JP2000159671A - Arterialization inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject inhibitor having angiotensin II antagonism, improved in effect, adverse effect, physical properties, complexity in handling, etc., by making the inhibitor include a specific compound (salt). SOLUTION: This inhibitor comprises (A) a compound (salt) of the formula [R1 and R2 are each a group capable of forming an anion or being converted into it; X is connection between phenylene and phenyl (through a spacer of <=2 atom chain); the ring A is a (substituted) benzene ring; R3 is a (substituted) hydrocarbon residue which may be bonded through a hetero atom] as an active ingredient. For example, 2-ethoxy-1- [2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl) benzimidazole-7-carboxylic acid (salt), etc., may be cited as the compound of the formula. This inhibitor is useful as a preventive or a therapeutic agent for various inflammatory diseases such as tumor, diabetic retinopathy, rheumatism, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to angiotensin
The present invention relates to a prophylactic or therapeutic agent for a tumor, diabetic retinopathy, various inflammatory diseases (such as rheumatism) based on the angiogenesis inhibitory action of a compound having an II antagonistic action.

[0002]

2. Description of the Related Art There are many diseases in which angiogenesis, a phenomenon in which the vascular system is newly constructed, is involved in the onset and progress of the disease. It is typical. In order for a solid tumor to grow, it is essential to provide a way to supply nutrients and oxygen and remove waste products by angiogenesis. In metastasis, which is a major problem in the current treatment of cancer, angiogenesis is an important step in terms of securing the path.
Diabetic retinopathy is an angiogenesis itself, and leads to blindness if left unchecked. Therefore, suppression of angiogenesis is considered to lead to prevention and treatment of the above-mentioned diseases, and search for angiogenesis inhibitors has been conducted. As a result, the clinical efficacy of several substances is currently under investigation [Folkman, J., Scientific American, 275 , 116 (1996).
September)].

[0003]

There is a need for an angiogenesis inhibitor that has been further improved in its effects, side effects, physical properties, handling complexity, and the like, as compared with the previously reported angiogenesis inhibitors.

[0004]

As a result of intensive studies to solve such problems, the present inventors have found that a compound having an angiotensin II antagonistic activity has an excellent angiogenesis inhibitory effect. As a result of further research based on the findings, the present invention has been completed. That is, the present invention relates to (1) a compound of the formula (I) having an angiotensin II antagonistic action

Embedded image (Wherein, R ¹ represents a group capable of forming an anion or a group capable of changing to an anion, X represents that a phenylene group and a phenyl group are bonded directly or via a spacer having an atomic chain of 2 or less; Represents an integer of 1 or 2, ring A represents a benzene ring which may further have a substituent, R ² represents a group capable of forming an anion or a group capable of forming an anion, and R ³ represents a heteroatom. An angiogenesis inhibitor comprising a compound represented by the formula (1) or a salt thereof: (2) angiotensin II antagonist The compound having an effect is 2
-Ethoxy-1-[[2 '-(1H-tetrazole-5
-Yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid or a salt thereof (1).
(3) a compound having an angiotensin II antagonistic action:
-(Cyclohexyloxycarbonyloxy) ethyl
2-ethoxy-1-[[2 ′-(1H-tetrazole-
5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate or a salt thereof according to the above (1); (4) the compound having an angiotensin II antagonistic activity is 2
-Ethoxy-1-[[2 '-(2,5-dihydro-5-
Oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7
-The agent according to the above (1), which is a carboxylic acid or a salt thereof;
And so on.

In the above formula (I), examples of the group capable of forming an anion as R ¹ (group having a hydrogen atom which can be released as a proton) include (1) a carboxyl group,
(2) a tetrazolyl group, (3) trifluoromethanesulfonic acid amide group (-NHSO ₂ CF _3), (4) a phosphate group, (5) a sulfonic acid group, (6) N, S, 1 of the O
5 to 7 members including 5 or more (preferably 5 to 6 members)
Member), a monocyclic optionally substituted heterocyclic residue.

The above-mentioned "5- to 7-membered (preferably 5- to 6-membered) monocyclic optionally substituted heterocyclic residue containing one or more of N, S, and O" Is, for example,

Embedded image

Embedded image And the bond between the heterocyclic residue represented by R ¹ and the phenyl group to which the heterocyclic residue is bonded is as described above when g in the above formula represents —NH— or the like. Carbon-
The bond may be formed not only through a carbon bond but also through one of a plurality of nitrogen atoms. For example, if R ¹

Embedded image In the above formula, g is _{-CH 2 -, - NH -,} - O- or -
S (O) m-,> = Z,> = Z 'and> =
Z ″ represents a carbonyl group, a thiocarbonyl group, or an optionally oxidized sulfur atom (eg, S, S (O),
S (O) ₂ or the like (preferably a carbonyl or thiocarbonyl group, more preferably a carbonyl group);
Represents an integer of 0, 1 or 2.

The heterocyclic residue represented by R ¹ includes, for example,-as a proton donor such as an oxadiazolone ring, an oxadiazolothione ring or a thiadiazolone ring.
A group having an NH- or -OH group and a carbonyl group, a thiocarbonyl group, a sulfinyl group, or the like as a proton acceptor at the same time is preferable. Further, the heterocyclic residue represented by R ¹ may form a condensed ring by bonding cyclic substituents. The preferred heterocyclic residue represented by R ^1, 5 or 6-membered ring Further, a 5-membered ring residue is preferable. R ¹
As the heterocyclic residue represented by

Embedded image [Wherein, i represents -O- or -S-, j is> = O,
> = S or> = S (O) m, wherein m has the same meaning as described above) (among others, 2,5-dihydro-
5-oxo-1,2,4-oxadiazol-3-yl, 2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl, 2,5-dihydro-5 Oxo-1,2,4-thiadiazol-3-yl, especially 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) is preferred.

The heterocyclic residue (R ¹ ) has tautomers as shown below. For example,

Embedded image There are three tautomers of a ', b' and c 'such as

Embedded image Is a heterocyclic residue containing all of the above a ′, b ′ and c ′.

The group capable of forming an anion as R ¹ is
At a substitutable position, it may be protected with an optionally substituted lower (C _1-4 ) alkyl group or acyl group (eg, lower (C _2-5 ) alkanoyl, benzoyl, etc.). Examples of the optionally substituted lower (C _1-4 ) alkyl group include (1) a halogen atom, nitro, lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy and the like. A lower (C _1-4 ) alkyl group which may be substituted with 1 to 3 phenyl groups (eg, methyl, triphenylmethyl, p-methoxybenzyl, p-nitrobenzyl, etc.); (C _1-4 ) alkoxy-lower (C _1-4 ) alkyl group (eg,
Methoxymethyl, ethoxymethyl, etc.), (3) Formula -C
H (R ⁴ ) -OCOR ^{5 wherein} R ⁴ is (a) hydrogen,
(B) a linear or branched lower alkyl group having 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, etc.) ), shows the (c) linear or branched lower alkenyl group or (d) a cycloalkyl group of 3-8 carbon atoms 2-6 carbon atoms (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.), R ⁵ Is (a) a linear or branched lower alkyl group having 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl,
Isopropyl, n-butyl, isobutyl, sec-butyl,
t-butyl, n-pentyl, isopentyl, neopentyl, etc.), (b) a linear or branched lower alkenyl group having 2-6 carbon atoms, (c) a cycloalkyl group having 3-8 carbon atoms (eg, cyclopentyl) , Cyclohexyl, cycloheptyl, etc.) or an optionally substituted aryl group (eg, a halogen atom, nitro, lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy, phenyl) Or a naphthyl group)
-3 lower alkyl groups (eg, benzyl, p-chlorobenzyl, phenethyl, cyclopentylmethyl, cyclohexylmethyl, etc.); (d) cycloalkyl having 3-8 carbon atoms or an optionally substituted aryl group (eg, halogen A lower alkenyl group having 2-3 carbon atoms substituted by an atom, nitro, phenyl or naphthyl group optionally having lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy, etc. (eg, , Such as those having an alkenyl moiety such as vinyl, propenyl, allyl and isopropenyl, such as cinnamyl); (e) optionally substituted aryl groups (eg, halogen atoms such as phenyl, p-tolyl, naphthyl, nitro, lower (C _1-4) alkyl, lower (C _1-4) such as phenyl or naphthyl group which may have a like alkoxy), (f) the number of carbon atoms -6 linear or branched lower alkoxy groups (eg, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, isopentyloxy, Neopentyloxy, etc.),
(G) a linear or branched lower alkenyloxy group having 2 to 8 carbon atoms (eg, allyloxy, isobutenyloxy, etc.), (h) a cycloalkyloxy group having 3 to 8 carbon atoms (eg, cyclopentyloxy, cyclohexyloxy,
Such as cycloheptyloxy), (i) cycloalkyl having 3 to 8 carbon atoms (eg, cyclopentyl, cyclohexyl,
Cycloheptyl, etc.) or an optionally substituted aryl group (eg, halogen atom, nitro, lower (C _1-4 ))
Lower alkoxy groups having 1 to 3 carbon atoms (eg, benzyloxy, phenethyloxy, cyclopentylmethoxy, cyclohexylmethoxy, etc.) substituted with alkyl, phenyl or naphthyl group optionally having lower (C _1-4 ) alkoxy, etc. Methoxy, ethoxy, n-propoxy, isopropoxy and the like having an alkoxy moiety), (j) cycloalkyl having 3 to 8 carbon atoms (eg, cyclopentyl, cyclohexyl, cycloheptyl and the like) or optionally substituted Aryl group (eg, halogen atom, nitro, lower (C _1-4 ) alkyl, lower (C _1-4 )
A lower alkenyloxy group having 2 to 3 carbon atoms substituted with a phenyl or naphthyl group which may have an alkoxy or the like (eg, having an alkenyloxy moiety such as vinyloxy, propenyloxy, allyloxy, isopropenyloxy such as cinnamyloxy) Or (k) an optionally substituted aryloxy group (eg, a halogen atom such as phenoxy, p-nitrophenoxy, naphthoxy, nitro, lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy And the like, which may have a phenoxy or naphthoxy group). Also,
The group capable of forming an anion as R ¹ is, for example, the above-mentioned optionally substituted lower (C _1-4 ) alkyl group or acyl group (eg, lower (C _2-5 ) alkanoyl, benzoyl, etc.). In addition to the protecting group, at a substitutable position, a lower (C _1-4 ) alkyl group which may be substituted (for example, the “substituted or substituted” exemplified as the protecting group for the group capable of forming an anion as R ¹ ). And lower (C _1-4 ) alkyl groups which may be mentioned), a halogen atom,
Nitro, cyano, lower (C _1-4 ) alkoxy, 1-2
And may have a substituent such as amino which may be substituted with a plurality of lower (C _1-4 ) alkyl.

In the above formula, a group capable of forming an anion as R ¹ (a group having a hydrogen atom which can be liberated as a proton) is a group which can be converted under biological or physiological conditions (for example, in vivo enzyme). Or a group capable of forming an anion by a reaction such as oxidation, reduction, or hydrolysis in a living body (so-called prodrug), or a cyano or N-hydroxycarbamimidoyl group. (—C (＝ N—OH) —NH ₂ ) or (1) a carboxyl group, (2) a tetrazolyl group, each of which is protected by an optionally substituted lower (C _1-4 ) alkyl group or an acyl group. (3) trifluoromethanesulfonic acid amide group (-NHSO ₂ CF _3), (4) a phosphate group, (5)
Sulfonic acid group, (6) one or two of N, S, O
A 5 to 7-membered (preferably 5 to 6-membered) monocyclic optionally substituted heterocyclic residue containing at least one heterocyclic residue which forms an anion represented by R ¹ by a chemical reaction. It may be a group that can be converted into a group that can be converted (a so-called synthetic intermediate).

As R ¹ , optionally substituted lower (C _1-4 ) alkyl (eg, methyl, triphenylmethyl, methoxymethyl, ethoxymethyl, p-methoxybenzyl, p-nitrobenzyl, etc.) or acyl Groups (eg, lower (C _2-5 ) alkanoyl, benzoyl, etc.)
Carboxyl, tetrazolyl or 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl (preferably tetrazolyl), which may be protected by, are preferred, and tetrazolyl is particularly preferred. .

In the above formula, X represents that an adjacent phenylene group and a phenyl group are bonded directly or via a spacer having an atom chain of 2 or less (preferably a direct bond). Any of divalent chains having 1 or 2 atoms constituting the straight chain portion may be used, and may have a side chain. Specifically, lower (C _1-4 ) alkylene having 1 or 2 atoms constituting a straight chain portion, —CO—, —O—, —S—, —NH—, —CO
_{-NH -, - O-CH 2} -, - S-CH 2 -, - CH = C
H- and the like. In the above formula, n represents an integer of 1 or 2 (preferably 1).

In the above formula, ring A represents a benzene ring which may further have a substituent other than substituent R ² , and examples of the substituent include (1) halogen (eg, F, Cl, Br
), (2) cyano, (3) nitro, (4) optionally substituted lower (C _1-4 ) alkyl, (5) lower (C
_1-4 ) alkoxy, (6) optionally substituted amino group (eg, amino, N-lower (C _1-4 ) alkylamino (eg, methylamino, etc.), N, N-di-lower (C _{1 -4} )
Alkylamino (eg, dimethylamino, etc.), N-arylamino (eg, phenylamino, etc.), alicyclic amino (eg, morpholino, piberidino, piperazino, N-phenylpiperazino, etc.), formula (7) -CO-D '
[Wherein D 'is a hydroxyl group or an alkyl moiety is a hydroxyl group, lower (C _1-4 ) alkoxy, lower (C _2-6 ) alkanoyloxy (eg, acetoxy, pivaloyloxy, etc.), lower (C _1-6 ) alkoxycarbonyl Oxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, etc.) or lower (C _3-6 ) cycloalkoxycarbonyloxy (eg, cyclohexyloxycarbonyloxy, etc.)
Represents a lower (C _1-4 ) alkoxy which may be substituted with, or (8) an optionally substituted lower (C _1-4 ) alkyl (an anion as R ¹ described above) And the same as the "optionally substituted lower (C _1-4 ) alkyl group" exemplified as the protecting group for the group capable of forming) or acyl (eg, lower (C _2-5 ) alkanoyl Benzoyl, etc.), which may be protected with tetrazolyl, a trifluoromethanesulfonic acid amide group, a phosphoric acid group or a sulfonic acid group.
These substituents are each substituted at a substitutable position on the benzene ring.
In addition to the substituent R ² , the substituent which the ring A further has may be a lower (C _1-4 ) alkyl which may be substituted (eg, a hydroxyl group, a carboxyl group, Lower (C) which may be substituted with halogen, etc.
_1-4) alkyl, etc.), are preferred, such as halogen, ring A other than the substituent R ² is more preferably has no substituent.

In the above formula, the group capable of forming an anion as R ² (group having a hydrogen atom which can be released as a proton) includes, for example, (1) a carboxyl group which may be esterified or amidated , (2) tetrazolyl group, (3) trifluoromethanesulfonic acid amide group (-NHSO ₂ CF _3), (4) a phosphate group, (5) and a sulfonic acid group. these groups are optionally substituted Lower alkyl groups (the same as the “optionally substituted lower (C _1-4 ) alkyl group” exemplified as the protecting group for the group capable of forming an anion as R ¹ ). ) Or an acyl group (eg, lower (C _2-5 ) alkanoyl, benzoyl, etc.)
A group capable of forming an anion or a group capable of forming an anion under biological or physiological conditions (for example, an in vivo reaction such as oxidation, reduction, or hydrolysis by an in vivo enzyme); Either may be used.

The carboxyl which may be esterified or amidated as R ² includes, for example,
-D [wherein D is (1) a hydroxyl group, (2) optionally substituted amino (for example, amino, N-lower (C _1-4 ) alkylamino, N, N-di-lower (C _{1- 4} ) alkylamino etc.) or (3) optionally substituted alkoxy {examples: (i) an alkyl moiety is a hydroxyl group, optionally substituted amino (eg, amino, N-lower (C _1-4 ) alkyl) Amino, N, N-di-lower (C _1-4 ) alkylamino, piperidino, morpholino, etc., halogen, lower (C _1-6 ) alkoxy, lower (C _1-6 ) alkylthio, lower (C _3-8 ) Cycloalkoxy or optionally substituted dioxorenyl (eg, 5-methyl-2-oxo-
A lower (C _1-6 ) alkoxy group optionally substituted with 1,3-dioxolen-4-yl or the like, or (ii)
Formula —O—CH (R ⁶ ) —OCOR ^{7 wherein} R ⁶ is (a)
Hydrogen, (b) a linear or branched lower alkyl group having 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, Neopentyl), (c) a linear or branched lower alkenyl group having 2 to 6 carbon atoms or (d) a cycloalkyl group having 3 to 8 carbon atoms (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.), R ⁷ is (a) a linear or branched lower alkyl group having 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n -Pentyl, isopentyl, neopentyl, etc.), (b) a linear or branched lower alkenyl group having 2 to 6 carbon atoms, (c) a cycloalkyl group having 3 to 8 carbon atoms (eg, cyclopentyl) , Cyclohexyl, cycloheptyl, etc.) or an optionally substituted aryl group (eg, a halogen atom, nitro, lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy, phenyl) Or a naphthyl group)
-3 lower alkyl groups (eg, benzyl, p-chlorobenzyl, phenethyl, cyclopentylmethyl, cyclohexylmethyl, etc.); (d) cycloalkyl having 3-8 carbon atoms or an optionally substituted aryl group (eg, halogen A lower alkenyl group having 2-3 carbon atoms substituted by an atom, nitro, phenyl or naphthyl group optionally having lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy, etc. (eg, , Such as those having an alkenyl moiety such as vinyl, propenyl, allyl and isopropenyl, such as cinnamyl); (e) optionally substituted aryl groups (eg, halogen atoms such as phenyl, p-tolyl, naphthyl, nitro, lower (C _1-4) alkyl, lower (C _1-4) such as phenyl or naphthyl group which may have a like alkoxy), (f) the number of carbon atoms -6 linear or branched lower alkoxy groups (eg, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, isopentyloxy, Neopentyloxy, etc.),
(G) a linear or branched lower alkenyloxy group having 2 to 8 carbon atoms (eg, allyloxy, isobutenyloxy, etc.), (h) a cycloalkyloxy group having 3 to 8 carbon atoms (eg, cyclopentyloxy, cyclohexyloxy,
Such as cycloheptyloxy), (i) cycloalkyl having 3 to 8 carbon atoms (eg, cyclopentyl, cyclohexyl,
Cycloheptyl, etc.) or an optionally substituted aryl group (eg, halogen atom, nitro, lower (C _1-4 ))
Lower alkoxy groups having 1 to 3 carbon atoms (eg, benzyloxy, phenethyloxy, cyclopentylmethoxy, cyclohexylmethoxy, etc.) substituted with alkyl, phenyl or naphthyl group optionally having lower (C _1-4 ) alkoxy, etc. Methoxy, ethoxy, n-propoxy, isopropoxy and the like having an alkoxy moiety), (j) cycloalkyl having 3 to 8 carbon atoms (eg, cyclopentyl, cyclohexyl, cycloheptyl and the like) or optionally substituted Aryl group (eg, halogen atom, nitro, lower (C _1-4 ) alkyl, lower (C _1-4 )
A lower alkenyloxy group having 2 to 3 carbon atoms substituted with a phenyl or naphthyl group which may have an alkoxy or the like (eg, having an alkenyloxy moiety such as vinyloxy, propenyloxy, allyloxy, isopropenyloxy such as cinnamyloxy) Or (k) an optionally substituted aryloxy group (eg, a halogen atom such as phenoxy, p-nitrophenoxy, naphthoxy, nitro, lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy Or the like, which may have a phenoxy or naphthoxy group, etc.).

R ² is preferably carboxyl which may be esterified, and specific examples thereof include, for example, —COOH and its salts, —COOMe, and —COOE.
t, -COOTBu, -COOPr, pivaloyloxymethoxycarbonyl, 1- (cyclohexyloxycarbonyloxy) ethoxycarbonyl, 5-methyl-2-oxo-1,3-dioxolen-4-ylmethoxycarbonyl, acetoxymethoxycarbonyl, Propionyloxymethoxycarbonyl, n-butylyloxymethoxycarbonyl, isobutylyloxymethoxycarbonyl, 1- (ethoxycarbonyloxy) ethoxycarbonyl, 1- (acetoxy) ethoxycarbonyl, 1- (isobutylyloxy) ethoxycarbonyl, cyclohexylcarbonyloxymethoxycarbonyl , Benzoyloxymethoxycarbonyl, cinnamyloxycarbonyl, cyclopentylcarbonyloxymethoxycarbonyl and the like; Conditions (e.g., in vivo reaction such as oxidation-reduction or hydrolysis by in vivo enzymes)
Or a group capable of chemically forming an anion (eg, COO ⁻ , a derivative thereof, etc.) or a group capable of changing the same, or a carboxyl group or a prodrug thereof. Good.

The above R ² is represented by the formula —CO—D [wherein
D is (1) a hydroxyl group or (2) an alkyl moiety is a hydroxyl group,
Amino, halogen, lower (C _2-6 ) alkanoyloxy (eg, acetooxy, pivaloyloxy, etc.), lower (C _3-8 ) cycloalkanoyloxy, lower (C _1-6 ) alkoxycarbonyloxy (eg, methoxycarbonyloxy, Ethoxycarbonyloxy, etc.), lower (C _3-8 ) cycloalkoxycarbonylyloxy (eg, cyclohexyloxycarbonyloxy, etc.), lower (C _3-8 )
_1-4 ) represents a lower (C _1-4 ) alkoxy which may be substituted with alkoxy or lower (C _3-8 ) cycloalkoxy], among which lower (C _1-4 ) alkyl Carboxyls esterified with (preferably methyl or ethyl) are preferred.

In the above formula, the “hydrocarbon residue” in the “hydrocarbon residue which may be bonded via a hetero atom and has a substituent” represented by R ³ includes, for example,
(1) alkyl group, (2) alkenyl group, (3) alkynyl group, (4) cycloalkyl group, (5) aryl group,
(6) An aralkyl group and the like are mentioned, and among them, an alkyl group, an alkenyl group and a cycloalkyl group are preferable. The alkyl group of the above (1) is a lower alkyl group having about 1 to 8 carbon atoms, which may be linear or branched, for example, methyl, ethyl, propyl, isopropyl,
Butyl, isobutyl, sec-butyl, t-butyl, pentyl, i-pentyl, hexyl, heptyl, octyl and the like. As the alkenyl group of the above (2),
The lower alkenyl group having about 2 to 8 carbon atoms may be linear or branched and includes, for example, vinyl, propenyl, 2-butenyl, 3-butenyl, isobutenyl, 2-octenyl and the like. The alkynyl group of the above (3) is a lower alkynyl group having about 2 to 8 carbon atoms and may be linear or branched. For example, ethynyl, 2-propynyl, 2-butynyl, 2-pentynyl, 2-pentynyl, Octynyl and the like. Examples of the cycloalkyl group of the above (4) include lower cycloalkyl having about 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The above alkyl group, alkenyl group, alkynyl group or cycloalkyl group is a hydroxyl group, an amino group which may be substituted (eg,
Amino, N-lower (C _1-4 ) alkylamino, N, N-dilower (C _1-4 ) alkylamino, etc.), halogen, lower (C _1-4 ) alkoxy group, lower (C _1-4 ) It may be substituted with an alkylthio group or the like. Examples of the aralkyl group (5) include phenyl-lower (C _1-4 ) alkyl such as benzyl and phenethyl, and examples of the aryl group (6) include phenyl.

The aralkyl group or aryl group described above may be, for example, halogen (eg, F, Cl, Br, etc.), nitro, or an optionally substituted amino group (eg, amino, N-lower (C _1-4 ) alkylamino, N, N-dilower (C _1-4 ) alkylamino, etc., lower (C _1-4 ) alkoxy (eg, methoxy, ethoxy, etc.), lower (C ₁ ) _-4 ) Alkylthio (eg, methylthio, ethylthio, etc.), lower (C _1-4 ) alkyl (eg, methyl, ethyl, etc.) and the like.
Among the above, “a hydrocarbon residue which may be bonded via a hetero atom and has a substituent represented by R ³ ”
As the "hydrocarbon residue" in, optionally substituted alkyl or alkenyl group (e.g., hydroxyl group, an amino group, optionally substituted by halogen or lower (C _1-4) alkoxy-lower (C _{1 -5} ) alkyl or lower ( _C2-5 ) alkenyl group), and
Lower (C _1-5 ) alkyl (more preferably, ethyl) is preferred. The “hetero atom” in the “hydrocarbon residue which may be bonded via a hetero atom and has a substituent” represented by R ³ includes —O—, —S (O) m- [ m
Represents an integer of 0 to 2], -NR '-[R' represents a hydrogen atom or a lower (C _1-4 ) alkyl], and among them, -O- is preferably used. Among the above-mentioned, as R ³ is, -O -, - S (O ) m- [m
Represents an integer of 0 to 2] or -NR '-[R' represents a hydrogen atom or a lower (C _1-4 ) alkyl], and may be a hydroxyl group, an amino group, a halogen or a lower group. (C _1-4 ) A lower (C _1-5 ) alkyl or lower (C _2-5 ) alkenyl group which may be substituted with a substituent selected from an alkoxy group is preferred.
Lower (C _1-5 ) alkyl or lower (C _1-5 ) alkoxy (more preferably ethoxy) is preferred.

Among the compounds having angiotensin II antagonistic activity represented by the formula (I), the compounds represented by the formula (I ')

Embedded image (Wherein, R ¹ represents (1) a carboxyl group, (2) a tetrazolyl group, or (3)

Embedded image [Wherein, i represents -O- or -S-, j is> = O,
> = S or> = S (O) m, wherein m has the same meaning as described above], and ring A is a lower (C ₁₎ which may be substituted other than the substituent R ^2. _-4 ) an alkyl (eg, a hydroxyl group, a carboxyl group, a lower (C _1-4 ) alkyl which may be substituted with a halogen or the like) or a benzene ring optionally substituted with a halogen (preferably a substituent R ² And R ² is a group represented by the formula —CO—D wherein D is (1) a hydroxyl group or (2) an alkyl moiety is a hydroxyl group, amino, halogen, lower (C _{2−). 6} ) alkanoyloxy (eg, acetooxy, pivaloyloxy, etc.), lower (C _3-8 ) cycloalkanoyloxy, lower (C _1-6 ) alkoxycarbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, etc.), lower (C _3-8 Cycloalkoxy carboxymethyl Niro alkoxy (e.g., such as cyclohexyloxycarbonyloxy), a lower (C _1-4) alkoxy or lower (C _3-8) be substituted with a cycloalkoxy optionally substituted lower (C _1-4) alkoxy R ³ represents —O—, —S (O) m— [m represents an integer of 0 to 2] or —NR ′ — [R ′ represents a hydrogen atom or lower (C _{1- 4} ) represents alkyl]], a hydroxyl group, an amino group, a halogen and a lower (C
_1-4 ) Lower (C _1-5 ) alkyl or lower (C _2-5 ) alkenyl group (preferably lower (C _1-5 ) alkyl or lower) which may be substituted with a substituent selected from an alkoxy group. (C _1-5 ) alkoxy; more preferably ethoxy). A benzimidazole-7-carboxylic acid derivative or a pharmacologically acceptable salt thereof, and the like, and particularly, 2-ethoxy-1-[[2 ′
-(1H-tetrazol-5-yl) biphenyl-4-
Yl] methyl] benzimidazole-7-carboxylic acid [Candesartan], 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-[[2'-
(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate [Candesartan cilexetil], pivaloyloxymethyl 2-ethoxy-1-[[2 ′-(1H-tetrazole- 5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate, 2-ethoxy-
1-[[2 ′-(2,5-dihydro-5-oxo-1,
2,4-oxadiazol-3-yl) biphenyl-4
-Yl] methyl] benzimidazole-7-carboxylic acid or a salt thereof is preferred. The above-mentioned benzimidazole derivatives are described in, for example, EP-425921, EP-4.
59136, EP-553879, EP-57812
5, EP-520423, EP-668272 and the like, or a method analogous thereto. When Candesartan cilexetil is used, it is preferable to use a stable C-type crystal described in EP-59136.

The compound having an angiotensin II antagonism used in the present invention may be itself or a pharmacologically acceptable salt or hydrate. As such a salt, when the compound having an angiotensin II antagonistic action has an acidic group such as a carboxyl group, an inorganic base (eg, an alkali metal such as sodium or potassium,
Alkaline earth metals such as calcium and magnesium) and organic bases (eg, trimethylamine, triethylamine,
Salts with organic amines such as pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine, and basic amino acids such as arginine, lysine, and ornithine). . When the compound having an angiotensin II antagonistic activity has a basic group such as an amino group, an inorganic acid or an organic acid (eg, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, carbonic acid, bicarbonate, formic acid, acetic acid, propionic acid,
Acidic amino acids such as trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid), aspartic acid, glutamic acid, etc. May be formed.

The compounds represented by the general formula (I) and their pharmaceutically acceptable salts have low toxicity,
Alternatively, by forming a pharmaceutical composition by mixing with a pharmaceutically acceptable carrier, angiogenesis can be achieved in mammals (eg, human, mouse, rat, rabbit, dog, cat, cow, pig, monkey, etc.). It can be used as an inhibitor.

Here, as the pharmacologically acceptable carrier, various organic or inorganic carrier materials commonly used as a preparation material are used, and excipients, lubricants, binders, disintegrants in solid preparations; It is formulated as a solvent, a solubilizing agent, a suspending agent, an isotonic agent, a buffering agent, a soothing agent and the like in the preparation. If necessary, pharmaceutical additives such as preservatives, antioxidants, coloring agents, sweeteners and the like can also be used.
Preferred examples of the excipient include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, dextrin, and the like. Pullulan, light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminate metasilicate and the like can be mentioned. Preferred examples of the lubricant include, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferred examples of the binder include, for example, pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan,
Hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like can be mentioned. Preferable examples of the disintegrant include lactose, sucrose, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, sodium carboxymethyl starch, light anhydrous silicic acid, low-substituted hydroxypropylcellulose and the like.

Preferred examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil and the like. Preferred examples of the dissolution aid include, for example, polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine,
Examples include sodium carbonate, sodium citrate, sodium salicylate, sodium acetate and the like. Preferred examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; Hydrophilic polymers such as polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose and hydroxypropylcellulose; polysorbates, and polyoxyethylene hydrogenated castor oil. Preferred examples of the tonicity agent include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like. Preferred examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate. Preferred examples of the soothing agent include benzyl alcohol and the like.

Preferred examples of the preservative include, for example, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Suitable examples of the antioxidant include, for example, sulfite, ascorbate and the like. Preferable examples of the coloring agent include, for example, water-soluble edible tar dyes (eg, edible dyes such as edible red Nos. 2 and 3, edible yellows 4 and 5, edible blues 1 and 2, water-insoluble lake dyes) (Eg, the aluminum salt of the water-soluble edible tar dye, etc.), natural pigments (eg, β-carotene, chlorophyll, red pepper, etc.) Preferable examples of the sweetener include, for example, sodium saccharin, dipotassium glycyrrhizinate, Aspartame, stevia and the like.

The dosage form of the pharmaceutical composition includes, for example, tablets,
Oral preparations such as capsules (including soft capsules and microcapsules), granules, powders, syrups, emulsions and suspensions; and injections (eg, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections) Non-injection preparations such as internal injections), instillations, external preparations (eg, transnasal preparations, transdermal preparations, ointments, etc.), suppositories (eg, rectal suppositories, vaginal suppositories, etc.), pellets, drops, etc. Oral preparations can be mentioned, and these can be safely administered orally or parenterally, respectively. The pharmaceutical composition can be produced by a method commonly used in the field of formulation technology, for example, a method described in the Japanese Pharmacopoeia and the like. Hereinafter, a specific production method of the preparation will be described in detail.

For example, oral preparations include, as active ingredients, excipients (eg, lactose, sucrose, starch, D-mannitol, etc.), disintegrants (eg, carboxymethylcellulose calcium, etc.), binders (eg, gelatinized Starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, etc.) or a lubricant (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.) is added and compression-molded, and then, if necessary, taste masking It is manufactured by coating with a coating base by a method known per se for the purpose of enteric or sustainability.
Examples of the coating base include a sugar coating base, a water-soluble film coating base, an enteric film coating base, and a sustained release film coating base. As a sugar coating base, sucrose is used, and talc, precipitated calcium carbonate, gelatin, gum arabic,
One or two selected from pullulan, carnauba wax, etc.
More than one species may be used in combination. As the water-soluble film coating base, for example, hydroxypropyl cellulose,
Cellulose polymers such as hydroxypropylmethylcellulose, hydroxyethylcellulose and methylhydroxyethylcellulose; synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E (Eudragit E (trade name), Rohm Pharma Co., Ltd.), polyvinylpyrrolidone; And the like.

Examples of the enteric film coating base include cellulosic polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose and cellulose acetate phthalate; methacrylic acid copolymer L [Eudragit L
(Trade name), Rohm Pharma Co., Ltd.), methacrylic acid copolymer LD (Eudragit L-30D55 (trade name), Rohm Pharma Co., Ltd.), methacrylic acid copolymer S [Eudragit S (trade name), Rohm Pharma Co., Ltd.]
And acrylic acid polymers; natural products such as shellac. Examples of the sustained-release film coating base include cellulosic polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS
Acrylic polymers such as [Eudragit RS (trade name), Rohm Pharma Co., Ltd.] and ethyl acrylate / methyl methacrylate copolymer suspension [Eudragit NE (trade name), Rohm Pharma Co., Ltd.] .
The above-mentioned coating bases may be used by mixing two or more kinds thereof at an appropriate ratio. Further, at the time of coating, a light-shielding agent such as titanium oxide, iron sesquioxide and the like may be used.

Injectable preparations contain an active ingredient as a dispersant (eg, polysorbate 80, polyoxyethylene hydrogenated castor oil 60, etc.), polyethylene glycol, carboxymethyl cellulose, sodium alginate, etc., and a preservative (eg, methyl paraben, propyl paraben, benzyl). Alcohol, chlorobutanol, phenol, etc.), isotonic agents (eg, sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose, etc.) and aqueous solvents (eg, distilled water, physiological saline, Ringer's solution, etc.) Alternatively, it is produced by dissolving, suspending or emulsifying in an oily solvent (eg, vegetable oils such as olive oil, sesame oil, cottonseed oil, corn oil, propylene glycol, etc.). At this time, if necessary, additives such as a solubilizing agent (eg, sodium salicylate, sodium acetate, etc.), a stabilizer (eg, human serum albumin, etc.), a soothing agent (eg, benzyl alcohol, etc.) may be used.

The compound represented by the general formula (I) and a pharmaceutically acceptable salt thereof have an excellent angiogenesis inhibitory effect and can be used in mammals (eg, human, mouse, rat, rabbit, dog, Cats, cattle, pigs, monkeys, etc.) as angiogenesis inhibitors. The angiogenesis inhibitor can be used for various diseases involving angiogenesis, such as tumors (eg, tumors).
Malignant melanoma, malignant lymphoma, digestive system (eg, stomach, intestine, etc.)
Cancer, lung cancer, pancreatic cancer, esophageal cancer, breast cancer, liver cancer, ovarian cancer, uterine cancer, prostate cancer, kidney cancer, bladder cancer, brain tumor, Kaposi sarcoma,
Hemangiomas, osteosarcomas, sarcomas, hemangio fibroids, uterine fibroids, etc.), inflammatory diseases (eg, rheumatoid arthritis, psoriasis, etc.), diabetic retinopathy, atherosclerosis (atherosclerotic lesion) (Including abnormal angiogenesis in abnormal capillary network formation).

The dose of the compound represented by the general formula (I) and a pharmaceutically acceptable salt thereof varies depending on the administration subject, administration route, target disease, symptoms and the like. When administered orally (body weight: 50 kg), the compound represented by the compound (I) as an active ingredient and a pharmaceutically acceptable salt thereof are usually administered in a single dose of about 0.001 to 500 mg, preferably 1 to 500 mg. It is desirable to administer this amount once to three times a day.

The compounds represented by the general formula (I) and their pharmaceutically acceptable salts can be used in combination with other therapeutic methods for the prevention and treatment of the above-mentioned diseases accompanied by angiogenesis. . Such treatment includes, for example, surgery (operation), radiotherapy, drug therapy, and the like. The timing of the combination is not particularly limited, and may be simultaneous or different. Drugs used in the above drug therapy (hereinafter abbreviated as concomitant drugs)
1) For example, thalidomide, linomastate, endostatin, angiostatin, carbamide triazole,
Angiogenesis inhibitors such as lepristatin, 6-O- (N-chloroacetylcarbamoyl) fumagillol, integrin αvβ3 inhibitor; 2) Antiestrogenic drugs such as tamoxifen, raloxifene, droloxifene, iodoxifene, eg megestol acetate Progestogens such as anastrozole, letrazole, borazole, aromatase inhibitors such as elemestane; antiprogestogens such as flutamide;
Antiandrogen drugs such as nilutamide, bicalutamide, cyproterone acetate, LHRH agonists or antagonists such as leapron, geserelin acetate,
Testosterone 5α-dihydroreductase inhibitors such as, for example, hunasteride, metalloprotease inhibitors such as, for example, marimastate, urokinase plasminogen activator receptor inhibitors, for example, EGF, FG
Cytostatic agents such as growth factor antibodies such as F, PDGF or HGF, growth factor receptor antibodies or growth factor signaling inhibitors such as tyrosine kinase inhibitors and serine / threonine kinase inhibitors;
3) Antifolates such as methotrexate, fluoropyrimidine derivatives such as 5-fluorouracil or antimetabolites such as purines and adenosine analogs such as doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, mitramycin Antitumor agents, for example, cisplatin, platinum derivatives such as carboplatin, for example, nitrogen mustard, melphalan, chlorambucin, busulfan, cyclophosphamide, ifosfamide, nitrosoureas, alkylating agents such as thiotefa, vinca alkaloids such as vincristine , Antimiotic drugs such as taxol, taxol derivatives such as taxotere, etc. or epifodov such as etofoside, tenifoside, etc. Rotokishin acids, cell growth inhibitors such as topoisomerase inhibitors such as amsacrine, or topotecan.

The administration time of the compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, and a concomitant drug is not limited, and these may be administered to a subject at the same time, The administration may be performed with a time lag. The dose of the concomitant drug can be appropriately determined based on the clinically used dose. The compounding ratio of the compound represented by the general formula (I) and a pharmaceutically acceptable salt thereof and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. .
For example, when the administration target is a human, the concomitant drug may be used in an amount of 0.01 to 100 parts by weight based on 1 part by weight of the compound represented by the general formula (I) and a pharmaceutically acceptable salt thereof.

[0034]

The compounds represented by the general formula (I) and pharmaceutically acceptable salts thereof have an excellent angiogenesis inhibitory action and can be used for various diseases associated with angiogenesis, such as tumors (eg, tumors). Malignant melanoma, malignant lymphoma, gastrointestinal (eg, stomach, intestine) cancer, lung cancer, pancreatic cancer, esophageal cancer, breast cancer, liver cancer, ovarian cancer, uterine cancer, prostate cancer, kidney cancer, bladder cancer, brain tumor, Kaposi Prophylactic / therapeutic drugs for sarcomas, hemangiomas, osteosarcomas, sarcomas, hemangiomas, uterine fibroids, etc.), inflammatory diseases (eg, rheumatoid arthritis, psoriasis), diabetic retinopathy, atherosclerosis, etc. Useful as

[0035]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described more specifically with reference to Test Examples and Examples. However, the present invention is not limited by these and does not depart from the scope of the present invention. It may be changed.

[0036]

Test Example 1 A urethane sponge was implanted subcutaneously in the back of a Syrian hamster, and basic fibroblast growth factor (bFGF) was administered into the sponge once a day for 7 days (0.3 μg /
Day). From the date of transplantation, 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-[[2 ′
-(1H-tetrazol-5-yl) biphenyl-4-
Yl] methyl] benzimidazole-7-carboxylate [hereinafter referred to as compound A] (0.5, 5, 10 m
g / kg) was orally administered once a day. Seven days after the transplantation, the sponge was taken out, and the amount of hemoglobin contained in the sponge was measured and used as an index of angiogenesis. As a result, Compound A
Was found to significantly suppress bFGF-induced angiogenesis in a dose-dependent manner

Test Example 2 (1) Recombinant vascular endothelial cell growth factor (rVEGF ₁₆₅ , Takeda Pharmaceutical) bound to heparin sepharose (Amersham Pharmacia Biotech) was placed in a urethane sponge (3 μg / sponge). This sponge was implanted subcutaneously into C57BL / 6N mice (9 weeks old, female, Charles River Japan). From the date of transplantation, angiotensin II [AII] (1 nmol, Sigma Chemical Co.) and 2-ethoxy-1-[[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl]
Benzimidazole-7-carboxylic acid [hereinafter referred to as Compound B
(100 nmol) was administered in a sponge once a day. Six days after transplantation, the sponge was taken out, and the amount of hemoglobin contained in the sponge was measured and used as an index of angiogenesis. Table 1 shows the results.

[Table 1] Hemoglobin amount (%; mean ± standard error) Control group 100 ± 27 VEGF administration group 329 ± 43 VEGF + AII administration group 538 ± 89 VEGF + AII + Compound B administration group 247 ± 49 (2) Binding to heparin sepharose (Amersham Pharmacia Biotech) After placing the recombinant mutant basic fibroblast growth factor (rbFGF, Takeda Pharmaceutical) in a urethane sponge (500 ng / sponge),
This sponge was implanted subcutaneously into C57BL / 6N mice (9 weeks old, female, Charles River Japan). 1- (cyclohexyloxycarbonyloxy) from the date of transplantation
Ethyl 2-ethoxy-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate [Compound A]
(10 mg / kg) was orally administered once a day. Six days after transplantation, the sponge was taken out, and the amount of hemoglobin contained in the sponge was measured and used as an index of angiogenesis. Table 2 shows the results
Shown in

[Table 2] Hemoglobin amount (%; mean ± standard error) Control group 100 ± 22 bFGF administration group 540 ± 78 bFGF + Compound A administration group 275 ± 19

Angiogenesis inhibitors containing the compound represented by the general formula (I) or a salt thereof according to the present invention as an active ingredient (eg, for treatment of tumors, inflammatory diseases, diabetic retinopathy, atherosclerosis, etc.) Can be produced, for example, by the following formulation. After mixing (1), (2) and 1/2 of (3) and (4), granulate. The remaining (4) is added thereto, and the whole is encapsulated in a gelatin capsule.

[0039] 2/3 of (1), (2), (3), (4) and (5)
And then granulate. The remaining (4) and (5) are added to the granules and pressed into tablets.

[0040] (1), (2) and (3) are dissolved in distilled water for injection so that the total volume is 2 ml, and sealed in an ampoule. All steps are performed under aseptic conditions.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 27/02 A61K 31/00 627A 35/04 635B // C07D 235/04 C07D 235/04 403/10 235 403/10 235 413/10 235 413/10 235 F term (reference) 4C063 AA01 BB06 CC47 CC58 DD26 EE01 4C086 AA01 AA02 BC39 BC62 BC71 GA07 GA09 MA01 MA04 NA14 ZA33 ZA45 ZA89 ZB11 ZB15 ZB26

Claims (4)

[Claims] 1. A compound of the formula having an angiotensin II antagonistic activity. (Wherein, R ¹ represents a group capable of forming an anion or a group capable of changing to an anion, X represents that a phenylene group and a phenyl group are bonded directly or via a spacer having an atomic chain of 2 or less; Represents an integer of 1 or 2, ring A represents a benzene ring which may further have a substituent, R ² represents a group capable of forming an anion or a group capable of forming an anion, and R ³ represents a heteroatom. Which represents a hydrocarbon residue which may be bonded through a group represented by the formula: or a salt thereof, or a salt thereof. 2. The compound having an angiotensin II antagonistic activity is 2-ethoxy-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid or a compound thereof. The agent according to claim 1, which is a salt. 3. The compound having an angiotensin II antagonistic action is 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] The agent according to claim 1, which is benzimidazole-7-carboxylate or a salt thereof. 4. A compound having an angiotensin II antagonistic activity is 2-ethoxy-1-[[2 '-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl. -4-yl] methyl] benzimidazole-7-carboxylic acid or a salt thereof.