CA2040955C - Benzimidazole derivatives, their production and use - Google Patents

Abstract

Benzimidazole derivatives of the formula (I):

(SEE FIG. I) wherein the ring A is a benzene ring which may optionally contain substitution in addition to the R' group; R1 is hydrogen or an optionally substituted hydrocarbon residue; R2 is 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; R' is carboxyl, an ester thereof, an amide thereof or a group capable of forming an anion or convertible to an anion; Y is -O-, -S(O)m- or -N(R4)- wherein m is an integer of 0, 1 or 2 and R4 is hydrogen or an optionally substituted alkyl group; and n is an integer of 1 or 2; and the pharmaceutically acceptable salts 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

2 ~

The subject matter of this Arp~ tion is closely related to that of ~n~iAn Patent Application Ser. N~. 2,02~,302 filed Oct. 23, 1990.
FIELD OF THE INVENTION
The present invention relates to novel benzimidazole derivatives having potent pharmacological actions and intermediates for the preparation thereof. More particularly, the present invention relates to compounds having potent anti-hypertensive activity and strong angiotensin ~ antagonistic activity, which are , useful as therapeutic agents for treating circulatory diseases such as hypertensive di~e~es, heart di~e~s (e.g. hypercardia, heart failure, cardiac infarction, etc.), strokes, cerebral apoplexy, nephritis, etc.

BACKGROUND OF THE INVENTION
The renin-angiotensin system is involved in the homeostatic function to control systemic blood pressure, the volume of body fluid, balance among the electrolytes, etc., associated with the aldosterone system. Development of angiotensin ~ converting enzyme inhibitors (ACE inhibitor) (this converting enzyme produces angiotensin ~ which possesses a strong vasoconstrictive action) has clarified the relation between the renin-angiotensin system and hypertension. Since angiotensin ~ constricts blood vessel to elevate blood pressure via the angiotensin ~ receptors on the cellular membranes, angiotensin ~ antagonists, like the ACE inhibitor, would be useful in treating hypertension caused by angiotensin.
It has been reported that various angiotensin ~ analogues such as saralasin, [Sar',Ile~]A ~, and the like, possess potent angiotensin ~ antagonist activity.
It has, however, been reported that, when peptide 3~ antagonists are a~ini~tered parenterally, their actions are not 20~5~

prolonged and, when administered orally, they are ineffective (M. A.
Ondetti and D. W. Cushman, Annual Reports in Medicinal Chemistry, 13, 82-91 (1978)).
It would be highly desirable to develop a non-peptide angiotensin ~ antagonist which overcomes these drawbacks. In the eariest studies in this field, imidazole derivatives having angiotensin ~ antagonist activity have been disclosed in Japanese Patent Laid Open No. 71073/1981; No. 71074/1981; No. 92270/1982; No.
157768/1983; USP No. 4,355,040, No. 4,355,040, etc. Later, i~proved imidazole derivatives are disclosed in European Patent Laid Open No.
0253310, No. 0291969, No. 0324377, Japanese Patent Laid Open No.
23868/1988; and No. 117876/1989. Further, pyrole, pyrazole, and triazole derivatives are disclosed as angiotensin ~ antagonists in European Patent Laid Open No. 0323841, and Japanese Patent Laid Open No. 287071/1989.
USP No. 4,880,804 discloses benzimidazole derivatives having an angiotensin ~ receptor antagonistic action, which are intravenously active in vivo in rats with renal hypertension.
Examples of such ben7i~ 70le derivatives are those represented by the following formula (A):

Cl 2 ~ /\C~) R27 ~ N/~ Rl. R~ (A) R2. N
wherein substituents, for ~x~rle, in the 5- and/or 6-position are hydroxymethyl, methoxy, formyl, chloro, or carboxy. Although most compounds among those exemplified are orally inactive, it is said that only the 6-hydroxymethyl and 6-chloro compounds are orally ~ 30 effective (100 mg/kg or less). It is, however, believed that the : ' .

.

9 5 ~
activity of even these disclosed compounds is insufficient for clinical uses.

SUMMARY OF THE INVENTION
The present invention provides novel benzimidazole derivatives having potent anti-hypertensive activity and strong angiotensin ~ antagonistic action, which are of practical value in clinical use as therapeutic agents.
The present inventors considered that compounds functioning to control the renin-angiotensin system as well as clinically useful for the treatment of circulatory diseases such as hypertensive diseases, heart diseases (e.g. hypercardia, heart failure, cardiac infarction, etc.), strokes, cerebral apoplexy, etc.
are required to have potent angiotensin ~ receptor antagonistic activity and to exert strong oral and long-lasting angiotensin antagonist action. Extensive investigations were made based on those consideration. As a result of this research, the present inventors have succeeded in synthesizing novel 2-substituted benzimidazole derivatives (I) possessing highly angiotensin ~
receptor antagonistic activity as well as exerting strong oral and long-lasting angiotensin ~ antagonistic and anti-hypertensive action and developed the present invention.
The present invention relates to benzimidazole derivatives having the formula I:
R~ (IH2~n ~ X ~

~ /~ Y -R' (I) wherein the ring A is a benzene ring which may optionally contain 204095~

substitution in addition to the R' group; R' is hydrogen or an optionally substituted hydrocarbon residue; R2 is 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; R' is carboxyl, an ester thereof, an amide thereof or a group capable of forming an anion or convertible to an anion; Y is -O-, -S(O) ~- or -N(R~)- wherein m is an integer of 0, 1 or 2 and R~ is hydrogen or an optionally substituted alkyl group; and n is an integer of 1 or 2;
and the pharmaceutically acceptable salts thereof.
These compounds are unexpectedly potent angiotensin ~
antagonists which are of value in the treatment of circulatory system d;~eA~es such as hypertensive diseases, heart diseases, strokes, nephritis, etc.
Another aspect of the present invention relates to pharmaceutical compositions comprising an effective amount of the benzimidazole derivative having the formula I and a pharmaceutically acceptable carrier useful in treating circulatory system diseases such as hypertensive diseases, heart diseases, strokes, renal failure, nephritis, etc., and processes for preparing such compounds and compositions.
Still another aspect of the present invention relates to a method for treating said circulatory system diseases of Anir~
which comprises ~mini~tering an effective amount of the ben7îmi~A~ole derivatives having the formula I or the pharmaceutical composition thereof to said animal.

BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 depicts a X ray scattering chart obtained in Experimental Example 1.

~. .
.

204095~

FIG. 2 depicts an IR spectrum pattern obtained in Experimental Example l.
FIG. 3 depicts a differential scanning calorimeter pattern obtained in Experimental Example 1.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides the benzimidazole derivatives (I) and the pharmaceutically acceptable salts thereof, which possess strong angiotensin ~ antagonist activity and are of value in the treatment of circulatory diseases such as hypertensive diseases, heart diseases, strokes, cerebral diseases, nephritis, etc., pharmaceutical compositions comprising an effective amount of the benzimidazole derivative having the formula I and a pharmaceutically acceptable carrier useful in treating said circulatory di~e~es, and processes for preparing such compounds and compositions.
The present invention further provides a method for treating said circulatory system diseases of ~nir~ls, which comprises ;t~min;stering an effective amount of the benzimidazole derivative (I) or the pharmaceutical composition thereof to said animal.
An important group of compounds according to the present invention are the compounds of the formula I":

R' (9H2)~ ~ X
~ N\ I R2 t~
~ N/~ Y R

wherein the ring A is a benzene ring which may optionally contain - substitution in addition to the R' group; R' is hydrogen or an optionally substituted hydrocarbon residue; R2 is a group capable of 2~95~

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; R' is carboxyl, an ester thereof or an amide thereof ; Y is -0-, -S(0) m~ or -N(R~)-wherein m is an integer of 0, 1 or 2 and R~ is hydrogen or anoptionally substituted alkyl group; and n is an integer of l or 2;
and the pharmaceutically acceptable salts thereof.

With regard to the foregoing formula (I), hydrocarbon residues for Rl include, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and aralkyl groups. Among them, alkyl, alkenyl, and cycloalkyl groups are preferable.
Alkyl groups for R' 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 Rl are lower alkenyl groups having 2 to about 8 carbon atoms, which may be straight or branched, and include, for example, vinyl, propenyl, 2-butenyl, 3-butenyl, isobutenyl, octenyl, and the like.
Alkynyl groups for R' are lower alkynyl groups having 2 to about 8 carbon atoms, which may be straight or branched, and include, for example, ethynyl, 2-propynyl, 2-butynyl, 2-pentynyl, 2-octynyl, and the like.
Cycloalkyl groups for R' are lower cycloalkyl groups having 3 to about 6 carbon atoms, and include, for example, cyclopropyl, cyclobutyl, cyclopentyl, and the like.
The above-mentioned alkyl, alkenyl, alkynyl, and cycloalkyl groups may be substituted with hydroxyl, an optionally substituted 20409~

amino group (e.g. aminoJ methylamino~ etc.), halogen, a lower (Cl ~) alkoxy group or the like.
Aralkyl groups for R' include, for example, phenyl-lower (Cl ~) 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 (Cl ~) alkoxy (e.g. methoxy, ethoxy, etc.), lower (Cl ~) alkyl (e.g. methyl, ethyl, etc.), or the like at various positions of the benzene ring.
Aryl groups for Rl include, for exampleJ phenyl and the aryl group may be substituted with, for example, halogen (e.g. F, Cl, BrJ etc.), nitroJ lower (Cl_~) alkoxy (e.g. methoxyJ ethoxyJ etc.)J
lower ~C,_~) alkyl (e.g. methylJ ethyl, etc.), or the like at various positions of the benzene ring.
Among the above-mentioned groups for R1, preferred examples are optionally substituted alkyl and alkenyl groups (e.g. lower (C~_s) alkyl and lower (C2 ~) alkenyl groups optionally substituted with hydroxylJ an amino groupJ halogen or a lower (C, ~) alkoxy group).
Examples of groups capable of forming an anion and groups convertible thereinto for R2 include carboxyl, tetrazolylJ trifluoro-methanesulfonic amide (-NHS02CF3) J phosphoric acidJ sulfonic acid~
cyanoJ lower (C1 4 ) alkoxycarbonyl, and the like. These groups may be protected with, for example, an optionally substituted lower alkyl group (e.g. lower ~C,_~) alkoxymethyl, optionally substituted arylmethylJ etc.) or an acyl group (e.g. lower (C2 5) alkanoyl, optionally substituted benzoylJ etc.). Such groups may include those which are capable of ~orming anions or convertible thereinto either chemically or under biological and/or physiological conditions (~or e~mplPJ _ vivo reaction such as oxidation-reduction or hydrolysis catalyzed by in vivo enzymes).

20409~

The compounds wherein R2 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:

N ~
wherein R is methyl, triphenylmethyl, 2-tetrahydropyranyl, tert-butyl, methoxymethyl, ethoxymethyl, or optionally substituted benzyl such as p-methoxybenzyl and p-nitrobenzyl), cyano and the like), are useful as synthetic intermediates.
Among the above-mentioned groups for R2, preferred examples are tetrazolyl groups optionally protected with optionally substituted lower alkyl or acyl, carboxyl groups optionally protected with optionally substituted lower alkyl, and trifluoromethanesulfonic amide.
Examples of carboxyl, esters thereof or amides thereof for R' include, for example, groups having the formula:
-C0-D' wherein D' is hydroxyl, optionally substituted amino (e.g.
amino, N-lower (C1 4) alkylamino, N,N-dilower (Cl ~) alkyl amino, etc.), or optionally substituted alkoxy [e.g. lower (Cl 6) alkoxy optionally substituted with hydroxyl, optionally substituted amino (e.g. amino, dimethylamino, diethylamino, piperidino, morpholino, etc.), halogen, lower (Cl_6) alkoxy, lower (C1 8) alkylthio or optionally substituted dioxolenyl (e.g. 5-methyl-2-oxo-1,3-dioxolen-4-yl, etc.) on the alkyl moiety and groups having the formula:
-OCH(R~)OCORa wherein R~ is hydrogen, strai~ht or branched lower alkyl havin~ 1 to 6 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, etc.), or cycloalkyl having 5 to 7 carbon atoms (e.g.
~, ~

20~0955 cyclopentyl, cyclohexyl, cycloheptyl, etc.) and Ra is straight or branched lower alkyl having l to 6 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, etc.), straight or branched lower alkenyl having 2 to about 8 carbon atoms (e.g. vinyl, propenyl, 2-butenyl, 3-butenyl, isobutenyl, octenyl, etc.), cycloalkyl having 5 to 7 carbon atoms (e.g. cyclopentyl, cyclohexyl, cycloheptyl, etc.), lower (C1 3) alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, etc.) which is substituted with optionally substituted aryl or cycloalkyl having 5 to 7 carbon atoms (e.g. benzyl, p-chlorobenzyl, phenethyl, cyclopentylmethyl, cyclohexylmethyl, etc.), lower (C2 3) alkenyl (e.g. vinyl, propenyl, allyl, isopropenyl, etc.) which is substituted with optionally substituted aryl or cycloalkyl having 5 to 7 carbon atoms (e.g. cinnamyl, etc.), optionally substituted aryl (e.g.
phenyl, p-tolyl, naphthyl, etc.), straight or branched lower alkoxy having l to 6 carbon atoms (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, etc.), straight or branched lower alkenyloxy having 2 to about 8 carbon atoms (e.g. allyloxy, isobutenyloxy, etc.), cycloalkyloxy having 5 to 7 carbon atoms (e.g. cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, etc.), lower (Cl_3) alkoxy (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, etc.) which is substituted with optionally substituted aryl or cycloalkyl having 5 to 7 carbon atoms (e.g. benzyloxy, phenethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, etc.), lower (C 2 - 3 ) alkenyloxy (e.g. vinyloxy, propenyloxy, allyloxy, isopropenyloxy, etc.) which is substituted with optionally substituted aryl or cycloalkyl having 5 to 7 carbon atoms (e.g. cinnamyloxy, etc.), optionally substituted aryloxy (e.g. phenoxy, p-nitrophenoxy, naphthoxy, etc.)]. Examples of groups capable of forming an anion 2040~

and groups convertible thereinto for R' may include, for example, tetrazolyl groups optionally protected with optionally substituted lower alkyl such as lower (C, ~) alkyl and lower (Cl 4 ) alkoxy lower (CJ ~) alkyl or acyl such as lower (C2 5) alkanoyl and optionally substituted benzoyl, trifluoromethanesulfonic amide, phosphoric acid, sulfonic acid, and the like. Examples of substituents for R' include -COOH and salts thereof, -COOMe, -COOEt, -COOtBu, -COOPr, pivaloyloxymethoxycarbonyl, 1-(cyclohexyloxycarbonyloxy)ethoxy-carbonyl, 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyloxycarbonyl, acetoxy-methyloxycarbonyl, propionyloxymethoxycarbonyl, n-butyryloxymethoxy-earbonyl, isobutyryloxymethoxyearbonyl, l-(ethoxycarbonyloxy)ethoxy-carbonyl, l-(aeetyloxy)ethoxycarbonyl, l-(isobutyryloxy)ethoxy-earbonyl, cyelohexylcarbonyloxymethoxycarbonyl, benzoyloxymethoxy-carbonyl, einnamyloxycarbonyl, cyelopentylcarbonyloxymethoxycarbonyl, etc. Such groups may include those which are capable of forming anions (e.g. -COO-, derivatives thereof, etc.) or convertible thereinto either chemically or under biological and/or physiologieal conditions (for example, in vivo reaetion sueh as oxidation-reduetion or hydrolysis eatalyzed by in vivo enzymes).
The ben7ene ring A may optionally contain substitution in ; addition to the R' group and such substituents include halogen (e.g. F, Cl, Br, etc.); nitro; cyano; optionally substituted amino ~e.g. amino, N-lower (C1 4) alkyl such as methylamino and ethylamino, N,N-dilower (C1 4) alkyl amino sueh as dimethylamino and diethyl-amino, N-arylamino sueh as phenylamino and naphthylamino, N-aralkyl-amino sueh as benzylamino and naphthylmethylamino, and alicyclie amino sueh as morpholino, piperidino~ piperazino and N-phenyl-piperazino]; groups having the formula: -W-R'3 wherein W is a ehemical bond, -O-, -S-, or -C-, : 11 ;~
.~

20409~5 and R' 3 iS hydrogen or an optionally substituted lower alkyl group (e.g. lower (Cl ~) alkyl optionally substituted with hydroxyl, optionally substituted amino (e.g. amino, dimethylamino? diethyl-amino, piperidino, morpholino, etc.), halogen or lower (Cl _4 ) alkoxy, etc.); groups having the formula: -(CH2)p-CO-D
wherein D is hydrogen, hydroxyl, optionally substituted amino (e.g. amino, N-lower (C, 4) alkylamino, N,N-dilower (Cl ~) alkyl amino, etc.), or optionally substituted alkoxy [e.g. lower (Cl 6) alkoxy optionally substituted with hydroxyl, optionally substituted amino (e.g. amino, dimethylamino, diethylamino, piperidino, morpholino, etc.), halogen, lower (Cl 6) alkoxy, lower (C, ~) alkylthio or optionally substituted dioxolenyl (e.g. 5-methyl-2-oxo-1,3-dioxolen 4-yl, etc.j on the alkyl moiety and groups having the formula: -OCH(R9)OCOR'0 wherein R9 is hydrogen, straight or branched lower alkyl having 1 to 6 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, etc.), or cycloalkyl having 5 to 7 carbon atoms (e.g. cyclopentyl, cyclohexyl, cycloheptyl, etc.) and R'~ is straight or branched lower alkyl having l to 6 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, etc.), straight or branched lower alkenyl having 2 to about 8 carbon atoms (e.g.
vinyl, propenyl, 2-butenyl, 3-butenyl, isobutenyl, octenyl, etc.), cycloalkyl having 5 to 7 carbon atoms (e.g. cyclopentyl, cyclohexyl, cycloheptyl, etc.), lower (C1 3) alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, etc.) which is substituted with optionally substituted aryl or cycloalkyl having 5 to 7 carbon atoms (e.g. benzyl, p-chlorobenzyl, phenethyl, cyclopentylmethyl, cyclohexylmethyl, etc.), lower (C2 3) alkenyl (e.g. vinyl, propenyl, allyl, isopropenyl, etc.) which is substituted with optionally substituted - . : , ' - ~ ' ' 20~09~a aryl or cycloalkyl having 5 to 7 carbon atoms (e.g. cinnamyl, etc.), optionally substituted aryl (e.g. phenylJ p-toluyl, naphthylJ etc.), straight or branched lower alkoxy having l to 6 carbon atoms (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, etc.), straight or branched lower alkenyloxy having 2 to about 8 carbon atoms (e.g. allyloxy, isobutenyloxy, etc.), cycloalkyloxy having 5 to 7 carbon atoms (e.g. cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, etc.), lower (C1 3 ) alkoxy (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, etc.) which is substituted with optionally substituted aryl or cycloalkyl having 5 to 7 carbon atoms (e.g. benzyloxy, phenethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, etc.), lower (C2 - 3 ) alkenyloxy (e.g. vinyloxy, propenyloxy, allyloxy, isopropenyloxy, etc.) which is substituted with optionally substituted aryl or cycloalkyl having 5 to 7 carbon atoms (e.g.
cinnamyloxy, etc.), optionally substituted aryloxy (e.g. phenoxy, p-nitrophenoxy, naphthoxy, etc.)], and p is 0 or l; tetrazolyl optionally protected with, for example, an optionally substituted lower alkyl group (e.g. lower (Cl_~) alkoxymethyl, optionally substituted arylmethyl, etc.) or an acyl group (e.g. lower (C2 s) alkanoyl, optionally substituted benzoyl, etc.); trifluoromethane-sulfonic amide; phosphoric acid; sulfonic acid; etc.
One or two of these substituents may be substituted at various positions of the benzene ring. When two substituents are present at the 4 and 5 or 5 and 6 positions on the ring A, th0y may be taken together to form a ring (e.g. ben7.~.n~., etc.). Such rings may be substituted with the same groups as for the ring A.
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 : ' ~

204095~
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 include lower (Cl 4 ) alkylene, -C- -0-, -S-, -N- -~ - ~~~~~~ -S-~ - etc.
0 H 0 H H ll H H
The most preferred X is a chemical bond between the phenylene group and the phenyl group.
Y represents that R' is bonded to the 2-position of ben7imid~701e through a hetero atom. Examples of Y include -0-, -S0 ~- wherein m is 0, 1, or 2, -N(R~)- wherein R4 is hydrogen or an optionally substituted lower (C~ 4) alkyl group, and the like, preferably -0-, -S-, and -NH-, more preferably -0- and -S-, especially -0-. R' and R~ may be taken together with the N atom attached thereto to form a heterocyclic ring (e.g. piperidino, morpholino, etc.).
When R' = H, the compounds having the formula (I) [Compound (I)] can exist in two tautomeric forms.
When the compounds of the present invention have several asymetric carbon atoms, they can thus exist in several stereochemical forms. The invention includes the mixture of isomers and the individual stereoisomers. It is intended that the present invention includes geometrical isomers, rotational isomers, enantiomers, racemates, and diastereomers.
The oompounds of the present invention can exist in any pro-drug form of those wherein R' is carboxyl or the anion therefrom.
Among the compounds represented by the above formula (I)) a , 20~0~5~
preferred embodiment of the invention is a compound of the formula:

R' CIH2 ~ ~ ~/ ( ~ (I') R~ ~N ~
wherein R' is lower (Cl_s) alkyl optionally substituted with hydroxyl, amino, halogen, or a lower (C, ~) alkoxy group (inter alia lower 0 (C2-3) alkyl); R' is -C0-D' wherein D' is hydroxyl, amino, N-lower (Cl ~) alkylamino, N,N-dilower (C1 4) alkyl amino, or lower (Cl ~) alkoxy optionally substituted with hydroxyl, amino, halogen, lower (C, ~) alkoxy, lower (C2 6) alkanoyloxy (e.g. acetyloxy, pivaloyloxy, etc.) or 1-lower (C1 6 ) alkoxycarbonyloxy (e.g. methoxycarbonyloxy, ethoxycarbonyloxy, cyclohexyloxycarbonyloxy, etc.) on the alkyl moiety, or tetrazolyl optionally protected with an optionally substituted lower (Cl ~) alkyl or acyl group (e.g. lower (C2 5) alkanoyl, benzoyl, etc.); R2 is tetrazolyl optionally protected with an optionally substituted lower (C,_~) alkyl (e.g. methyl, triphenylmethyl (trityl), methoxymethyl, ethoxymethyl, p-methoxy-benzyl, p-nitrobenzyl, etc.) or acyl group (e.g. lower (C2_~) alkanoyl, benzoyl, etc.), or carboxyl optionally protected with an optionally substituted lower (C1 4) alkyl group (e.g. methyl, triphenylmethyl (trityl), methoxymethyl, ethoxymethyl, p-methoxy-benzyl, p-nitrobenzyl, etc.); R" is hydrogen, halogen, lower (C1_4) alkyl, lower (C1_4 ) alkoxy, nitro or -C0-D" wherein D" is hydroxyl or lower (Cl 2) alkoxy optionally substituted with hydroxyl, lower (Cl ~) alkoxy, lower (C2_6) alkanoyloxy (e.g. acetyloxy, pivaloyloxy, etc.) or 1-lower (C,_6) alkoxycarbonyloxy (e.g. methoxycarbonyloxy, ethoxycarbonyloxy, cyclohexyloxycarbonyloxy, etc.) on the alkyl :

2 ~

moiety, or amino optionally substituted with lo~er (Cl 4 ) alkyl (inter alia hydrogen, lower (C1 4) alkyl, or halogen, more preferably hydrogen); and Y is -0-, -S-, or -N(R~)- wherein R~ is hydrogen or an lower (Cl 4 ) alkyl group;
and the pharmaceutically acceptable salts thereof.
The compounds (I) of the present invention may be prepared by several reaction schemes, as illustrated beiow for a preferred compound.
Scheme A

N III ~ N
/~ Y - Rl > /~ Y - R' I

wherein R1, R2, R', A, X, Y and n have the above-defined ~ning~ and Z is halogen.
Scheme B
~=N~ :
CN N ~ NH
~ (CIH2)n~X~ (CIH2)n~X~

Ia ~ N ~ Ib ~ 25 wherein each group has the above-defined ~~~ning.

: 3Q

20409~

Scheme C

~ CH2) n~X~ ~ ( 1H2) n ~X~

i'~Y--R ' ~ ~N/'~Y--R ' wherein R', R', A, X, Y and n have the above-defined meanings, and Rs is optionally substituted lower (C, 6) alkyl.
Scheme D

(CH2) D~X~ ~ ~C112) n~X~
[~NH C(OR')., ~ ~0--R' wherein each group has the above-defined meaning.
Scheme E

~ (CH2)n~X~) ~ ~CH2)n~X~
~NH ~ IV > ~N~ OH

wherein each group has the above-defined -~ning, ~ Scheme F

1 ~ R 2 R 2 ~ (fjH2)n~X~ ~ (IH2)n~X~
OH > ~N~ OR

wherein each group has the above-defined meaning.

::

20~0~
Scheme G

(CH2)D~X~). (CH2)n~X~
~ NH > ~ N'~ SH

wherein each group has the above-defined meaning.
Scheme H

. (9H2) n~X~ R~ (9H2) n~X~
~ N~ SH > ~ N~ S -R' wherein each group has the above-defined ~P~ning.
Scheme I

(CH2)n ~ xR ~(CH2) n~ R~

(~NH2 IV ~ CS--NHRI V

. (9H2) n~X~
N,~NHR ~ :.

wherein each group has the above-defined --n;nE.

- .
.
:' :

2~09~
Scheme I' R (CH2)n~X~ R~ (CH2)n~X~
H If > ~ ~ Z

~- (CH2) n ~X~

~ N~ Y -R' wherein each group has the above-defined meaning.
Scheme I"

(CH2)D ~ X ~ R~ (IH2)n ~ X
~ N~ S -Rl ~ ~ N/~ S -R' ~ (CH2)D ~ X
> [~ /~ Y - R I
I

~: wherein each group has the above-defined r- ~ning.
Scheme J

R2 1~2 R600~ (qH2) D ~ X ~ H00~ (CH2) D ~ X
Y - Rl ~ ~ /~ Y - R' Ij Ik 20409~
wherein each group has the above-defined meaning.
Scheme K

N~R N Nll ~ (CIH2) n~X~ ~ (CH2) D ~X~
~ /~ Y - Rl > ~ N~ Y R Im wherein each group has the above-defined meaning.
Scheme L

~=N~ ~R
N~<NH N~N
HOO(CH2)n~X~ H00 ( IH2)n~X~
1 5 ~ /~Y--R ' ~ /~Y--R
In Io ~ R ~=~
N~N N~NH

R~00 (CH2)n~X~ R~oo (CH2)n~X~
3, ~N/~Y _ R ' ~ [~ ~Y--R I

Ip Iq wherein A, R, R1, X, Y and n have the above-defined -~nings, and R6 is lower (C,_6) alkyl optionally substituted with lower tC2 6) alkanoyloxy, l-lower (Cl 6) alkoxycarbonyloxy or the like as defined for R'.
The reaction as illustrated in Scheme A is an alkylation using an alkylating agent in the presence of a base, One molar portion of the compound (II) is employed with approximately 1 to 3 ;~ 30 moles of the base and 1 - 3 moles of the alkylating agent.

, - ' ' ' . ~' '~ ''. ; ' ,, 20~0~5~

The reaction is conventionally conducted in solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran, acetone, ethylmethylketone, and the like. Examples of such bases include sodium hydride, potassium t-butoxide, potassium carbonate, sodium carbonate, and the like.
Examples of such alkylating agents include substituted halides ~e.g.
chlorides, bromides, iodides, and the like), substituted sulfonate esters (e.g. p-toluenesulfonate esters, and the like), etc.
The reaction conditions may vary depending on the combination of the base and the alkylating agent. Advantageously, the reaction is carried out at ice-cooling to room temperature for about 1 - 10 hours.
In the said alkylation, a mixture of two isomers, (I) and (I"') is usually obtained depending on the position of the N atom to bP alkylated. While the production ratio of Compound (I) and Compound (I"') varies with the reaction conditions employed and the substituents on the ben7imi~701e ring, these two compounds can be obtained easily as pure products respectively by conventional isolation and/or purification methods (e.g. recryst~lli7~tion, column chromatography and the like).
The nitrile compound (Ia) is reacted with various azides to form the tetrazole compound (Ib) as illustrated in Scheme B. One molar portion of the compound (Ia) is employed with 1 - 5 moles of the azide. The reaction is conventionally conducted in solvents such as dimethylformamide, dimethylacetamide, toluene, benzene, and the like. Examples of such azides include trialkyltin azide (e~g.
trimethyltin azide, tributyltin azide, triphenyltin azide, etc.), hydrogen azide and ammonium salts thereof, and the like. In the case where the organotin azide compound is employed, 1 - 4 moles of the azide are employed per compound (Ia) and the reaction is carried out ', ', 2 0 ~
in toluene or benzene by heating under reflux for a period of 1 - 4 days. When the hydrogen azide or its ammonium salt is used, 1 - 5 moles of sodium azide and ammonium chloride or tertiary amine (e.g.
triethylamine, tributylamine, etc.) are employed per compound (Ia) and the reaction is conducted in dimethylformamide at about 100~C -120~C for about 1 - 4 days. During this reaction, it is preferable to facilitate the reaction by adding an appropriate amount of sodium azide and ammonium chloride. In this case, improvement may sometimes be observed in reaction time and yield by the addition of the azide compound in suitable fractions.
The ester (Ic) is hydrolyzed in the presence of alkali to give the carboxylic acid (Id) as illustrated in Scheme C. This reaction is conducted usually in a solvent such as aqueous alcohol (e.g. methanol, ethanol, methyl cellosolve, etc.) by using alkali in an amount of about 1 to 3 mol. relative to 1 mol. of Compound (Ic).
Examples of such alk~ include sodium hydroxide, potassium hydroxide, etc. The reaction is conducted at temperatures ranging from room temperature to about 100~C for about 1 to 10 hours, preferably around the boiling point of the solvent for about 2 to 5 hours.
m e 2-alkoxy derivative (Ie) is obtained by reacting phenylenediamine (IV) with alkyl orthocarbonate as illustrated in Scheme D. The reaction is conducted in the presence of an acid by using alkyl orthocarbonate of about 1 to 3 mol. relative to Compound (IV). Examples of such alkyl orthocarbonates include orthocarbonates of, for example, methyl, ethyl, propyl, isopropyl, butyl, etc.
And, by using ,for example, acetic acid or p-toluenesulfonic acid, the reaction is accelerated to afford a ring-closed compound in a good yield. As the reaction solvent, halogenated hydrocarbons and ethers can be employed but, usually, it is more convenient to conduct 20~0~
the reaction without a solvent. The reaction is usually conducted at about 70 to 100~C for about 1 to 5 hours. In this reaction, a dialkoxyimino compound is produced as the reaction intermediate, which is then ring-closed into the 2-alkoxy compound (Ie) in the presence of the acid in the reaction system. It is also possible to isolate the reaction intermediate, which is then subjected to ring-closure reaction in the presence of an acid to form the 2-alkoxy compound (Ie).
The phenylene~i~mino compound (IV) is reacted with various reagents to give the 2-keto compound (or the 2-hydroxy compound, If) as illustrated in Scheme E. This reaction is conducted by using a carbonylating reagent (e.g. urea, diethyl carbonate, bis(1-imidazolyl)ketone, etc.) in an amount of about 1 to 5 mol. relative to 1 mol. of Compound (IV) and, usually, by using~ among others, halogenated hydrocarbons (e.g. methylene chloride, chloroform, etc.)~
alcohols (e.g. methanol, ethanol, etc.) or amides (e.g. di~ethyl-formamide, dimethylacetamide, etc.).
The 2-hydroxy compound (If) is selectively O-alkylated with a Meerwein reagent to give the 2-alkoxy compound (Ig) as illustrated in Scheme F. This reaction is conducted by using the Meerwein reagent in an amount of about 1 to 3 mol. relative to Compound (If), usually, employing, as the solvent, halogenated hydrocarbons (e.g.
methylene chloride, chloroform, etc.) or ethers (e.g. methyl ether, ethyl ether, etc.). Examples of such Meerwein reagents include, among others, trimethyl oxonium fluoroborate (Me30~BF4-), triethyl oxonium fluoroborate (Et30+BF4-), etc. These are preferably used by in situ preparation according to the method described in literature references [H. Meerwein, Org. Syn. 46. 113 ; and 120(1966)]. The reaction is preferably conducted at temperatures ranging from about room temperatures to the boiling point of the :
:
. .

20409~
solvent used for about 2 to 20 hours.
The phenylene diamino compound (IV) is reacted wlth various reagents in an organic solvent to give the 2-mercapto compound (Ih) as illustrated in Scheme G. Relative to 1 mol; of the phenylene diamino compound (IV), about 1 to 3 mol. of a thiocarbonylating agent (e.g. carbon disulfide, thiourea, potassium xanthate, etc.) or isothiocyanate (e.g. methyl isothiocyanate, ethyl isothiocyanate, etc.) is used. As the reaction solvent, alcohols (e.g. methanol, ethanol, etc.), amides (e.g. dimetylformamide, dimethylacetamide, etc.) or the like can be used. The reaction is preferably conducted at temperatures ranging from room temperatures to the boiling point of the solvent used for about 5 to 20 hours.
The 2-mercapto compound (Ih) is alkylated in the presence of a base in an organic solvent to give the alkylthio compound (Ii) as illustrated in Scheme H. The reaction is conducted by using, relative to 1 mol. of Compound (Ih), about 1 to 3 mol. of the base and about 1 to 3 mol. of the alkylating agent usually in a solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, acetone, ethyl methyl ketone, ethanol, methanol and water. As the base, there is used sodium hydroxide, potassium carbonate, sodium carbonateJ sodium hydride, potassium t-butoxide, potassium hydroxide or the like. As the alkylating agent, there is used, for example, a halide (e.g. methyl iodide, ethyl iodide, propyl iodide, butyl iodide, and bromide or chloride thereof). The reaction is conducted usually at temperatures ranging from ice-cooling to the boiling point of the solvent used, while the reaction conditions vary with the base, the alkylat~ing agent and the solvent employed.
The phenylenediamine (IV) is reacted with isothiocyanate to ~ form the thiourea compound (V), which is then subjected to '~ 30 desulfurization-cyclization to give the 2-substituted amino , ~, :

'. ' ", . - ', ~ , ' ' ',:

'-'' 2 0 ~

compound ~Ij) as illustrated in Scheme I. The reaction is conducted by using about 1 to 3 mol. of isothiocyanate relative to 1 ~ol. of Compound (IV) usually in halogenated hydrocarbons (e.g. chloroform, methylene chloride, etc.), ethers (e.g tetrahydrofuran, dioxane, etcO), aromatic hydrocarbons (e.g. benzene, toluene, etc.), alcohols (e.g. methanol, ethanol, etc.), acetonitrile, dimethylformamide or the like. The reaction can also be conducted without these solvents.
Examples of such isothiocyanates include isothiocyanates of methyl, ethyl, propyl, isopropyl, butyl, etc. The reaction is conducted preferably at temperatures ranging from room temperatures to about 50~C for about 10 to 60 hours. The desulfurization-cyclization can be conducted in a manner as described below.
The reaction is conducted, in halogenated hdyrocarbons (e.g. HgCl2), by using about 1 to 3 mol. of a metal halide (e.g.
HgCl2) relative to 1 mol. of the thiourea (V) obtained by the above-mentioned method. The reaction is conducted preferably at temperatures ranging from room temperature to the boiling point of a solvent employed for about 3 to 10 hours. The reaction can also be conducted by using about 1 to 3 mol. of methyl iodide relative to 1 mol. of thiourea (V) in alcohols (e.g. methanol or ethanol), preferably at temperatures rangin~ from room temperature to about the boiling point of the solvent for about 3 to 15 hours.
The 2-halogeno compound (V') readily prepared from the compound (If) is reacted with various nucleophilic reagents to form the compound (I) as illustrated in Scheme I'. The reaction can be carried out according to the procedures as described in known references (e.g. D. Harrison and J. J. Ralph, J. Chem. Soc., 1965, 236). The compound (If) is reacted with a halogenating reagent (e.g.
phosphorus oxychloride, phosphorus trichloride, etc.) to form the 2-halogeno compound (V') which is reacted with various nucleophilic 2~40~5~

reagents (e.g. alcohols, mercaptans, amines, etc.) in a suitable organic solvent to give the compound (I). The reaction conditions may vary depending on the nucleophilic reagent employed. Upon the reaction with alcohols, alcoholates (e.g. sodium methoxide, sodium ethoxide, sodium propoxide, etc.) derived from alcohols and sodium metal are preferably used. As the reaction solvent, alcohols then used for nucleophilic reagents can be employed. Relative to 1 mol.
of the compound (V'), there is used about 2 to 5 mol. of an alcoholate. Advantageously, the reaction is usually conducted at approximately the boiling point of the solvent used for about 1 to 3 hours. Upon the reaction with amines, about 3 to 10 mol. of an amine is used relative to 1 mol. of the compound ~V').
As the reaction solvent, alcohols (e.g. ethanol, etc.) are employed but, an excess amount of amines can be used. Advantageously, the reaction is usually conducted at temperatures ranging from about the boiling point of the solvent to 150UC for about 1 to 10 hours.
Upon the reaction with mercaptans, about 2 to 5 mol. of a mercaptan is used relative to 1 mol. of the compound (V'). The reaction is preferably conducted in the presence of about 1 to 3 mol. of an base (e.g. sodium carbonate, potassium carbonate, etc.) relative to Compound (IV). Examples of solvents include acetonitrile, alcohols, halogenated hydrocarbons (e.g. chloroform, dichloroethane, etc.), ethers (e.g. tetrahydrofuran, dioxane, etc.) or amides (e.g.
dimethylformamide, dimethylacetamide, etc.). The reaction can be conducted preferably at temperatures ranging from 50~C to about the boiling point of the solvent for about 1 to 5 hours.
The compound (Ih) is reacted with an oxidi~lng reagent (e.g. m-chloroperbenzoic acid, etc.) to form the sulfoxide or sulfone .
compound (Ih') which is reacted with various nucleophilic reagents (e.g. alcohols, amines, mercaptans, etc.) to give the compound (I) , ' ' ' ~ - .

204~

as illustrated in Scheme I". The oxidation of the compound (Ih) to the sulfoxide or sulfone compound (Ih') is preferably conducted in solvents including halogenated hydrocarbons (e.g. dichloromethane, chloroform, dichloroethane, etc.), ethers (e.g. tetrahydrofuran, dioxanel'etc.) and the like. Examples of such oxidizing reagents include organic peracids such as m-chloroperbenzoic acid, N-halosuccinimides such as N-bromosuccinimide, etc. Generally, the oxidizing reagent is employed in an equal or slightly excess amount when compared to the compound (Ih). The sulfoxide can be produced by one mole of the oxidizing reagent and the sulfone compound (Ih') by two moles. The reaction is preferably conducted at temperatures ranging from about ice-cooled temperature to room temperature for about 3 to 10 hours.
The reaction of the compound (Ih') into the compound (I) is conducted in essentially the same manner as mentioned in Scheme I'.
The carboxylic acid (Ik) is formed by the ~lk~l;ne hydrolysis of the carboxylic acid ester compound (I;) as illustrated in Scheme J. The reaction is conducted by using about 1 to 3 mol. of alkali relative to 1 mol. of Compound (Ij) usually in a solvent such as an aqueous alcohol (e.g. methanol, ethanol, methyl cellosolve, etc.). Examples of such ~lk~ include sodium hydroxide, potassium hydroxide or the like. The reaction is conducted at temperatures ranging from room temperature to about 100~C for about 1 to 10 hours, preferably at about the boiling point of a solvent used for about 3 to 5 hours The protected tetrazole derivative (Il) is deprotected to give Compound (Im) as depicted in Scheme K~ Conditions of the deprotection depend on the protective group (R) then used. When R is triphenylmethyl, 2-tetrahydropyranyl, methoxymethyl, ethoxy methyl or the like, it is convenient to conduct the reaction in an aqueous 20~0~5~

alcohol (e.g. methanol, ethanol, etc.) containing about 0.5N to 2N
hydrochloric acid or acetic acid at about room temperatures for about 1 to 10 hours.
The compound (Iq) is prepared by protecting the tetrazole group in the presence of a base, and then the carboxyl group to give the ester compound (Ip), followed by removing the protective group under acid conditions as illustrated in Scheme L. In the reaction to obtain Compound (Io) from Compound (In), an alkylating agent is used in an amount of about 1 to 1.5 mol. relative to 1 mol. of Compound ~In). Examples of the solvents to be used for the reaction include halogenated hydrocarbons such as chloroform, methylene chloride and ethylene chloride, ethers such as dioxane and tetrahydrofuran, acetonitrile, pyridine, etc. Examples of such bases include potassium carbonate, sodium carbonate, triethylamine, pyridine, etc.
Examples of such alkylating agents include halides such as triphenyl-methyl chloride and methoxy methyl chloride, etc. While reaction conditions vary with combinations of the base and the alkylating agent employed, it is preferable to conduct the reaction by using triphenylmethyl chloride at temperatures ranging from ice-cooling to room temperature for about 1 to 3 hours in methylene chloride in the presence of triethylamine. In the reaction for producing Compound (Ip) from Compound (Io) thus obtained, the alkylating agent is '-used in an amount of about 1 to 3 mol. relative to 1 mol. of Compound (Iq). Examples of the reaction solvent include amides such as dimethylformamide and dimethylacetamide, acetonitrile, dimethyl-sulfoxide, acetone, ethyl methyl ketone, etc. Examples of the base include potassium carbonate, sodium carbonate, sodium hydride, potassium t-butoxide, etc. ~amr1es of such alkylating agents include halides such as cyclohexyl 1-iodoethyl carbonate, ethyl 1-iodoethyl carbonate, pivaloyloxymethyl iodide, etc. While reaction 20~09~
conditions vary with combinations of the base and the alkylating agent employed, it is preferable to subject Compound (Io) to reaction in DMF, by adding the alkylating agent in the presence of potassium carbonate, at about room temperatures for about 30 minutes to one hour.
The reaction for deprotecting Compound (Ip) thus obtained is conducted preferably in a manner similar to the reaction (K).
When trityl group is used as the protecting group of tetrazole group, it is preferable to conduct the reaction in methanol or ethanol, while adding lN-HCl, at about room temperatures for about 30 minutes to one hour.
The reaction products obtained as above by the reaction processes (A) to (L), can be easily isolated and/or purified by or according to conventional methods such as, for example, evaporation of solvents, extraction by water or organic solvents, concentration, neutralization, recryst~lli7.~tion, distillation, column chromatography and the like. The compounds (I) thus produced via the reaction processes as depicted in Schemes A to L can be isolated and/or purified from the reaction mixture according to conventional methods such as, for example, recrystall;7.~tion and column chromatographyJ to obtain a cryst~lline product.
The compounds obtained as above by the reaction processes : (A) to (L), may be in the form of solvates or salts (including addition salts) derived from pharmaceutically or physiologically acceptable acids or bases. These salts include but are not limited to the following: salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, nitric acid, phosphoric acid and, as the case may be, such organic acids as acetic acid, oxalic acid, succinic acid, citric acid, ascorbic acidJ lactic acid, p-toluenesulfonic acid, methanesulfonic acid, fumaric acid, :

20dO9 tartaric acid and maleic acid. Other salts include salts with ammonium, alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases (e.g. trialkyl-amines, dibenzylamine, ethanolamine, triethanolamine, N-methyl-morpholine, etc).
And, by conventional means, the compounds (I) can be formed as salts with non-toxic, physiologically or pharmaceutically acceptable acids or bases, for example salts with an inorganic acid such as hydrochloride, sulfate or nitrate, and, depending on compounds, salts with an organic acid such as acetate, oxalate, succinate or maleate, salts with an alkali metal such as sodium salt or potassium salt, or salts with an ~lk~line earth metal such as calcium salt.
For the synthesis of these compounds (I), the starting compounds (II) and (IV) can be synthesized by or according to the methods described in, for example, the following literature references or methods analogous thereto, namely, by the reactions (M), ~N), (O) and (P) as depicted below.
(1) P. N. Preston, The Chemistry of Heterocyclic Compounds, Vol. 40, ed. by P. N. Preston, John Wiley & Sons Inc., New York (1981), pp. 1-286, (2) E. S. Schipper and A. R. Day, Heterocyclic Compounds, Vol. 5, ed.
by R. C. Elderfield, John Wiley L Sons Inc., New York (1965), pp. 194-297, (3) N. J. Leonard, D. Y. Curtin, & K. M. Beck, J. Am. Chem. Soc. 6~, 2459 (1947), (4) S. Weiss, H. Miohaud, H. Prietzel, & H. Kromer, Angew. Chem. 85, 866 (1973), (5) W. B. Wright, J. Heterocycl. Chem., 2, 41 (1965), (6) A. M. E. O~ar, Synthesis, 1974, 41, .

20~0~

(7) D. J. Brown & R. K. Lynn, J. Chem. Soc.(Perkin I), 1974, 349, (8) J. A. Van Allan & B. D. Deacon, Org. Syn., 30, 56 (1950), (9) S. P. Singh, S. S. Parmar & B. R. Pandey, J. Heterocycl. Chem., 14~ 1093 (1977), (10) S. Nakajima, I. Tanaka, T. Seki & T. Anmo, Yakugaku Zasshi, 78, 1378 (1959), (11) K. Seno, S. Hagishita, T. Sato & K. Kuriyama, J. Chem. Soc., Perkin Trans. 1984, 2013, (12) D. R. Buckle et al., J. Med. Chem., 30, 2216 (1987), (13) R. P. Gupta, C. A. Larroquette & K. C. Agrawal, J. Med. Chem., 25, 1342 (1982), etc.
Scheme M

R, R, R, ~ COOH ~ COCl ~ CON 9 VI \ VII VIII

NO
IX X

(CIH2)n ~ X ~ R, (CIH2)D ~ X

NO2 ~ NO2 XII

~H2)D ~ X

~ NH~ IV
[wherein R2, R', A, X and n are of the same ~ ~n;nE as defined above;
and R3 stands for a lower (Cl_b) alkyl group].
.

.. . . . .

'' ~ .

20~095~
Scheme M' Z IIIb ~ NH IV

X' ~ XII R 2 H / OHC ~ X ~
NCOOR3 ~ ~ NH2 IIIc ¦ Z~&~(CH2)n-l~X~

IIId ~NH-Q-(CH,) ~X~

~ NH -~CH2) n~X~

NH, IV
wherein R2, R~, R', A, 2, X and n are of the same -~~n;ng as defined above.
Sch~ M and M' illustrate the process for preparing important intermediates which are useful in synthesizing the compound (I) of the present invention.
These oompounds oan be produoed aooording to the above-mentioned referenoes. The compound ~VI~ is converted by the Curtius ; reaction into the carbamic acid compound (X) followed by alkylation and subsequent reduction of nitro to form the ~;~r;no compound (IV).
In the rearrangement of Compound (VI) to Compound (X), Compound (X) is 2 0 ~

produced in a high yield according to conventional procedures of the Curtius rearrangement: the acid chloride (VII) -~ the acid azide (VIII) ~ the isocyanate (IX) -~ Compound (X). The compound (VI) is conveniently heated with diphenylphosphoryl azide (DPPA) in the presence of triethylamine in DMF to form the isocyanate (IX) via the acid azide (VIII) followed by reaction of an alcohol to give the compound (X) in a high yield. The compound (X) thus obtained is alkylated in the same manner as in Scheme A to form the compound (XI).
In the reaction, it is convenient to heat the reaction mixture under reflux for about 4 - 6 hours in the presence of potassium carbonate as a base in acetonitrile. The compound (XI) is heated under reflux in an alcohol containing a mineral acid (e.g. hydrochloric acid, sulphuric acid, etc.) or an organic acid (e.g. trifluoroacetic acid, etc.), for about 1 - 2 hours to give the compound (XII). Various reducing reagents (e.g. raney nickel, stannic chloride, etc.) can be employed in the reduction of the nitro compound (XII) to the ~ ino compound (IV). Among them, the combination of ferric chloride and hydrazine ~ hydrate in an alcohol is the most convenient. Further, the compound (IV) can be prepared by various techniques other than those mentioned above.
The compound (X') commercially available or readily obtained by known methods in the art is preferably reacted with the amine (IIIb) in the presence of a base (e.g. potassium carbonate, sodium carbonateJ amines, etc.) in an organic solvent (e.g. alcohols, ethersJ halogenated hydrocarbons, amides, etc.) at temperatures ranging from about the boiling point of the solvent to 100~C for about 5 to 20 hours.
The compound (X") readily obtained by acid treatment of the compound (X) is subjected to condensation under dehydration conditions including azeotropic removal of water (or in the presence of a 204~5~

dehydrating agents) in an organic solvent (e.g. ethers, halogenated hydrocarbons, aromatic hydrocarbons, etc.) followed by reaction with a reducing reagent (e.g. NaCNBH3, etc.) to form the compound (XII).
The condensation under dehydration conditions can be accelerated by using conventional acid or base catalysts.
'rhe compound (X") is reacted with the acid chloride (IIId), preferably in the presence of a base (e.g. pyridine, triethylamine, dimethylaminopyridine, etc.) in an organic solvent (e.g. halogenated hydrocarbons, pyridine, etc.) at temperatures ranging from room temperature to about the boiling point of the solvent for about 2 to 20 hours, to the amide (XI'). The resulting amide (XI') is reacted with a reducing reagent (e.g. sodium aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, etc.) to form the diamino (IV).
Scheme N
~ R &

XIV XIII IIa [wherein each group is of the same ~PAning as defined above].
Scheme 0 NH2 > ~ /~ OR' XIV IIb [wherein each group is of the same r-~ning as defined above].
Scheme P

NH2 ~ ~ ~ NHR' XIV IIc 2~0~55 [wherein each group is of the same meaning as defined above].
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 Compound (XV) to halogenomethylation in accordance with the methods described in literature references, for example;
1) J. R. E. Hoover, A. W. Chow, R. J. Stedman, N. M. 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. Gor~ich, J. Am. Chem. Soc., 78, 2217 (1956), 4) M. Orchin and E. Oscar Woolfolk, J. Am. Chem. Soc., 67, 122 (1945), etc.
Scheme Q

X - ~ > ZCH2 ~ X
XV IIIa [wherein each group is of the same '~ning as defined above].
The compound (IIIa') can also be readily prepared according to the methods described in L. N. Pridgen, L. Snyoler and J. Prol, Jr., J. Org. Chem., 54, 1523 (1989) as illustrated in Scheme R, followed by halogenation (R'2=Me) or halogenomethylation (R12=H).

2 0 ~
Scheme R

H2N ~ Rl2 ~ Br. Mg CHO > ~ CH=N
O~e OMe C~O 1. NH20H.HCl R~ ~ 2. Ac20 Rl2 ~ > (IIIa') XIV XX
[wherein Rl2 is hydrogen or methyl].
Further, among the starting compounds (III), the compound (III) wherein n denotes 2, i e. the compound (IIIb) can be obtained from the compound (IIIa) in accordance with the reaction (S).
Scheme S

ZCH2 ~ X ~ > NC -CH2 ~ X
IIIa XVI

> EtOOC--CH2~X~ -- ' HOH2C--CH2~X~
XVII XVIII

> Z--(CH 2) 2 ~X ~) IIIb ~wherein each group is of the same l~n;ng as defined above].
The compounds and the salts thereof thus produced are less toxic, strongly inhibit the vasoconstrictive and hypertensive actions of angiotensin ~ , exert a hypotensive effect in anir~ in partioular mammals (e.g. human, dog, rabbit, rat, etc.), and therefore they are useful as therapeutics for not only hypertension but also . .
,:

2 ~ S

circulatory di~e~es such as heart failure (hypertrophy of the heart, cardiac insufficiency, cardiac infarction or the like), strokes, cerebral apoplexy, nephropathy and nephritis. The compounds (I) and salts thereof according to the present invention strongly inhibit vasoconstriction and hypertension derived by angiotensin ~ and therefore possess potent anti-hypertensive activity in animals, more specifically mammal ani~ (e.g. humans, dogs, pigs, rabbits, rats, etc.). Further, the compounds (I) and salts thereof according to the present invention are of quite low toxicity and clinically useful in treating not only hypertension but also circulatory system diseases such as heart and brain diseases, strokes, renal failures, nephritis and the like.
For therapeutic use, the compounds (I) and salts thereof can be orally, parenterally, by inhalation spray, rectally, or topically ~Amini~tered as pharmaceutical compositions or formulations (e.g.
powders, granules, tablets, pills, capsules, injections, syrups, emulsions, elixirs, suspensions, solutions and the like) comprising at least one such compound alone or in admixture with pharmaceutically acceptable carriers, adjuvants, vehicles, excipients and/or diluents. The pharmaceutical compositions can be formulated in accordance with conventional methods. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intraperitoneal injections, or infusion techniques. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wettin~ agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or su~pen~ion in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in water. Among the acceptable vehicles or solvents that may be employed are water, 20~0~

Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. ~or this purpose any bland fixed oil or fatt;y acid may be employed including natural, synthetic, or semi-synthetic fatty oils or acids, and natural, synthetic, or semi-synthetic mono-, di-, or triglycerides.
Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable non-irritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug. Solid dosage forms for oral a~mini~tration may include powders, granules, tablets, pills, and capsules as mentioned above. In such solid dosage forms, the active compound may be a~mix~d with at least one additive such as sucrose, lactose, celluloses, mannitol, maltitol, dextran, starches, agars, alginates, chitins, chitosans, pectins, tragacanth gums, arabic gums, gelatins, collagens, casein, albumin, and synthetic or semi-synthetic polymers or glycerides. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents as magnesium stearate, preservatives such as parabens and sorbic acid, antioxidants such as ascorbic acid, a-tocoPherol and cysteine, disintegrants, binders, thickening, buffering, sweetening, flavoring, and perfuming agents.
Tablets and pills can additionally be prepared with enteric coatings.
Liquid dosage forms for oral ~m;ni~tration may include pharmaceutically acceptable e ~l~ion~, syrups, elixirs, s~pen~ions, solutions contA1ning inert diluents commonly used in the art, such as water.
Specific dose levels for any particular patient will be employed depending upon a variety of factors including the activity . .

~ . .

2 0 ~
of specific compounds employed, the age, body weight, general health, sex, diet, time of ad~ini.stration, route of a~mini~tration~ rate of excretion, drug combination, and the severity of the particular disease undergoing therapy. The dose varies with the diseases to be treated, symptoms, subjects and admini~tration routes, and it is desirable 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 ~m; ni ~trations when used as an agent for the therapy in adults.
For example, when used for treating adult essential hypertension, the active ingredient will preferably be administered in an appropriate amount, for example, about 10 mg to 100 mg a day orally and about 5 mg to 50 mg a day intravenously. The active ingredient will preferably be admini~tered in equal doses two or three times a day.
The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds.
Examples By the following formulation examples, working examples, experimental examples and reference examples, the present invention will be explained more concretely, but they should not be interpreted as limiting the invention in any manner.
Examples of abbreviations in this specification are as fo~lows:
Me: methyl, Et: ethyl, Tet: tetrazolyl, cycl: cyclo-, Pr:
propyl, Bu: butyl, Pen: pentyl, Bu: butyl, Hex: hexyl, Hep: heptyl, Ph: phenyl, DMF: dimethylformamide, and THF: tetrahydrofuran.
Formulation ~Amples When the compound (I) of the present invention is used as a therapeutic agent for circulatory failures such as hypertension, heart d;~e~es, strokes, kidney diseases, etc., it can be used in 20~09~
accordance with, for example, the following formulations.
1. Capsules (1) 2-ethoxy-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]
methyl]benzimidazole-7-carboxylic acid 10 mg 5 (2) lactose 90 mg (3) fine cryst~11inP 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 filled into gelatin capsules.
2. Tablets (1) 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]
methyl]benzimidazole-7-carboxylic acid 10 mg (2) lactose 35 mg (3) corn starch 150 mg (4) fine cryst~11;ne cellulose 30 mg (~) magnesium stearate 5 mg one tablet230 mg (1), (2), (3), two thirds of (4) and a half of (5) are mixed and granulated. To the granules are added the rP~ ders of (4) and (5), followed by subjecting the granules to compression molding.
3. In~ections (1) 2-methylthio-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]
methyl]be~ idazole-7-carboxylic acid disodium salt 10 mg (2) inositol 100 mg (3) benzyl alcohol 20 mg one ampoule130 mg 20~0~5~
(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) l-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate 10 mg (2) lactose 90 mg (3) fine cryst~lline cellulose 70 mg 10 (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 filled into gelatin capsules.
5. Tablets (1) l-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl]b~n7im;dazole-7-carboxylate 10 mg (2) lactose 35 mg 20 (3) corn starch 150 mg (4) fine cryst~ll;n~ cellulose 30 mg (5) magnesium stearate 5 mg one tablet230 mg (1), (2), (3), two thirds of (4) and a half of (5) are mixed and granulated. To the granules are added the rem.ind~rs of(4) and (5), followed by sub~ecting the granules to compression molding.

2~0~5~

6. Injections (1) 2-ethoxy-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]
methyl]benzimidazole-7-carboxylic acid disodium 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 volume 2 ml, which is filled into an ampoule. The whole process is conducted under sterile conditions.

Reference Example 1 2-Propoxybenzimidazole To a solution of o-phenylenedj~;ne (2 g) in propyl orthocarbonate (5 ml) was added acetic acid (1.1 ml) and the solution was stirred at 80~C for 3 hours. To the reaction mixture was added ethyl acetate, and the solution was washed with an aqueous solution of sodium hydrogen carbonate and water, then dried (Na2S0~), followed by concentration to dryness. The concentrate was purified by column chromatography on silica gel to give crystals. Recryst~ tion from ethyl acetate - benzene afforded colorless crystals (1.54 g, 47%), m.p. 163-164~C.
Reference Example 2 Ethyl 2-carboxy-3-nitrobenzoate A mixture of 3-nitrophthalic acid (35 g) in ethanol (300 ml) cont~nin~ conc. sulfuric acid (20 ml) was heated under reflux for 24 hours. The solvent was evaporated in _acuo and the residue was poured into cald water (700 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with ~ 30 aater and shaken with an aqueous solution of potassium carbonate.

'~ ~

2~409~

The aqueous layer was made acidic with hydrochloric acid and the mixture was extracted with methylene chloride. The organic layer was washed with water, then dried, followed by evaporation of the solvent. The resultant solid (29 g, 74%) was used for the subsequent reaction without purification.
'H-NMR(9OMHz, CDCl3) ~ : 1.43(3H,t), 4.47(2H,q), 7.70(1H,t), 8.40(2H,d), 9.87(1H,br s) IR(Nujol) cm~': 1725, 1535, 1350, 1300, 1270 Reference Example 3 Ethyl 2-t-butoxycarbonylamino-3-nitrobenzoate A mixture of ethyl 2-carboxy-3-nitrobenzoate (23.9 g) and thionyl chloride (12 ml) in benzene (150 ml) were heated under reflux for 3 hours. The reaction mixture was concentrated to dryness.
The resultant acid chloride (26 g, quantitative) was dissolved in methylene chloride (20 ml). The solution was added dropwise to a mixture of sodium azide (9.75 g) in dimethylformamide(DMF) (20 ml) with stirring vigorously. The reaction mixture was poured into a mixture of ether-hexane (3 : 1, 200 ml) and water (250 ml) to separate into two layers. The organic layer was washed with water, then dried, followed by evaporation of the solvent. The residue was dissolved in t-butanol (200 ml) and the solution was heated gradually with stirring, followed by heating under reflux for 2 hours. The reaction mixture was concentrated in vacuo to give an oily product (30 g).
iH-NMR(9OMHz, CDCl3) ~: 1.40(3H,t), 1.53(9H,s), 4.43(2H,q)J
7.23(1H,t), 8.03-8.27(2HIm), 9.70(1H,br s) IR(Neat) cm-': 3320, 2980, 1740, 1585, 1535, 1500, 1440, 1375, 1265, 1155 :

.: .
.
'' 2~40~
Working Exa~ple 1 Ethyl 2-[[2'-cyanobiphenyl)]amino]-3-nitrobenzoate To a solution of ethyl 2-t-butoxycarbonylamino-3-nitro-benzoate (20 g) in tetrahydrofuran (50 ~l) was added, while stirring under ice-cooling, sodium hydride (60% dispersion in mineral oil, 2.8 g). The mixture was stirred at room temperature for 20 minutes and to the mixture were then added 4-(2-cyanophenyl)benzyl bromide (18 g) and potassium iodide (360 mg), followed by heating for 10 hours under reflux. The solvent was evaporated to dryness and the residue was partitioned between water (250 ml) and ether (200 ml).
The organic layer was washed with water, dried and concentrated to give a yellow syrup. The syrup was dissolved in a mixture of trifluoroacetic acid (60 ml) and methylene chloride (40 ml) and the solution was stirred for one hour at room temperature. The reaction mixture was concentrated to dryness and to the residue was added ethyl ether (200 ml) to give crystals. The crystals were collected by filtration, washed with ether to give pale yellow crystals (22.1 g, 85~), m.p. 118-119~C.
1H-NMR(9OMHz,CDCl3) ~ : 1.37(3H,t), 4.23(2H,s), 4.37(2H,q)~
6.37(1H,t), 7.33-7.83(9HJm), 7.97-8.20(2H,m) IR(Nujol)cm-1: 3280, 2220, 1690, 1575, 1530, 1480, 1450, 1255, 1105, Working Example 2 Ethyl 3-amino-2-[~2'-cyanobiphenyl-4-yl)methyl]amino]benzoate To a solution of ethyl 2-[[(2'-cyanobiphenyl-4-yl)methyl]-amino]nitrobenzoate (10.4 g) in ethanol (50 ml) was added stannous dichloride dihydrate (28.1 g) and the mixture was stirred at 80~C
for two hours. The solvent was evaporated to dryness. To the ice-cooling mixture of the residue in ethyl acetate (300 ml) was added dropwise 2N NaOH (500 ml) with stirring. The aqueous layer was :

20~â~

extracted with ethyl acetate (200 ml x 2). The organic layers were combined, washed with water, and dried. The solvent was evaporated to clryness and the residue was purified by column chromatography on sillca gel to give crystals. Recryst~11i7~tion from ethyl acetate -hex~me gave colorless crystals (7.3 g, 79%), m.p. 104-105~C.
H-NMR(200MHz, CDCl 3) ~: 1. 33(3H,t), 4.23(2H,s), 4.27(2H,q), 6.83-6.93(2H,m), 7.35-7.55(7H,m), 7.64(1H,dt), 7.76(dd) IR(KBr) cm~': 3445, 3350, 2220, 1680, 1470, 1280, 1240, 1185, 1160, 1070, 1050, 1020, 805, 750 Working Example 3 Ethyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-methoxybenzimidazole-7-earboxylate Aeetie aeid (0.2 g) was added to a solution of ethyl 3-amino-2-[[2'-eyanobiphenyl-4-yl)methyl]amino]benzoate (1.1 g) in methyl orthoearbonate (5 ml). The mixture was stirred at 80~C for one hour. The reaetion mixture was coneentrated, and the eoneentrate was extraeted with ethyl aeetate. The organie layer was then washed with an aqueous solution of sodium hydrogen earbonate and water.
The solvent was evaporated in vaeuo to give erystals.
Reeryst~11i7~tion from ethyl aeetate - benzene afforded eolorless erystals (1.09 g, 90%), m.p. 160-161~C.
'H-NMR(200MHz, CDCl3) ~ : 1.23(3H,t), 4.23(2H,q), 4.26(3H,s), 5.72(2H,s), 7.09(2H,d), 7.20(1H,t), 7.38-7.48(4H,m), 7.58-7.66(2H,m), 7.73-7.79(2H,m) IR(KBr) em~l: 3000, 2220, 1725, 1560, 1465, 1440, 1415, 1285, 1250, 1220, 1040, 760, 750, 740 ,~
, 2 ~ a Wor~ing Example 4 Ethyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxybenzimidazole-7-carboxylate Acetic acid (0.2 g) was added to a solution of ethyl 3-amino-2-N-[2'-cyanobiphenyl-4-yl)methyl]aminobenzoate (1.0 g) in ethyl orthocarbonate (5 ml). The mixture was stirred at 80~C for one hour. The reaction mixture was concentrated, and the concentrate was dissolved in ethyl acetate. The solution was washed with an aqueous solution of sodium hydrogen carbonate and water. The solvent was evaporated to give crystals. Recryst~11i7~tion from ethyl acetate -benzene afforded colorless crystals (0.79 g, 69%), m.p. 131-132~C.
Elemental Analysis for C26H23N303 :
C(%) H(%) N(%) Calcd.: 73.39; 5.45; 9.88 Found : 73.36; 5.42 9.83 'H-NMR(200MHz, CDCl3) ~ : 1.24(3H,t), 1.49(3H,t), 4.24(2H,q), 4.68(2H,q), 5.72(2H,s), 7.10(2H,d), 7.19(1H,t), 7.38-7.46(4H,m), 7.56-7.66(2H,m), 7.73-7.77(2H,m) IR(KBr) cm~l: 2220, 1720, 1550, 1480, 1430, 1280, 1245J 1215, 1040, 760, 740 Working Example 5 Ethyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-propoxyben7;r;d~7Ole-7-carboxylate Acetic acid (0.2 g) was added to a solution of ethyl 3-amino-2-N-[[(2'-cyanobiphenyl-4-yl)methyl]amino]benzoate (0.9 g) in propyl orthocarbonate (5 ml). The mixture was stirred at 80aC for one hour. The reaction mixture was concentrated, and the concentrate was dissolved in ethyl acetate. The solution was washed with an aqueous solution of sodium hydrogen carbonate. The solvent was evaporated to give crystals. Recryst~11;7~tion from ethyl acetate - ben7en~

20a~5~

afforded colorless crystals (0.72 g, 68%), m.p. 90-92~C.
Elemental Analysis for C27H2sN303 :
C(~ %) N(~) Calcd.: 73.79; 5.73; 9.56 Found : 73.84; 5.79; 9.54 H-MMR(200MHz, CDCl3) o : 1.01(3H,t), 1.25(3H,t), 1.80-1.97(2H,m), 4.24(2H,q), ~.57(2H,q), 5.72(2H,s), 7.11(2H,d), 7.19(1H,t), 7.38-7.46(4H,m), 7.56-7.66(2H,m), 7.73-7.77(2H,m) IR(KBr) cm~': 2220, 1725, 1550, 1480, 1460, 1430, 1370, 1280, 1245, 1210, 1115, 1040, 760, 750, 740 Working Example 6 Ethyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-mercaptobenzimidazole-7-carboxylate A mixture of ethyl 3-amino-2-N-[[(2'-cyanobiphenyl-4-yl)-methyl]amino]benzoate (5.6 g) and sodium 0-ethyl dithiocarbonate (7.3 g) in ethanol (50 ml) was heated for 8 hours under reflux. The reaction mixture was concentrated and the residue was dissolved in water. The solution was adjusted to pH 3-4 with hydrochloric acid.
Precipitating crystals were collected by filtration, followed by recryst~lli7~tion from ethanol to afford yellow crystals (5.0 g, 80%), m.p. 225-227~C.
'H-NMR(200MHz, DMS0-d6) o~: 1.08(3H,t), 4.12(2H,q), 5.90(2H,brs), 7.08(2H,d), 7.27(1H,t), 7.38-7.59(6H,m), 7.76(1H,dt), 7.92(1H,dd) IR(KBr) cm-': 2210, 1720, 1460, 1440, 1420, 1375, 1335, 1265, 1180, 1135, 1115, 1100, 985, 760, 740 ' ' ., ' . '- ~ ~ :
. ~. . .
,, ., - - ,', .

2 ~

Reference Example 4 Methyl 2-[[(2'-cyanobiphenyl)methyl]amino]-3-nitrobenzoate A mixture of ethyl 2-[[(2'-cyanobiphenyl)methyl]amino]-3-nitrobenzoate (5 g) and sodium hydride (60% dispersion in mineral oil, 1.62 g) in methanol (50 ml) was stirred at room temperature for one day. The reaction mixture was concentrated and the residue was poured into a saturated aqueous solution of sodium hydrogen carbonate (100 ml), followed by extraction with chloroform. The organic layer was washed with water, dried and concentrated to dryness to give crystals. Recrystallization from ethyl acetate - hexane afforded pale yellow crystals (3.98 g, 83%), m.p. 106-108~C.
'H-NMR(200MHz, CDCl3) o~: 3.81(3H,s), 3.97(2H,br s), 4.23(2H,s), 6.40(1H,br s), 6.88-6.91(2H,m), 7.34-7.55(7H,m), 7.65(1H,dt,J=1.2, 7.7Hz), 7.77(1H,dd,J=1.4,8.0Hz) IR(KBr) cm~': 3410, 3350, 2225, 1695, 1485, 1470, 1290, 1200, 780, Working Example 7 Methyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxybenzimidazole-7-carboxylate Acetic acid (0.37 g) was added to a solution of methyl 3-amino-2-[[(2'-cyanobiphenyl-4-yl)methyl]amino]benzoate (2.03 g) in ethyl orthocarbonate (5 ml), and the mixture was stirred at 80~C for one hour. The reaction mixture was concentrated to dryness and the residue was dissolved in ethyl acetate. The solution was washed with an aqueous solution of sodium hydrogen carbonate and water. The solvent was evaporated in vacuo to give crystals.
Recryst~ 7~tion from ethyl acetate - hexane afforded colorless crystals (2.01 g, 86%), m.p. 168.5-169.5~C.

2 0 ~
Elemental Analysis :
C(%) H(%) N(%) Calcd.: 72.98; 5.14; 10.21 Found : 72.71; 5.12; 9.97 5 'H-NMR(200MHz,CDCl3) o~: 1.42(3H,t,J=7.1Hz), 3.71(3H,s), 4.63(2H,q,J=7.lHz), 5.59(2H,s), 7.09(2H,d,J=8.4Hz), 7.20(1H,t,J=7.9Hz), 7.45-7.59(5H,m), 7.69-7.80(2H,m), 7.92(1H,dd,J=1.4,7.8Hz) IR(KBr) cm~': 2225, 1725, 1550, 1480, 1430, 1350, 1280, 1250, 1040, 10760, 750 Reference Example 5 Ethyl 2-[[(2'-cyanobiphenyl-4-yl~methyl]amino]-3-(3-ethylthioureido)benzoate A mixture of ethyl 3-amino-2-[[(2'-cyanobiphenyl-4-yl)-methyl]amino]benzoate (1.61 g), ethyl isothiocyanate (1.5 ml) and ethanol (1 ml) was stirred at room temperature for 3 days. The reaction mixture was dissolved in ethyl acetate and the solution was washed with water, dried and concentrated to dryness to give crystals. Recryst~11i7~tion from ethyl acetate - hexane afforded pale yellow crystals (1.92 g, 91%), m.p. 108-110~C.
H-NMR~200MH~,CDCl3) o~: 1.15(3H,t), 1.40(3H,t), 3.50-3.70(2H,brs), 4.37(2H,q), 4.56(2H,d), 6.07(1H,t), 6.78(1H,t), 7.19-7.24(1HJm), 7.38-7.53(6H,m), 7.63(1H,dt), 7.72-7.76(1H,m), 7.99(1H,dd), 8.29(1H,br s) IR(KBr) cm~l: 3375, 3320, 3150, 2975, 2220, 1740, 1680, 1540, 1510, 1450, 1300, 1225, 1180, 1150, 760, 750 ; ~ 3o ' ~:

2 0 ~
Reference Example 6 Ethyl 2-[[(2'-cyanobiphenyl-4-yl)methyl]amino]-3-(3-propylthioureido)benzoate In substantially the same manner as Reference Example 5, desired pale yellow syrup (2.0 g, 98%) was obtained from ethyl 3-amino-2-[[(2'-cyanobiphenyl-4-yl)methyl]amino]benzoate (1.6 g), propyl isothiocyanate (1.5 ml) and ethanol (1 ml).
'H-NMR(200MHz,CDCl3) ~ : 0.88(3H,t), 1.40(3H,t), 1.48-1.67(2H,m), 3.42-3.68(2H,br s), 4.37(2H,q), 4.56(2H,d), 6.13(1H,t), 6.78(1H,t), 7.21-7.25(1H,m), 7.36-7.53(6H,m), 7.64(1H,dt), 7.73-7.77(1H,m), 7.99(1H,dd), 8.20-8.40(1H,br s) IR(Neat)cm-': 3325, 3175, 2960, 2930, 2875, 2220, 1710, 1690, 1590, 1475, 1360, 1175, 1140, 1090, 1020, 760 Working ~xample 8 Ethyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethylamino-benzimidazole-7-carboxylate Methyl iodide (4.5 g) was added to a solution of ethyl 2-[[(2'-cyanobiphenyl-4-yl)methyl]amino]-3-(ethylthioureido)benzoate (1.8 g) in ethanol (50 ml), and the mixture was heated under reflux for 12 hours. To the reaction mixture was added lN-HCl (60 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated to dryness and the concentrate was dissolved in ethyl acetate. The solution was washed with an aqueous solution of sodium hydrogen carbonate and water and dried. The solvent was evaporated to dryness and the residue was purified by column ohromatography on silica gel to afford yellow syrup (0.96 g, 58~).
'H-NMR(200MHz,CDCl3) ~ : 1.23(6H,t), 3.48-3.62(2H,m), 4.09(1H,t), 4.23(2H,q), 5.57(2H,s), 7.15(1H,t), 7.25(2H,d), 7.40-7.77(8H,m) 2~0~

IR(Neat)cm-': 3400, 3225, 2975, 2930, 2210, 1710, 1610, 1570, 148 0, 1425, 1365, 1320, 1270, 1250, 1210, 1130, 1100, 106 0, 770, 750 Working Example 9 Ethyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-propylamino-benzimidazole-7-carboxylate In substantially the same manner as Working F.~ p~ e 8, desired yellow syrup (1.2 g, 65~) was obtained from a solution of ethyl 2-[[(2'-cyanobiphenyl-4-yl)methyl]amino]-3-(3-propyl~hioure ido)-benzoate (2.0 g) and methyl iodide (4.8 g) in ethanol (50 ml).
H-NMR(200MHz,CDCl3) ~ : 0.87(3H,t), 1.25(6H,t), 1.52-1.70(2H,m), 3.42-3.52(2H,m), 4.12(1H,t), 4.25(2H,q), 5.58(2H,s), 7.16(1H
,t), 7.29(2H,d), 7.41-7.78(8H,m) IR(Neat)cm~': 3400, 3250, 2975, 2950, 2890, 2225, 1715, 1620, 159 0, 15709 1480, 1430, 1370, 1285, 1220, 1135, 1070, 760 Working Example 10 Methyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-methoxybenzimida zole-7-carboxylate A solution of 5.2M sodium methoxide in methanol (0.5 ml ) was added to a solution of ethyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-methoxyb~n7i~ 70le-7-carboxylate (1.3 g) in methanol (50 ml).
The mixture was heated for 4 hours under reflux. The reaction mixture was concentrated, and the precipitated crystals were collected by filtration. Recryst~11i7~tion from methanol afforded colorless prisms (1.1 g, 85%), m.p. 149-150~C.
Elemental Analysis for C94HIgN303:
C(%) H(%) N(%) Calcd.: 72.53; 4.82; 10.57 Found : 72.38; 4.93; 10.44 ......... . .

20~5~

'H-NMR(200MHz,CDCl3) ~ : 3.75(3H,s), 4.26(3H,s), 5.69(2H,s), 7.09(2H,d), 7.23(1H,t), 7.37-7.46(3H,m), 7.55-7.65(2H,m), 7.72-7.78(2H,m) Reference Example 7 5Methyl 2-[[(2'-cyanobiphenyl-4-yl)]methyl]amino-3-(3-methylthioureido)benzoate The above compound was synthesized (86 % yield) in substantially the same manner as Reference Example 5.
m.p. 152-155~C.
101H-NMR(200MHz,CDCl3) ~ : 3.05-3.07(3H,br s), 3.92(3H,s), 4.58(2H,d), 6.04-6.08(1H,br s), 6.77(1H,t), 7.22-7.26(1H,m), 7.39-7.52(6H,m), 7.63(1H,dt), 7.75(1H,dd), 7.97(1H,dd), 8.28(1H,br s) IR(KBr) cm~l: 3375, 3325, 3175, 2220, 1680, 1590, 1540, 1500, 1480, 1450, 1435, 1265, 1230, 1190, 1145, 1050, B30, 760, Working Example 11 Methyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-methylamino-ben7;~id~70le-7-carboxylate The above compound was synthesized as a syrup (42~ yield) in substantially the same manner as Working Example 8.
H-NMR(200MHzlCDCl3) ~ : 3.11(3H,d), 3.73(3H,s), 4.22(1H,q), 5.54(2H,s), 7.17(1H,t), 7.27(2H,d), 7.41-7.79(8H,m) IR(Neat)cm -1 3400, 3250, 3025, 2950, 2220, 1720, 1625, 1610, 1580, 1480, 1410, 1340, 1280, 1240, 1210, 1130, 1060, 750 Reference ~ -p1e 8 2-Propoxy-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl~ethyl]-b~n7~id~7,~le Sodium hydride (60% dispersion in mineral oil, 0.24 g) was added to a stirred solution of 2-propoxybenzimidazole (0.71 g) in DMF
(10 ml) under ice-cooling. The mixture was stirred for 20 minutes, , .

, . ~

2~09~5 to which was added N-triphenylmethyl-5-[2-(4-bromomethylbiphenyl]-tetrazole (2.3 g), followed by stirring at room temperature for 5 hours. To the reaction mixture was added ice-water, the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated to dryness. The concentrate was dissolved in methanol (50 ml), to which was added lN-HCl (15 ml), followed by stirring at ~0~C for 2 hours. The reaction mixture was concentrated, to which were added water (15 ml) and ethyl acetate (15 ml). The mixture was made ~lk~l~ne with lN NaOH and shaken.
The aqueous layer was adjusted to pH 3-4 with lN-HCl and then extracted with chloroform. The organic layer was washed with water, dried and concentrated to dryness. The concentrate was purified by column chromatography on silica gel to yield crystals.
Recryst~ tion from ethyl acetate - methanol gave colorless crystals (0.58 g, 35%), m.p. 177-179~C (decomp.).
Elemental Analysis for C24H22N60:
C(%) H(%) N(%) Calcd.: 70.23; 5.40; 20.47 Found: 69.93; 5.43; 20.22 20 'H-NMR(200MHz,DMSO-d6) ~ : 0.95(3H,t), 1.70-1.88(2H,m), 4.46(2H,t), 5.23(2H,s), 7.04-7.10(4H,m), 7.20(2H,d), 7.38-7.43(2H,m), ; 7.48-7.70(4H,m) IR(KBr) cm~': 1540, 1535, 1485, 1475, 1450, 1425, 1385, 1285, 1270, 10ll0, 980, 755, 745 Working Example 12 Methyl 2-butylamino-1-[(2'-cyanobiphenyl-4-yl)methyl]-benzimidazole-7-carboxylate The title compound was prepared from methyl [[(2'-cyano-biphenyl-4-yl)methyl]amina]-3-(butylureido)benzoate in substantially the same manner as Working Example 8. The yield was quantitative.

2~9~

'H-NMR(200MHz,CDCl3) ~: 0.89(3H,t), 1.21-1.39(2H,m), 1.45-1.60(2H,m), 3.50-3.65(3~,brs), 3.42(3H,s), 4.56(2H,d), 6.08(1H,t), 6.78(1H,t), 7.21-7.30(1H,m), 7.39-7.54(6H,m), 7.64(1H,dt), 7.75(1H,dd), 7.98(1H,dd), 8.26(1H,brs) Working Example 13 Methyl 2-(N-ethylmethylamino)~ (2'-cyanobiphenyl-4-yl)-methyl]benzimidazole-7-carboxylate A mixture of sodium hydride (60~ dispersion in mineral oil, 0.13 g) in DMF (5 ml) was stirred under ice-cooling for 5 min. and methyl 2-ethylamino-1-[(2'-cyanobiphenyl-4-yl)methyl]benzimidazole~7-carboxylate (0.95 g) was added to the mixture, followed by stirring for 10 min. To the mixture was added methyl iodide (0.2 ml) and the mixture was stirred for 20 min. To the reaction mixture was added water and the mixture was extracted with ethyl acetate.
The extract was washed with water, dried and evaporated to dryness.
The residue was purified by column chromatography on silica gel to give crude cristals, which were recrystalli7~d from ethyl acetate -hexane to afford colorless nee.~le~ (0.88 g, 82%), m.p. 66-69~C.
'H-NMR(200MHz,CDCl3) ~ : 1.25(3H,t), 3.03(3H,s), 3.36(2H,q), 3.73(3H,s), 5.60(2H,s), 6.88(2H,d), 7.16(1H,t), 7.34-7.49(5H,m), 7.59(1H,dt), 7.73(1H,dd), 7.'78(1H,dd) IR(KBr) cm~l: 2210, 1710, 1540, 1530, 1435, 1420, 1385, 1300, 1275, 1250, 1005, 760 Reference Example 9 Methyl 1-~(2'-cyanobiphenyl-4-yl)methyl~-2-oxo-2,3-dihydro-benzimidazole-7-carboxylate To a solution of methyl 2-[(2'-cyanobiphenyl-4-yl)-methylamino]-3-methoxycarbonylaminobenzoate (10.5 g) in methanol (100 ml) was added NaOMe (10 g), and the mixture was heated under reflux for 20 hours. The reaction mixture was neutralized with '' '' ' . ~ ;

, 2~409~

lN-HCl and concentrated to dryness. The residue was extracted with chloroform - water. The organic layer was washed with water, dried and evaporated to dryness. The resulting crystals were recrystallized from chloroform - methanol to afford colorless needles (8.67 g, 89%), m.p. 250-253nC.
'H-NMR(200MHz,DMS0-d6) ~ : 3.65(3H,s), 5.35(2H,s), 7.04-7.16(3H,m), 7.24-7.28(2H,m), 7.48-7.59(4H,m), 7.76(1H,dt), 7.92(1H,dd) IR(KBr) cm~l: 2210, 1720, 1690, 1635, 1430, 1390, 1270, 1255, 760, 750, 730l 690 Reference Example 10 Methyl 2-chloro-1-[(2'-cyanobiphenyl-4-yl)methyl]-benzimidazole-7-carboxylate A mixture of methyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-oxo-2,3-dihydroben7imi~7Ole-7-carboxylate (8.02 g) in phosphorus oxychloride (30 ml) was heated under reflux for 8 hours.
The reaction mixture was concentrated and the resulting residue was poured into ice-water. The mixture was extracted with chloroform.
The extract was washed with water, dried and evaporated. The residue was purified ~y column chromatography on silica gel to give crystals, which were recryst~lli7ed from chloroform - methanol to afford colorless needles (2.2 g, 28%), m.p. 154-157~C.
H-NMR(200MHz,CDCl3) ~ : 3.78(3H,s), 5.95(2H,s), 7.06(2H,d), 7.31(lH,t), 7.39-7.48(4H,m), 7.58-7.66(1H,m), 7.71-7.77(2H,m), 7.93(1H,dd) IR(KBr) cm~': 224~, 1720, 1480, 1450, 1440, 1425, 1370, 1350, 1290, 1270, 1200, 11509 1120, 1000, 775, 760, 750 ,, . ~:

20~a~
Reference Example 11 Methyl 2-[(2'-cyanobiphenyl-4-yl)methylamino]-3-methoxy-carbonylaminobenzoate To a stirred solution of methyl 3-amino-2-[(2'-cyanobiphenyl-4-yl)methylamino]benzoate (10 g) in pyridine (50 ml) was added dropwise methyl chloroformate (9.0 ml) under ice-cooling The mixture was stirred at room temperature for 3 hours and concentrated. The residue was extracted with ethyl acetate.
The extract was washed with water, dried and evaporated.
The residue was recryst~lli7Pd from ethyl acetate - hexane to afford pale yellow needles (10.5 g, 90%), m.p. 113-115~C.
H-NMR(200MHz,CDCl3) ~ : 3.80(3H,s), 3.83(3H,s), 4.11(2H,d), 6.29(1H,brs), 7.09(1H,t), 7.40-7.80(10H,m), 8.19(1H,d) Working Example 14 Methyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-morpholino-benzimidazole-7-carboxylate A mixture of methyl 2-chloro-1-[(2'-cyanobiphenyl-4-yl)-methyl]benzimidazole-7-carboxylate (0.8 g) in morpholine (15 ml) was stirred at 100nC for 2 hours and the reaction mixture was concentrated to dryness. The residue was extracted with ethyl acetate. The extract was washed with water, dried and evaporated.
The resulting crystals were recrystallized from ethyl acetate -hexane to afford colorless prisms (0.69 g, 77%).
'H-NMR(200MHz,CDCl3) o~: 3.38(4H,t), 3.72(3H,s), 3.90(4H,t), 5.63(2H,s), 6.89(2H,d), 7.20(1H,t), 7.37-7.65(6H,m), 7.74(1H,dd), 7.82(1H,dd) IR(KBr) cm~': 2225, 1715, 1520, 1440, 1415, 1280, 1260, 1220, 1130, 1120, 1010, 860, 770, 760, 750 : :

.

20~09~5 Working Example 15 Methyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-piperidino-benzimidazole-7-carboxylate The title compound was prepared in substantially the same manner as Working Example 14. Yield: 81%, m.p. 119-121~C.
'H-NMR(200MHz,CDCl3) o~: 1.62-1.77(6H,m), 3.31-3.36(4H,m), 3.73(3H,s), 5.58(2H,s), 6.88(2H,d), 7.15(1H,t), 7.35-7.49(5H,m), 7.56-7.64(1H,m), 7.73(1H,dd), 7.79(1H,dd) IR(KBr) cm~': 2225, 1720, 1530, 1445, 1410, 1385, 1305, 1285, 1265, 1250, 1130, 1110, 770, 750 Reference Example 12 Methyl 2-[(2'-methoxycarbonylbiphenyl-4-yl)methylamino]-3-nitrobenzoate To a solution of methyl 2-tert-butoxycarbonylamino-3-nitrobenzoate (1.84 g) in acetonitrile (10 ml) was added a solution of 4-(2'-methoxycarbonylbiphenyl-4-yl)methyl bromide (1.9 g) in acetonitrile (5 ml) and potassium carbonate (0.86 g) and the reaction mixture was heated under reflux for 20 hours. The reaction mixture was concentrated to dryness and the resulting residue was extracted with ethyl acetate and water. The organic layer was washed with water, dried and evaporated. The residue was purified by column chromatography on silica gel to give pale yellow syrup. The syrup was dissolved in ethanol (10 ml) and 20% hydrochloric acid in ethanol (4 ml) was added to the solution. The reaction mixture was stirred at room temperature for 22 hours and concentrated to dryness.
The residue was dissolved in ethyl acetate and the solution was washed with saturated aqueous sodium bicarbonate and water, drled and evaporated to afford yellow syrup (1.39 g, 53%).
H-NMR(200MHzJCHCl3) o : 3.61(3H,s), 3.89(3H,s), 4.21(2H,d), 6.72(1H,t)J 7.30t4HJd)J 7.36(1HJdd)J 7.42(1HJdd)J ~.53(1H,dd), .,,...................................... ~ ~

20~0~
7.82(tH,dd), 8.00(1H,dd), 8.10(1H,dd) Reference Example 13 Methyl 3-amino-2~[(2'-methoxycarbonylbiphenyl-4-yl)methyl-amino]benzoate The title compound was prepared as pale yellow syrup from methyl 2-[(2'-methoxycarbonylbiphenyl-4-yl)methylamino]-3-nitrobenzoate in substantially the same manner as Working Example 2. Yield: 79%.
H-NMR(200MHz,CHCl3) ~ : 3.63(3H,s), 3.80(3H,s), 3.97(2H,brs), 4.22(2H,d), ~.40(1H,brs), 6.82-6.92(2H,m), 7.23-7.44(7H,m), 7.53(1H,dt), 7.79-7.83(1H,m) IR(Neat)cm -1 3450, 3360, 2970, 1730, 1700, 1470, 1460, 1450, 1440, 1290, 1250, 1200, 770, 750 Working Example 16 Methyl 2-eth~xy-1-[(2'-methoxycarbonylbiphenyl-4--yl~methyl]-benzimidazole-7-carboxylate The title compound was prepared as colorless plates from methyl 3-amino-2-[(2'-methoxycarbonylbiphenyl-4-yl)methylamino]-benzoate in substantially the same manner as Working Example 4.
Yield: 72%, m.p. 112-113~C.
IH-NMR(200MHz,CHCl3) ~ : 1.50(3H,t), 3.55(3H,s), 3.77(3H,s), 4.68(2H,q), 5.65(2H,s), 6.99(2H,d), 7.17(2H,d), 7.17(1H,t), 7.31-7.55(4H,m), 7.73(1H,dd), 7.77(1H,dd) IR(Neat)cm -1 1730, 1710, 1545, 1470, 1430, 1380, 1340, 1320, 1270, 1250, 1235, 1210, 1120, 1080, 1030, 750, 740, 710 ~ ~ 30 :~ ' -20~0~

Working Example 17 Methyl 2-butoxy-1-[(2'-cyanobiphenyl-4-yl)methyl]benzimidazole-7-carboxylate The title compound was prepared as colorless needles in substantially the same manner as Working Example 7.
Yield: 75%, m.p. 74-75~C.
H-NMR(200MHz,CDCl3) ~ : 0.95(3H,t), 1.35-1.54(2H,m), 1.77-1.90(2H,m) J
3.76(3H,s), 4.60(2H,t), 5.69(2H,s), 7.10(2H,d), 7.17(1H,t), 7.43(4H,d), 7.54-7.65(2H,m), 7.74~2H,dd) IR(KBr) cm~': 2220, 1725, 1560, 1490, 1470, 1440, 1395, 1320, 1295, 1265, 1245, 1120, 1050, 1020, 770 Working Example 18 Methyl 2-allyloxy-1-[(2'-cyanobiphenyl-4-yl)methyl]benzimidazole-7-carboxylate The title compound was prepared as colorless plates in substantially the same manner as Working Example 7.
Yield: 73%, m.p. 118-119~C.
'H-NMR(200MHz,CDCl3) ~ : 3.76(3H,s), 5.12(2H,m), 5.33(1H,m), 5.43(1H,m), 5.72(2H,s), 6.02-6.21(1H,m), 7.11(2H,d), 7.19(1H,t), 7.44(4H,d), 7.56-7.66(2H,m), 7.75(2H,dd) IR(KBr) cm-': 2220, 1705, 1540, 1470, 1460, 1425, 1410, 1400, 1330, 1300, 1270, 1250, 1225, 1205, 1100, 1015, 995, 760, 750, 740, 730 Working Example 19 Methyl 2-ethylamîno-1-[(2'-cyanobiphenyl-4-yl)methyl]-ben~;lid~70le-7-carboxylate The title compound was prepared as colorless crystals (3.2 g, 32%) according to the procedure for Working Example 8 from methyl 2-[[(2'-cyanobiphenyl-4-yl)methyl]amino]-3-(3-ethyl-thioureido)benzoate (10.5 g), which was synthesized from methyl - 2~9~a 3-amino-2-[[(2'-cyanobiphenyl-4-yl)methyl]amino]benzoate in substantially the same manner as Reference Example 5.
H-NMR(200MHz,CDCl3) ~ : 1.24(3H,t), 3.49-3.63(2H,m), 4.06(1H,t), 5.55(2H,s), 7.16(1H,t), 7.27(2H,d), 7.41-7.79(8H,m)~ IR(KBr) cm~': 3275, 2225, 1720, 1620, 1610, 1580, 1570, 1480, 1350, 1275, 1240, 1215, 1100, 1070, 770, 760 Working Example 20 2-Cyano-4'-methylbiphenyl 20a) N-(2-Methoxyphenyl)methylidenecyclohexylamine A solution of anisaldehyde (21 g) and cyclohexylamine (15 g) in chloroform (100 ml) was stirred at room temperature for 2 hours and evaporated to afford brown syrup (35 g, quantitative).
H-NMR(200MHz,CDCl3) ~ : 1.21-1.87(10H,m), 3.14-3.28(1H,m), 3.86(3H,s), 6,88-7.00(2H,m), 7.36(1H,m), 7.95(2H,dd), 8.75(1H,s) 20b) 4'-Methyl-2-biphenylcarbaldehyde To a suspension of ~agnesium metal (1.1 g) in THF (3 ml) was added dropwise a solution of 4-bromotoluene (7.5 g) in THF
(10 ml) under gentle reflux. The resulting solution of the Grignard reagent was added dropwise to an ice-cooled, stirred solution of N-(2-methoxyphenyl)methylidenecyclohexylamine (4.3 g) in THF (30 ml).
The reaction mixture was stirred at room temperature for 1.5 hours, followed by heating under reflux for 7 hours. After addition of ice-water, the reaction mixture was acidified with conc. hydrochloric acid. The reaction mixture was extracted with ethyl acetate and the extract was washed with lN-hydrochloric acid and water, dried and evaporated to dryness. The residue was purified by column chromatography on silica gel to give pale yellow syrup (2.0 g, 51%).
H-NMR(200NHz,CDCl3) ~ : 2.43(3H,s), 7.28(4H,s), 7.42-7.51(2H,m), 7.63(1H,t), 8.02(1H,d), 10.00(1H,s) :........ .

2~'3~
20c) 2-Cyano-4'-methylbiphenyl A mixture of 4'-methyl-2-biphenylcarbaldehyde (2.0 g) and hydroxyamine hydrochloride (1.0 g) in pyridine (10 ml) was stirred at room temperature for 15 min., followed by addition of acetic anhydride (4.1 g). The reaction mixture was stirred at 90 - 100~C
for 1 hr. and concentrated to dryness. After addition of water to the residue, the precipitated crystals were collected by filtration.
Recryst~11i7~tion from hexane gave colorless needles (1.5 g, 79%).
'H-NMR(9OMHz,CDCl3) ~ : 2.40(3H,s), 7.2-7.8(8H,m) The title compound can be readily converted into Compoud (IIIa') according to the known references as mentioned above.

Working Example 21 Methyl 2-carboxy-3-nitrobenzoate To a suspension of 3-nitrophthalic acid (211 g) and methyl orthoformate (127 g) in methanol (420 ml) was added conc. sulfuric acid (20 ml) dropwise with stirring. The reaction mixture was heated under reflux for 18 hours and concentrated to dryness.
After addition of water (30 ml) to the residue, the mixture was stirred at 3 - 103C for one hour. The precipitated crystals were recryst~l1i7Pd from ethyl acetate - hexane to give pale yellow prisms (185 g, 82~), m.p. 166-168~C.
'H-NMR(200MHz, CDCl3) ~ : 4.03(3H,s), 7.74(1H,t), 8.39(1H,dd), 8.42(1H,dd) Working Example 22 Methyl 2-tert-butoxycarbonylamino-3-nitrobenzoate To a solution of methyl 2-carboxy-3-nitrobenzoate (7.23 g) in DMF (50 ml) was added diphenylphosphoryl azide (11.3 g) at room temperature and then triethylamine t6.7 ml) was added dropwise to the stirred reaction mixture. After stirring at room temperature 2 ~

for 3 hours, tert-butanol (54 ml) was added to the stirred reaction mixture. After stirring at room temperature for 30 min., the reaction mixture was gradually warmed, then heated under reflux for 1 hour and evaporated to dryness. The resultant residue was dissolved in ethyl acetate, washed with dilute hydrochloric acid, aqueous sodium bicarbonate, and water, and then dried. After evaporation of the solvent, methanol was added to the resultant residue and the mixture was cooled to give colorless crystals (6.7 g, 70~).
'H-NMR(200MHz, CDCl3) ~ : 1.50(9H,s), 3.96(3H,s), 7.23(1H,t), 8.10(1H,dd), 8.17(1H,dd) IR(KBr) cm~': 3360, 1730, 1705, 1580, 1520, 1490, 1440, 1365, 1355, 1310, 1270, 1240, 1150, 870, 835, 770, 725, 705 Working Example 23 Methyl 2-[[N-tert-butoxycarbonyl-N-(2'-cyanobiphenyl-4-yl)methyl]amino]-3-nitrobenzoate A solution of methyl 2-tert-butoxycarbonylamino-3-nitro-benzoate (0.6 g), 2-(4-bromomethylphenyl)benzonitrile (0.54 g) and K2COa (0.28 g) in acetonitrile (10 ml) was heated under reflux for 4 hours and concentrated to dryness. Water was added to the resultant residue and the mixture was extracted with ethyl acetate.
The extract was washed with water, dried and evaporated to dryness.
The residue was purified by column chromatography on silica gel to give crystals. Recryst~11;7~tion from ethyl acetate - hexane afforded colorless prisms (0.83 g, 85%), m.p. 153-15~~C.
1H-NMR(200MHz,CDCl3) ~ : 1.35(9H,s), 3.70(3H,s), 4.63(1H,d), 4.80(1H,d), 7.23-7.29(3H,m), 7.39-7.53(6H,m), 7.59-7.67(1H,m), 7.75(1H,dd), 7.93(1H,dd), 7.99(1H,dd), 8.05(1H,dd), 8.11(lH,dd) IR(KBr) cm~': 2220, 1700, 1530, 1390, 1360, 1315, 1290, 1160, 765 ,.

2 ~

Working Example 24 Methyl 2-[[2'-cyanobiphenyl-4-yl)methyl]amino]-3-nitrobenzoate A mixture of methyl 2-[[N-tert-butoxycarbonyl-N-(2'-cyano-biphenyl-4-yl)methyl]amino]-3-nitrobenzoate (0.49 g) in 20%
HCl-ethanol (3 ml) and ethyl acetate (3 ml) was stirred at room temperature for 1 hour. After evaporation of the solvent, to the residue was added methanol and saturated aqueous sodium bicarbonate to give crystals. Tne crystals were collected by filtration and recrystallized from chloroform - methanol to give pale yellow crystals (0.3 g, 77%), m.p. 140-141~C.
H-NMR(200MHz, DMS0-d6) ~ : 3.84(3H,s), 4.26(2H,m), 6.86(1H,t), 7.46(2H,d), 7.54-7.65(4H,m), 7.79(1H,d)g 7.95(dd), 8.05-8.11(2H,m), 8.67(1H,t) Working Example 25 Methyl 3-amino-2-[[(2'-cyanobiphenyl-4-yl)methyl]amino]-benzoate A mixture of methyl 2-[[2'-cyanobiphenyl-4-yl)methyl]amino]-3-nitrobenzoate (10 g), ~eCl3 ~ 6H20 (0.1 g), activated charcoal (1 g) in a mixture of methanol (100 ml) and THF (50 ml) was heated under reflux for 30 min. Hydrazine hydrate (7.2 ml) was added dropwise to the reaction mixture and the mixture was then heated under reflux for 14 hours. The insoluble material was removed from the reaction mixture by filtration and the filtrate was concentrated to dryness. Aqueous sodium bicarbonate was added to the resulting residue and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and evaporated to dryness.
The residue was purified by column chromatography on silica gel to give crystals. Recryst~ tion from isopropyl ether afforded pale yellow nee~l~s (6.0 g, 64%), m.p. 110-111~C.
3o 204~9~

H-NMR(200MHz,CDCl3) 0 : 3.81(3H,s), 3.97(2H,brs), 4.23(2H,d), 6.39(1H,t), 6.84-6.93(2H,m), 7.26-7.55(8H,m), 7.64(1H,dt), 7.77(1H,dd) Working Example 26 Methyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-(2,2,2-trifluoroethoxy)benzimidazole-7-carboxylate The title compound was prepared as pale yellow crystals from methyl 3-amino-2-[[(2'-cyanobiphenyl-4-yl)methyl]amino]benzoate and 2,2,2-trifluoroethyl orthocarbonate according to the procedure for Working Example 3. Yield: 25%, m.p. 143-145~C.
Elemental Analysis for C25H,8F3N303:
C(%) H(%) N(%) Calcd.: 64.52; 3.90; 9.03 Found: 64.35; 3.95; 8.98 1H-NMR(200MHz,CDCl3) ~ : 3.80(3H,s), 5.01(2H,q), 5.74(2H,s), 7.13(2H,d), 7.23(1H,t), 7.38-7.47(4H,m), 7.58-7.66(2H,m), 7.72-7.78(2~,m) IR(KBr) cm-': 2225, 1735, 1550, 1465, 1430, 1305, 1280, 1270, 1250, 1170, 1060, 770, 750, 745 Working Example 27 Ethyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxyben7i~idazole-7-carboxylate To a solution of ethyl 2-chloro-1-[(2'-cyanobiphenyl-4-yl)-methyl]benzimidazole-7-carboxylate (1.0 g) in ethanol (30 ml) was added NaOEt (0.17 g) and the mixture was heated under reflux for 1 hour. The reaction mixture was concentrated to dryness.
The resultant residue was dissolved in ethyl acetate and the solution was washed with water, and then dried. After evaporation of the solvent, the residue was purified by column chromatography on silica gel to give the title compound as colorless crystals(O.37 g, 70%).

' .

2 0 ~

1H-NMR and IR spectra indicate that the product according to this Working Example is completely identical with that obtained in Working Example 4.
Reference Example 14 2-(4-Formylphenyl)benzonitrile A mixture of 2-(4-bromomethylphenyl)benzonitrile (12 g) and sodium bicarbonate (26 g) in dimethyl sulfoxide (150 ~l) was heated at 120~C for 5 hours with stirring. After addition of water, the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated to dryness. The residue was purified by column chromatography on silica gel to give crystals.
Recrystallization from chloroform - isopropyl ether gave colorless nee~le~ (5.77 g, 63%).
'H-NMR(200MHz,CDCl3) 0~: 7.49-7.58(2H,m), 7.67-7.84(4H,m), 8.00-8.05(2H,m), 10.10(1H,s) Reference Example 15 2-(4-Aminomethylphenyl)benzonitrile A mixture of 2-(4-brc~ thylphenyl)benzonitrile (12 g) and potassium phtalimide (15 g) in DMF (200 ml) was stirred at 70~C for 5 hours. After addition of water, the mixture was extracted with methylene chloride. The extract was washed with water, dried and concentrated to dryness to give crystals. Recrystalli7~tion from ethyl acetate - isopropyl ether gave colorless crystals.
To a suspension of the crystals in methanol (500 ml) was added hydrazine hydrate (10 ml) and the mixture was refluxed for 12 hours.
After evaporation of the solvent, the residue was dissolved in ethyl acetate and the solution was washed with lN-NaOH and water.
The organic layer was dried and concentrated to dryness to give crystals (14.2 g, 93~).
'H-NMR(200MHz,CDCl7) ~ : 1.56(2H,brs), 3.88(2H,s),7.27-7.78(8H,m) 2 0 ~

Working Example 28 Ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylate A mixture of ethyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxybenzimidazole-7-carboxylate (0.7 g) and trimethyltin azide (0.7 g) in toluene (15 ml) was heated under reflux for 4 days.
The reaction mixture was concentrated to dryness and to the residue were added methanol (20 ml) and lN-HCl (10 ml). The mixture was stirred at room temperature for 30 minutes and adjusted to pH 3 to 4 with lN NaOH. After removal of the solvent, the residue was partitioned between chloroform and water. The organic layer was washed with water and dried, and the solvent was evaporated to dryness to give a syrup. The syrup was purified by column chromatography on silica gel to give crystals. Recryst~11i7ation from ethyl acetate - benzene afforded colorless crystals (0.35 g, 45%), m.p. 158-159~C.
Elemental Analysis for C26H2~N603:
C(%) H~%) N(%) Calcd.: 66.65; 5.16; 17.94 Found : 66.61; 5.05; 17.84 tH-NMR(200MHz,CDCl3) ~ : 1.09(3H,t), 1.43(3H,t), 4.02(2H,q), 4.30(2H,q), 5.57(2H,s), 6.71(2H,d), 6.83-6.96(4H,m), 7.27-7.31(lH,m), 7.40(1H,dd), 7.55-7.66(2H,m), 8.04-8.09(1H,m) IR(KBr) cm-': 1720, 1605, 1540, 1470, 1430, 1250, 1040, 750 Working Example 29 2-Ethoxy-1-[~2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl]-bçn7j~idazole-7-carboxylic acid A solution of ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl]methyl]ben7;~ 70le-7-carboxylate (0.24 g) and lN
NaOH (1.5 ml) in ethanol (4 ml) was stirred at 80~C for one hour.

-. ..
~ . - . .' . ~ ' ' .

~ ' ~ ~ . '' 2 ~ 5 ~

The reaction mixture was concentrated, and the concentrate was extracted with water and ethyl acetate. The aqueous layer was adjusted to pH 3-4 with 1N-HCl to give crystals. Recrystallization of the crystals from ethyl acetate - methanol afforded colorless crystals (0.15 g, 67%), m.p. 183-185~C.
Elemental Analysis for C2 ~H2nN603.1/5H20:
C~) H(%) N(%) Calcd.: 64.91; 4.63; 18.93 Found : 65.0~; 4.51; 18.77 'H-NMR(200MHzJDMSO-d6) o : 1.38(3H,t), 4.58(2H,q), 5.63(2H,s), 6.97(4H,q), 7.17(1H,t), 7.47-7.68(6H,m) IR(KBr) cm~l: 1710, 1550, 1480, 1430, 1280, 1240, 1040, 760 Working Example 30 Ethyl 2-propoxy-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylate A mixture of ethyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-propoxyb~n7ir;~7~1e-7-carboxylate (0.69 g) and trimethyltin azide (0.7 g) in toluene (15 ml) was heated for 4 days under reflux.
The reaction mixture was concentrated to dryness and to the mixture was added methanol (20 ml) and lN-HCl (10 ml). After stirring at room temperature for 30 minutes, the mixture was adjusted to pH 3-4 with lN NaOH. After removal of the solvent, the residue was extracted with chloroform-water. The organic layer was washed with water and dried, and the solvent was evaporated to dryness to give a syrup. The syrup was purified by column chromatography on silica gel to give crystals. Recryst~ 7~tion from ethyl acetate - benzene afforded colorless crystals (0.31 g, 43%), m.p. 157-159~C.

:~

~ , .

2 ~

Elemental Analysis for C27H26N~O3:
C(%) H(~) N(%) Calcd.: 67.21; 5.43; 17.42 Found : 67.26; 5.45; 17.28 'H-NMR(200MHz,CDCl3) ~ : 1.03(3H,t), 1.13(3H,t), 1.75-1.92(2H,m), 4.05(2H,q), 4.23(2H,q), 5.57(2H,s), 6.75(2H,d), 6.90(2H,d), 6.96(2H,d), 7.28-7.33(1H,m), 7.39-7.44(2H,m), 7.57-7.62(2H,m), 8.07-8.11(1H,m) IR(KBr) cm-': 1720, 1540, 1470, 1430, 1280, 1250, 1130, 1020, 750 Working Example 31 2-Propoxy-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl]-benzimidazole-7-carboxylic acid A solution of ethyl 2-propoxy-1-[[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.23 g) in ethanol (4 ml) cont~ining lN-NaOH (1.5 ml) was heated at 80~C for 2 hours.
The reaction mixture was concentrated to dryness and the residue was extracted with water and ethyl acetate. The aqueous layer was adjusted to pH 3-4 with lN-HCl to give crystals. Recryst~11i7~tion from ethyl acetate - methanol afforded colorless crystals (0.15 g, 69~)J m-p. 174-175~C.
Elemental Analysis for C2~H22N603Ø3H2O:
C(%) H(%) N(%) Calcd.: 65.29; 4.95; 18.27 Found : 65~41; 4.92; 18.20 ~H-NMR~200MHz,DMSO-d6) ~ : 0.92(3H,t), 1.70-1.87(2H,m), 4.47(2H,q), 5.63(2H,s), 6.96(4H,dd), 7.16(1H,t), 7.42-7.67(6H,m) IR(KBr) cm~': 1700, 1550, 1430, 1290, 1240, 765 .

- - --20~0~55 Working Example 32 Ethyl 2-mercapto-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylate A mixture of ethyl [1-(2'-cyanobiphenyl-4-yl)methyl]-2-mercaptobenzimidazole-7-carboxylate (4.1 g) and trimethyltin azide (8.0 g) in toluene (100 ml) was heated for 4 days under reflux.
The solvent was evaporated to dryness and the residue was stirred in a mixture of conc. hydrochloric acid (2 ml) and methanol (20 ml) at room temperature for 20 minutes. To the reaction mixture was added lN-NaOH to adjust to about pH 4 and then the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated to dryness to give crystals.
Recryst~1i7~tion from chloroform gave colorless crystals (5.0 g, 89%), m.p. 263-264~C (decomp.).
1 Elemental Analysis for C2~H20N602S.1/2H2O:
C(%) H(%) N(%) Calcd.: 61.92; 4.55; 18.05 Found : 61.99; 4.30; 17.86 1H-NMR(200MHz,DMSO-d6) ~ : 1.t0~3H,t), 4.09(2H,q), 5.82(2H,br s), 6.87(2H,d), 7.0~(2H,d), 7.26~1H,t), 7.37-7.69(6H,m) IR(KBr) cm~': 1720, 1460, 1440, 1365, 1340, 1260, 1180, 1145, 1150, 1110, 990, 745 Working Example 33 Ethyl 2-methylthio-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl~-methyl]ben~;r;dazole-7-carboxylate To a solution of ethyl 2-mercapto-1-~2'-(lH-tetrazol-5-yl)biphenyl-4-yl]benzimidazole-7-carboxylate (0.68 g) in ethanol (10 ml) containing lN-NaOH (3.0 ml) was added methyl iodide (0.24 g), and the mixture was stirred at room temperature for 2 hours.
The reaction mixture was neutralized with dilute hydrochloric acid to : ~ ' . ..

2 0 ~

give crystals. The crystals were purified by column chromatography on silica gel. Recrystallization from ethyl acetate afforded colorless prisms tO.31 g, 44%), m.p. 207-208~C (decomp.).
Elemental Analysis for C25H22N6O2S:
C(%) H(%) N(%) Calcd.: 63.81; 4.71; 17.86 Found : 63.55; 4.81; 17.50 H-NMR(200MHz,DMSO-d6) ~ : 1.13(3H,t), 2.77(3H,s), 4.14(2H,q), 5.62(2H,s), 6.84(2H,d), 7.26(1H,t), 7.46-7.70(5H,m) IR(KBr) cm~l: 1705, 1480, 1450, 1420, 1360, 1340, 1275, 1255, 1190, 1140, 1100, 1025, 990, 770, 750 Working Example 34 Ethyl 2-ethylthio-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]b~n7i mi ~A7.~1e-7-carboxylate To a solution of ethyl 2-mercapto-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.91 g) in ethanol (13 ml) containing lN-NaOH (4 ml) was added ethyl iodide (0.34 g), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was adjusted to pH 4 with dilute hydrochloric acid to give crystals. The crystals were collected by filtration and purified by column chromatography on silica gel.
RecrystA11i7Ation from ethyl acetate gave colorless prisms (0.55 g, 57%), m.p. 153-154~C (decomp.).
Elemental Analysis for C26H2~N6O2S:
C(~) H(g) N(g) Calcd.: 64.44; 4.99; 17.34 Found : 64.37; 5.05; 17.20 'H-NMR(200MHz,CDCl3) ~ : 1.19(3H,t), 1.37(3H,t), 3.20(2H,q), 4.12(2H,q), 5.67(2H,s), 6.75(2H,d), 6.92(2H,d), 7.05(1H,t), 7.26-7.34(2H,m), 7.50(1H,dd), 7.53-7.63(2H,m), 8.05-8.11(lH,m) ....

20~0~

IR(KBr) cm~': 1715, 1450, 1420, 1365, 1345, 1280, 1195, 1145, lllO, 1035, 1015, 990, 760, 745 Working Example 35 Ethyl 2-propylthio-1-[~2'-(lH-tetrazol-S-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate Propyl iodide (0.37 g) was added to a solution of ethyl 2-mercapto-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl]-ben7imidazole-7-carboxylate (0.91 g) in ethanol (13 ml) containing lN NaOH (4.0 ml) and the mixture was stirred at room temperature for 5 hours. The reaction mixture was adjusted to about pH 4 with dilute hydrochloric acid to give crystals. The crystals were collected by filtration and purified by column chromatography on silica gel. Recryst~ tion from ethyl acetate - hexane gave colorless prisms (0.4 g, 40%), m.p. 177-178~C (decomp.).
e-~r~al Analysis for C27H26N602S:
C(~) H(%) N(%) Calcd.: 65.04; 5~26; 16.85 Found : 64.88; 5.25; 16.78 'H-NMR(200MHz,CDCl3) ~ : 1.04(3H,t), 1.19(3H,t), 1.76(2H,m), 3.18(2H,t), 4.12(2H,q), 5.69(2H,s), 6.75(2H,d), 6.93(2H,d), 7.05(1H,t), 7.27-7.34(2H,m), 7.50(1H,dd), 7.54-7.63(2H,m), 8.07-8.12(1H,m) IR(KBr) cm~': 1715, 1450, 1420, 1380, 1365, 1350, 1280, 1260, 1190, 1145, 1035, 1020, 990, 760, 745 Working Example 36 2-Methylthio-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]-methyl]bPn~il da70le-7-carboxylic acid A solution of ethyl 2-methylthio-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl]ben7;m;d~7nle-7-carboxylate (0.2 g) in a methanol (5 ml) solution cont~;n;ng lN NaOH (1.3 ml) was heated under 204~

reflux for 2 hours. The reaction mixture was adjusted to about pH 4 with dilute hydrochloric acid to give crystals. The crystals were collected by filtration, and recrystallized from ethyl acetate -hexane to give colorless crystals (0.17 g, 81%), m.p. 223-225~C
(decomp.).
Elemental Analysis for C23H18N6O2S.1/2C~H8O2 C(~) H(%) N(%) Calcd.: 61.72; 4.56; 17.27 Found : 61.59; 4.54; 17.54 'H-NMR(200MHz,DMSO-d6) ~ : 2.75(3H,s), 5.76(2H,s), 6.88(2H,d), 7.01(2H,d), 7.25(1H,t), 7.47-7.66(5H,m), 7.82(1H,d) IR(KBr) cm~': 1710, 1485, 1450, 1420, 1370, 1345, 1320, 1280, 1245, 1195, 1150, 990, 780, 760 Working Example 37 2-Ethylthio-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylic acid A solution of ethyl 2-ethylthio-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]ben7;mi~70le-7-carboxylate (0.35 g) in a 0ethanol (7 ml) solution containing lN NaOH (2.2 ml) was heated under reflux for 2 hours. After evaporation of the solvent, the aqueous residue was adjusted to about pH 3-4 with lN-HCl to give crystals. The crystals were collected by filtration.
Recryst~11;7~tion from ethyl acetate - methanol gave colorless crystals (0.21 g, 54%), m.p. 209-210~C (decomp.).
Elemental Analysis for C2~HzoN6O2S:
C(%) H(%) N(%) Calcd.: 63.14; 4.42, 18.41 Found : 62.89; 4.35; 18.15 'H-NMR(200MHz,DMSO-d6) ~ : 1.39(3H,t), 3.36(2H,q), 5.76(2H,s), 6.87(2H,d), 7.01(2H,d), 7.25(1H,t), 7.47-7.69(5H,m), "' 2 0 ~

7.82(1H,dd) IR(KBr) cm-': 1695, 1450, 1415, 1350J 1275, 1225J 1190J 118OJ 1145J
755, 740 Working Example 38 2-Propylthio-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylic acid A solution of ethyl 2-propylthio-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.25 g) in methanol (5 ml) containing lN-NaOH (1.5 ml) was heated under reflux for 2 hours. After removal of the solvent, the aqueous residue was adjusted to about pH 3-4 with lN-HCl to give crystals.
The crystals were collected by filtration. RecrystA11;7~tion from ethyl acetate - hexane gave colorless crystals (0.21 g, 91%)J
m.p. 222-223~C (decomp.).
Elemental Analysis for C25H2,N602S:
C(%) H(%) N(%) Calcd.: 63.95; 4.51; 17.90 Found : 63.78; 4.85; 17.59 'H-NMR(200MHzJDMSO-d6) 0~: 0.99(3H,t), 1.67-1.85(2H,m), 3.35(2H,t), 5.77(2H,s), 6.87(2H,d), 7.01(2H,d)J 7.25(1HJt)J 7.46-7.70(5H,m), 7.82(1H,dd) IR(KBr) cm-': 1700, 1450, 1280J 1240J 1195, 1145, 755, 740 Working Example 39 Methyl 2-ethoxy-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl]ben7i idA7ole-7-carboxylate A mixture of methyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxyben7i~i~A70le-'i-carboxylate (1.85 g) and trimethylt~n azide (2.80 g) in toluene (15 ml) were heated under reflux for one day.
The reaction mixture was concentrated to dryness. To the residue were added methanol (50 ml) and lN-HCl (20 ml) and the mixture was , 2~0~

stirred at room temperature for 30 minutes. The reaction mixture was adjusted to about pH 3-4 with 1N-NaOH. After removal of the solvent, the residual syrup was purified by column chromatography on silica gel to give crystals. RecrystA11i7Ation from ethyl acetate - benzene gave colorless crystals (1.16 g, 56%), m.p. 191-193aC (decomp.).
Elemental Analysis for C25H22N603.1/5H20:
C(%) H(%) N(%) Calcd.: 65.58; 4.75; 18.53 Found : 65.55; 4.93; 18.35 IH-NMR(200MHz,CDCl3) ~ : 1.43(3H,t,~=7.0Hz)), 3.57(3H,s), 4.30(2H,q,J=7.0Hz), 5.54(2H,s), 6,72(2H,d,J=8.2), 6.84-6.97(4H,m), 7.28-7.33(1H,m), 7.40(1H,dd,J=1.8,7.0Hz), 7.57-7.62(2H,m), 8.03-8.07(1H,m) IR(KBr) cm-': 1720, 1550, 1475, 1430, 1280, 1250, 1040, 755, 735 Working Example 40 Ethyl 2-ethylamino-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]b~n7.;ril1A~ole-carboxylate A mixture of ethyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethylaminoben7;m;~Azole-7-carboxylate (1.23 g) and trimethyltin azide (2.80 g) in toluene (15 ml) was heated for 40 hours under reflux. Precipitates were collected by filtration and suspended in methanol (50 ml). To the suspension was added lN-HCl (15 ml), and the mixture was stirred at room temperature for 10 minutes.
The reaction mixtùre was adjusted to about pH 5 with lN-NaOH, followed by extraction with chloroform. The organic layer was washed with water, dried and concentrated to dryness. The residue was purified by column chromatography on silica gel to give crystals. RecrystA11i~Ation from methanol - ethyl acetate gave colorless crystals (~.83 g, 61%), m.p. 166-168~C.
IH-NMR(200MHz,CDCl3) ~ : 1.13(3H,t), 1.21(3H,t), 343(2H,q), .. . .

2~ q~

4.13(2H,q), 5.48(2H,s), 6.78(2H,d), 6.99(2H,d), 7.07(1H,t), 7.22(1H,dd), 7.42-7.49(2H,m), 7.54-7.69(3H,m) IR(KBr) cm~': 1720, 1650, 1310, 1285, 765, 755, 750 Working Example 41 Ethyl 2-propylamino-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate A solution of ethyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-propylaminobenzimidazole-7-carboxylate (1.20 g) and trimethyltin azide (2.7 g) in toluene (15 ml) was heated for 50 hours under 0 reflux. Precipitates were collected by filtration and suspended in methanol (20 ml). After addition of lN-HCl (15 ml), the reaction mixture was stirred at room temperature for 10 minutes. The mixture was adjusted to about pH 5 with 1N-NaOH, followed by extraction with chloroform. The organic layer was washed with water, dried and concentrated to dryness. The concentrate was purified by column chromatography on silica gel to give crystals. Recryst;tlli7~tion from methanol - ethyl acetate gave colorless crystals (10 g, 77%), m.p. 170-172~C.
'H-NMR(200MHz,CDCl3) ~ : 0.89(3H,t), 1.14(3H,t), 1.52-1.70(2H,m), 3.35(2H,t), 4.14(2H,q), 5.49(2H,s), 6.77(2H,d), 6.99(2H,d), 7.05(1H,t), 7.21(lH,dd), 7.39-7.47(2H,m), 7.50-7.65(3H,m) IR(KBr) cm~t: 1720, 1670, 1660, 1290, 1270, 760 Working Example 42 2-Ethoxy-1-[[2'-(N-triphenylmethyltetrazol-5-yl)-25 biphenyl-4-yl]methyl]benzir~dazole-7-carboxylic acid To a solution of 2-ethoxy-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl~methyl]benzimidazole-7-carboxylic acid (2.07 g) in methylene chloride (10 ml) were added trityl chloride (1.59 g) and triethylamine (0.8 ml). The mixture was stirred at room temperature ~or one hour. The reaction mixture was washed with water, dried ' ' 2 ~

and concentrated to dryness. The residue was purified by column chromatography on silica gel to give crystals.
Recrystallization of crude crystals thus obtained from ethyl acetate - benzene gave colorless crystals (2.12 g, 66%), m.p.
168-170~C.
Elemental Analysis for C43H3~N603:
C(%) H(%) N(%) Calcd.: 75.64; 5.02; 12.31 Found : 75.37; 4.96; 12.20 'H-NMR(200MHz,CDCl3) ~ : 1.40(3H,t), 4.61(2H,q), 5.58(2H,s), 6.76(2H,d), 6.91~6.96(8H,m), 7.12(1H,t), 7.17-7.41(12H,m), 7.60(1H,dd), 7.73-7.82(2H,m) Working Example 43 Pivaloyloxymethyl 2-ethoxy-1-~r2'-(lH-tetrazol-5-yl)-biphenyl-4-yl]benzimidazole-7-carboxylate To a solution of 2-ethoxy-1-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]ben7imidazole-7-carboxylic acid (2.2 g) in DMF (10 ml) were added potassium carbonate (0.53 g) and pivaloyloxymethyl iodide (0.94 g), and the mixture was stirred for 30 minutes at room temperature. To the reaction mixture was added water and the mixture was extracted with ethyl acetate.
The organic layer was washed with water and dried. After removal of the solvent, the residue was dissolved in methanol (30 ml) and lN-HCl (6 ml). The mixture was stirred for one hour at room temperature. The reaction mixture was concentrated to dryness and the residue was partitioned between water and ethyl acetate.
The organic layer was washed with water and dried. After removal of the solvent, the residue was purified by column chromatography on silica gel to give crystals. The crystals were recryst~ll;7~d from ethyl acetate - hexane to give colorless crystals - , -- .

21~0~

(1.13 g, 63%), m.p. 104-106~C.
Elemental Analysis for C3 oH3oN60s.1/5C~H~02.1/5C6HI 4 C(%) H(%) N(%) Calcd.: 65.06; 5.90; 14.32 Found : 64.79; 5.85; 14.43 H-NMR(200MHz,CDCl3) ~ : 1.13(9H,s), 1.44(3H,t), 4.3~(2H,q), 5.61(2H,s), 5.68(2H,s), 6.80(2H,d), 6.93(2H,d), 6.99-7 11(2H,m), 7.33-7.37(1H,m), 7.49-7.54(1H,m), 7.59-7.62(2H,m), 8.03-8.07(1H,m) ~0 Working Example 44 l-(Cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate To a solution of 2-ethoxy-1-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (0.5 g) in DMF (5 ml) were added potassium carbonate (0.12 g) and cyclohexyl l-iodoethyl carbonate (0.26 g). The mixture was stirred for one hour at room temperature. To the reaction mixture was added water and the mixture was extracted with ethyl acetate.
The organic layer was washed with water and dried. After removal of the solvent, the residue was dissolved in methanol (10 ml) and to the solution was added 1N-HCl (2 ml). The mixture was stirred for one hour at room temperature. The reaction mixture was concentrated to dryness and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water and dried. After removal of the solvent, the residue was purified by column chromatography on silica gel to give colorless powder (0.21 g, 47%), m.p. 103-106~C.

. .

2~09~

Elemental Analysis for C93N3~N606:
C(%) H(%) N(%) Calcd: 64.91; 5.61; 13.76 Found : 64.94; 5.71; 13.66 To the powder (1 g) obtained as above was added ethanol (6 ml). The mixture was stirred for 3 hours at room temperature and allowed to stand under ice-cooling. The mixture was then stirred for one hour at temperatures not higher than 10~C.
Resultant crystals were collected by filtration and washed with cold ethanol. The crystals were dried at 25~C for 9 hours under reduced pressure, then at 35~C for further 18 hours to obtain white powdery crystals (0.94 g), m.p. 158-166~C (decomp.).
Elemental Analysis for C93H3~N606:
C(%) H(%) N(%) Calcd.: 64.91; 5.61; 13.76 Found : 64.73; 5.66; 13.64 H-NMR (200MHz) ~ : 1.13-1.84(16H,m), 4.28-4.55(3H,m), 5.65(2H,d), 6.72(1H,q), 6.81(2H,d), 6.93(2H,d), 7.03(1H,t), 7.22-7.23(1H,m), 7.31-7.36(1H,m), 7.52-7.60(3H,m), 8.02-8.07(1H,m) IR(KBr) cm-': 2942, 1754, 1717, 1549, 1476, 1431, 1076, 1034, 750 MS(m/z) : 611 ~M+H]~
Working Example 45 Methyl 2-methoxy-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl]be~7ir;~70le-7-carboxylate Methyl [1-(2'-cyanobiphenyl-4-yl)methyl]-2-methoxy-ben7i~td~70le-7-carboxylate (0.60 g) and trimethyltin azide (1~5 g) in toluene (15 ml) were heated for 40 hours under reflux.
Precipitated crystals were dissolved in methanol (10 ml) and to the solution was added lN-HCl (3 ml). The mixture was stirred for 10 minutes at room temperature and the methanol was evaporated.

.

"

'"' 2~4~5~

The aqueous residue was adjusted to pH 3-4 with lN-NaOH, followed by extraction with ethyl acetate. The organic layer was washed with water and dried. After removal of the solvent, the residue was purified by column chromatography on silica gel to give crystals.
The crystals were recrystalli7ed from ethyl acetate to give colorless prisms (0.65 g, 65%), m.p. 165-166~C.
Elemental Analysis for C24H2DN603.1/lOH20:
C(%) H(%) N(%) Calcd.: 65.18; 4.60; 19.00 Found : 64.91; 4.49; 18.99 'H-NMR(200MHz,CDCl3) ~ : 3.64(3H,s), 3.93(3H,s), 5.55(2H,s), 6.75(2H,d), 6.90-7.01(4H,m), 7.31-7.36(1H,m), 7.49(1H,dd), 7.55-7.64(2H,m), 8.03-8.07(1H,m) Working Example 46 2-Methoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylic acid To a solution of methyl 2-methoxy-1-[[2'-(lH-tetrazol-5-yl)-biphenyl-4-yl]methyl]ben7imidazole-7-carboxylate (0.22 g) in methanol (10 ml) was added lN-NaOH (1.5 ml). The mixture was heated for 6 hours under reflux. The reaction mixture was concentrated to dryness and to the residue was added water. The mixture was adjusted to pH 3-4 with lN-HCl to give crystals. Recryst~11i7~tion from methanol-chloroform gave colorless needl~ (0.17 g, 77%), m.p. 208-209~C.
Elemental Analysis for C23Hl8N603Ø7H20:
C(%) H(%) N(%) Calcd.: 62.92; 4.45; 19.14 Found : 62.81; 4.08; 19.19 ~H-NMR(200MHz,DMSO-d6) & : 4.15(3HJs), 5.63(2H,s), 6.90(2H,d), 7.00(2H,d), 7.18(1HIt), 7.46-7.70(6H,m) :

"' 20~09~

Working Example 47 2-Ethylamino-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-benzimidazole-7-carboxylic acid To a solution of ethyl 2-ethylamino-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]benzimidazole-7-carboxylate (0.52 g) in ethanol (5 ml) was added lN-NaOH (4 ml), and the mixture was stirred for 2 hours at 80~C. The reaction mixture was concentrated to dryness and the aqueous residue was adjusted to pH 4-5 with lN-HCl to give crystals. The crystals were collected by filtration and recryst~11;7Pd from methanol-chloroform to give colorless crystals (0.3 g, 63.4%), m.p. 240-242nC.
Elemental Analysis for C2 4H21N7O2.1.1H2O:
C(%) H(%) N(%) Calcd.: 62.76; 5.09; 21.35 Found : 62.65; 5.15; 21.23 H-NMR(200MHz,DMSO-d6) ~ : 1.20(3H,t), 3.43(2H,q), 5.62(2H,s), 6.85(2H,d), 6.99(2H,d), 7.10(1H,t), 7.34(1H,d), 7.44-7.68(5H,m) Working Example 48 2-Propylamino-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylic acid In substantially the same manner as Working ~ .le 47, the above compound was obtained in a yield of 73%, m.p. 244-246~C.
Elemental Analysis for C2 sH23N702.1/2H20:
C(%) H(%) N(%) Calcd.: 64.92; 5.23; 21.20 Found : 64.79; 5.27; 21.08 2 ~

In substantially the same manner as Working Example 43, the following compounds (Working Examples 49-53) were synt,hesi7Pd.
Working Example 49 (5-Methyl-2-oxo-1,3-dioxolen-4-yl)methyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate Yield: 55%, m.p. : 122-125~C (decomp.) Elemental Analysis for C29H2~N606.CHCl3:
C(%) H(%) N(%) Calcd.: 53.63; 3.75, 12.51 Found : 53.32; 3.58; 12.24 'H-NMR(200MHz,CDCl3) o~: 1.43(3H,t), 2.11(3H,s), 4.40(2H,q), 4.80(2H,s), 5.58(2H,s), 6.79(2H,d), 6.94(2H,d), 7.02(1H,t), 7.15(1H,dd), 7.35-7.39(1H,m), 7.49-7.63(3H,m), 8.00-8.04(1H,m) Working Example 50 Acetoxymethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl~b~n7;~ 70le-7-carboxylate Yield: 38%, m.p.: 152-154~C (decomp.) Elemental Analysis ~or C27H2~N60s:
C(%) H(%) N(%) Calcd.: 63.27; 4.72; 16.40 Found : 63.55; 4.70; 16.18 'H-NMR(200MHz,CDCl3) ~ : 1.43(3H,t), 2.01(3H,s), 4.33(2H,q), 5.61(2H,s), 5.69(2H,s), 6.81(2H,d), 6.93(2H,d), 7.01(lH,t), 7.13(1H,d), 7.33-7.38(1H,m), 7.53-7.62(3H,m), 8.03-8.07(1H,m) 2 ~

Working Example 51 Propionyloxymethyl 2-ethoxy-1-[[2'-(lH-tetrazol-5-yl)-biphenyl-4-yl]methyl]benzimidazole-7-carboxylate Yield: 60%, m.p.: 145-150~C (decomp.) Elemental Analysis for C28H26N60sØ2C7H8:
C(%) H(%) N(%) Calcd.: 64.79; 5.10; 15.42 Found : 64.70; 5.10; 15.44 'H-NMR(200MHz,CDCl3) ~ : 1.04(3H,t), 1.44(3H,t), 2.29(2H,q), 4.40(2H,q), 5.6!(2H,s), 5.71(2H,s), 6.82(2H,d), 6.92-7.14(3H,m), 7.20(1H,m), 7.33-7.38(1H,m), 7.53-7.61(3H,m), 8.03-8.08(1H,m) Working Example 52 Butyryloxymethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate Yield: 36%, m.p.: 96-100~C
Elemental Analysis for C2~H28N60sØ4CqH3:
C(%) H(%) N(%) Calcd.: 66.15; 5.45; 14.55 Found : 66.11; 5.44; 14.65 ~H-NMR(200MHz,CDCl3) ~ : 0.85(3H,t), 1.44(3H,t), 1.55(2H,m), 2.24(2H,q), 4.38(2H,q), 5.61(2H,s), 5.70(2H,s), 6.81(2H,d), 6.93(2H,d), 7.00(1H,t), 7.20(1H,m), 7.33-7.38(1H,m), 7.52-7.61(3H,m), 8.01-8.10(1H,m) ~ .

2~0~

Working Example 53 Isobutyryloxymethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)bi-phenyl-4-yl]methyl]benzimidazole-7-carboxylate Yield: 53%, m.p.: 143-145 n C
Elemental Analysis for C29H2aN60sØ1C~H8:
C(%) H~%) N(%) Calcd.: 64.88; 5.28; 15.29 Found : 65.04; 5.25; 15.18 'H-NMR(200MHz,CDCl3) ~ : 1.09(6H,d), 1.44(3H,t), 2.50(1H,m), 4.38(2H,q), 5.61(2H,s), 5.70(2H,s), 6 81(2H,d), 6.91-7.00(3H,m), 7.19(1H,m), 7.33-7.37(1H,m), 7.51-7.63(3H,m), 8.02-8.07(1H,m) In substantially the same manner as Working Example 44, the following compounds (Working Examples 54-56) were synthesized.
Working Exa~ple 54 1-(Ethoxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl]methyl]bPn7i~id~70le-7-carboxylate Yield: 44%, m.p.: 85-87~C
Elemental Analysis for C2aH2aN6o6~o~3H2o C(%) H(%) N(%) Calcd.: 61.98; 5.13; 14.95 Found : 62.11; 5.02; 14.69 ~H~NMR(200MHz~CDCla) ~ : 1.20(3H,t), 1.30(3H,d), 1.41(3H,t), 4.03-4.22(3H,m), 4.31-4.47(1H,m), 5.61(2H,s), 6.62-6.72(3H,m), 6.80-6.95(4H,m), 7.29-7.32(1H,m), 7.47(1H,dd), 7.54-7.64(2H,m), 7.97-8.01(1HJm) ~, ' .
.

2 ~

Working Example 55 1-Acetoxyethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate Yield: 31%, m.p.: 105-107~C
Elemental Analysis for C28H26N60sØ5H20:
C(%) H~%) N(%) Calcd.: 62.80; 5.08; 15.69 Found : 62.77; 4.69; 15.85 'H-NMR(200MHz,CDCl3) ~ : 1.46(3H,t), 1.49(3H,d), 4.47-4.62(2H,m), 5.59(1H,d), 5.83(1H,d), 6.84t1H,q), 6.90(2H,d), 7.03(2H,d)J
7.11(1H,t), 7.34-7.39(1H,m), 7.49(1H,d), 7.53-7.61(3H,m), 8.07-8.11(lH,m) Working Example 56 1-(Isopropoxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl]ben7;mi~70le-7-carboxylate Yield: 33%, m.p.: 74-76~C
Elemental Analysis for C9oH3oN60s.1.5H20:
C(%) H(%) N(%) Calcd.: 61.95; 5.72; 14.45 Found : 62.02; 5.43; 14.20 'H-NMR(200MHz,CDCl3) ~ : 1.20(3H,d), 1.21(3H,d), 1.30(3H,d), 1.42(3H,t), 4.08-4.24(1H,m), 4.34-4.50(1H,m), 4.79(1H,m), ~5.61(2H,s), 6.62-6.75(3H,m), 7.27-7.32(1H,m), 7.48(1H,dd), 7.54-7.64(2H,m), 7.98-8.03(1H,m) .

2~0~

Working Example 57 2-Methylamino-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-benzlmidazole-7-carboxylic acid The above compound was synthesized by substantially the same manner as Working Examples 40 and 47.
Yield: 40%, m.p.: 247-250~C (decomp.) Elemental Analysis for C23H,9N702.2.0H20:
C(%) H(%) N(%) Calcd.: 59.86; 5.02; 21.25 Found : 59.99; 4.89; 21.36 'H-NMR(200MHz,CDCl3) ~ : 2.94(3H,s), 5.64(2H,s), 6.82(2H,d), 6.99(2H,d), 7.02(1H,t), 7.31(lH,d), 7.42-7.63(5H,m) In substantially the same manner as Working Example 43, the following compounds (Working Examples 58-60) were synthesized.
Working Example 58 Cyclohexylcarbonyloxymethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate Yield: 54%, m.p.: 140-142~C
Elemental Analysis for C32H32N60~:
C(%) H(%) N(%) Calcd.: 66.19; 5.55; 14.47 Found : 65.93; 5 46; 14.39 H-NMR(200MHz,CDCl3) ~ : 1.21-1.87(13H,m), 2.20-2.32(1H,m), 4.47(2H,q), 5.60(2H,s), 5.73(2H,s), 6.86(2H,d), 7.07(1H,t), 7.27-7.40(3H,m), 7.54-7.61(2H,m), 8.05-8.09(1H,m) 2 ~ 3 Working Example 59 Benzoyloxymethyl 2-ethoxy-1-[[2'-1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate Yield: 47%, m.p.: 138-142~C
Elemental Analysis for C32H26N60sØ5H20Ø1C~HaO2:
C(%) H(%) N(%) Calcd.: 65.67; 4.76; 14.18 Found : 65.71; 4.66; 13.96 'H-NMR(200MHz,CDC13) ~ : 1.43(3H,t), 4.36(2H,q), 5.60(2H,s), 5.98(2H,s), 6.74(4H,s), 6.99(1H,t), 7.09-7.14(1H,m), 7.21-7.36(3H,m), 7.50-7.59(4H,m), 7.90(2H,d), 8.02-8.06(1H,m) Working Example 60 (E)-cinnamoyloxymethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)bi-phenyl-4-yl]methyl]b~n7;-idazole-7-carboxylate Yield: 56%, m.p.: 146-147~C
Elemental Analysis for C~H28N60sØ4C~H802:
C(%) H(%) N(%) Calcd.: 67.16; 5.07; 13.20 Found : 66.97; 4.86; 13.28 'H-NMR(200MHz,CDCl3) ~ : 1.44(3H,t), 4.45~2H,q), 5.61(2H,s), 5.87(2H,s), 6.33(1H,d), 6.84(2H,d), 6.96(2H,d), 7.05(1H,t), 7.31-7.57(10H,m), 7.65(1H,d), 8.00-8.04(1H,m) In substantially the same manner as Working Examples 43 and 44, the following compounds (Working Examples 61-63) were synthesized.

2 ~

Working Example 61 Cyclopentylcarbonyloxymethyl 2-ethoxy-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate Yield: 54%, m.p.: 136-138~C
Elemental Analysis for C3lH30N60s:
C(%) H(%) N(%) Calcd.: 65.71; 5.34; 14.83 Found : 65.59; 5.33; 14.67 'H-NM~(200MHz,CDCl3) ~ : 1.41-1.84(11H,m), 2.61-2.76(1H,m), 4.43(2H,q), 5.61(2H,s), 5.72(2H,s), 6.84(2H,d), 6.96(2H,d), 7.05(1H,t), 7.22-7.26(1H,m), 7.35-7.39(1H,m), 7.53-7.61(3H,m), 8.03-8.08(1H,m) Working Example 62 Pivaloyloxymethyl 2-ethylamino-1-[[2'-(lH-tetrazol-5-yl)bi-phenyl-4-yl]methyl]benzimidazole-7-carboxylate Yield: 59%, m.p.: 130-135~C
Elemental Analysis for C30H3,N70~Ø4CHC13Ø2H20:
C(%) H(%) N(%) Calcd.: 60.36; 5.30; 16.21 Found : 60.20; 5.20; 16.08 'H-NM~(200MHz,CDCl3) ~ : 1.12(9H,s), 1.20(3H,t), 3.43(2H,q), 5.52(2H,s), 5.81(2H,s), 6.80(2H,d), 6.99(2H,d), 7.08(1H,t), 7.24(1H,dd), 7.43-7.68(5H,m) 20~0~

Working Example 63 1-(Cyclohexyloxycarbonyloxy)ethyl 2-ethylamino-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate Yield: 76%, m.p.: 149-152~C
Elemental Analysis for C33H3sN70sØ5H20:
C(~) H(g) N(%) Calcd.: 64.06; 5.86; 15.85 Found : 64.27; 6.02; 15.86 'H-NMR(200MHz,CDCl3) o~: 1.12-1.88(16H,m), 3.38-3.47(2H,m), 4.48-4.59(1H,m), 5.51(2H,s), 6.75-6.88(5H,m), 7.04(1H,t), 7.29-7.40(2H,m), 7.47-7.51(3H,m), 7.91-7.95(1H,m) Working Example 64 Methyl 2-allyloxy-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylate The title compound was prepared as colorless crystals from methyl 2-allyloxy-1-[(2'-cyanobiphenyl-4-yl)methyl]ben7;m;~70le-7-carboxylate according to the procedure for Working Example 28.
Yield: 30%, m.p.: 154-156~C.
Elemental Analysis for C26H22N603Ø5H20:
C(%) H(%) N(~) Calcd.: 65.67; 4.88; 17.67 Found : 65.63; 4.71; 17.68 H-NMR(200MHz,CDCl3) ~ : 3.75(3H,d), 4.58-4.61(lH,m), 4.92-4.95(1H,m), 5.18-5.48(2H,m), 5.52(2H,d), 5.83-6.15(1H,m), 6.98-7.05(2H,m), 7.09-7.17(2H,m), 7.35-7.44(2H,m), 7.47-7.60(3H,m), 8.09-8.19(1H,m) IR(KBr) cm~': 1720, 1670, 1550, 1470, 1430, 1280, 1250, 1025, 760, 2~0~

Working Example 65 Methyl 2-butoxy-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylate The title compound was prepared as colorless needles from methyl 2-butoxy-1-[(2'-cyanobiphenyl-4-yl)methyl]benzimidazole-7-carboxylate according to the procedure for Working Example 28.
Yield: 91%, m.p.: 146-148~C.
Elemental Analysis for C21H26N603:
C(%) H(%) N(%) Calcd.: 67.21; 5.43; 17.42 Found : 67.00; 5.45; 17.49 'H-NMR(200MHz,CDCl3) ~ : 0.99(3H,t), 1.37-1.55(2H,m), 1.74-1.88(2H,m), 3.61(3H,s), 4.2?(2H,t), 5.53(2H,s), 6.75(2H,d), 6.90(2H,d), 6.97(2H,d), 7.30-7.34(1H,m), 7.41(2H,dd), 7.57-7.61(2H,m), 8.04-8.09(1H,m) IR(KBr) cm~': 1720, 1600, 1540, 1470, 1430, 1270, 1250, 1020, 750 Working Example 66 Methyl 2-butylamino-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylate The title compound was prepared as colorless crystals from methyl 2-butylamino-1-[(2'-cyanobiphenyl-4-yl)methyl]benzimidazole-7-carboxylate according to the procedure for Working Example 41.
Yield: 42%, m.p.: 216-218~C.
Elemental Analysis for C27H27N702.H20:
C(%) H(%) N(%) Calcd.: 64.91; 5.85; 19.63 Found : 64.86; 5.68; 19~41 'H-NMR(200MHz,DMS0-d6) ~: 0.91(3H,t), 1.25-1.43(2H,m), 1.52-1.67(2H,m), 3.65(3H,s), 5.47(2H,s), 6.79(2H,d), 6.98-7.05(3H,m), 7.18(1H,dd), 7.42-7.64(5H,m) 2 ~

IR(KBr) cm~': 1720, 1665, 1660, 1650, 1430, 1260, 745 Working Example 67 Methyl 1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl]-2-morpholinobenzimidazole-7-carboxylate The title compound was prepared as colorless crystals from methyl l-E (2'-cyanobiphenyl-4-yl)methyl]-2-morpholinobenzimidazole-7-carboxylate according to the procedure for Working Example 41.
Yield: 62%, m.p.: 163-167nC.
Elemental Analysis for C2 7H2 sN703 . 0. 6CHCl3:
C(%) H(%) N(%) Calcd.: 58.45; 4.55; 17.29 Found : 58.66; 4.36; 17.54 'H-NMR(200MHz,CDCl3) o~: 3.33(4H,t), 3.73(3H,s), 3.90(4H,t), 5.44(2H,s), 6.62(2H,d), 6.97(2H,d), 7.17(1H,t), 7.33-7.38(1H,m), 7.43-7.50(2H,m), 7.55-7.61(2H,m), 8.08-8.13(1H,m) IR(KBr) cm~l: 1730) 1600, 1530, 1455, 1420, 1405, 1280, 1260, 1120, 1110, 1000, 760, 750, 740 Working Example 68 Methyl 1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-2-piperidinobenzimidazole-7-carboxylate The title compound was prepared as colorless crystals from methyl 1-~(2'-cyanobiphenyl-4-yl)methyl]-2-piperidinobenzimidazole-7-carboxylate according to the procedure for Working Example 41.
Yield: 47%, m.p.: 146-150nC.
Elemental Analysis for C2 8H27NqO2Ø8CHCl3:
C(%) H(%) N(%) Calcd.: 58.72; 4.76; 16.64 Found : 58.69; 4.66; 16.75 2 ~

'H-N~R(200MHz,CDCl3) O~: 1.72(6H,brs), 3.11(4H,m), 3.61(3H,s), 5.38(2H,s), 6.45(2H,d), 6.80(2H,d), 6.89-6.96(2H,m), 7.28-7.37(2H,m), 7.56-7.64(2H,m), 8.01-8.06(1H,m) IR(KBr) cm~': 1715, 1600, 1530, 1450, 1420, 1415, 1405, 1300, 1280, 1260, 1240, 1215, 1130, 770, 760, 750 Working Example 69 Methyl 2-ethylmethylamino-1-~[2'-t1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate The title compound was prepared as colorless crystals from methyl 2-ethylmethylamino-1-[(2'-cyanobiphenyl-4-yl)methyl]~
benzimidazole-7- carboxylate according to the procedure for Working Example 41.
Yield: 54%, m.p.: 130-136~C (decomp.).
Elemental Analysis for C86H25N702Ø6H20:
C(%) H(%) N(%) Calcd.: 59.26; 4.79, 18.19 Found : 59.04; 4.95; 18.05 'H-NMR(200MHz,CDCl3) ~ : 1.19(3H,t), 2.57(3H,s), 3.22(2H,m), 3.62(3H,s), 5.40(2H,s), 6.43(2H,d), 6.78-6.94(4H,m), 7.30-7.34(1H,m), 7.57(1H,dd), 7.59-7.63(2H,m), 7.99-8.04(1H,m) IR(KBr) cm~': 1720, 1600, 1540, 1435, 1400, 1300, 1280, 1255, 1015, 750, 740 Working Example 70 Z-Piperidino-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl]-benzimidazole-7-carboxylic acid The title compound was prepared as colorless crystals from methyl 1-[~2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-2-piperidino-benzimidazole-7-carboxylate according to the procedure for Working Example 29.
Yield: 91%, m.p.: 215-218~C (decomp.).

~: .

' 2 ~ ~ 0 ~'3 Elemental Analysis for C 2 7 H2sN702Ø5CHCl 3:
C(%) H(%) N(%) Calcd.: 61.25; 4.77; 18.18 Found : 60.95; 4.70; 17.90 IH-NMR(200MHz,DMSO-d6) ~ : 1.65(6H,brs), 3.24(4HJbrs), 5.48(2H,s), 6.71(2H,d), 6.92(2H,d), 7.17(1H,t), 7.42-7.48(2H,m), 7.54-7.67(2H,m) IR(KBr) cm~': 1685, 1530, 1450, 1440, 1420, 1400, 1285, 1270, 1245, 750, 730 Working Example 71 2-Morpholino-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl]-ben7i m; ~A 70le-7-carboxylic acid The title compound was prepared as colorless crystals from methyl 2-morpholino-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-b~n7im;d~70le-7-carboxylate according to the procedure for Working Example 29.
Yield: 59%, m.p.: 202-206~C (decomp.).
Elemental Analysis for C2~H23N~03Ø6CHCl3:
C(%l H(%) N(%) Calcd.: 57.76; 4.30; 17.73 Found : 57.55; 4.25; 17.66 H-NMR(200MHz,DMS0-d6) ô : 3.24(4H,brs), 3.76(4H,brs), 5.56(2H,s), 6.72(2H,d), 6.93(2H,d), 7.16(1H,t), 7.41-7.70(6H,m) IR(KBr) cm~': 1690, 1535, 1460, 1450, 1420, 1410, 1290, 1260, 1245, 1120, 760, 740 _g l_ 2 ~

Working Example 72 2-(N-Ethylmethylamino)-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid The title compound was prepared as colorless crystals from methyl 2-(N-ethylmethylamino)-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylate according to the procedure for Working Example 47.
Yield: 66%, m.p.: 204-206~C (decomp.).
Elemental Analysis f~r C25H23N702Ø5H20:
C(%) H(%) N(%) Calcd.: 64.92; 5.23; 21.20 Found : 65.22; 5.31; 21.11 'H-NMR(200MHz,CDCl3) ~ : 1.13(3H,t), 2.93(3H,s), 3.27(2H,m), 5.54(2H,s), 6.68(2H,d), 6.92(2H,d), 7.13(1H,t), 7.43-7.48(2H,m), 7.53-7.67(2H,m) IR(KBr) cm~~: 1725, 1620J 1550, 1540, 1460, 1440, 1420, 1300, ~250, Working Example 73 2-Butylamino-1-~[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-b~n7;~ 70le-7-carboxylic acid The title compound was prepared as colorless crystals from methyl 2-butylamino-1-[~2'-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl]-ben7i~;dazole-7-carboxylate according to the procedure for Working Example 47.
Yield: 67~, m.p.: 213-216~C (decomp.).
Elemental Analysis for C26H2sN702.H20:
C(%) H(%) N(%) Calcd.: 64.32; 5.60; 20.19 Found : 64.07; 5.77; 20.16 . :.. '.' ' " : ' ' 2 ~

H-NMR(200MHz,DMSO-d6) ~ : 0.89(3H,t), 1.22-1.41(2H,m), 1.51-1.66(2H,m), 3.34-3.43(2H,m), 5.65(2H,s), 6.83(2H,d), 6.97-7.05(3H,m), 7.29(1H,dd), 7.40-7.67(5H,m) IR(KBr) cm~l: 1660, 1580, 1540, 1485, 14407 1380, 1340, 1215, 850, 810, 780, 760, 750 Working Example 74 2-Ethoxy-1-~(2'-carboxybiphenyl-4-yl]methyl]ben7imidazole-7-carboxylic acid To a solut~on of methyl 2-ethoxy-1-~(2'-methoxycarbonyl-biphenyl-4-yl)methyl]benzimidazole-7-carboxylate (0.7 g) in methanol (10 ml) was added lN NaOH (5 ml) and the mixture was stirred at 80~C
for 3 hours. After evaporation of the methanol, the aqueous residue was neutralized with lN hydrochloric acid to give crystals.
The crystals were recrystAl1i7ed from methanol - chloroform to afford colorless crystals (0.54 g, 83%), m.p. 213-215~C.
Elemental Analysis for C24H~oN2O~:
C(%) H(%) N(%) Calcd.: 69.22; 4.84; 6.73 Found : 68.98; 4.89; 6.71 'H-NMR(200MH~,DMSO-d6) ~ : 1.42(3H,t), 4.61(2H,q), 5.68(2H,s), 7.01(2H,d), 7.13-7.56(7H,m), 7.64-7.71(2H,m) IR(Neat)cm-': 1725, 1545, 1460, 1420, 1380, 1280, 1260, 1230, 1205, 1120, 1030, 750 Working Example 75 Methyl 2-ethylamino-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzlmidazole-7-carboxylate The title compound was prepared as colorless crystals from methyl 2-ethylamino-1-[(2'-cyanobiphenyl-4-yl)methyl] ben7.; ri dazole-7-carboxylate according to the procedure for Working Example 41.
Yield: 63%, m.p.: 256-258aC.

o~

Elemental Analysis for C25H23N702.H20:
C(%) H(%) N(%) Calcd.: 63.68; 5.34; 20.79 Found : 63.9g; 5.09; 20.68 'H-NMR(200MHz,DMS0-d6) ~ : 1.21(3H,t), 3.40-3.60(2H,m), 3.63(3H,s), 5.47(2H,s), 6.78(2H,d), 6.98-7.05(3H,m), 7.18(1H,dd), 7.42-7.66(5H,m) IR(Neat)cm~': 1710, 1660, 1650, 1645, 1430, 1340, 1300, 1280, 1250, 1050, 740 Working Example 76 Methyl 1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl]-2-(2,2.2-trifluoroethoxy)ben7; mi dazole-7-carboxylate The title oompound was prepared as colorless nee~le~
(0.37 g, 77%) from methyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-(2,2.2-trifluoroethoxy)b~n7imi~70le-7-carboxylate (0.48 g) according to the procedure for Working Example 28.
m.p.: 210-212~C.
Elemental Analysis for C26H1gF3N603:
C(%) H(%) N(%) Calcd.: 59.06; 3.77; 16.53 Found : 59.02; 3.71; 16.36 'H-NMR(200MHz,CDCl3) o~: 3.82(3H,s), 5.01(2H,q), 5.64(2H,s), 6.99(2H,d), 7.14(2H,d), 7.25(1H,t), 7.37-7.41(lH,m), 7.51-7.63(3H,m), 7.71(lH,dd), 8.17-8.22(1H,m) IR(KBr) cm~': 1710, 1550, 1425, 1275, 1240, 1180, 1160, 1055, 750 .

2~d~

Working Example 77 1-[[2'-(1H-tetrazol~5-yl)biphenyl-4-yl]methyl]-2-(2,2.2-trifluoroethoxy)benzimidazole-7-carboxylic acid The title compound was prepared as colorless crystals (0.23 g, 88~) from methyl 1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]-methyl]-2-(2,2.2-trifluoroethoxy)benzimidazole-7-carboxylate (0.27 g) according to the procedure for Working Example 47.
m.p.: 204-206~C.
Elemental Analysis for C24H,qF3N603.H20:
C(%) H(%) N(%) Calcd.: 57.26; 3.60; 16.69 Found : 57.09; 3.59; 16.72 'H-NMR(200MHz,DMS0-d6) ~ : 5.28(2H,q), 5.66(2H,s), 6.98(4H,d), 7.23(1H,t), 7.44-7.68(5H,m), 7.72(1H,dd) IR(KBr) cm~': 1690, 1540, 1470, 1430, 1270, 1225, 1210, 1160, 1050, The following compounds as listed in Table 1 are prepared according to the procedures for Reference Examples and Working Examples disclosed herein.

.
.

. .

20~9S~

R2~ TAEaE 1 N~R
Rs ' R6 -CH2~

d R" R2 ~ R3 ~ R4 A Rs ~ R6 -.

78 OEt Me H H Tet C0OH
79 OE t 0Me H H Tet COOH
OEt NHMe H H Tet CCOH
81 OEt F H H Tet CCOH
82 OE t Cl H H Tet CCOH
83 OEt Br H H Tet OOOH
84 OEt CF3 H H Tet COOH
OEt H Me H Tet COOH
86 OE t H OMe N Tet 00OH
87 OE t H NHMe H Tet CCOH
88 OE t H F H Tet OOOH
89 OE t H Cl H Tet COOH
OEt H Br H Tet CXX~H
91 OEt H CF3 H Tet CCOH
92 OE t H H Me Tet COOH
93 OEt H H OMe Tet CCOH
94 OEt H H NHMe Tet CCOH .
OEt H H F Tet CCOH
96 OEt H H Cl Tet COOH
97 OEt H H Br Tet CCOH
98 OEt H H CF3 Tet 00OH
99 OEt Me ' H H OCOH CCOH
100 OE t H Me H 00OH CCOH
101 OEt H H Me CCOH C0OH
102 OEt H H H CCOH m OH
103 OE t Cl H H CCOH CCOH

.

.. .. . . . .

--TABLE t (continued) C~ In~ R'~ R2. R3. R4. Rs. R
t~o.
104 OEt H C1 H OOOH CCOH
105 OEt H Cl H CCOH OOOH
106 SEt Me H H Tet OOOH
107 NHMe H Me H Tet OOOH
108 OMe H H Me Tet OOOH
109 OPr H H H Tet OOOH
110 SMe Me H H Tet OOOH
111 OMe H H H Tet Tet 112 OE t H H H Tet Tet 113 OEt Me H H Tet Tet 114 OEt H ~ ; Tet COOH

115 OE t ~ j H Tet OCOH
116 OEt H H H Tet OOOCH2000-cyclo-Pr 117 OEt H H H Tet COOCH2~CO sec-Bu 118 OEt H H H Tet COOCH2 W ~ n-Bu 119 OEt H H H Tet COOCH20CO-cyclo-Bu 120 OEt H H H Tet OOOCH20CO-n-Pen 121 OEt H H H Tet COOCH20CC-i-Pen 122 OEt H H H Tet COOCH20CO sec r~
123 OEt H H H Tet COOCH2000-n-Hex 124 OEt H H H Tet COOCH20C(}sec-Hex 125 OEt H H H Tet COOCH20C ~ n-Hep 126 OEt H H H Tet OOO~H20COCH2Ph 127 OEt H H H Tet OOOCH(Me) CCOEt 128 OEt H H H Tet COO~H(Me) 000 n-Pr 129 OEt H H H Tet OOOCH(Me)-OCO-i-Pr 130 OEt H H H Tet OOOCH(Me) ~ CO ~ ycl ~ Pr 131 OEt H H H Tet OOO~H(Me) 00 ~ n-Bu 132 OE t H H H Tet OOOCH(Me) OC ~ i-Bu 133 OEt H H H Tet OOOCH(Me) OCO sec-Bu 134 OEt H H H Tet COOCH(~ ) ~ CO tert-Bu 2 ~ S ~

TA~LE 1 (continued) R'~ R2. R9~ R4. R~~ R6.
135 OEt H H H Tet COOCH(Me) 000 cyclo-Bu 136 OEt H H H Tet COOCH(Me) 000 n-Pen 137 OEt H H H Tet COOCH(Me) CCO i-Pen 138 OEt H H H Tet COOCH(Me) ~ CO ~ c-Pen 139 OE t H H H Tet C00CH(Me) OCO cycl ~ Pen 140 OEt H H H Tet COOCH(Me) OCO n-Hex 141 OEt H H H Tet C00CH(Me) ~ i-Hex 142 OEt H H H Tet COOCH(Me) OCO ~ c 11~
143 OEt H H H Tet COOCH(Me)-OCO~cyclo-Hex 144 OEt H H H Tet CGOCH(Me) ~ n-Hep 145 OE t H H H Tet a)OCH(Et) OCO n-Pr 146 OEt H H H Tet C00CH(Pr) ~ n-Bu 147 OE t H H H Tet C0OCH(iPr) OCO n-Pr 148 OE t H H H Tet COOCH(Me) ~ OMe 149 OE t H H H Tet OOOCH(Me){X ~ n-Pr 150 OE t H H H Tet C(X)CH(Me) OCO ~ i-Bu 151 OE t H H H Tet COOCH(Me)-CC~}~ ec-Bu 152 OE t H H H Tet COOCH(Me) OC ~ n-Pen 153 OEt H H H Tet COOCH(Me) OCO ~ i-Pen 154 OEt H H H Tet COO ~ (Me) ~ CO ~ cyclo-Pen155 OE t H H H Tet COOCH(Me)-{XX}~3-n-Hex 156 OE t H H H Tet COOCH(Me)-{XX}~O-cyclo-Hex :~ 157 OE t H H H Tet COOCH(Me)-CXX~3-cyclo-Hep 158 OMe H H H Tet COOCH2000-tert-Bu 159 OPr H H H Tet CXXX~H20CO-tert-Eu 160 OMe H H H Tet OOOCH(Me) ~ cycl ~ H~x 161 OPr H H H Tet COOCH(~e) ~ 00 ~ cyclo-Hex 162 NHEt H H H Tet CCOCH2000-tert-Bu 163 I~lEt N H H Tet COOGH20CO ~ cycl ~ Hex :~
~,~

2 0 ~ S ~

Experimental Example 1 Stable C-type crystalline l-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl]-benzimidazole-7-carboxylate and preparation thereof l-(Cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate is usually purified by column chromatography on silica gel and the eluted fraction is concentrated to dryness to give amorphous powders.
The powder is unstable by heat and impractical in production.
For solving this problem, the present inventors made extensive experiments on cryst~lli7~tion of the subject compound and discovered C-type crystalline form. The C-type crystal is unexpectedly stable by heat and quite useful for production. The C-type crystal of the title compound has approximately the following lattice spacings:
3.5 angstrom; middle 3.7 angstrom; weak 3.8 angstrom; middle 4.0 ang~ro ; middle 4.1 angstrom; weak 4.3 angstrom; weak 4.4 angstrom; middle 4.6 angstrom; middle 4.8 angstrom; middle 5.1 angstrom; middle 5.2 angstrom; weak 6.9 angstrom; weak 7.6 angstrom; weak 8.8 angstrom; middle 9.0 angstrom; strong 15.9 angstrom; weak 2 ~ 5 ~

IR spectrum (KBr tablet) of the C-type crystal is shown in Figure 2 with the significant absorption maxima at 2942, 1754, 1717, 1615, 1549, 1476 and 750 cm-' and its melting point is 158-166~C
(decomposition). Representative X ray chart (powder method), IR spectra (KBr tablet) and differential scanning calorimeter patterns are shown in Figures 1-3, respectively.
The C-type crystal of 1-(cyclohexyloxycarbonyloxy)ethyl-2-ethoxy-1-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl]-benzimidazole-7-carboxylate has advantages, for example;
1. It improves heat stability and practical utility.
2. Residual solvent can be minimized in crystals.
3. It can achieve industrial and clinical developments and KiVe ecomomical benefits.
The concentrated residues, amorphous powders, andJor crystals except for the C-type crystal for obtaining the subject compound, are stirred in a suitable solvent to form the desired C-type crystal. In case where the C-type crystal is not formed, a small amount of the C-type crystal can be added as a seed to allow cryst~ tion. Examples of such solvents are not limited to, as 2~ long as they afford the C-type crystal, but include lower alcohols (e.g. methanol, ethanol, isopropyl alcohol, etc.), a mixture of lower alcohol and water and a mixture of lower alkyl ketone (e.g. acetone, etc.) and water. Amounts of solvents used are not limited to, but practically, 2 to 30-fold per weight of the crystal. Ratias of lower alcohol vs. water and lower alkyl ketone vs. water are not limited to, but preferably 4:1 to 1:1. Stirring temperatures are not limited to, but -5~C to 40~C, preferably oac to 25~C.

Experimental Example 2 Inhibition of binding of angiotensin ~ to angiotensin receptor [Method]
An experiment of inhibition on the binding of angiotensin (A ~ ) to A ~ receptor was conducted by modifying the method of Douglas et al. [Endocrinology, 102, 685-696 (1978)]. An A ~
receptor membrane fraction was prepared from bovine adrenal cortex.
The compound of the present invention (10 -~M or 10-7M) and '25I-angiotensin ~ ('2sI-A ~) (1.85 kBq/50 ~ 1) were added to the receptor mambrane fraction, and the mixture was incubated at room temperature for one hour. The receptor-bound and free '25I-A
were separated through a filter (Whatman GF/B filter), and the radioactivity of l2~I-A ~ bound to the receptor was measured.
[Results]
The results relating to the compounds of the present invention are shown in Table 2.

2 ~ 5 ~

Experimental Example 3 Inhibitory effect of the compound of the present invention on pressor action of A~
~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 ~n;r~l~ 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 ~m;ni~tration of the drug, the pressor action due to intravenous administration of A ~ (100 ng/kg) as the control was measured. The drugs were orally 1 ~min;~tered, then, at each point of the measurement, A ~ was ~m;n;~tered intravenously, and the pressor action was similarly measured. By comparing the pressor action before and after ~ ni~tration of the drug, the percent inhibition by the drug on A ~ -induced pressor action was evaluated.
[Results]
The results relating to the compounds of the present invention are shown in Table 2.
:

::

, .

' .

R~ CIH 2 ~ ~C3 TABLE 2 ~ N/~ Y -R' Working Radioreceptor Pressor Response Example R' Y R2 R' Assay to A ~ (p.o.) No. 1xlO ~ 7 M lxlO - 6 M 3~g/kg 28 Et O Tet COOEt 46 82 +++ a) 29 Et O Tet COOH 61 91 +++
Pr O Tet COOEt 16 48 +++
31 Pr O Tet COOH 40 79 +++
33 Me S Tet CO OE t 2 26 +
34 Et S Tet COOEt 17 54 +++
Pr S Tet COOEt 7 32 NT
36 Me S Tet COOH 51 82 +++
37 Et S Tet COOH 41 80 +++
38 Pr S Tet COOH 6 50 ++i 39 Et O Tet COOMe 58 89 +++
Et NH Tet COOEt 54 83 +++
41 : Pr NH Tet COOEt 45 57 NT b) O
43 Et O Tet COOCH20CtBu 74 94 +++
~ CH3 0 44 Et O Tet COO~H-OCO- O 32 77 +++
Me O Tet COOMe 17 67 +++
46 Me O Tet COOH 66 88 +++
47 Et NH Tet COOH 84 96 +++

: ~ :
~ .

. .
- : ' ~
, .: , . .

2~ ~9~

TABLE 2 (continued) Workin~ RadioreceptorPressor Response Example Rl Y R2 R' Assay to A ~ (p.o.) No. lxlO ~ 7 M lxlO - 6 M 3mg/kg 48 Pr NH Tet COOH 67 92 ++
o 49 Et O Tet ~ 66 91 +++

Et O TetCOOCH20COCH3 63 92 +++
51 Et O TetCOOCH20COEt 44 84 +++
52 Et O TetCOOCH20COPr 48 84 +++
53 Et O TetCOOCH20COiPr 55 85 +++

54 Et O Tet I 11 42 81 +++
COOCH-OCOEt Et O Tet I 11 63 91 +++

56 Et O Tet I 11 31 76 +++
COOCH-OCOiPr 57 Me NH Tet COOH 41 79 NT
58 Et O Tet COOCH20CO ~ 55 84 +++
59 Et O Tet COOCH20CO ~ 37 69 +++
Et O Tet COOCH=CH - ~ 44 81 +++
61 Et O Tet COOCH20CO ~ 54 89 +++

62 . Et NH Tet COOCH20COtBu 48 87 ++~

63 Et NH Tet COOCH-OCO- O 19 61 +++
~ a) + t+ 2 70% > ++ 2 50% 2 + > 30% > -'~ b) NT, not tested - I ~ 4 -- '~

2~09~

It is understood that the preceding representative examples may be varied within the scope of the present invention by one skilled in the art to achieve essentially the same results.
As many widely different embodiments of this invention may be made without departing from the spirit and scope thereof, it is to be understood that this invention is not limited to the specific embodiments thereof except as defined in the appended claims.

.
.

Claims (9)

1. A crystal of 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-([2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate.

2. A crystal according to claim 1, which has approximately the following lattice spacings:

3.5 angstrom; middle 3.7 angstrom; weak 3.8 angstrom; middle

4.0 angstrom; middle 4.1 angstroms weak 4.3 angstrom; weak 4.4 angstrom; middle 4.6 angstrom; middle 4.8 angstroms middle

5.1 angstrom; middle 5.2 angstrom; weak

6.9 angstrom; weak

7.6 angstrom; weak

8.8 angstrom; middle

9.0 angstrom; strong 15.9 angstrom; weak.

3. A pharmaceutical composition for antagonizing angiotensin II which comprises a therapeutically effective amount of 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-y1]methyl]benzimidazole-7-carboxylate or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier, excipient or diluent therefor.

4. A pharmaceutical composition for antagonizing angiotensin II which comprises a therapeutically effective amount of a crystal according to claim 1 in admixture with a pharmaceutically acceptable carrier, excipient or diluent therefor.

5. A pharmaceutical composition for antagonizing angiotensin II which comprises a therapeutically effective amount of a crystal according to claim 2 in admixture with a pharmaceutically acceptable carrier, excipient or diluent therefor.

6. 1-(Cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate or a pharmaceutically acceptable salt thereof.