JP3099096B2 - Thienoimidazole derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel thienoimidazole derivative having excellent pharmacological action and an intermediate thereof. More specifically, the present invention has potent angiotensin II antagonism and blood pressure lowering action,
General formula useful as a therapeutic agent for cardiovascular diseases such as heart disease (cardiac hypertrophy, heart failure, myocardial infarction), stroke, renal disease with proteinuria, and arteriosclerosis

Embedded image [In the formula, ring A represents a thiophene ring which may further have a substituent other than the group represented by formula R ³ , and R ¹ may be bonded via hydrogen or a hetero atom, and R ² and R ³ each represent a group capable of forming an anion or a group capable of forming an anion; and X represents a phenylene group and a phenyl group directly or a spacer having an atomic chain of 2 or less. And n represents an integer of 1 or 2] and a salt thereof.

[0002]

2. Description of the Related Art The renin-angiotensin system, together with the aldosterone system, is involved in homeostatic functions such as systemic blood pressure, fluid volume, and electrolyte balance. The relationship between the renin-angiotensin system and hypertension has been clarified by the development of an angiotensin II (AII) converting enzyme inhibitor (ACE inhibitor) that produces angiotensin II having strong vasoconstriction. Because angiotensin II contracts blood vessels and raises blood pressure via angiotensin II receptors on cell membranes, its antagonists can be used to treat angiotensin-induced hypertension as well as ACE inhibitors. Many angiotensin II analogs such as salaracin, [Sar ¹ , Ala ⁸ ] AII and the like have been reported to have potent angiotensin II antagonism. However, peptidic antagonists have been reported to have a short duration of action when administered parenterally and are ineffective when administered orally [MA Ondetti and DW Cushman, Annual Repo
rts in Medicinal Chemistry, 13 , 82-91 (1978)].

[0003]

On the other hand, non-peptidic angiotensin II antagonists have been studied to solve the problems of these peptidic angiotensin II antagonists. That is, the earlier imidazole derivatives having angiotensin II antagonistic activity are disclosed in JP-A-56-71073, 56-71074, 57-9227.
0,58-157768, USP 4,355,040
And USP 4,340,598. Thereafter, EP-0253310, EP-0291969, E
P-0324377, JP-A-63-23868 and JP-A-1-117876 include improved imidazole derivatives, and EP-0323841 and JP-A-1-287707 include pyrrole, pyrazole and triazole derivatives. And USP 4,880,
No. 804 discloses a benzimidazole derivative as an angiotensin II antagonist.

[0004]

Means for Solving the Problems The present inventors have studied renin-
In order to act as a therapeutic agent for cardiovascular diseases such as hypertension, heart disease (cardiac hypertrophy, heart failure, myocardial infarction, etc.), stroke, etc., the compound acts as an angiotensin II receptor Intensive research has been conducted on the basis that it is necessary to have an antagonistic action and have a strong and sustained angiotensin II antagonistic action and antihypertensive action by oral administration. As a result, it has been found that the novel substituted thienoimidazole derivative (I) has a strong angiotensin II receptor antagonistic action and also has a sustained and strong AII antagonistic action and an antihypertensive action by oral administration. completed.

That is, the present invention provides

Embedded image [In the formula, ring A represents a thiophene ring which may further have a substituent other than the group represented by formula R ³ , and R ¹ may be bonded via hydrogen or a hetero atom, and R ² and R ³ each represent a group capable of forming an anion or a group capable of changing to an anion, and X represents a phenylene group and a phenyl group directly or a spacer having an atom chain of 2 or less. And n represents an integer of 1 or 2] and a salt thereof. With respect to the general formula (I), examples of the hydrocarbon residue as R ¹ include an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, and an aralkyl group.
Alkenyl groups and cycloalkyl groups are preferred.

The alkyl group as R ¹ is a lower alkyl group having about 1 to 8 carbon atoms and 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. The alkenyl group as R ¹ is a lower alkenyl group having about 2 to 8 carbon atoms, which may be linear or branched. For example, vinyl, propenyl, 2-butenyl, 3-butenyl, isobutenyl, 2-octenyl And so on.
The alkynyl group as R ¹ is a lower alkynyl group having about 2 to 8 carbon atoms and may be linear or branched, and includes, for example, ethynyl, propynyl, butynyl, octynyl and the like. The cycloalkyl group as R ¹ has 3 to 6 carbon atoms.
Lower cycloalkyl, for example, cyclopropynyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The above alkyl group, alkenyl group, alkynyl group and cycloalkyl group are a hydroxyl group, an optionally substituted amino group (eg, amino, methylamino, etc.), a halogen, a lower (C _1-4 ) alkylthio group, It may be substituted by a lower (C _1-4 ) alkoxy group or the like. The aralkyl group as R ¹ includes, for example, phenyl-lower (C _1-4 ) alkyl such as benzyl and phenethyl,
The aralkyl group may be located at any position on the benzene ring, for example, halogen (eg, F, Cl, Br, etc.), nitro, lower (C
_1-4 ) Alkoxy (e.g., methoxy, ethoxy, etc.), lower (C
_1-4 ) It may have a substituent such as alkyl (eg, methyl, ethyl and the like). As the aryl group as R ¹ ,
For example, phenyl may be mentioned, and the aryl group may be located at any position on the benzene ring, for example, halogen (eg, F, Cl, Br, etc.), nitro, lower (C _1-4 ) alkoxy (eg, methoxy, ethoxy, etc.) , Lower (C _1-4 ) alkyl (eg, methyl, ethyl, etc.). The hydrocarbon residue as R ¹ may be bonded to the imidazole skeleton via a hetero atom, and specific examples of the hetero atom include —O—, —S (O) m — [where m is 0 , 1 or 2. ], -N (R ⁵ )-, wherein R ⁵ represents hydrogen or an optionally substituted lower (C _1-4 ) alkyl group, and the like; -S- and -NH- are preferred. Among the above-mentioned hydrocarbon residues as R ¹ , a lower alkyl group which may be bonded to an imidazole ring via a heteroatom and has about 1 to 6 carbon atoms and which may be substituted, and the like are preferable. 1 to 1 carbon atoms bonded to the imidazole ring via a sulfur atom
About 4 lower alkyl groups are preferred.

Examples of the group capable of forming an anion as R ² or R ³ or a group capable of changing to an anion include, for example, carboxyl, tetrazolyl, trifluoromethanesulfonic acid amide (—NHSO ₂ CF ₃ ), phosphoric acid, sulfonic acid, cyano , Low grade
(C _1-4 ) alkoxycarbonyl and the like, and these groups may be substituted with lower alkyl (eg, lower (C
_1-4 ) alkyl, etc.) or an acyl group (eg, lower (C _2-5 ) alkanoyl, optionally substituted benzoyl, etc.) and the like, and can be protected under biological or physiological conditions (eg, Any group can be used as long as it is a group capable of forming an anion or a group capable of chemically forming an anion by an in vivo reaction such as oxidation / reduction or hydrolysis by an in vivo enzyme.

Further, when R ² or R ³ is chemically (for example,
A group capable of forming an anion or a group capable of changing the anion (eg, by oxidation / reduction or hydrolysis) (for example, an optionally protected tetrazole group (eg, a compound represented by the formula

Embedded image [Wherein R is methyl, triphenylmethyl, 2-tetrahydropyranyl, methoxymethyl, ethoxymethyl, optionally substituted benzyl (eg, p-methoxybenzyl, p
-Nitrobenzyl etc.). And the like), cyano, etc.) are useful as synthetic intermediates. R ² is preferably a tetrazole or carboxyl group optionally protected by a lower alkyl group or an acyl group which may be substituted, and trifluoromethanesulfonic acid amide.

As R ³ , a carboxyl group which may be esterified or amidated (eg, a compound of the formula --CO--D ')
Wherein D ′ is i) a hydroxyl group, ii) optionally substituted amino (eg, amino, N-lower (C _1-4 ) alkylamino,
N, N-di-lower (C _1-4 ) alkylamino and the like) or iii)
Optionally substituted alkoxy {eg, a) an alkyl moiety having a hydroxyl group, optionally substituted amino (eg, amino,
Dimethylamino, diethylamino, piperidino, morpholino, etc.), halogen, lower (C _1-6 ) alkoxy, lower
(C _1-6 ) alkylthio or dioxolenyl which may be substituted (eg, 5-methyl-2-oxo-1,3-
Dioxen-4-yl) or a lower (C _1-6 ) alkoxy group which may be substituted, or b) a compound of the formula —OCH (R ⁷ ) O
COR ^{8 wherein} R ⁷ is (1) hydrogen, (2) a linear or branched lower alkyl having 1 to 6 carbon atoms (eg, methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, etc., or (3) a cycloalkyl group having 5-7 carbon atoms (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.) Wherein R ⁸ is (1) a linear or branched lower alkyl group having 1 to 6 carbon atoms (eg, methyl, ethyl, n-
Propyl, isopropyl, n-butyl, isobutyl, s
ec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, etc.), (2) lower alkenyl group having 2-8 carbon atoms (eg, vinyl, propenyl, allyl, isopropenyl, etc.), (3) 5 carbon atoms -7 cycloalkyl group
(Eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.), (4) C1-5 substituted with cycloalkyl having 5-7 carbon atoms (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.) or aryl group (eg, phenyl, etc.) -3 lower alkyl (eg, benzyl, p-chlorobenzyl, phenethyl, cyclopentylmethyl, cyclohexylmethyl, etc.), (5) cycloalkyl having 5-7 carbon atoms
(Eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.) or an aryl group (eg, phenyl, etc.) substituted with a lower alkenyl group having 2-3 carbon atoms (eg, cinnamyl, etc., vinyl, propenyl, allyl, isopropenyl, etc.) cycloalkyl having alkenyl portions - or an aryl -C _2-3 alkenyl), (6) aryl group such as phenyl group which may be substituted (e.g., phenyl, p- tolyl, naphthyl, etc.), (7) carbon A linear or branched lower alkoxy group of the formulas 1-6 (eg, methoxy, ethoxy,
n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, etc.), (8) straight-chain or branched having 2 to 8 carbon atoms Lower alkenyloxy group (eg, allyloxy, isobutenyloxy, etc.), (9) cycloalkyloxy group having 5-7 carbon atoms (eg,
Cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, etc., (10) cycloalkyl having 5-7 carbon atoms (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.) or aryl group (eg, optionally substituted phenyl, etc.) A substituted lower alkoxy group having 1 to 3 carbon atoms (eg, cycloalkyl- or aryl having an alkoxy moiety such as methoxy, ethoxy, n-propoxy, isopropoxy such as benzyloxy, phenethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy); —C _1-3 alkyl, etc.), (11) cycloalkyl having 5-7 carbon atoms (eg, cyclopentyl, cyclohexyl,
C 2-3 substituted with an aryl group (eg, optionally substituted phenyl, etc.)
Lower alkenyloxy group (eg, cycloalkyl having an alkenyloxy moiety such as vinyloxy, propenyloxy, allyloxy, isopropenyloxy such as cinnamyloxy)
Or an aryloxy group (examples of such aryl -C _2-3 alkenyl, etc.), or (12) an optionally substituted phenoxy group, phenoxy, p- nitrophenoxy, and a group represented by showing a naphthoxy, etc.)]} Or a protected tetrazolyl group (eg, alkyl (eg, lower (C _1-4 ) alkyl)) or acyl (eg, lower (C _2-5 ) alkanoyl, Preferred are, for example, optionally substituted benzoyl) and optionally protected tetrazolyl). Preferred examples of the substituents R ^3, -COOH and its salts, -COOMe, -C
OOEt, -COOTBu, -COOPr, pivaloyloxymethoxycarbonyl, 1- (cyclohexyloxycarbonyloxy) ethoxycarbonyl, 5-methyl-2-oxo-1,3-dioxolen-4-ylmethoxycarbonyl, acetoxymethyloxycarbonyl , Propionyloxymethoxycarbonyl, n-butylyloxymethoxycarbonyl, isobutylyloxymethoxycarbonyl, 1
-(Ethoxycarbonyloxy) ethoxycarbonyl, 1-
(Acetyloxy) ethoxycarbonyl, 1- (isobutylyloxy) ethoxycarbonyl, cyclohexylcarbonyloxymethoxycarbonyl, benzoyloxymethoxycarbonyl, cinnamyloxycarbonyl, cyclopentylcarbonyloxymethoxycarbonyl, and the like,
It can form anions (eg, COO ⁻ , derivatives thereof, etc.) under biological or physiological conditions (eg, in vivo reactions such as oxidation / reduction or hydrolysis by in vivo enzymes) or chemically. Any group can be used as long as it is a group or a group that can be changed to the group. R ³ is a carboxyl group;
Alternatively, a prodrug thereof may be used, and R ³ may be one which is converted physiologically or chemically into an anion in vivo or the like.

The thiophene ring A may further have a substituent other than the group represented by the formula R ³ , such as halogen (eg, F, Cl, Br, etc.), nitro, cyano, substituted 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 (e.g., morpholino, piperidino, piperazino,
N-phenylpiperazino, etc.)], a formula -WR ⁶ [wherein W represents a bond, -O-, -S- or -C (= 0)-, and R ⁶ is hydrogen or substituted Lower alkyl group which may be substituted (e.g., hydroxyl group, optionally substituted amino group (e.g., amino, etc.), halogen, lower (C _1-4 ) _1-4 ) alkyl, etc.)]
A group represented by the formula:-(CH ₂ ) l -CO-D wherein D is
i) hydrogen, ii) hydroxyl, iii) amino, iV) N-lower ( _C1-4 ) alkylamino, V) N, N-dilower ( _C1-4 ) alkylamino or Vi) alkyl moiety is a) Hydroxyl group, b) optionally substituted amino (e.g., amino, dimethylamino, diethylamino,
Piperidino, morpholino, etc.), c) halogen, d) formula -OC
(R ⁷ ) HOCOR ⁸ wherein R ⁷ and R ⁸ are as defined above, e) lower (C _1-6 ) alkoxy, f) lower
(C _1-6 ) alkylthio, or g) optionally substituted dioxorenyl (eg, 5-methyl-2-oxo-1,3-
A lower (C _1-6 ) alkoxy group which may be substituted with dioxolen-4-yl or the like, and 1 represents 0 or 1. Or a group represented by the formula (e.g., lower (C _1-4 )
Alkyl, etc.) or acyl (e.g., lower (C _2-5 ) alkanoyl, optionally substituted benzoyl, etc.) optionally protected tetrazolyl, trifluoromethanesulfonic acid amide, phosphoric acid or sulfonic acid, etc. Can be

X represents that an adjacent phenylene group and a phenyl group are bonded directly or via a spacer having an atomic chain of 2 or less.
Any linear chain may be used as long as it is a divalent chain having 1 or 2 atoms, and may have a side chain. Specifically, lower (C _1-4 ) alkylene, -C (O)-,-
O-, -S-, -N (H)-, -C (= O) -N (H)-,-
_{O-C (H 2) -} , - S-C (H 2) -, - C (H) = C (H) - and the like, such as.

Among the compounds represented by the above formula (I),

Embedded image [Wherein, R ¹ represents a lower (C _1-6 ) alkyl group which may be bonded via a heteroatom, and R ³ has the formula —CO—D ′, wherein D ′ is a hydroxyl group, an amino, N-lower (C _1-4 ) alkylamino, N, N-dilower (C _1-4 ) alkylamino or an alkyl moiety is a hydroxyl group, amino, halogen, lower (C _2-6 ) alkanoyloxy (eg, acetyloxy , Piperoyloxy, etc.), 1-lower (C _1-6 ) alkoxycarbonyloxy
(E.g., methoxycarbonyloxy, ethoxycarbonyloxy, cyclohexyloxycarbonyloxy, etc.) or a lower (C _1-4 ) alkoxy optionally substituted with a lower (C _1-4 ) alkoxy. Lower (C _1-4 ) alkyl) or acyl group (eg, lower (C _2-5 )
Alkanoyl, benzoyl, etc.) which may be protected with tetrazolyl, wherein R ² is a lower optionally substituted
(C _1-4 ) alkyl (e.g., methyl, triphenylmethyl, methoxymethyl, ethoxymethyl, p-methoxybenzyl, p-
Nitrobenzyl) or acyl group (e.g., lower
(C _2-5 ) represents a tetrazolyl or carboxyl group (preferably tetrazolyl) which may be protected by an alkanoyl, benzoyl or the like, and R ⁴ is hydrogen, halogen, lower (C
_1-4 ) alkyl, lower (C _1-4 ) alkoxy, nitro, formula-
CO-D ″ [wherein D ″ represents a hydroxyl group or a lower (C _1-2 ) alkoxy] or an amino (preferably a lower (C _1-4 ) alkyl) which may be substituted with a lower (C _1-4 ) alkyl Hydrogen, lower (C _1-4 ) alkyl, halogen, more preferably hydrogen)
The compound (I-1) or the compound (I-
2) [More preferably, compound (I-1)] is preferable.

Production Method The compound of the above general formula (I) can be produced, for example, by the following method. Reaction (a)

Embedded image Wherein A, R ¹ , R ² , R ³ , X and n are as defined above.
Z represents a halogen atom. Reaction (b)

Embedded image [Wherein the symbols are as defined above. ] Reaction (c)

Embedded image [Wherein, R ¹ , R ² , X, Z and n are as defined above. ] Reaction (d)

Embedded image [Wherein, R ¹ , R ² , R ⁴ , X and n are as defined above. R ⁶
Represents lower alkyl. ] Reaction (e)

Embedded image [Wherein, R ² , R ³ , A, X and n are as defined above. R
⁹ represents a lower hydrocarbon residue which may be substituted. Reaction (f)

Embedded image [Wherein, R ² , R ³ , R ⁹ , A, X and n are as defined above. R ¹⁰ represents a lower hydrocarbon residue which may be substituted. Reaction (g)

Embedded image [Wherein, R ¹ , R, A, X and n are as defined above. R ¹¹
Is a group of the formula -C (R ⁷⁾ HOCOR ⁸ described above. ] Reaction (h)

Embedded image [Wherein, R ¹ , R ³ , A, X and n are as defined above. ]

In the above reaction (a), alkylation is carried out by the action of an alkylating agent in the presence of a base. Compound (I
I) About 1 to 3 mol of a base and 1 to 3 mol of an alkylating agent are used per 1 mol of dimethylformamide,
The reaction is performed in a solvent such as dimethylacetamide, dimethylsulfoxide, acetonitrile, acetone, and ethyl methyl ketone. As such a base, sodium hydride, potassium t-butoxide, potassium carbonate, sodium carbonate and the like are used. As such an alkylating agent, substituted halides (eg, chloride, bromide and iodide), substituted sulfonic esters (eg, methyl p-toluenesulfonate) and the like are used.

The reaction conditions vary depending on the combination of the base and the alkylating agent to be used.
It is preferably performed in about 10 hours. In the alkylation reaction, a mixture of two isomers (I) and (I ') is usually obtained depending on the position of the N atom to be alkylated. Compound (I) and
Although the formation ratio of (I ') varies depending on the reaction conditions used and the substituent on the thiophene ring, these two products can be easily separated by ordinary means of separation and purification (recrystallization, column chromatography, etc.). It can be obtained as a pure product.

In the reaction (b), the compound (Ib) is obtained by deprotecting the appropriately protected tetrazole derivative (Ia). In this reaction, conditions for deprotection vary depending on the protecting group (R) used. When R is triphenylmethyl, 2-tetrahydropyranyl, methoxymethyl or ethoxymethyl, etc., in a hydroalcoholic solution containing about 0.5N to 2N hydrochloric acid or acetic acid (eg, methanol, ethanol, etc.) at about room temperature, It is convenient and convenient to react for about 1 to 10 hours.

The reaction (c) is a reaction of a halogenating agent to obtain a halide (Id). The reaction is usually carried out in a solvent using about 1 to 5 mol of a halogenating agent per 1 mol of compound (Ic). Examples of the halogenating agent include chlorinating agents (eg, chlorine, N-chlorosuccinimide, etc.), brominating agents (eg, bromine, N-bromosuccinimide,
N-bromoacetic acid amide), a fluorinating agent (eg, fluorine, etc.) and the like are used. Examples of the solvent include halogenated hydrocarbons (eg, chloroform, dichloromethane, dichloroethane, carbon tetrachloride, etc.), ethers (eg, diethyl ether, dioxane, tetrahydrofuran (THF), etc.), acetic acid, trifluoroacetic acid, and the like. . The reaction conditions vary depending on the combination of the halogenating agent and the solvent to be used, but it is usually preferable to perform the reaction under ice-cooling to about room temperature for about 1 to 10 hours.

Reaction (d) is carried out in the presence of an ester (Ie) in the presence of an alkali.
Is hydrolyzed to obtain a carboxylic acid (If). The reaction is usually carried out in a solvent such as an alcohol containing water (eg, methanol, ethanol, methyl cellosolve, etc.) using about 1 to 3 mol of alkali per 1 mol of compound (Ie). As the alkali, sodium hydroxide, potassium hydroxide and the like are used. The reaction is performed at room temperature to about 100 ° C. for about 1 to 40 hours, preferably at about the boiling point of the solvent, for about 5 to 40 hours.

In the reaction (e), an alkylthio compound (Ih) is obtained by alkylating a 2-mercapto compound (Ig) in an organic solvent in the presence of a base. Usually, dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, 1 to 3 mol of a base and 1 to 3 mol of an alkylating agent are used per 1 mol of the compound (Ig).
Perform in a solvent such as acetone, ethyl methyl ketone, ethanol, methanol, or water. As the base, caustic soda, potassium carbonate, sodium carbonate, sodium hydride, potassium t-butoxide, potassium hydroxide and the like are used. As the alkylating agent, a halide (eg, methyl iodide, ethyl iodide, propyl iodide, butyl iodide, or a bromide or chloride thereof) or the like is used.
The reaction conditions vary depending on the base, the alkylating agent and the solvent to be used.
Perform in about an hour.

In the reaction (f), the compound (Ih) is treated with a suitable oxidizing agent (eg, m-chloroperbenzoic acid or the like) to give a sulfoxide (Ih).
The compound (Ij) is obtained by reacting various nucleophiles (eg, alcohols, amines, mercaptans, etc.) with i). The reaction of oxidizing the compound (Ih) to obtain the sulfoxide form and the sulfone form (Ii) is usually carried out using a halogenated hydrocarbon (eg, dichloromethane, chloroform, dichloroethane, etc.) or an ether (eg, tetrahydrofuran, dioxane, etc.) in a solvent. Used as Examples of the oxidizing agent include organic peracids such as m-chloroperbenzoic acid, and N-halocarboxylic acid amides such as N-bromosuccinimide. It is preferable to use such an oxidizing agent in a slightly excessive amount relative to 1 mol of the compound (Ih). That is, a sulfoxide compound can be obtained by using 1 mol of the oxidizing agent, and a sulfone compound can be obtained by using about 2 mol of the oxidizing agent. In general, the reaction is preferably performed under ice cooling to about room temperature for about 3 to 10 hours.

In the reaction (f), the sulfoxide or sulfone derivative (Ii) obtained as described above is reacted with various nucleophiles to obtain a compound (Ij). Reaction conditions vary depending on the nucleophile used. In the reaction with alcohols, it is preferable to use alcoholates (eg, sodium methoxide, sodium ethoxide, sodium propoxide, etc.) easily obtained from alcohols and metallic sodium. As a reaction solvent, an alcohol used as a nucleophile at that time is used.
It is preferable to react about 5 to 5 times the alcoholates at about the boiling point of the solvent for about 1 to 3 hours. In the reaction with the amines, the amine is used in an amount of about 3 to 10 times based on 1 mol of the compound (Ii). Usually, alcohols (eg, ethanol and the like) are used as the solvent, but a large excess of the amine can be used as the solvent. The reaction conditions are about the boiling point of the solvent to 15
The reaction is preferably performed at about 0 ° C. for about 1 to 10 hours.

In the above reaction (g), the tetrazole group is protected in the presence of a base, and then the carboxyl group is protected and the ester (I)
m) and then the protecting group is removed under acidic conditions to give the compound
(In). The reaction for obtaining the compound (Il) from the compound (Ik) is carried out using about 1 to 1.5 mol of an alkylating agent per 1 mol of the compound (Ik). Examples of the reaction solvent include halogenated hydrocarbons such as chloroform, methylene chloride and ethylene chloride, ethers such as dioxane and tetrahydrofuran, acetonitrile and pyridine. As such a base, potassium carbonate, sodium carbonate, triethylamine, pyridine and the like are used. As such an alkylating agent, a halide such as triphenylmethyl chloride and methoxymethyl chloride is used. The reaction conditions vary depending on the combination of the base and the alkylating agent used at that time, but it is preferable to react triphenylmethyl chloride in methylene chloride in the presence of triethylamine at about ice-cooling to about room temperature for about 1 to 3 hours.

The reaction for obtaining the compound (Im) from the compound (Il) thus obtained is carried out using about 1 to 3 mol of an alkylating agent per 1 mol of the compound (Il). Examples of such a reaction solvent include amides such as dimethylformamide and dimethylacetamide, acetonitrile, dimethylsulfoxide, acetone, and ethylmethylketone. Examples of such a base include potassium carbonate, sodium carbonate, sodium hydride, potassium t-butoxide and the like. Such alkylating agents include cyclohexyl 1-iodoethyl carbonate, ethyl
A halide such as 1-iodoethyl carbonate and pivaloyloxymethyl iodide is used. The reaction conditions vary depending on the combination of the base and the alkylating agent used at that time, but it is preferable to add the alkylating agent in DMF in the presence of potassium carbonate in DMF and react at room temperature for about 30 minutes to 1 hour.

The reaction for deprotecting the compound (Im) thus obtained is preferably carried out in the same manner as in the reaction (b). As a reaction condition when a trityl group is used as a protecting group for the tetrazole group, 1N-hydrochloric acid in methanol or ethanol is added, and the reaction is preferably performed at room temperature for about 30 minutes to 1 hour.

In the reaction (h), the nitrile form (Io) is reacted with various azides in an organic solvent to convert the nitrile form (Io) into the tetrazole form (Ib). The azide compound is used in an amount of about 1 to 5 mol per 1 mol of the compound (Io), and the reaction is usually carried out in a solvent such as dimethylformamide, dimethylacetamide, toluene and benzene. Examples of such azide compounds include trialkyltin azides (eg, trimethyltin azide, tributyltin azide, triphenyltin azide, etc.), hydrazoic acid and ammonium salts thereof. When an organic tin azide compound is used, it is 1 to 4 with respect to the compound (Io).
The reaction is carried out for about 1 to 4 days while heating and refluxing in toluene or benzene using about twice the molar amount. When reacting hydrazic acid or its ammonium salt, sodium azide and ammonium chloride or a tertiary amine (eg, triethylamine, tributylamine, etc.) are added to the compound (Io) in an amount of 1: 1.
Dimethylformamide (DMF)
The reaction is preferably performed at about 100 to 120 ° C. for about 1 to 4 days. During this time, by adding the azide compound in an appropriate amount, the reaction time, yield and the like may be sometimes improved.

After completion of the reaction, the reaction products obtained in reactions (a) to (h) as described above can be easily isolated by a conventional isolation and purification method, for example, a method such as column chromatography and recrystallization. You can do it. In addition, these compounds
(I) is a salt with an acid or base which is physiologically acceptable according to a conventional method, for example, a salt with an inorganic acid such as hydrochloride, sulfate, nitrate, etc., depending on the compound, acetate, oxalate, succinate, maleate Salts with organic acids such as acid salts, salts with alkali metals such as sodium salts and potassium salts, and salts with alkaline earth metals such as calcium salts can be derived.

Among these compounds, the starting compound (II) is exemplified by (1) B. Heinz and R. Hellmuth, Monatsh. Chem., 107 ,
299 (1976), (2) Y. Tominaga. H. Fujito, Y. Matsuda
and G. Kobayashi, Heterocycles, 6 , 1871 (1977), (3)
T. Tominaga, H. Fujito, Y. Matsuda and G. Kobayash
i, Heterocycles, 12, 401 (1979), (4) BR Fishwick,
DK Rowles and CJM Stirling, J. Chem. Soc.,
Chem. Commun., 1983 , 834, (5) Ph. Rossy, FGM V
ogel, W. Hoffmann, J. Paust and A. Neurrenbach, Tet
rahedronLett., 22 , 3493 (1981), (6) F. Outurquin and
P. Claude, Bull. Soc. Chim. Fr., 1983 , 153, (7) C.
Galvez, F. Garcia and J. Garcia, J. Chem. Researc
h, 1985 , 296 and the like, or a method analogous thereto.

Among the starting compounds (III), as the compound (IIIa) wherein n is 1, commercially available compounds can be used, and methods known in the literature such as 1) JRE Hoover, AW Chow, RJ Stedman, N.
M. Hall, HS Greenberg, MM Dolan and RJ Fe
riauto, J, Med.Chem., 7 , 245 (1964), 2) RJ Stedman, JRE Hoover, AW Chow, M.
M. Dolan, NM Halland RJ Feriauto, J. Med. Ch
em., 7 , 251 (1964), 3) H. Gilman and RD Gorsich, J. Am. Chem. Soc.,
78 , 2217 (1956), 4) Compound (IV) can be easily obtained by halogenomethylation according to the method described in M. Orchin and E. Oscar Woolfolk, 67 , 122 (1945) and the like. Can be. Reaction (i)

Embedded image [Wherein the symbols are as defined above. Further, among the starting compound (III), compounds wherein n is 2
(IIIb) can be obtained by reacting compound (IIIa) according to reaction (j). Reaction (j)

Embedded image [Wherein the symbols are as defined above. ]

The compound (I) and a salt thereof produced as described above have a low toxicity, strongly suppress the vasoconstriction and blood pressure increasing effects of angiotensin II, and are useful for animals, particularly mammals.
(E.g., humans, dogs, rabbits, rats, etc.) show a blood pressure lowering effect, not only as a therapeutic agent for hypertension,
It is useful as a therapeutic agent for cardiovascular diseases such as heart disease (cardiac hypertrophy, heart failure, myocardial infarction), stroke, renal disease accompanied by proteinuria, and arteriosclerosis. When used as such a medicament, the compound
(I) and a salt thereof, or a suitable pharmacologically acceptable carrier, excipient, mixed with a diluent, powder, granules,
It can be administered orally or parenterally in dosage forms such as tablets, capsules, and injections.

The dose varies depending on the target disease, symptom, administration subject, administration method, etc., but when administered as a therapeutic agent for essential hypertension in adults, the daily dose is 1 to 50 mg by oral administration,
For intravenous injection, it is preferable to administer the daily dose of 1 to 30 mg in two or three divided doses.

[0032]

EXAMPLES The present invention will be described below in more detail with reference to Formulation Examples, Reference Examples, Examples and Experimental Examples, but it goes without saying that these do not limit the present invention. Formulation ExamplesWhen the compound (I) of the present invention is used as a therapeutic agent for a circulatory system disease such as hypertension, heart disease, stroke, renal disease accompanied by proteinuria, and arteriosclerosis, for example, the following formulation is used. Can be used.

1. Capsule (1) 2-ethylthio-4-methyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d ] Imidazole-6-carbonic acid 10 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg 1 capsule 180 mg (1), (2) and 1/2 of (3) and (4) And then granulating. The remaining (4) is added to this, and the whole is encapsulated in a gelatin capsule. 2. Tablets (1) 2-Ethylthio-4-methyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole-6 -Carbonic acid 10 mg (2) Lactose 35 mg (3) Corn starch 150 mg (4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg One tablet 230 mg 2/1/2 of (1), (2), (3), (4) After mixing 1/2 of 3 and (5), granulate. The remaining (4) and (5) are added to the granules and pressed into tablets. 3. Injections (1) 2-ethylthio-4-methyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole- 6-Carbonic acid sodium salt 10 mg (2) Inosit 100 mg (3) Benzyl alcohol 20 mg 1 ampule 130 mg (1), (2), and (3) are dissolved in distilled water for injection so that the total volume is 2 ml, and the solution is added to an ampoule. Encapsulate. All steps are performed under aseptic conditions.

4. Capsule (1) 2-methoxy-4-methyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] Imidazole-6-carboxylate 10mg (2) Lactose 90mg (3) Microcrystalline cellulose 70mg (4) Magnesium stearate 10mg 1 capsule 180mg One half of (1), (2) and (3) and (4) After mixing, granulate. The remaining (4) is added to this, and the whole is encapsulated in a gelatin capsule. 5. Tablet (1) 2-Methoxy-4-methyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole-6 Carbonic acid 10mg (2) Lactose 35mg (3) Corn starch 150mg (4) Microcrystalline cellulose 30mg (5) Magnesium stearate 5mg 1 tablet 230mg 2/3 of (1), (2), (3), (4) And 1/2 of (5)
And then granulating. The remaining (4) and (5) are added to the granules and pressed into tablets. 6. Injection (1) 2-methoxy-4-methyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole-6 -Sodium carboxylate 10mg (2) Inosit 100mg (3) Benzyl alcohol 20mg 1 ampule 130mg (1), (2), and (3) are dissolved in distilled water for injection to a total volume of 2 ml and sealed in ampoules. I do. All steps are performed under aseptic conditions.

7. Capsules (1) Acetoxymethyl 2-methoxy-4-methyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4 -D] Imidazole-6-carboxylate 10 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg 1 capsule 180 mg (1), (2) and (3) and (4) After mixing, granulate. The remaining (4) is added to this, and the whole is encapsulated in a gelatin capsule. 8. Tablets (1) Acetoxymethyl 2-methoxy-4-methyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imi Dazole-6-carboxylate 10 mg (2) lactose 35 mg (3) corn starch 150 mg (4) microcrystalline cellulose 30 mg (5) magnesium stearate 5 mg 1 tablet 230 mg of (1), (2), (3), (4) 2/3 and 1/2 of (5)
And then granulating. The remaining (4) and (5) are added to the granules and pressed into tablets.

Reference Example 1 2-butylthieno [3,4-d] imidazole 3,4-diaminothiophene (1.7 g) and ethyl valeroimidate hydrochloride (3.0 g) were added to ethanol (30 ml), and the mixture was added at room temperature. I stirred for 1.5 hours. Ethyl acetate and saturated aqueous sodium bicarbonate were added to and dissolved in the residue obtained by concentrating the reaction solution. The organic layer was washed with water, dried and concentrated to dryness. The residue was purified by silica gel column chromatography, and the resulting crude crystals were recrystallized from isopropyl ether to yield colorless crystals.
(0.72 g, 27%). Melting point 118-120 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.95 (3H, t),
1.35-1.54 (2H, m), 1.73-1.88 (2H, m), 2.79 (2H, t), 6.
75 (2H, brs), 8.50 (1H, br s). IR (KBr) cm ^-1 : 3200-2200,1530,1480,1440,139
0, 1240, 1230, 1160, 830, 815, 760, 740.

Reference Example 2 Methyl 2,3-dihydro-4-methyl-2-oxothi
Eno [3,4-d] imidazole-6-carboxylatemethyl 3,4-diamino-2-methylthiophene-5
-Carboxylate (1.9 g) and N, N'-dicarbonyldiimidazole (1.8 g) were added to DMF (10 ml).
Stir at 0 ° C. for 1 hour. When water was added to the reaction solution, crystals precipitated. Recrystallization from methanol gave colorless needles (2.0
g, 95%). 341-343 ° C (dec.) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 2.33 (3H,
IR (KBr) cm ^-1 : 3320, 3150, 1735, 1680, 1590, 144
5, 1360, 1285, 1200, 1100, 975, 810, 755, 745. Elemental analysis value C ₈ H ₈ N ₂ O ₃ S

Reference Example 3 Methyl 2,3-dihydro-4-methyl-2-thioxo
Thieno [3,4-d] imidazole-6-carboxylatemethyl 3,4-diamino-2-methylthiophene-5
-Carboxylate (1.0 g) and N, N'-thiocarbonyldiimidazole (1.1 g) were added to DMF (5 ml).
Stirred at C for 1 hour. Water was added to the reaction solution, and the precipitated crystals were recrystallized from DMF-water to give colorless prisms (1.2.
g, quantitative). 285-288 ° C (dec.) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 2.41 (3H,
s), 3.76 (3H, s), 12.5 (1H, br s). IR (KBr) cm ^-1 : 1700, 1570, 1485, 1440, 1425, 141
5, 1330, 1200, 1180, 1100, 750.

Reference Example 4 Methyl 2-ethylthio- 4 -methylthieno [3,4-d]
Imidazole-6-carboxylate methyl 2,3-dihydro-4-methyl-2-thioxothieno [3,4-d] imidazole-6-carboxylate
A mixture of (1.1 g), ethyl iodide (0.75 g) and 2N sodium hydroxide (2.4 ml) in methanol (30 ml) was stirred at room temperature for 3 hours. The reaction solution was concentrated and water was added to precipitate crystals. Recrystallization from ethyl acetate-hexane gave colorless prisms (1.0 g, 83%). 159-160 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.44 (3H, t),
2.62 (3H, s), 3.30 (2H, q), 3.87 (3H, s), 9.55 (1H, brs). IR (KBr) cm ^-1 : 1690, 1675, 1665, 1650, 1620, 154
5, 1465, 1440, 1330, 1320, 1240, 1120, 1105.

Reference Example 5 Methyl 4-methylthieno [3,4-d] imidazole-6
-Carboxylate methyl 3,4-diamino-2-methylthiophene-5
-Carboxylate (1.9 g) was heated at reflux in formic acid (5 ml) for 4 hours. Water was added to the residue obtained by concentrating the reaction solution, and the insolubles were removed by filtration. The filtrate was neutralized with sodium bicarbonate water, and the precipitated crystals were recrystallized from methanol to give light brown prism crystals.
(0.2 g, 38%). 266-267 ° C (dec.) Elemental analysis value As C ₈ H ₈ N ₂ O ₂ S ¹ H-NMR (90 MHz, DMSO-d ₆ ) δ: 2.60 (3H, s),
3.79 (3H, s), 8.20 (1H, s). IR (KBr) cm ^-1 : 1690, 1525, 1505, 1465, 1440, 137
0, 1315, 1300, 1265,1200, 1160, 1100, 945, 875,
760.

The following compounds were synthesized in the same manner as in Reference Example 4.

Embedded image

Reference Example 13 2-butyl-1-[[2 '-(1H-tetrazole-5-
Yl) biphenyl-4-yl] methyl] thieno [3,4-d]
Imidazole 2-butylthieno [3,4-d] imidazole (0.54 g)
Sodium hydroxide (60% oily,
0.13 g) and stirred under ice-cooling for 15 minutes.
-[2- (N-Trityltetrazol-5-yl) phenyl] benzyl bromide (1.7 g) was added, and the mixture was stirred at room temperature for 2 hours. After water was added to the reaction solution, the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated to dryness. The residue was purified by silica gel column chromatography, and the trityl compound obtained was converted into methanol (18 ml) and chloroform (6 ml).
And 1N hydrochloric acid (7.5 ml) was added thereto, followed by stirring at room temperature for 1 hour. After concentrating the reaction solution, the mixture was adjusted to pH 3 to 4 with 1N sodium hydroxide solution and extracted with chloroform. Washing the organic layer with water,
After drying, it was concentrated to dryness. Crystals obtained by purifying the residue by silica gel column chromatography were recrystallized from ethyl acetate-methanol to give colorless crystals (0.53 g, 41%).
I got Melting point 209-211 ° C ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 0.88 (3H,
t), 1.27-1.46 (2H, m), 1.59-1.74 (2H, m), 5.22 (2H, m
s), 6.66 (1H, d), 7.05 (1H, d), 7.08 (2H, d), 7.18 (2H,
d), 7.50-7.71 (4H, m). IR (KBr) cm ^-1 : 1595, 1520, 1470, 1440, 1430, 140
0, 815, 770, 760, 725. Elemental analysis: C ₂₃ H ₂₂ N ₆ S · 0.2H ₂ O

Reference Example 14 Methyl 2-ethylthiothieno [3,4-d] imidazole
-6-carboxylate 14a) methyl 3,4-diaminothiophene-2-ca
Ruboxilate FGM Vogel, J. Paust & A. Neurrenbach, Liebigs
Ann. Chem., 1972 (1980) and A. Fliri & K. Hohen
The title compound was obtained as colorless crystals by the method described in the literature of lohe-Oehringen, Chem. Ber., 113 , 607 (1980). mp. 95-97 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 3.83 (3H, s),
6.40 (1H, s). 14b) Methyl 2-mercaptothieno [3,4-d] imid
Dazole-4-carboxylate The title compound was obtained as pale yellow crystals in the same manner as in Reference Example 3 from methyl 3,4-diaminothiophen-2-carboxylate obtained in Reference Example 14a). Melting point 250-255 ° C (decomposition) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 3.79 (3
H, s), 7.13 (1H, s). 14c) Methyl 2-ethylthiothieno [3,4-d] imi
Dazole-6-carboxylate Methyl 2-mercaptothieno obtained in Reference Example 14b)
From [3,4-d] imidazole-4-carboxylate,
The title compound was obtained as colorless prism crystals in the same manner as in Reference Example 4. Melting point 164-165 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.48 (3H, t), 3.
32 (2H, q), 3.91 (3H, s), 7.18 (1H, s), 9.21 (1H, brs).

Embodiment 1Methyl 2-ethylthio-4-methyl-1-[[2'-
(1H-tetrazol-5-yl) biphenyl-4-i
[Methyl] thieno [3,4-d] imidazole-6-cal
Boxylate Methyl 2-ethylthio-4-methylthieno [3,4-d]
D of imidazole-6-carboxylate (0.77 g)
To a MF (8 ml) solution was added sodium hydride (60% oil) under ice-cooling.
0.13 g) and stirred for 15 minutes before adding 4-
[2 '-(N-trityltetrazol-5-yl) phenyi
[Benzyl] bromide (1.8 g) and added at room temperature for 2 hours.
I'm sorry. Water was added to the reaction solution, and extracted with ethyl acetate.
Was. The organic layer was washed with water, dried and concentrated to dryness. Spill the residue
Purify by Kagel column chromatography and fraction 1
(1-substituted) and a second fraction (3-substituted) were obtained.
The yellow syrup (trityl form) obtained from the first fraction
Dissolved in a mixture of roform (10 ml) -methanol (35 ml)
And add 1N hydrochloric acid (1.7 ml) and stir at room temperature for 1 hour.
I did. Water was added to the residue obtained by concentrating the reaction solution, and 1
After adjusting the pH to 3-4 with N sodium hydroxide, chloroform
Extracted. The extract is washed with water, dried and concentrated.
Is purified by silica gel column chromatography.
The resulting crude crystals were recrystallized from ethyl acetate-methanol.
Colorless needles (0.69 g, 46%) were obtained. Melting point 216-218 ° C (dec.) Elemental analysis value C_{twenty four}H_{twenty two}N₆O_TwoS_TwoAs

Reference Example 15Methyl 2-ethylthio-4-methyl-3-[[2'-
(1H-tetrazol-5-yl) biphenyl-4-i
[Methyl] thieno [3,4-d] imidazole-6-cal
Boxylate The crystals obtained from the second fraction described in Example 1 were
Dissolved in methanol (5 ml) and 1N salt
After adding acid (1.0 ml), the mixture was stirred at room temperature for 1 hour.
After adjusting the pH to 3 to 4 with 1N NaOH, the residue obtained by concentration is obtained.
Water was added to the mixture and extracted with chloroform. Extract to water
Washing and drying (Na_TwoSO_Four) And concentrated to dryness. Got
The residue was purified by silica gel column chromatography.
Crystals were obtained. From chloroform-isopropyl ether
Recrystallization afforded pale yellow crystals (0.1 g, 7%). mp. 192-196 ° C (decomposition) Elemental analysis C_{twenty four}H_{twenty two}N₆O_TwoS_TwoAs ¹H-NMR (200 MHz, CDCl_Three) δ: 1.37 (3H, t),
2.28 (3H, s), 3.28 (2H, q), 3.73 (3H, s), 5.20 (2H, s), 7.01-
7.11 (4H, m), 7.32-7.37 (1H, m), 7.44-7.59 (2H, m), 7.90-7.
94 (1H, m). IR (KBr) cm^-1： 1690,1530,1440,1410,1360,1310,128
0,1270,1190,1110,760.

Example 2 2-ethylthio-4-methyl-1-[[2 '-(1H-te
Trazol-5-yl) biphenyl-4-yl] methyl]
Methyl thieno [3,4-d] imidazole-6-carboxylate 2-ethylthio-4-methyl-1-[[2'-
(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole-6-carboxylate (0.25 g) was dissolved in methanol (8 ml) and 1N aqueous sodium hydroxide (1.5 ml). And heated under reflux for 12 hours. The pH of the reaction solution was adjusted to 3 to 4 with 1N hydrochloric acid, and water was added. The precipitated crystals were recrystallized from methanol-ethyl acetate to give colorless needles (0.16 g, 67%). Melting point 194-195 ° C (dec.) Elemental analysis value As C ₂₃ H ₂₀ N ₆ O ₂ S ₂ ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.34 (3H,
t), 2.54 (3H, s), 3.24 (2H, q), 5.66 (2H, s), 7.02-7.12
(4H, m), 7.51-7.72 (4H, m). IR (KBr) cm ^-1 : 1680, 1600, 1530, 1445, 1300, 122
0, 1190, 1165, 1085,775, 750.

Reference Example 16 2-ethylthio-4-methyl-3-[[2 '-(1H-te
Trazol-5-yl) biphenyl-4-yl] methyl]
Thieno [3,4-d] imidazole-6 carboxylic acid Methyl 2-ethylthio-4-methyl-3-[[2 '-(1H-tetrazol-5-yl)
From biphenyl-4-yl] methyl] thieno [3,4-d] imidazole-6-carboxylate (0.1 g), the title compound was obtained as pale brown crystals (0.06 g). mp. As 192-195 ° C. (decomposition) Elemental analysis _{C 23 H 20 N 6 O 2} S 2 · H 2 O ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.39 (3H,
t), 2.28 (3H, s), 3.35 (2H, q), 5.28 (2H, s), 7.08 (4H, s), 7.5
3-7.74 (4H, m). IR (KBr) cm ^-1 : 1610,1600,1530,1
435, 1410, 1400, 1360, 1350, 1
280, 1260, 1110, 750.

Embodiment 3Methyl 4-methyl-1-[[2 ′-(1H-tetrazo
Ru-5-yl) biphenyl-4-yl] methyl] thieno
[3,4-d] imidazole-6-carboxylate Methyl 4-methylthieno [3,4-d] imidazole-6
-To a solution of carboxylate (0.20 g) in DMF (2 ml)
Add sodium hydride (60% oily, 48 mg) under ice-cooling and add 1
After stirring for 5 minutes, 4- [2 '-(N-trityl tetrate)
Lazol-5-yl) phenyl] benzylbromide
(0.68 g) and stirred at room temperature for 1 hour. reaction
Water was added to the liquid and extracted with ethyl acetate. Washing the extract with water,
After drying, it was concentrated to dryness. The obtained residue is
Purified by column chromatography, fraction 1 and fraction 2
Got a minute. The oil obtained from the first fraction is chloroform
(3 ml)-dissolved in methanol (12 ml) and 1N hydrochloric acid
(0.5 ml) and stirred at room temperature for 1 hour. Solvent
Add water to the residue obtained by distillation, and add 1N-caustic soda.
After adjusting the pH to 3 to 4 with water, the mixture was extracted with chloroform. Lottery
The residue is washed, dried and concentrated to dryness.
Purified by silica gel column chromatography. Get
The crystals were recrystallized from ethyl acetate-hexane to give colorless needles.
Crystals (0.12 g, 28%) were obtained. Melting point 188-189 ℃ elemental analysis value C_{twenty two}H₁₈N₆O_TwoS ・ 0.2H_TwoAs O ¹H-NMR (200 MHz, DMSO-d₆) δ: 2.59 (3H,
s), 3.71 (3H, s), 5.65 (2H, s), 7.06 (2H, d), 7.14 (2H,
d), 7.49-7.71 (4H, m), 8.40 (1H, s) .IR (KBr) cm^-1: 1680, 1600, 1530, 1425, 1330, 127
5, 1225, 1140, 1080,880, 750.

Reference Example 17Methyl 6-methyl-1-[[2 '-(1H-tetrazo
Ru-5-yl) biphenyl-4-yl] methyl] thieno
[3,4-d] imidazole-4-carboxylate The crystals obtained from the second fraction described in Example 3 were
Solution (3 ml) -methanol (12 ml) and 1N hydrochloric acid
(0.5 ml) and stirred at room temperature for 1 hour. Solvent
Add water to the residue obtained by distillation and add 1N sodium hydroxide solution
Then, the mixture was adjusted to pH 3 to 4 and extracted with chloroform. Extract
Is washed with water, dried and concentrated to dryness.
Purified by Kagel column chromatography. Got
The crystals were recrystallized from ethyl acetate-methanol to
A rhythmic crystal (50 mg, 12%) was obtained. Melting point 225-227
℃ (dec.) Elemental analysis value C_{twenty two}H₁₈N₆O_TwoS ・ 0.2H_TwoAs O ¹H-NMR (200 MHz, DMSO-d₆) δ: 2.29 (3H,
s), 3.73 (3H, s), 5.42 (2H, s), 7.10 (4H, s), 7.52-7.72
(4H, m), 8.51 (1H, s). IR (KBr) cm^-1: 1690, 1500, 1445,1435, 1330, 1285,
 1200, 1110.

Reference Example 18 5- [4 '-(4,6-dibromo-2-butylthieno [3,
4-d] Imidazol-1-yl) methylbiphenyl-
2-yl] tetrazole K salt 2-butyl-1-[[2 '-(1H-tetrazol-5-
Yl) biphenyl-4-yl] methyl] thieno [3,4-d]
Bromine (0.15 g) was added to a solution of imidazole (0.15 g) in acetic acid (3 ml).
A solution of 11 g) in acetic acid (0.5 ml) was added dropwise. After stirring at room temperature for 1 hour, the solvent was distilled off. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried. The residue obtained by distilling off the solvent was purified by silica gel column chromatography. The obtained syrup was dissolved in methanol (1 ml), and 2-ethylhexanoic acid K salt (87 mg) was added. Toluene (10 ml) was added, the mixture was concentrated under reduced pressure, and the resulting precipitate was collected by filtration and dried to give a powder crystal (47 mg, 21%). 246-248 ° C (dec.) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 0.85 (3H,
t), 1.28-1.42 (2H, m), 1.55-1.70 (2H, m), 5.30 (2H, m
s), 6.98 (2H, d), 7.13 (2H, d), 7.24−7.37 (3H, m), 7.52
−7.57 (1H, m). IR (KBr) cm ⁻¹ : 1490, 1475, 1405, 1355, 1110, 760. Elemental analysis value C ₂₃ H ₁₉ Br ₂ KN ₆ S · 0.5H ₂ O

Example 4 4-methyl-1-[[2 '-(1H-tetrazol-5-
Yl) biphenyl-4-yl] methyl] thieno [3,4-d]
Methyl imidazole-6-carboxylate 4-methyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno
[3,4-d] imidazole-6-carboxylate (0.1
A solution of g) in 1N sodium hydroxide (1.5 ml) and methanol (5 ml) was heated at reflux for 2 days. The reaction solution was neutralized with 1N hydrochloric acid, and the generated crystals were recrystallized from methanol-ethyl acetate to give colorless crystals (0.1 g, quantitative). Melting point: 187-189 ° C (dec.) Elemental analysis: C ₂₁ H ₁₆ N ₆ O ₂ S 1/4 MeOH 1 /
As 2H ₂ O ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 2.57 (3H,
s), 5.66 (2H, s), 7.05 (2H, d), 7.18 (2H, d), 7.48-7.70
(4H, m), 8.36 (1H, s). IR (KBr) cm ^-1 : 1680, 1605, 1525, 1505, 1330, 125
5, 1240, 1215, 1150,775, 765.

Example 5 Pivaloyloxymethyl 2-ethylthio-4-methyl
-1-[[2 '-(1H-tetrazol-5-yl) bifu
E-4-yl] methyl] thieno [3,4-d] imidazole
5 -a-carboxylate 5a) 2-ethylthio-4-methyl-1-[[2 '-(N
-Trityltetrazol-5-yl) biphenyl-4-
Yl] methyl] thieno [3,4-d] imidazole-6-cal
Bon acid 2-ethylthio-4-methyl -1 - [[2 '- ( 1H- tetrazol-5-yl) biphenyl-4-yl] methyl]
Thieno [3,4-d] imidazole-6-carboxylic acid (0.
92 g) and triethylamine (0.3 ml) in dichloromethane (20 ml).
g) was added and stirred at room temperature for 30 minutes. After the reaction solution was washed with water and dried, the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to obtain crystals. Recrystallization from ethyl acetate-hexane gave colorless needles (1.36 g, 98%). mp. As 138-140 ° C. Elemental analysis _{C 42 H 34 N 6 O 2} S 2 ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.34 (3H, t),
2.62 (3H, s), 3.22 (2H, q), 5.51 (2H, s), 6.88-7.04 (10H, m),
7.16-7.32 (10H, m), 7.39-7.44 (2H, m), 7.85-7.90 (1H, m). IR (KBr) cm ^-1 : 1690,1650,1600,1530,1445,1410,131
0,1260,1230,1190,1160,755,740,690.

[0053]5b) Pivaloyloxymethyl 2-ethyl
Lucio -4-methyl-1-[[2 '-(1H-tetrazo
Le-5 -Yl) biphenyl-4-yl] methyl] thieno
[3,4-d] imidazole-6-carboxylate DMF of the trityl compound (0.6 g) obtained in Example 5a)
(5ml) solution with K_TwoCO_Three(0.15 g) and iodide
Add baroyloxymethyl (0.25 g) and add 1
It was time stirring. Add water to the reaction mixture and extract with ethyl acetate.
Issued. After the extract was washed with water and dried, the solvent was distilled off.
The obtained syrup was dissolved in methanol (10 ml) -chloroform.
(5 ml), and 1N hydrochloric acid (6 ml) was added.
Stirred at room temperature for 30 minutes. Obtained by concentrating the reaction
Water was added to the residue and extracted with chloroform. Extract to water
After washing and drying, the solvent was distilled off. The obtained residue is
Purified by Kagel column chromatography to form a colorless powder
Crystals (0.33 g, 67%) were obtained. mp. 107-110 ° C (decomposition) Elemental analysis value C₂₉H₃₀N₆O_FourS_TwoAs ¹H-NMR (200 MHz, CDCl_Three) δ: 1.14 (9H, s),
1.42 (3H, t), 2.63 (3H, s), 3.30 (2H, q), 5.67 (2H, s), 7.14-
7.25 (4H, m), 7.40-7.45 (1H, m), 7.50-7.64 (2H, m), 8.17-8.
21 (1H, m). IR (KBr) cm^-1： 2975,1750,1730,1700,1600,1480,145
0,1320,1230,1165,1130,1080,1060,1030,985,750,730.

Example 6 1- (Cyclohexyloxycarbonyloxy) ethyl
2-ethylthio-4-methyl- 1-[[2 '-(tetra
5-yl) biphenyl - 4-yl] methylation] Ji
Obtained in d Bruno [3,4-d] imidazole-6-carboxylate Example 5a) 2-ethylthio-4-methyl-1
[[2 '-(N-Trityltetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole-6-carboxylic acid (0.6 g) in DMF (5 ml) solution ₂ CO ₃ (0.15 g), 1- (cyclohexyloxycarbonyloxy) ethyl chloride (0.21 g) and potassium iodide (85 mg) were added, and the mixture was stirred at 60 ° C for 1 hour. Water was added to the reaction solution, which was extracted with ethyl acetate. After the extract was washed with water and dried, the solvent was distilled off. 1N hydrochloric acid (6 ml) was added to a solution of the obtained syrup in methanol (10 ml) and chloroform (5 ml), and the mixture was stirred at room temperature for 30 minutes. Water was added to the residue obtained by concentrating the reaction solution, and the mixture was extracted with chloroform. After the extract was washed with water and dried, the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to give a colorless powdery crystal (0.3
6g, 66%). mp. As 105-108 ° C. (decomposition) Elemental analysis _{C 32 H 34 N 6 O 5} S 2 ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.17-1.85 (16
H, m), 2.64 (3H, s), 3.31 (2H, q), 4.46-4.58 (1H, m), 5.68 (2
H, d), 6.87 (1H, q), 7.14 (4H, s), 7.41-7.46 (1H, m), 7.48-7.
63 (2H, m), 8.08-8.13 (1H, m). IR (KBr) cm ^-1 : 2950,1755,1690,1450,1320,1275,126
0,1230,1165,1050,1020,1000,935,900,750.

Embodiment 7Methyl 4-methyl-2-methylthio-1-[[2'-
( 1H-tetrazol-5-yl) biphenyl-4-i
[Methyl] thieno [3,4-d] imidazole-6-ca Lubo
Xylate As in Example 1, methyl 4-methyl-2-methyl
Luthiothieno [3,4-d] imidazole-6-carboxy
From the compound (0.94 g) to give pale yellow needles
(0.85 g, 45%). mp. 221-225 ° C (decomposition) Elemental analysis value C_{twenty three}H₂₀N₆O_TwoS_Two・ 0.4H_TwoAs O ¹H-NMR (200 MHz, DMSO-d₆) δ: 2.56 (3H,
s), 2.65 (3H, s), 3.69 (3H, s), 5.63 (2H, s), 7.06 (4H, s), 7.5
0-7.70 (4H, m). IR (KBr) cm^-1： 1700,1600,1460,1430,1425,1320,123
5,1185,1170,1090,750.

Example 8 Methyl 4-methyl-2-propylthio-1-[[2'-
(1H-tetrazol-5-yl) biphenyl-4-i
[Methyl] thieno [3,4-d] imidazole-6- carbo
Xylate In the same manner as in Example 1, methyl 4-methyl-2-propylthiothieno [3,4-d] imidazole-6-carboxylate (1.0 g) was used to give the title compound as colorless plate crystals (1.0 g). , 53%). mp. 222-226 ° C (decomposition) Elemental analysis value As C ₂₅ H ₂₄ N ₆ O ₂ S ₂ .0.5H ₂ O ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 0.95 (3H,
t), 1.63-1.80 (2H, m), 2.55 (3H, s), 3.24 (2H, t), 3.68 (3H,
s), 5.63 (2H, s), 7.05 (4H, s), 7.51-7.71 (4H, m). IR (KBr) cm ^-1 : 1700,1600,1455,1430,1320,1240,116
5,1085,750.

REFERENCE EXAMPLE 19 Methyl 4-methyl-2-propylthio-3-[[2'-
(1H-tetrazol-5-yl) biphenyl-4-i
[Methyl] thieno [3,4-d] imidazole-6- carbo
Xylate In the same manner as in Reference Example 15, the title compound was converted from methyl 4-methyl-2-propylthiothieno [3,4-d] imidazole-6-carboxylate (1.0 g) to colorless crystals (82 mg, 4%). As obtained. mp. 203-208 ° C (decomposition) Elemental analysis value As C ₂₅ H ₂₄ N ₆ O ₂ S ₂ .0.5H ₂ O ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.00 (3H,
t), 1.68-1.86 (2H, m), 2.29 (3H, s), 3.36 (2H, t), 3.78 (3H,
s), 5.31 (2H, s), 7.03-7.12 (4H, m), 7.51-7.73 (4H, m). IR (KBr) cm ^-1 : 1690,1530,1440,1430,1410,1360,134
0,1320,1270,1190,1105,1070,755.

Embodiment 9Methyl 2-allylthio-4-methyl-1-[[2'-
( 1H-tetrazol-5-yl) biphenyl-4-i
[Methyl] thieno [3,4-d] imidazole-6-ca Lubo
Xylate In the same manner as in Example 1, methyl 2-allylthio-4-
Methylthieno [3,4-d] imidazole-6-carboxy
(0.85 g) from colorless needles (0.7 g, 44
%). mp. 203-205 ° C (decomposition) Elemental analysis value C_{twenty five}H_{twenty two}N₆O_TwoS_TwoAs ¹H-NMR (200 MHz, DMSO-d₆) δ: 2.56 (3H,
s), 3.67 (3H, s), 3.95 (2H, d), 5.12-5.18 (1H, m), 5.28-5.37
(1H, m), 5.63 (2H, s), 5.87-6.08 (1H, m), 7.06 (4H, s), 7.51-
7.72 (4H, m). IR (KBr) cm^-1： 1680,1595,1450,1425,1315,1235,116
0,1085,750.

Reference Example 20Methyl 2-allylthio-4-methyl-3-[[2'-
( 1H-tetrazol-5-yl) biphenyl-4-i
[Methyl] thieno [3,4-d] imidazole-6 − Cal
Boxylate In the same manner as in Reference Example 15, methyl 2-allylthio-4
-Methylthieno [3,4-d] imidazole-6-carboxy
From sylate (0.7 g), colorless needles (16 mg, 1.
0%). mp. 132-140 ° C (decomposition) Elemental analysis C_{twenty five}H_{twenty two}N₆O_TwoS_Two・ 0.5H_TwoAs O ¹H-NMR (200 MHz, DMSO-d₆) δ: 2.29 (3H,
s), 3.77 (3H, s), 4.06 (2H, d), 5.16-5.22 (1H, m), 5.30 (2H,
s), 5.34-5.44 (1H, m), 5.93-6.16 (1H, m), 7.02-7.12 (4H,
m), 7.49-7.67 (4H, m).

Embodiment 10Methyl 2-isopropylthio-4-methyl-1-
[[2 '-(1H-tetrazol-5-yl) biphenyl
-4-yl] methyl] thieno [3 , 4-d] Imidazole- 6
-Carboxylate In the same manner as in Example 1, methyl 2-isopropylthio
-4-Methylthieno [3,4-d] imidazole-6-cal
From boxylate (0.82 g), colorless needles (0.62) were obtained.
g, 41%). mp. 210-214 ° C (decomposition) Elemental analysis value C_{twenty five}H_{twenty four}N₆O_TwoS_TwoAs ¹H-NMR (200 MHz, DMSO-d₆) δ: 1.40 (6H,
d), 2.56 (3H, s), 3.68 (3H, s), 3.89-4.03 (1H, m), 5.61 (2H,
s), 7.03 (4H, s), 7.49-7.70 (4H, m) .IR (KBr) cm^-1： 1680,1590,1445,1425,1325,1315,124
0,1160,1150,1085,750.

Reference Example 21Methyl 2-isopropylthio-4-methyl-3-
[[2 '-(1H-tetrazol-5-yl) biphenyl
-4-yl] methyl] thieno [3 , 4-d] Imidazole- 6
-Carboxylate In the same manner as in Reference Example 15, methyl 2-isopropylthio
O-4-methylthieno [3,4-d] imidazole-6
From carboxylate (0.82 g), colorless crystals (12
mg, 0.8%). mp. 132-138 ° C (decomposition)¹ H-NMR (200 MHz, DMSO-d₆) δ: 1.46 (6H,
d), 2.29 (3H, s), 3.77 (3H, s), 4.01-4.19 (1H, m), 5.28 (2H,
s), 7.00-7.11 (4H, m), 7.47-7.66 (4H, m).

Embodiment 11Methyl 2-butylthio-4-methyl-1-[[2'-
( 1H-tetrazol-5-yl) biphenyl-4-i
[Methyl] thieno [3,4-d] imidazole-6-ca Lubo
Xylate In the same manner as in Example 1, methyl 2-butylthio-4-
Methylthieno [3,4-d] imidazole-6-carboxy
(1.10 g) to pale yellow prism crystals (0.8 g,
40%). mp. 196-198 ° C (decomposition) Elemental analysis value C₂₆H₂₆N₆O_TwoS_TwoAs ¹H-NMR (200 MHz, DMSO-d₆) δ: 0.88 (3H,
t), 1.29-1.47 (2H, m), 1.60-1.75 (2H, m), 2.55 (3H, s), 3.26
(3H, t), 3.68 (3H, s), 5.62 (2H, s), 7.04 (4H, s), 7.50-7.70
(4H, m). IR (KBr) cm^-1： 1690,1600,1450,1430,1420,1315,123
0,1160,1085,750.

Reference Example 22Methyl 2-butylthio-4-methyl-3-[[2'-
( 1H-tetrazol-5-yl) biphenyl-4-i
[Methyl] thieno [3,4-d] imidazole-6-ca Lubo
Xylate In the same manner as in Reference Example 15, methyl 2-butylthio-4
-Methylthieno [3,4-d] imidazole-6-carboxy
Light yellow prism crystals (12m
g, 0.6%). mp. 108-110 ° C (decomposition) Elemental analysis value C₂₆H₂₆N₆O_TwoS_Two・ H_TwoAs O ¹H-NMR (200 MHz, DMSO-d₆) δ: 0.93 (3H,
t), 1.34-1.52 (2H, m), 1.66-1.81 (2H, m), 2.28 (3H, s), 3.38
(3H, t), 3.76 (3H, s), 5.29 (2H, s), 7.01-7.11 (4H, m), 7.49-
7.67 (4H, m).

Example 12 Methyl 2-hexylthio-4-methyl-1-[[2'-
(1H-tetrazol-5-yl) biphenyl-4-i
[Methyl] thieno [3,4-d] imidazole-6- carbo
Xylate In the same manner as in Example 1, methyl 2-hexylthio-4
From -methylthieno [3,4-d] imidazole-6-carboxylate (1.25 g), colorless needles (0.75 g,
31%). mp. As 135-136 ° C. (decomposition) Elemental analysis _{C 28 H 30 N 6 O 2} S 2 ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.88 (3H, t),
1.26-1.45 (6H, m), 1.67-1.82 (2H, m), 2.58 (3H, s), 3.27 (3
H, t), 3.77 (3H, s), 5.73 (2H, s), 7.14-7.24 (4H, m), 7.38-
7.42 (1H, m), 7.49-7.63 (2H, m), 7.17-8.22 (1H, m). IR (KBr) cm ^-1 : 1680,1595,1450,1425,1315,1235,119
0,1160,1085,750.

REFERENCE EXAMPLE 23 Methyl 2-hexylthio-4-methyl-3-[[2'-
(1H-tetrazol-5-yl) biphenyl-4-i
[Methyl] thieno [3,4-d] imidazole-6- carbo
Xylate In the same manner as in Reference Example 15, methyl 2-hexylthio-
From 4-methylthieno [3,4-d] imidazole-6-carboxylate (1.25 g), pale yellow crystals (18 mg,
0.7%). mp. As 152-154 ° C. (decomposition) Elemental analysis _{C 28 H 30 N 6 O 2} S 2 · 0.4H 2 O ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.89 (3H, t),
3.31 (3H, t), 3.74 (3H, s), 5.22 (2H, s), 7.03-7.13 (4H, m),
7.32-7.37 (1H, m), 7.46-7.60 (2H, m), 7.95-8.00 (1H, m).

Embodiment 13Methyl 2-cyclohexylthio-4-methyl-1-
[[2 '-(1H-tetrazol-5-yl) biphenyl
-4-yl] methyl] thieno [3,4-d] imidazole -6
-Carboxylate As in Example 1, methyl 2-cyclohexylchi
O-4-methylthieno [3,4-d] imidazole-6-ca
From ruboxylate (0.65 g), colorless needles (0.4) were obtained.
8g, 42%). mp. 169-171 ° C (decomposition) Elemental analysis C₂₈H₂₈N₆O_TwoS_Two・ 0.5H_TwoAs O ¹H-NMR (200 MHz, CDCl_Three) δ: 1.25-1.77 (8
H, m), 2.08-2.17 (2H, m), 2.61 (3H, s), 3.77 (3H, s), 3.83-3.
95 (1H, m), 5.74 (2H, s), 7.14-7.24 (4H, m), 7.38-7.43 (1H,
m), 7.49-7.63 (2H, m), 8.19-8.23 (1H, m). IR (KBr) cm^-1： 1690,1605,1450,1440,1320,1240,117
0,1100,760.

Example 14 2-Allylthio-4-methyl-1-[[2 '-(1H-te
Trazol-5-yl) biphenyl-4-yl] methyl]
Methyl thieno [3,4-d] imidazole-6-carboxylate 2-allylthio-4-methyl-1-[[2'-
(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole-6-carboxylate (0.59 g) was added to tetrahydrofuran (10 m
l) and a mixture of water (5 ml)
Monohydrate (0.15 g) was added and the mixture was stirred at 50 ° C for 20 hours. Water was added to the residue obtained by concentrating the reaction solution, and 1N
The pH was adjusted to 3 to 4 with hydrochloric acid. The precipitated crystals were
Recrystallization from ethyl acetate gave colorless crystals (0.35 g, 60
%). mp. 135-136 ° C (decomposition) Elemental analysis value As C ₂₄ H ₂₀ N ₆ O ₂ S ₂ .0.6H ₂ O ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 2.54 (3H,
s), 3.93 (2H, d), 5.10-5.16 (1H, m), 5.27-5.36 (1H, m), 5.66
(2H, s), 5.85-6.06 (1H, m), 7.06 (4H, s), 7.50-7.70 (4H, m). IR (KBr) cm ^-1 : 1675,1595,1525,1440,1300,1220 , 118
0,1160,1080,925,770,750.

Example 15 4-Methyl-2-methylthio-1-[[2 '-(1H-te
Trazol-5-yl) biphenyl-4-yl] methyl]
Thieno [3,4-d] imidazole-6-carboxylic acid In the same manner as in Example 14, methyl 4-methyl-2-methylthio-1-[[2 ′-(1H-tetrazol-5-yl) biphenyl-4 The title compound was obtained as colorless crystals (0.35 g, 51%) from -yl] methyl] thieno [3,4-d] imidazole-6-carboxylate (0.71 g). mp. As 188-190 ° C. (decomposition) Elemental analysis _{C 22 H 18 N 6 O 2} S 2 · 0.2H 2 O ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 2.54 (3H,
s), 2.64 (3H, s), 5.66 (2H, s), 7.03-7.13 (4H, m), 7.51-7.71
(4H, m). IR (KBr) cm ^-1 : 1650,1640,1590,1530,1450,1435,134
0,1325,1305,1170,750.

Example 16 4-Methyl-2-propylthio-1-[[2 '-(1H-
Tetrazol-5-yl) biphenyl-4-yl] methyl
Ru ] thieno [3,4-d] imidazole-6-carboxylic acid In the same manner as in Example 14, methyl 4-methyl-2-propylthio-1-[[2 ′-(1H-tetrazol-5-
Yl) biphenyl-4-yl] methyl] thieno [3,4-d]
The title compound was obtained as colorless crystals (0.5 g, 62%) from imidazole-6-carboxylate (0.84 g). mp. 161-162 ° C (decomposition) Elemental analysis value As C ₂₄ H ₂₂ N ₆ O ₂ S ₂ .0.4H ₂ O ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 0.95 (3H,
t), 1.61-1.80 (2H, m), 2.53 (3H, s), 3.23 (2H, t), 5.67 (2H,
s), 7.02-7.11 (4H, brs), 7.49-7.71 (4H, m). IR (KBr) cm ^-1 : 1680,1600,1530,1
445, 1305, 1225, 1190, 1185, 1
165,770,750.

Reference Example 24 4-Methyl-2-propylthio-3-[[2 '-(1H
-Tetrazol-5-yl) biphenyl-4-yl] me
Tyl] thieno [3,4-d] imidazole-6-carboxylic acid In the same manner as in Example 14, methyl 4-methyl-2-propylthio-3-[[2 ′-(1H-tetrazol-5-
Yl) biphenyl-4-yl] methyl] thieno [3,4-d]
From imidazole-6-carboxylate (45 mg):
The title compound was obtained as colorless crystals (28 mg, 65%). mp. 192-197 ° C ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 0.99 (3H,
t), 1.67-1.85 (2H, m), 2.28 (3H, s), 3.35 (2H, t), 5.29 (2H,
s), 7.08 (4H, s), 7.52-7.73 (4H, m).

Example 17 2-isopropylthio-4-methyl-1-[[2 '-(1
H-tetrazol-5-yl) biphenyl-4-yl]
Methylation] thieno [3,4-d] imidazole-6-Cal Bonn
In a similar manner to acid example 14, methyl 2-isopropylthio-4-methyl-1-[[2 ′-(1H-tetrazole-
5-yl) biphenyl-4-yl] methyl] thieno [3,4
-D] imidazole-6-carboxylate (0.55
g) to give the title compound as colorless needles (0.37 g, 68
%). mp. 182-184 ° C (decomposition) Elemental analysis value As C ₂₄ H ₂₂ N ₆ O ₂ S ₂ .0.5H ₂ O ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.39 (6H,
d), 2.55 (3H, s), 3.88-4.03 (1H, m), 5.66 (2H, s), 7.06 (4H,
s), 7.51-7.72 (4H, m). IR (KBr) cm ^-1 : 1650,1640,1590,1530,1450,1430,138
0,1310,1240,1160,1150,930,770,750.

Example 18 2-butylthio-4-methyl-1-[[2 '-(1H-te
Trazol-5-yl) biphenyl-4-yl] methyl]
Thieno [3,4-d] imidazole-6-carboxylic acid In the same manner as in Example 14, methyl 2-butylthio-4
-Methyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole-6-carboxylic acid (0.65 g) from the title compound Was obtained as colorless needles (0.47 g, 74%). mp. 161-163 ° C (decomposition) Elemental analysis value As C ₂₅ H ₂₄ N ₆ O ₂ S ₂ .0.4H ₂ O ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 0.89 (3H,
t), 1.28-1.47 (2H, m), 1.60-1.74 (2H, m), 2.54 (3H, s), 3.25
(3H, t), 5.66 (2H, s), 7.07 (4H, s), 7.50-7.70 (4H, m). IR (KBr) cm ^-1 : 1640,1590,1530,1450,1315,1160,77
0,750.

Example 19 2-hexylthio-4-methyl-1-[[2 '-(1H-
Tetrazol-5-yl) biphenyl-4-yl] methyl
Ru ] thieno [3,4-d] imidazole-6-carboxylic acid In the same manner as in Example 14, methyl 2-hexylthio-
4-methyl-1-[[2 '-(1H-tetrazol-5-
Yl) biphenyl-4-yl] methyl] thieno [3,4-d]
The title compound was obtained as colorless needles (0.47 g, 78%) from imidazole-6-carboxylate (0.6 g). mp. As 150-152 ° C. (decomposition) Elemental analysis _{C 27 H 28 N 6 O 2} S 2 · 0.7H 2 O ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 0.89 (3H,
t), 1.21-1.39 (6H, m), 1.60-1.77 (2H, m), 2.53 (3H, s), 3.24
(3H, t), 5.65 (2H, s), 7.01-7.10 (4H, m), 7.49-7.70 (4H, m). IR (KBr) cm ^-1 : 1650,1640,1600,1530,1460,1440 , 132
0,1260,1250,1160,775,750.

Embodiment 202-cyclohexylthio-4-methyl-1-[[2'-
( 1H-tetrazol-5-yl) biphenyl-4-i
[Methyl] thieno [3,4-d] imidazole-6-ca Lubo
Acid As in Example 14, methyl 2-cyclohexyl
Thio-4-methyl-1-[[2 '-(1H-tetrazole
-5-yl) biphenyl-4-yl] methyl] thieno [3,
4-d] imidazole-6-carboxylate (0.4
g) to give the title compound as colorless needles (0.25 g, 64
%). mp. 187-190 ° C (decomposition) Elemental analysis value C₂₇H₂₆N₆O_TwoS_Two・ 0.5H_TwoAs O ¹H-NMR (200 MHz, DMSO-d₆) δ: 1.32-1.7
3 (8H, m), 2.00-2.10 (2H, m), 2.54 (3H, s), 3.77-3.90 (1H,
m), 5.66 (2H, s), 7.05 (4H, s), 7.50-7.71 (4H, m) .IR (KBr) cm^-1： 1640,1600,1540,1460,1450,1440,133
5,1320,1260,1250,1160,940,760.

Example 21 Methyl 2-ethylthio-1-[[2 '-(1H-tetra
Zol-5-yl) biphenyl-4-yl] methyl] thie
Bruno [3,4-d] in the same manner as imidazole-6-carboxylate Example 1, methyl 2- Echiruchiochieno
[3,4-d] imidazole-6-carboxylate (0.1
5 g) to give the title compound as colorless needles (0.35 g, 3
6%). mp. As 204-206 ° C. (decomposition) Elemental analysis _{C 23 H 20 N 6 O 2} S 2 ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.41 (3H, t),
3.21 (2H, q), 3.79 (3H, s), 5.74 (2H, s), 6.93 (1H, s), 7.10-
7.20 (4H, m), 7.38-7.42 (1H, m), 7.53-7.64 (2H, m), 8.15-8.
20 (1H, m). IR (KBr) cm ^-1 : 1700,1585,1450,1430,1420,1320,125
0,1230,1165,1100,1045,755,745.

REFERENCE EXAMPLE 25 Methyl 2-ethylthio-1-[[2 '-(1H-tetra
Zol-5-yl) biphenyl-4-yl] methyl] thie
In the same manner as Bruno [3,4-d] imidazole-4-carboxylase preparative Example 15, from methyl 2- Echiruchiochieno [3,4-d] imidazole-4-carboxylate (0.5 g), the title compound Colorless needles (0.27
g, 27%). mp. As 173-175 ° C. (decomposition) Elemental analysis _{C 23 H 20 N 6 O 2} S 2 · 0.1H 2 O ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.41 (3H, t),
3.34 (2H, q), 3.79 (3H, s), 5.09 (2H, s), 6.54 (1H, s), 7.10 (4
H, q), 7.30-7.34 (1H, m), 7.47-7.58 (2H, m), 7.96-8.00 (1H, m
m). IR (KBr) cm ^-1 : 1700,1520,1440,1430,1415,1400,136
0,1350,1310,1190,1160,1100,760.

Example 22 2-ethylthio-1-[[2 '-(1H-tetrazole-
5-yl) biphenyl-4-yl] methyl] thieno [3,4
-D] Imidazole-6-carboxylic acid In the same manner as in Example 14, methyl 2-ethylthio-1
From-[[2 '-(1H-tetrazol-5-yl] methyl] thieno [3,4-d] imidazole-6-carboxylate (0.2 g), the title compound was converted to colorless needles (0.17 g).
g, 87%). mp. As 199-201 ° C. (decomposition) Elemental analysis _{C 22 H 18 N 6 O 2} S 2 · 0.2H 2 O ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.34 (3H,
t), 3.24 (2H, q), 5.67 (2H, s), 7.02-7.12 (4H, m), 7.49-7.70
(5H, m). IR (KBr) cm ^-1 : 1690,1590,1500,1440,1410,1360,134
0,1315,1240,1180,750,735.

Reference Example 26 2-ethylthio-1-[[2 '-(1H-tetrazole-
5-yl) biphenyl-4-yl] methyl] thieno [3,4
-D] Imidazole-4-carboxylic acid In the same manner as in Example 14, methyl 2-ethylthio-1
From-[[2 '-(1H-tetrazol-5-yl] methyl] thieno [3,4-d] imidazole-4-carboxylate (0.15 g), the title compound was converted to colorless needles (0.1
g, 68%). mp. 220-222 ° C (decomposition) Elemental analysis value As C ₂₂ H ₁₈ N ₆ O ₂ S ₂ .0.5H ₂ O ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.39 (3H,
t), 3.35 (2H, q), 5.18 (2H, s), 7.09 (2H, d), 7.14 (1H, s), 7.2
3 (2H, d), 7.51-7.73 (4H, m). IR (KBr) cm ^-1 : 1675,1520,1435,1360,1335,1290,127
0,1250,1180,1160,770,745.

Embodiment 23Methyl 2-methoxy-4-methyl-1-[[2 '-(1
H-tetrazol-5-yl) biphenyl-4-yl]
Me Tyl] thieno [3,4-d] imidazole-6-cal Boki
Silat 23a) Methyl 1-[(2'-cyanobiphenyl-4
-Yl) methyl] -2- Ethylthio-4-methylthieno
[3,4-d] imidazole-6-carboxylate Methyl 2-ethylthio-4-methylthieno [3,4-d]
D of imidazole-6-carboxylate (5.7 g)
To a MF (30 ml) solution was added sodium hydride (60 ml) under ice cooling.
% Oily, 0.98g) and stirred for 20 minutes.
(2'-cyanobiphenyl-4-yl) methyl bromide
(7.25 g) in DMF (20 ml) was added dropwise at room temperature.
And stirred for one hour. Water is added to the reaction solution and ethyl acetate is added.
Extracted. After the extract was washed with water and dried, the solvent was distilled off.
The obtained residue is subjected to silica gel column chromatography.
Crystals obtained by purification are reconstituted from ethyl acetate-hexane.
Crystallization gave pale yellow prism crystals (7.6 g, 77%). mp. 149-151 ° C¹ H-NMR (200 MHz, CDCl_Three) δ: 1.42 (3H, t), 2.
63 (3H, s), 3.31 (2H, q), 3.78 (3H, s), 5.76 (2H, s), 7.29 (2H,
d), 7.38-7.51 (4H, m), 7.58-7.66 (1H, m), 7.72-7.77 (1H, m
m). IR (KBr) cm^-1： 2220,1690,1600,1450,1430,1315,130
0,1230,1160,1085,770,750.

23b) Methyl 1-[(2′-cyanobif
Enyl-4-yl) methyl] -2-ethylsulfinyl-
4-methylthieno [3,4-d] imidazole-6-carbo
Xylate To a solution of the ethylthio compound (7.2 g) obtained in Example 23a) in dichloromethane (100 ml) was added m-chloroperbenzoic acid (3.3 g) under ice cooling, and the mixture was stirred for 1 hour. The reaction solution was washed with saturated sodium bicarbonate water and water, dried, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to obtain crystals. Recrystallization from ethyl acetate-hexane gave pale yellow crystals (7.0 g, 94%). mp. 150-151 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.26 (3H, t), 2.
72 (3H, s), 2.99-3.30 (2H, m), 3.82 (3H, s), 5.97 (1H, d), 6.4
3 (1H, d), 7.32 (2H, d), 7.39-7.52 (4H, m), 7.59-7.68 (1H,
m), 7.73-7.76 (1H, m). IR (KBr) cm ^-1 : 2220,1700,1590,1530,1450,1435,131
5,1230,1160,1090,1070,770,750.

23c) Methyl 1-[(2′-cyanobif
Enyl-4-yl) methyl] -2-methoxy-4-methyl
Thieno [3,4-d] imidazole-6-carboxylate Example 23b) obtained in ethylsulfinyl body (1.0
To a solution of g) in methanol (20 ml) was added 28% sodium methylate (0.62 g of a methanol solution), and the mixture was refluxed for 30 minutes. The crystals obtained by concentrating the reaction solution were recrystallized from ethyl acetate-methanol to obtain pale yellow prism crystals (0.79 g, 88%). mp. As 181-182 ° C. Elemental analysis _{C 23 H 19 N 3 O 3} S ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.58 (3H, s),
3.79 (3H, s), 4.15 (3H, s), 5.63 (2H, s), 7.34 (2H, d), 7.38-
7.51 (4H, m), 7.58-7.67 (1H, m), 7.72-7.77 (1H, m). IR (KBr) cm ^-1 : 2225,1700,1620,1580,1540,1460,145
0,1440,1400,1385,1335,1235,1110,1060,770,760.

23d) Methyl 2-methoxy-4-methyl
Ru-1 -[[2 '-(1H-tetrazol-5-yl) bi
Phenyl-4-yl] methyl] Chi eno [3,4-d] imidazo
Cyano body obtained in Lumpur 6-carboxylate Example 23c) (0.75 g) and trimethylsilyl azide (1.85 g) in toluene (2
0 ml) under reflux for 24 hours. Water was added to the residue obtained by concentrating the reaction solution, followed by extraction with chloroform. After the extract was washed with water and dried, the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to obtain crystals. Recrystallization from ethyl acetate-methanol gave colorless needles (0.67 g, 80%). mp. As 173-175 ° C. (decomposition) Elemental analysis _{C 23 H 20 N 6 O 3} S · 0.3H 2 O ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.36 (3H, s),
3.74 (3H, s), 3.97 (3H, s), 5.57 (2H, s), 7.10-7.20 (4H, m),
7.38-7.43 (1H, m), 7.49-7.64 (2H, m), 8.09-8.13 (1H, m). IR (KBr) cm ^-1 : 1700,1615,1575,1540,1470,1460,144
0,1410,1390,1380,1340,1320,1230,1100,1070,1000,76
0.

Example 24 Methyl 2-ethoxy-4-methyl-1-[[2 '-(1
H-tetrazol-5-yl) biphenyl-4-yl]
Methylation] thieno [3,4-d] imidazole-6-Cal Boki
Silato 24a) ethyl 1-[(2'-cyanobiphenyl-4-
Yl) methyl] -2-ethoxy-4-methylthieno [3,4
-D] Imidazole-6-carboxylate The ethylsulfinyl obtained in Example 23b) (1.0
g) was heated to reflux in ethanol (20 ml) containing metallic sodium (0.167 g) for 30 minutes. The crystals obtained by concentrating the reaction solution were recrystallized from ethyl acetate-methanol to obtain pale yellow needles (0.86 g, 89%). mp. 153-155 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.31 (3H, t), 1.
43 (3H, t), 2.57 (3H, s), 4.28 (2H, q), 4.55 (2H, q), 5.64 (2H,
s), 7.37 (2H, d), 7.43-7.51 (4H, m), 7.59-7.67 (1H, m), 7.73
-7.77 (1H, m).

24b) Methyl 1-[(2′-cyanobif
Enyl-4-yl) methyl] -2-ethoxy-4-methyl
Thieno [3,4-d] imidazole-6-carboxylar
Ethyl ester obtained in preparative Example 24a) (0.86 g)
Of methanol (20 ml) in aqueous solution (20 ml)
Sodium methylate (methanol solution, 0.75 g)
Was added and heated under reflux for 3 hours. Crystals obtained by concentrating the reaction solution were recrystallized from ethyl acetate-methanol to obtain colorless needles (0.78 g, 94%). mp. 155-156 ° C Elemental analysis: as C ₂₄ H ₂₁ N ₃ O ₃ S ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.44 (3H, t),
2.57 (3H, s), 3.81 (3H, s), 4.55 (2H, q), 5.63 (2H, s), 7.37 (2
H, d), 7.42-7.51 (4H, m), 7.59-7.67 (1H, m), 7.73-7.77 (1H,
m). IR (KBr) cm ^-1 : 2225,1690,1620,1570,1535,1450,133
0,1215,1060,760.

24c) Methyl 2-ethoxy-4-methyl
Ru-1 -[[2 '-(1H-tetrazol-5-yl) bi
Phenyl-4-yl] methyl] Chi eno [3,4-d] imidazo
The title compound was obtained as colorless needles (0.66 g, 79%) from the cyano form (0.76 g) obtained in Example 24b) in the same manner as in Example 23d). Was. mp. 193-195 ° C (decomposition) Elemental analysis value C ₂₄ H ₂₂ N ₆ O ₃ S ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.41 (3H, t),
2.37 (3H, s), 3.75 (3H, s), 4.37 (2H, q), 5.57 (2H, s), 7.13 (2
H, d), 7.22 (2H, d), 7.37-7.42 (1H, m), 7.49-7.63 (2H, m), 8.
10-8.15 (1H, m). IR (KBr) cm ^-1 : 1685,1610,1570,1530,1440,1430,138
0,1330,1230,1060,750.

Embodiment 25Methyl 4-methyl-2-propoxy-1-[[2'-
( 1H-tetrazol-5-yl) biphenyl-4-i
[Methyl] thieno [3,4-d] imidazole-6-ca Lubo
Xylate 25a) Methyl 1-[(2'-cyanobiphenyl-4-
Yl) methyl] -4-methyl-2-propoxy-thieno
[3,4-d] Imi Dazol-6-carboxylate In the same manner as in Example 23c), the dye obtained in Example 23b) was obtained.
The tylsulfinyl compound (1.0 g) was treated with sodium propanoate.
(Propanol of sodium metal (0.2 g))
(20 ml solution), and heat to reflux for 30 minutes.
This was obtained as colorless needles (0.4 g, 41%). mp. 188-190 ° C (decomposition) Elemental analysis value C_{twenty five}H_{twenty three}N_ThreeO_ThreeS ・ 0.2H_TwoAs O ¹H-NMR (200 MHz, CDCl_Three) δ: 0.96 (3H, t),
1.73-1.91 (2H, m), 2.57 (3H, s), 3.81 (3H, s), 4.44 (2H, t),
5.64 (2H, s), 7.36 (2H, d), 7.42-7.51 (4H, m), 7.54-7.67 (1
H, m), 7.73-7.78 (1H, m). IR (KBr) cm^-1： 2200,1685,1610,1570,1530,1440,143
0,1360,1220,1090,750.

25b) Methyl 4-methyl-2-propo
Xy- 1-[[2 '-(1H-tetrazol-5-yl)
Biphenyl-4-yl] methyl] thieno [3,4-d] Imida
Zole-6-carboxylate In the same manner as in Example 23c), the cyano compound (0.37 g) obtained in Example 25a) was converted into trimethyltin azide (0.85).
g) and refluxed in toluene (15 ml) for 16 hours.
The title compound was obtained as colorless needles (0.35 g, 86%). mp. As 206-208 ° C. (decomposition) Elemental analysis _{C 25 H 24 N 6 O 3} S ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.95 (3H, t),
1.70-1.88 (2H, m), 2.38 (3H, s), 3.76 (3H, s), 4.27 (2H, t),
5.57 (2H, s), 7.13 (2H, d), 7.23 (2H, d), 7.37-7.41 (1H, m),
7.49-7.64 (2H, m), 8.09-8.14 (1H, m). IR (KBr) cm ^-1 : 1690,1620,1575,1535,1470,1450,144
0,1410,1370,1350,1340,1240,1070,970,760.

Embodiment 26Methyl 2-ethylamino-4-methyl-1-[[2'-
(1H-tetrazol-5-yl) biphenyl-4-i
[Methyl] thieno [3,4-d] imidazole-6 Carbo
Xylate 26a) Methyl 1 -[(2'-cyanobiphenyl-4-
Yl) methyl] -2-ethylamino-4-methyl Lucieno
[3,4-d] imidazole-6-carboxylate The ethylsulfinyl compound obtained in Example 23b) (0.9
1 g), a 70% aqueous solution of ethylamine (10 ml) and
A mixture of ethanol (10 ml) was placed in an autoclave at 80 ° C.
For 3 hours. The residue obtained by concentrating the reaction mixture to dryness
The residue was dissolved in ethyl acetate, washed with water and dried. Distill solvent
Silica gel column chromatography
And purified. The obtained crystals were washed with ethyl acetate-hexane.
To give colorless needles (0.45 g, 53%).
Was. mp. 190-191 ° C¹ H-NMR (200 MHz, CDCl_Three) δ: 1.18 (3H, t), 2.
56 (3H, s), 3.38-3.52 (2H, m), 3.76 (3H, s), 3.96 (1H, t), 5.7
3 (2H, s), 7.32 (2H, d), 7.40-7.56 (4H, m), 7.60-7.69 (1H,
m), 7.74-7.79 (1H, m). IR (KBr) cm^-1： 3390,2225,1670,1620,1600,1545,152
0,1450,1435,1340,1330,1240,760,750.

[0089]26b) Methyl 2-ethylamino-4-
Methyl -1-[[2 '-(1H-tetrazol-5-i
Le) Biff Enyl-4-yl] methyl] thieno [3,4-d] i
Midazole-6-carboxylate In the same manner as in Example 23d), the screen obtained in Example 25a) was obtained.
Ano form (0.45 g) and trimethyltin azide (1.1
g) in toluene (20 ml) under reflux for 24 hours.
To give the title compound as colorless needles (0.27 g, 52
%). mp. 252-255 ° C Elemental analysis value C_{twenty four}H_{twenty three}N₇O_ThreeS ・ 0.5H_TwoAs O ¹H-NMR (200 MHz, CDCl_Three) δ: 1.14 (3H, t),
2.40 (3H, s), 3.32 (2H, q), 3.64 (3H, s), 5.58 (2H, s), 7.03 (4
H, s), 7.49-7.70 (4H, m). IR (KBr) cm^-1： 1705,1680,1670,1630,1480,1440,134
0,1335,1270,1220,1095,1075,760.

Example 27 Methyl 4-methyl-2-propylamino-1-[[2 '
-(1H-tetrazol-5-yl) biphenyl-4-
B le] methyl] thieno [3,4-d] imidazole-6-Cal
Boxylate 27a) methyl 1-[(2'-cyanobiphenyl-4-
Yl) methyl] -4-methyl-2-propylamino-thiye
Bruno [3,4-d] Lee imidazole-6-carboxylate Example 23b) obtained in ethylsulfinyl body (1.0
A mixture of g) and propylamine (20 ml) was heated at reflux for 3 days. The residue obtained by concentrating and drying the reaction solution was dissolved in ethyl acetate, washed with water and dried. The residue obtained by distilling off the solvent was purified by silica gel column chromatography. The obtained crystals were recrystallized from ethyl acetate-hexane to give pale yellow needles (0.72 g, 75%). mp. 148-150 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.82 (3H, t), 1.
47-1.66 (2H, m), 2.56 (3H, s), 3.33-3.42 (2H, m), 3.78 (3H,
s), 3.97 (1H, t), 5.75 (2H, s), 7.34 (2H, d), 7.41-7.57 (4H,
m), 7.61-7.69 (1H, m), 7.75-7.80 (1H, m). IR (KBr) cm ^-1 : 3375,2200,1680,1660,1615,1590,154
0,1520,1440,1330,1230,1090,1070,750.

27b) Methyl 4-methyl-2-prop
Rumin- 1-[[2 '-(1H-tetrazol-5-i
Le) Biff Eniru 4-yl] methyl] thieno [3,4-d] Lee
Midazole-6-carboxylate In the same manner as in Example 23d), the cyano compound (0.7 g) obtained in Example 27a) and trimethyltin azide (1.62) were obtained.
g) in toluene (20 ml) with heating under reflux for 24 hours to give the title compound as colorless needles (0.66 g, 77
%). mp. As 204-208 ° C. (decomposition) Elemental analysis _{C 25 H 25 N 7 O 2} S · 0.5CHCl 3 ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.82 (3H, t), 1.
46-1.64 (2H, m), 2.40 (3H, s), 3.25 (2H, t), 3.66 (3H, s), 5.6
1 (2H, s), 7.04 (4H, s), 7.49-7.70 (4H, m). IR (KBr) cm ^-1 : 1705,1670,1660,1630,1550,1480,146
0,1440,1350,1340,1250,1215,1080,760.

Example 28 2-methoxy-4-methyl-1-[[2 '-(1H-teto
Lazol-5-yl) biphenyl-4-yl] methyl] thio
Eno [3,4-d] imidazole-6-carboxylic acid In the same manner as in Example 14, the title compound was obtained from the methyl ester obtained in Example 23 (0.5 g) by colorless needles (0.3 g, 61%). mp. As 187-189 ° C. (decomposition) Elemental analysis _{C 22 H 18 N 6 O 3} S · 0.5H 2 O ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 2.47 (3H,
s), 4.05 (3H, s), 5.51 (2H, s), 7.04 (2H, d), 7.12 (2H, d), 7.5
0-7.70 (4H, m). IR (KBr) cm ^-1 : 1660,1620,1580,1540,1450,1400,138
5,1375,1340,1320,1240,990,760,750.

Example 29 2-ethoxy-4-methyl-1-[[2 '-(1H-tetra
Lazol-5-yl) biphenyl-4-yl] methyl] thio
Eno [3,4-d] imidazole-6-carboxylic acid In the same manner as in Example 14, the title compound was converted from the methyl ester obtained in Example 24 (0.45 g) to colorless needles (0.34 g, 75%). mp. As 171-172 ° C. (decomposition) Elemental analysis _{C 23 H 20 N 6 O 3} S · H 2 O ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.31 (3H,
t), 2.46 (3H, s), 4.46 (2H, q), 5.49 (2H, s), 7.04 (2H, d), 7.1
3 (2H, d), 7.47-7.67 (4H, m). IR (KBr) cm ^-1 : 1680,1615,1570,1540,1460,1420,139
0,1380,1350,1335,1320,1230,750.

Example 30 4-Methyl-2-propoxy-1-[[2 '-(1H-te
Trazol-5-yl) biphenyl-4-yl] methyl]
Thieno [3,4-d] imidazole-6-carboxylic acid In the same manner as in Example 14, the title compound was converted from the methyl ester (0.23 g) obtained in Example 25 to colorless needles (0.16 g, 67%). mp. 173-175 ° C (decomposition) Elemental analysis value As C ₂₄ H ₂₂ N ₆ O ₃ S ・ 0.7H ₂ O ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 0.86 (3H,
t), 1.61-1.79 (2H, m), 2.46 (3H, s), 4.36 (2H, t), 5.51 (2H,
s), 7.04 (2H, d), 7.14 (2H, d), 7.48-7.70 (4H, m). IR (KBr) cm ^-1 : 1680,1615,1570,1565,1535,1450,137
0,1335,1230,750.

Example 31 2-ethylamino-4-methyl-1-[[2 '-(1H-
Tetrazol-5-b le) biphenyl-4-yl] methylcarbamoyl
Ru] thieno [3,4-d] imidazole-6-carboxylic acid In the same manner as in Example 14, the title compound was obtained from the methyl ester obtained in Example 26 (0.2 g) by colorless needles (0.2 g). 2 g, 91%). mp. As 201-205 ° C. (decomposition) Elemental analysis _{C 23 H 21 N 7 O 2} S · 0.5CHCl 3 ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.13 (3H,
t), 2.39 (3H, s), 3.31 (2H, q), 5.62 (2H, s), 7.04 (4H, s), 7.4
9-7.69 (4H, m). IR (KBr) cm ^-1 : 1660,1630,1560,1530,1460,1450,138
0,1360,1340,1100,965,780,760,740.

Example 32 4-Methyl-2-propylamino-1-[[2 '-(1H
-Tetrazol-5- yl) biphenyl-4-yl] me
[Tyl] thieno [3,4-d] imidazole-6-carboxylic acid In the same manner as in Example 14, the title compound was obtained from the methyl ester (0.46 g) obtained in Example 27 as colorless needles (0.4%). 2 g, 48%). mp. 206-209 ° C (decomposition) Elemental analysis value As C ₂₄ H ₂₃ N ₇ O ₂ S · 1.5H ₂ O ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 0.81 (3H,
t), 1.44-1.62 (2H, m), 2.38 (3H, s), 3.23 (2H, t), 5.63 (2H,
s), 7.04 (4H, s), 7.48-7.70 (4H, m). IR (KBr) cm ^-1 : 1670,1660,1630,1550,1545,1460,135
0,1340,760.

Example 33 2-ethoxy-1-[[2 '-(1H-tetrazole-5-
Yl) biphenyl-4 -yl] methyl] thieno [3,4-d]
33 -Imidazole-6-carboxylic acid 33a) methyl 1-[( 2'- cyanobiphenyl-4-
Yl) methyl] -2-et Chiruchiochieno [3,4-d] Imi
Dazole-6-carboxylate The methyl 2-ethylthiothieno obtained in Reference Example 14c)
[3,4-d] imidazole-4-carboxylate (1.8
To a solution of 1 g) in DMF (15 ml) was added sodium hydride (60% oil, 0.33 g) under ice-cooling, and (2'-cyanobiphenyl-4-yl) methylbromide (2.25 g) in DMF.
(10 ml) solution was added dropwise and stirred at room temperature for 60 hours.
Water was added to the reaction solution, extracted with ethyl acetate, and the extract was washed with water and dried. The residue obtained by distilling off the solvent was purified by silica gel column chromatography to obtain crystals.
Recrystallization from ethyl acetate-hexane gave colorless needles. mp. 140-142 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.45 (3H, t), 3.
32 (2H, q), 3.81 (3H, s), 5.79 (2H, s), 7.21 (1H, s), 7.31 (2H,
d,), 7.38-7.53 (4H, m), 7.59-7.67 (1H, m), 7.73-7.77 (1H,
m). 33b) Methyl 1-[( 2'-cyanobiphenyl-4-
B) methyl] -2-et Chi Rusuru nyl thieno [3,4
-D] Imidazole-6-carboxylate From the ethylthio form (1.6 g) obtained in Example 33a),
In the same manner as in Example 23b), the title compound was obtained as colorless prisms (1.2 g, 72%). mp. 118-119 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.30 (3H, t), 3.
08-3.36 (2H, m), 3.86 (3H, s), 6.02 (1H, d), 6.47 (1H, d), 7.3
3 (2H, d), 7.40-7.53 (4H, m), 7.57 (1H, s), 7.60-7.68 (1H,
m), 7.73-7.77 (1H, m).

33c) Methyl 1-[(2'-cyanobif)
Eniru -4 - yl) methyl] -2-et Tokishichieno [3,
4- d] Imidazole-6-carboxylate The compound (0.8 g) obtained in Example 33b) was treated with sodium ethanolate (0.19 g of sodium metal and ethanol 1).
(Prepared from 0 ml) and heated to reflux for 20 minutes. The residue obtained by concentrating and drying the reaction solution was dissolved in ethyl acetate-water.
After drying the organic layer, the solvent was distilled off, and the residue obtained was dissolved in methanol (10 ml). After adding 28% sodium methanolate (0.75 g), the mixture was heated under reflux for 8 hours.
The residue obtained by concentrating the reaction solution to dryness was purified by silica gel column chromatography. The obtained crystals were recrystallized from ethyl acetate-hexane to give colorless needles (0.33 g,
41%). mp. 130-131 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.46 (3H, t), 3.
84 (3H, s), 4.57 (2H, q), 5.66 (2H, s), 7.05 (1H, s), 7.35-7.5
2 (6H, m), 7.59-7.67 (1H, m), 7.67-7.78 (1H, m). 33d) methyl 2-ethoxy- 1-[[(2 '-(1H-
Tetrazol-5-b le) biphenyl-4-yl] methylcarbamoyl
Le] thieno [3,4-d] imidazole-6-Thira
The compound (0.3 g) obtained in the above Example 33c) and trimethyltin azide (0.74 g) were heated to reflux in toluene (10 ml) for 24 hours. The reaction solution was concentrated to dryness, and the obtained residue was partitioned between chloroform and water. After the organic layer was washed with water and dried, the solvent was distilled off. Crystals obtained by purifying the residue by silyl column chromatography were recrystallized from ethyl acetate-methanol to obtain colorless needles (0.2 g, 60%). mp. 186-188 ° C (decomposition) Elemental analysis value As C ₂₃ H ₂₀ N ₆ O ₃ S · 0.3H ₂ O ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.33 (3H, t),
3.74 (3H, s), 4.48 (2H, q), 5.50 (2H, s), 7.04 (2H, d,), 7.13
(2H, d,), 7.44 (1H, s), 7.50-7.70 (4H, m). IR (KBr) cm ^-1 : 1705,1615,1575,1570,1510,1455,14
20,1390,1345,1245,770.

33e) 2-ethoxy-1- [[2 '-(1H
- tetrazol-5-yl) biphenyl-4-yl] menu
[Tyl] thieno [3,4-d] imidazole-6-carboxylic acid From the compound (0.145 g) obtained in Example 33d), the title compound (0.08 g, 55%) was obtained in the same colorless manner as in Example 14. Obtained as crystals. mp. 159-162 ° C (decomposition) Elemental analysis value As C ₂₂ H ₁₈ N ₆ O ₃ S · 0.5H ₂ O ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.32 (3H,
t), 4.47 (2H, q), 5.53 (2H, s), 7.05 (2H, d), 7.15 (2H, d), 7.3
5 (1H, s), 7.49-7.69 (4H, m). IR (KBr) cm ^-1 : 1690,1680,1600,1560,1450,1380,133
0,1220,750.

Example 34 5-Methyl-2-propyl-6- (1H-tetrazole
- 5-yl) -1 - [[2 '- (1H- tetrazol - 5
Yl) biphenyl-4-yl] methyl] thieno [2,3-d]
Imidazole 34a) Methyl 3-amino-4-cyano-5-methyl
Thiophene-2-Cal Bokishira preparative sodium hydride (60% in oil, 2.0 g) and THF (5 m
l) and malononitrile (3.
A solution of 3 g) in THF (10 ml) was added dropwise. After stirring for 10 minutes, the ethyl dithioacetate (6.0 g) T
An HF (10 ml) solution was added dropwise at room temperature, and the mixture was further stirred for 20 minutes. The residue obtained by concentrating the reaction solution to dryness was washed with THF.
(40 ml) and dissolved in methyl chloroacetate (5.4 ml).
g) in THF (10 ml) was added dropwise at room temperature. After stirring for 30 minutes, isopropanol (50 ml) and sodium methylate (28% methanol solution, 1 ml) were added, and the mixture was stirred at room temperature for 3.5 hours. Water was added to the reaction solution, and the precipitated crystals were recrystallized from ethyl acetate to give colorless prism crystals.
(4.6 g, 47%). mp. 209-210 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.58 (3H, s), 3.
83 (3H, s), 5.76 (2H, br s).

[0102] 34b) Methyl 3-Buchiri arylamino -4
-Cyano-5-methylthiophene-2-carboxylar
The compound obtained in Preparative Example 34a) and (2.0 g) and butyryl chloride (1.1 g) was heated under reflux for 5 h in dioxane (30 ml). The crystals obtained by concentrating the reaction solution were treated with ethyl acetate-
Recrystallization from hexane gave colorless needles (2.5 g, 93
%). mp. 124-125 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.03 (3H, t),
1.80 (2H, .m), 2.46 (2H, t), 2.68 (3H, s), 3.89 (3H, s), 9.40
(1H, brs). 34c) methyl 3- [N-butyryl-N- (2'-sia
Roh biphenyl-4-b) methyl] amino-4-cyano
5-Methylthiophen-2 -carboxylate The compound obtained in Example 34b) (2.6 g), 2-cyano-4'-bromomethylbiphenyl (3.0 g) and potassium carbonate (1.5 g) were mixed with acetonitrile. (50 ml) and refluxed for 12 hours. The residue obtained by concentrating and drying the reaction solution was dissolved in ethyl acetate-water, and the organic layer was washed with water and dried.
The solvent was distilled off, and the obtained residue was purified by silica gel column chromatography to obtain a colorless syrup (4.5 g, quantitative). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.90 (3H, t), 1.
68 (2H, m), 2.08 (2H, t), 2.64 (3H, s), 3.73 (3H, s), 4.91 (1H,
d), 5.00 (1H, d), 7.31 (2H, d), 7.38-7.48 (4H, m), 7.63 (1H, d
t), 7.74 (1H, d). 34d) 3- [N-butyryl-N- (2'-cyanobife)
4- yl) methylation] amino-4-cyano-5-main switch
Luthiophene-2-carboxylic acid The compound (4.5 g) obtained in Example 34c) was treated with methanol.
(45 ml) and 2N NaOH (7.4 ml) at room temperature.
I stirred for 5 hours. The reaction mixture was concentrated, dissolved in water, added with 1N hydrochloric acid (15 ml), and extracted with ethyl acetate.
After washing the organic layer with water and drying, the solvent is distilled off to give a white powder.
(4.0 g, 93%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.89 (3H, t),
1.59-1.77 (2H, m), 1.98-2.21 (2H, m), 2.66 (3H, s), 4.76 (1
H, d), 5.16 (1H, d), 7.29-7.49 (6H, m), 7.63 (1H, dt), 7.71 (1
H, d).

34e)tert-butyl 3- [N-butylyl
Le-N- (2'-cyanobiphenyl − 4-yl) methyl]
A Mino-4-cyano-5-methylthiophene-2-cal
Bamate The carboxylic acid obtained in Example 34 d) (2.4 g),
Nyl phosphoric acid azide (DPPA, 3.2 g) and triethyl alcohol
Min (1.2 g) in tert-butanol (25 ml) at room temperature
After stirring for 20 minutes, the mixture was heated under reflux for 1.5 hours. Anti
The residue obtained by concentrating the reaction solution to dryness was dissolved in ethyl acetate.
Was. After washing with water and drying, the solvent
Purified by silica gel column chromatography. Get
The resulting crystals were recrystallized from ethyl acetate-hexane to give
Prism crystals (2.2 g, 79%) were obtained. mp. 171-172 ° C¹ H-NMR (200 MHz, CDCl_Three) δ: 0.91 (3H, t,),
1.37 (9H, s), 1.58-1.78 (2H, m), 1.96-2.16 (2H, m), 2.56 (3
H, s), 4.41 (1H, d), 5.32 (1H, d), 6.29 (1H, br s), 7.39-7.65
(6H, m), 7.65 (1H, dt), 7.77 (1H, d). 34f)2-amino-3- [N-butyryl-N- (2'-
Cyanobiphenyl-4 -Yl) methyl] amino-4-si
Ano-5-methylthiophene 20 of the carbamate (2.1 g) obtained in Example 34 e)
% Hydrogen chloride-methanol (40 ml) mixed solution for 1 hour
Shed. The reaction mixture was concentrated to dryness, and saturated sodium bicarbonate water was added to the residue.
And extracted with ethyl acetate. After washing and drying the organic layer,
The solvent was distilled off. The obtained residue is ethyl acetate-hexane
To give colorless needles (0.93 g, 66%).
Was. mp. 160-161 ° C¹ H-NMR (200 MHz, CDCl_Three) δ: 0.91 (3H, t,),
1.61-1.72 (2H, m), 2.06-2.15 (2H, m), 2.51 (3H, s), 3.20 (2
H, brs), 3.96 (1H, d), 5.76 (1H, d), 7.41-7.51 (6H, m), 7.66
(1H, dt), 7.47 (1H, d). 34g)6-cyano-1-[(2′-cyanobiphenyl-
4 -Yl) methyl] -5 − Methyl-2-propylthieno
[2,3-d] imidazole 10% salification of the compound obtained in Example 34f) (1.9 g)
A solution of hydrogen-ethanol (55 ml) was heated to reflux for 5 days.
Saturated sodium bicarbonate water was added to the residue obtained by concentrating the reaction solution,
Extracted with ethyl acetate. After washing and drying the extract, remove the solvent.
Distilled off. The obtained residue is subjected to silica gel column chromatography.
Purify by luffy to give pale yellow powder (1.6 g, 89%)
Obtained.¹ H-NMR (200 MHz, CDCl_Three) δ: 1.02 (3H, t), 1.
85 (2H, m), 2.70 (3H, s), 2.79 (2H, t), 5.47 (2H, s), 7.21 (2H, s
d), 7.41-7.57 (4H, m), 7.65 (1H, dt), 7.76 (1H, d).

34h)5-methyl-2-p Ropil-6-
(1H-tetrazol-5-yl) -1-[[2 ′-(1H-
Tetrazol-5-yl) biphenyl-4-yl] methyl
Le] j Eno [2,3-d] imidazole Compound (1.2 g) obtained in Example 34 g) and trimethyl
Return tin azide (2.9 g) in toluene (30 ml) for 3 days
Flow heating was performed. The precipitated syrup was washed with methanol (20 ml).
And 1N hydrochloric acid (12 ml) and stir at room temperature for 30 minutes.
I'm sorry. The reaction solution was adjusted to pH 3 to 4 with 1N NaOH and
Roloform extraction was performed, and the extract was washed with water and dried. Distill solvent
Silica gel column chromatography
And purified. The obtained crystals are washed with methanol-ethyl acetate.
Recrystallized from light yellow needles (0.87 g, 62%)
Obtained. mp. 237-238 ° C (decomposition) Elemental analysis value C_{twenty four}H_{twenty two}N_TenAs S-MeOH ¹H-NMR (200 MHz, DMSO-d₆) δ: 0.92 (3
H, t), 1.67 (2H, m), 2.53 (3H, s), 2.73 (2H, t), 5.51 (2H, s),
6.61 (2H, d), 6.90 (2H, d), 7.46 (1H, d), 7.51-7.71 (3H, m). IR (KBr) cm^-1： 1570,1500,1465,1445,1020,1000,91
5,780,760.

Example 35 4-Methyl-2-propyl-1-[[2 '-(1H-tetra
5-yl) biphenyl-4-yl] methylation] Chie
Bruno [3,4-d] imidazole-6-phosphate 35a) tert-butyl 3-amino-4- Etokishikaru
Bonyl-5-methylthiophene- 2-carboxylate Ethyl cyanoacetate analogously to Example 34a).
(5.7 g) to give the title compound as colorless prisms (2.5 g,
17%). mp. 87-88 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.39 (3H, t), 1.
55 (9H, s), 2.62 (3H, s), 4.34 (2H, q). 35b) tert-butyl 3-butyrylamino-4-eth
Butoxycarbonyl-5-Mechiruchi thiophene-2-carboxy
The title compound was converted from the compound (2.5 g) obtained in Example 35a) to a colorless syrup (2.8) in the same manner as in Example 34b).
g, quantitative). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.01 (3H, t), 1.
33 (3H, t), 1.55 (9H, s), 1.75 (2H, m), 2.38 (2H, t), 2.58 (3H, t
s), 4.30 (2H, q), 9.58 (1 H, brs). 35c) tert-butyl 3 -[[N-butyryl-N- (2 '
-Cyanobiphenyl -4-yl) methyl] amino] -4
- ethoxycarbonyl-5-methyl-2-
Carboxylate The title compound was converted to a colorless syrup (3.8 g) from the compound (2.8 g) obtained in Example 35b) in the same manner as in Example 34c).
g, 97%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.89 (3H, t), 1.
19 (3H, t), 1.46 (9H, s), 1.65 (2H, m), 2.08 (2H, t), 2.66 (3H, t
s), 3.86-4.41 (2H, m), 4.52 (1H, d), 5.04 (1H, d), 7.31 (2H,
d), 7.38-7.46 (4H, m), 7.62 (1H, dt), 7.75 (1H, d).

35d)2-tert-butoxycarbonyl-
3-[[N-butyryl-N- (2′- Cyanobiphenyl-
4- Yl) methyl] amino] -5-methylthiophene-4
−f Rubonic acid The compound (1.9 g) obtained in Example 35c) was converted to 1N NaO
H (5.6 ml) and ethanol (20 ml).
The mixture was stirred at -80 ° C for 6 hours. The reaction solution was concentrated to dryness,
1N Hydrochloric acid was added to make the mixture acidic, and the precipitated crystals were collected by filtration. I
Recrystallized from isopropyl ether-ethyl acetate to give a colorless needle
Crystals (1.2 g, 67%) were obtained. mp. 157-158 ° C (decomposition)¹ H-NMR (200 MHz, CDCl_Three) δ: 0.87 (3H, t), 1.
51 (9H, s), 1.55-1.75 (2H, m), 1.98-2.18 (2H, m), 2.64 (3H, m
s), 4.24 (1H, d), 5.40 (1H, d), 7.30-7.47 (6H, m), 7.63 (1H,
d), 7.73 (1H, d) .35e)tert-butyl 4 -Amino-3-[[N-butylyl
Ru-N- (2'-sia Nohdiphenyl-4-yl) methyl] amino] -5
− Tiltiophen-2-carbo Xylate From the carboxylic acid (1.2 g) obtained in Example 35d),
The title compound was converted to a colorless syrup (1.
0 g, quantitative).¹ H-NMR (200 MHz, CDCl_Three) δ: 0.88 (3H, t), 1.
54 (9H, s), 1.63 (2H, m), 1.99-2.06 (2H, m), 2.17 (3H, s), 4.0
2 (1H, g), 5.75 (1H, d), 7.34-7.50 (6H, m), 7.65 (1H, dt), 7.7
5 (1H, d). IR (Neat) cm^-1: 3430,3350,2220,1710,1660.35f)Ethyl 1-[(2'-cyanobiphenyl-4-
Yl) methyl] -4-me Tyl-2-propyl-thieno
[3,4-d] imidazole-6-carboxylate The compound (1.0 g) obtained in Example 35e) was chlorinated with 10%
Dissolve in hydrogen-ethanol (16 ml) and heat to reflux for 63 hours
did. To the residue obtained by concentrating the reaction solution was added heavy
And extracted with ethyl acetate. The extract was washed with water and dried
Thereafter, the solvent was distilled off. Residue is silica gel column chromatography
Pale yellow syrup purified by chromatography (0.14 g,
14%).¹ H-NMR (200 MHz, CDCl_Three) δ: 0.99 (3H, t), 1.
27 (3H, t), 1.78 (2H, m), 2.66 (2H, t), 2.67 (3H, s), 4.23 (2H,
q), 5.86 (2H, s), 7.18 (2H, d), 7.39-7.53 (4H, m), 7.63 (1H, d
t), 7.75 (1H, d). IR (Neat) cm^-1： 2210,1685,1545,1480,1440,1405,136
0,1325,1230,1195,1090,755,730.

35 g) Ethyl 4-methyl- 2-propy
Le -1 - [[2 '- ( 1H- tetrazole Lumpur 5-yl) bi
Phenyl-4-yl] methyl] Chie Bruno [3,4-d] imidazo
Lumpur-6-carboxylate Example 35f) the compound obtained in the (0.14 g), colorless prisms of the title compound in the same manner as in Example 23d) (0.
09g, 56%). mp. 214-215 ° C Elemental analysis: as C ₂₆ H ₂₆ N ₆ O ₂ S · 0.2H ₂ O ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.97 (3H, t),
1.29 (3H, t), 1.76 (2H, m), 2.56 (3H, s), 2.59 (2H, t), 4.23 (2
H, q), 5.78 (2H, s), 7.08 (2H, d), 7.18 (2H, d), 7.37-7.43 (1
H, m), 7.55-7.61 (2H, m), 8.13-8.18 (1H, m) .IR (KBr) cm ^-1 : 1690,1540,1325,1230,1095,750.35h) 4-Methyl-2 -Propyl-1-[[2 '-( 1H
- tetrazol -5 - b le) biphenyl-4-yl] menu
Chill] thieno [3,4-d] imidazole-6-month carboxylic acid Example 35 g) of the compound obtained in the (0.09 g), colorless prisms of the title compound in the same manner as in Example 14 (0.0
63g, 76%). mp. 206-207 ° C (decomposition) Elemental analysis value As C ₂₄ H ₂₂ N ₆ O ₂ S · 0.2H ₂ O ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 0.88 (3
H, t), 1.62 (2H, m), 2.55 (3H, s), 2.56 (2H, t), 5.79 (2H, s),
7.03 (4H, m), 7.49-7.71 (4H, m) .IR (KBr) cm ^-1 : 1690-1600,1540,1470,1360,1230,120
0,770.

Embodiment 36Acetoxymethyl 2-methoxy-4-methyl-1-
[[2 '-(1H-tetra Zol-5-yl) biphenyl
-4-yl] methyl] thieno [3,4-d] imidazo Roux
6-carboxyla To The title compound was synthesized in the same manner as in Example 5. 36a)2-methoxy-4-methyl Ru-1-[[2 '-(N-
Trityl tetrazo Ru-5-yl) biphenyl-4-
Yl] methyl] thieno [3,4-d] imidazole- 6-ka
Rubonic acid From the tetrazole compound (1.0 g) obtained in Example 28,
In the same manner as in Example 5a), the title compound was obtained as colorless crystals (0.1%).
(65 g, 41%). mp. 178-180 ° C¹ H-NMR (200 MHz, DMSO-d₆) δ: 2.48 (3H,
s), 3.95 (3H, s), 5.47 (2H, s), 6.82-6.87 (6H, m), 6.99-7.08
(4H, m), 7.25-7.63 (12H, m), 7.76-7.80 (1H, m) .IR (KBr) cm^-1： 1675,1570,1530,1450,1395,1220,75
0,740,710,690.36b)Acetoxymethyl 2-methoxy-4-methyl
-1- [[2 '-(1H − Torazol-5-yl) biph
Enyl-4-yl] methyl] thieno [3,4-d] i Midazo
Ole-6-carboxylate The compound obtained in Example 36a) (0.51 g) and chloroform
Starting from chill acetate (0.2 g), as in Example 5b)
To give the title compound as colorless crystals (0.156 g, 60%).
Obtained. mp. 156-158 ° C (decomposition) Elemental analysis value C_{twenty five}H_{twenty two}N₆O_TwoAs S ¹H-NMR (200 MHz, CDCl_Three) δ: 2.05 (3H, s),
2.49 (3H, m), 4.06 (3H, m), 5.54 (2H, s), 5.81 (2H, s), 7.14-
7.23 (4H, m), 7.40-7.44 (1H, m), 7.51-7.65 (2H, m), 8.15-8.
19 (1H, m). IR (KBr) cm^-1： 1750,1700,1610,1570,1455,1450,140
0,1380,1365,1330,1240,1200,1000,980.

Example 37 2-ethyl-5-methyl-1-[[2 '-(1H-tetrazo
Lumpur-5-yl) Biff Eniru 4-yl] methyl] thieno
[2,3-d] imidazole-6-carboxylic acid The title compound was synthesized in the same manner as in Examples 34 and 35. 37a) tert-butyl 4-ethoxycarbonyl-5
Methyl-3-Puropioniruami Roh thiophene-2-Cal
Boxylate From the compound (3.0 g) obtained in Example 35a) and propionyl chloride (1.1 ml), the title compound was obtained as a yellow syrup (3.29 g, 92%) in the same manner as in Example 34b). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.24 (3H, t), 1.
32 (3H, t), 1.55 (9H, s), 2.43 (2H, q), 2.58 (3H, s), 4.29 (2H,
q), 9.56 (1H, br s). IR (Neat) cm ^-1 : 3325,1720,1690,1670,1570,1410,136
0,1240,1160,1050. 37b) tert-butyl 3 -[[N- (2'-cyanobife
4- yl) method Chi le -N- propionyl] amino] -
4-ethoxycarbonyl-5-methylthiophen-2-
Carboxylate From the compound (3.29 g) obtained in Example 37a), the title compound was converted to a pale yellow syrup (4.
3 g, 84%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.10 (3H, t), 1.
19 (3H, t), 1.46 (9H, s), 2.13 (2H, q), 2.65 (3H, s), 3.81-4.1
0 (2H, m), 4.50 (1H, d), 5.04 (1H, d), 7.30 (2H, d), 7.38-7.45
(4H, m), 7.58-7.66 (1H, m), 7.73-7.77 (1H, m) .37c) 3- [N- ( 2' -cyanobiphenyl-4-yl)
Methyl -N- propyl propionyl] amino-4- Etokishika
Carbonyl-5-Mechiruchiofu E emission-2-phosphate in Example 37b) the compound obtained in the (4.3 g), Example 34d) and the title compound was synthesized in analogy colorless needles (3.27
g, 85%). mp. 120-122 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.09 (3H, t), 1.
28 (3H, t), 2.03-2.27 (2H, m), 2.72 (3H, s), 4.06-4.25 (2H,
m), 4.44 (1H, d,), 5.13 (1H, d), 7.27-7.47 (6H, m), 7.58-7.6
6 (1H, m), 7.71-7.74 (1H, m).

37d) Ethyl 2-amino- 3-[[N-
(2'-cyanobiphenyl-4-y) methyl -N- flop
Ropioni Le] amino] -5-methylthiophene-4-Cal
Boki Shirato Example 37c) the compound obtained in the (3.14 g), was obtained as in Example 34e) and 34f) light yellow title compound was prepared in analogy to syrup (1.56g, 53%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.08 (3H, t), 1.
33 (3H, t), 2.07-2.18 (2H, m), 2.58 (3H, s), 3.83 (1H, d), 4.2
5 (2H, q), 5.67 (1H, d), 7.41-7.50 (6H, m), 7.61-7.69 (1H,
m), 7.72-7.76 (1H, m). IR (Neat) cm ^-1 : 3420,3325,2200,1700,1650,1630,138
0,1310,1295,1215,1050,760,750.37e) ethyl [1- (2'-cyanobiphenyl-4-
Yl) methyl] -2-an ethyl-5-methylthieno [2,3
-D] Imidazole-6-carboxylate From the compound (1.56 g) obtained in Example 37d), the title compound was converted to colorless needles (0.3) in the same manner as in Example 34g).
g, 20%). mp. 136-138 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.22 (3H, t), 1.
37 (3H, t), 2.75 (3H, s), 2.77 (2H, q), 4.23 (2H, q), 5.79 (2H,
s), 7.09 (2H, d), 7.40-7.51 (4H, m), 7.59-7.68 (1H, m), 7.74
-7.78 (1H, m). IR (KBr) cm ^-1 : 2220,1705,1475,1400,1375,1365,132
5,1290,1235.

37f)Ethyl 2-ethyl -5-methyl
-1-[[2'-(1H-tetrazo Le -5-yl) biff
Enyl-4-yl) methyl] thieno [2,3-d] imidazo
Roux 6-carboxylate From the compound obtained in Example 37e) (0.27 g),
The title compound was obtained in the same manner as in Example 34h) by colorless needles (0.23).
g, 71%). mp. 114-116 ° C Elemental analysis value C_{twenty five}H_{twenty four}N₆O_TwoS ・ 0.5C_FourH₈O_TwoAs ¹H-NMR (200 MHz, CDCl_Three) δ: 1.14 (3H, t),
1.18 (3H, t), 2.51 (2H, q), 2.62 (3H, s), 4.14 (2H, q), 5.61 (2
H, s), 6.72 (2H, d), 6.97 (2H, d), 7.35-7.41 (1H, m), 7.56-7.
65 (2H, m), 7.95-8.02 (1H, m). IR (KBr) cm^-1： 1705,1500,1410,1325,1300,1240,121
0,1045,755. 37g)2-ethyl-5-methyl-1-[[2 '-(1H −
Tetrazole-5 Yl) biphenyl-4-yl] methyl
Ru] thieno [2,3- d] Imidazole-6-carboxylic acid From the compound (0.13 g) obtained in Example 37f),
The title compound was obtained as colorless crystals (0.09 g,
80%). mp. 272-274 ° C (decomposition) Elemental analysis value C_{twenty three}H₂₀N₆O_TwoS ・ 0.3H_TwoAs O ¹H-NMR (200 MHz, DMSO-d₆) δ: 1.17 (3
H, t), 2.67 (2H, q), 2.69 (3H, s), 5.76 (2H, s), 6.91 (2H, d),
7.04 (2H, d), 7.49-7.71 (4H, m). IR (KBr) cm^-1： 1680,1490,1480,1405,1375,1325,130
0,1240,1205,1070,750,705.

Example 38 Methyl 2-ethyl-5-methyl-1-[[2 '-(1H-
Tetrazol-5- yl) biphenyl-4-yl] methyl
Le] thieno [2,3-d] imidazole-6-Cal Bokishira
Over preparative Example 37f) obtained in ethyl ester (0.057 g)
Containing sodium methanolate (50 mg) in methanol
(2 ml) and refluxed for 5 hours. After the reaction solution was concentrated to dryness, it was dissolved in water and adjusted to pH 4 with 1N hydrochloric acid. The precipitated crystals were recrystallized from ethyl acetate-methanol to obtain colorless crystals (0.037 g, 73%). mp. 242-245 ° C (decomposition) Elemental analysis value As C ₂₄ H ₂₂ N ₆ O ₂ S · 0.1H ₂ O ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.19 (3
H, t), 2.67 (3H, s), 2.70 (2H, q), 3.63 (3H, s), 5.63 (2H, s),
6.88 (2H, d), 7.04 (2H, d), 7.48-7.70 (4H, m) .IR (KBr) cm ^-1 : 1710,1500,1450,1440,1410,1300,1230,1
060,770.

Embodiment 39Methyl 2-ethylthio-4-phenyl-1-[[2'-
(1H-tetrazole-5 -Yl) biphenyl-4-i
[Methyl] thieno [3 , 4-d] Imidazole- 6-cal
Boxylate 39a)Methyl 3,4-diami No-5-phenylthio
Offen-2-carboki Silat K. Hartke et al. [K. Hartke and B. Seib, Pharmazi
e,twenty five, 517 (1970)] to give the title compound.
Obtained. 148-150 ° C (lit, 118 ° C)¹ H-NMR (200 MHz, DMSO-d₆) δ: 3.76 (3
H, s), 7.38-7.53 (3H, m), 7.58-7.64 (2H, m), 7.69 (4H, b
r) 39b)Methyl 2-mercapto-4-phenylthiye
No [3,4-d] imidazo - 6-carboxylate Methyl 3,4-diamino-5-phenylthiophene
2-carboxylate (1.5 g) and thiocarbonyl
A solution of diimidazole (1.1 g) in DMF (5 ml) was added for 1 hour.
While stirring at 50 ° C. Water is added to the reaction solution,
The crystals were recrystallized from DMF-water to give pale yellow crystals (1.7 g,
Quantitative). Melting point 294-296 ° C (decomposition) Elemental analysis value C₁₃H_TenN_TwoO_TwoS_TwoAs ¹H-NMR (200 MHz, DMSO-d₆) δ: 3.82
(3H, s), 7.34 to 7.51 (3H, m), 7.72 to 7.77 (2H, m) IR (KBr) cm^-1: 1685, 1640, 1575, 1550, 1500,
1475, 1440, 1410, 1280, 1195, 1170, 1140, 1015, 95
5,830,750,720,680.

39c) Methyl 2-ethylthio-4-
Phenyl thieno [3,4-d] imidazole-6-
Xylatemethyl 2-mercapto-4-phenylthieno [3,4-
d] imidazole-6-carboxylate (1.7 g),
A solution of ethyl iodide and 2N NaOH (3 ml) in methanol (30 ml) was stirred for 6.5 hours at room temperature. The reaction solution was concentrated to dryness, water was added to the residue, and the resulting crystals were recrystallized from methanol-ethyl acetate to give pale yellow needles (1.
(3 g, 68%). As mp 214-215 ° C. Elemental analysis _{C 15 H 14 N 2 O 2} S 2 ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.43
(3H, t), 3.33 (2H, q), 3.83 (3H, s), 7.31-7.39 (1H, m),
7.44-7.52 (2H, m), 8.05-8.19 (2H, m) IR (KBr) cm ^-1 : 1640, 1610, 1485, 1455, 1435,
1320, 1280, 1255, 1195, 1125, 1020, 755. 39d) Methyl 2-ethylthio-4-phenyl-1
-[[2 '-(1H-tetrazol-5-yl) biphenyl
-4 -yl] methyl] thieno [3,4-d] imidazole-
6-carboxylate In the same manner as in Example 1, methyl 2-ethylthio-4-
From phenylthieno [3,4-d] imidazole-6-carboxylate (1.3 g), the title compound was converted to colorless needles.
(1.4 g, 61%). 214-216 ° C (decomposition) Elemental analysis value As C ₂₉ H ₂₄ N ₆ O ₂ S ₂ .0.2H ₂ O ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.41
(3H, t), 3.35 (2H, q), 3.73 (3H, s), 5.67 (2H, s), 7.05 (2
H, d), 7.11 (2H, d), 7.34-7.71 (7H, m), 8.07-8.13 (2H, m) IR (KBr) cm ^-1 : 1680, 1595, 1485, 1440, 1430,
1320, 1300, 1280, 1255, 1255, 1235, 1180, 1170, 11
10, 1045, 960, 915, 750.

Example 40 2-ethylthio-4-phenyl-1-[[2 ′-(1H-te
Trazol-5-yl) biphenyl-4-yl] methyl]
Thieno [3,4- d] imidazole-6-carboxylic acid In the same manner as in Example 2, methyl 2-ethylthio-4-
The title compound was prepared from phenyl-1-[[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole-6-carboxylate (0.9 g). Obtained as yellow needles (0.64 g, 73%). Melting point: 229-230 ° C (decomposition) Elemental analysis: C ₂₈ H ₂₂ N ₆ O ₂ S ₂ .0.5H ₂ O ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.40
(3H, t), 3.34 (2H, q), 5.71 (2H, s), 7.06 (2H, d), 7.13 (2
H, d), 7.32-7.71 (7H, m), 8.08-8.12 (2H, m) IR (KBr) cm ^-1 : 1635, 1585, 1525, 1485, 1450,
1320, 1310, 1280, 1165, 770, 760.

Embodiment 41Methyl 2-ethylthio-4-propyl-1-[[2'-
(1H-tetrazole-5 -Yl) biphenyl-4-i
[Methyl] thieno [3 , 4-d] Imidazole- 6-cal
Boxylate 41a)Methyl 3,4-diami No-5-propylthio
Offen-2-carboki Silat K. Hartke et al. [K. Hartke and B. Seib, Pharmazi
e,twenty five, 517 (1970)] to give the title compound.
Obtained. 185 ° C (decomposition)¹ H-NMR (90 MHz, DMSO-d₆) δ: 0.97 (3H,
t), 1.43-1.83 (2H, m), 2,80 (2H, t), 3.73 (3H, s), 8.33
(5H, brs) IR (Nujol) cm^-1: 3400, 3310, 2730, 2540, 16
95, 1630, 1495, 1320. 41b)Methyl 2-mercapto-4-propylthiye
No [3, 4-d] Imidazo Ole-6-carboxylate The title compound was obtained in the same manner as in Example 39b),
Obtained as zum crystals (95%). 255-260 ° C (decomposition)¹ H-NMR (90 MHz, DMSO-d₆) δ: 0.90 (3H,
t), 1.43-1.83 (2H, m), 2.73 (2H, t), 3.20 (1H, s), 4.77
(3H, s), 12.50 (1H, br s) IR (Nujol) cm^-1: 3160, 3100, 1670, 1575, 14
35, 1330, 1310, 1205, 1110.

41c) Methyl 2-ethylthio-4-
Propyl-thieno [3,4-d] imidazole-6-
Xylate In the same manner as in Example 39c), the title compound was converted into colorless needles.
(93%). 135-136 ° C ¹ H-NMR (90 MHz, CDCl ₃ ) δ: 1.00 (3H, t),
1.43 (3H, t), 1.60-1.93 (2H, m), 2.97 (2H, t), 3.30 (2H, t
q), 3.87 (3H, s), 9.30 (1H, brs) IR (Nujol) cm ^-1 : 3220, 1665, 1615, 1440, 13
15, 1210, 1105. 41d) Methyl 2-ethylthio-4-propyl-1
-[[2 '-(1H-tetrazol-5-yl) biphenyl
-4 -yl] methyl] thieno [3,4-d] imidazole-
6-Carboxylate In the same manner as in Example 1, the title compound was converted into colorless needles (50%).
%). Melting point 162-163 ° C Elemental analysis: C ₂₆ H ₂₆ N ₆ O ₂ S ₂ .H ₂ O ¹ H-NMR (90 MHz, CDCl ₃ ) δ: 1.00 (3H,
t), 1.40 (3H, t), 1.60-2.00 (2H, m), 2.93 (2H, t), 3.27
(2H, t), 3.73 (3H, s), 5.70 (2H, s), 7.07-7.67 (7H, m),
8.07-8.23 (1H, m) IR (Nujol) cm ^-1 : 3360,2720,1685,1600,14
50, 1430, 1325, 1245, 1170.

Example 42 2-ethylthio-4-propyl-1-[[2 '-(1H-te
Trazol-5-yl) biphenyl-4-yl] methyl]
Thieno [3,4- d] imidazole-6-carboxylic acid In the same manner as in Example 2, the title compound was converted into colorless needles (82%).
%). Melting point 187-188 ° C (decomposition) Elemental analysis value As C ₂₅ H ₂₄ N ₆ O ₂ S ₂ ¹ H-NMR (90 MHz, DMSO-d ₆ ) δ: 1.00 (3
H, t), 1.40 (3H, t), 1.63-2.03 (2H, m), 2.97 (2H, t), 3.2
7 (2H, q), 5.70 (2H, s), 7.07 (2H, d), 7.17 (2H, d), 7.43-
7.73 (4H, m) IR (Nujol) cm ^-1 : 2720, 1635, 1590, 1530, 14
50, 1385, 1320, 1260, 1160, 755.

Example 43 Methyl 4-methyl-2-pentafluoroethyl-1-
[[2 '- (1H- tetrazole Lumpur 5-yl) biphenyl -
4-yl] methyl] thieno [3,4-d] imidazole -6
-Carboxylate 43a) methyl 4-methyl-2-pentafluoroe
Chiruchieno [3,4-d] imidazole-6-carboxy
To a solution of methyl 3,4-diamino-5-methylthiophene -2
A solution of -carboxylate (1.0 g) in pentafluoropropionic acid (8.9 g) was stirred at 100 ° C for 6 hours.
The reaction solution was concentrated to dryness, and the residue was suspended in water. After making it basic with potassium carbonate solution and extracting with ethyl acetate, the organic layer was washed with water, dried and concentrated to dryness. The residue was purified by silica gel column chromatography, and the resulting crystals were recrystallized from isopropyl ether-hexane to give colorless plate crystals.
(0.86 g, 51%). As mp 156-157 ° C. Elemental analysis _{C 10 H 7 F 5 N 2} O 2 S IR (KBr) cm ^-1 : 1695, 1620, 1560, 1440, 1375,
1330, 1300, 1280, 1220, 1150, 1110, 1030, 840, 75
5,750,735. 43b) Methyl 4-methyl-2-pentafluoroe
Tyl-1- [[2 ′-(1H-tetrazol-5-yl) bi
Fe-4-yl] methyl] thieno [3,4-d] Imida
Zole-6-carboxylate The title compound was converted to colorless needles in the same manner as in Example 39d).
(26%). Melting point: 184-186 ° C Elemental analysis: as C ₂₄ H ₁₇ F ₅ N ₆ O ₂ S ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.75 (3H,
s), 3.80 (3H, s), 6.00 (2H, s), 7.10 (2H, d), 7.20 (2H,
d), 7.39-7.44 (1H, m), 7.51-7.63 (2H, m), 8.21-8.26 (1
H, m) IR (KBr) cm ^-1 : 1705,1600,1550,1480,1450,
1440, 1420, 1345, 1320, 1260, 1240, 1225, 1200, 11
90, 1140, 1110, 1095, 1045, 960, 940, 755, 735.

Embodiment 444-methyl-2-pentafluoroethyl-1-[[2′-
(1H-tetrazole-5 -Yl) biphenyl-4-i
[Methyl] thieno [3 , 4-d] Imidazole- 6-cal
Boric acid The title compound was converted into colorless crystals (32%) in the same manner as in Example 2.
As obtained. Melting point 201-202 ° C (decomposition) Elemental analysis value C_{twenty three}H₁₅F_FiveN₆O_TwoS ・ 0.2H_TwoAs O ¹H-NMR (200 MHz, DMSO-d₆) δ: 2.69
(3H, s), 6.00 (2H, s), 6.96 (2H, d), 7.04 (2H, d), 7.50-
7.67 (4H, m) IR (KBr) cm^-1: 1645, 1540, 1260, 1210, 1140,
1110, 960, 940, 745.

Example 45 Methyl 2-heptafluoropropyl-4-methyl-1
- [[2 '- (1H- tetrazol-5-yl) biphenyl
4-yl] methyl] thieno [3,4-d] imidazole -
6-carboxylate 45a) methyl 2-heptafluoropropyl-4-
Mechiruchie Bruno [3,4-d] imidazole-6-carboxy
Silate In a similar manner to Example 43a), the title compound was obtained as colorless prisms (53%). Melting point: 147-148 ° C Elemental analysis: C ₁₁ H ₇ F ₇ N ₂ O ₂ S ¹ H-NMR (200 Hz, CDCl ₃ ) δ: 2.76 (3H, s),
3.92 (3H, s), 9.80 (1H, brs) IR (KBr) cm ^-1 : 1700, 1620, 1560, 1440, 1375,
1350, 1330, 1280, 1220, 1200, 1180, 1150, 1105, 98
0,910,865,760,745,730. 45b) Methyl 2-heptafluoropropyl-4-
Methyl-1 -[[2 ′-(1H-tetrazol-5-yl)
Biff Eniru-4-yl] methyl] thieno [3,4-d] Imi
Dazol-6-carboxylate The title compound was obtained in the same manner as in Example 39b).
(33%). As mp 144-145 ° C. Elemental analysis _{C 25 H 17 F 7 N 6} O 2 S ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.76 (3H,
s), 3.81 (3H, s), 5.99 (2H, s), 7.09 (2H, d), 7.20 (2H,
d), 7.39-7.44 (1H, m), 7.51-7.63 (2H, m), 8.23-8.27 (1
H, m) IR (KBr) cm ^-1 : 1700,1600,1545,1480,1435,
1330, 1235, 1205, 1130, 1120, 1090, 905, 860, 75
5,735.

Example 46 2-Heptafluoropropyl-4-methyl-1-[[2 ′
-(1H-tetrazol- 5-yl) biphenyl-4-i
[Methyl] thieno [3,4-d] imidazole -6-cal
The title compound was converted into colorless needles (54
%). 204-205 ° C (decomposition) Elemental analysis value As C ₂₄ H ₁₅ F ₇ N ₆ O ₂ S ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 2.69 (3
H, s), 5.99 (2H, s), 6.93 (2H, d), 7.04 (2H, d), 7.49-7.7
0 (4H, m) IR (KBr) cm ^-1 : 1645,1540,1335,1220,1120,
870, 850.

Example 47 Methyl 2-ethylthio-4-methylthio-1-[[2 ′
-(1H-tetrazol- 5-yl) biphenyl-4-i
[Methyl] thieno [3,4-d] imidazole -6-cal
Bokishirato 47a) Methyl 3,4-diamine Roh-5-methylthio
Thiophene-2 Kishirato K. Hartke et al. [K. Hartke and B. Seib, Pharmazi
e, 25 , 517 (1970)] to give the title compound. Melting point 95-97 ° C ¹ H-NMR (90 MHz, CDCl ₃ ) δ: 2.33 (3H, s),
3.60 (2H, br s), 3.80 (3H, s), 5.27 (2H, br s) IR (Nujol) cm ^-1 : 3450, 3400, 3350, 1670, 16
20, 1495, 1450, 1425, 1320, 1250, 1130. 47 b) Methyl 2-mercapto-4-methylthiothio
In the same manner as eno [3, 4-d] imidazole-6-carboxylate Example 39 b), as a pale yellow prisms of the title compound (77%). 240-242 ° C (decomposition) ¹ H-NMR (90 MHz, DMSO-d ₆ ) δ: 2.53 (3H,
s), 3.27 (1H, br s), 3.77 (3H, s), 12.77 (1H, br s) IR (Nujol) cm ^-1 : 3200, 3125, 3075, 3020, 16
80, 1625, 1555, 1490, 1430, 1330, 1290, 1190, 116
5,1070. 47c) Methyl 2-ethylthio-4-methylthiothio
In the same manner as eno [3,4-d] imidazole-6-carboxylate Example 39c), the title compound colorless needles
(93%). Melting point 170-172 ° C ¹ H-NMR (90 MHz, CDCl ₃ ) δ: 1.43 (3H, t),
2.67 (3H, s), 3.33 (2H, q), 3.87 (3H, s), 9.23 (1H, brs) IR (Nujol) cm ^-1 : 3200,1655,1615,1510,14
40, 1315, 1150. 47d) Methyl 2-ethylthio-4-methylthio-
1-[[2 '-(1H-tetrazol-5-yl) biphenyl
Ru- 4-yl] methyl] thieno [3,4-d] imidazole
-6-carboxylate In the same manner as in Example 1, the title compound was converted into colorless needles (79%).
%). Melting point: 200-201 ° C Elemental analysis: as C ₂₄ H ₂₂ N ₆ O ₂ S ₃ ¹ H-NMR (90 MHz, CDCl ₃ ) δ: 1.43 (3H,
t), 3.13 (3H, s), 3.30 (2H, q), 3.83 (3H, s), 5.67 (2H,
s), 7.07-7.63 (7H, m), 7.93-8.07 (1H, m) IR (Nujol) cm- ¹ : 2750, 1680, 1590, 1510, 14
45, 1425, 1330, 1320, 1235, 1170, 755.

Embodiment 482-ethylthio-4-methylthio-1-[[2 '-(1H-
Tetrazol-5-yl ) Biphenyl-4-yl] methyl
Ru] thieno [3,4-d] imidazole-6-ca Rubonic acid The title compound was converted into colorless needles (29) in the same manner as in Example 2.
%). Melting point 176-178 ° C (decomposition) Elemental analysis C_{twenty three}H₂₀N₆O_TwoS_Three・ 0.5H_TwoAs O ¹H-NMR (90 MHz, CDCl_Three) δ: 1.33 (3H,
t), 2.67 (3H, s), 3.27 (2H, q), 5.67 (2H, d), 7.07 (4H,
s), 7.43-7.73 (4H, m) IR (Nujol) cm^-1: 1630, 1575, 1500, 1450, 13
20, 1165, 755.

Embodiment 49Methyl 2-isopropoxy-4-methyl-1-[[2 ′
-(1H-tetrazole- 5-yl) biphenyl-4-i
[Methyl] thieno [3,4-d] imidazole -6-cal
Boxylate 49a)Methyl 1-[(2'-cyanobiphenyl-4
-Yl) methyl] -2-a Sopropoxy-4-methylthio
Eno [3,4-d] imidazole-6-carboxylate In the same manner as in Example 23c), methyl 1-[(2′-cy
Anobiphenyl-4-yl) methyl] -2-ethylsphere
Nyl-4-methylthieno [3,4-d] imidazole-6
-From carboxylate, the title compound was obtained as colorless crystals (45
%). ¹ H-NMR (200 Hz, CDCl_Three) δ: 1.39 (6H, d),
2.56 (3H, s), 3.81 (3H, s), 5.25-5.40 (1H, m), 5.62 (2H,
s), 7.35-7.51 (6H, m), 7.59-7.67 (1H, m), 7.73-7.77 (1
H, m). 49b)Methyl 2-isopropoxy-4-methyl-
1-[[2 '-(1H-tetrazol-5-yl) biphenyl
Roux 4-yl] methyl] thieno [3,4-d] imidazole
-6-carboxylate The title compound was obtained as pale yellow crystals in the same manner as in Example 23d).
(48%). Melting point 170-173 ° C (decomposition) Elemental analysis value C_{twenty five}H_{twenty four}N₆O_ThreeS ・ 0.5H_TwoAs O ¹H-NMR (200 MHz, CDCl_Three) δ: 1.39 (6H,
d), 2.52 (3H, s), 3.80 (3H, s), 5.21-5.34 (1H, m), 5.58
(2H, s), 7.16 (2H, d), 7.31 (2H, d), 7.34-7.41 (1H, m),
7.50-7.63 (2H, m), 8.17-8.22 (1H, m) IR (KBr) cm^-1: 1690, 1615, 1570, 1530, 1440,
1380, 1370, 1330, 1320, 1240, 1100, 755.

Embodiment 502-isopropoxy-4-methyl-1-[[2 '-(1H-
Tetrazol-5-yl ) Biphenyl-4-yl] methyl
Ru] thieno [3,4-d] imidazole-6-ca Rubonic acid The title compound was converted into colorless crystals (46) in the same manner as in Example 14.
%). 184-188 ° C (decomposition) Elemental analysis value C_{twenty four}H_{twenty two}N₆O_ThreeS ・ H_TwoAs O ¹H-NMR (200 MHz, DMSO-d₆) δ: 1.27
(6H, d), 2.38 (3H, s), 5.04-5.17 (1H, m), 5.70 (2H, s),
7.01 (2H, d), 7.08 (2H, d), 7.23-7.36 (3H, m), 7.48-7.53
(1H, m). IR (KBr) cm^-1: 1620, 1570, 1540, 1450, 1445,
1420, 1410, 1380, 1330, 1250, 750.

Embodiment 51Methyl 2-trifluoromethyl-4-methyl-1-
[[2 '-(1H-tetrazo Ru-5-yl) biphenyl-
4-yl] methyl] thieno [3,4-d] imidazo Rule-6
-Carboxylate 51a)Methyl 2-trifluoromethyl-4-methyl
Lucieno [3,4-d] i Midazole-6-carboxyla
To In the same manner as in Example 43a), the title compound was obtained as colorless platelets.
(55%). Melting point 192-193 ° C elemental analysis C₉H₇F_ThreeN_TwoO_TwoAs S ¹H-NMR (200 Hz, CDCl_Three) δ: 2.74 (3H,
s), 3.92 (3H, s), 10.10 (1H, brs) IR (KBr) cm^-1: 1700, 1620, 1560, 1435, 1370,
1345, 1290, 1220, 1200, 1180, 970, 755, 730. 45b)Methyl 2-trifluoromethyl-4-methyl
Ru-1-[[2 '-(1H-tetrazol-5-yl) bifu
Eni Ru-4-yl] methyl] thio Eno [3,4-d] imidazo
Ole-6-carboxylate The title compound was converted into colorless needles (46) in the same manner as in Example 1.
%). 229-230 ° C (decomposition) Elemental analysis C_{twenty three}H₁₇F_ThreeN₆O_TwoAs S ¹H-NMR (200 MHz, CDCl_Three) δ: 2.75 (3H,
s), 3.81 (3H, s), 5.96 (2H, s), 7.13 (2H, d), 7.21 (2H,
d), 7.39-7.44 (1H, m), 7.51-7.63 (2H, m), 8.22-8.26 (1
H, m) IR (KBr) cm^-1: 1700, 1560, 1450, 1415, 1290,
1250, 1195, 1140, 1125, 755.

Example 52 2-trifluoromethyl-4-methyl-1-[[2 '-(1
H-tetrazol-5- yl) biphenyl-4-yl] me
[Tyl] thieno [3,4-d] imidazole-6 -carboxylic acid The title compound was converted to colorless needles (2
1%). Melting point: 226-228 ° C (decomposition) Elemental analysis: C ₂₂ H ₁₅ F ₃ N ₆ O ₂ S ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 2.69
(3H, s), 5.94 (2H, s), 6.98 (2H, d), 7.05 (2H, d), 7.50-
7.71 (4H, m) IR (KBr) cm ^-1 : 1645, 1550, 1200, 1145, 760, 7
50.

EXPERIMENTAL EXAMPLE 1 Access to angiotensin receptor
Ngiotensin-II binding inhibitory effect [Experimental method] The method of Douglas et al. [Endocrinology, 102 ,
685-696 (1978)], and an angiotensin II (A-II) -receptor binding inhibition experiment was performed. A-II receptor membrane fraction was prepared from bovine adrenal cortex. The compound of the present invention (10 ⁻⁶ M or 10 ⁻⁷ M) and ¹²⁵ I-angiotensin II ( ¹²⁵ I-AII) (1.85 kBq / 50 μl) were added to the receptor membrane fraction, and incubated at room temperature for 1 hour. . Filter bound and free ¹²⁵ IA-II (Whatman G
F / Bfilter) and ¹²⁵ I-
The radioactivity of A-II was measured.

[Experimental results] The experimental results of the compound of the present invention are shown in [Table 1]. EXPERIMENTAL EXAMPLE 2 Application of the present invention to angiotensin pressor reaction
Inhibitory effect of compound [Experimental method] JcI: SD rats (9 weeks old, male) were used. On the day before the experiment, the femoral artery and vein were inoculated with a cannula under anesthesia with pentobarbital Na, and the animals were kept under fasting conditions and water-free intake until immediately before the experiment. On the day of the experiment, the arterial cannula was connected to a blood pressure transducer and the mean blood pressure was recorded on a polygraph. Prior to drug administration, the pressor response due to intravenous administration of control angiotensin II (A-II) (100 ng / kg) was determined. The drug was orally administered, and then A-II was intravenously administered at each measurement point. Similarly, the pressor response was determined and the response before and after drug administration was compared to determine the inhibition rate. [Experimental results] The experimental results of the compound of the present invention are shown in [Table 1].

[0105]

[Table 1]

────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ identification code FI A61P 13/02 A61P 13/02 43/00 116 43/00 116 (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 495/04 103 A61K 31/415 CA (STN) REGISTRY (STN)

Claims (24)

(57) [Claims] (1) Formula (1) [In the formula, ring A represents a thiophene ring which may further have a substituent other than the group represented by formula R ³ , and R ¹ may be bonded via hydrogen or a hetero atom, and R ² represents a hydrocarbon group which may be protected by a lower alkyl group or an acyl group which may be substituted, (1) a carboxyl group, (2) a tetrazolyl group, and (3) a trifluoro group. A methanesulfonic acid amide group, (4) a phosphoric acid group, (5) a sulfonic acid group, (6) a cyano group or (7) a lower (C _1-4 ) alkoxycarbonyl group, and R ³ is (A) esterified Alternatively, a carboxyl group which may be amidated or a tetrazolyl group which may be protected, or (B) a lower alkyl group or an acyl group which may be substituted (B) Ruboxyl group, (2) tetrazolyl group, (3) trifluoromethanesulfonic acid amide group,
(4) a phosphoric acid group, (5) a sulfonic acid group, (6) a cyano group or (7) a lower (C _1-4 ) alkoxycarbonyl group, and X represents a phenylene group and a phenyl group directly or an atomic chain of 2 or less. Indicates that they are linked via a spacer,
and n represents an integer of 1 or 2.] or a salt thereof. 2. R ¹ is attached via a heteroatom,
2. The compound according to claim 1, which is an optionally substituted hydrocarbon residue. ^3. The compound according to claim 1, wherein R ³ is a carboxyl group which may be esterified. 4. Apart wherein the ring A is represented by the formula R ³ (1)
Halogen, (2) nitro, (3) cyano, (4) amino, (5) N-lower (C _1-4 ) alkylamino, (6) N,
N-di-lower (C _1-4 ) alkylamino, (7) phenylamino, (8) morpholino, piperidino, piperazino, N
-Phenylpiperazino, formula (9) -WR ⁶ [wherein W
Represents a bond, -O-, -S- or -C (= O)-;
⁶ is hydrogen or hydroxyl, amino, halogen and lower
(C _1-4 ) lower (C _1-4 ) alkyl which may be substituted with a substituent selected from alkoxy].
(10) Formula — (CH ₂ ) ₁ —CO—D wherein D is i) hydrogen, i
i) hydroxyl group, iii) amino, iv) N-lower (C _1-4 ) alkylamino, v) N, N-di-lower (C _1-4 ) alkylamino or vi) alkyl moiety is a) hydroxyl group, b) Amino, dimethylamino, diethylamino, piperidino, morpholino, c) halogen, d) formula-
OC (R ⁷ ) HOCOR ^{8 wherein} R ⁷ is (1) hydrogen, (2) a lower alkyl group having 1 to 6 carbon atoms or (3) a cycloalkyl group having 5 to 7 carbon atoms, and R ⁸ is (1) lower alkyl group having 1 to 6 carbon atoms, (2) lower alkenyl group having 2 to 8 carbon atoms, (3) cycloalkyl group having 5 to 7 carbon atoms, (4) cycloalkyl having 5 to 7 carbon atoms Or 1 to 1 carbon atoms substituted with phenyl
(5) cycloalkyl having 5 to 7 carbon atoms or lower alkenyl group having 2 to 3 carbon atoms substituted with phenyl, (6) phenyl, p-tolyl, naphthyl, (7)
A lower alkoxy group having 1 to 6 carbon atoms, (8) a lower alkenyloxy group having 2 to 8 carbon atoms, (9) a cycloalkyloxy group having 5 to 7 carbon atoms, (10) a cycloalkyl or phenyl having 5 to 7 carbon atoms A lower alkoxy group having 1 to 3 carbon atoms substituted with (11) a lower alkenyloxy group having 2 to 3 carbon atoms substituted with cycloalkyl or phenyl having 5 to 7 carbon atoms, (12) phenoxy, (13) p -Nitrophenoxy or
(14) a group represented by naphthoxy], e) lower (C _1-6 )
Alkoxy, f) lower (C _1-6 ) alkylthio, or g) 5
Represents a lower (C _1-6 ) alkoxy group which may be substituted with -methyl-2-oxo-1,3-dioxolen-4-yl, and 1 represents 0 or 1. And (11) a lower (C _1-4 ) alkyl, a lower (C _2-5 ) alkanoyl or a tetrazolyl group optionally protected with benzoyl, a trifluoromethanesulfonic acid amide group, and a phosphoric acid group, respectively. Or a thiophene ring which may have a substituent selected from a sulfonic acid group, wherein R ¹ is (1) hydrogen or (2) (a) a hydroxyl group, (b)
Amino, (c) methylamino, (d) halogen, (e)
A lower (C _1-4 ) alkylthio group and (f) a lower (C _1-4 )
A lower alkyl group having 1 to 8 carbon atoms which may be substituted with a substituent selected from an alkoxy group, (a) a hydroxyl group,
(B) amino, (c) methylamino, (d) halogen,
(E) a lower (C _1-4 ) alkylthio group and (f) a lower
(C _1-4 ) a lower alkenyl group having 2 to 8 carbon atoms which may be substituted by a substituent selected from an alkoxy group, (a)
A substituent selected from a hydroxyl group, (b) amino, (c) methylamino, (d) halogen, (e) a lower (C _1-4 ) alkylthio group and (f) a lower (C _1-4 ) alkoxy group. Optionally substituted lower alkynyl group having 2 to 8 carbon atoms, (a) hydroxyl group, (b) amino, (c) methylamino, (d) halogen, (e) lower (C _1-4 ) alkylthio group, (F) a lower cycloalkyl group having 3 to 6 carbon atoms which may be substituted with a substituent selected from a lower (C _1-4 ) alkoxy group, and (a) halogen, ( b) nitro, (c) a lower (C _1-4) alkoxy and (d) a lower (C _1-4) phenyl which may have a substituent group selected from alkyl - lower (C _1-4) alkyl (A) halogen at any position on the group and the benzene ring,
A hydrocarbon residue selected from (b) nitro, (c) lower (C _1-4 ) alkoxy and (d) phenyl optionally having a substituent selected from lower (C _1-4 ) alkyl Wherein the hydrocarbon residue is -O-, -S (O) m- [wherein
m represents 0, 1 or 2. ] And -N (R ⁵⁾ - [wherein, R ⁵ may be bonded to the imidazole skeleton through a hydrogen or a lower (C _1-4) heteroatoms selected from an alkyl group indicates a], R Wherein ² is (1) a tetrazolyl group or a carboxyl group each of which may be protected by a group selected from lower (C _1-4 ) alkyl, lower (C _2-5 ) alkanoyl and benzoyl, or (2) trifluoromethanesulfone R ³ is a group represented by the formula (1): —CO—D ′, wherein D ′ is i) a hydroxyl group,
ii) amino, N-lower (C _1-4 ) alkylamino, N, N-
Di-lower (C _1-4 ) alkylamino or iii) a) the alkyl moiety is hydroxyl, amino, dimethylamino, diethylamino, piperidino, morpholino, halogen, lower
(C _1-6 ) alkoxy, lower (C _1-6 ) alkylthio or 5-methyl-2-oxo-1,3-dioxolene-
A lower (C _1-6 ) alkoxy group optionally substituted with 4-yl, or b) a compound of the formula —OCH (R ⁷ ) OCOR ⁸ [wherein R ⁷
Is (1) hydrogen, (2) a lower alkyl group having 1 to 6 carbon atoms or
(3) a cycloalkyl group having 5 to 7 carbon atoms, wherein R ⁸ is (1)
A lower alkyl group having 1 to 6 carbon atoms, (2) a lower alkenyl group having 2 to 8 carbon atoms, (3) a cycloalkyl group having 5 to 7 carbon atoms, and (4) a cycloalkyl or phenyl having 5 to 7 carbon atoms. A substituted lower alkyl group having 1 to 3 carbon atoms, (5) a cycloalkyl group having 5 to 7 carbon atoms or a lower alkenyl group having 2 to 3 carbon atoms substituted with phenyl, (6) phenyl,
p-tolyl, naphthyl, (7) a lower alkoxy group having 1 to 6 carbon atoms, (8) a lower alkenyloxy group having 2 to 8 carbon atoms, (9)
Cycloalkyloxy group having 5 to 7 carbon atoms, (10) carbon number 5
A lower alkoxy group having 1 to 3 carbon atoms substituted with cycloalkyl or phenyl of 7 to 7 carbon atoms; (11) a lower alkoxy group substituted with cycloalkyl or phenyl of 5 to 7 carbon atoms;
~ 3 lower alkenyloxy groups, (12) phenoxy, (13) p
-Nitrophenoxy or (14) naphthoxy]]] or (2) lower
A tetrazolyl group which may be protected by a group selected from (C _1-4 ) alkyl, lower (C _2-5 ) alkanoyl and benzoyl, wherein X is (1) a bond, and (2) Lower (C _1-4 ) alkylene having 1 or 2 atoms, (3) −
C (O)-, (4) -O-, (5) -S-, (6)-
N (H)-, (7) -C (= O) -N (H)-, (8) -O-
_{C (H 2) -, (} 9) -S-C (H 2) - or (10) -C
The compound according to claim 1, wherein (H) = C (H)-. 5. The method according to claim 5, wherein the hetero atom is -O-, -S- or -NH.
The compound according to claim 1, which is-. 6. The compound according to claim 1, wherein R ¹ is a lower alkyl group having 1 to 6 carbon atoms which may be bonded to the imidazole ring via a hetero atom. 7. The compound according to claim 1, wherein R ¹ is a lower alkyl group having 1 to 4 carbon atoms bonded to the imidazole ring via an oxygen or sulfur atom. 8. The ring A is of the formula: In having a skeleton represented, compound of claim 1, wherein a good thiophene ring optionally further substituted in addition to the group represented by the formula R ^3. 9. R ¹ is attached via a heteroatom,
9. The compound according to claim 8, which is an optionally substituted hydrocarbon residue. 10. The compound according to claim 8, wherein R ³ is a carboxyl group which may be esterified. 11. The compound according to claim 1, wherein X is a bond. 12. The compound according to claim 1, wherein n is 1. 13. A compound of the formula [Wherein, R ¹ represents a lower (C _1-6 ) alkyl group which may be bonded via a hetero atom, and R ³ represents a group represented by the formula (A)
D 'wherein D' is (1) a hydroxyl group, (2) amino, (3)
N-lower (C _1-4 ) alkylamino, (4) N, N-di-lower
(C _1-4 ) alkylamino or (5) alkyl moiety is hydroxyl, amino, halogen, lower (C _2-6 ) alkanoyloxy, 1-lower (C _1-6 ) alkoxycarbonyloxy, 1-cyclohexyloxycarbonyloxy Or lower (C _1-4 ) alkoxy optionally substituted with lower (C _1-4 ) alkoxy], (B) lower (C _1-4 ) alkyl, lower (C _2-5) ) Represents a tetrazolyl group which may be protected by a group selected from alkanoyl and benzoyl, wherein R ² is methyl, triphenylmethyl, methoxymethyl, ethoxymethyl, p-methoxybenzyl, p-nitrobenzyl, lower (C _{2 -5)} indicates alkanoyl and may optionally be protected respectively by a group selected from benzoyl (1) tetrazolyl group or (2) a carboxyl group, R ⁴ is hydrogen, halogen, lower C _1-4)
Alkyl, lower (C _1-4 ) alkoxy, nitro, formula —CO
-D '' wherein D '' represents a hydroxyl group or a lower (C _1-2 ) alkoxy, or an amino optionally substituted with a lower (C _1-4 ) alkyl. A compound represented by the formula or a salt thereof. 14. The compound according to claim 13, wherein R ¹ is a lower (C _1-6 ) alkyl group bonded via a hetero atom. 15. The method according to claim 13, wherein R ² is a tetrazolyl group.
A compound as described. 16. The compound according to claim 13, wherein R ⁴ is hydrogen, lower (C _1-4 ) alkyl or halogen. 17. A compound of the formula [Wherein, R ¹ represents a lower (C _1-6 ) alkyl group which may be bonded via a hetero atom, and R ³ represents a group represented by the formula (A)
D 'wherein D' is (1) a hydroxyl group, (2) amino, (3)
N-lower (C _1-4 ) alkylamino, (4) N, N-di-lower
(C _1-4 ) alkylamino or (5) alkyl moiety is hydroxyl, amino, halogen, lower (C _2-6 ) alkanoyloxy, 1-lower (C _1-6 ) alkoxycarbonyloxy, 1-cyclohexyloxycarbonyloxy Or lower (C _1-4 ) alkoxy optionally substituted with lower (C _1-4 ) alkoxy], (B) lower (C _1-4 ) alkyl, lower (C _2-5) ) Represents a tetrazolyl group which may be protected by a group selected from alkanoyl and benzoyl, wherein R ² is methyl, triphenylmethyl, methoxymethyl, ethoxymethyl, p-methoxybenzyl, p-nitrobenzyl, lower (C _{2 -5)} indicates alkanoyl and may optionally be protected respectively by a group selected from benzoyl (1) tetrazolyl group or (2) a carboxyl group, R ⁴ is hydrogen, halogen, lower C _1-4)
Alkyl, lower (C _1-4 ) alkoxy, nitro, formula —CO
-D '' wherein D '' represents a hydroxyl group or a lower (C _1-2 ) alkoxy, or an amino optionally substituted with a lower (C _1-4 ) alkyl. A compound represented by the formula or a salt thereof. 18. The compound according to claim 17, wherein R ¹ is a lower (C _1-6 ) alkyl group bonded via a hetero atom. 19. The method according to claim 17, wherein R ² is a tetrazolyl group.
A compound as described. 20. The compound according to claim 17, wherein R ⁴ is hydrogen, lower (C _1-4 ) alkyl or halogen. 21. The formula: [Wherein, R ¹ is hydrogen or a hydrocarbon residue which may be bonded via a hetero atom and may be substituted;
R ² may be protected with a lower alkyl group or an acyl group which may be substituted (1) carboxyl group, (2) tetrazolyl group, (3) trifluoromethanesulfonic acid amide group, (4) phosphoric acid A group represented by (5) sulfonic acid group, (6) cyano group or (7) lower (C _1-4 ) alkoxycarbonyl group, R ^{6 ′} represents a hydrogen atom or a lower alkyl group, and R ⁴ represents hydrogen or halogen. , Lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy, nitro,
Formula -CO-D "[wherein, D" is a hydroxyl group or a lower (C
_1-2 ) represents alkoxy] or a lower (C)
_1-4 ) an amino optionally substituted with alkyl, X
Indicates that the phenylene group and the phenyl group are bonded directly or via a spacer having an atomic chain of 2 or less, and n is 1
Or an integer of 2] or a salt thereof. 22. The compound according to claim 2, wherein R ¹ is an optionally substituted hydrocarbon residue bonded via a heteroatom.
2. The compound according to 1. (23) 2-ethylthio-4-methyl-1-
[[2 ′-(1H-tetrazol-5-yl) biphenyl-
4-yl] methyl] thieno [3,4-d] imidazole-6
Carboxylic acid, acetoxymethyl 2-methoxy-4-methyl-1-[[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole-6-carboxy , 2-methoxy-4-methyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole-6-carboxylic acid, 2 -Ethoxy-4-methyl-1-
[[2 ′-(1H-tetrazol-5-yl) biphenyl-
4-yl] methyl] thieno [3,4-d] imidazole-6
Carboxylic acid, 2-propoxy-4-methyl-1-[[2 ′
-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] thieno [3,4-d] imidazole-6-carboxylic acid or a salt thereof. 24. The formula: [In the formula, ring A represents a thiophene ring which may further have a substituent other than the group represented by formula R ³ , and R ¹ may be bonded via hydrogen or a hetero atom, and R ² represents a hydrocarbon group which may be protected by a lower alkyl group or an acyl group which may be substituted, (1) a carboxyl group, (2) a tetrazolyl group, and (3) a trifluoro group. A methanesulfonic acid amide group, (4) a phosphoric acid group, (5) a sulfonic acid group, (6) a cyano group or (7) a lower (C _1-4 ) alkoxycarbonyl group, and R ³ is (A) esterified Alternatively, a carboxyl group which may be amidated or a tetrazolyl group which may be protected, or (B) a lower alkyl group or an acyl group which may be substituted (B) Ruboxyl group, (2) tetrazolyl group, (3) trifluoromethanesulfonic acid amide group,
(4) a phosphoric acid group, (5) a sulfonic acid group, (6) a cyano group or (7) a lower (C _1-4 ) alkoxycarbonyl group, and X represents a phenylene group and a phenyl group directly or an atomic chain of 2 or less. Indicates that they are linked via a spacer,
n represents an integer of 1 or 2], or an angiotensin II antagonist comprising the salt thereof.