Angiotensin II receptor blocking benzimidazoles

Substituted benzimidazoles such as ##STR1## and pharmaceutically suitable salts thereof are useful as angiotensin II blockers. These compounds have activity in treating hypertension and congestive heart failure.

TECHNICAL FIELD 
This invention relates to novel substituted benzimidazoles, and processes 
for their preparation, pharmaceutical compositions containing them and 
pharmaceutical methods using them. 
BACKGROUND OF THE INVENTION 
The compounds of this invention inhibit the action of the hormone 
angiotensin II (AII) and are useful therefore in alleviating angiotensin 
induced hypertension. The enzyme renin acts on a blood plasma 
.alpha.-globulin, angiotensinogen, to procude angiotensin I, which is then 
converted by angiotensin converting-enzyme to AII. The latter substance is 
a powerful vasopressor agent which has been implicated as a causitive 
agent for producing high blood pressure in various mammalian species, such 
as the rat, dog, and man. The compounds of this invention inhibit the 
action of AII at its receptors on target cells and thus prevent the 
increase in blood pressure produced by this hormone-receptor interaction. 
By administering a compound of this invention to a species of mammal with 
hypertension due to AII, the blood pressure is reduced. The compounds of 
this invention are also useful for the treatment of congestive heart 
failure. 
K. Matsumura, et al., in U.S. Pat. No. 4,207,324 issued June 10, 1980 
discloses 1, 2-disubstituted-4-haloimidazole-5-acetic acid derivatives of 
the formula: 
##STR2## 
wherein R.sup.1 is hydrogen, nitro or amino; R.sup.2 is phenyl, furyl or 
thienyl optionally substituted by halogen, lower alkyl, lower alkoxy or 
di-lower alkylamino; R.sup.3 is hydrogen or lower alkyl and X is halogen; 
and their physiologiclly acceptable salts. These compounds have diuretic 
and hypotensive actions. 
Furukawa, et al., in U.S. Pat. No. 4,355,040 issued Oct. 19, 1982 discloses 
hypotensive imidazole-5-acetic acid derivatives having the formula: 
##STR3## 
wherein R.sup.1 is lower alkyl, cycloalkyl, or phenyl optionally 
substituted; X.sup.1, X.sup.2, and X.sup.3 are each hydrogen, halogen, 
nitro, amino, lower alkyl, lower alkoxy, benzyloxy, or hydroxy; Y is 
halogen and R.sup.2 is hydrogen or lower alkyl; and salts thereof. 
Furukawa, et al., in U.S. Pat. No. 4,340,598, issued July 20, 1982, 
discloses hypotensive imidazole derivatives of the formula: 
##STR4## 
wherein R.sup.1 is lower alkyl or, phenyl C.sub.1-2 alkyl optionally 
substituted with halogen or nitro; R.sup.2 is lower alkyl, cycloalkyl or 
phenyl optionally substituted; one of R.sup.3 and R.sup.4 is 
--(CH.sub.2).sub.n COR.sup.5 where R.sup.5 is amino, lower alkoxyl or 
hydroxyl and n is 0, 1, 2 and the other of R.sup.3 and R.sup.4 is hydrogen 
or halogen; provided that R.sup.1 is lower alkyl or phenethyl when R.sup.3 
is hydrogen, n=1 and R.sup.5 is lower alkoxyl or hydroxyl; and salts 
thereof. 
Furukawa et al., in European patent application No. 103,647 discloses 
4-chloro-2-phenylimidazole-5-acetic acid derivatives useful for treating 
edema and hypertension of the formula: 
##STR5## 
where R represents lower alkyl and salts thereof. 
The metabolism and disposition of hypotensive agent 
4-chloro-1-(4-methoxy-3-methylbenzyl)-2-phenyl-imidazole-5-acetic acid is 
disclosed by H. Torii in Takeda Kenkyushoho, 41, No. 3/4, 180-191 (1982). 
Copending U.S. patent application Ser. No. 884,920 filed July 11, 1986, now 
abandoned, discloses antihypertensive imidazoles of the formula. 
##STR6## 
R.sup.2, R.sup.3 and R.sup.4 are each independently H; Cl; Br; I; F; 
NO.sub.2 ; alkyl of 1 to 4 carbon atoms; alkoxy of 1 to 4 atoms; CO.sub.2 
H; CO.sub.2 R.sup.9 ; NHSO.sub.2 R.sup.10 ; CONHOR.sup.11 ; NHCOR.sup.12 ; 
NHNO.sub.2 ; SO.sub.2 NHR.sup.11 ; 
##STR7## 
aryl; or furyl; R.sup.5 is H; alkyl of 1 to 6 carbon atoms; allyl benzyl; 
R.sup.6 is alkyl of 3 to 10 carbon atoms, alkenyl or perfluoroalkyl of 3 to 
10 carbon atoms; cycloalkyl of 3 to 8 carbon atoms; cycloalkylalkyl, 
cycloalkylalkenyl of 4 to 10 carbon atoms; ech of the above groups 
containing 0 or 1 --O--, --S--, --SO--, --SO.sub.2, or --NH-- linkage 
optionally substituted with 0 or 1 groups selected from F, Cl, Br, I, 
--OR.sup.11 or --CO.sub.2 R.sup.14 ; phenyl or benzyl optionally 
substituted with 0 to 2 halogens, alkoxy of 1 to 4 carbon atoms, alkyl of 
1 to 4 carbon atoms or nitro; perfluorophenyl; 
R.sup.7 is H, F, Cl, Br, I, NO.sub.2, CF.sub.3 or CN; 
R.sup.8 is alkyl of 1 to 10 carbon atoms, containing 0 or 1 --O--, --S--, 
--SO, --SO.sub.2, or NH; phenyl-alkenyl wherein the aliphatic portion is 2 
to 6 carbon atoms, alkenyl of 3 to 10 carbon atoms, 
##STR8## 
CONR.sup.18 R.sup.19, --(CH.sub.2).sub.m -imidazol-1-yl, 
--(CH.sub.2).sub.m -1, 2, 3-triazoyl optionally substituted with one or 
two groups selected from CO.sub.2 R.sup.14 or alkyl of 1 to 4 carbon 
atoms, --(CH.sub.2).sub.m -tetra-zolyl, 
##STR9## 
R.sup.9 is 
##STR10## 
R.sup.10 is alkyl of 1 to 6 carbon atoms or perfluoroalkyl of 1 to 6 
carbon atoms, or (CH.sub.2).sub.p C.sub.6 H.sub.5 ; 
R.sup.11 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon 
atoms, phenyl or benzyl; 
R.sup.12 is perhaloalkyl of 1 to 6 carbon atoms; 
R.sup.13 is --CO.sub.2 H; --CO.sub.2 R.sup.9 ; 
##STR11## 
--PO.sub.3 H; --C(CF.sub.3).sub.2 OH; --C(CF.sub.3).sub.2 NH.sub.2 ; 
--NHSO.sub.2 R.sup.10 ; --CONHOR.sup.11 ; --NHCOR.sup.12 ; NHNO.sub.2 ; 
--SO.sub.2 NHR.sup.11 ; 
##STR12## 
R.sup.14 is H, alkyl or perfluoroalkyl of 1 to 8 carbon atoms, cycloalkyl 
of 3 to 6 carbon atoms, phenyl or benzyl; 
R.sup.15 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon 
atoms, phenyl, benzyl, acyl of 1 to 4 carbon atoms, phenacyl; 
R.sup.16 is H, alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 6 carbon 
atoms, (CH.sub.2).sub.p C.sub.6 H.sub.5, OR.sup.17, or NR.sup.18 R.sup.19 
; 
R.sup.17 is H, alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 6 carbon 
atoms, or phenyl; 
R.sup.18 and R.sup.19 independently are H, alkyl of 1 to 4 carbon atoms, 
pheny;, benzyl or taken together form a ring of the formula 
##STR13## 
Q is NR.sup.20, O or CH.sub.2 ; R.sup.20 is H, alkyl of 1-4 carbon atoms, 
or phenyl; 
R.sup.21 is alkyl of 1 to 6 carbon atoms, --NR.sup.22 R.sup.23, or 
##STR14## 
R.sup.22 and R.sup.23 independently are H, alkyl of 1 to 6 carbon atoms, 
benzyl, or are taken together as (CH.sub.2).sub.u where u is 3-6; 
R.sup.24 is H, CH.sub.3 or --C.sub.6 H.sub.5 ; 
R.sup.25 is NR.sup.27 R.sup.28, OR.sup.28, NHCONH.sub.2, NHCSNH.sub.2, 
##STR15## 
R.sup.26 is hydrogen, alkyl with from 1 to 6 carbonatoms, benzyl, or 
allyl; 
R.sup.27 and R.sup.28 are independently hydrogen, alkyl with from 1 to 5 
carbon atoms, or phenyl; 
R.sup.29 and R.sup.30 are independently alkyl of 1-4 carbon atoms or taken 
together are --(CH.sub.2).sub.q --; 
X is a carbon-carbon single bond, --CO--, --O--, --S--, 
##STR16## 
--SCH.sub.2 --, --CH.sub.2 S--, --NHC(R.sup.27)(R.sup.28), --NHSO.sub.2 
--, --SO.sub.2 NH--, --C(R.sup.27)(R.sup.28)NH--, --CH.dbd.CH--, 
--CF.dbd.CF--, --CH.dbd.CF--, --CF.dbd.CH--, --CH.sub.2 CH.sub.2 --, 
--CF.sub.2 CF.sub.2 --, 
##STR17## 
Y is O or S; m is 1 to 5; 
n is 1 to 10; 
p is 0 to 3; 
q is 1 to 3; 
r is 0 to 2; 
s is 0 to 5; 
t is 0 or 1; 
and pharmaceutically acceptable salts of these compounds; 
provided that: 
(1) the R.sup.1 group is not in the ortho position and when R.sup.1 is 
CO.sub.2 H, then it is also not in the meta position; 
(2) when R.sup.1 is 
##STR18## 
X is a single bond, and R.sup.13 is CO.sub.2 H, 
##STR19## 
then r.sup.13 must be in the ortho or meta position; or when R.sup.1 and 
X are as above and R.sup.13 is NHSO.sub.2 R.sup.10, R.sup.13 must be 
ortho; 
(3) when R.sup.1 is 
##STR20## 
and X is other than a single bond, then R.sup.13 must be ortho except 
when X =NR.sup.17 CO and R.sup.13 is NHSO.sub.2 R.sup.10, then R.sup.13 
must be ortho or meta; 
(4) when R.sup.1 is 4-CO.sub.2 H or a salt thereof, R.sup.6 cannot be 
S-alkyl; 
(5) when R.sup.1 is 4-CO.sub.2 H or a salt thereof, the substituent on the 
4-position of the imidazole cannot be CH.sub.2 OH, CH.sub.2 OCOCH.sub.3, 
or CH.sub.2 CO.sub.2 H; 
(6) when R.sup.1 is 
##STR21## 
X is --NR.sup.17 CO, and R.sup.13 is 2-CO.sub.2 H, then R.sup.6 cannot be 
C.sub.6 H.sub.5 (CH.sub.2).sub.3 ; 
(7) when R.sup.1 is 
##STR22## 
X is --CH.sub.2 O--, and R.sup.13 is 2-CO.sub.2 H, then R.sup.6 is not 
C.sub.2 H.sub.5 S or (C.sub.6 H.sub.5).sub.2 CH(CH.sub.2).sub.2 S. 
Copending U.S. patent application Ser. No. 050,341 filed May 22, 1987 as a 
continuation-in-part of U.S. Ser. No. 884,920, and U.S. patent application 
Ser. No. 07/142,580, filed simultaneously herewith, as a 
continuation-in-part of U.S. Ser. No. 050,341, also disclose 
antihypertensive imidazoles. U.S. application Ser. No. 07/141,669 filed 
simultaneously herewith, discloses antihypertensive, pyrroles, pyrazoles 
and triazoles. 
Pals et al., Circulation Research, 29, 673 (1971) describe that the 
introduction of a sarcosine residue in position 1 and alanine in position 
8 of the endogenous vasoconstrictor hormone AII to yield an (octa)peptide 
that blocks the effects of AII on the blood pressure of pithed rats. This 
analog, [Sar.sup.1, Ala.sup.8 ] AII, initially called "P-113" and 
subsequently "Saralasin", was found to be one of the most potent 
competitive antagonists of the actions of AII, although, like most of the 
so-called peptide-AII-antagonists, it also possessed agonistic actions of 
its own. Saralasin has been demonstrated to lower arterial pressure in 
mammals and man when the (elevated) pressure is dependent on circulating 
AII (Pals et al., Circulation Research, 29, 673 (1971); Streeten and 
Anderson, Handbook of Hypertension, Vol. 5, Clinical Pharmacology of 
Antihypertensive Drugs, A. E. Doyle (Editor), Elsevier Science Publishers 
B.V., p. 246 (1984). However, due to its agonistic character, saralasin 
generally elicits pressor effects when the pressure is not sustained by 
AII. Being a peptide, the pharmacological effects to saralasin are 
relatively short-lasting and are only manifest after parenteral 
administration, oral doses being ineffective. Although the therapeutic 
uses of peptide AII-blockers, like saralasin, are severely limited due to 
their oral ineffectiveness and short duration of action, their major 
utility is as a pharmaceutical standard. 
To date there are no known non-peptide antagonists of AII which are useful 
orally or which bind in vitro in the IC.sub.50 ranges we observe, other 
than the compounds disclosed in U.S. Ser. Nos. 884,920 and 050,341, and in 
the two applications filed simultaneously herewith which are mentioned 
above. 
SUMMARY OF THE INVENTION 
According to the present invention there are provided novel compounds of 
formula (1) which have angiotensin II-antagonizing properties and are 
useful as antihypertensives. 
##STR23## 
where R.sup.1 is --CO.sub.2 H, --NHSO.sub.2 CF.sub.3, or 
##STR24## 
R.sup.2 is H, halogen, NO.sub.2, methoxy, or alkyl of 1 to 4 carbon atoms; 
R.sup.3 is alkyl of 1 to 6 carbon atoms, alkenyl or alkynyl of 3 to 6 
carbon atoms both of which may be optionally substituted with a halogen 
atom, --OR.sup.4 or up to two --CO.sub.2 R.sup.4 ; with the proviso that 
when R.sup.3 is methyl it must be substituted with --OR.sup.4 or 
--CO.sub.2 R.sup.4 ; 
R.sup.4 is H, or alkyl of 1-4 carbon atoms; 
R.sup.5 is H, alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 6 carbon 
atoms, (CH.sub.2).sub.m C.sub.6 H.sub.5, OR.sup.6, or NR.sup.7 R.sup.8 ; 
R.sup.6 is H, alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 6 carbon 
atoms or phenyl; 
R.sup.7 and R.sup.8 independently are H, alkyl of 1 to 4 carbon atoms, 
phenyl, benzyl or taken together with nitrogen form a ring of the formula 
##STR25## 
Q is NR.sup.9, O, or CH.sub.2 ; R.sup.9 is H, alkyl of 1 to 4 carbon 
atoms, or phenyl; 
R.sup.10 is alkyl of 1 to 6 carbon atoms; 
A is H, alkyl of 1 to 10 carbon atoms, C.sub.r F.sub.2r+1 where r=1-6, C 
.sub.6 F.sub.5, halogen, alkoxy of 1 to 6 carbon atoms; 
##STR26## 
B is H, alkyl of 1 to 10 carbon atoms, C.sub.r F.sub.2r+1 where r=1-6, 
C.sub.6 F.sub.5, halogen or alkoxy of 1 to 6 carbon atoms; 
X is a carbon-carbon single bond, --CO--, --O--, --NHCO--, or --OCH.sub.2 
--; 
n is 1 to 6; 
m is 0 to 3; 
p is 0 to 1; 
and pharmaceutically acceptable salts of these compounds; 
provided that: 
(1) when R.sup.3 is methyl it must be substituted with --OR.sup.4 or 
--CO.sub.2 R.sup.4 ; 
(2) when R.sup.3 is --CH.dbd.CH--CO.sub.2 Et, then X is not --NHCO. 
(3) when R.sup.3 is CH.sub.2 OH, CH.dbd.CHCO.sub.2 H or CH.sub.2 CH.sub.2 
CO.sub.2 H and A and B arae hydrogen, then X cannot be a carbon-carbon 
single bond. 
(4) when R.sup.1 is --CO.sub.2 H, R.sup.3 is butyl, and X is a 
carbon-carbon single bond, then A is not 5-Cl. 
(5) when R.sup.1 is --CO.sub.2 H, R.sup.3 is CH.sub.2 OCH.sub.3 and X is a 
carbon-carbon single bond, then A is not 5-CH.sub.2 OH. 
Preferred for their antihypertensive activity are benzimidazoles of Formula 
(1) and pharmaceutically acceptable salts of these compounds. where: 
R.sup.1 is --CO.sub.2 H, --NHSO.sub.2 CF.sub.3 ; 
##STR27## 
R.sup.2 is hydrogen; 
R.sup.3 is alkyl of 3 to 6 carbon atoms, alkenyl or alkynyl of 3 to 6 
carbon atoms each of which may be optionally substituted with --OR.sup.4 
or CO.sub.2 R.sup.4 ; 
R.sup.5 is H, alkyl of 1 to 5 carbon atoms, OR.sup.6 or NR.sup.7 R.sup.8 ; 
R.sup.6 is H, alkyl of 1 to 5 carbon atoms; 
A is halogen, alkoxy of 1 to 6 carbon atoms; 
##STR28## 
B is H; and pharmaceutically acceptable salts thereof. 
More preferred are compounds of the preferred scope where: 
R.sup.3 is alkyl of 3 to 5 carbon atoms, alkenyl or alkynyl of 3 to 5 
carbon atoms each of which may be optionally substituted with OH, 
OCH.sub.3, CO.sub.2 H or CO.sub.2 CH.sub.3 ; 
##STR29## 
n is 1-2; X is a carbon-carbon single bond; or --NHCO--; and 
pharmaceutically acceptable salts thereof. 
Specifically preferred compounds because of their antihypertensive activity 
are: 
(a) 
2-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-6-hydrozymethylbenzimidazole ( 
b) 2-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-5-hydroxymethylbenzimidazole 
(c) 2-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-6-methoxybenzimidazole 
(d) 2- 
(1-Butenyl)-1-[(2'-carboxybiphenyl-4-yl)-methyl]-6-hydroxymethylbenzimidaz 
ole; 
(e) 2-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-6-chlorobenzimidazole; and 
pharmaceutically suitable salts thereof. 
Pharmaceutically suitable salts include both the metallic (inorganic) salts 
and organic salts; a list of which is given in Remington's Pharmaceutical 
Sciences, 17th Edition, page 1418 (1985). It is well known to one skilled 
in the art that an appropriate salt form is chosen based on physical and 
chemical stability, flowability, hygroscopicity and solubility. Preferred 
salts of this invention for the reasons cited above include potassium, 
sodium, calcium and ammonium salts. 
Also within the scope of this invention are pharmaceutical compositions 
comprising a suitable pharmaceutical carrier and a compound of Formula 
(1), processes for preparing the compounds and methods of using the 
compounds of Formula (1) to treat hypertension, and congestive heart 
failure. 
Note that throughout the text when an alkyl substituent is mentioned, the 
normal alkyl structure is meant (i.e., butyl is n-butyl) unless otherwise 
specified. 
It should be noted that, in the foregoing structural formula, when a 
substituent can be present in more than one position it can be selected 
independently at each occurrence. For example, if R.sup.4 is present as 
part of both the definition of R.sup.3 and A and/or B it need not be 
defined as the same substituent. 
Synthesis 
The novel compounds of Formula (1) can be prepared using the reactions and 
techniques described in this section. The reactions are performed in a 
solvent appropriate to the reagents and materials employed and suitable 
for the transformation being effected. It is understood by those skilled 
in the art of organic synthesis that the functionality present on the 
benzimidazole and other portions of the molecule must be consistent with 
the chemical transformations proposed. This will frequently necessitate 
judgment as to the order of synthetic steps, protecting groups required, 
and deprotection conditions. Throughout the following section, not all 
compounds of Formula (1) falling into a given class may necessarily be 
prepared by all methods described for that class. Substituents on the 
starting materials may be incompatible with some of the reaction 
conditions required in some of the methods described. Such restrictions to 
the substituents which are compatible with the reaction conditions will be 
readily apparent to one skilled in the art and alternative methods 
described must then be used. 
Generally, the compounds of formula (1) can be prepared by direct 
alkylation onto benzimidazole (2) with an appropriately protected benzyl 
halide, tosylate or mesylate (3) in the presence of base as shown in 
Scheme I. Preferably, the metallic benzimidazolide salt is prepared by 
reacting benzimidazole (2) with a proton acceptor such as MH where M is 
lithium, sodium or potassium in a solvent such as dimethylformamide (DMF) 
or by reacting it with a metal alkoxide of formula MOR where R is methyl, 
ethyl, t-butyl or the like in an alcohol solvent such as ethanol or 
t-butanol, or a polar aprotic solvent such as DMF. The benzimidazole salt 
is dissolved in an inert aprotic solvent such as DMF, and treated with an 
appropriate alkylating agent (3). Alternatively, benzimidazole (1) can be 
alkylated with a benzyl halide (3; where Y=Br or Cl) in the presence of a 
base such as sodium carbonate, potassium carbonate, triethylamine or 
pyridine. The reaction is run in an inert solvent such as DMF or DMSO at 
20.degree. C. to the refluxing temperature of the solvent for 1-10 hours. 
When A and B are not equivalent, mixtures of two regioisomer alkylation 
products are obtained. These isomers possess distinct physical and 
biological properties and can be separated and isolated by conventional 
separation techniques such as chromatography and/or crystallization. 
An alternative synthesis for benzimidazole compounds of formula (1) is 
described in Scheme II. R1 Scheme I:? ? 
##STR30## 
The functionalized benzylamines (4) can be made from the corresponding 
benzyl halide, tosylate or mesylate (3) via displacement with a nitrogen 
nucleo-phile, a procedure familiar to one skilled in the art. This 
displacement may be achieved using azide ion, ammonia, or phthalimide 
anion, etc., in a neutral solvent such as DMF, DMSO etc., or under phase 
transfer conditions. The benzyl halide (3) can be made by a variety of 
benzylic halogenation methods familiar to one skilled in the art, for 
example benzylic bromination of toluene derivatives with 
N-bromosuccinimide in an inert solvent such as carbon tetrachloride in the 
presence of a radical initiator such as benzoyl peroxide at temperatures 
up to reflux conditions. 
Reaction of a benzylamine (4) with an o-halogen substituted nitrobenzene 
(5) affords the corresponding nitro compound (6). 
O-Phenylenediamine intermediates (7) can be obtained from the corresponding 
nitro compounds (6) by reduction. A variety of reduction procedures may be 
used such as Fe/acetic acid [D. C. Owsley, J. J. Bloomfield, Synthesis, 
118 (1977)], stannous chloride [F. D. Bellamy, Tetrahedron Lett., 839 
(1984)] or careful hydrogenation over a metal catalyst such as palladium. 
Reaction of (7) with a carboxylic acid under a variety of conditions some 
of which are described in the disclosure for Scheme III, equation (b) 
provides the desired compound (1). 
The benzimidazole compounds (2) are readily available by any of a number of 
standard methods. Several of these synthetic routes are illustrated in 
Scheme III. 
As shown in Scheme III, equation (a), a variety of benzimidazoles can be 
prepared by reduction of acylated o-nitroanilines (8) with various 
reducing agents such as Sn/HCl [H. Hubner, Ann., 208, 278 
(1881)]SnCl.sub.2 /HCl [L. I. Smith, et al., J. Am. Chem. Soc., 57, 1289 
(1935)], and Fe/acetic acid [M. A. Phillips, J. Chem. Soc., 2393 (1928)]. 
Another method for the conversion of an acylated o-nitroaniline into a 
2-substituted benzimidazole (1) involves heating the compound with ferrous 
oxalate at a temperature in the range of 220.degree.-225.degree. C. [H. C. 
Waterman, et al., J. Org. Chem., 14, 289 (1949)]. The transformation of an 
acylated o-nitroaniline into a benzimidazole (2) can also be effected by 
electrolytic reduction [K. Brand, et al., Ber. 39, 4058 (1906)] or by 
catalytic hydrogenation [R. Adams, et al., J. Am. Chem. Soc., 70, 2667 
(1948)]. 
Alternatively, benzimidazoles (2) can be synthesized by reacting an 
o-phenylenediamine and a carboxylic acid [M. A. Phillips, J. Chem Soc., 
1409 (1930)], or an acid anhydride as shown in Scheme III, equation (b). 
One method involves refluxing an equimolar mixture of a substituted 
o-phenylenediamine and a carboxylic acid or an acid anhydride in dilute 
hydrochloric acid. Benzimidazole (2) can also be prepared by reaction of 
an appropriately substituted o-phenylenediamine and an ester. Reaction of 
an acid amide and an o-phenylenediamine as described in S. Von 
Niementowski, Ber., 30, 3062 (1897) also results in the formation of 
benzimidazoles of formula (2). 
Alternatively, as shown in Scheme III equation (c), heating the 
hydrochloride salt of an o-phenylene-diamine with a nitrile at elevated 
temperatures (.about.200.degree. C.) results in the formation of a 
2-substituted benzimidazole (2) [E. L. Holljes and E. C. Wagner, J. Org. 
Chem., 9, 31 (1944)]. 
Benzimidazole (2) can also be prepared by reaction of o-phenylenediamine 
with an iminoether or an iminothioester as shown in equation (d) [F. E. 
King et al., J. Chem. Soc., 1396 (1949)]. 
##STR31## 
Substituents A and B can be incorporated into the benzene ring at the 
beginning of the synthesis such that the desired compounds (2) can be 
obtained via Scheme III, or A and B can be derived from suitable synthetic 
precursors at a later stage in the synthesis. 
As shown in Scheme IV, the hydroxymethyl groups can be easily converted to 
the corresponding halide, mesylate or tosylate moieties by a variety of 
methods familiar to one skilled in the art. Preferably, alcohol (9) is 
converted to the chloride (11) with thionyl chloride in an inert solvent 
at temperatures of 20.degree. C. to the reflux temperature of the solvent. 
Alkylation of (9) with alkyl halides in the presence of a base such as 
sodium hydride in a solvent such as THF or glyme at 0.degree.-80.degree. 
C. gives (10). 
##STR32## 
Chloride (11) may be displaced by a variety of nucleophiles by nucleophilic 
displacement reaction procedures, familiar to one skilled in the art. For 
example, excess sodium cyanide in DMSO may be used to form cyanomethyl 
derivatives (12) at temperatures of 20.degree. C. to 100.degree. C. 
Nitrile intermediate (12) can be hydrolyzed to carboxylic acid derivative 
(13) by a variety of methods. Preferably, treatment with a 1:1 (v:v) 
mixture of concentrated aqueous HCl/glacial acetic acid at reflux 
temperatures for 2-96 hours or by treatment with 1.about.6N sodium 
hydroxide in an alcohol solvent such as ethanol or ethylene glycol for 
2-96 hours at temperatures from 20.degree. C. to reflux can be used. The 
nitrile functionality can also be hydrolyzed in two steps by first 
stirring in sulfuric acid to form the amide followed by hydrolysis with 
sodium hydroxide or a mineral acid to give the carboxylic acid (13). 
Carboxylic acid (13) can be esterified by a variety of methods without 
affecting other parts of the molecule. Preferably, (13) is refluxed in a 
mixture of HCl and an alcohol solution for 2-48 hours to give esters (14). 
The hydroxymethyl group on compound (9) can be readily oxidized to an 
aldehyde group by means of an oxidizing agent such as manganese dioxide as 
shown in Scheme V. The aldehyde (15) will undergo chain extension 
reactions such as the Wittig and Wittig-Horner reactions, and enter into 
typical carbon-carbon bond forming reactions with Grignard and lithium 
reagents as well as with compounds bearing activated methylene groups, 
known to one skilled in the art of organic synthesis. 
##STR33## 
The ether (18) can be prepared from the alcohol (17) as shown in Scheme VI, 
equation (a) by methods such as treatment of (17) in a solvent such as DMF 
or DMSO with potassium t-butoxide, sodium hydride, or the like followed by 
treatment with R.sup.4 Y at 25.degree. C. for 1-20 hours, where Y is a 
halogen, tosylate or mesylate. 
##STR34## 
Hydroxymethyl derivative (17) may be acylated to give (19) by a variety of 
procedures. As shown in Scheme VI, equation (b), acylation can be achieved 
with 1.about.3 equivalents of an acyl halide or an anhydride in a solvent 
such as diethyl ether, tetrahydrofuran, methylene chloride or the like in 
the presence of a base such as pyridine or triethylamine. Alternatively, 
(17) may be acylated by reaction with a carboxylic acid and 
dicyclohexylcarbodiimide (DCC) in the presence of a catalytic amount of 
4-(N,N-dimethylamino)pyridine (DMAP) via the procedure described by A. 
Hassner, Tetrahedron Lett., 4475 (1978). Treatment of (17) with a solution 
of carboxylic acid anhydride in pyridine optionally with a catalytic 
amount of DMAP at temperatures of 20.degree.-100.degree. C. for 2-48 hours 
is the preferred method. 
The hydroxymethyl group in compound (17) can be activated for displacement 
by reacting it with thionyl chloride; PCl.sub.5 or with carbon 
tetrachloride/triphenylphosphine to form the corresponding 
chloro-derivative. By a similar reaction, bromo and iodo derivatives can 
be obtained. The hydroxymethyl group can also be activated by forming the 
corresponding p-toluenesulfonate, methanesulfonate and trifluoromethane 
sulfonate derivatives as illustrated in Scheme VI, equation (c). 
The amino derivative (21) can be obtained by treating compound (20) with 
ammonia. Alternatively, the chloro group can be displaced by sodium azide 
to give an azide intermediate which affords the amine (21) upon reduction 
with hydrogen (H.sub.2) over a noble metal catalyst or with a reducing 
agent such as chromous chloride [W. K. Warburton, J. Chem. Soc., 2651 
(1961)]. The amine (21) can be converted to carbamate (22) by standard 
procedures familiar to one skilled in the art as illustrated by equation 
(c). 
The hydroxymethyl compound (17) can be oxidized to aldehyde (23) by 
treatment with an oxidizing agent such as manganese dioxide. Reaction of 
aldehyde (23) with an appropriate Grignard reagent affords alcohol (24) 
which can be oxidized to ketone derivative (25) by standard oxidizing 
procedures familiar to one skilled in the art. 
The halomethylbiphenyl ether (29) is prepared as shown in Scheme VII. An 
Ullman ether condensation of the phenol (26) and a halobenzoic acid as 
described in Russian Chemical Reviews, 43, 679 (1974) provides the 
intermediate carboxylic acid (27). The conversion of (27) into (28) is 
accomplished by diazomethane or by a Fischer esterification method. 
Halogenation to give halomethyldiphenylether (29) can be accomplished by 
refluxing (28) in an inert solvent such as carbon tetrachloride in the 
presence of a N-halosuccinimide and an initiator such as 
azobisisobutyronitrile. 
##STR35## 
Compounds (1) where the X linkage is a carbon-carbon bond are prepared by 
alkylation of benzimidazole (2) with suitable halomethyl biphenyl 
intermediates (30), as shown in Scheme VIII. 
##STR36## 
The halomethylbiphenyl intermediates (30) are prepared by Ullman coupling 
of two iodobenzene derivatives as described in "Organic Reactions", 2, 6 
(1944) to provide intermediates which are in turn halogenated to provide 
(30). 
Alternatively, the substituted biphenylprecursors (31), where R.sup.1 
.dbd.o--CO.sub.2 CH.sub.3 can be prepared as illustrated in Scheme VIII, 
path (b), which involves oxazoline compounds as key intermediates [A. I. 
Meyers and E. D. Michelich, J. Am. Chem. Soc., 97, 7383 (1975)]. 
As shown in Scheme IX, compounds where X is --CO--can be prepared by 
alkylation of imidazoles (2) with the requisite benzoylbenzyl halides. 
Carboalkoxybenzoylbenzyl halides (32) are prepared by benzylic 
halogenation of the corresponding toluoylbenzene precursors (33) by a 
variety of methods known to one skilled in the art. For example, 
methyl-2-(4-methylbenzoyl) benzoate can be refluxed for 2-48 hours with 
N-bromosuccinimide, benzoylperoxide and carbon tetrachloride to effect 
benzylic bromination. After alkylation of the imidazole with the 
benzoylbenzyl halide of compound (34), the ester group can be hydrolyzed 
to the corresponding carboxylic acid (35) with a base such as sodium 
hydroxide or potassium hydroxide in an alcoholic aqueous solvent such as 
methanol/H.sub.2 O. 
##STR37## 
As shown in Scheme X, compound (38) in which R.sup.1 .dbd.CO.sub.2 H can be 
easily prepared, for example, by reacting aniline precursor (37) with a 
phthalic anhydride derivative in an appropriate solvent such as benzene, 
chloroform, ethyl acetate, etc. [M. L. Sherrill, F. L. Schaeffer, E. P. 
Shoyer, J. Am. Chem. Soc., 50, 474 (1928)]. 
The 4-nitrobenzylintermediate (36) can be obtained by direct alkylation 
onto benzimidazole with a 4-nitrobenzyl halide, tosylate or mesylate in 
the presence of a base such as sodium hydride. 
When R.sup.1 is NHSO.sub.2 CF.sub.3 or tetrazolyl, compound (38) can be 
obtained by reacting aniline (37) with the requisite acid chloride by 
either a Schotten-Baumann procedure, or simply stirring in a solvent such 
as methylene chloride in the presence of a base such as sodium 
bicarbonate, pyridine, or triethylamine. 
Likewise, aniline (37) can be coupled with an appropriate carboxylic acid 
via a variety of amide or peptide bond forming reaction such as DCC 
coupling, azide coupling, mixed anhydride synthesis, or any other coupling 
procedure familiar to one skilled in the art. 
##STR38## 
Compounds of formula (1) where X is --OCH.sub.2 are prepared as shown in 
Scheme XI. 
##STR39## 
As illustrated in Scheme XI, hydrolysis of benzylether (39) or methyl ether 
(40) affords hydroxy compound (41) which can be alkylated with the 
appropriate benzyl halide to give (42). In the case of the methyl ethers 
(40), the hydrolysis step can be effected by heating the ether at 
temperatures of 50.degree.-150.degree. C. for 1-10 hours in 20-60% 
hydrobromic acid, or heating at 50.degree.-90.degree. C. in acetonitrile 
with 1-5 equivalents of trimethylsilyl iodide for 10-50 hours followed by 
treatment with water. Hydrolysis can also be carried out by treatment with 
1-2 equivalents of boron tribromide in methylene chloride at 
10.degree.-30.degree. C. for 1-10 hours followed by treatment with water, 
or by treatment with an acid such as aluminum chloride and 3-30 
equivalents of sulfur-containing compound such as thiophenol, 
ethanedithiol, or dimethyl disulfide in methylene chloride at 
0.degree.-30.degree. C. for 1-20 hours followed by treatment with water. 
For compound (39), hydrolysis can be accomplished by refluxing in 
trifluoroacetic acid for 0.2-1 hours or by catalytic hydrogenolysis in the 
presence of a suitable catalyst such as 10% palladium on carbon. 
Deprotonation of (41) with a base, such as sodium methoxide, sodium 
hydride or the like in a solvent such as dimethylformamide or 
dimethylsulfoxide at room temperature followed by alkylation with an 
appropriated benzyl halide at 25.degree. C. followed by stirring for 2-20 
hours affords ethers of formula (42). 
The compounds of this invention and their preparation can be understood 
further by the following examples, but should not constitute a limitation 
thereof. In these examples, unless otherwise indicated, all temperatures 
are in degrees centigrade.