solvent hexane / acet
One = 2/3) and repurified to obtain the compound (XIII-
8) (0.0911 g, yield 61.7%) was obtained. ¹ H-NMR (CDCl ₃ ): δ 0.84 (t, 3H,
J = 7.3 Hz), 1.28 (sext, 2H, J =
7.3 Hz), 1.58 (quint, 2H, J = 7.
3 Hz), 2.49 (t, 2H, J = 7.3 Hz),
2.70 (dd, 1H, J = 6.0, 15.1 Hz),
2.80 (d, 1H, J = 15.1Hz), 3.25-
3.70 (b, 8H), 3.92 (s, 3H), 4.2
6 (d, 1H, J = 15.1 Hz), 4.90 (d, 1
H, J = 15.1 Hz), 5.02, 5.07 (eac
hd, each 1H, J = 17.4 Hz), 5.3
5 (s, 1H), 5.96 (d, 1H, J = 6.0H
z), 7.09 (d, 2H, J = 8.3 Hz), 7.1
7-7.35 (m, 10H), 8.02 (d, 2H, J
= 8.3 Hz) IR (ν _max KBr): 3460, 1725, 164
5,1455,1433,1415,1280,123
0,1113,750,700cm ^-1

Example 22, Method B Step (l) 4-[[(S) -2-Butyl-1-[(2'-cyanobiphenyl-4-yl) methyl] -5-diphenylacetyl-4,5. , 6,7-Tetrahydro-1H-imidazo [4,5-c] pyridin-6-yl] carbonyl] morpholine (XIII-10) Compound (XIV-10) (0.3301 g, 0.000
542 mol), DCCl (0.1455 g, 0.00
0705 mol), HBTA (0.0953 g, 0.0
00705 mol), morpholine (0.06
ml, 0.000705 mol) with dryTHF (5.
0 ml) and stirred at room temperature for 48 hours. The insoluble matter was filtered off, washed with THF, and the filtrate / washing solution was concentrated to obtain a crude product (0.5500 g). This is subjected to silica gel column chromatography (hexane / acetone =
2/3) and purified to give compound (XIII-10)
(0.1764 g, yield 48.0%) was obtained as a white foam. ¹ H-NMR (CDCl ₃ ): δ 0.87 (t, 3H, J
= 7.3 Hz), 1.32 (sext, 2H, J = 7.
3 Hz), 1.64 (quint, 2H, J = 7.3H)
z), 2.55 (t, 2H, J = 7.3 Hz), 2.7
7 (dd, 1H, J = 6.0, 15.1 Hz), 2.8
6 (d, 1H, J = 15.1 Hz), 3.20-3.8
0 (b, 8H), 4.29 (d, 1H, J = 15.6H
z), 4.90 (d, 1H, J = 15.6 Hz), 5.
04 (d, 1H, J = 17.0 Hz), 5.09 (d,
1H, J = 17.0 Hz), 5.37 (s, 1H),
5.99 (d, 1H, J = 6.0 Hz), 7.20-
7.85 (m, 18H), IR (ν _max , KBr / disk): 3430, 164
0, 1450, 1408, 1228, 1113, 76
A compound was synthesized in the same manner as 0,700 cm ^-1 . The results are shown in Tables 16 and 17.

[0094]

[Table 16]

[0095]

[Table 17]

Example 23, Method B Step (m) 4-[[(S) -2-n-butyl-1-[(4carboxyphenyl) methyl] -5-diphenylacetyl-4,
5,6,7-Tetrahydro-1H-imidazo [4,5-
c] pyridin-6-yl] carbonyl] morpholine (I
-29) Compound (XIII-8) (0.0761 g, 0.000
12 mol) (THF / MeOH = 1/1) (1.5
2 ml) and dissolved in 1N NaOH _aq (0.38 ml)
Was added and left for 16.5 hours. After concentrating the reaction solution, 1N
HCl _aq (0.43 ml) was added (PH4) for acid precipitation, and the obtained oily substance was dissolved in CHCl ₃ , washed with water, and washed with Na ₂ S.
O _{4 was} dried and concentrated to obtain the compound (I-29) as a white foam substance (0.0735 g, yield 98.8%). NMR, IR, MASS, elemental analysis ¹ H-NMR (CDCl ₃ + D ₂ O): δ 0.84
(T, 3H, J = 7.3 Hz), 1.27 (sext,
2H, J = 7.3 Hz), 1.57 (quint, 2
H, J = 7.3 Hz), 2.55 (t, 2H, J = 7.
3 Hz), 2.70 (dd, 1H, J = 6.0, 15.
6Hz), 2.86 (d, 1H, J = 15.6Hz),
3.30-3.65 (b, 8H), 4.24 (d, 1
H, J = 15.6 Hz), 5.06 (d, 1H, J = 1
7.4 Hz), 5.10 (d, 1H, J = 17.4H)
z), 5.12 (d, 1H, J = 15.6 Hz), 5.
43 (s, 1H), 5.97 (d, 1H, J = 6.0H
z), 7.12 (d, 2H, J = 8.3 Hz), 7.1
7-7.33 (m, 10H), 8.09 (d, 2H, J
= 8.3 Hz) IR (ν _max , KBr): 3460, 1715, 164
6,1453,1412,1270,1230,111
5,745,700 cm ^-1

Example 24, Method B Step (n) 4-[[(S) -1-[(4-amino-3-methylphenyl) methyl] -5-diphenylacetyl-4,5,5
6,7-Tetrahydro-1H-imidazo [4,5-c]
Pyridin-6-yl] carbonyl] morpholine (I'-
1) Compound (XIII-3) (1.079 g, 0.001)
74 mol) was dissolved in 10 ml of ethyl acetate, tin chloride dihydrate (1.9632 g, 0.00870 mol) was added, and the mixture was stirred for 30 minutes in an 80 ° C. oil bath under a nitrogen stream. After cooling the reaction solution, a 5% aqueous solution of sodium carbonate was added to neutralize and concentrate, and the residue was extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated to obtain a pale yellow foamy substance. This was purified by subjecting it to silica gel column chromatography (chloroform / methanol = 70/1) to obtain 0.8781 g of compound (I′-1) (yield 91.9%) as a white foamy substance. ¹ H-NMR (CDCl ₃ ): δ 2.10 (s, 3
H), 2.74 (dd, 1H, J = 6.4, 15.6H)
z), 3.20 (d, 1H, J = 15.6 Hz), 3.
2-3.8 (b, 10H), 4.29 (d, 1H, J =
14.8 Hz), 4.75 (d, 1H, J = 14.8H
z), 4.80 (d, 1H, J = 15.0 Hz), 4.
90 (d, 1H, J = 15.0 Hz), 5.35 (s,
1H), 6.01 (d, 1H, J = 6.4Hz), 6.
62 (d, 1H, J = 8.3 Hz), 6.80 (d, 1)
H, J = 8.3 Hz), 6.81 (s, 1H), 7.1
-7.4 (m, 11H) MASS (EI): 550 (M ⁺ )

Example 25, Method B Step (o) 4-[[(S) -2-Butyl-5-diphenylacetyl-1-[(2 '-(1H-tetrazol-5-yl) biphenyl-4- Iyl) methyl] -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridine-6
-Yl] carbonyl] morpholine (I-31) compound (XIII-10) (0.1644 g, 0.00
To a solution of 0243 mol) in o-xylene (2.5 ml) was added trimethyltin azide (0.0998 g, 0.0
(00485 mol) was added, and the mixture was stirred under a nitrogen stream in a 120 ° C. oil bath for 90 hours. After cooling the reaction solution, the insoluble matter was collected by filtration, washed with hot toluene and dried under vacuum. The pale yellow solid obtained was dissolved in MeOH (1.8 ml) and
N HCl _{a q} . (0.9 ml) was added and the mixture was stirred at room temperature for 15 minutes. 1N NaOH _{a q} . Add PH4
And concentrated, and the residue was extracted with CHCl ₃ . The chloroform layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated to obtain a pale yellow foamy substance. This is silica gel column chromatography (chloroform / methanol = 10/1).
The compound (I-31) (0.1281)
g, yield 73.3%) was obtained as a white foam. ¹ H-NMR (CDCl ₃ + D ₂ O): δ 0.92 (t,
3H, J = 7.3 Hz), 1.35 (sext, 2HJ
= 7.3 Hz), 1.52-1.73 (m, 2H),
1.38-2.75 (m, 4H), 3.20-3.67
(M, 8H), 3.76 (d, 1H, J = 15.1H
z), 4.54 (d, 1H, J = 15.1 Hz), 4.
92 (d, 1H, J = 16.5 Hz), 5.05 (d,
1H, J = 16.5 Hz), 5.14 (s, 1H),
5.81 (bs, 1H), 6.92-7.96 (m, 1
8H), IR (ν _max , KBr / disk): 3425, 163
5,1445,1405,1225,1108,74
8,700 cm ^-1 MASS (FAB): 721 (M ⁺ )

Example 26, Method B Step (p) 4-[[(S) -5-diphenylacetyl-1-
[(2 '-(1H-Tetrazol-5-yl) biphenyl-4-yl) methyl] -4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-6-yl] carbonyl ] Morpholine (I-24) Compound (XIII-5) (1.1103g) (0.00
122%) in THF (11 ml) solution with 12% HC
laq (5.5 ml) was added, and the mixture was stirred at room temperature for 4 hours.
10% NaOH aq. Was added to neutralize and then concentrated. 1N NaOHaq. Was added and dissolved, and the insoluble matter was filtered off. The filtrate was diluted with 1N HClaq. Add PH4
And extracted with CHCl ₃ . The chloroform layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated to obtain a pale yellow foamy substance. This was purified by subjecting to silica gel column chromatography (chloroform / methanol = 10/1), and compound (I-24) (0.7413 g, yield 91.
1%) as a white foam. ¹ H-NMR (D ₂ O + NaOD) δ: 2.71 (dd,
1H, J = 7.2 Hz), 2.80 (d, 1H, J = 1
5.1 Hz), 3.2-3.8 (b, 8H), 4.27
(D, 1H, J = 15.1 Hz), 5.85 (b, 1
H), 6.8-8.1 (m, 19H) MASS (FAB): 665 (M ⁺ ) Elemental analysis value C ₃₉ H ₃₆ N ₈ O ₃ C (%) H (%) N (%) calculation Value 70.46 5.46 16.86 Measured value 70.55 5.40 16.71

Example 27, Method B Step (q) 4-[[(S) -1-[[4- (2-carboxybenzamido) -3-methyl] phenyl] methyl] -5-diphenylacetyl-4, 5,6,7-Tetrahydro-1H
-Imidazo [4,5-c] pyridin-6-yl] carbonyl] morpholine (I-23) compound (I'-1) (0.8007 g, 0.00146
phthalic anhydride (0.3236 g, 0.00219 mol) in a solution of ethyl acetate in 12 ml of ethyl acetate at room temperature with stirring.
Of ethyl acetate (3.3 ml) was added and the mixture was stirred for 23 hours. The reaction solution was filtered, and the obtained white solid was washed with ethyl acetate and then dried to give compound (I-23) (0.8
691 g, yield 85.5%, m.p. p. 191-196
C) was obtained. ¹ H-NMR (D ₂ O + NaOD) δ: 2.24 (s.3)
H), 2.30, 2.75 (each dd, 1H, J
= 5.6, 16.1 Hz), 2.95, 3.11 (ea)
ch d, 1H, J = 16.1 Hz), 3.2-3.8
(B, 8H), 3.9-4.1 (m, 1H), 5.70
(B, 1H), 6.9-8.0 (m, 17H), 9.7
(B, 1H) MASS (FAB): 698 (M ⁺ ) Elemental analysis value C ₄₁ H ₃₉ N ₅ O ₆ C (%) H (%) N (%) calculated value 70.57 5.63 10.04 Actual value 70.79 5.48 10.01 In the same manner, the compounds in Table 18 and Tables 19-1 and 19-2 were synthesized.

[0101]

[Table 18]

[0102]

[Table 19-1]

[Table 19-2] The compounds in Tables 20-1 and 20-2 were synthesized.

[0103]

[Table 20]

Example 28, Method B Step (r) (S) -3- (2-n-Butyl-1-triphenylmethylimidazol-5-yl) -2- (triphenylmethylamino) propane-1- All (XXIV-3) Compound (XIX-3) (1.0288 g, 0.0012)
A solution of 9 mol) in dryTHF (10 ml) was stirred under ice-cooling, and 1.0 M (nBu) ₄ NF / THF (2.6 m) was added.
1, 0.00258 mol), and cooled with ice for 30 minutes,
Further, the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into water and E
After extraction with tOAc, the organic layer was washed with sat. NaClaq. Wash, dry with Na ₂ SO ₄ and concentrate to a white foam (1.0
896 g, 100% up) was obtained. This is subjected to silica gel column chromatography (hexane / aceton).
e = 5/1) and purified to give compound (XXIV-3)
(0.7912 g, yield 89.8%) was obtained as a white foam. ¹ H-NMR (CD ₂ Cl ₂ ): δ 0.59 (t, 3)
H, J = 7.3 Hz), 0.91 (sext, 2H, J
= 7.3 Hz), 1.11 (quint, 2H, J =
7.3 Hz), 1.55 (bs, 1H, OH), 1.7
8-1.85 (m, 3H), 2.03 (b, 1H, N
H ), 2.23 (dd, 1H, j = 3.2, 14.4H)
z), 2.80 (b, 1H, C H ), 2.95 (dd,
1H, J = 6.4, 11.5 Hz), 3.48 (dd,
1H, J = 3.2, 11.5 Hz), 6.14 (s, 1
H), 7.10-7.51 (m, 30H) IR (ν _max , KBr): 3452, 3105, 290.
0,2975,2905,1510,1456,141
0,1160,1036,766,744,702,6
A compound was synthesized in the same manner as 40 cm ⁻¹ . Shown in the table.

[0105]

[Table 21]

Example 29, Method B Step (s) (S) -3- (2-n-Butyl-1-triphenylmethylimidazol-5-yl) -2- (trimethylphenylamino) propanoic acid (XXV- 3) Compound (XXIV-3) (0.4063 g, 0.000
596 mol) in DMF (4.0 ml), PDC
(0.7845 g, 0.00208 mol) was added, and the mixture was stirred at room temperature for 8 hours. The reaction solution was poured into water and CH ₂
After extraction with Cl ₂ , the organic layer was washed with water and washed with sat. NaClaq.
Wash, dry with Na ₂ SO ₄ and concentrate to a reddish brown oil (0.5
745 g, 100% up) was obtained. This is subjected to silica gel column chromatography (hexane / aceton).
e = 2/1 → 1/2, and CHCl ₃ / MeOH = 30
/ 1) and purified to give compound (XXV-3) (0.1
(256 g, yield 39.3%) was obtained as a pale yellow oil. ¹ H-NMR (CDCl ₃ ): 0.59 (t, 3H, J =
7.3 Hz), 0.91 (sext, 2H, J = 7, 3)
Hz), 1.16 (quint, 2H, J = 7.3H)
z), 1.68-1.79 (m, 3H), 2.31 (d
d, 1H, J = 9.1, 15.3 Hz), 3.53
(D, 1H, J = 9.1 Hz), 5.93 (s, 1
H), 7.04-7.45 (m, 30H) IR (ν _max , KBr): 3025, 2980, 17
15, 1608, 1510, 1460, 1410, 13
90, 1370, 1190, 1158, 910, 73
A compound was synthesized in the same manner as 0,703 cm ⁻¹ . It shows in Table 22.

[0107]

[Table 22]

Example 30, Method B Step (t) (S) -2-Amino-3- (2-n-butyl-1H-imidazol-5-yl) propanoic acid (X
XV'-3) ', and (S) -2-n-butyl-4,
5,6,7-Tetrahydro-1H-imidazo [4,5-
c] Pyridine-6-carboxylic acid, hydrochloride (XXVI-3) compound (XXV-3) (0.3308 g, 0.0004
75 mol) with 1N HClaq. (3.3 ml) 37%
HCHOaq (0.2 ml) was added, 40 minutes at room temperature,
The mixture was stirred in a 120 ° C. oil bath for 4 hours. After cooling the reaction solution, the insoluble matter was filtered off, washed with water, the aqueous layer was washed with Et ₂ o, and then concentrated.
After drying, compound (XXVI-3) (0.1401 g)
Yield 99.5%) was obtained as a yellow viscous material. ¹ H-NMR (D ₂ O + NaOD) δ: 0.95 (t, 3
H, J = 7.3 Hz), 1.40 (sext, 2H, J
= 7.3 Hz), 1.80 (quint, 2H, J =
7.3 Hz), 3.03 (t, 2H, J = 7.3H)
z). 3.0-3.4 (m, 2H), 3.8-4.3
(M, 2H) MASS (FAB): 223 (M-2HCl) A compound was similarly synthesized. It shows in Table 23.

[0109]

[Table 23] Compound (XXV-3) (0.3001 g, 0.0004
3 mol), 1N HClaq. (3.0 ml),
The same reaction operation was performed using 37% HCHOaq. Compound (XXV′-3) (0.1225
g, 100% yield) was obtained as a yellow viscous material. ¹ H-NMR (D ₂ O + NaOD) δ: 0.96 (t, 3
H, J = 7.3 Hz, 1.39 (sext, 2H, J
= 7.3 Hz), 1.82 (quint, 2H, J =
7.3 Hz, 2.5-3.7 (m, 3H), 3.07
(T, 2H, J = 7.3 Hz), 6.85 (bs, 1
H) MASS (FAB): 211 (M-2HCl) A compound was synthesized in the same manner. It is shown in Table 24.

[0110]

[Table 24]

Example 31, Method B Step (u) (S) -2-n-butyl-5-diphenylacetyl-
4,5,6,7-Tetrahydro-1H-imidazo [4,5-c] pyridine-6-carboxylic acid (XXVII-3) diphenylacetic acid (0.3114g, 0.00147mo)
l), DCCl (0.3027g, 0.00147mo)
l), HBTA (0.1983g, 0.00147mo)
l) was dissolved in dry THF (8.0 ml), and the solution was added to room temperature for 2 times.
Stir for 0 minutes. Compound (XXVI-3) (0.
1358 g, 0.000458 mol) dry TH
F (2.7 ml) solution and dry triethylam
ine (0.13 ml, 0.000963 mol) was added, and the mixture was stirred at room temperature for 16 hours. The insoluble matter was filtered off, washed with THF, and the filtrate / washing solution was concentrated to give a crude oil (0.3065
g) was obtained. This (THF / MeOH = 1/1)
(6.0 ml) and dissolved in 1N HClaq (2.0 m
l) was added and allowed to stand for 8 hours, then (THF / MeO)
H = 1/1) (6.0 ml), 1N NaOHaq
(4.0 ml) was added and left for 8 hours. The reaction solution was concentrated and purified by silica gel column chromatography (chloroform / methanol = 10/1) to give the compound (X
XVII-3) (0.0829 g, yield 43.3%) was obtained as a white foam. ¹ H-NMR (D ₂ O-NaOD) δ: 0.92 (t, 3
H, J = 7.2 Hz), 1.39 (sext, 2H, J
= 7.2 Hz), 1.82 (quint, 2H, J =
7.2 Hz), 2.3-2.9 (m, 4H), 3.9-
4.8 (m, 2H), 5.51 (s, 1H), 5.73
(Bs, 1H), 7.1-7.7 (m, 1OH)) MASS (FAB): 417 (M ⁺ ). A compound was synthesized in the same manner. It shows in Table 25.

[0112]

[Table 25]

Example 32, Method B Step (v) (S) -2-n-butyl-1-[(4-methoxycarbonylphenyl) methyl] -5-diphenylacetyl-
4,5,6,7-Tetrahydro-1H-imidazo [4
5-c] pyridine-6-carboxylic acid (XIV-8) compound (XXVII-3) (0.0791 g, 0.00
(0189 mol) in a dry DMF (1.6 ml) solution was added with methyl 4- (bromomethyl) b.
enzoate (0.0521g, 0.000227m
ol), K ₂ CO ₃ (0.0314 g, 0.000227)
mol) was added and the mixture was vigorously stirred at room temperature for 20 hours. The reaction mixture was poured into water, extracted with EtOAc, washed with water, dried over anhydrous sodium sulfate, and concentrated to give a pale yellow oily substance. This was purified by subjecting it to silica gel column chromatography (hexane / acetone = 1/2) to obtain the compound (XIV-8,
0.0331 g) (mp 176-180 ° C.), its 3-position isomer (0.0382 g), a mixture of both (0.00
18 g, yield 68.2%) was obtained as colorless crystals. MASS (FAB): 566 (M ⁺ )

Example 33 1. Binding test with receptor The total binding in the presence of each drug was measured as follows. That is, a test drug having a predetermined concentration (dissolved in dimethyl sulfoxide, and then 2-fold diluted with a buffer attached to the drug discovery system was used for the assay; 0.025 m
1), tracer (0.025 ml), and receptor (0.2 ml) to make a total of 0.25 ml, and incubated (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), the reaction solution was suction filtered (AT _1).
GF / C filter paper was used for AT ₂ and GF / B filter paper was used for AT ₂ )
did. The filter paper (tracer / receptor conjugate) after suction filtration is a γ-well counter (ARC-500, Alo
ka). Non-specific binding was determined by adding a large excess of displacer and operating in the same manner. The specific binding of the test drug at a predetermined concentration was the total binding minus the nonspecific binding. In AT ₁ and AT ₂ , a test drug and a control drug were used at predetermined concentrations, and the ratio (%) at which the test drug inhibited the binding between the radioligand and the receptor was determined. The substance is antagonize receptor AT ₁ and AT ₂ angiotensin II, the AT ₂ is that of the inner R ¹ is H for the substance, and R ¹ is the other than H, especially antagonizing AT _1. USP 5,091,39
The 0, compounds claimed including comparative substance regardless of R ^1, it has been described that selectively antagonize AT _2, this application inventors, the present substance and comparative substance is R ¹ It was found that the difference specifically antagonized the AT ₁ and AT ₂ receptors, respectively, and that the activity of this substance far exceeded that of the comparative substance.

[0115]

[Table 26] Binding inhibition rate (%) at 1 μM of test substance Test substance AT ₁ AT ₂ Main substance NO. I-1 0 100 〃 I-2 0 100 〃 I-7 0 100 〃 I-12 100 0 〃 I-17 100 0 〃 I-19 100 0 This substance No. I-21 100 This substance No. I-23 100 This substance No. I-24 100 This substance No. I-30 100 This substance No. I-31 100 This substance No. I-32 100 This substance No. I-40 100 Comparative substance No. PD123177 0 65 Comparative substance No. Dup753 70 0 Comparative substance 1 0 71 Comparative substance 2 0 72 Comparative substance 26 78 0 Comparative substance 27 0 76 Comparative substance 50 75 0

At AT ₁ Receptor: Rabbit adrenal tracer: ³ H-Angiotensin II Control drug: DuP 753 (displacer): DuP 753 AT ₂ Receptor: Bovine cerebellar cortex tracer: ¹²⁵ I-Tyr ⁴ -Angiotensin II (displacer) ): Angiotensin II (human)

PD123177

[0118]

[Chemical formula 23] And DuP753

[0119]

[Chemical formula 24] Is Bioorganic & MedicalChe
misty Letters, 1 (12), 711-
716, 1991. It is described in.

[0120]

[Chemical 25]

Comparative substances 1, 2, 26, 27 and 50 were described in USP 5,091,390 (table).
1) A compound.

[0122]

[Table 27] Comparative substance R ¹ R ² R ³ X R ⁴ R ⁶ 1 H COOH COCH (ph) ₂ NHCO COOH 3-CH ₃ 2 H COOCH ₃ COCH (ph) ₂ NHCO COOH 3-CH ₃ 26 C ₃ H ₇ COOH COCH (ph) ₂ single bond tetrazole 3-CH ₃ 27 H COOH COCH (ph) ₂ single bond tetrazole H 50 C ₃ H ₇ COOH CHCH (ph) ₂ single bond tetrazole H

[Table 18-1]

[Table 18-2]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI technical display location C07D 403/10 233 7602-4C 403/12 233 7602-4C // (C07D 403/10 233: 00 257: 00) (C07D 403/12 233: 00 257: 00)

Claims (14)

[Claims] 1. A compound represented by the general formula (I): Or a pharmaceutically acceptable salt thereof. [Wherein R ¹
Is a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, C
₃ -C ₆ alkenyl group, C ₃ -C ₆ alkynyl group, R ²⁰ -
(CH _{2) n} - (wherein, R ²⁰ is, C ₃ -C ₈ cycloalkyl group, a naphthyl group, a phenyl group, or, C ₁ -C ₄ alkyl group, a halogen atom, a trifluoromethyl group, a hydroxy group, A C ₁ -C ₄ alkoxy group, a C ₁ -C ₃ acyloxy group,
Amino group, N-mono-C ₁ -C ₄ alkylamino group, N-
Di-C ₁ -C ₄ alkylamino group, C ₁ -C ₄ thioalkyl group, C ₁ -C ₃ alkylsulfonyl group, nitro group, or —NHCOR ²¹ (wherein R ²¹ is a C ₁ -C ₃ alkyl group. , Phenyl group, C ₁ -C ₃ alkylphenyl group, or phenyl substituted with 1 to 5 of any of amino or C _{1 to} C ₄ alkylaminophenyl group), and n is 1 to 6 It is an integer. ), R ²⁰ -C (O)-
(In the formula, R ₂₀ has the same meaning as described above.) Or R ²⁰ −
CH (OH)-(in the formula, R ²⁰ has the same meaning as described above), R ² represents a carbamoyl group, a mono- or di-C ₁ -C ₆ alkylcarbamoyl group, or a 4- to 6-membered ring. Is a heterocyclic carbamoyl group, R is an amino group, a carboxy group, a (1H-tetrazol-5-yl) phenyl group, a carboxyphenyl group, a carboxybenzamide group, a (1H-tetrazol-5-yl) benzamide group, a carboxy group. Phenylcarbamoyl group, or (1H-
It is a tetrazol-5-yl) phenylcarbamoyl group, and R ³ is —CH ₂ (phenyl), —CH (phenyl).
_2, -CH (phenyl) CH _3, -CH (phenyl) (cyclohexyl), - CH ₂ CH ₂ (phenyl), - CH ₂
(C ₁ -C ₆ alkoxyphenyl), or a -CH ₂ (hydroxyphenyl), R ^4, R ^7, and R ⁸ are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group. ] 2. R ₁ is a hydrogen atom or a C ₁ -C ₆ alkyl group, and R ² is —CONH ₂ , —CONHCH ₃ , —
_{CON (CH 3) 2, -CONH} (C 2 H 5), - CON
(C ₂ H ₅ ) ₂ , embedded image And R is an amino group, a carboxy group, 2- (1H-
Tetrazol-5-yl) phenyl group, 2-carboxyphenyl group, carboxybenzamide group, 2- (1H-
A tetrazol-5-yl) benzamide group, a 2-carboxyphenylcarbamoyl group, or a 2- (1H-tetrazol-5-yl) phenylcarbamoyl group, and R
³ is —CH (phenyl) ₂ , —CH ₂ (phenyl), —
CH (phenyl) CH _3, -CH (phenyl) (cyclohexyl), - CH ₂ CH ₂ (phenyl), - CH ₂ (p
- methoxyphenyl), or a -CH ₂ (p-hydroxyphenyl), R ^4, R ^7, and R ⁸ are each independently hydrogen atom or a C ₁ -C ₂ alkyl group, in claim 1 The described compound or a pharmaceutically acceptable salt thereof. 3. A compound represented by the general formula (VIII ′): Or a salt thereof. [In the formula, R ¹ represents a hydrogen atom, a halogen atom, a C _{1 to} C ₆ alkyl group, a C _{3 to} C ₆ alkenyl group, a C _{3 to} C ₆ alkynyl group, R ²⁰ — (CH ₂ ) _n — (in the formula, , R ²⁰ is a C ₃ -C ₈ cycloalkyl group, a naphthyl group,
Phenyl group, or, C ₁ -C ₄ alkyl group, a halogen atom, a trifluoromethyl group, hydroxy group, C ₁ -C ₄ alkoxy, C ₁ -C ₃ acyloxy group, an amino group, N-
Mono -C ₁ -C ₄ alkylamino group, N- di -C ₁ -C ₄ alkylamino group, C ₁ -C ₄ thioalkyl radical, C ₁ -C ₃ alkylsulfonyl group, a nitro group or a -NHCO,
1 to any one of R ²¹ (in the formula, R ²¹ is a C _{1 to} C ₃ alkyl group, a phenyl group, a C _{1 to} C ₃ alkylphenyl group, or an amino or a C _{1 to} C ₄ alkylaminophenyl group)
Is phenyl substituted with 5 and n is 1-6
Is an integer. ^{), R 20 -C (O)} -. ( Wherein, R ²⁰ is as defined above), or R ²⁰ -CH (OH) -
(Wherein R ²⁰ has the same meaning as described above), and R ⁴
Is a hydrogen atom or a C ₁ -C ₆ alkyl group, and R ⁶ is
A nitro group, a (1-triphenylmethyl-1H-tetrazol-5-yl) phenyl group, a cyano group, a C ₁ -C ₃ alkoxycarbonyl group, or a cyanophenyl group, and R
₇ and R ⁸ are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group, R ⁹ is a hydrogen atom or a t-butoxycarbonyl group, and R ¹⁰ is a hydrogen atom or C ₁ -C ₆ It is an alkyl group. ] 4. R ¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group, R ⁴ is a hydrogen atom or a C ₁ -C ₂ alkyl group, R ⁶ is a nitro group, 2- (1 -Triphenylmethyl-1H-tetrazol-5-yl) phenyl group or a 2-cyanophenyl group, R ⁷ and R ⁸ are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group, R 7 ^Ten
Is a hydrogen atom or a C ₁ -C ₆ alkyl group.
Or a salt thereof. 5. A compound represented by the general formula (XXVIII): Or a salt thereof. [In the formula, R ¹ represents a hydrogen atom, a halogen atom, a C _{1 to} C ₆ alkyl group, a C _{3 to} C ₆ alkenyl group, a C _{3 to} C ₆ alkynyl group, R ²⁰ — (CH ₂ ) _n — (in the formula, , R ²⁰ is a C ₃ -C ₈ cycloalkyl group, a naphthyl group,
Phenyl group, or, C ₁ -C ₄ alkyl group, a halogen atom, a trifluoromethyl group, hydroxy group, C ₁ -C ₄ alkoxy, C ₁ -C ₃ acyloxy group, an amino group, N-
Mono -C ₁ -C ₄ alkylamino group, N- di -C ₁ -C ₄ alkylamino group, C ₁ -C ₄ thioalkyl radical, C ₁ -C ₃ alkylsulfonyl group, a nitro group or a -NHCO,
1 to any one of R ²¹ (in the formula, R ²¹ is a C _{1 to} C ₃ alkyl group, a phenyl group, a C _{1 to} C ₃ alkylphenyl group, or an amino or a C _{1 to} C ₄ alkylaminophenyl group)
Is phenyl substituted with 5 and n is 1-6
Is an integer. ), R ²⁰ —C (O) — (in the formula, R ²⁰ has the same meaning as described above), or R ²⁰ —CH (OH) —.
(Wherein R ²⁰ has the same meaning as described above) and R ¹⁵
Is —CH ₂ —R ¹⁷ (wherein R ¹⁷ is a hydroxy group or a t-butyldimethylsilyloxy group), or —
C (O) -R ¹⁷ (in the formula, R ¹⁷ has the same meaning as described above), and R ¹⁶ is a hydrogen atom or a triphenylmethyl group. (However, when R ¹ and R ¹⁶ are hydrogen atoms, R ¹⁵ is not —CH ₂ —OH, and when R ¹ is a hydrogen atom or a methyl group and R ¹⁶ is a hydrogen atom. , R ¹⁵ is not —COOH.)] 6. A compound represented by the general formula (XXIX): Or a salt thereof. [In the formula, R ¹ represents a hydrogen atom, a halogen atom, a C _{1 to} C ₆ alkyl group, a C _{3 to} C ₆ alkenyl group, a C _{3 to} C ₆ alkynyl group, R ²⁰ — (CH ₂ ) _n — (in the formula, , R ²⁰ is a C ₃ -C ₈ cycloalkyl group, a naphthyl group,
Phenyl group, or, C ₁ -C ₄ alkyl group, a halogen atom, a trifluoromethyl group, hydroxy group, C ₁ -C ₄ alkoxy, C ₁ -C ₃ acyloxy group, an amino group, N-
Mono -C ₁ -C ₄ alkylamino group, N- di -C ₁ -C ₄ alkylamino group, C ₁ -C ₄ thioalkyl radical, C ₁ -C ₃ alkylsulfonyl group, a nitro group or a -NHCO,
1 to any one of R ²¹ (in the formula, R ²¹ is a C _{1 to} C ₃ alkyl group, a phenyl group, a C _{1 to} C ₃ alkylphenyl group, or an amino or a C _{1 to} C ₄ alkylaminophenyl group)
Is phenyl substituted with 5 and n is 1-6
Is an integer. ^{), R 20 -C (O)} -. ( Wherein, R ²⁰ is as defined above), or R ²⁰ -CH (OH) -
(Wherein R ²⁰ has the same meaning as described above) and R ¹⁵
Is —CH ₂ R ¹⁷ (wherein R ¹⁷ is a hydroxy group or t-
Butyldimethylsilyloxy group) or -C (O) -R ¹⁷
(Wherein R ¹⁷ has the same meaning as described above), and R ^{17
3 'is} a hydrogen atom, -COCH ₂ (phenyl), - COC
H (phenyl) _2, -COCH (phenyl) CH _3, -C
OCH (phenyl) (cyclohexyl), -COCH ₂
CH _{2 (phenyl), - COCH 2 (C 1} ~C 6 alkoxyphenyl), or -COCH ₂ (hydroxyphenyl)
Is. (However, when R ¹ and R ^{3 ′} are hydrogen atoms, R ¹⁵ is not —COOH.) 7. R ¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group, R ¹⁵ is —COOH, and R ^{3 ′} is —CO.
The compound or salt thereof according to claim 6, which is CH (phenyl) ₂ or —COCH (phenyl) (cyclohexyl). 8. A compound represented by the general formula (XXX): Or a salt thereof. [In the formula, R ¹ represents a hydrogen atom, a halogen atom, a C _{1 to} C ₆ alkyl group, a C _{3 to} C ₆ alkenyl group, a C _{3 to} C ₆ alkynyl group, R ²⁰ — (CH ₂ ) n- (wherein , R ²⁰ is a C ₃ -C ₈ cycloalkyl group, a naphthyl group,
Phenyl group, or, C ₁ -C ₄ alkyl group, a halogen atom, a trifluoromethyl group, hydroxy group, C ₁ -C ₄ alkoxy, C ₁ -C ₃ acyloxy group, an amino group, N-
Mono -C ₁ -C ₄ alkylamino group, N- di -C ₁ -C ₄ alkylamino group, C ₁ -C ₄ thioalkyl radical, C ₁ -C ₃ alkylsulfonyl group, a nitro group or a -NHCO,
1 to any one of R ²¹ (in the formula, R ²¹ is a C _{1 to} C ₃ alkyl group, a phenyl group, a C _{1 to} C ₃ alkylphenyl group, or an amino or a C _{1 to} C ₄ alkylaminophenyl group)
Is phenyl substituted with 5 and n is 1-6
Is an integer. ^{), R 20 -C (O)} -. ( Wherein, R ²⁰ is as defined above), or R ²⁰ -CH (OH) -
(Wherein R ²⁰ has the same meaning as described above) and R ^{3 ′}
Is a hydrogen atom, -COCH ₂ (phenyl), -COCH
(Phenyl) ₂ , -COCH (Phenyl) CH ₃ , -CO
CH (phenyl) (cyclohexyl), - COCH ₂ C
H ₂ (phenyl), - COCH ₂ (C ₁ -C ₆ alkoxyphenyl), or -COCH a ₂ (hydroxyphenyl), R ^4, R ^7, and R ⁸ each independently represent a hydrogen atom or a C ₁ To C ₆ alkyl group, R ⁶ is a nitro group,
(1-Triphenylmethyl-1H-tetrazole-5-
Yl) phenyl group, cyano group, C ₁ -C ₃ alkoxycarbonyl group, or cyanophenyl group, and R ^{15 ′} is —
CH ₂ -R ¹⁹ (wherein, R ¹⁹ is hydrogen atom or a C ₁ -C ₆ alkyl group.), Or -C (O) -R ¹⁹ (wherein, R
¹⁹ has the same meaning as above. ). ] 9. R ¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group, and R ^{3 ′} is —COCH (phenyl) ₂ or —
COCH (phenyl) (cyclohexyl), R ⁶
Is a nitro group, 2- (1-triphenylmethyl-1H-
A tetrazol-5-yl) phenyl group, a cyano group, a methoxycarbonyl group, or a 2-cyanophenyl group,
R ⁴ , R ⁷ , and R ⁸ are each independently a hydrogen atom or a C _{1 to} C ₂ alkyl group, and R ¹⁹ is a hydrogen atom or C ₁ to
The compound according to claim 8, which is a C ₂ alkyl group, or a salt thereof. 10. A compound represented by the general formula (XIII): Or a salt thereof. [Wherein R ¹ is a halogen atom,
C ₁ -C ₆ alkyl group, C ₃ -C ₆ alkenyl group, C ₃ -C ₆
Alkynyl _{^{group, R 20 - (CH 2)}} n - ( wherein, R ²⁰ is, C
_{3 to} C ₈ cycloalkyl group, naphthyl group, phenyl group, or C _{1 to} C ₄ alkyl group, halogen atom, trifluoromethyl group, hydroxy group, C _{1 to} C ₄ alkoxy group, C ₁
To C ₃ acyloxy group, amino group, N-mono-C _{1 to} C ₄
Alkylamino group, N-di-C ₁ -C ₄ alkylamino group, C ₁ -C ₄ thioalkyl group, C ₁ -C ₃ alkylsulfonyl group, nitro group, or —NHCOR ²¹ (wherein,
R ²¹ is phenyl substituted with 1 to 5 C ₁ -C ₃ alkyl groups, phenyl groups, C ₁ -C ₃ alkylphenyl groups, or amino or C ₁ -C ₄ alkylaminophenyl groups). And n is an integer from 1 to 6. ), R ²⁰ —C (O) — (in the formula, R ²⁰ has the same meaning as described above), or R ²⁰ —CH (OH) — (in the formula, R ²⁰
Has the same meaning as above. ), R ^{2 ′} is an amino group, a mono- or di-C ₁ -C ₆ alkylamino group, or a 4- to 6-membered heterocyclic amino group, and R ³ is —CH ₂
(Phenyl), - CH (phenyl) _2, -CH (phenyl) CH _3, -CH (phenyl) (cyclohexyl),
-CH ₂ CH _{2 (phenyl), - CH 2 (C 1} ~C 6 alkoxyphenyl), or -CH ₂ (hydroxyphenyl)
And R ⁴ , R ⁷ , and R ⁸ are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group, R ⁶ is a nitro group, (1-triphenylmethyl-1H-tetrazole-
5-yl) phenyl group, C ₁ -C ₃ alkoxycarbonyl group, cyano group, or 2-cyanophenyl group. ] 11. R ¹ is a hydrogen atom or a C ₁ -C ₆ alkyl group, and R ^{2 ′} is —NH ₂ , —NHCH ₃ , —N (C
_{H 3) 2, -NH (C} 2 H 5), N (C 2 H 5) 2, embedded image And R ³ is —CH (phenyl) ₂ , —CH (phenyl) (cyclohexyl), R ⁴ , R ⁷ , and R
⁸ is each independently a hydrogen atom or a C ₁ -C ₂ alkyl group, R ⁶ is a nitro group, 2- (1-triphenylmethyl-1H-tetrazol-5-yl) phenyl group,
The compound or a salt thereof according to claim 10, which is a methoxycarbonyl group, a cyano group, or a 2-cyanophenyl group. 12. An angiotensin II antagonist comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof. 13. A compound represented by the general formula (I): An AT ₁ receptor antagonist of angiotensin II, which comprises the compound or a pharmaceutically acceptable salt thereof. [Wherein R ¹ is a halogen atom, a C _{1 to} C ₆ alkyl group, a C _{3 to} C ₆ alkenyl group, a C _{3 to} C ₆ alkynyl group, R 1
_{^{20 - (CH 2) n -}} ( wherein, R ²⁰ is, C ₃ -C ₈ cycloalkyl group, a naphthyl group, a phenyl group, or, C ₁ -C ₄ alkyl group, a halogen atom, a trifluoromethyl group, a hydroxy Group, C ₁ -C ₄ alkoxy group, C ₁ -C ₃ acyloxy group, amino group, N-mono-C ₁ -C ₄ alkylamino group,
N-di-C ₁ -C ₄ alkylamino group, C ₁ -C ₄ thioalkyl group, C ₁ -C ₃ alkylsulfonyl group, nitro group,
Or —NHCOR ²¹ (wherein R ²¹ is a C _{1 to} C ₃ alkyl group, a phenyl group, a C _{1 to} C ₃ alkylphenyl group, or an amino or a C _{1 to} C ₄ alkylaminophenyl group)
Is phenyl substituted with 1 to 5 of any of the above, and n is an integer of 1 to 6. ), R ²⁰ -C (O)-
(In the formula, R ²⁰ has the same meaning as described above.) Or R ²⁰ −
CH (OH)-(in the formula, R ²⁰ has the same meaning as described above), R ² represents a carbamoyl group, a mono- or di-C ₁ -C ₆ alkylcarbamoyl group, or a 4- to 6-membered ring. Heterocyclic carbamoyl group, R is amino group, carboxy group, (1H-tetrazol-5-yl) phenyl group, carboxyphenyl group, carboxybenzamide group, (1H-tetrazol-5-yl) benzamide group, carboxyphenyl Carbamoyl group, or (1H-
It is a tetrazol-5-yl) phenylcarbamoyl group, and R ³ is —CH ₂ (phenyl), —CH (phenyl).
_2, -CH (phenyl) CH _3, -CH (phenyl) (cyclohexyl), - CH ₂ CH ₂ (phenyl), - CH ₂
(C ₁ -C ₆ alkoxyphenyl), or a -CH ₂ (hydroxyphenyl), R ^4, R ^7, and R ⁸ are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group. ] 14. A compound represented by the general formula (I): An AT ₂ receptor antagonist of angiotensin II, which comprises the compound or a pharmaceutically acceptable salt thereof. [Wherein R ¹ is a hydrogen atom, R ² is a carbamoyl group, a mono- or di-C ₁ -C ₆ alkylcarbamoyl group, or a 4- to 6-membered heterocyclic carbamoyl group, and R is , Amino group, carboxy group, (1H-tetrazol-5-yl) phenyl group, carboxyphenyl group,
Carboxybenzamide group, (1H-tetrazole-5
- yl) benzamide group, carboxy phenyl carbamoyl group, or (a 1H- tetrazol-5-yl) phenylcarbamoyl group, R ³ is, -CH ₂ (phenyl), - CH (phenyl) _2, -CH (phenyl) C
H _3, -CH (phenyl) (cyclohexyl), - CH ₂
CH ₂ (phenyl), —CH ₂ (C ₁ -C ₆ alkoxyphenyl), or —CH ₂ (hydroxyphenyl),
R ⁴ , R ⁷ , and R ⁸ are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group. ]