CA2054465A1 - Thienoimidazole derivatives, their production and use - Google Patents

Abstract

Abstract of the Disclosure Benzimidazole derivatives of the formula (I):
(I) wherein the ring A is a thiophene ring which may optionally contain substitution in addition to the R3 group; R1 is hydrogen or optionally substituted hydrocarbon residue which may be bonded through a hetero atom; R2 and R3 are independently a group capable of forming an anion or a group convertible thereinto; X is a direct bond or a spacer having an atomic length of two or less between the phenylene group and the phenyl group; and n is an integer of 1 or 2; or a salt thereof, have potent angiotensin II
antagonistic activity and antihypertensive activity, thus being useful as therapeutic agents for treating circulatory system diseases such as hypertensive diseases, heart diseases (e.g. hypercardia, heart failure, cardiac infarction, etc.), strokes, cerebral apoplexy, nephritis, etc.

Description

- 1 - 2(~5~a~6S

THIENOIMIDAZOI.E DERIVATIVES, THEIR
Pl'ODUCTION AND USE
FIELD OF THE INVENTION
This invention relates to novel thienoimidazole clerivatives having potent pharmacological actions and intermediates for the synthesis thereof.
More particularly, the present invention relates to compounds represented by the general formula (I):

R~ 2)n ~ X

~CN~
~wherein the ring A is a thiophene ring which may optionally contain substitution in addition to the R3 group; Rl is hydrogen or optionally substituted hydrocarbon residue which may be bonded through a hetero atom; R2 and R3 axe independentl~ a group capable of forming an anion or a group convertible thereinto; X is a direct bond or a spacer having an atomic length of two or less between the phenylene group and the phenyl group; and n is an integer of 1 or 2] or salts thereof, having strong angiotensin II
antagonistic activity and potent anti-hypertensive activity, which are useful as therapeutic agents for treating circulatory diseases such as hypertensive diseases, heart diseases (e.g. hypercardia, heart failure, cardiac infarction, etc.), cerebral apoplexy, nephritis with proteinuria, arteriosclerosis, etc.
BACKGROUND OF THE INVENTION
The renin-angiotensin system is involved in the homeostatic function to control systemic blood pressure, the volume of body fluicl, balance among the electrolytes, etc., associated with the aldosterone system. Development of angiotensin II converting enzyme inhibitors (ACE inhibitor) (this converting - 2 - ~ ~5~465 enzyme produces angiotensin II which possesses a strong vasoconstrictive action) has clarified the relation between the renin-angiotensin system and hypertension.
Since angiotensin II constricts blood vessel to elevate blood pressure via the angiotensin II receptors on the cellular membranes, angiotensin II antagonists, like the ~CE inhibitor, would be useful in treating hypertension caused by angiotensin. It has been reported that various angiotensin II analogues such as saralasin, [Sarl, Ala8]AII, and the like, possess potent angiotensin II antagonis~t activity. It has, however, been reported that, when peptide antagonists are administered parenterally, their actions are not prolonged and, when administered orally, they are ineffective [M. A. Ondetti and D. W. Cushman, Annual Reports in Medicinal Chemistry, 13, 82-91(1978)].
On the other hand, for solving the problems observed in these peptide antagonists, studies on non peptide angiotensin II antagonists have been conducted.
In ~the earliest studies in thi.s field, imidazole derivatives having angiotensin II antagonist activit~
have been disclosed in Japanese Patent Unexamined Publication Nos. 71073/1981, 71074/1981, 92270/1982, and 15768/1983, USP 4,355,040 and USP 4,340,598, etc.
Later, improved imidazole derivati~es are disclosed in EP-0253310, EP-0291969, EP-0324377, and Japanese Patent Vnexamined Publication No. 23868/1988 and Japanese Patent Unexamined Publication No. 117876/1989. And, as angiotensin II antagonists, pyrrole, pyrazole and triazole derivatives are disclosed in EP-0323841 and Japanese Patent Unexamined Publication No. 287071/1989, while benzimidazole derivatives are disclosed in USP
4,880,80~.
DETAILED DESCRIPTION OF THE INVENTION
The present inventors considered that compounds functioning to control resin-angiotensin system as well _ 3 _ ~a~s44~s as clinically useful for the treatment of circulatory diseases such ~s hypertensive diseases, heart diseases (e.g. hypercardia, heart failure, cardiac infarction, etc.), cerebral apoplexy, etc. are required to have potent angiotensin II receptor antagonistic activity and to show a strong and long-lasting angiotensin II
antagonistic and hypotensive action by oral administration, and they have diligently conducted research work on the basis of the above consideration.
As a result of this research, the present inventors have found that novel substituted thienoimidazole derivatives (I) have a potent angiotensin II receptor antagonistic activity as well as exerting strong oral and long-lasting angiotensin II
antagonistic and anti-hypertensive action, and they have developed further research work to accomplish the present invention.
~ore specifically, the present invention relates to compounds of the formula (I):

(In2~n ~NN'~' [wherein the ring A is a thiophene ring which may optionally contain substitution in addition to the R3 group; R1 is hydrogen or optionally substituted hydrocarbon residue which may be bonded through a hetero atom; R2 and R3 are independently a group capable of forming an anion or a group convertible thereinto; X is a direct bond or a spacer having an atomic length of two or less between the phenylene group and the phenyl group; and n is an integer of 1 or 2] or salts thereof.
With regard to the foregoing general formula (I), hydrocarbon residues for R1 incl.ude, for e~ample, - ~ - 2C!S~46~;

alkyl, alkenyl, alkynyl, cyc]oalkyl, aryl and aralkyl groups. Among them, alkyl, alkenyl and cycloalkyl groups are preferable.
Alkyl groups for Rl are lower alkyl groups having 1 to about 8 carbon atoms, which may be straight or branched, and include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, i-pentyl, hexyl, heptyl, octyl, and the like.
Alkenyl groups for R are lower alkenyl groups having 2 to about 8 carbon atoms, which may be straight or branched, and include r for example, vinyl, propenyl, 2-butenyl, 3-butenyl, isobutenyl, 2-octenyl, and the like.
Alkynyl groups for Rl are lower alkynyl groups having 2 to about 8 carbon atoms, which may be straight or branched, and include, for example, ethynyl, propynyl, butynyl, octynyl, and the like.
Cycloalkyl groups ~or R1 are lower cycloalkyl groups having 3 to about 6 carbon atoms, and include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
The above~mentioned alkyl, alkenyl~ alkynyl and cycloalkyl groups may be substituted with hydroxyl, an optionally substituted amino group (e.g. amino, methylamino, etc.), halogen, a lower (Cl4) alkylthio group, a lower (C14) alkoxy group or the like.
Aralkyl groups for R1 include, for example, phenyl-lower (C14~ alkyl such as benzyl, phenethyl, and the like, and the aralkyl group may be substituted with, for example, halogen (e.g. F, Cl, Br, etc.), nitro, lower (C14) alkoxy (e.g. methoxy, ethoxy, etc.), lower (C14) alkyl (e.g~ methyl, ethyl, etc.), or the like at optional positions o~ the benzene ring.
Aryl groups for Rl include, for example, phenyl, and the aryl group may be substituted with, ~or example, halogen (e.g. F, Cl, Br, etc.), nitro, lower ~446S
- 5 - 24205-gO7 (Cl 4) alkoxy (e.g. methoxy, ethoxy, etc.) lower (Cl 4) alkyl (e.g. methyl, ethyl, etc.), or -the like at optional positions of the benzene ring.
Hydrocarbon residues for Rl may be bonded ~o the imidazole skeleton through a hetero atom. Examples of the hetero atom include -O-, ~S()m- [wherein m denotes 0, 1 or 2], -N(R5)-~wherein R stands for hydrogen or an optionally substituted lower (Cl 4~ alkyl group], preferably -O-, -S- and -NH-.
Among the above-mentioned hydrocarbon residues for Rl, optionally substituted lower alkyl groups having 1 to about 6 carbon atoms, which may be bonded to the imidazole ring through a hetero atom, or the like are preferable, and lower alkyl groups having 1 to about 4 carbon atoms, which are bonded to the imida-zole ring through oxygen or sulfur atom, are more preferable.
Examples of groups capable of forming an anion or groups convertible thereinto for R2 or R3 include carboxyl, tetra-zolyl, trifluoromethanesulfonamido (-NHSO2CF3), phosphoric acid residue (-PO3H), sulfonic acid residue (-SO3H), cyano, and the like. Among these groups, carboxyl, tetrazolyl, phosphoric acid residue and sulfonic acid residue may be protected with, for ex-ample, an optionally substituted lower alkyl group (e.g. lower (Cl 4) alkyl, etc.~ or an acyl group (e.g. lower (C2 5) alkanoyl, optionally substituted benzoyl, etc.)~ Such groups may include those which are capable of forming anions or convertible thereinto either chemically or physiologically, i.e. under physiological conditions (for example, ln vlvO reaction such as oxidation, ~2Q~i446~i reduction or hydrolysis catalyzed by in vivo enzymes).
The compounds wherein R2 or R3 is a group capable of forming an anion or convertible thereinto chemically (e.g. by oxidation, reduction or hydrolysis) (for example, an optionally protected tetrazolyl group) (e.g. a group having the formula:

\~-- NX/ R
N
- N
[wherein R stands for Cl 4 alkyl (e.g. methyl), triphenyl-methyl, 2-tetrahydropyranyl, C1 4 alkoxy-Cl 4 alkyl (e.g. methoxy-methyl and ethoxymethyl), ben~yl optionally substituted by for example Cl 4 alkoxy or nitro (e.g. p-methoxybenzyl, p-nitrobenzyl, etc.)], cyano and the like) are useful as synthetic intermediates.
Among the abo~e-mentioned groups for R2, preferred examples are tetrazolyl or carboxyl groups optionally protected with optionally substituted lower alkyl or acyl group, and tri-fluoromethanesulfonamido.
Preferable groups for R3 include carboxyl groups op-tionally esterified or amidated (e.g. groups having the formula:
-CO-D' [wherein D' is i) hydroxyl group, ii) optionally substituted amino (e.g~ amino, N-lower (Cl 4)alkylamino , N,N-dilower (Cl 4) alkylamino, etc.) or iii) optionally substituted alkoxy (e.g. a) lower (Cl 6) alkoxy group optionally whose alkyl moiety may be substituted with hydroxyl group, optionally sub-stituted amino (e.g. amino, dimethylamino, diethylamino, piperidino, ~s'~
- 7 - 242~5-907 morpholino, etc.), halogen, a lower (Cl_6) alkoxy, a lower (C1_6) alkylthio, or optionally substituted dioxolenyl (e.g. 5-methyl-2-oxo-1,3-dioxolen-4-yl, etc.), or b) a group having the formula:
-oCH(R7)oCoR8 [wherein R7 is (1) hydrogen, (2) Cl 6 straight or branched lower alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, etc.), or (3) C5 7 cycloalkyl (e.g. cyclopentyl, cyclohexyl, cycloheptyl, etc.) and R8 is (1) Cl 6 straight or branched lower alkyl (e.g.
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, etc.) r (2) C2_~ lower alkenyl (e.g. vinyl, propenyl, allyll isopropenyl, etc.), (3) C5 7 cycloalkyl ~e.g. cyclopentyl, cyclohexyl, cycloheptyl, etc.), 14) Cl_3 lower alkyl (e.g. benzyl, p-chlorobenzyl, phenethyl, cyclopentylmethyl, cyclohexylmethyl, etc.), substituted with C5 7 cycloalkyl (e.g. cyclopentyl, cyclohexyl, cycloheptyl, etc.) or aryl (e.g. phenyl, etc.), (5) C2 3 lower alkenyl (e.g. cinnamyl, etc. such as cycloalkyl~ or aryl-C2 3 alkenyl, etc. having alkenyl moiety such as vinyl, propenyl, allyl, isopropenyl, etc.), sub-stituted with C5 7 cycloalkyl (e.g. cyclopentyl, cyclohexyl, cycloheptyl, etc.) or aryl (e.g. phenyl, etc.), (6) C6 1O aryl such as optionally substituted phenyl (e.g. phenyl, p-tolyl, naphthyl, etc.), (7) Cl 6 straight or branched lower alkoxy (e.g.
methoxy, ethoxy, n~propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, etc., (8) C2 8 straight or branched lower alkenyloxy (e.g. allyloxy, isobutenyloxy, etc.), (9) C5 7 cycloalkyloxy (e.g. cyclopentyloxy, ~C~544~iS
- 7a - 24205-907 cyclohexyloxy, cyclohep-tyloxy, etc.), (10) Cl 3 lower alkoxy substituted with C5 7 cycloalkyl (e.g. cyclopentyl, cyclohexyl, cycloheptyl, etc.) or C6 10 aryl (e.g. optionally substituted phenyl, etc.) [where the substituted alkoxy includes cycloalkyl-or aryl-Cl 3 alkoxy having alkoxy moiety such as methoxy, ethoxy, n-propoxy, isopropoxy, etc. (e.g. benzyloxy, phenethyloxy, cyclo-pentylmethyloxy, cyclohexylmethyloxy, etc.)], (11) C2 3 lower alkenyloxy substituted ~ith C5 7 cycloalkyl (e.g. cyclopentyl, cyclohexyl, cycloheptyl, etc.) or C6 10 aryl (e-g- optionally substituted phenyl, etc.) ~said substituted alkenyloxy includes cycloalkyl- or aryl-C2 3 alkenyloxy having alkenyloxy moiety such as vinyloxy, propenyloxy, allyloxy, isopropenyloxy, etc. (e.g.
cinnamyloxy, etc.)], or (12) C6 10 aryloxy such as optionally substituted phenoxy (e.g. phenoxy, p-nitrophenoxy, naphthoxy, etc.) or optionally protected tetrazolyl (e.g. tetrazolyl option-ally protected with alkyl ~e.g. lower (Cl 4) alkyl, etc.) or acyl (e.g. lower (C2 5) alkanoyl, optionally substituted 2(~Sas46S

benzoyl, etc.)). Preferable examples of substituents for R3 include -COOH and salts thereof, -COOMe, -COOEt, -COOtBu, -COOPr, pivaloyloxymethoxycarbonyl, 1-(cyclohexyloxycarbonyloxy)ethoxycarbonyl, 5-methyl-2-oxo-1,3-dioxolen-4-ylmethoxycarbonyl, acetoxymethyloxycarbonyl, propionyloxymethoxycarbonyl, n-butyryloxymethoxycarbonyl, isobutyryloxymethoxycarbonyl, 1-(ethoxycarbonyloxy)ethoxycarbonyl, 1-(acetyloxy)ethoxycarbonyl, 1-(isobutyryloxy)ethoxycarbonyl, cyclohexylcarbonyloxymethoxycarbonyl, benzoyloxymethoxycarbonyl, cinnamyloxycarbonyl, cyclopentylcarbonyloxymethoxycarbonyl, etc. Such groups may include those which are capable of forming anions (e.g. COO~, derivatives thereof, etc.) or convertible thereinto either chemically or physiologically i.e. under physiological conditions (for example, in vivo reaction such as oxidation, -reduction or hydrolysis catalyzed by in vivo enzymes).
And, R3 may be carboxyl or a prodrug derivative thereof, or R3 may be groups convertible into anion physiologically or chemically _ vivo.
The thiophene ring A may optionally contain substitution in addition to the R3 group, and example of such substituents include halogen (e.g. F, Cl, Br, etc.); nitro; cyano; optionally substituted amino [e.g.
amino, N-lower (Cl4) alkylamino (e.g. methylamino, etc.), N,N-dilower (C14) alkylamino (e.g.
dimethylamino, etc.), N-arylamino (e.g. phenylamino, etc.), alicyclic amino (e.g. morpholino, piperidino, piperazino, N-phenylpiperazino, etc.), etc.]; groups having the foL~ula: -W-R6 [wherein W is a chemical bond, -O-, -S- or -C(=O)-, and R6 is hydrogen or an optionally substituted lower alkyl group (e.g. a lower (Cl4) alkoxy group optionally substituted with ~054~S

9 2420s-so7 hydroxyl, optionally substituted amino (e.g. amino, etc.), halogen, lower (Cl 4) alkyl, etc., etc.]; groups having the formula -(CH2)Q-CO-D [wherein D is i) hydrogen, ii) hydroxyl, iii) amino, iv) N-lower (C14) alkylamino, v) N,N-dilower (C14) alkylamino or vi) a lower (C~6) alkoxy group whose alkyl moiety is optionally substituted with a) hydroxyl, b) optionally substituted amino (e.g. amino, dimethylamino, diethylamino, piperidino, morpholino, etc.), c) halogen, d) groups having the formula: -oC(R7)HoCoR
[wherein R7 and R8 are of the same meaning as defined above], e) lower (Cl6) alkoxy, f) lower (Cl6) alkylthio, or g) a lower (~1-6) alkoxy group optionally substituted with optionally substituted dioxolenyl (e.g. 5-methyl-2-oxo-1,3-dioxolen-4-yl, etc.), and ~
denotes 0 or 1]; tetrazolyl optionally protected with alk~l (e.g. lower (C14) alkyl, etc.) or acyl (e.g.
lower (C25) alkanoyl, optionally substituted benzoyl, etc.); trifluoromethanesulfonamido; phosphoric acid residue; or sulfonic acid residue.
X shows that the adjacent phenylene group is bonded to the phenyl group directly or through a spacer with an atomic chain of 2 or less~ As the spacer, any one can be exemplified, so long as it is a divalent chain in which the number of atoms constituting the straight chain is 1 or 2, and it may have a side chain.
Examples of such spacers includs lowex (C14) alkylene, -C(O)-, -O-, -S-, -N(H)-, -C(=O)-N(H)-, -O-C(H2)~
C(H2)-, -C(H)=C(H)_, etc.
Among the compounds represented by the above formula (I), preferable embodiments of the present inventîon are a compound (I-1) or a compound (I-2) [more preferably the compound (I-l)] having the formula:

2q:~5~L6S

S~ ~ or R~
~ [1- 23 [wherein R1 is a lower (Cl6) alkyl group optionally bonded through a hetero atom; R3 is a group of -CO-D' [wherein D' is hydroxyl, amino, N-lower (Cl4~
alkylamino, N,N-dilower (Cl4) alkylamino or lower (Cl4) alkoxy optionally substituted with hydroxyl, amino, halogen, lower (C26) alkanoyloxy te.g. acetYlXYr pivaloyloxy, etc.), 1-lower (Cl6) alkoxycarbo~yloxy (e.g. methoxycarbonyloxyt ethoxycarbonyloxy, cyclohexyloxycarbonyloxy, etc.) or lower (Cl4) alkoxy on the alkyl moiety, or tetrazolyl optionally protected with a lower (Cl4) alkyl or acyl group (e.g. lower (C2 5) alkanoyl, benzoyl, etc.); R2 is tetrazolyl or carboxyl (preferably tetrazolyl) optionally protected with an optionally substituted lower (Cl4) alkyl (e.g.
methyl, triphenylmethyl, me-thoxymethyl, ethoxymethyl, p-methoxybenzyl, p-nitrobenzyl, etc.) or acyl group (e.g. lower (C2 5) alkanoyl, benzoyl, etc.); and R4 is hydrogen, halogen, lower ~Cl4) alkyl, lower (C
alkoxy, nitro, a group of -CO-D" [wherein D~ is hydroxyl or lower (Cl2) alkoxy] or amino optionally substituted with lower (Cl4) alkyl (preferably hydrogen, lower (Cl4) alkyl, halogen, more preferably hydrogen)].
Production Method The compounds of the above-mentioned general formula (I) can be prepared by several reaction schema, as illustrated below.
Reaction (a) ~0,S4465 B~ C~n- ~ X ~ ~ 2~n ~ ~ ~
~ m ~ ~ N ~ ~z ~ I~ or I ~
[wherein A, R1, R2, R3, X and n have the above-de~ined meanings and z is halogen]
Reaction (b) 1~ N~N
R$ ~l~s)~X~ ~ 2)n~

~CNN~' (~?~
Ia ~b ~wherein each symbol ha~ the above-defined meaning]
Reaction (c) 2 _~ Z

S~ - ~ S~ B~
Ic ~ Id [wherein Rll R2, X, Z and n have the above-defined meanings]
Reaction (d) ~ R

S~CN~ S~' R4 ~4 ~e I

2Q5a~5 [wher~in R1, R2, R4, X and n have the above-defined meanings and R6 is lower alkyl]
Reaction (e) ) n~X ~ 2) n~X~

~ N~
Ig Ih ~wherein R~, R3, A, X and n have thP above-defined meanings, and R9 is an optionally substituted lower hydrocarbon residue]
Reaction (f) R~ (C~n ~ X ~ B~ I n ~ N)~S-R9 ~ ~ S-~
I~ li ~3 ~I}12?n~x-~s ~ ~ ~ y_RI
I~

[wherein R2, R3, R9, A, X, Y and n have the abo~e-defined meanings, and R10 is an optionally substituted lower hydrocarbon residue]

Reaction (g) 2~5~L~L65 _ 13 --~N~N~ N~l a~ ~CI~2}l,~x~ ~ooc ~C~2~n~X~) ~1~R~
Ik II

~ ~
X~ a~n~ ~c ~ n~X~) <~N'~
n [wherein ~1, R, A, X and n have the above-defined meanings, and Rll is the group shown by the above-mentioned formula- -C(R )~OCOR ]
Reaction (h) ~N
C~{ ~IEI
R~ 2) n~ C~{~)n~X~) (~CN~ --~N~
I~) Ib [wherein R1, R3, A, X and n have the above-defined meanings]
The above-illustrated reaction (a) is an alkylation using an alkyla~ing agent in the presence of a base.
The alkylation is conducted, employing approximately l to 3 moles each of khe base and the alkylating agent relative to one mole of the compound z1~i44~;5 ~ 24205-907 (II), u~ually in a solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, acetone, ethylmethylketone, etc.
Examples of the base include sodium hydride, potassium ~-butoxide, potassium carbonate and sodium carbonate.
As the alkylating agent, use is macle of, for example, substituted halides (e.g. chlorides, bromides, iodides and the like), substituted sulfonate esters (e.g. methyl p-toluenesulfonate or the like), etc.
While the reaction conditions may ~ary depending on the combination of the base and the alkylating agent, it is preferable to conduct the reaction usually at 0C to room temperature for 1 to 10 hours.
In the said alkylation, a mixture of two isomers, (I) and ~I') is usually obtained depending on the position o~ the N atom to be alkylated. While the production ratio of Compound (I) and Compound (I') varies with the reaction conditions then employed and the substituents on the thiophene ring, these two compounds can be obtained easily as pure products respectively by conventional isolation and purification methods (e.g. recrystallization, column chromatography and the like).
The reaction (b) is to obtain the compound (Ib) by subjecting the appropriately protected tetrazole derivative (Ia) to deprotection.
In this reaction, the deprotec~ion conditions vary with the protecting group (R) employed. When R is triphenyl methyl, 2-tetrahydropyranyl, methoxymethyl or ethoxymethyl, the reaction is conveniently conducted in an aqueous alcohol le.g. methanol, ethanol, etc.) containing about 0.5 N to about 2N hydrochloric acid or acetic acid at room temperature for 1-10 hours.
The reaction (c) is to obtain the halide (Id) by 23!~5~6~

allowing a halogenating agent to react. This reaction is conducted, using about 1-5 moles of the halogenating agent, usually in a solvent. As the halogenating agent, use is made of, for example, a chlorinating agent (e.g. chlorine, N~chlorosuccinimide, etc.), a brominating agent (e.g. bromine, N-bromosuccinimide, N-bromoacetamide, etc.), a fluorinating agent (e.g.
fluorine, etc.), etc. As the solvent, use is made of halogenated hydrocarbons (e.g. chloroform, dichloromethane, dichloroethane, carbon tetrachloride, etc.), ethers (e.g. diethyletherr dioxane, tetrahydrofuran(THF), etc.), acetic acid, trifluoroacetic acid, etc.
While the reaction conditions may vary depending on the combination of the halo~enating agent and the solvent employed, it is preferable to conduct the reaction usually at 0C to room temperature for about 1 - 10 hours.
The reaction (d) is to obtain carboxylic acid (~f) by subjecting the ester (Ie) to hydrolysis. The hydrolysis is conducted, using about 1 to 3 moles of alkali relative to 1 mole of the compound (Ie), usually in a solvent such as an a~ueous alcohol (e.g. methanol, ethanol, methyl cellosolve, etc.). As the alkali, use is made of, for e~ample/ sodium hydroxide, potassium hydroxide, etc.
The reaction is conducted at room temperature to 100C for 1 - 40 hours, preferably around the boiling point of the solvent for about 5 - 40 hours.
The reaction (e) is to obtain the alkylthio compound (Ih) by subjecting the 2-mercapto compound (Ig) to alkylation in an organic solvent in the presence of a base.
The reaction is conducted, using 1 to about 3 moles of a base and 1 to about 3 moles of an alkylating agent realtive to 1 mole of the compvund (Ig), usually in a solvent such as dimethylformamide, dimethylacetamide r dimethylsulfoxide, acetonitrile, acetone, ethylmethyl ketone, ethanol, methanol, water, etc.
As the base, use is made of caustic soda, potassium carbonate, sodium carbonate, sodium hydride, potassium t-butoxide, potassium hydroxide, etc.
As the alkylating agent, use is made of halogenides (e.g. methyl iodide, ethyl iodide, propyl iodide, butyl iodide or bromides or chlorides thereof).
While the reaction conditions may vary depending on the base, the alkylating agent and the solvent then employed, the reaction is conducted usually at 0C to the boiling point of the solvent for 1 - 5 hours.
The reaction (f) is to obtain the compound (Ij) by leading the compound (Ih) to the sulfoxide (Ii) with a suitable oxidizing agent (e.g. m-chlorobenzoic acid, etc.), followed by the reaction with various nucleophilic reagents (e.g. alcohols, amines, mercaptans, etc.).
The reaction for obtaining the sulfoxide and sulfone compound tIi) by oxidation of the compound (Ih) is conducted usually in solvent ~uch as halogenated hydrocarbons (e.g. dichloromethane, chloroform, dichloroethane, etc.) or ethers ~e.g. tetrahydrofuran, dioxane, etc.). As the oxidizing agent, mention is made of an organic peracid e.g. m-chloroperbenzoic acid, etc., N-halocarboxylic amides e.g. N-bromosuccinic imide, etc., among others. Such oxidizing agents are preferably employed in a little excess amount to the e~uivalent relative to 1 mole of the compound (Ih). More specifically, use of l mole of the oxidizing agent gives a sulfoxide compound, while use of about 2 moles of the oxidizing agent afiords a sulfone compound. The reaction is preferably conducted usually at 0C to room temperatures ~or 3 - 10 hours.

6~;i Further, the reaction (f) is to obtain the compound tIj) by allowing the sulfoxide or sulfone compound (Ii) prepared as above to react with various nucleophilic reagents.
The reaction conditions may vary depending on ~the nucleophilic reagent employed. In the reaction with alcohols, alkoxides (e.g. sodium methoxide, sodium ethoxide, sodium propoxide, etc.) derived from the alcohol and sodium metal are preferably used. As the reaction solvent, alcohols used for nucleophilic reagents are used, and an alkoxide of about 2 to 5 times as much amount relative to 1 mole of the compound (Ii) is allowed to react usually for about 1 to 3 hours at approximately the boiling point of the solvent.
In the reaction with amines, about 3 to 10 moles of an amine is used relative to 1 mole of the compound (Ii). As the solvent, alcohols (e.~. ethanol, etc.) are usually employed, but a large excess volume of amines can be used as well. The reaction is preferably conducted at the boiling point of the solvent to 150C
for l - 10 hours.
The reaction (g) is to obtain the compound (In) by protecting the tetrazole group in the presence of a base, then protecting the carboxyl group to give the ester compound (Im), followed by removing the protective group under acid conditions.
In the reaction to obtain the compound (Il) from the compound (Ik), an alkylating agent is used in an amount of about 1 to 1.5 mole relative to 1 mole of the compound (Ik). Examples of the solvents to be used for the reaction include halogenated hydrocarbons such as chloroform, methylene chloride, ethylene chloride, etc., ethers such as dioxane, tetrahydrofuran, etc., acetonitxile, pyridine, etc.
Examples of such bases include potassium carbonate, sodium carbonate, triethylamine, pyridine, 8 ~2Q~6S

etc.
Examples of such alkylating agents include halides such as triphenylmethyl chloride, methoxy methyl chloride, etc.
While reaction conditions vary with combinations of the base and the alkylating agent employed, ît is preferable to conduct the reaction b~ using t.riphenylmethyl chloride at 0C to room temperature for 1 - 3 hours in methylene chloride in the presence of triethylamine.
In the reaction for producing the compound (Im) from the compound (Il) thus obtained, an alkylating agent is used in an amount of about 1 ~o 3 moles relative to 1 mole of the compound (Il).
~xamples of the solvents to be used or the reaction include amides such as dimethylformamide, dimethylacetamide, etc., acetonitrile, dimethylsulfoxide, acetone, ethyl methyl ketone, etc.
Examples of the base include potassium carbonate, sodium carbonate, sodium hydroxide, potassium t butoxide, etc.
Examples of the alkylating agent include halides such as cyclohexyl 1-iodoethyl carbonate, ethyl 1-iodoethyl carbonate, pivaloyloxymethyl iodide, etc.
While reaction conditions vary with combinations of the base and the alkylating agent then employed, it is preferable to subject the compound (Il) to reaction in DMF, by adding the alkylating agent in the presence of potassium carbonate, at room temperatures for 30 minutes to one hour.
The reaction for deprotecting the compound (Im) thus obtained is conducted preferably in a manner similar to the reaction (h).

When trityl group is used as the protecting group of tetrazole group, it is preferable to conduct the 19 - ~S~4~5 reaction in methanol or ethanol, while adding lN-HCl, at about room temperatures for about 30 minutes to one hour.
The reaction (h) is to convert the nitrile compound (Io) into the tetrazole compound (Ib) by allowing the former to react with various azides in an organic solvent.
This reaction is conducted, using about 1 to 5 moles of an azide compound relative to 1 mole of the compound (Io), usually in a solvent such as dimethylformamide, dimethylacetamide, toluene, benzene, etc.
Examples of such azides include trialkyltin azide (e.g. trimethyltin azide, tributyltin azide, triphenyltin azide, etc.) and hydrazoic acid or its ammonium salt.
When an organotin azide compound is employed, the reaction is allowed to proceed, by using 1 to 4 times as much moles of the azide compound relative to the compound (Io), for about 1 to 4 days under reflu~ in toluene or ben~ene. And r when hydrazoic acid or its ammonium salt is subjected to the reaction, it is preferable to allow the reaction to proceed, by using about 1 to 5 times as much moles of sodium azide and ammonium chloride or tertiary amine (e.g.
triethylamine, tributylamine, etc.) relative to the compound (Io), in dimethylfo~mamide (DMF) at lOn -120C for 1 - 4 days. In this case, improvement may sometimes be observed in reaction time and yield by the addition of the azide compound in suitable fractions.
The reaction products obtained as above by the reactions (a) to (h) can be easily isolated by conventional isolation and purification methods, for example, column chromatography, recrystallization and the like.
Incidentally, these compounds (I) can be led, by - 20 - ~ ~54465 conventional m thods, to salts with physiologically acceptable acids or bases. These salts include, for example, salts with an inorganic acid such as hydrochloric acid, sulfuric acidr nitric acid or the like and, depending on the compounds, salts with an organic acid such as acetic acid, nitric acicl, succinic acid, maleic acid or the like r salts with an alkali metal such as sodium, potassium or the like, and salts with an alkaline earth metal such as calcium or the like.
Among these compounds, the starting compound (II) can be synthesized by the methods described inr for example r the following literature references or methods analogous thereto.
(1) B. ~einz and R. Hellmuth, Monatsh, Chem., 107r 299(1976), (2) ~. Tominaga, H. Fujitor Y. Matsuda and G.
Kobayashi, Heterocycles, 6, 1871(1977~, (3) T. Tominaga, H, Fujito, Y. Matsuda and G.
Kobayashi r Heterocycles r 12 r 401 ( 1979 ) r (4) B. R. Fishwick r D . K . Rowles and C. J. M.
Stirlingr J. Chem. Soc. r Chem. Commun. r 1983r 834r (5) Ph. Ros~y, F. G. M. Vogelr W. Hoffmann, J. Paust and A. Neurrenbach, Tetrahedron Lett., 22, 3493( 1981~ r (6) F. Outurquin and P. Claude, Bull. Soc. Chim. Fr., 1983, 153 r (7) C. Galvez r F. Garcia and J. Garcia, J. Chem.
Research, 19 85 ~ 296 And, among the starting compounds (III), the compound (III) wherein n denotes 1, i.e. the compound (IIIa), is commercially available, or can be readily obtained also by subjecting a compound (IV) to halogenometh~lation according to the methods described in literature references, for example;
1) J. R. E. Hoover, A. W. Chow, R. J. Stedman, N. M.

- 21 - ~ ~5~5 Hall, H. S. Greenberg, M. M. Dolan and R. J.
Feriauto, J. Med. Chem., 7, 245 (1964), 2) R. J. Stedman, J. R. E. Hoover, A. W. Chow, M. M.
Dolan, N. M. Hall and R. J. Feriauto, J. Med. Chem., 7, 251 (1964), 3) H. Gilman and R. D. Gorsich, J. Am. Chem. Soc., 78, 2217 (1956), 4) M. Orchin and E. Oscar Woolfolk, 67, 122 (1945) Reaction (i) ~ R2 ~ - ~ '~ ZC~X~

rv ma [wherein each symbol is of the same meaning as defined above]
Further, among the starting compounds (III), the compound (III) wherein n denotes 2, i.e. the compound (IIIb) can be obtained by subjecting the compound (IIIa) to the reaction in accordance with the reaction (i) Reaction (j) 22 - 2~5~65 ~2 R2 ~C~X~ ~ ~X~
ma ~

~2 B2 EtOOC-C~ ~ X ~ ~ H0~2C~ ~ X-~I
~2 C~ 2~X~) mb [wherein each symbol has the same meaning as above]
The compounds ~I~ and the salts thereof thus produced are less toxic, strongly inhibit the vasoconstrictive and hypertensive actions of angiotensin II, exert a hypotensive effect in animals, in particular mammals (e.g. human, dog, rabbit, ratl etc.), and therefore they are useful as therapeutics for not only hypertension but also circulatory diseases such as heart failure (hypertrophy of the heart, cardiac insufficiency, cardiac infarction or the like), cerebral apoplexy, nephritis with proteinuria, axteriosclerosis, etc.
For such therapeutic use as above, the compounds (I) and salts thereof can be orally or non-orally administered as pharmaceutical compositions or formulations, e.g. powders, granules, tablets, capsules, injections and the like, comprising at least one such compound alone or in admixture with pharmaceutically acceptable carriers, excipients or diluents.
The dose varies wi.th the diseases -to be treated, symptoms, subjects and adminis~ration routes, and it is ~s~s pr0ferable that a daily dose of 1 to 50 mg for oral administration or 1 to 30 mg for intravenous injection is divided into 2 to 3 administrations when used as an agent for the therapy of essential hypertension of adult human.
LWorking Examples]
By the following formulation examples, reference examples, working examples and experimen~al examples, the present invention will be explained more concretely, but they should not be interpreted as limiting the invention in any manner.
Formulation Examples When the compound (I) of the present invention is used as a therapeutic agent for circulatory disturbances such as hypertensionr heart diseases, cerebral apoplexy, nephritis with protelnuria, arterioscelosis, etc., it can be used in accordance with, for example, the following formulations.
1. Capsules (l) 2-ethylthio-4-methyl-1-[[2'-(lH-tetrazol-5-yl)-biphenyl-4-yl]methyl]thieno[3,4-d]imidazole-6-carboxylic acid 10 mg (2) lactose 90 mg (3) fine crystalline cellulose 70 mg (4) magnesium stearate 10 mg one capsule 180 mg (1), (2), (3) and a half of (4) are mixed and granulated. To the granules is added the remainder of (4), and the whole is illed into gelatin capsules.
2. Tablets (1) 2-ethylthio-4-methyl-1-[[2'-(lH-tetrazol-5-yl)-biphenyl-4-yl]methyl]thieno~3,4-d]imidazole-6-carboxylic acid 10 mg (2) lactose 35 mg (3) corn starch 150 mg (4) fine crystalline cellulose 30 mg ;~5~65 - 2~ - 24205-907 (5) magnesium stearate 5 mg one tablet 230 mg (1), (2), (3), two thirds of (4) and a half of (5) are mixed and granulated. To the granules are added the remainders of (4) and (5), followed by subjecting the mixture to compression molding.
3. Injections (l) 2-ethylthio-4-methyl-1-[[2'-(lH--tetrazol-5-yl)-biphenyl-4-yl]methyl]thieno[3,4-d]imidazole-6-carboxylic acid sodium salt lO mg (2) inositol 100 mg (3) benzyl alcohol 20 mg one ampoule 130 mg (1), (2~ and (3) are dissolved in distilled water for injection to make the whole volume 2 ml, which is filled into an ampoule. The whole process is conducted under sterile conditions.
4. Capsules (1) 2-Methoxy-4-methyl-1-[[2'-(lH-tetrazol-5-yl)-biphenyl-4-yl]methyl]thieno[3,4-d]imidazole-6-carboxylic acid 10 mg (2) lactose 90 mg (3) fine crystalline cellulos~ 70 mg (4) magnesium stearate lO mg one capsule 180 mg (l), (2), (3) and a half of (4) are mixed and granulated. To the granules is added the remainder of (4), and the whole is filled into gelatin capsules.
5. Tablets (1) 2-Methoxy-4-methyl-1-[[2'-(lH tetrazol-5-yl)-biphenyl-4-yl]methyl]thieno[3,4-d]imidazole-6-carboxylic acid 10 mg (2) lactose 35 mg (3) corn starch 150 mg (4) fine crystalline cellulose 30 mg (5) magnesium stearate 5 mg 2~5~qlL65 one tablet 230 mg (1), (2), ~3), two thirds of (4) and a half of (5) are mixed and granulated. To the granules are added the remainders of (4) and (5), followed by subjecting the mixture to compression molding.
6. Injecti.ons (1) 2-Methoxy-4-methyl-1-[[2'-(lH-tetrazol-5-yl)-biphenyl-4-yl]methyl]thieno[3,4-d]imidazole-6-carboxylic acid sodium salt 10 mg (2) inositol 100 mg (3) benzyl alcohol 20 mg one ampoule 130 mg (1), (2) and (3) are dissolved in distilled water for injection to make the whole ~olume 2 ml, which is filled into an ampoule. The whole process is conducted under sterile conditions.
7. Capsules (1) Acetoxymethyl 2-Methoxy-4-methyl-1-~[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl~thieno[3,4-d]imidazole-6-carboxylate10 mg (2) lactose 90 mg (3) fine crystalline cellulose 70 mg (4) magnesium stearate 10 mg one capsule 180 mg 25 (1), (2)/ (3) and a half of (4) are mixed and granulated. To the granules is added the remainder of (~), and the whole is filled into gelatin capsules.

8. Tablets (1) Acetoxymethyl 2-Methoxy-4-methyl-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl]thieno[3,4-d]imidazole-6-carboxylate10 mg (2) lactose 35 mg ~3) corn starch 150 mg (4) fine crystalline cellulose 30 mg (5) magnesium stearate 5 mg one tablet 230 mg 21C54~5 (1), (2), (3) and two thirds of (4) and a half of (5) are mixed and granulated. To the granules is added the remainder of (4) and ~5), followed by sub~ecting the mixture to compression molding.
Reference Example 1 2-Butylthieno r 3,4-dlimidazole A mixture of 3,4-diaminothiophene (1.7 g) and ethyl valeroimidate hydrochloride (3.0 g) in ethanol (30 ml) was stirred at room temperatures for 1.5 hour.
The reaction mixture was concentrated and the residue was dissolved in a mixture of ethyl acetate and a saturated a~ueous solution of sodium hydrogencarbonate.
The organic layer was washed with water, dried and concentrated to dryness. The concentrate was purified by silica gel column chromatography t~ give crystals.
Recrystallization from isopropyl ether afforded colorless crystals (0.72 g, 27%), m.p. 118-120C.
H-NMR(200MHz, CDC13)~: 0.95(3H,t), 1.35-1-54(2H,m)l 1.73-1.88(2H,m), 2.79(2H,t), 6~75(2H,br s), 8.50(1H,br s).
IR(KBr)cm 1:3200~2200, 1530, 1480, 1440, 1390, 1240, 1230, 1160, 830, 815, 760, 740.
Reference Example 2 Methvl 2,3-dihydro-4-methyl-2-oxothieno r 3,4-dlimidazol-6-carboxylate A mixture of methyl 3,4-diamino-2~me~hylthiophene-5-carboxylate (1.9 g) and N,N~-dicarbonyl diimidazole (1.8 g) in DMF (10 ml) was stirred at 50C for one hour. To the reaction mixture was added water to give crystals. Recrystallization from methanol gave colorless needles (2.0 g, 95%), m.p. 341-343C(dec.).
H-NMR(200MHz,DMSO-d6)~: 2.33(3H,s), 3.74(3H,s), 10.71(1H,s), 11.06(1H,s).
IR(KBr)cm :3320, 3150, 1735, 1680, 1590, 1445, 1360, 3~ 1285, 1200, 1100, 975, 810, 755, 745.
Elemental Analysis for C8H8N2O3S:

2~ 6S

C(%) H(%~ N(%) Calcd.: 45.28; 3.80; 13.20 Found : 45.44 3.72; 13.23 Reference Example 3 Methyl 2,3-dihvdro-4-methYl-2-thioxothienor3,4-d~
imidazole-6-carboxylate A mixture of methyl 3,4-diamino-2-methylthiophene-5-carboxylate (1.0 g) and N,N~-thiocarbonyldiimidazole (l.l g) in DMF (5 ml) was stirred at 50C for one hour.
To the reaction mixture was added ~ater to gi~e crystals. Recrystallization from DMF-water afforded colorless prisms (1.2 g, quantitatively), m.p. 285-288C (dec.) lH-NMR(200MHz,DMSO--d6)~: 2.41(3H,s)/ 3.76(3H,s), 12.5(1H,br s).
IR(KBr)cm 1:1700, 1570, 1485, 1440, 1425, 1415, 1330, 1200, 1180, 1100, 750.
Reference Example 4 Methvl 2-ethYlthio-4-methYlthieno~3,4-dlimidazole-6-carboxylate ~ mixture of methyl 2,3-dihydro-4 methyl--2-thioxothieno[3,4-d]imidazole 6-carboxylate (1.1 g), ethyl iodide (0.75 g), 2N NaOH (2.4 ml) and methanol (30 ml) was stirred at room temperature for 3 hours.
The reaction mixture was concentrated, to which was added water to give crystals. Recrystallization from ethyl acetate hexane afforded colorless prisms (1.0 g, 83~), m.p. 159-160C.
H-NMR(200MHz,CDCl3)&: 1.44(3H,t), 2.62(3H,s), 3.30(2H,q), 3.87(3H,s), 9.55(1H,br s).
IR(K~r)cm 1:1690, 1675, 1665, 1650, 1620, 1545, 1465, 1440, 133~, 1320, 1240, 1120, 1105.
Reference Example 5 Methyl 4-methYlthieno r 3,4-dlimidazole-6-carboxylate A mi~ture of methyl 3,4-diamino-2-methylthiophene-5-carboxylate (1.9 g) in formic acid (5 ml) was heated _ 28 - 2~5~65 under reflux for 4 hoursO The reaction mixture was concentrated, to which was added water, then insolubles were filtered off. The filtrate was neutralized with an aqueous solution of sodium hydrogencarbonate to give crystals. Recrystallization from methanol afforded pale brown prisms (0.2 g, 38%~, m.p. 266-267C(dec.).
Elemental Analysis for C8H8N2O2S:
C(%) H(%) N(%) Calcd.: 48.97; 4.11; 14.28 Calcd.: 49.05; 3.95; 14.12 H-NMR(9OMHz,DMSO-d6)~: 2.60(3H,s), 3.79(3H,s), 8.20(1H,s) IR(KBr)cm 1 1690, 1525, 1505, 1465, 1440, 1370, 1315, 1300, 1265, 1200, 1160, 1100, 945, 875, 760.
In substantially the same manner as Reference Example 4, the following compounds were synthesized.

- 29 _ 2C~

R~S~
N~
El COOlle = _ .
Ref . ~Yield m . p . lH NMR IR
Ex .( % ) ( C ) (20 OMHz, (KBr ) cm~
l _ 6 Me 56 178-179 2.62 (3H, s ), 3275, 2.73(3H,s) ~ 1670, 3.87 (3H, s ) 1620, 460, l3220 _ _ ~_ 7 Pr 89 110-111 l .06 (3H,t ), 3300, 1.72- 1680, 1.90 t 2H,m), 1670, 2.62(3HrS) ~ 1650, 3.28 (2H,t ), 1620, 3.87(3Hts) ~ 1540, 9.20 ( lH,brs ) 1444O, 2155, 8 iPr 72 135-136 1.46 (6H,d), 1690, 2.63 (3H, s ) ~ 1620, 3.88 (3H, s ) ~ 1540, 3.91- 1460, 4.12 ( lH,m), 1360, 9.23 ( lH,hrs ) 1210, 1100, - - ?50 2~ 5 All 72 142-144 2.63(3H,s), 3200, (Allyl) 3.87(3H,s), 1660 3.92(2H,td), 1650, 5.21(lH,qd)~ 1620, 5.37(lH,qd), 1540, 5.93- 1460, 6.13(1H,m), 1440, 9.23(1H,brs) 1320, 1220, 713000, l _ _ I
Bu 88 114-115 0.95(3H,t), 3275, 1.38- 3225, 1.57(2H,m), 1670, 1.69- 1650, 1.83(2H,m), 1460, 2.62(3H/S), 1440, 3.30(2H,t~, 1315, 3.87(3Hrs)~ 1300, 9.16(lH,b~s) 1220, 1100, _ _ 730 11 Hex 88 110-111 0.89(3H,t), 3275, 1.27- 1665, 1.49(6Hrm)~ 1610, 1.69- 154~, 1.85(2H,m), 1460, 2.62(3H,S)~ 1450, 3.29(2H~t), 1435, 3.87(3H,s), 1300, 9.17(lH,brs~ 121100, I
12 cyclo- 52 142-143 1.26- 1710, Hex 1.80(8H,m), 1700, 2.09- 1620, 2.18(2H,m), 1460, 2.63(3H,S)I 1430, 3.77- 1370, 3.87(lH,m), 1310, 3.87(3H,s), 1210, 9.09(lH,brs) 1190, _ _ _ Reference Example 13 2-Butyl-l-r r 2~-(lH-tetrazol-5-yl!biphenyl-4-yllmethY
thieno r 3,4-dlimidazole To a solution of 2-butylthieno[3,4-d~imidazole (0.54 g) in DMF (3 ml) was added sodium hydride (60 - 31 - ~ ~5-~65 oil, 0.13 g). The mixture was stirred for 15 minutes under ice-cooling, to which was added 4-[2-(N-trityltetrazole5-yl)phenyl]benzyl bromide, followed by stirring for 2 hours at room temperature. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The or~anic layer was washed with water, dried and concentrated to dryness.
The concentrate was purified by silica gel column chromatography. The trityl compound thus obtained was dissol~ed in a mixture of methanol (18 ml) and chloroform (6 ml). To the solution was added lN
hydrochloric acid (7.5 ml), and the mixture was stirred for one hour at room temperature. The reaction mixture was concentrated to dryness and the residue was suspended with H2O. The mixture was ad~usted to pH 3-4 and extracted with chloroform. The organic layer was washed with water, dried and concentrated to dryness.
The concentrate was purified by silica gel column chromatography to give crystals. Xecrystallization from ethyl acetate - methanol afforded colorless crystals (0.53 g, 41%), m.p. 209-211C.
lH-NMR(200MHz,DMSO-d6)~: 0.88(3H,t), 1.27-1.46(2H,m), 1.59-1.74(2H,m), 5.22(2H,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, 1400, 815, 770, 760, 725.
Elemental Analysis for C23H22N6SØ2H2O:
C(%) H(%) N(%) Calcd.: 66.07; 5.40; 20.10 Found : 66.10; 5.25; 20.29 Reference Example 14 M_ hyl 2-ethylthiothieno r 3,4-dlimidazole-6--carboxylate 14a) Methyl 3.4-diaminothiophene-2-carboxy~ate The title compound was obtained as colorless _ 32 - 2~5~

crystals according to the methods described in F. G. M.
Vogel, J. Paust & A. Neurrenbach, Liebigs Ann. Chem., 1972(1980) and A. Fliri & K. Hohenlohe-Oehringen, Chem.
Ber., 113, 607(1980).
M.p. 95-97C
H-NMRl2MHZ,CDC13)~: 3.83(3H~s), 6.~0(1H,s).
14b) Methyl 2-mercaptothieno r 3,4-dlimidazole-4-carboxvlate The title compound was obtained as pale yellow crystals from methyl 3,4-diaminothiophene-2-carboxylate obtained in Reference Example 14a) by the same procedures for Reference Example 3, m.p. 250-255C
(decomp.).
H-NMR(200~Hz, DMSO-d6)~: 3.79~3H,s), 7.13(1H,s).
14c) Methyl 2-ethylthiothienor3,4 dlimidazole-6-carboxYlate The title compound was obtained as colorless prisms from methyl 2-mercaptothieno[3,4-d]imidazole-4-carboxylate obtained in Reference Example 14b) by the same procedure for Reference Example 4r m.p. 164-165C.
H-NMR(200MHz, CDC13)~: 1.48(3H,t), 3.32(2H,q), 3.91(3H,s), 7.18(1H,s), 9.21(1H,br s).
Working Example 1 Methyl 2-ethylthio-4-methyl-1- r r 2'-(lH-tetrazol-5-yl ! -biPhenyl-~-yllmethyllthienot3,4-dlimidazole-6-carboxylate To a solution of methyl 2-ethylthio-4-methylthieno[3l4-d]imidazole-6-carboxylate (0.77 g) in DMF ()3 ml) was added sodium hydride (60% oil, 0.13 g) under ice-cooling, and the mixture was stirred for 15 minutes, to which was added 4-[2'-(N-trityltetrazol-5-yl)phenyl}benzyl bromide (1.8 g), followed by stirring for 2 hours at room temperature. To the reaction mixture was added water and the mixtu.re was extracted with ethyl acetate. The organic layer was washed with water, dried and then concentrated to dryness. The _ 33 2(:~5~

concentrate was purified by silica gel column chromatography to give the first fraction (1-substituted compound) and the second fraction (3-substituted compound). ~he yellow syrup (trityl compound) obtained frorn the first fraction was dissolved in a mixture of chloroform (10 ml) and methanol (35 ml). To the solution was added lN-HCl (1.7 ml), and the mixture was stirred for one hour at room temperature. The reaction mixture was concentrated to dryness and to the mixture was added water. The mixture was adjusted to pH 3-4 with lN
NaOH, followed by extraction with chloroform. The extract was washed with water r dried and concentrated.
The concentrate was purified by silica gel column chromatography. Crude crystals thus obtained were recrystallized from ethyl acetate - methanol to afford colorless needles (0.69 g, 4~), m.p. 216-218C (dec.).
Elemental Analysis for C24H22N6O2S2:
C(%) H(%) N~) Calcd.: 58.76; 4.52; 17.13 Found : 58.48; 4.41; 16.89 Reference Example 15 Methyl 2-ethylthi--4-methyl-3- r r 2'-~lH-tetrazol-5-yl)-biphenyl-4-yl]methyllthieno~3,4-d~imidazole-6=
carbo3y1ate The crystals obtained from the second fraction described in Working Example 1 were dissolved in chloroform (5 ml). To the solution was added lN HCl (1.0 ml), and the mixture was stirred for one hour at room temperature. The reaction mixture was adjusted to pH 3-4 with lN NaOH and concentrated to dryness. To the concentrate was added water and the mixture was extracted with chloroform. The extract was washed with water and dried (Na2SO4) and concentrated to dryness.
The concentrate was purified by silica gel column chromatography to give crystals. Recrystallization - 34 - ~C5~6s from chloroform - isopropyl ether afforded pale yellow crystals (0.1 g, 7%), m.p. 192-196C (dec.) Elemental Analysis for C24H22N602S2.
~(%) ~(~) N(%~
Calcd.: 58.76; 4.52; 17.13 Found : 59.16; 4.65; 17.31 1H-NMR(200MHz,CDCl3)~: 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(lH,m), 7.44-7.59(2H,m), 7.90--7.94(1H,m).
IR(KBr)cm 1 1690, 1530, 1440, 1410, 1360, 1310, 1280, 1270, 1190, 1110, 760.
~orking Example 2 2-Ethylthio-4-methyl~ r 2~-(lH-tetrazo1-5-yl!bLphenYl-4-yllmethYllthienor3,4-dlimidazole-6-carboxylic acid Methyl 2-ethylthio-4-methyl-1-[[2'~(lH-tetrazol-5-yl)biphenyl-4-yl]methyl]thieno[3/4~d]imidazole-6-carboxylate (0.25 g) was dissolved in a mixture of methanol (8 ml) and lN NaOH (1.5 ml). The solution was heated for 12 hours under reflux. The reaction solution was adjusted to pH 3-4 with hydrochloric acid.
Water was added to the reaction mixture, then precipi~ating crystals were recrystallized from methanol ~ ethyl acetate to afford colorless needles (0.16 g, 57%), m.p. 194-195C (dec.).
Elemental Analysis for C23H20N602S2:
C(%) H(%) N(%) Calcd.: 57.97; 4.23; 17.63 Found : 57.68; 4.36; 17.49 lH-NMR(200MXz,DMSO-d6)~: 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, 1220, 1190, 1165, 1085, 775, 750 ~ 35 - ~ ~5~6S

Reference Example 16 2-Eth~lthio-~-methyl-~I r 2'-(1~-tetrazol_5-yl)biphenyl-4-yllmethyllthieno r 3,4-dlimidazole~6-carboxylic acid In substantially the same procedure as Working Example 2, the title compound was obtained as pale brown crystals (0.06 g) from methyl ~-ethylthio-4-methyl-3~[[2'-(lH-tetrazol-5-yl)biphenyl-~yl]methyl]thieno[3,4-d]imidazole-6-carboxylate (0.1 g), m.p. 192-195C (dec.).
Elemental Analysis for C23H20N6O2S2.H2O:
C(%) H(~) N(%) Calcd.. 57.32; 4.31; 17.44 Found : 57.51; 4.37; 17.12 lH-NMR(200MHz,DMSO-d6)~: 1.39(3H,t), 2.28(3H,s), 3.35(2H,q), 5.28(2H,s), 7.08(4H,s), 7.53-7.74(4H,m).
IR(KBr)cm 1 1610, 1600, 1530, 1435, 1410, 1400, 1360, 1350, 1280, 1110, 750 Working Example 3 Methyl_4-methyl~ r 2~-(lH-tetrazol-5 yl)biphenYl~4-yllmethyllthieno~3,4-dlimidazole-6-carboxylate To a solution of methyl 4-methylthieno[3,4-d]-imidazole-6-carboxylate (0.20 g) in DMF (2 ml) was added sodium hydride (60% oil, 48 mg) under ice-cooling. The mixture was stirred for 15 minutes, to which was added 4-[2~-(N-trityltetrazol-5-yl)phenyl]benzylbromide (0.68 g), followed by stirring for one hour at room temperature. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated to dryness. The concentrate was purified by silica gel column chromatography to give the first fraction and the second fraction. The oily substance obtained from the first fraction was dissolved in chloroform (3 ml) - methanol (12 ml), to which was added lN-HCl (0.5 ml), and the mixture was stirred for one hour at room temperature. The solvent - 36 - ~ ~5~6S

was evaporated in vacuo. To the residue was added water, whose p~I was adjusted to 3-4 with lN NaOH, followed by extraction with chloroform. The extract was washed with water, dried and concentrated to dryness. The concentrate was purified by silica gel column chromatography. The crystals thus obtained were recrystallized from ethyl acetate -hexane to afford colorless needles (0.12 g, 28%), m.p. 188-189C.
Elemental A~lalysis for C2~H18N6O2SØ2H2O:
C(%) H(%) N(%) Calcd.: 60.87; 4.27; 19.36 Found : 60.83; 4.17; 19.24 H-NMR(200MHz,DMSO-d6)~: 2.59(3H,s), 3.71(3H,s), 5.65(2H,s), 7.06(2H,d), 7.14(2H,d), 7.4~-7.71(4H,m), 8.40(1H,S).
IR(KBr)cm 1:1680, 1600, 1530, 1425, 1330, 1275, 1225, 1140~ 1080, 88~, 750.
Reference Example 17 Methyl 6-methyl-1- r r 2'-(lH-tetrazol-5-Yl)biphenYl-4-~llmethyllthieno[3~4-d]imidazole-4-carboxylate The crystals obtained from the second iraction described in Working Example 3 were dissolved in chloroform (3 ml) - methanol (12 ml). To the solut.ion was added lN HCl (0.5 ml), and the mixture was stirred for one hour at room temperature. The solvent was evaporated in vacuo and to the residue was added water.
The mixture was adjusted to pH 3-4 with lN NaOH, followed by extraction with chloroform. The extract was washed with water, dried and concentrated to dryness. The concentrate was purified by silica gel column chromatography. The crystals thus obtained were recrystallized from ethyl acetate - methanol to afford pale yellow prisms (50 mg, 12%), m.p. 225-227C (dec.).

2C~5~L65 Elemental Analysis for C22H18N602S.O.2H20:
C(%) H(~) N(%) Calcd.: 60.87; 4.27; 19.36 Found : 60.83; 4.20; 19/30 S lH-NMR(200MHz,DMSO-d6) :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- r 4'-(4~6-Dibromo-2-butvlthieno r 3,4-dlimidazol-1-y~)-methylbipheny~-2-ylltetrazole K salt To a solution of 2-butyl-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl]thieno[3,4-d]imidazole (0.15 g) in acetic acid (3 ml) was added dropwise a solution of bromine (0.11 g) in acetic acid (0.5 ml). The mixture was stirred for one hour at room temperature, then the solvent was evaporated Ln vacuo. To the residue was added waterl which was extracted with ethyl acetate.
The organic layer was washed with water and dried. The solvent was evaporated in vauo, and the residue was purified by silica gel column chromatography. The syrup thus obtained was dissolved in methanol (1 ml), to which was added 2-ethyl hexanoic acid K salt (87 mg). To the mixture was added toluene (10 ml), which was concentrated under reduced pressure. Resulting precipitates were collected by filtration and dried to give fine crystals (47 mg, 21%), m.p. 246-248C (dec.).
H-NMR(200MHz,DMSO-d6)~: 0.85(3H,t), 1.28-1.42(2H,m), 1.55-1.70(2H,m), 5.30(2H,s), 6.98(2H,d), 7.13(2H,d), 7.24-7.37(3H,m), 7.52-7.57(lH,m).
IR(KBr)cm : 1490, 1475, 1405, 1355, 1110, 760.
Elemental Analysis for C23H1gBr2KN6SØ5H2O~
C(%) H(%) N(%) Calcd.: 44.60; 3.25; 13.57 Found : 44.49; 3.15; 13.59 Working Example 4 _ 38 - Z~5~65 4-Methyl~ (lH-tetrazol-5-yl~biphenvl-4-yllmethyllthienor3,4-dlimidazole-6-carboxyLic acid A solution of methyl 4-methyl-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl]thieno[3,4-d]imidazole-6-carboxylate (0.1 g~ in a mixtuxe of lN NaOH (1.5 ml) and methanol (5 ml) was heated for two days under reflux. The reaction mixture was neutralized with lN
HCl to give crystals. Recrystallization from methanol - ethyl acetate afforded colorless crystals (0.1 g, quantitatively), m.p. 187-189C (dec.).
Elemental Analysis for C21H16N6O2S.1/4MeOH.1/2H2O:
C(~) H(%) N(%) Calcd.: 59.43; 4.22; 19.57 Found : 5g.52; 4.21; 19.32 H-NMR(230MHz,DMSO-d6)~: 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, 1255, 1240, 1215, 1150, 775, 765.
Working Example 5 Pi~aloyl~ymethyl 2-ethylthio-4-methyl-1-[[2'-(lH-tetraz 1-5-vl!biphen~1-4-yl~methyl~thieno[3,4=d]-imldazole_6-carboxylate 5a ! 2-Ethylthio-4-methyl-l- r ~ 2~-(N-trityltetrazol-5-yl)biphenyl-4-yl~_thyllthieno r 3,4-dlimidazole-6-carboxylic acid Trityl chloride (0.6 g) was added to a solution of 2-ethylthio-4-methyl-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl~thieno[3,4-d]imidazole-6-carboxylic acid (0.g2 g) and triethylamine (0.3 ml) in dichloromethane (20 ml). The mixture was stirred for 30 minutes at room temperature. The reaction mixture was washed with water, dried, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography to give crystals. Recrystallization from ethyl acetate - hexane afforded colorless needles (1.36 g, 98~), m.p. 138-140C.

- 39 - 2~4~S

Elemental Analysis for C~2H34N6O2S2:
C(%) H(%) N(%) Calcd.: 70.17; 4.77; 11.69 Found : 69.99; 4.74; 11.65 1H-NMR(200MHz,CDC13)~: 1.34(3Hrt), 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, 1310, 1260, 1230, 1190, 1160, 755, 740, 690.
5b! Pivaloyloxymethyl 2-ethylthio-4-meth~l-1-rr2'-(lH-tetrazol-5-Yl~biPhenyl-4 yllmethv~lthienor3~4-dlimidazole-6-carboxylate To a solution of the trityl compound (0.6 g) obtained in Working Example Sa) in DMF (5 ml) were added K2CO3 (O.lS g) and pivaloyloxymethyl iodide (0.25 g), and the mixture was stirred for one hour at room temperature. To the reaction mixture was added water, which was extracted with ethyl acetate. The extract was washed with water and dried, followed by evaporation of the solvent to give a syrupy substance.
The syrup was dissolved in methanol (10 ml) -chloroform (5 ml). 'rO the solution was added lN HCl (6 ml), and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was concentrated, to which was added water, followed by extraction with chloroform. The extract was washed with water and dried, followed by evaporating in vacuo the solvent.
The residue was purified by silica gel column chromatography to afford colorless powdery crystals (0.33 g, 67%), m.p. 107-110C (dec.).
Elemental Analysis for C29H30N6O4S2:
C(%) H(%) N(%) Calcd.: 58.96; 5.12; 14.23 Found : 58.84; 5.37; 13.93 H-NMR(200MH~,CDCl3)~: 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), ~ o 2C!5-9~46S

7.40-7.45(lH,m), 7.50-7.64(2H,m), 8.17-8.21(lH,m) IR(KBr)cm : 2975, 1750, 1730, 1700, 1600, 1480, 1450, 1320, 1230, 1165, 1130, 1080, 1060, 1030, 985, 750, 730.
Working Example 6 1-(cyclohexyloxvcarbonyloxy)ethyl 2-ethYlthio-4-methyl-1- r r 2~-(tetrazol-5-yl ! biphenyl ~-yllmethyllthieno r 3,4-dlimidazole-6-carbox~late To a solution of 2 ekhylthio 4-methyl-1-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl~methyl~thieno[3,4-d]imidazole-6~carboxylic acid (0.6 g) obtained in Working Example 5a) in DMF (5 ml) were added K2CO3 (0.15 g), 1-(cyclohexyloxycarbonyloxy)ethyl chloride (0.21 g) and potassium iodide (85 mg). The mixture was stirred for one hour at 60 C. To the reaction mixture was added water, which was extracted with ethyl acetate. The extract was washed with water and dried, then the solvent was evaporated in vacuo to give a syrupy substance, which was dissolved in methanol (10 ml) and chloroform (5 ml). To the solu-tion was added lN HCl (6 ml), and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was concentrated to dryness, -to which was added water, followed by extraction with chloroform. The extract was washed with water and dried, then the s,olvent was evaporated in vacuo. The residue was purified by silica gel column chromatography to afford colorless powdery crystals (0.36 g, 66%), m.p. 105 108C (dec.).
Elemental Analysis for C32H34N6O5S2:
C(%) H(%) N(%) Calcd.: 59.42; 5.30; 12.99 Found : 59.66; 5.56; 12.58 lH-NMR(200MHz,CDC13)~: 1.17-1.85(16H,m), 2.64(3H,s), 3.31(2H,q), 4.46-4.58(lH,m), 5.68(2H,d), 6.87(lH,q), 7.14(4H,s~, 7.41-7.46(1H,m), 7.48~7.63(2H,m), 8.08-8.13(lH,m) - 41 - ~ ~5~4~S

IR(KBr)cm-l 2950, 1755, 1690, 1450, 1320, 1275, 1260, 1230, 1165r 1050, 1020, 1000, 935, 900, 750.
Working Example 7 Methyl 4-methyl-2-methylthio~ r2'-LlH-tetrazol-5-Yl)-biphenyl-4-yllmethyllthienor3,4-dlimidazole-6~
carboxylate By substantially the same proceduxe as Working Example 1, khe title compound was obtained as pale yellow needles (0.85 g, 45%) from methyl 4-methyl-2-methylthiothieno[3,4-d]imidazole-6-carboxylate (0.94 g), m.p. 221-225C.
Elemental Analysis for C23H20N6O2S2 4H2O
C(%) H(%) N(%) Calcd.: 57.10; 4.33; 17.37 Found : 57.34; 4O30; 17.19 lH-N~R(200MHz,DMSO-d6)~: 2.56(3H,s), 2-65(3H,s), 3.69(3H,s), 5.63(2H,s), 7.06(4H,s), 7.50-7.70(4H,m).
IR~XBr)cm 1 1700, 1600, 1460, 1430, 1425, 1320, 1235, 1185, 1170, 1090, 750.
Working Example 8 Methyl 4-methyl-2-prop~lthio-1- r ~ 2'-(lH-tetrazol-S-Yl)-biphenyl-4-vllmethyllthienor3,4-dlimidazole-6-carboxylate By substantially the same procedure as Working Example 1, the title compound was obtained as colorless plates (1.0 g, 53~) from methyl 4-methyl-2-propylthiothieno[3,4-d]imidazole-6-carboxylate (1.0 g), m.p. 222-226C (dec.).
Elemental Analysis for C25H24N602S2Ø5H20:
C(%) H(%) N(%) Calcd.: 58.46; 4.91; 16.36 Found : 58.39; 4.87; 16.31 H NMR(200MHz,DMSO-d6)~: 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, 1165, - 42 - 2~5~S

1085, 750-Reference Example 19 Methvl 4-methyl-2-proPylthio-3- r r 2'~llH tetrazol-5-Yl)-biphenyl-4-yllmethyllthieno r 3,4-dlimidazole-6-carboxylate By subst~ntially the same procedure as Reference Example 15, the title compound was obtained as colorless crystals (82 mg, 4%) from methyl 4-methyl-2-propylthiothieno~3,4-d]imidazole-6-carboxylate (1.0 g), m.p. 203-208C (dec.).
Elemental Analysis for C25H24N62S25H20 C(%) H(%) N(%) Calcd.: 58.46; 4.91; 16.36 Found : 58.55; 4.76; 16.12 lH-NMR(200MHz,DMSO-d6)~: 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, 1340, 1320, 1270, 1190, 1105, 1070, 755.
Working Example 9 Methyl 2-allylthio-4-meth~l-1- r r 2'-(lH-tetrazol-5-~LL-biphenvl-4-yllmethyllthienor3,4-dlimidazole-6-carboxylate By substantially the same procedure as Working Example 1, colorless needles (0.7 g, 44%) were obtained from methyl 2-allylthio-4-methylthieno~3,4-d]imidazole-6-carboxylate, m.p. 203-205C (dec.).
Elemental Analysis for C25H22N6O2S2:
C(%) H(%) N(%) Calcd.: 59.74; 4.41; 16.72 Found : 59.51; 4.36; 16.59 lH-NMR(200MHz,DMSO-d6)~: 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).

~:~!5qL~L65 IR(KBr)cm-1 1680, 1595, 1450, 1425, 1315, 1235, 1160, 1085, 7S0.
Reference Example 20 Methyl ?-allylthio-4-methyl 3-~[2'-~lH-tetrazol-5-yl~-biphenyl-4-y~J-ethyllthieno~3~4-dlimidazole-6 carboxylate By substan-tially the same procedure as Reference Example 15, colorless needles (16 mg, 1.0%) were obtained from methyl 2-allyl~hio-4-methylthieno[3,4-d]imidazole-6-carboxylate (0.7 g), m.p. 132-140 C
(dec.).
Elemental Analysis for C25H22N602S2Ø5H20:
C(~) H(%) N(%) Calcd.: 58.69; 4.53; 16.43 Found : 58.73; 4.36; 16.27 1H-NMR(200MHz,DMSO-d6)~: 2.29(3H,s), 3-77(3H,s)~
4.06(2H,d) J 5.16~5.22(lH,m), 5.3Q(2H,s), 5.34 5.44(lH,m), 5.93-6.16(lH,m), 7.02-7.12(4H,m), 7.49-7.67(4Hrm)-Working Example 10 Methyl 2-isopropylthio-4-methyl-1- r r 2'-~lH-tetrazol-5-yl!biphenyl-4-yllmethyllthienor3,4-dlimidazole-6-carboxylate By substantially the same procedure as Working Example 1, colorless needles (0.62 g, 41%) were obtained from methyl 2-isopropylthio-4-methylthieno[3,4-d]imidazole-6-carboxylate tO.82 g), m.p. 210-214C (dec.).
Elemental Analysis for C25H24N6O2S2:
C(%) H(%) N(~) Calcd.- 59.50; 4.79; 16.65 Found : 59.36; 4.80; 16.71 lH-NMR(200MHz,DMSO d6)~: 1.40(6H,d), 2.56(3H,s), 3.68(3H,s), 3.89-4.03(1H,m), 5.61(2H,s)r 7.03(4H,s), 7.49-7.70(4~,m).
IR(KBr)cm 1 1680, 1590, 1445, 1425, 1325, 1315, 1240, _ ~4 - ~ ~5~65 1160, 1150, 1085, 750.
Reference Example 21 Methyl 2-isopropvlthio-4-methyl-3- r r 2'-(lH-tetrazol-5-Yl)biphenyl-4-yllmethyllthienor3,4-dlimidazole-6-carboxylate By substantially the same procedure as RPference Example 15, colorless crystals (12 mgr 0.8~) were obtained from methyl 2-isopropylthio-4-methylthieno[3,4-d~imidazole-6carboxylate (0.82 g), m.p. 132-138C (dec.).
H-NMR(200MHz,DMSO-d6)~: 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).
Working Example 11 Methyl 2-butYlthio-4-methYl-1- r r 2'-(lH-tetraz_1-5-Yl!-biphenyl-4-yllmethyllthienor3,4-dlimidazole-6-carboxylate By substantially the same procedure as Working Example 1, pale yellow prisms (0.8 g, 40~) were obtained from methyl 2-butylthio-4-methylthieno[3,4-d]imidazole-6-carboxylate (1.10 g), m.p. 196-198C
(dec.)~
Elemental Analysis for C28H26N6O2S2:
C(%) H(%) N(%) Calcd.: 60.86; 5.05; 16.20 Found : 59.86; 5.04; 15.96 H-NMR(200MHz,DMSO~d6)~: 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 : 1690, 1600, 1450, 1430, 1420/ 1315, 1230, 1160, 1085, 750.
Reference Example 22 Methyl 2-but~lthio-4-methyl-3- r r 2~-(lH-tetrazol-5-Y
biphenyl-4-yllmethyllthienoL3,4-dlimidazole-6-carboxylate By substantially the same procedure as Reference 2~S~L6~

Example 15, pale yellow prisms (12 mg, 0.6%) were obtained from methyl 2-butylthio-4-methylthieno[3,4-d]imidazole-6-carboxylate (1.10 g), m.p. 108-110C
(dec.).
Elemental ~talysis for C26H26N6O2S2.H2O:
C(%) H(%) N(%) Calcd.: 58.19; 5.26; 15.66 Found : 58.48; 4.93; 15.21 lH-NMR(200MHz,DMSO-d6)~: 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).
Working Example 12 Methyl 2-hexylthio-4-methyl-1- r r 2'-~lH-tetrazol-5-Yl~-biphenyl-4-yllmethyllthieno~3,4-dlimidazole-6-carboxylate By substantially the same procedure as Working Example 1, colorless needles (0.75 g, 31~) were obtained from methyl 2-hexylthio-4-methylthieno[3,4-d]imidazole-6-carboxylate (1.25 g), m.p. 135-136C
(dec.).
Elemental A~talysis for C28H30N6O2S2:
C(%) H(%) N(%~
Calcd.: 61.51; 5.53; 15.37 Found : 61.28; 5.53; 15.30 H-NMx(2ooMHz~cDcl3)~: 0-88(3H,t), 1-26-1-45(6H~m)~
1.67-1.82(2H,m), 2.58t3H,s), 3.27(3H,t), 3.77(3H,s), 5.73(2H,s), 7.14-7.24(4H,m), 7.28-7.42(1H,m), 7.49-7.63(2H,m), 7.17-8.22(lH,m).
IR(KBr)cm 1 1680, 1595, 1450, 1425, 1315, 1235, 1190, 1160, 1085, 750.
Reference Example 23 Methyl 2-hexy1__io-4-methYl-3- rr 2'-(lH--tetrazol-5-Yll-bipheny:l-4-yllmeth~llthienor3,4-dlimiclazole-6-carboxylate By substctntially the same procedure as Reference 2C5~65 Example 15, pale yello~ crystals ~18 mg, 0.7%) were obtained from methyl 2-hexylthio-4-methylthieno[3 t 4-d]imidazole-6-carboxylate (1.25 g), m.p. 152-154C
(dec.).
Elemental Analysis for C2~H30N6O2S2Ø4H2O:
C(%) N(%) N(%) Calcd.: 60.72; 5.60; 15.17 Found : 60.91; 5.36; 15.18 lH-NMR(200MHz,CDC13)~: 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(lH,m), 7.46-7.60(2H,m), 7.95-8.00(lH,m).
Working Example 13 Methyl 2-cYclohexyl-4-methyl-1- r r2'-(lH-tetrazol-5-vl ! -biphenvl-4~Yllmethyllthieno r 3,4-dlimidazole-6-carboxYlate By substantially the same procedure as Working Example 1, colorles6 needlas (0.48 g, 42%), were obtained from methyl 2-cyclohexylthio-4-methylthieno[3,4-d]imidazole-6~carboxylate (0.65 g), m.p.l69-171C (dec.).
Elemental Analysis for C28H28N6O2S2Ø5H2O:
C(%) H(%) N(%) Calcd.: 60.74; 5.28; 15.18 Found : 60.93; 5.21; 15.15 1H-NMR(200NHz,CDC13)~: 1.25-1.77(8H,m), 2.08-2.17(2H,m), 2.61(3H,s), 3.77(3HJS)r 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(lH,m).
IR(KBr)cm 1 1690, 1605, 1450, 1440, 1320, 1240, 1170, 1100~ 760.
Working Example 14 2-Allylthio-4-methyl-1- r r 2'-(lH-tetrazol-5-Yl!bi~henYl-4-yllmethyllthienor3,4-dlimidazole-6-carboxylic acid To a solution of methyl 2-allylthio-4-methyl-1-[[2'~(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]thieno[3,4-d]imidazole-6-carboxylate (0.59 g) in a mixture of - 47 ~
~5'~4~
tetrahydrofuran (10 ml) and water (5 ml) was added lithium hydroxide.monohydrate (0.15 g), and the mixture was stirred for 20 hours at 50C. The reaction mixture was concentrated to dryness and to the residue was added water. The solution was adjusted to pH 3-4 with lN HCl to give crystals. Recrystallization from methanol - ethyl acetate afforded colorless crystals tO.35 g, 60%), m.p.l35-136C (dec.).
Elemental Analysis for C24H20N6Q2 2 2 C(%) H(%) N(%) Calcd.: 57.72; 4.28; 16.83 Found : 57.74; 4.26' 16.98 lH-NMR(200MHz,DMSO-d6)~: 2.54(3H,s), 3.93(2H,d), 5.10-5.16(1H,m), 5.27-5.36(1H,m)l 5.66(2H,s), 5.85-6.06(lH,m), 7.06(4H,s), 7.50-7.70(4H,m).
IRtKBr~cm 1 1675, 1595, 1525, 1440l 1300l 1220, 1180, 1160, 1080, 925, 770, 750 Working Example 15 4-Methyl-2-methylthio-1- r r 2~-(lH-tetrazol-5-Yl)biphenyl-4-yllmethyllthienor3~4-dlimidazole-6-carboxylic acid In substantially the same manner as Working Example 14, the title compound was obtained as colorless crystals (0.35 g, 51%) from methyl 4-methyl-2-methylthio-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl]thieno[3,4-d]imidazole-6-carboxylate (0.71 g), m.p. 188-190C (dec.).
Elemental Analysis for C22H18N6O2S2 2 C(%) H(%) N(%) Calcd.: 55.69; 3.98; 18.03 Found : 56.59; 3.79; 18.01 1H-NMR(2ooMHz~DMso-d6)~: 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, 1340, 1325, 1305, 1170, 750.
Working Example 16 2~54~iS

4-Methy]-2-propylthio-1- r ~ 2'-(lH~tetrazol-5-yl!biphenyl-4-yllmethyllthienor3,4-dlimidazole-6-carboxylic acid In substantially the same manner as Working Example 14, the title compound was obtained as colorless crystals (0.5 g, 62%) from methyl 4-methyl-2-propylthio-1-~[2'-(lH-tetrazol-5 yl)biphenyl-4-yl]methyl]thieno[3,4-d]imidazole-6-carboxylate (0.84 g), m.p. 161-162C (dec.).
Elemental Analysis for C24H22N6O2S2Ø4H2O:
C(%) H(%) N(%) Calcd.: 57.91; 4.62; 16.88 Found : 57.90; 4.43; 16.90 1H-NMR(2ooMHz,DMso-d6)~: 0.95(3H,t), 1-61-1-80(2M,m)~
2.53(3H,s), 3.23(2H,t), 5.67(2H,s)t 7.02-7.11(4H,brs), 7.49-7.71(4H,m).
IR(XBr)cm : 1680, 1600, 1530, 1445, 1305, 1225, 1190, 1185, 1165, 770, 750.
Reference Example 24 4-Methyl-2-propylthio-3- r r 2'-tlH-tetrazol-5-yl)biphenyl-4-yllmethYllthieno r 3,4-dlimidazole~6-carboxylic acid In substantially the same manner as Working Example 14, the title compound was obtained as colorless crystals (28 mg, 65%) from methyl 4-methyl-2-propylthio-3 [[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl]thieno[3,4-d]imidazole-6-carboxylate (45 mg), m.p. 192-197C.
1H-NMR(200MHz,DMSO-d6)~: 0.99(3H,t), 1.67-1.85(2H,m), 2.28(3H,s), 3.35(2H,t), 5.29(2H,s), 7.0~(4H,s), 7-5~-7.73(4H,m)-Working Example 17 2-Isopropylthio-4-methyl-1- r r2'-~lH-tetrazol-5-Yl!-biphenyl-4-yllmethyllthieno r 3,4-dlimidazole-6-carboxYlic acid _ ~9 _ ~ ~5~S

In substantially the same manner as Working Example 14, the title compound was obtained as colorless needles (0.37 g, 68%) from methyl 2-isopropyl-4-methyl-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl]thieno[3,4-d]imidazole-6-carboxylate (0.55 g), m.p.182-184C (dec.).
Elemental Analysis for C24H22N6O2 2 C(%) H(%) N(%) Calcd.: 57.70; 4.64; 16.82 Found : 57.87; 4.95; 16.88 lH-NMR(200MHz,DMSV-d6)~: 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, 1530r 1450, 1430, 1380, 1240, 1160, 1150, 930, 770, 750.
Working Example 18 2-Butylthio-4-methyl-1- r r 2 ~ - f lH-tetrazol-5-Yl ? biPhenYl-4-Yllmethyllthieno r 3,4-dlimidazole-6-carboxYlic acid In substantially the same manner as Working Example 14, the title compound was obtained as colorless needles (0.47 g, 74%) from methyl 2~
butylthio-4-methyl-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl]thieno[3~4-d]imidazole-6-carboxylic acid (0.65 g), m.p.l61-163C tdec.).
Elemental Analysis for C25H2~N6O2S2Ø4H2O:
C(%) H(~) N(%) Calcd.: 58.67; 4.88; 16.42 Found : 58.64j 4.60; 16.58 H-NMR(200MHz,DMSO-d~)~: 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 l 1640, 1590, 1530, 1450, 1315, 1160, 770, Working Example 19 2-Hexylthio-4-methyl-1- r r 2'-(lH-tetrazol-5-Yl!biphenYl-4-yllmethyllthieno r 3,4-dlimidazole-6-carboxylic acid In substantially the same manner as Working - 50 - Z~5 Example 14, the title compound was obtained as colorless needles (0.47 g, 78%) from methyl 2-hexylthio-4-meth~l-1-[[2'-(lH-te~raæol-5-yl)biphenyl-4-yl]methyl]thieno[3,4-d]imidazole-6-carboxylate (0.6 g), m.p.l50-152C (dec.).
Elemental Analysis for C27H28N602S2.O7H20:
C(%) ~ ) N~%) Calcd.: 59.47; 5.43; 15.41 Found : 59031; 5.36; 15.51 1H-NMR(200MHz,DMSO-d6)~: 0.89(3H,t), 1.21-1.39(6H,m), l.fiO-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, 1320, 1260, 1250, 1160, 775, 750.
Working Example 20 2-Cyclohexyl-4-methyl-1-~2'~1H-tetrazol-5- -ylLbiphenyl-4-yllmethyllthieno r 3,4-dlimidazole-6-carboxylic acid In substantially the same manner as Working Example 14, the title compound was obtained as colorless needles (0.25 g, 64%) from methyl 2-cyclohexylthio-4-methyl~l-[[2'-(lH-tetrazol-5-yl)-biphenyl-4-yl]methyl]thieno[3/4-d]imidazole-6-carboxylate (0.4 g~, m.p.l87-190C (dec.).
Elemental Analysis or C27H26N602S2 2 C(~) H(~) N(%) Calcd.: 60.09; 5.04; 15.57 Found : 60.02; 4.81; 15.51 1H-NMR(200MHz,DMSO-d6)~: 1.32-1.73(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, 1600l 1540, 1460, 1450, 1440, 1335, 1320, 1260, 1~50, 1160, 940, 760.
Working Example 21 Methyl 2-ethylthio-1- r r 2' (lH-tetrazol-5-yl !biPhenyl-4-yllmethvllthienor3,4-dlimidazole-6-carboxylate - 51 ~ 4~5 In substantially the same manner as Working Example 1, the title compound was obtained as colorless needles (0.35 g, 36%) from methyl 2-ethylthiothieno[3~4-d]imidazole-6-carboxylate tO.5 g), m.p.204-206C (dec.).
Elemental Analysis for C23H20N6O2S2:
C(%) H(%) N(%3 Calcd.: 57.97; 4.23; 17.63 Found : 57.79; 3.96; 17.44 H-NMR(200MHz,CDC13)~: 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(lH,m), 7.53-7.64(2H,m), 8.15-8.20(lH,m).
IR(KBr)cm 1 1700, 1585, 1450, 1430, 1420, 1320, 1250, 1230, 1165, 1100, 1045, 755, 745.
Reference Example 25 Methyl 2-ethylthio-1- r r 2'-(lH-tetrazol-5-Yl)bl~envl-4-y11methvllthieno r 3~4-dlimida2o1e-4-carboxYlate In substantially the same manner as Reference Example 15, the title compound was obtained as colorless needles (0.27 g, 27%) from methyl 2-ethylthiothieno[3,4~d]imidazole-4-carhoxylate (0.5 g), m.p. 173-175C (dec.).
Elemental Analysis for C23H20N6O2S2. 2 C(%) H(%) N(%) Calcd.: 57.75; 4.26; 17.57 Found : 57.91; 4.07; 17.22 H-NMR(2ooMHz,cDcl3)~: 1-41t3H~t)~ 3.34(2H~q)~
3.79(3H,s), 5.09(2H,s), 6.54(1H,s), 7-10(4H~q)~ 7.30-7.34(1H,m), 7.47-7.58(2H,m), 7.96-8.00(1H,m).
IR(KBr)cm : 1700, 1520, 1440, 1430, 1415/ 1400, 1360, 1350, 1310, 1190, 1160, 1100, 760.

Working Example 22 2-EthYlthio-l-.r r 2'-(lH-tetrazol-5-vl~biphenvl-4-5 yllmeth~llthienor3,4-dlimidazole-6-carboxYlic acid In substantially the same manner as Working - 52 - Z~5~6~

Example 14, the title compound was obtained as colorless needles (0.17 g, 87%) from methyl 2-ethylthio-1-[[2'-(lH-tetrazol-5-yl]methyl]thieno[3,4-d]imidazole-6-carboxylate (0.2 g), m.p. 199-201~C.
Elemental Analysis for C22H18N6O2S2.0-2H2 C(%) H(~) N(%) Calcd.: 56.47; 4.01; 17.96 Found : 56.68; 3.68; 17.59 lH-NMR(200MHz,DMSO-d6)~: 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, 1340, 1315, 1240, 1180, 750, 735.
Reference Example 26 2-Ethylthio-1- r r 2~-(lH tetrazol-5-yl ! biphenYl-4-yllm~h~JLthieno r 3,4-dlimidazole-4-carboxylic_acid In substantially the same manner as Working Example 14, the title compound was obtained as colorless needles (0.1 g, 68%) from methyl 2-ethylthio-1-[[2'-(lH-tetrazol-5-yl]methyl]thieno[3,4-d]imidazole-4-carboxylate (0.15 g), m.p.220-222C (dec.).
Elemental Analysis for C22H18N602S2.O.SH20:
C(~) H(%) N(%) Calcd.: 56,04; 4.06; 17.82 Found : 55.86; 4.10; 17.93 lH-NMR(2ooMHz~DMso-d6)~: 1.39(3H,t), 3-35(2H,q)~
5.18(2H,s), 7-09(2H,d), 7.14(1H,s), 7.23(2H,d), 7.51-7.73(4H,m)-IR(KBr)cm : 167S, 1520, 1435, 1360, 1335, 1290, 1270, 1250, 1180, 1160, 770, 745.
Working Example 23 Methyl 2-methoxy-4-methy].-1-rr2'-(lH-tetrazol-5-Yl!-biphenyl-4-yllmethyllthienor3,4-dlimidazole-6-23a) methyl 1-r(2'-cyanobiphen~1-4-Yl!methYl1-2-ethylthio 4-methylthienor3,4-dlimidazole-6-carboxYlate _ 53 ;Z~5 To a solution of methyl 2-ethylthio-4-methylthieno~3~4-d]imidazole-6-carboxylate (5.7 g) in DMF (30 ml) was added sodium hydride (60~ oil, 0.98 g) under ice-cooling. After stirring the reaction mixture for 20 minutes, to the mixture was added dropwise a solution of (2'-cyanobiphenyl-4-yl)methyl bromide (7.25 g) in DME (20 ml~, followed by stirring for one hour at room temperature. To the reaction mixture was added water, which was extracted with ethyl acetate. The extract was washed with water and dried, then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography to give crystals. Recrystallization from ethyl acetate -hexane afforded pale yellow prisms (7.6 g, 77%), m.p.149-151C.
lH-NMR(200MHz,CDC13)~: 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(lH,m), 7.72-7.77(lH,m).
IR(KBr)cm 1 2220, 1690, 1600, 1450, 1430, 1315, 1300, 1230, 1160, 1085, 770, 750.
23b ! Methyl 1- r ~ 2'-cyanobiphenyl-4-vl!methY11-2-ethylsulfinyl-4-methYlthieno r 3,4-dlimidazole-6-carboxylate To a solution of the ethylthio compound t7.2 g) obtained in Working Example 23a~ in dichloromethane (100 ml) was added m-chloroperbenzoic acid (3.3 g) under ice-cooling and the mixture was stirred for one hour. The reaction mixture was washed with a saturated aqueous solution of hydrogencarbonate and water. The solution was dried and concentrated to dryness. The residue was purified by silica gel column chromatography to give crystals. Recrystallization from ethyl acetate - hexane afforded pale yellow crystals (7.0g, 94%), m.p.150-151C.
1H-NMR(200MHz,CDC13)~: 1.26(3H,t), 2-72(3Hrs)~ 2-99-3.30(2H,m), 3.82(3H,s), 5.97(1H,d), 6.43(1H,d), 5~ 2~S~L6S

7.32(2H,d), 7.39-7.52(4H,m), 7.59-7.68~1H,m), 7.73-7.76tlH,m).
IR(KBr)cm 1 2220, 1700, 15~0, 1530, 1450, 1435, 1315, 1230, 1160, lO90, 1070, 770/ 750.
23c) Methyl 2-methoxv-4-methYl-l-r(2'-cYanobiPhen~
4-yl!methyllthieno r 3~4-dlimidazole-6-carboxvlate To a suspension of the ethyl sulfinyl compound tl.0 g) obtained in Working Example 23b) in methanol (20 ml) was added 28% sodium methoxide (methanol solution, 0.62 g). The mixture was heated for 30 minutes under reflux. The reaction mixture was concentrated to dryness to give crystals.
Recrystallization from ethyl acetate - methanol afforded pale yellow prisms (0.79 g, 88%), m.p.181-182~C.
Elemental Analysis for C23HlgN3O3S:
C(%) H(~) N(~) Calcd.: 66.17; 4.59; 10.07 Found : 66.29; 4.60; 9.79 lH NMR(200MHz,CDC13)~: 2.58(3H,s), 3.79(3H,s), 4.15(3Hrs), 5.63(2H,s), 7.34(2H,d), 7.38-7.51(4H,m), 7.58-7.67(lH,m), 7.72-7.77(lH,m)O
IR(~Br)cm 1 2225, 1700, 1620, 1580, 1540, 1460, 1450, 1440, 1400, 1385, 1335, 1235, 1110, 1060, 770, 760.
23dL Methyl 2-methoxy-4-methyl-l- r r 2'-(lH-tetrazol-5-Yl!biPhenyl-4-yllmethyllthienor3 4-dlimidazole-6-carboxylat_ A mixture of the cyano compound (0.75 g) obtained in Working Example 23c) and trimethylsilyl azide (1.85 g) in toluene (20 ml) were heated under reflux for 24 hours. The reaction mixture was concentrated, to which was added water, followed by extraction with chloroform. The extract was washed with water and dried, then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography to give crystals. Recrystallization S~4 - 55 ~

from ethyl acetate methanol afforded colorle~s needles (0.67 g, 80%), m.p.173-175C (dec.).
Elemental Analysi5 for C23H2oN6o3s~oo3H3o C(%) H(%) S Calcd.: 59.29, 4.46; 18.04 Found : 59.50; 4.60; 17.74 H-N~R(200MHz,CDC13)~: 2.36(3H,s), 3.74(3H,5), 3.97(3H,s), 5.57(2H,s), 7.10-7.20(4H,m), 7.38-7.43(lH,m), 7.49-7.64(2H,m), 8.09-8.13(lH,m).
IR(KBr)cm 1 1700, 1615, 1575, 1540, 1470, 1460, 1440, 1~10, 1390, 1380, 1340, 1320, 1230, 1100, 1070, 1000, 760.
WorXing Example 24 Methyl 3-ethoxy-4-methyl-1- r r 2~-(lH-tetrazol-5-Yl)-bi~enyl-4-yllmethyllthienor3,4-dlimidazole-6-carboxylate 24a ! Eth~l 2-ethoxy-4-methvl-1-L(2'-cyanobiphenYl-4-Yllmethyllthieno r 3c4-dlimidazole-6-carboxYlate A mixture of the ethyl sulfoxide (1.0 g) obtained in Working Example 23b) in ethanol (20 ml) containing sodium methoxide (0.167 g) was refluxed for 30 minutes.
The reaction mixture was concentrated to dryness to give crystals and recrystallization from ethyl acetate - ethanol afforded pale yellow needles (0.86 g, 89%), m.p.153-155C.
1H-NMR(200MHz,CDC13)~: 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(1HIm), 7.73-7.77(lH,m).
24b! Methvl 2-ethoxy-4-meth~l-1-r(2'-c~anobiPhenyl-4-yl ! methyllthieno r 3,4-dlimidazole-6-carboxylate To a suspension (20 ml) of the e~hyl ester (0.86 g) obtained in Working Example 24a) in methanol (20 ml) was added 28% sodium methoxide (methanol solution, 0.75 g), and the mixture was refluxed for 3 hours. The reaction mixture was concentrated to dryness to give ~ 5~ S-~6s crystals and recrystallization from ethyl acetate -methanol afforded colorless needles (0.78 g, 94%), m.p.155-156C.
Elemental Analysis for C24H21N3O3S:
C(~) H(%) N(%) Calcd.: 66.80; 4.91; 9.74 Found : 66.69; 4.78; 9.67 lH-NMR(200NHz,CDC13)~: 1.44(3H,t), 2.57(3X,s), 3.81(3H,s), 4.55(2~,q), 5.63(2H,s), 7.37(2H,d), 7-42-7.51(4H,m), 7.59-7.67(lH,m), 7.73-7.77(1H,m).
IR(KBr)cm 1 2225, 1690, 1620, 1570, :L535, 1450, 1330, 1215, 1060, 760.
24c ! Methyl 2-ethoxy-4-methvl-1- r r 2'-(lH-tetrazol--5-yl!biphenvl-4-yllmethyllthienor3,4-dlimidazole-6-carboxYlate In substantially the same manner as Workin~
Example 23d), the title compound was obtained as colorless needles (0.66 g, 79%) from the cyano compound (0.76 g) obtained in Working Example 24b), m.p.l93-195C (dec.).
Elemental Analysis for C24H~2N603S:
C(%) H(%) ~(%) Calcd.: 60.75; 4.67; 17.71 Found : 60.48; 4.53; 17.45 1H-NMR(200MHz,CDC13)~: 1.41(3H,t), 2.37(3H,s), 3.75(3H,s), 4.37(2H,d), 5-57(2H,s)~ 7.13(2H,d), 7.22(2H,d), 7.37-7.42(1H,m), 7.49-7.63(2H,m), 8.10-8.15~lH,m).
IR(KBr)cm 1:1685, 1610, 1570, 1530, 1440, 1430, 1380, 1330, 1230, 1060, 750.
Working Example 25 Methyl 4-methyl-2-pxopoxy-l-r[2r-~lH-tetrazol-5-yl ! -biphenYl-4--yllmethyllthienor3~4-dlimidazole-6 carboxylate 25a! Methyl 4-methyl-2-propoxy-1-r~2'-cyanobiphenYl=
4-yl!methyllthieno~3,4-dlimidazole-6-carboxylate _ 57 _ 2~5~5 In substantially the same manner as Working Example 23c), the title compound was obtained as colorless needles (0.4 g, 41%) by heating the ethylsulfinyl compound (1.0 g) obtained in Working Example 23b) under reflux for 30 minutes in sodium propoxide (solution of sodium methoxide (0.2 g) in propanol (20 ml)), m.p.188-190~C (dec.~.
Elemental Analysis for C25H23N3O3SØ2H2O:
C(~) H(%) N(%) Calcd.: 66.86, 5.25; 9.36 Found : 66.78; 5.09; 9.25 lH-NMR(200MHz,CDC13)~: 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), 7.42-7.5~(4H,m), 7.54-7.67(lH,m), 7.73-lS 7.78(lH,m).
IR(KBr)cm 1 2200, 1685, 1610, 1570, 1530, 1440, 1430, 1360, 1220, 1090, 750.
25b ! Methyl 4-methyl-2-proPoxy-l- r r 2'-~lH-tetrazol-5-Yl!biphenyl-4-~llmethyllthieno r 3,4-dlimidazole-6-carbox~late In su~stantially the same manner as Working Example 23c), the tltle compound was obtained as colorless needles (0.35 g, 86~) by subjecting the cyano compound (0.37 g) obtained in Working Example 25a) to heating for 16 hours under reflux in a mix~ure of trimethyl tin azide (0.85 g) and toluene (15 ml), m.p.206-208C (dec.).
Elemental Analysis for C25H24N603S:
C(%) H(%) N(%) Calcd.: 61.46; 4.95; 17.20 Found : 61.31; 4.89; 17.07 H-NMR(200MHz,CDC13)~: 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(lH,m).
IR(KBr)cml: 1690, 1620, 1575, 1535, 1470, 1450, 1440, 5~ 2~5~65 1410, 1370, 1350, 1340, 1240, 1070, 970, 760.
Working Example 26 Methyl 2-ethylamino-4-methyl-1-~ r 2~-(lH-tetrazol-5-yl ! -I=slgy~ L~L~ethvllthieno r 3,4-dlimidazole-6-carboxylate 26a ! Methyl 2-ethylamino-4-methyl-1= r ( 2~-cyanobiphenyl-4-yl!methyllthieno~3,4-dlimidazole-6-carboxylate A mixture of the ethylsulfinyl compound (0.91 g) obtained in Working Example 23b) in a mixture of a 70%
aqueous solution of e~hylamine (10 ml) and ethanol (lQ
ml) was heated at S0C in an autoclave for 3 hours.
The reaction mixture was concentrated to dryness. The concentrate was dissolved in ethyl acetate, washed with water and dried. The solvent was evaporated in vacuo, then the residue was purified by column chromatography on silica gel to give crystals. Recrystallization from ethyl acetate - hexane afforded colorless needles (0.45 g, 53%), m.p.190-191C.
H-NMR(200MHz,CDC13)~: 1.18(3H,t), 2.56(3H,s), 3.38-3.52(2~I,m), 3.76(3H,s), 3.96(1H,t), 5.73(2H,s), 7.32(2H,d), 7.40-7.56(4H,m), 7.60-7.69(lH,m), 7.74-7.79(1H,m~.
IR(RBr)cm 1 3390, 2225, 1670, 1620, 1600, 1545, 1520, 1450, 1435, 1340, 1330, 1240, 760, 750.
26b ! Methyl 2-ethylamino-4-methYl-1- r r 2'-tlH-tetrazol-5-yl ! biphenyl-4-~llmethyllthieno r 3,4-dlimidazole-6-carboxylate In substantially the same manner as Working Example 23d), the title compound was obtained as colorless needles (0.27 g, 52%) by heating the cyano compound (0.45 g) obtained in Working Example 25a) and trimethyltin azide (1.1 g) for 24 hours ullder reflux in toluene (20 ml), m.p.252-255C.
Elemental Analysis for C24H23N7O2SØ5H2O:

_ 59 _ ~ ~ S~ ~ S

C(%) ~(%) N(%) Calcd.: 59.74; 5.01; 20.32 Found : 59.76; 4.84; 20.18 1H-NMR(200~Iz,CDCl3)~: 1.14(3H,t), 2-40(3H~S)I
3.32(2H,q), 3.64(3H,s), 5.58(2H,s)l 7.03(4H/s), 7-49-7.70(4H,m)-IR(XBr)cm 1 1705, 1680l 1670, 1630, 1480, 1440, 1340, 1335, 1270, 1220, 1095, 1075, 760.
Working Example 27 Methyl 4-methYl-2-ProPYlamino-l- r r 2'-(lH-tetrazol-5-yl)biphenvl-4-yllmethyllthienor3,4-dlimidazole-6-carboxYlate 27a ~ Methyl 4-methyl-2-pro~ylamino-1-~(2'-cyano biphenyl-4-yl)methyllthieno r 3,4-dlimidazole-6-carboxylate A mixture of the ethyl sulfinyl compound (1.0 g) obtained in Working Example 23b) and propylamine (20 ml) was heated under reflux for 3 days. The reaction mixture was concentrated to dr~ness. The concentrate was dissolved in ethyl acetate, washed with water and dried, followed by evaporating in vacuo the solvent.
The residue was purified by column chromatography on silica gel to ~ive crystals. Recrystallization from ethyl acetate - hexane afforded pale yellow needles (0.72 g, 75%~, m.p.148-150C.
H-NMR(200MHz,CDC13)~: 0.82(3H,t), 1.47-1.66(2H,m), 2.56(3~I,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 : 3375, 2200, 1680, 1660, 1615, 1590, 1540, 1520, 1440, 1330, 1230, 1090, 1070, 750.
27b ! Meth~l 4-meth~1-2-propylamino-1- r r 2~-(lH-tetrazol-5-yl!biphenyl-4 yllmethyllthienor3,4-dl-imidazole-6-carboxylate In substantially the same manner as Working Example 23d), the title compound was obtained as X~5/~L46S

colorless needles (0.66 g, 77~) by refluxing a mixture of the cyano compound ~0.7 g) obtained in Working Example 27a) and trimethyltin azide (1.52 g) in toluene (20 ml) for 24 hours.
m.p.204-208C (dec.) Elemental Analysis for C2sH2sN7O2S0 5CHC13 C(%) H(%) N(%) Calcd.: 55.~7; 4.70; 17.92 Found : 56.08; 4.54; 17.68 1H-NMR(200MHz,CDC13)~: 0.82(3H,t), 1.46-1.64(2H,m), 2.40(3H,s), 3.25(2H,t), 3.66(3H,s~, 5.61(2H,s), 7.04(4H,s), 7.49-7.70(4H,m).
IR(KBr)cm 1 1705, 1670, 1660, 1630, 1550, 14~0, 1460, 1440, 1350, 1340, 1250, 1~15, 1080, 760.
Working Example 28 2-Methoxy-4-meth~1~ 2~-(lH-tetrazol-5-yl!biphenyl-4-~llmethyl~hieno r 3,4-dlim dazole-6-carboxylic acid By substantially the sama procedure as Working Example 14, the title compound was obtained as colorless needles (0.3 g, 61~) from the methyl ester (0.5 g) obtained in Working Example 23.
m.p.187-189C (dec.) Elemental Analysis for C22H18N6O3SØ5H2O:
C(%) H(%) N~%) Calcd.: 58.01; 4.20; 18.45 Found : 57.79; 4.29; 18.35 lH-NMR(200MHz,DMSO-d6)~: 2.47(3H,s), 4.05(3H,s), 5.51(2H,s), 7.04(2H,d), 7.12(2H,d), 7.50-7.70(4H,m).
IR(KBr)cm 1 1660, 1620, 1580, 1540, 1450, 1400, 1385, 1375, 1340, 1320, 1240, 9gO, 760, 750.
Working Example 29 2-Ethoxy-4-methYl-l- r r 2~-(lH-tetrazol-5-yl ! biphenyl-4-yllmethyllthienoL3,4-dlimidazole-6-carboxylic acid ~y substantially the same procedure as Working Example 14, the title compound was obtained as colorless needles (0.34 g, 75%) from the methyl ester ~(~5~1465 - 61 ~-(0.45 g) obtained in Working Example 24.
m.p.171-172C (dec.) Elemental Analysis for C23H20N6O3S.H2O:
C(%) H(%) N(%) Calcd.: 57.73; 4.63; 17.56 Found : 57.88; 4.67; 17.20 H-NMR(200MHz,DMSO-d6)~: 1.31(3H,t), 2.46(3H,s), 4.46(2~,~), 5.49(2H,s), 7.04(2H,d), 7.13(2H,d), 7.47-7.~7(4Hrm)-IR(XBr)cm 1 1680, 1615, 1570, 1540, 1460, 1420, 1380, 1350, 1335, 1320r 1230, 750.
Working Example 30 4-Methyl-2-propoxy-1- r r 2'-(lH-tetrazol-5-yl ? -bi~henYl-4-~llmethyl]thieno r 3,4-dlimidazole-6-carboxYlic acid In substantially the same manner as Working Example 14/ the title compound was obtained as colorless needles ~0.16 gr 67%) from the methyl ester (0.23 g) obtained in Working Example 25.
m.p.173-175C (dec.) Elemental Analysis for C24H22N603S.O.7H20:
C(%) H(%) N(~) Calcd.: 59.17; 4.84; 17.25 Found : 59.09; 4.73; 17.34 H-NMR(200MHzrDMSO-d6)~ 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, 1555, 1535, 1450, 1370, 1335, 1230, 750.
Working Example 31 2-Ethylamino-4-methyl-1-r r 2'-(lH-tetrazol-5-yl)biphen~ 4-yl~methyl]thienor3~4-dlimidazole-6 carboxylic acid In substantially the same manner as Working Example 14, the title compound was obtained as colorless needles (0.2 g, 91~) from the methyl ester (0.2 g) obtained in Working Example 26.

2(~ 6~

m.p.201-205C (dec.), Elemental Analysis for C23H21N7O2SØ5CHC13:
C(%) H(%) N(%) Calcd.: 54.36; 4.17; 18.88 Found : 54.34; 4.14; 18.67 H-NMR(200MHz,DMSO-d6)~: 1.13(3H,s), 2.39(3H,s) 3.31(2H,q), 5.62(2H,s), 7.04(4H,s), 7.49-7.69(4H,m).
IR(KBr)cm 1 1660, 1630, 1560, 1530, 1460, 1450, 1380, 1360, 1340, llO0, 965, 780, 760, 740.
Working Example 32 4-Methyl-2-propylamino-l- ~ r 2'-(lH-tetrazol-5-Yl~biphenyl-4-yllmethyl~thieno~3,4-dlimidazole-6-carboxylic acid In substantially the same manner as Working Example 14, the title compound was obtained as colorless needles (0.2 g, 48%) from the methyl ester compound (0.46 g) obtained in Working Example 27.
m.p.206-209C (dec.) Elemental Analysis for C24H23N7O2S.1.5H2O:
C(%) H(%) N(%) Calcd.: 57.59; 5.24; 19.59 Found : 57.86; 5.15; 19.62 H-NMR(200MHz,DNSO-d6)~: 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 l 1670, 1660, 1630, 1550, 1545, 1460, 1350, 1340, 760.
Working Example 33 2-Ethoxy-1-LL_'-(lH-tetrazol-5-yllbiphenyl-4-ylLmethyllthieno r 3,4-dlimidazole-6-carboxvlic acid 33a) Methyl 1- r ( 2'-cyanobiphenyl-4-yl!methyll-2-ethylthiothieno r 3,4-dlimidazole-6 carboxylate To a solution of methyl 2-ethylthiothieno[3,4-d]-imidazole-4-carboxylate (1.81 g) obtained in Reference Example 14c) in DMF (15 ml) was added sodium hydride (60% oil, 0.33 g) under ice-cooling. To the mixture - 63 - ~ ~5~65 was added dropwise a solution of ~2'-cyanobiphenyl-4-yl)methyl bromide (2.25 g) in DMF (10 ml) and the reaction mixture was stirred for 60 hours at room temperature. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel to give crystals.
Recrystallization from ethyl acetate - hexane afforded colorless needles, m.p.l40-142C.
H~NMR(200MHz,CDC13)~: 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(lH,m), 7.73-7.77(lH,m).
33b) Methvl 1-r(2'-cyanobiPhenyl-4-yl!meth~11-2-eth~lsulfinYlthieno r 3,4-d1imidazole-6-carboxylate In substantially the same manner as Working Exampl~ 23b), the title compound was obtained as colorless prisms (1.2 g, 72%) from the ethylthio `
compound (1.6 g) obtained in Working Example 33a).
m.p.118-119C
lH-NMR(200MHz,CDC13)~: 1.30(3~,t), 3.08-3.36(2H,m), 3.86(3H,s), 6.02(1H,d), 6.47(1H,d), 7.33(2H,d), 7.40-7.53~4H,m), 7.57(1H,s), 7.60-7.68(1H,m), 7.73-7.77(lH,m).
33c) Methyl 2-ethoxy-1- r ( 2'-cyanobiphenYl-4-yl)methyl]thienoL3,4-dlimidazole-6-carboxylate A mixture of the compound obtained in Working Example 33b~ (0.8 g) in sodium ethoxide ethanolate (prepared from 0.19 g of sodium methoxide and 10 ml of ethanol) was heated for 20 minutes under reflux. The reaction mixture was concentrated to dryness and the residue was dissolved in ethyl acetate - water. ~he organic layer was dried and the solvent was evaporated in vacuo. The residue was dissolved in methanol (10 ml), to which was added 28% sodium methanolate (0.75 g), followed by heating for 8 hours under reflux. The - 64 - ZC5~6S

reaction mixture was concentrated to dryness and the residue was purified by column chromatography on silica gel to give crystals. Recrystallization from ethyl acetate - hexane afforded colorless needles (0.33 g, 41%), m.p.130-131C.

lH-NMR(200MHz,CDC13)~: 1.46(3H,t), 3.84(3H,s), 4.57(2H,q), 5.66(2H,s), 7.05(1H,s), 7.35-7.52(6H,m), 7.59--7,67(lH,m), 7.67-7.78(lH,m).
33d) Methyl 2-ethoxy-1-r r ~2'-(lH tetrazol-$-Yl)-biphenyl-4-~llmethyllthienor3,4-d~imidazole-6-carboxylate A mixture of the compound obtained in Working Example 33c) (0.3 g) and trimethylsilyl azide (0.74 g) in toluene (10 ml) was heated for 24 hours under reflux. The reaction mixtur~ was concentrated to dryness, and the residue was partitioned be~ween chloroform and water. The organic layer was washed with water and dried, then the solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel to give crystals.
Recrystallization from ethyl acetate - methanol afforded colorless needles (0.2 g, 60 %), m.p.186-188C
(dec.).
Elemental Analysis for C23H2oN6O3SØ3H2O:
C(%~ H(~ N(~) Calcd.: 59.29; 4.46; 18.04 Found : 59.23; 4.38; 17.93 lH-NMR(200MHz,CDC13)~: 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, 1420, 1390, 1345, 1245, 770.
33e) 2-Ethox~-l-rr ? ' - ( lH-tetrazol-5-Yl)biphenyl-4 Yilm~hYllthienor3~4-d~imidazole-6-carboxylic acid In substantially the same manner as Working Z~5'1~65 Example 14, the kitle compound (0.08 g, 55%) was obtained as colorless crystals from the compound obtained in Working Example 33d) (0.145 g).
m.p.159-162C (dec.) Elemental Analysis for C22H18N6O3SØ5H2O:
C~%) H(%) N(~) Calcd.: 58.01; 4.20; 18.45 Found : 58.03; 4.26; 18.19 1H-NMR(2ooMHz~Mso-d6)~: 1.32(3H,t), 4047(2H,q), 5.53(2H,s), 7.05(2H,d), 7.15(2H,d), 7.35(1H,s), 7.49-7.69(4H,m~.
IR(KBx)cm 1:1690, 1680, 1600, 1560, 1450, 1380, 1330, 1200, 75~.
Working Example 34 5-Methyl~2-propyL_6-(lH-tetrazol -S-Y1 ~ r~ 2'~1H-tetrazol-5-~ biphenvl~4-yllmethyllthienor2.3~
dlimidaæole 34a) Methyl 3-amino~4~cyano-5 methylthio~hene-2=
carboxylate To a stirred mixture of sodium hydride (60% oil, 2.0 g) in THF (5 ml) was added dropwise a solution of malononitrile (3.3 g) in THF (lQ ml) under ice-cooling.
The mixture was stirred for 10 minutes, to which was then added dropwise a solution of ethyl dithioacetate (6.0 g) in THF (10 ml) at room temperature. After stirring for further 20 minutes, the reaction mixture was concentrated to dryness, and the residue was dissolved in THF (40 ml). To the solution was added dropwise a solution of methyl chloroacetate (5.4 g) in THF (10 ml) at room temperature. The mixture was stirred for 30 minutes, to which were then added a solution of sodium methoxide (28~ methanol solution, 1 ml) in isopropanol (50 ml), followed by stirring for 3.5 hours at room temperature. To the reaction mixture was added water to give crystals. Recrystallization ;2~S~4~S
- 66 - 242~5-907 from ethyl acetate afforded colorless prisms (4.6 g, 47~), m.p.209-210C.
lH-NMR(200MHz,CDC13)~: 2.58(3H,s), 3.83(3H,s), 5.76(2H,br s).
34b) Methyl 3-butyrylamino-4-cyano-5-methylthiophene-2-carboxylate A solution of the compound ohtained in Working Example 34a) (2.0 g) and butyryl chloride (2~0 g) in dioxane (30 ml) were heated for 5 hours under reflux.
The reaction mix~ure was concentrated to dryness to give crystals. Recrystallization from ethyl acetate -hexane afforded colorless needles (2.5 g, g3~, m.p.124-125C.
lH-NMR(200MHz,CDC13)~: 1.03(3H,t), 1.80(2H,m), 2.46(2H,t), 2.68(3H,s), 3.89(3H,s), 9.40(1H,br s).
34c) Methyl 3-rN-butyrYl-N-(2'-cyanobiPhenYl-4 methyllamino-4-cyano-5-methyl~hiophene-2-carboxylate A mixt~re of the compound obtained in Working Example 34b) (2.6 g), 2-cyano-4'-bromomethylbiphenyl (3.0 g) and potassium carbonate (1.5 g) in acetonitrile (50 ml) were heated for 12 hours under reflux. The reaction mixture was concentrated to dryness, and the residue was dissolved in ethyl acetate - water. The organic layer was washed with water and dried. The sol~ent was evaporated in vacuo, and the residue was purified by column chromatography on silica gel to afford a colorless syrupy product (4.5 g, quantitative).
lH-NMR(200MHz,CDC13)~: 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(lH,d), 7.31(2H,d), 7.38-7.48(4H,m), 7.63(lH,dt), 7.74(lH,d).
34d) 3-~N-butyryl-N-(2~-cyanobiphenyl-4-vllmeth amino-4-cyano-5-methylthiophene-2-carboxylic acid A mixture o~ the compound obtained in Working Example 34c) (4.5 g) in a mixture of methanol (45 ml) ~l~s~s ~ 67 -and 2N-NaOH (7.4 ml) was stirred for 1.5 hour at room temperature. The reaction mixture was concentrated in vacuo and the residue was dissolved in water. To the solution was added lN HCl (15 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried, then the solvent was evaporated in vacuo to give a white powder (4.0 g, 93%).
lH-NMR(200MHz,CDC13)~: 0.89(3H,t), 1.59-1.77(2H,m~, 1.98-2.21(2H,m), 2.66(3H,s), 4.76(lH,d), 5.16(lH,d), 7.29-7.49(6H,m), 7.63(lH,dt), 7.71(lH,d).
34e) tert-Butyl 3- r N-butyrYl-N-(2'-cyanobiphenYl-4-yl!methyllamino-4-cyano-5-methylthiophene-2-carbamate A mixture of carboxylic acid obtained in Working Example 34d) (2.4 g), diphenylphosphoric acid azide (DPPA, 3.2 g) and triethylamine (1.2 g) in tert-butanol (25 ml) w~re stirred for 20 minutes at room temperature, followed by heating under reflux for 1.5 hour. The reaction mixture was concentrated to dryness, and the residue was dissolved in ethyl acetate. The solution was washed with water and dried, then tha solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel to give crystals. Recrystallization from ethyl acetate -hexane afforded colorless prisms (2.2 g, 79~), m.p.171-172C.
H-NMR(200MHz,CDC13)~: 0.91(3H,t), 1.37(9H,s), 1.58-1.78(2H,m), 1.96-2.16(2H,m), 2.56(3H,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-rN-butyryl-N-(2'-cyanobiphenvl-4-yl ! -methYl1amino-4-cyano-5-methYlthiophene A mixture of the carbamate obtained in Working Example 34e) (2.1 g) in 20% hydrogen chloride -methanol (40 ml) was heated for one hour under reflux.

2~51L~L65 The reaction mixture was concentrated to dryness and to the residue was added a saturated aqueous solution of NaHCO3, followed by extraction with eth~l acetate. The organic layer was washed with water and dried~ then the solvent was evaporated in vacuo. The residue was crystalli~ed form ethyl acetate - hexane to afford colorless needles (0.93 g, 66%), m.p.l60-161C.
H-NMR~200M~Iz,CDC13)~: 0.91(3H,t), 1.61-1.72(2H,m), 2.06-2.15(2H,m), 2.51(3H,s~, 3.20~2H,br s), 3.96(1H,d), 5.76(1H,d)~ 7.41-7.51(6H,m), 7.66(1H,dt), 7.47(1H,d).
34~) 6-CYano-l~r(?'-cYanobiPhenYl-4-Yl)methY11-5-methyl-2-propylthienoL2~3-dlimidazole A solution of the compound obtained in Working Example 34f) (1.9 g) in 10% hydrogen chloride - ethanol (55 ml) was heated for 5 days under reflux. The reaction mixture was concentrated to dryness and to the residue W2S added a saturated aqueous solution of Na~CO3, followed by extraction with ethyl acetate. The extract was washed with water and dried, then the solvent was evaporated }n vacuo. The residue was purified by column chromatography on silica gel to af~ord pale yellow powder (1.6 g, 89%).
lH-NMR(200MHz,CDC13)~: 1.02(3H,t), 1.85(2H,m), 2.70(3H,s), 2.79(2H,t), 5.47(2H,s), 7-21(2H~d)~ 7-41-7.57(4H,m), 7.65(1H,dt), 7.76(1H,d).
34h) 5-MethYl-2-propyl-6-(lH-tetrazol-5-yl ! -1- r r 2~-(lH-tetrazol-5-yl)bi~hen~1-4-YllmethYllthieno r 2,3-dl imida~ole A mixture of the compound obtained in Working Example 34g) (1.2 g) and trimethyltin a~ide (2.9 g) in toluene (30 ml) were heated for 3 days under reflux.
The precipitated syrupy product was dissolved in a mixture of methanol (20 ml) and lN HCl (12 ml). The solution was stirred for 30 minutes at room temperature. The reaction mixture was adjusted to pH
3-4 with lN NaOH. The reaction mixture was extracted 2(~ 65i with chloroform. The extract was washed with water and dried, then the solvent was evaporated in vacuo. The residue was purified by column chromatography on silica yel to give crystals. Recrystallization from methanol - ethyl acetate afforded pale yellow needles (0.87 g, 62%), m.p.237~238C (dec.).
Elemental Analysls for C24H22NlOS-MeOH:
C(%) H(%) N(%) Calcd.: 58.35; 5.09; 27.22 Found : 58.44; 4.93; 27.45 lH-NNR(200MHz,DMSO-d6)~: 0.92(3H,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, 915, 780, 760.
Working Example 35 4-Methyl~2-propyl~l~ r ~ 2~-(lH-tetrazol-5-Yl!biphenyl~4-yllmethyllthieno~3,4-dlimidazole-6-carboxylic acid 35a) tert-Butyl 3-amino-4-ethoxycarbonyl-5-methvlthiophene-2-carboxylate In substantially the same manner as Working Example 34a), the title compound was obtained as colorless prisms (2.5 g, 17 %) from ethyl cyanoacetate (5.7 g).
m.p.87-88C
H-NMR(200MHz,CDC13)~: 1.39~3H,s), 1.55(9H,s), 2.62(3H,s~/ 4.34(2H,q).
35b) tert-ButYl 3-butyrylamino-4-ethoxYcarbonyl-5-methvlthiophene-2-carboxylate In substantially the same manner as Working Example 34b), the title compound was obtained as colorless s~rup (2.8 g, quantitatively) from the compound (2.5 g) obtained in Woxking Example 35a).
l~-NMR(200~z,CDC13)~: 1.01(3H,t), 1.33(3H,t), 1.55(9H,s), 1.75(2H,m), 2.38(2H,t), 2.58(3H,s), 4.30(2HI~), 9.58(1H,br s).

~2~5~465 _ 70 _ 24205~9~7 35c) tert-Butyl 3-~ r N-butvryl-N-(2'-cvanobiphenyl-4-Yl!meth~l1amino-4-ethoxycarbonyl-5-methylthiophene-2-carboxYlate In substantially the same manner as Working Example 34c), the title compound was obtained as colorless syrup (3.8 g, 97%) from the compound (2.8 g) prepared in Working Example 35b).
H-NMR~2ooMHz~cDcl3)~: 0.89(3~,t), 1-19(3H~t)~
1.46(9H,s), 1.65(2H,m), 2.08(2H,t), 2.66(3H,s), 3.86-4.41(2H,m), 4.52(1H,d), 5.04(1H,d), 7.31(2H,d), 7.38-7.46t4H,m), 7.62(1H,dt~, 7.75(1H,d).
35d) 2-tert-Butox~carbonyl-3-~rN-butYr~l N-t2'-cyanobiphen~l-4-yl)methYllaminol-S-methylthiophe-ne--4 carboxylic acid The compound obtained in Working Example 35c) (1.9 g) was dissolved in a mixture of lN NaOH (5.6 ml) and ethanol (20 ml), and the solution was stirred for 6 hours at 70 to 80C. The raaction mixture was concentrated to dryness and the residue was acidified by the addition of lN HCl to give crystals.
Recrystallization from isopropyl ether -ethyl acetate afforded colorless needles (1.2 g, 67%), m.p.157-158C
ldec. ) .
H~NMR(200MHz,CDC13)~: 0.87(3H,t), 1~51(gH/s)r 1-55-1.75(2H,m), 1.98-2.18(2H,m) r 2.64(3H,s), 4.24(1H,d), 5.40(lH,d), 7.30-7.47(6H,m), 7.63(lH,d), 7.73(lH,d).
35e) tert-Butyl 4-amino-3- r r N-butyryl-N-t2'-c~anobiphenvl-4-yl)methyllaminol-5-methylthio~hene-2-carboxylate By substantially the same procedure as Working Example 34e), the title compound was obtained as colorless syrup (1.0 g, quantitatively) from the carboxylic acid (1.2 g) prepared in Working Example 35d).
1H-NMR(2ooMHz,cDcl3)~: 0.88(3H,t), 1-54(9H~s)~

2~5~6S

1.63(2H,m), 1.99-2.06(2H,m), 2.17(3H,s), 4~02(1H,g), 5.75(1H,d), 7.34-7.50(6H,m), 7.65(1H,dt), 7.75(1H,d).
IR(Neat)cm 1:3430, 3350, 2220, 1710, 1660.
35f) Eth~1 4-methyl-2-propyl-1-~2'-cyanobiphenyl-4-yl)methyllthieno r 3,4-dlimidazole-6-carboxylate The compound obtained in Working Example 35e) (1.0 g) was dissolved in 10% hydrogen chloride - ethanol (16 ml). The solution was heated for 63 hours under reflux. The reaction mixture was concentrated to dryness and to the residue was added an aqueous solution of sodium hydrogencarbonate, followed by extraction with ethyl acetate. The extract was washed with water and dried, then the solvent was ev~porated in vacuo. The residue was purified by column chromatography on silica gel to afford a pale yellow syrupy product (0.14 g, 14~).

H-NMR(200MXz,CDC13)~. 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,dt), 7.75(1Hrd).
IR(Neat)cm 1:2210, 1685, 1545, 1480, 1440, 1405, 1360, 1325, 1230, 1195, 1090, 755, 730.
35g) Ethyl 4-methvl-2-~ro~vl-1- r r 2'-(lH-tetrazol-5-Yl~biphenyl-4-yllmet-hvllthieno r 3,4-dlimidazole-6-s~YL~
In substantially the same manner as Working Example 23d), the title compound was obtained as colorless prisms (0.09 g, 56%) from the compound (0.14 g) prepared in Working Example 35f).
m.p.214-215C
Elemental Analysis for C26H26N6O2SØ2H2O:
C(%) H(%) N(%) Calcd.: 63.71; 5.43; 17.14 Found : 64.07; 5.50; 16.75 lH-NMR(200MHz,CDC13)~: 0.97(3H,t), 1.29(3H,t), ~(~5~6S

1.76(2H,m), 2.56(3H,s), 2.59(2H,t), 4.23(2H,q), 5.78(2H,s), 7.08t2H,d), 7.18(2H,d), 7.37-7.43(1H,m), 7.55-7.61(2H,m)/ 8.13-8.18(lH,m).
IR(KBr)cm 1:1690, 1540, 1325, 1230, 1095r 750-35h) 4-Methyl-2-ProPy~ r L2'-(lH-tetrazol-5-yl)-biphenyl-4-yllmethyllthieno r 3,4-dlimidazole-6-carboxylic acid By substantially the same procedure as Working Example 14, the title compound was obtained as colorless prisms (0.063 g, 76%) from the compound (Q.09 g) prepared in Working Example 35g).
m.p. 206-207C (dec.) Elemental Analysis for C24H22N6O2 2 C(%) H(%) N(%) Calcd.: 62.38; 4.88; 18.18 Found : 62.42; 4.73; 17.94 H-NMR~200~Hz,DMSO-d6)~: 0.88(3H,t), 1.62(2H,m), 2.55(3H,s), ~.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, 1200, 770.
Wor~ing Example 36 Acetoxymekhvl 2-methoxy-4-methyl-1- r r 2'-~lH-tetrazol-5-Yl)biphenyl-4-yllmethyllthienor3,4-dlimidazole-6-carboxylate In substantially the same manner as Working Example 5, the title compound was synthesized.
36a) 2-~ethoxy-4-methyl-1- r r 2'-~N-tritvltetrazol-5-3 o Yl ! biphenyl-4-yllmethYllthienor3,4-dlimidazole-6-carboxylic acid In substantially the same manner as Working Example 5a), the title compound was obtained as colorless crystals (0.65 g, 41~) from the tetrazole compound (1.0 g) preapred in Working Example 28.
m.p.178-180C

~5~65 lH-NMR(200MHz,DMSO-d6)~: 2.4S(3H,s), 3.95(3H,s), 5.47~2EI,s), 6.82-6.87(6H,m), 6.99-7.0~(4H,m), 7.2S-7.63(12H,m), 7.67-7.80(1H,m).
I~(KBr)cm :1675, 1570, 1530, 1450, 1395, 1220, 750, 710, 69U.
36b) Acetoxymethyl 2-methoxy-4-methyl-1- r r 2'-(lH-tetrazol 5-y~biphenyl-4-yllmethYllthieno r 3,4-dl-imidazole-6-carboxylate In substantially the same manner as Working Example 5b), the title compound was obtained as colorless crystals (0.156 g, 60~) from the compound (0.51 g) prepared in Working Example 36a) and chloromethyl acetate (0.2 g).
m.p.156-158C (dec.) Elemental Analysis for C25H22N6O2S:
C(%) H(%) N(%) Calcd.: 57.91; 4.28; 16.21 Found : 57.83; 4.28; 16.14 H-NMR(200MHz,CDCl3)~: 2.05(3H,s), 2-49(3Hrm)~
4.06(3H,m), 5.54(2H,s), 5.81(2H,s), 7.14-7.23(4H,m), 7.40-7.44(lH,m), 7.51-7.65(2H,m), 8.15-8.19(1~I,m).
IR(KBr)cm l:1750r 1700, 1610, 1570, 1455, 1450, 1400, 1380, 1365, 1330, 1240, 1200, 1000, 980.
Working Example 37 2-Ethyl-5-methyl-l- r r 2'-(lH tetrazol-5-yl!biPhenY-l-4 yl~methyllthienor2,3-dlimidazole-6-carboxylic acid By substantially the same procedures as Working Examples 34 and 35, the title compound was synthesized.
37a) tert-ButYl 4-ethoxycarbonyl-5-methYl-3-ProPionylaminothiophene-2-carboxylate In substantially the same manner as Working Example 34b), the title compound was obtained as a yellow syrupy product (3.29 g, 92%) from the compound (3.0 g) prepared in Working Example 35a) and propionyl chloride (1.1 ml).

2~5~L6~

lH-NMR(200MHz,CDC13)~: 1.24(3H,t), 1.32(3H,t), 1.55(9H,s), 2.43(2H,~), 2.58(3H,s), 4.29(2H,q), 9.56(1H,br s).
IR(Neat)cm 1 3325, 1720, 1690, 1670r 1570, 1410, 1360, 1240, 11~0, 1050.
37b) tert-Butyl 3-~rN-(2'-cyanobiphenyl-4-yl)methyl-N-propionyll_minol-4-ethoxycarbonyl-5-methylthiophene-2=carboxvlate In substantially the same manner as Working Example 34c), khe title compound was obtained as a pale yellow syrupy product (4.3 g, 84%) from the compound produced in Working Example 37a).
H-NMR(200MHz/CDC13)~: 1.10(3H,t)~ 1.19(3H,t), 1.46~9Hrs), 2.13(2H,q), 2.65(3H,s), 3.81-4.10~2H,m), 4.50(lH,d), 5.04(lH,d), 7.30(2H,d), 7.3d-7.45(4H,m), 7.58-7.66(lH,m), 7.73-7.77(lH,m).
37c) 3-~N-(2'-cyanobiphenyl-4-y ~ethYl-N-propionyllamino-4-ethoxycarbonyl-5-methylthiophene-2-carboxylic acid In substantially the same manner as Working Example 34d), the title compound was obtained as colorless needles (3.27 g, 85%) from the compound (4.3 g) prepared in Working Example 37b).
m.p.120-122C
H-NMR(200MHz,CDC13)~: 1.09(3H,t)r 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(lH,d), 7.27-7.47(6H,m), 7.58-7.66(lH,m), 7.71-7.74(lH,m).
37d) Eth~l 2-amino-3- r r N-~2'-c~anobiphenyl-4-yl~methyl-N-propionyllaminol-5-methylthiophene-4-carboxylate By substantially the same procedures as Working Examples 34e) and 34f), the title compound was obtained as a pale yellow syrup (1.56 g, 53%) from the compound (3.14 g) prepared in Working Example 37c).

- 75 _ '~5~6~

H NM~(2MHZrCDC13)~ 03(3H,t), 1.33(3H,t), 2.07-2.18(2H,m), 2.58(3H,s), 3.83(1H,d), 4.25(2H,q), 5.67(1H,d), 7.41-7.50(6H,m), 7.61-7.69(1H,m), 7.72-7.76(lH,m).
IR~Neat)cm 1 3420, 3325, 2200, 1700, 1650, 1630, 1380, 1310, 1295, 1215, 1050, 760, 750.
37e) Ethyl ~ 2'-cyanobiphenyl-4-yl)methYll-2~
ethyl-S-methylthieno r 2~3-dlimidazole 6-carboxvlate In substantially the same manner as Working Example 34g), the title compound was obtained as colorless needles (0.3 g, 20 %) from the compound (1.56 g) produced in Working Example 37d).
m.p.136-138C
H-NMR(200MHz,CDC13)~: 1.22(3M,t), 1.37(3H,t), 2.75(3H,s), 2.77t2H,q), 4.23(2X,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(lH,m).
IR(KBr)cm 1:2220, 1705, 1475, 1400, 1375, 1365, 1325, 1290, 1235.
37f) Ethy~ 2-ethyl-5-methvl-1- r r 2'-~lH-tetrazol-5-Yl!biphenyl-4-yl)methyllthienor2,3-dlimidazole-6-carboxylate In substantially the same manner as Working Example 34h~, the title compound was obtained as colorless needles (0.23 g, 71~) from the compound produced in Working Example 37e).
m.p.114-116C
Elemental AnalysiS for C25H24N62S Sc4H82 C(%) H(%) N(%) Calcd.: 62.77; 5.46; 16.27 Found : 62.65; 5.41; 16.29 1H-NMR(200MHz,CDC13)~ 1.14(3H,t), 1-18(3H,t), 2.51(2H,q), 2.62(3H,s), 4.14(2H,q), 5.61(2H,s), 6.72(2H,d), 6.97(2H,d), 7.35-7.41(lH,m), 7.56-7.65(2H,m), 7.95-8.02(lH,m).
IR(KBr)cm 1:1705, lS00, 1410, 1325, 1300, 1240, 1210, ~(!5~)5 1045, 755.
37g) 2-Ethyl-5-methyl-1- r r 2'-(lH-tetraæol-S-yl)-biphenyl-4-yllmethyllthieno r 2,3-dlimidazole-6-carboxylic acid In substantially the same manner as Working Example 14, the title compound was obtained as colorless crystals (O.Og g, 80%~ from the compound (0.13 g) produced in Working Example 37f).
m.p.272 274C (dec.) Elemental ~nalysis or C23H20N6O2 2 C(%) H(%l N(%) Calcd.: 61.40; 4.61; 18.68 Found : 61.45; 4.61;. 18.52 1H-NMR(200MHz,DMSO-d6)~: 1.17(3H,t), 2.67(2H,q), 2.69(3H,s), 5.76(2H,s), 6.91(2H,d), 7.04(2M,d), 7.49-7.71(4H,m)-IR(KBr)cm 1:1680, 1490, 1480, 1405, 1375, 1325, 1300, 1240, 1205, 1070, 750, 705.
Working Example 38 Methyl 2-ethyl-5-methyl~ r 2'-~lH-tetrazol-5-yl)biphenyl-4-yllmethyllthienor2,3-dlimidazole-6-carboxylate A solution of the ethyl ester (0.057 g) o~tained in Working Example 37f) in methanol (2 ml) containing sodium methoxide (50 m~) was heated under reflux. The reaction mixture was concentrated to dryness, which was dissolved in water, followed by adjusting the pH to about 4 with lN HCl to give crystals.
Recrystallization from ethyl acetate - methanol afforded colorless crystals (0.037 g, 73%), m.p.242-245C (dec.).
Elemental Analysis for C24H22N6O2S.O.lH2O:
C(%) H(%) N(%) Calcd.: 62.62; 4.86; 18.26 Found : 62.53; 4.94; 17.95 lH-NMR(200M~z,DMSO-d6)~: 1.19(3H,t), 2.67(3H,s), ~ 77 ~ 65 2.70(2H,q), 3.63(3H,s), 5.63(2H,s), 6.88(2H,d), 7.04(2H r d), 7.48-7.70(4H,m).
IR(KBr)cm 1:1710, 1500r 1450r 1440r 1410, 1300, 1230, 1060, 770.
Working Example 39 Methyl 2-Ethylthio-4-phenyl~l- r~ 2'-(lH-tetr~zol-5-yl!biphenyl-4-yllmethyllthienor3~4-dlimidazole-6 carboxylate 39a ! Methyl 3 4-Diamino-5-PhenylthioPhene-2-carboxylate The title compound was prepared by the sameprocedure reported ~y K. Hartke et al., [K. Hartke and B. Seib, Pharmazie, 2S, 517 (1970)].
m.p. 148-150C (lit, 118C) 1H-NMR(200MHz,DMSO-d6)~: 3.76(3H,s), 7.38-7.53(3H,m), 7.58-7.64(2H,m), 7.69(4H,br).
39b ! Me:thYl 2 -Mercapto - 4 -phenYlthi eno r 3,4-dlimidazole-6-carboxylate A solution of methyl 3,4-diamino-5-phenylthiophene~2-carboxylate (1.5 g) and thiocarbonyldiimidazole (1.1 g) in DMF (5 mQ) was stirred at 50C for 1 hr. To the reaction mixture was added water to give crystals, which were recrystallized from DMF-H2O to give pale yellow crystals (1.7 g, quant.).
m.p. 294-296C (d) Elemental Analysis for C13HloN2O2S2:
C(%) H(%) N(%) Calcd.: 53.77; 3.47; 9.65 Found : 53.72; 3.49; 9.67 lH-NMR(200MHz,DMSO-d6)~: 3.82(3H,s), 7.34-7.51(3H,m), 7.72-7.77(2H,m) IR(KBr)cm1:1685, 1640, 1575, 1550, 1500, 1475, 1440, 1410, 12~0, 1195, 1170l 1140, 1015, 955, 830, 750, 720, 680.
39c ! Methyl 2-EthYlthio-4-Phenylthieno r 3, 4-- 78 - 2~ 6S

.dlimidazole-6-carboxylate A solution of methyl 2-mercapto-4-phenylthieno[3,4-d]imidazole~6-carboxylate (1.7 g), ethyl iodide and 2N NaOH (3 mQ) in methanol (30 mQ) was stirred at room -temperature for 6.5 hr. ~he reaction solution was concentrated to dryness and the residue was triturated with H2O to give a crystalline product.
Recrystallization from MeOH-EtoAc to give pale yellow needles (1.3 g, 68%).
m.p. 214~215C
Elemental Analysis for C15H14N2O2S2:
C(%) H(%) N(%) Calcd.: 56.58; 4.43; 8.80 Found : 56.55; 4.63; 8.84 lH-NMR(200MHz,DMSO-d6)~: 1.43~3H,t), 3.33(2H,~), 3.83(3H,s), 7.31-7.39(lH,m), 7.44-7.52(2H,m), 8.05-8.09(2H,m) IR(KBr)cm~l:1640, 1610, 1485, 1455, 1435, 1320, 1280, 1255, 1195, 1125, 1020, 755 39d!_ Methyl 2-Ethylthio-4-phenyl-1-rr2'~(1H-tetrazol-5-yl ! biphenyl-4-yllmethyllthienor3,4-dlimidazole-6-carboxylate The title compound was obtained by the same procedure for Working Example 1 as colorless needles (1.4 g, 61%) from methyl 2-ethylthio~4~
phenylthieno[3,4-d]imidazole-6-carboxylate (1.3 g).
m.p. 214-216C (d) Elemental Analysis for C29H24N602S2-0.2H20:
C(%) H(%) N(%) Calcd.: 62.62; 4.42; 15.11 Found : 62.54; 4.22; 15.03 lH-NMR(200MHz,DMSO-d6)~: 1.41(3H,t), 3.35(2H,q), 3.73(3I-I,s), 5.67(2H,s), 7.05(2H,d), 7.11(2H,d), 7.34-7.71(7H,m), 8.07-8.13(2H,m) IR(KBr)cm1:1680, 1595, 1485, 1440, 1430, 1320, 1300, 1280, 1255, 1235, 1180, 1170, 1110, 1045, 960, 915, 750 Working Example 40 2-Ethvlthio-4-PhenYl-l- r ~ny~l-4-yllmethYlLthieno r 3,4-dlimidazole-6-carboxylic acid The title compound was obtained as yellow needles (0.64 g, 73%) from methyl 2-ethylthio~4-phenyl-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methy:L]thieno[3,4-d]imidazole-6-carboxylate (0.9 g) by the same procedure for Working Example 2.
m.p. 229-230C ~d) Elemental Analysis for C28H22N6O2S~ O 5H2O
C(~) H(%) N(%) Calcd.: 61.41; 4.23; 15.35 Found 61.69; 3.95; 15.31 1H-NMR(200MHz,DMSO-d6)~: 1.40(3H,t), 3.34(2H,q~, 5.71(2H,s), 7.06(2H,d), 7.13(2H,d), 7.32-7.71(7H~m), 8.08-8.12(2H,m) IR(KBr)cml:1635, 1585, 1525, 1485, 1450, 1320, 1310, 1280, 1165, 770, 760 Working Example 41 Methyl 2-Ethylthio-4-propyl-1- r r 2'-ilH-tetrazol-5-yl)biphenyl-4-yllmethyllthienor3,4-dlimidazole-6-carboxylate 41a) MethY1 3,4-diamino-5-Propvlthio~hene-2-carboxyalte The title compound was prepared by the same procedure reported by K. Hartke et al., [K. Hartke and B. Seib, Pharmazie, 25, 517(1970)]
m.p. 185C (d) 1H-NMR(9OMHz,DMSO-d6)~: 0.97(3H,t), 1.43-1.83(2H,m), 2.80(2H,t), 3.73(3H,s), 8.33(5H,brs) IR(Nujol)cml:3400, 3310, 2730, 2540, 1695, 1630, 1495, 4lb ! Methyl 2-Mercapto-4-proPYlthieno r 3,4-dlimidazole-6-carboxyalte The title compound was obtained as pale yellow 2~5~5 prisms in 9S% yield by the same procedure for Working Example 39b).

m.p. 255-260C (d) 1H-NMR(90M~IZ~DMso-d6)~: 0-90(3H,t), 1.43-1.83(2H,m), 2.73(2H,t), 3.20(1H,s)l 4.77(3H,s), 12.50(1H,brs) IR(Nujol)cm :3160, 3100, 1670, 1575, 1435, 1330, 1310, 1205, 1110 41c) _Methyl 2-Ethylthio-4-ProPvlthieno r 3,4-dlimidazole-6-carboxyalte The title compound was obtained as colorless needles in 93% yield by the same procedure for Working Example 39c).
m.p. 135-136C
H-NMR(9OMHz,CDCQ3)~: 1.00~3H,t), 1.43(3H,t), 1-60-1.93(2H,m), 2.97(2H,t), 3.30(2H,q), 3.87(3H,s), 9.30(lH,brs) IR(Nujol)cm1:3220, 1665, 1615, 1440, 1315, 1210, llOS
41d! Methyl 2-Ethylthio-4-propyl-l-rr2'-(lH-tetrazol-5-yl ! biphenyl-4-YllmethYllthieno~3~4-dlimidazole-6-carboxYalte The title compound was obtained as colorless needles in 50% yield by the same procedure for Working Example 1.
m.p. 162-163C
Blemental Analysis for C26H26N602S2-H20:
C(%) H(%) N(%) Calcd.: 58.19; 5.26; 15.66 Found : 58.47; 5.20; 15.65 1H-NMR(9OMHz,CDCQ3)~: 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 :3360, 2720, 1685, 1600, 1450, 1430, 1325, 1245, 1170 Working Example 42 2-EthYlthio-4-PrOPyl-l- r r 2'-(lH-tetrazol-5-yl!biphenyl-- 81 - ~ 65 4-yllmethyllthienoL~l4-dlimidazole-6-carboxylic acid The title compound was obtained as colQrless needles in 82% yield by the same procedure for Working Example 2.
m.p. 187-188C (d) Elemental Analysis for C25H24N6O2S2 C(%) H(%) N(%) Calcd.: 59.50; 4.79; 16.65 Found : 5g.35; 4.56; 16.69 lH-NMR(9ONHz,DMSO-d6)~: 1.00(3H,t), 1.40(3H,t), 1.63-2.03(2H,m), 2.97(2H,t), 3.27(2H,q), 5.70(2H,s), 7.07(2H,d), 7.17(2H,d), 7.43-7.73(4H,m) IR~Nu~ol)cml:2720, 1635, 1590, 1530, 1450, 1385, 1320, 1260, 1160, 755 Working Example 43 Methyl_4-Methyl-2-pentafluoroethvl-1-~ r 2'-tlH-tetrazol~
; 5-yl ! biphenyl-4 -Yl lmethYllthieno r 3,4-dlimidazole-6-carboxylate 43a) Methyl 4-Methyl-2-pentafluoroeth~lthieno r 3,4-dlimidazole-6-carboxylate A mixture of methyl 3,4-diamino-5-methylthiophene-2-carboxylate (1.0 g) in pantafluoropropionic acid ~8.9 g) was stirred at 100C for 6 hr. The reaction solution was concentrated to dryness and the residue was suspensed in water. The mixture was made basic with aqueous solution of K2CO3, followed by extraction with ethyl acetate. ~he organic layer was washed with water, dried and concentrated to dryness. The residue was purified by silica gel column chromatography to give crystals. Recrystallization from isopropyl ether-hexane gave colorless plates (0.86 g, 51%).
m.p. 156-157C
Elemental Analysis for C1oH7F5N2O2S:
C~%) H~%) N(%) Calcd.: 38.22; 2.25; 8.91 Found : 38.23; 2.45; 8.87 - 82 - ~ ~5~5 IR(KBr~cm :1695, 1620, 1560, 1440, 1375, 1330, 1300, 1280, 1220, 1150, 1110, 1030, 84~, 755, 750, 735 43b ! Methyl 4-Methyl-2--pentafluoroeth~ rl2'-(lH-tetrazol-5-~l)biphenv1-4-yllmethyllthieno~3~4-dlimidazole-6-carboxylate The title compound was obtained as colorless needles in 26% yield by the same procedure for Working Example 39d).
m.p. 184-186C
Elemental Analysis for C24H17F5N6O2S:
C(%) H(%) N(%) Calcd.: 52.56; 3.12; 15.32 Found : 52.42; 2.89; 15.06 H-NMR(200MHz,CDCQ3)~: 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(lH,m) IR(KBr)cml:1705, 1600, 1550, 1480, 1450, 1440, 1420, 1345, 1320, 1260, 1240, 1225, 1200, 1190, 1140, 1110, 1095, 1045, 96~, 940, 755, 735 Working Example 44 4-Methyl-2-~entafluoroethYl-l- r r 2'-(lH-tetrazol-S-Yl ! biphenyl-4 -yl lmethyl lthieno r 3,4-dlimidazole-6-carboxylic acid The title compound was obtained as colorless 25 crystals in 32% yield by the same procedure for Working Example 2.
m.p. 201-202C (d) Elemental Analysis for C23H15F5N6O2S 2 C(~) H(%) N(%) Calcd.: 51.34; 2.88; 15.62 Found : 51.29; 2.92; 15.48 lH N~R(200MHz,DMSO-d6)~: 2.69(3H,s), 6.00(2H,s), 6.96(2H,d), 7.04(2H,d), 7.50-7.67(4H,m) IR(KBr)cml:1645, 1540, 1260, 1210, 1140, 1110, 960, 940, 745 Working Example 45 - 83 - ~ ~5 Methyl 2-Heptafluoropropyl-4-methYl-l-r r 2'-llH-te~razol-5-y~biphenyl-4-yllmethyllthienoL3,4- ~`
dlimidazole-6-carboxylate 45a ! MethYl 2-HeptafluoroPropYl-4-methYlthieno~3,4-dlimidazole-6-carboxylate The title compound was obtained as colorless prisms in 53% yield by the same procedure for Working Example 43a).
m.p. 147-148C
Elemental Analysis for C11H7F7N2O2S:
C(%) H(%) N(%) Calcd.: 36.27; 1.94; 7.69 Found : 36.38; 1.83; 7.99 H-~MR(200MHz,CDCQ3)~: 2.76(3H.s), 3.92(3Hrs), 9.80(lH,brs) IR(KBr)cml:1700, 1620, 1560r 1440, 1375r 1350r 1330r 1280r 1220, 1200, 1180, 1150, 1105r 980r 910, 865, 760, 745, 730 4Sb !_ Methyl 2-HePtafluoroPropyl-4-methyl-1- r r 2'-(lH-tetrazol-5-vl)biphenyl-4-YllmethYllthienOr3,4-dlimidazole-6-carboxvlate The title compound ~as obtained as colorless needles in 33% yield by the same procedure for Working Example 39b).
m.p. 144-145C
Elemental Analysis for C25H17F7N6O2S:
C(%) H(%) ~(%) Calcd.: 50.17; 2.86; 14.04 Found : 50.03; 2.95; 13.84 lH-NMR(200MHz,CDCQ3)~: 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(12H,m), 8.23-8.27(lH,m) IR(KBr)cm :1700, 1600, 1545, 1480, 1435, 1330, 1235, 1205, 1130, 1120, 1090, 905, 860, 755, 735 Working Example 46 2-Heptafluoropropyl-4-methyl-1- r r 2'-tlH-tetrazol-5-- ~4 ~ fi~

carboxylic acid The title compound was obtained as colorless needles in 54~ yield by the same procedure for Working Example 2.
m.p. 204-205C (d) Elemental Analysis for C24H15F7N6O2S:
C(%~ H(%) N(%) Calcd.: 49.32; 2.59; 14.38 Found : 49.01; 2.88; 14.28 lH-NMR(200MHz,DMSO-d6)~: 2.69(3H,s)r 5.99(2H,s), 6.93(2H,d), 7.04(2H,d)/ 7.49-7.70(4H,m) IR(KBr)cm :1645, 1540, 1335, 1220, 1120, 870, 850 Working Example 47 Me_hyl 2-Ethylthio-4-methylthio-1- r r 2'-(lH-tetrazol-5-yl~ biphenyl-4-yllmeth ~lthienor3~4-dlimidazole-6-c~
47a ! Methyl 3,4-diamino-5-methylthiothiophene 2-carboxylate The title compound was prepared by the similar procedure described by K. Hartke et al., [K. Hartke and B. Seib, Pharmazie, 25, 517(1970)].
m.p. 95-97C
H-NMR(90MHz,CDCQ3)~: 2.33(3H,s), 3-60(2H~brs)~
3.80(3H,s), 5.27(2H,brs) IR(Nujol)cm :3450, 3400, 3350, 1670, 1620, 1495, 1450, 1425, 1320, 1250, 1130 47b) Meth~l 2-Mercapto-4-methylthiothieno~3,_4-~ dazole-6-carboxYlate The title compound was obtained as yellow prisms in 77% yield by the same procedure for Working Example 39b).
m.p. 240-242C (d) 1H~NMR(9OMHz,DMSO-d6)~: 2.53(3H,s), 3.27(1H~brs), 3.77(3H,s), 12.77(1H,brs) ;2(~S'~6S
~ 85 -IR(NIljol)cm~:3200, 3125, 3075, 3020, 1680, 1625, 1555, 1490, 1430, 1330, 1290, 1190, 1165, 1070 47c ! Meth~l 2-Ethylthio-4-methylthiothienOr3,4-dlimidazole-6-carboxylate The title compound was obtained as colorless needles in g3% yield by the same procedure for Working Example 39c).
m.p. 170-172C
1H~NMR(9OMHz,CDCQ3)~: 1.43(3H,t), 2.67(3H,s), 3-33(2H,q), 3~87(3Hrs)~ 9.23(1H,brs) IR(Nujol)cml:3200, 1655, 1615, 1510, 1440r 1315, 1150 47dl Methyl 2-Eth~lthio-4-methylthio-1- r r 2'-(lF~-tetrazol-5-yl)bi~henYl-4-Yllmethvllthieno r 3,4-dlimidazole-6-carboxylate The title compound was obtained as colorless needles in 79% yield by the same procedure for Working Example 1.
m.p. 200-201C
Elemental Analysis for C24H22N602S3:
C(%) H(~) N(%) Calcd.: 55.15; 4.24; 16.08 Found : 55.08; 4.14; 15.95 lH-NMR(9OMHz,CDCQ3)~: 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(lH,m) IR(Nujol)cml:2750, 1680, 1590, 1510, 1445, 1425, 1330, 1320, 1235, 1170, 755 Working Example 48 _ h lthio-4-me~hylthio-1- r r 2'-(.lH-tetrazol-5-yl!biphenyl-4=yllmethyllthienor3,4-dlimdidazole-6-carboxylic acid The title compound was obtained as colorless needles in 29% yield by the same procedure ~or Working Example 2.
m.p. 176-178C (d) S

Elemental Analysis for C23H20N6O2 3 2 C(%) H(%) Nt%) Calcd.: S3.37; 4.09; 16.23 Found : 53.67; 3.84; 16.52 H-NMR(9OMHz,CDCQ3)~: 1.33(3H,t), 2.67(3H,s), 3.27(2H,q), 5.67(2H,s), 7.07(4H,s), 7.43-7.73(4H,m), IR(Nujol)cm :1630, 1575, 1500, 1450, 1320, 1165, 755 Working Example 49 Methyl 2-Isopropoxy-4-methyl-1- U2'-~lH-tetrazol-5-yl!biphenyl-4-yllmethylltheinor3 4-dlimidazole-6-carboxylate 49a ! Methyl 2-Isopropoxy-1- r ( 2'-cyanobiphenyl-4-yl!methyll-4-methylthienor3,,4-dlimidazole-6-car~oxylate The title compound was obtained as colorless crystals in 45% yield by the same procedure for Working Example 23c) starting from methyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethylsulfinyl-4 methylthieno[3,4-d~imidazole-6-carboxylate.
lH NMR(200MHz,CDCQ3)~: 1.39(6HId), 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(lH,m), 7.73-7.77(lH,m) 49b ! Methyl 2-Isopropoxy-4-methYl-l- r 2'-(lH-tetrazol-5-yl!biphenyl-4-vllmethYllthienOr3~4-dlimidazole-6-carboxylate The title compound was obtained as pale yellow crystals in 48% yield by the same procedure for Working Example 23d).
m.p. 170-173C (d) Elemental Analysis for C25H24N603S-O.5H20:
C(%) H(%) N(%) Calcd.: 60.35; 5.06; 16.89 Found : 60.13; 5.02; 16.93 H-NMR(200MXz,CDCe~ 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(lH,m) 2(~5~L465 IR(KBr)cml:1690, 1615, 1570, 1530, 1440, 1380, 1370, 1330, 1320, 1240, llO0, 755 Working Example 50 2-IsoproPOxY-4-methY~ r 2t-(lH-tetrazol-5-yl)biphenyl-4-Yllmethyllthieno~3,4-dlimidazole-6-carboxylic acid The title compound was obtained a~ colorless crystals in 46% yield by the same procedure for Working Example 14.
m.p. 184-188C (d) Elemental Analysis for C24H22M~O3S-H2O:
C(%) H(%) N(~) Calcd.: 59.49; 4.9g; 17.34 Found : 59.19; 4.68; 17.21 H-NMR(200MHz,DMSO-d6)~: 1.27(6H,d)r 2.38(3H,s), 5.04-5.17(1H,m), 5.70(2Hrs), 7.01(2H,d), 7.08(2H,d), 7.23-7.36(3H.m), 7.48-7.53(1Hrm) IR(KBr)cml:1620~ 1570, 1540, 1450, 1445, 1420, 1410, 1380, 1330r 1250, 750 Working Example 51 Methyl 2-Trifluoromethyl~4-methyl-1-LL2'-(lH-tetrazol 5-Yl!biPhenyl-4-yllmethyllthieno,r3,4-dlimidazole-6-carboxylate 51a~ Methyl 4-Methyl-2-trifluoromethvlthienO r 3,4-dlimidazole-6-carboxYlate The title compound was obtained as colorless plates in 55% yield by the same procedure for Working Example 43a).
m.p. 192-193C
Elemental Analysis for CgH7F3N2O2S
C(%) H(%) N(%) Calcd.: 40.91; 2.67; 10.60 Found : 40.30; 2.63; 10.55 lH-NMR(200MHz,CDCQ3)~: 2.74(3H,s), 3.92(3H,s), lO.l(lH,brs) IR(KBr)cm1:1700, 1620, 1560, 1435, 1370, 1345, 1290, 1220, 1180, 970, 755, 730 S'~65i - ~8 -51b~ MethYl 2-Trifluoromet~yl-4-methrl-l-r~2'-(lH-tetrazol-5-yl~biphenyl-4-yllmethyllthienor3,4-dlimidazole-6-carboxylate The title compound was obtained as colorless needles in 46% yield by the same procedure for Working Example 1.
m.p. 229-230C ~d) Elemental Analysis for C23H17F3N5O2S:
C(%) H(%) N(%) Calcd.: 55.42; 3.44; 16.86 Found : 55.36; 3.51; 17.13 H-NMR(200MHz,CDCQ3)~: 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(lH,m) IR~KBr)cml:1700, 1560, 1450, 1415, 1290, 1250, 1195, 1140, 1125, 755 Working Example 52 2-Trifluoromethyl-4-methyl-1- r r 2'~lH-te~razol-5-Yl!biphenyllmethyllthienor3,4-dlimidazole-6-carboxylic acid The title compound was obtained as colorless needles in 21% yield by the same procedure for Working Example 14.
m.p. 226-228C (d) Elemental Analysis for C22H15F3N6O2S:
C(%) H(%) N(%) Calcd.: 54.54; 3.12; 17.35 Found : 54.48; 2.99; 17.40 lH-NMR(200MHz,DMSO-d6)~: 2.69(3H,s), 5.94(2H,s), 6.98(2H,d), 7.05(2H,d), 7.50-7.71(4H,m) IR(KBr)cml:1645, 1550, 1200, 1145, 760, 750 Experimental Example 1 Inhibitor~ Effect of Bindinq of Anqiotensi _ II to Anqiotensin RecePtor [Method]
An experiment of inhibition on the bindiny of 89 ~ ~ S ~ ~ S

angiotensin II (A-II) receptor was conducted by modifying the method of Douglas et al. ~Endocrinology, 102, 6~5-696 (197~)]. ~n A-II receptor membrane fraction was prepared from bovine adrenal cortex.
The compound of the present invention (10 6M or 10 M) and125I-angiotensin II tl25I-A-II) (1.85 kB~/50 ~l) were added to the receptor membrane fraction, and the mi~ture was incubated at room temperature for one hour. The receptor-bound and free 125I-A-II were separated through a filter (Whatman GF/B filter), and the radioactivity of 125I-A-II bound to the receptor - was measured.
[Results]
The results relating to the compounds of the present inven~ion are shown in [Table 1].
Experimental Example 2 Inhibitory ~ect of the ComPound of the Present Invention on Pressor Action o~ Anqiotensin [Method]
Jcl: SD rats (9 week old, male) were employed. On the previous day of the experiment, these animals were applied with cannulation into the femoral artery and vein under anesthesia with pentobarbital Na. The animals were fasted but allowed to access freely to drinking water until the experiment was started. Just on the day of conducting the experiment, the artery cannula was connected with a blood-pressure transducer, and the average blood pressure was recorded by means of polygraph. Before administration of the drug, the pressor action due to intravenous administration of angiotensin II (A-II) (100 ng/kg) as the control was measured. The drugs were orally administered, then, at each point of the measurement, A~II was administered intravenously, and the pressor action was similarly measured. By comparing the pressor action before and after ad~ninistration of the drug, the percent - 90 - Z~5~465 inhibition by th~ drug on A-II-induced pressor action was evaluated.
[Results]
The results relating to the compounds of the present invention are shown in ~Table 1].

- 91 - Z(~S~L6~;i ~CE~Jn ~9 ~3 J~ ~ R~

R~

, _ _ _ =
Working Rl ~2 R3 R4 Radi.oreceptor Pressor Example Assay Response . 1 x l x 1 mg/kg r~ ~ _ 10-7M 1o-6M (P ~ ? _ 1 SEt Tet COOMe _ Me 68_ 91 +a~
2 SEt Tet COOH Me 18 64 +++
_ _ SEt Tet O Me 59 89 +++

COOCM20C Bu 6 SEt Tet O Me 46 84 +++
COOCIHeOCO/~--H~\
_ _ 7 _ SMe Tet COOMe Me 55 77 + _ SMe Tet COOH Me 14 50 +++
_ _ .. I
17 SiPr Tet COOH Me 26 _ 64 +++
18 SBu Tet COOH Me 33 66 +
_ _ 22 SEt Tet COOH H 45 8 4 ++
___ _ _ _ _ 28 OMe Tet COOH Me 19 65 +++ _ _29 OEt Tet COOH Me 39 67 NTb~
30 OPr _Tet COOH Me 33 72_ NT _ 31 NHEt Tet COOH Me 26 75NT
36 OMe Tet O Me 73 92+++
. __ ~ COOCH20CCH3 a) -~+ 2 70% > -~+ 2 50% ~ ~ 2 30% > -b) N.T. = not tested

Claims (42)

1. A compound of the formula:
(I) [wherein:
the ring A is a thiophene ring which may, in addition to the R3 group, optionally have a substituent selected from the group consisting of halogen, nitro, cyano, amino, N-C1-4 alkyl-amino, N,N-di-C1-4 alkylamino, phenylamino, morpholino, piperidino, piperazino, N-phenylpiperazino, tetrazolyl (which is optionally protected by C1-4 alkyl, C2-5 alkanoyl or benzoyl), trifluoro-methanesulfonamido, phosphoric acid residue, sulfonic acid residue, -W-R6 (wherein W is a chemical bond, -O-, -S- or -CO- and R6 is hydrogen, C1-4 alkoxy, hydroxyl-substituted C1-4 alkoxy, amino, halogen or C1-4 alkyl), or -(CH2)?-CO-D (wherein D is i) hydrogen, ii) hydroxyl, iii) amino, iv) N-C1-4 alkylamino, v) N,N-di-C1-4 alkylamino or vi) C1-6 alkoxy whose alkyl moiety may optionally be substituted with a) hydroxyl, b) amino, dimethylamino, diethyl-amino, piperidino or morpholino, c) halogen, d) -OC(R7)HOCOR8 [wherein R7 is (1) hydrogen, (2) C1-6 alkyl, or (3) C5-7 cyclo-alkyl and R8 is (1) C1-6 alkyl, (2) C2-8 alkenyl, (3) C5-7 cyclo-alkyl, (4) C1-3 alkyl substituted with C5-7 cycloalkyl or phenyl which may optionally be further substituted with chlorine, (5) C2-3 alkenyl substituted with C5-7 cycloalkyl or phenyl, (6) C6-10 aryl, (7) C1-6 alkoxy, (8) C2-8 alkenyloxy, (9) C5-7 cyclo-alkyloxy, (10) C1-3 alkoxy substituted with C5-7 cycloalkyl or C6-10 aryl, (11) C2-3 alkenyloxy substituted with C5-7 cyclo-alkyl or C6-10 aryl, (12) C6-10 aryloxy in which the aryl may optionally be further substituted by nitro or tetrazolyl that may optionally be protected with C1-4 alkyl, C2-5 alkanoyl or benzoyl], (e) C1-6 alkoxy, (f) C1-6 alkylthio or (g) 5-methyl-2-oxo-1,3-dioxolen-4-yl, and ? is 0 or 1;
R1 is hydrogen or hydrocarbon residue which is selected from the group consisting of C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, phenyl and phenyl-C1-4 alkyl, each of the alkyl, alkenyl, alkynyl and cycloalkyl being optionally substituted by hydroxyl, amino, mono- or di-C1-4 alkylamino, halo-gen, C1-4 alkylthio or C1-4 alkoxy and the phenyl in each of the said phenyl or phenyl-C1-4 alkyl being optionally substituted with halogen, nitro, C1-4 alkoxy or C1-4 alkyl and which may optionally be bonded to the imidazole skeleton through a hetero atom -O-, -S(O)m- (wherein m is 0, 1 or 2) or -N(R5)- (where R5 is hydrogen or C1-4 alkyl);
R2 and R3 are independently a group capable of form-ing an anion or a group convertible thereto and are selected from the group consisting of (a) -NHSO2CF3, (b) phosphoric acid residue, (c) sulfonic acid residue, (d) cyano, (e) tetrazolyl of the formula:

[wherein R is C1-4 alkyl, triphenylmethyl, 2-tetrahydropyran-yl, C1-4 alkoxy-C1-4 alkyl, cyano or benzyl optionally substituted with C1-4 alkoxy or nitro]
and (f) optionally esterified or amidated carboxyl of the formula:
-CO-D' [wherein D' is i) hydroxyl, ii) amino, N-lower alkylamino or N,N-dilower alkylamino, iii) C1-6 alkoxy whose alkyl moiety may be substituted with hydroxyl, amino, dimethylamino, diethylamino, piperidino, morpholino, halogen, C1-6 alkoxy, C1-6 alkylthio or 5-methyl-2-oxo-1,3-dioxolen-4-yl or iv) a group of the formula:
OCH(R7)OCO R8 (in which R7 and R8 are as defined above);
X is a direct bond or a spacer selected from the group consisting of C1-4 alkylene, -CO-, -O-, -S-, -NH-, -CONH-, -OCH2-, -SCH2- and -CH=CH-; and n is an integer of 1 to 2]
or a pharmaceutically acceptable salt thereof.

2. The compound or salt according to claim 1, wherein the compound has the formula:

[I-1]

or [I-2]

[wherein R4 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, nitro, -CO-D" (in which D" is hydroxyl or C1-2 alkoxy) or amino optionally substituted by one or two C1-4 alkyl, and the other symbols have the meanings given in claim 1].

3. A compound of the formula wherein the ring A is a thiophene ring which may optionally contain substitution in addition to the R3 group; R1 is hydrogen or optionally substituted hydrocarbon residue which may be bonded through a hetero atom; R2 and R3 are independently a group capable of forming an anion or a group convertible thereinto; X is a direct bond or a spacer having an atomic length of two or less between the phenylene group and the phenyl group; and n is an integer of 1 or 2; or a salt thereof.

4. A compound according to claim 3, wherein the hydrocarbon residue is an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or aralkyl group.

5. A compound according to claim 3, wherein the hydrocarbon residue is an alkyl, alkenyl, alkynyl, or cycloalkyl group, which may be substituted with hydroxyl, an optionally substituted amino group, halogen or a lower (C1-4) alkoxy group.

6. A compound according to claim 3, wherein R1 is a lower (C1-5) alkyl or lower (C2-5) alkenyl group which may be optionally substituted with hydroxyl, an amino group, halogen or a lower (C1-4) alkoxy group and which may be bonded through a hetero atom.

7. A compound according to claim 5, wherein the alkyl is a lower alkyl group having 1 to about 8 carbon atoms, which may be straight or branched.

8. A compound according to claim 7, wherein the lower alkyl group is unsubstituted or substituted with hydroxyl, an optionally substituted amino group, halogen or a lower (C1-4) alkoxy group.

9. A compound according to claim 3, wherein R1 is a lower alkenyl group having 2 to about 8 carbon atoms, which may be straight or branched.

10. A compound according to claim 5, wherein the aryl group is phenyl which may be substituted with halogen, nitro, lower (C1-4) alkoxy, or lower (C1-4) alkyl.

11. A compound according to claim 4, wherein the aralkyl group is phenyl-lower (C1-4) alkyl which may be substituted with halogen, nitro, lower (C1-4) alkoxy, or lower (C1-4) alkyl.

12. A compound according to claim 3, wherein the hetero atom is -O-, -S(O)m- wherein m is 0, 1 or 2 or -N(R5)- wherein R5 is hydrogen or an optionally substituted lower (C1-4) alkyl.

13. A compound according to claim 3, wherein R2 and R3 are independently carboxyl, tetrazolyl, trifluoromethanesulfonic amide, phosphoric acid, sulfonic acid, cyano, or lower (C1-4) alkoxycarbonyl, which may be protected with an optionally substituted lower alkyl group or an acyl group.

14. A compound according to claim 3, wherein R2 and R3 are independently tetrazolyl group optionally protected with optionally substituted lower alkyl or acyl, a carboxyl group optionally protected with optionally substituted lower alkyl or acyl, or trifluoromethanesulfonic amide.

15. A compound according to claim 3, wherein R2 is a tetrazolyl group.

16. A compound according to claim 3, wherein R3 is a group having the formula: -CO-D' wherein D' is hydroxyl, optionally substituted amino or optionally substituted alkoxy.

17. A compound according to claim 3, wherein R' is a group having the formula: -CO-D' wherein D' is hydroxyl or optionally substituted alkoxy.

18. A compound according to claim 17, wherein D' is hydroxyl, a lower (C1-6) alkoxy group optionally substituted with hydroxyl, optionally substituted amino, halogen, lower (C1-6) alkoxy, lower (C1-6) alkylthio or optionally substituted dioxolenyl on the alkyl moiety, or a group having the formula:
-OCH(R7)OCOR8 wherein R7 is hydrogen, straight or branched lower alkyl having 1 to 6 carbon atoms, or cycloalkyl having 5 to 7 carbon atoms and R8 is straight or branched lower alkyl having 1 to 6 carbon atoms, straight or branched lower alkenyl having 2 to about 8 carbon atoms, cycloalkyl having 5 to 7 carbon atoms, lower (C1-3) alkyl which is substituted with optionally substituted aryl or cycloalkyl having 5 to 7 carbon atoms, lower (C2-3) alkenyl which is substituted with optionally substituted aryl or cycloalkyl having 5 to 7 carbon atoms, optionally substituted aryl, straight or branched lower alkoxy having 1 to 6 carbon atoms, straight or branched lower alkenyloxy having 2 to about 8 carbon atoms, cycloalkyloxy having 5 to 7 carbon atoms, lower (C1-3) alkoxy which is substituted with optionally substituted aryl or cycloalkyl having 5 to 7 carbon atoms, lower (C2-3) alkenyloxy which is substituted with optionally substituted aryl or cycloalkyl having 5 to 7 carbon atoms, or optionally substituted aryloxy.

19. A compound according to claim 3, wherein R3 is a group capable of forming an anion or convertible thereinto either chemically or under biological and/or physiological conditions.

20. A compound according to claim 3, wherein R3 is a group capable of forming the residue: -COO- or convertible thereinto.

21. A compound according to claim 3, wherein R3 is a group having the formula: -CO-D' wherein D' is hydroxyl, amino, N-lower (C1-4) alkylamino, N,N-dilower (C1-4) alkylamino or lower (C1-4) alkoxy optionally substituted with hydroxyl, amino, halogen, lower (C2-6) alkanoyloxy, 1-lower (C1-6) alkoxycarbonyloxy, or lower (C1-4) alkoxy on the alkyl moiety; or tetrazolyl optionally protected with an optionally substituted lower (C1-4) alkyl or acyl.

22. A compound according to claim 3, wherein the ring A of the formula: is a thiophene ring of the formula: which may optionally contain substitution in addition to the R3 group.

23. A compound according to claim 3, wherein the ring A may contain, in addition to the R1 group, a substituent being selected from the group consisting of halogen, nitro, cyano, optionally substituted amino, a group having the formula: -W-R6 wherein W is a chemical bond, -O-, -S-, or , and R6 is hydrogen, an optionally substituted lower alkyl group, a group having the formula: -(CH2)?-CO-D
wherein D is hydrogen, hydroxyl, optionally substituted amino, or optionally substituted alkoxy, and ? is 0 or 1, tetrazolyl optionally protected with an optionally substituted lower alkyl group or an acyl group, trifluoromethanesulfonic amide, phosphoric acid, or sulfonic acid.

24. A compound according to claim 3, wherein the ring A contains no substitution in addition to the R3 group.

25. A compound according to claim 3, wherein X is a chemical bond, lower (C1-4) alkylene, , -O-, -S-, , , , , or .

26. A compound according to claim 1, wherein X is a chemical bond between the phenylene group and the phenyl group.

27. A compound according to claim 1, wherein n is 1.

28. A compound according to claim 1, wherein the hydrocarbon residue is bonded through a hetero atom.

29. A compound according to claim 3, which is a compound of the formula (I-1):

(I-1) wherein R1 is lower (C1-6) alkyl optionally bonded through a hetero atom; R3 is -CO-D' wherein D' is hydroxyl, amino, N-lower (C1-4) alkylamino, N,N-dilower (C1-4) alkyl amino, or lower (C1-4) alkoxy optionally substituted with hydroxyl, amino, halogen, lower (C1-4) alkoxy, lower (C2-6) alkanoyloxy or 1-lower (C1-6) alkoxycarbonyloxy on the alkyl moiety, or tetrazolyl optionally protected with an optionally substituted lower (C1-4) alkyl or acyl group; R2 is tetrazolyl or carboxyl optionally protected with an optionally substituted lower ( C1-4) alkyl or acyl group; R4 is hydrogen, halogen lower (C1-4) alkyl, lower (C1-4) alkoxy, nitro, -CO-D" wherein D" is hydroxyl or lower (C1-2) alkoxy, or amino optionally substituted with lower (C1-4) alkyl; or a pharmaceutically acceptable salt thereof.

30. A compound according to claim 29, wherein the hetero atom is -O-, -S- or -NH-.

31. A compound according to claim 29, in which R3 is -CO-D' wherein D' is hydroxyl, or lower (C1-4) alkoxy optionally substituted with hydroxyl, lower (C1-4) alkoxy, lower (C2-6) alkanoyloxy or 1-lower (C1-6) alkoxycarbonyloxy on the alkyl moiety.

32. A compound according to claim 29, in which R2 is tetrazolyl

33. A compound according to claim 29, in which R4 is hydrogen, lower (C1-4) alkyl, or halogen.

34. A compound according to claim 29, in which R4 is hydrogen.

35. A compound according to claim 1, which is 2-ethylthio-4-methyl-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl]thieno[3,4-d]imidazole-6-carboxylic acid.

36. A compound according to claim 1, which is acetoxymethyl 2-methoxy-4-methyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]thieno[3,4-d]imidazole-6-carboxylate.

37. A compound according to claim 1, which is 2-methoxy-4-methyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]thieno[3,4-d]imidazole-6-carboxylic acid.

38. A compound according to claim 1, which is 2-ethoxy-4-methyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]thieno[3,4-d]imidazole-6-carboxylic acid

39. A compound according to claim 1, which is 2-propoxy-4-methyl-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl]thieno[3,4-d]imidazole-6-carboxylic acid

40. A pharmaceutical composition for antagonizing angiotensin II which comprises a therapeutically effective amount of a compound according to claim 3 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutical acceptable carrier, excipient or diluent.

41. A method for producing compound of the formula (I) as defined in claim 1, which comprises reacting a compound of the formula:

(II) (wherein R1, R3 and A have the meanings given in claim 1) with a compound of the formula:

(III) (wherein R2, X and n have the meanings given in claim 1 and Z is halogen), and, where required, converting a compound of the formula (I) into a pharmaceutically acceptable salt thereof.

42. A use of a compound according to any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for antagonizing angiotensin II.