WO1993006828A1 - Medicament for the treatment of anxiety - Google Patents

Abstract

The present invention relates to the use of certain angiotensin II receptor antagonists in the manufacture of a medicament for the treatment of anxiety.

Description

MEDICAMENT FOR THE TREATMENT OF ANXIETY FIELD OF THE INVENTION

The present invention relates to a method of treating disorders of the central nervous system, in particular anxiety, by the administration of certain angiotensin II (AII) receptor antagonists.

BACKGROUND OF THE INVENTION

Interruption of the renin-angiotensin system with converting enzyme (ACE) inhibitors, such as captopril, has proven to be clinically useful in the treatment of certain disease states, such as hypertension and congestive heart failure [Abrams, et al., Federation Proc., 43:1314 (1984)]. Recent studies also have shown that ACE inhibitors have the ability to reduce anxiety in models of neophobia or

suppressed behavior [Costall, et al., Pharmacol. Biochem. Behav., 36:13 (1990)]. Since AII is the biologically active component of the renin-angiotensin system responsible for the system's effects, the most direct approach towards inhibition of the renin-angiotensin system and in particular AII-indiced anxiety would be blockade of angiotensin II at its receptor.

Anxiety is characterized by a combination of unpleasant feelings, such as tension, guilt, apprehension, dependency, and loss of confidence, and physical disturbances, such as altered breathing, increased heart rate, increased sweating, and gastrointestinal upset. While the disease state of anxiety is not yet fully understood, the structure

elucidation of the macromolecular complex comprising anxiety has increased the likelihood that the specificity of future therapeutics can be improved. Since AII receptors are present in the brain, [Neuroscience, 18:837 (1986)], the compounds of this invention inhibit, block and antagonize the action of the hormone AII at its receptor, and are therefore useful in regulating and moderating angiotensin II induced anxiety.

SUMMARY OF THE INVENTION

The present invention provides a new method of treating anxiety in a mammal which comprises administering to a subject in need thereof an effective non-toxic amount of certain angiotensin II receptor antagonists.

The present invention also provides for the use of certain angiotensin II receptor antagonists in the

manufacture of a medicament for the treatment of anxiety. DESCRIPTION OF THE INVENTION

The present invention is a therapeutic method for

treating anxiety in mammals. The method utilizes a class of antagonists which have been previously prepared and evaluated as effective AII receptor antagonists. Examples of suitable angiotensin II receptor antagonists include the following:

Substituted imidazoles of the formula (I):

in which :

R¹ is adamantyl, phenyl, biphenyl, or naphthyl, with each aryl group being unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C₁-C₆alkyl, nitro, A-CO₂R , tetrazol-5-yl, C₁-C₆alkoxy, hydroxy,

SC₁-C₆alkyl, SO-NHR⁷, NHSO₂R⁷, SO₃H, CONR⁷R⁷, CN,

SO-C₁-C₆-alkyl, NHSO₂R⁷, PO(OR⁷)-, NR⁷R⁷, NR⁷COH,

NR⁷COC₁-C₆-alkyl, NR⁷CON(R⁷)₂, NR⁷COW, W, SO-W;

m is 0-4;

2

R is C₂-C₁₀alkyl, C₃-C₁₀alkenyl, C₃-C₁₀alkynyl,

C₃-C₆Cycloalkyl, or (CH₂)_0-8phenyl unsubstituted or

substituted by one to three substituents selected from

C₁-C₆alkyl, nitro, Cl, Br, F, I, hydroxy, C^Cgalkoxy,

NR⁷R⁷, CO₂R⁷, CN, CONR⁷R⁷, W, tetrazol-5-yl,

NR⁷COC₁-C₆alkyl, NR⁷COW, SC₁-C₆-alkyl, SO₂W, or

SO₂C₁-C₆-alkyl;

X is a single bond, S, NR⁷, or O;

R³ is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl,

COOR⁷ ₇ CONR⁷R⁷, NO₂, W, CN, NR⁷R⁷, or phenyl; R⁴ and R⁵ are independently hydrogen, C₁-C₆alkyl, thienyl-Y-, furyl-Y-, pyrazolyl-Y-, imidazolyl-Y-, pyrrolyl¬

Y-, triazolyl-Y-, oxazolyl-Y-, isoxazolyl-Y-, thiazolyl-Y-, pyridyl-Y-, or tetrazolyl-Y-, except that R ⁴ and R⁵ are not both selected from hydrogen and C,-Cgalkyl and each

heterocyclic ring is unsubstituted or substituted by

C₁-C₆-alkyl, C₁-C₆-alkoxy, Cl, Br, F, I, NR⁷R⁷, CO ₂R⁷,

SO₂NHR , SO₃H, or CONR⁷R⁷, OH, NO₂, W, SO₂W, SC₁-C₆alkyl, SO₂C₁-C₆alkyl, NR⁷COH, NR⁷COW, or NR⁷COC₁-C₆alkyl;

Y is a single bond, O, S, or C₁-C₆alkyl which is straight or branched or optionally substituted by phenyl or benzyl, wherein each of the aryl groups is unsubstituted or substituted by halo, NO₂, CF₃, C₁-C₆alkyl, C₁-C₆alkoxy, CN, or CO₂R⁷;

R⁶ is -Z-COOR⁸ or -Z-CONR⁷R⁷;

Z is a single bond, vinyl, -CH₂-O-CH₂-, methylene optionally substituted by C₁-C₆alkyl, one or two benzyl groups, thienylmethyl, or furylmethyl, or -C(O)NHCHR⁹-, wherein R ⁹ is H, C₁-C₆alkyl, phenyl, benzyl, thienylmethyl, or furylmethyl;

^{W is} C_nF_2n+1;

A is -(CH₂)_q-, -CH=CH-, -O(CH₂)_n-, or -S(CH₂)_n-;

each R independently is hydrogen, C₁-C₆alkyl, or

(CH₂)_qphenyl;

each n independently is 1-3;

each g independently is 0-4; and

R ⁸ is hydrogen, C₁-C₆alkyl, or 2-di (C₁-C₆alkyl)-amino2-oxoethyl; or a pharmaceutically acceptable salt thereof. Preferred compounds included within the scope of

formula (I) are:

(E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid,

(E)-3-[2-n-butyl-1-{(4-carboxy-2,3-dichlorophenyl)- methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid,

(E)-3-[2-n-butyl-1-{(2-chloro-4-carboxyphenyl)methyl}- 1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid, and (E)-3-[2-n-butyl-1-{(4-carboxynaphth-1-yl)methyl}-1H- imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid; or a pharmaceutically acceptable salt thereof.

Particularly preferred is (E)-3-[2-n-butyl-1-{(4- carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl- 2-propenoic acid and (E)-3-[2-n-butyl-1-{(4-carboxynaphth-1- yl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid; or a pharmaceutically acceptable salt thereof. Most preferred is E)-3-[2-n-butyl-1-{(4- carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl- 2-propenoic acid methanesulfonate.

The compounds of formula (I) are prepared following the methods described in European Patent Publication Number EP 0 403 159, published on December 19, 1990.

Substituted imidazoles of the formula (II):

in which:

R¹ is adamantyl, phenyl, biphenyl, or naphthyl, with each aryl group being unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C₁-C₆alkyl, nitro, A-CO₂R⁷, tetrazol-5-yl, C₁-C₆alkoxy, hydroxy, SC₁-C₆alkyl, SO₂NHR⁷, NHSO₂R⁷, SO₃H, CONR⁷R⁷,

CN, SO₂C₁-C₆alkyl, NHSO₂R⁷, PO(OR⁷)₂, NR⁷R⁷, NR⁷COH,

NR⁷COC₁-C₆alkyl, NR⁷CON(R⁷)₂, NR⁷COW, W, SO₂W;

m is 0-4;

R ² is C₂-C₁₀alkyl, C₃-C₁₀alkenyl, C₃-C₁₀alkynyl,

C₃-C₈Cycloalkyl, or (CH₂)_0-8phenyl unsubstituted or substituted by one to three substituents selected from C₁-C₆alkyl, nitro, Cl, Br, F, I, hydroxy, C₁-C₆alkoxy, NR⁷R⁷, CO₂R⁷, CN, CONR⁷R⁷, W, tetrazol-5-yl,

NR⁷COC₁-C₆alkyl, NR⁷COW, SC₁-C₆alkyl, SO₂W, or

SO₂C₁-C₆alkyl;

X is a single bond, S, NR⁷, or O;

R ³ is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl, COOR⁷, CONR⁷R⁷, NO-, W, CN, NR⁷R⁷, or phenyl;

R ⁴ and R⁵ are independently hydrogen, C₁-C₆alkyl, phenyl-Y-, naphthyl-Y-, or biphenyl-Y-, wherein the aryl groups are unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C₁-C₆alkoxy, hydroxy, CO₂R⁷, CN, NO₂, tetrazol-5-yl, SO₃H, CF₃,

CONR⁷R⁷, SO₂NHR⁷, C₁-C₆alkyl, or NR⁷R⁷, or by

methylenedioxy, phenoxy or phenyl, except that R ⁴ and R5 are not both selected from hydrogen;

Y is a single bond, O, S, or C₁-C₆alkyl which is straight or branched or optionally substituted by phenyl or benzyl, wherein each of the aryl groups is

unsubstituted or substituted by halo, NO₂, CF-,

C₁-C₄alkyl, C₁-C₄alkoxy, CN, or CO₂R⁷;

R⁶ is -Z-COOR⁸ or -Z-CONR⁷R⁷;

Z is a single bond, vinyl, -CH₂-O-CH₂-, methylene optionally substituted by C₁-C₄alkyl, one or two benzyl groups, thienylmethyl, or furylmethyl, or -C(O)NHCHR ⁹-, wherein R ⁹ is H, C₁-C₄alkyl, phenyl, benzyl, thienylmethyl, or furylmethyl; W is C_nF_2n+1;

A is -(CH₂)_q-, -CH=CH; -O(CH₂)_n- or -S(CH₂)_n;

each R⁷ independently is hydrogen, C₁-C₄alkyl, or

(CH₂)_qphenyl;

each n independently is 1-3;

each q independently is 0-4; and

R⁸ is hydrogen, C₁-C₆alkyl, or 2-di (C₁-C₄alkyl)- amino-2-oxoethyl; or

R⁵ and R⁶ are both hydrogen, R⁴ is -Z-COOR⁸ and Z is other than a single bond; or a pharmaceutically

acceptable salt thereof.

Preferred compounds included within the scope of formula (II) are:

(E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-benzyl-2-propenoic acid,

(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(3-methoxyphenyl)methyl-2-propenoic acid, and

(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(3,4-methylendioxyphenyl)methyl-2-propenoic acid; or a pharmaceutically acceptable salt thereof.

The compounds of formula (II) are prepared following the methods described in European Publication Number

EP 0 403 158, published on December 19, 1990.

Substituted imidazoles of the formula (III):

in which:

R ¹ is adamantyl or phenyl, biphenyl, or naphthyl, with each aryl group being unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C₁-C₆alkyl, nitro, CO₂R⁷, C₁-C₆alkoxy, hydroxy, SC₁-C₆alkyl,

SO₂C₁-C₆alkyl, tetrazol-5-yl, SO₂NHR⁷, NHSO₂R⁷,

SO₃H, PO(OR⁷)₂, CONR⁷R⁷, CN, NR⁷R⁷, NR⁷COH, NR⁷COC₁-C₆alkyl, NR⁷CON(R⁷)₂, NR⁷COW, SO₂W, or W;

R is C₂-C₁₀alkyl, C₃-C₁₀alkenyl, (CH₂)_0-8-C_{3- 6}cycloalkyl, or (CH₂)_0-8phenyl unsubstituted or substituted by one to three substituents selected from C₁-C₆alkyl, nitro, Cl, Br, F, I, hydroxy, C₁-C₆alkoxy, NR⁷R⁷, CO₂R⁷, CN,

CONR⁷R⁷, W, NR⁷COH, NR⁷COC₁-C₆alkyl, NR⁷COW, SO₂W, SO₂C₁- C₆alkyl, or SC₁-C₆alkyl;

X is a single bond, S, or O;

m is 0-4;

R ³ is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl,

C₁-C₆alkyl, NR⁷R⁷, CO₂R⁷, CONR⁷R⁷, NO₂, CN, phenyl, or W;

R⁴ and R⁵ are each independently hydrogen, C₁-C₆alkyl, C₃-C₆Cycloalkyl, thienyl-Y-, furyl-Y-, pyrazolyl-Y-,

imidazolyl-Y-, thiazolyl-Y-, pyridyl-Y-, tetrazolyl-Y-, pyrrolyl-Y-, triazolyl-Y-, oxazolyl-Y-, isoxazolyl-Y-, or phenyl-Y-, with each aryl or heteroaryl group being

unsubstituted or substituted by C₁-C₆alkyl, C₁-C₆alkoxy, Cl, Br, F, I, NR⁷R⁷, CO₂R⁷, SO₂NHR⁷, SO₃H, OH, NO₂, CONR⁷R⁷, W,

SO₂C₁-C₆alkyl, SO₂W, SC₁-C₆alkyl, NR⁷COH, NR⁷COW, or

NR⁷COC₁-C₆alkyl;

Y is C₁-C₆alkyl which is straight or branched or a single bond;

R⁶ is Z-tetrazol-5-yl;

Z is a single bond, vinyl, or methylene unsubstituted or substituted by C₁-C₄alkyl, one or two benzyl groups, thienylmethyl, or furylmethyl;

W is C_nF_2n+1, wherein n is 1-4; and each R⁷ independently is hydrogen or C₁-C₆alkyl;

or a pharmaceutically acceptable salt thereof.

Preferred compounds included within the scope of formula (III) are:

(E)-1-[2-n-butyl-1-{(4-carboxyρhenyl)methyl}-1H- imidazol-5-yl]-2-(1H-tetrazol-5-yl)-3-(2-thienyl)-1-propene,

(E)-1-[2-n-butyl-1-{(4-(1H-tetrazol-5-yl)phenyl)- methyl}-1H-imidazol-5-yl]-2-(1H-tetrazol-5-yl)-3-(2- thienyl)-1-propene, and

(E)-1-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H- imidazol-5-yl]-2-(1H-tetrazol-5-yl)-3-(2-thienyl)-1- propene; or a pharmaceutically acceptable salt thereof. The compounds of formula (III) are prepared following the methods described in European Publication Number

EP 0 425 211, published on May 2, 1991.

Substituted imidazoles of the formula (IV):

in which:

R is adamantyl or phenyl, biphenyl, or naphthyl, with each aryl group being unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C₁-C₆alkyl, nitro, CO₂R⁷, C₁-C₆alkoxy, hydroxy, SC₁-C₆alkyl,

SO₂C₁-C₆alkyl, tetrazol-5-yl, SO₂NHR⁷, NHSO₂R⁷, SO₃H,

PO(OR⁷)₂, CONR⁷R⁷, CN, NR⁷R⁷, NR⁷COH, NR⁷COC₁-C₆alkyl,

NR⁷CON(R⁷)₂, NR⁷COW, SO₂W, or W; R¹ is C₂-C₁₀alkyl, C₃-C₁₀alkenyl, (CH₂)_0-8C_{3- 6}cycloalkyl, or (CH₂)_0-8phenyl unsubstituted or substituted by one to three substituents selected from C₁-C₆alkyl, nitro, Cl, Br, F, I, hydroxy, C₁-C₆alkoxy, NR R , CO₂R , CN, CONR⁷R⁷, W, NR⁷COH, NR⁷COC₁-C₆alkyl, NR⁷COW, SC₁-C₆alkyl,

SO₂C₁-C₆alkyl, or SO₂W;

R is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl,

C₁-C₆alkyl, NR⁷R⁷, CO₂R⁷, CONR⁷R⁷, NO₂, CN, phenyl, or W;

X is a single bond, S, or 0;

R³ is H, C_1-6alkyl, C_3-6alkenyl, COC_1-5alkyl, or

(CH₂)_0-3phenyl;

R is H, C_1-6alkyl, C_3-6alkenyl, or (CH₂)_0-3-phenyl;

R⁵ is CO₂R⁷, CONR⁷R⁷, or tetrazol-5-yl;

each n independently is 0-4;

R⁶ is phenyl, naphthyl, 2- or 3-thienyl, 2- or 3-furyl,

2-, 3-, or 4-pyridyl, pyrimidyl, imidazolyl, thiazolyl, triazolyl, triazolyl, tetrazolyl, pyrazolyl, pyrrolyl, oxazolyl, or isoxazolyl, with each aryl or heteroaryl group being unsubstituted or substituted by C₁_₆alkyl, C_1-6alkoxy, Cl, Br, F, I, NR⁷R⁷, CO₂R⁷, CONR⁷R⁷, SO₃H, SO₂NHR⁷, OH, NO₂ W, SO₂C₁-C₆alkyl, SO₂W, SC₁-C₆alkyl, NR⁷COH, NR⁷COW, or

NR⁷COC₁-C₆alkyl;

W is C_mF_2m+1, wherein m is 1-4; and

each R independently is H or C_1-6alkyl;

or a pharmaceutically acceptable salt thereof.

Preferred compounds included within the scope of

formula (II) are:

N-[{1-(4-carboxyphenyl)methyl]-2-n-butyl-1H-imidazol-5-yl}methyl]-ß-(2-thienyl)alanine,

N-[{1-(2-chlorophenyl)methyl]-2-n-butyl-1H-imidazol-5-yl}methyl]-ß-(2-thienyl)alanine, and

N-[{1-[(2-chlorophenyl)methyl]-2-n-butyl-1H-imidazol-5-yl}methyl]phenylalanine; or a pharmaceutically acceptable salt thereof.

The compounds of formula (IV) are prepared following the methods described in European Publication Number

EP 0 427 463, published on May 15, 1991.

Substituted imidazoles of the formula (V):

in which:

R is adamantyl, or naphthyl, biphenyl, or phenyl, with each aryl group being unsubstituted or substituted by one to three substituents selected from halo, C_1-6alkyl, C_{1- 6}alkoxy, OH, CN, CO₂R³, tetrazol-5-yl, SO₃H, SO₂NHR³, NO₂, W, SC_1-6alkyl, SO₂C_1-6alkyl, NHSO₂R³, PO(OR³)₂, CONR³R³,

NR³R³, NR3COH, NR³COC_1-6alkyl, NR³CON (R³)₂, NR³COW, or SO₂W;

R¹ is C_2-10alkyl, C_3-10alkenyl, (CH₂)_0-8C_3-6cycloalkyl, or (CH₂)_0-8phenyl unsubstituted or substituted by one to three substituents selected from C_1-6alkyl, C_1-6alkoxy, halo, OH, NO₂, NR³R³, W, CO₂R³, CN, CONR³R³, NR³COH,

tetrazol-5-yl, NR³COC_{1- 6}alkyl , NR³COW, SC_1-6alkyl, SO₂W, or SO₂ C_1-6alkyl;

X is a single bond, S, NR³, or O;

m is 0-4;

R² is H, C_1-6alkyl, halo, W, CHO, CH₂OH, CO₂R³,

CONR ³R³, NO₂, CN, NR³R³, or phenyl;

each R³ independently is H or C_1-6alkyl;

R⁴ is H, C_1-8alkyl, thienyl-Y-, furyl-Y-, pyrazolyl-Y-, imidazolyl-Y-, thiazolyl-Y-, pyridyl-Y-, tetrazolyl-Y-, pyrrolyl-Y-, triazolyl-Y-, oxazolyl-Y-, isoxazolyl-Y-, or phenyl-Y-, with each aryl or heteroaryl group being

unsubstituted or substituted by C_1-6alkyl, C_1-6alkoxy, halo,

NR³R³, CO₂R³, OH, NO₂, SO₂NHR³, SO₃H, CONR³R , W, SO₂W, SC_{1- 6}alkyl, SO₂C_1-6alkyl, NR³COH, NR³COW, or NR³COC_1-6alkyl;

R⁵ is CO₂R³, CONR³R³, or tetrazol-5-yl;

W is C_qF_2q+1, wherein q is 1-4;

Y is a single bond or C1-6alkyl which is straight or branched; and

n is 0-5; or a pharmaceutically acceptable salt

thereof.

Preferred compounds included within the scope of formula (V) are N-[{2-n-butyl-1-(2-chlorophenyl)methyl-1H- imidazol-5-yl}methylcarbonyl]-L-phenylalanine and N-[{2-n- butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5- yl}methylcarbonyl]-L-(2-thienyl)alanine; or a

pharmaceutically acceptable salt thereof. The compounds of formula (V) are prepared by the

methods described in European Publication Number

EP 0 437 103, published on July 17, 1991.

Substituted imidazoles of the formula (VI):

in which:

R¹ is adamantyl, or phenyl, biphenyl, or naphthyl, with each aryl group being unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C₁-C₆alkyl, nitro, CO₂R⁷, tetrazol-5-yl, C₁-C₆alkoxy, hydroxy, SC₁-C₆alkyl, SO-NR⁷R⁷, NHSO₂R⁷, SO₃H, CONR⁷R⁷, CN,

SO-C₁-C₆alkyl, or C_nF_2n+1;

R² is C₂-C₁₀alkyl unsubstituted or substituted by

CO-H, OH, or NR⁷R⁷, C₃-C₁₀alkenyl, C₃-C₁₀alkynyl,

C₃-C₆Cycloalkyl, or (CH₂)_0-8phenyl unsubstituted or

substituted by one to three substituents selected from C₁-C₆alkyl, nitro, Cl, Br, F, I, hydroxy, C₁-C₆alkoxy,

NR⁷R⁷, CO₂R⁷, CN, or CONR⁷R⁷;

X is a single bond, S, or O;

R ³ is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl,

COOR⁷, CONR⁷R⁷, NO-, or C_nF_2n+1;

each n is 1-3;

m is 0-4;

R⁴ is CO₂R⁷, CONR⁷R⁷, or tetrazol-5-yl;

Y is a single bond or a carbonyl group;

R⁵ is hydrogen, C₁-C₆alkyl, C₃-C₆Cycloalkyl,

(CH₂)_0-4phenyl, or (CH₂)_0-3CH-diphenyl wherein each phenyl group independently is unsubstituted or substituted by one to three substituents selected from C₁-C₆alkyl, nitro, Cl, Br, F, I, hydroxy, C₁-C₆alkyl, NR⁷R⁷, CO₂R⁷,or CONR⁷R⁷;

R⁶ is hydrogen or C_1-6alkyl; and

each R⁷ independently is hydrogen, C₁-C₄alkyl, or (CH₂)_0-4phenyl; or a pharmaceutically acceptable salt thereof.

Preferred compounds included within the scope of formula (VI) are 3-[(2-chlorophenyl)methyl]-2-propylthio-N-butrylhistidine and 3-[(2-chlorophenyl)methyl]-2-n-butyl-N-butyrylhistidine; or a pharmaceutically acceptable salt thereof. The compounds of formula (VI) are prepared by the methods described in Patent Cooperation Treaty Publication Number WO 92/000.8, published January 9, 1992.

Substituted imidazoles of the formula (VII) :

in which:

R¹ is adamantylmethyl, or phenyl, biphenyl, or naphthyl, with each aryl group being unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I,

C_1-6alkyl, nitro, CO₂R⁸, tetrazol-5-yl, C_1-6alkoxy, hydroxy, SC_1-4alkyl, SO₂NHR⁸, NHSO₂R⁸, SO₃H, CONR⁸R⁸, CN,

SO₂ C_1-4alkyl, or C_nF_2n+1, wherein n is 1-3;

R² is C_2-10alkyl, C_3-10alkenyl, C_3-10alkynyl,

C_3-6cycloalkyl, or (CH₂)_0-8-phenyl unsubstituted or

substituted by one to three substituents selected from

C_1-6alkyl, nitro, Cl, Br, F, I, hydroxy, C_1-6alkoxy, NR⁸R⁸, CO₂R⁸, CN, or CONR⁸R⁸;

X is a single bond, S, or 0;

R³ is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl, CO₂R⁸, CONR ⁸R⁸, NO₂, or C_nF_2n+1, wherein n is 1-3;

q is 0 to 4;

mis 0 to 2;

R⁴ is H or C_1-6alkyl;

z is 0 to 1;

R⁵ is C_3-6alkyl, C_3-6alkenyl, phenyl-Y-, 2- or 3- thienyl-Y-, 2- or 3-furyl-Y-, 2-, 3-, or 4-pyridyl-Y-, tetrazolyl-Y-, triazolyl-Y-, imidazolyl-Y-, pyrazolyl-Y-, thiazolyl-Y-, pyrrolyl-Y-, or oxazolyl-Y-, with each aryl ring being unsubstitued or substitued by C_1-6alkyl, Cl, Br, F, I, C_1-6alkoxy, NR⁸R⁸, CO₂R⁸, or CONR⁸R⁸;

Y is a single bond or C_1-6alkyl which is branched or unbranched;

R⁶ is CO₂R⁸, CONR⁸R⁸, or tetrazol-5-yl;

R ⁷ is H, CO₂R⁸, or C_1-6alkyl; and

each R⁸ independently is hydrogen, C_1-6alkyl, or

(CH₂)₀_₄phenyl;

or a pharmaceutically acceptable salt thereof.

A preferred compound included within the scope of formula (VII) is 3-[2-n-butyl-1-{(2-chlorophenyl)-methyl}- 1H-imidazol-5-yl]-2-benzylpropanoic acid or a

pharmaceutically acceptable salt thereof.

The compounds of formula (VII) are prepared by the methods described in Patent Cooperation Treaty Publication Number WO 92/02510, published February 20, 1992.

Substituted imidazoles of the formula (VIII):

in which:

R¹ is adamantylmethyl, or phenyl, biphenyl, or naphthyl, with each aryl group being unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C₁-C₆alkyl, nitro, CO₂R⁵ C₁-C₆alkoxy, hydroxy, SC₁-C₆alkyl, SO₂C₁-C₆alkyl, tetrazol-5-yl, SO₂NHR⁵, NHSO₂R⁵ SO₃H, PO(OR⁵)₂ CONR⁵R⁵ CN, NR⁵R⁵, NR⁵COH, NR⁵COC₁-C₆alkyl, NR⁵CON(R⁵)₂, NR⁵COW, SO₂W, or W;

R² is C₂-C₁₀alkyl, C₃-C₁₀alkenyl, (CH₂)_0-8- C_3-6cycloalkyl, or (CH₂)_0-8phenyl unsubstituted or

substituted by one to three substituents selected from C₁- C₆alkyl, nitro, Cl, Br, F, I, hydroxy, C₁-C₆alkoxy,

tetrazol-5-yl, NR⁵R⁵ CO₂R⁵, CN, CONR⁵R⁵, W, NR⁵COH,

NR⁵COC1-C6-alkyl, NR⁵COW, SO₂W, SO2C1-C6alkyl, or SC1- C6alkyl;

X is a single bond, S, NR⁵, or O;

n is 0-4;

R³ is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl,

C₁-C₆alkyl, NR⁵R⁵, CO₂R⁵, CONR⁵R⁵, NO₂, CN, phenyl, or W;

R ⁴ is CO₂R⁵, CONR⁵R⁵, or tetrazol-5-yl;

Z is hydrogen, Cl, Br, F, I, C₁-C₆alkyl, C₁-C₆alkoxy, hydroxy, CN, NO₂, CO₂R⁵, COR⁵R⁵, W, phenyl-Y-, naphthyl-Y-, thienyl-Y-, furyl-Y-, pyrozolyl-Y-, imidazolyl-Y-,

thiazolyl-Y-, triazolyl-Y-, tetrazolyl-Y-, pyrrolyl-Y-, triazolyl-Y-, oxazolyl-Y-, or isoxazolyl-Y-, with each aryl or heteroaryl group being unsubstituted or substituted by C₁-C₆alkyl, C₁-C₆alkoxy, Cl, Br, F, I, CO₂R⁵, hydroxy, NO₂, CN, CINR⁵R⁵, or W;

Y is a single bond or C₁-C₆alkyl, which is straight or branched;

W is CmF_2m+1, wherein m is 1-4,; and

each R⁵ independently is H or C₁-C₆alkyl; or a

pharmaceutically acceptable salt thereof.

A preferred compound included within the scope of formula (VIII) is 3-[2-n-butyl-1-{(2-chlorophenyl)methyl}- 1H-imidazol-5-yl]benzoic acid or a pharmaceutically acceptable salt thereof.

The compounds of formula (VIII) are prepared by the methods described in Patent Cooperation Treaty Publication Number WO 92/09278, published June 11, 1992.

Substituted benzimidazoles of the formula (IX):

in which:

R¹ is -C(O)NH-CH(Y)- (CH₂)_n-aryl, -C(O)NH-CH(Y)- (CH₂)_n-heteroaryl, or phenyl unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C_1-6alkyl, C_1-6alkoxy, OH, CN, NO₂, CO₂R⁷, tetrazol-5-yl,

CONR⁴R⁴, SO₃H, C_mF_2m+1, SC_1-6alkyl, or SO₂C_1-6alkyl;

R² is hydrogen, C_2-10alkyl, C_3-10alkenyl, C_3-6-cycloalkyl, C_mF2_m+1, or (CH₂)_0-8phenyl unsubstituted or substituted by one to three substituents selected from

C_1-6alkyl, C_1-6alkoxy, Cl, Br, F, I, OH, NO₂, C_mF_2m+1, CO₂R⁴, or NR⁴R⁴;

R³ is -(CH₂)_n-Y, -CH=CY-(CH₂)_n-aryl, -CH=CY-(CH₂)_n-heteroaryl, - (CH₂)_n-C(O)-NH-CH(Y)-(CH₂)_n-aryl, -(CH)₂)_n- C(O)-NH-CH(Y)-(CH₂)_nheteroaryl, -(CH₂)_m-NH-CH(Y)-(CH₂)_n-aryl or - (CH₂)_m-NH-CH(Y)-(CH₂)_n-heteroaryl, when R¹ is an optionally substituted phenyl group; or H when R¹ is

-C(O)NH-CH(Y)-(CH₂)_n-aryl or -C(O)NH-CH(Y)-(CH₂)_n- heteroaryl;

Y is CO₂R⁴ or tetrazol-5-yl;

X is Cl, Br, F, I, C_mF_{2 m+1} , C_1-6alkyl, C_1-6alkoxy, OH, O-phenyl, CO₂R⁷, tetrazol-5-yl, CN, or (CH₂)_0-4phenyl unsubstituted or substituted by Cl, Br, F, I, C..__galkyl, C_1-6alkoxy, OH, C_mF_{2 m+1}, CN, CO₂R⁴, NO₂, or NR⁴R⁴;

aryl is phenyl, biphenyl, or naphthyl wherein each aryl group is unsubstituted or substituted by Cι_galkyl,

C_1-6alkoxy, Cl, Br, F, I, OH, NO₂, CF₃, CO₂R⁴, or NR⁴R⁴; heteroaryl is 2- or 3-thienyl, 2-, or 3-furanyl, 2-,

3-, or 4- pyridyl, pyrimidyl, imidazolyl, thiazolyl, triazolyl, or tetrazolyl wherein each heteroaryl group is unsubstituted or substituted by C_1-6alkyl, C_1-6alkoxy,

Cl, Br, F, I, OH, NO₂, CF₃, CO₂R⁴, or NR⁴R⁴;

each m independently is 1-3;

each n independently is 0-2; and

4

each R independently is H or C_1-6alkyl; or a

pharmaceutically acceptable salt thereof. Preferred compounds included within the scope of formula (IX) are:

5-bromo-2-n-butyl-1-(2-chlorophenyl)methyl-1H-benzimidazole-7-carboxylic acid,

2-n-butyl-1-(2-chlorophenyl)methyl-1H-benzimidazole-7-carboxylic acid, and

2-n-butyl-1-(4-carboxyphenyl)methyl-5-chloro-1H-benzimidazole-7-carboxylic acid;

or a pharmaceutically acceptable salt thereof. The compounds of formula (IX) are prepared following the methods described in Patent Cooperation Treaty

Publication Number WO 91/16313, published October 31, 1991. Substituted imidazoles of the formula (X):

in which:

R¹ is Het, wherein Het is defined as a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic ring, which is either saturated or

unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group

consisting of N, O, S, wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quarternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring and wherein the Het is unsubstituted or substituted by any accessible stable combination of up to three substituents selected from the group consisting of C₁-C₆alkyl, C₁-C₆alkoxy, Cl, Br, F, I, NR⁷R⁷, A-CO₂R⁷, CONR⁷R⁷, SO₃H, SO₂NHR⁷, OH, NO₂, W, SO₂C₁-C₆alkyl, SO₂W, SC₁-C₆alkyl, NR⁷COW, or NR⁷COC₁-C₆alkyl, wherein W is C_nF_2n+1, in which n is 1-3 and wherein A is -CH=CH-, -(CH₂)_0-4-, -Q-CH(R⁹)-, or -Q-(CH₂)_1-2-U-(CH₂)_1-2-, in which Q is O, S, NH, or

N C_1-6alkyl, U is absent or present as O, S, NH, or

N C_1-6alkyl, and R⁹ is hydrogen, phenyl, or benzyl;

m is 0-4;

R² is C₂-C₁₀alkyl, C₃-C₁₀alkenyl, C₃-C₁₀alkenyl, C₃-C₆cycloalkyl, or (CH₂)_0-8phenyl unsubstituted or substituted by one to three substituents selected from C₁-C₆alkyl, nitro, Cl, Br, F, I, hydroxy, C₁-C₆alkoxy, NR⁷R⁷, CO₂R⁷, CN, CONR⁷R⁷, W, tetrazol-5-yl,

NR⁷COC₁-C₆alkyl, NR⁷COW, SC₁-C₆alkyl, SO₂W, or

SO₂C₁-C₆alkyl;

X is a single bond, S, NR⁷, or 0;

R³ is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl, COOR⁷, CONR⁷R⁷, NO₂, W, CN, NR⁷R⁷, or phenyl;

R⁴ and R⁵ are independently hydrogen, C₁-C₆alkyl, phenyl-Y-, biphenyl-Y-, naphthyl-Y-, 2- or 3-thienyl-Y-, 2- or 3-furyl-Y-, 2-, 3- or 4- pyridyl-Y-, pyrazolyl-Y-, imidazolyl-Y-, pyrrolyl-Y-, triazolyl-Y-, oxazolyl-Y-, isoxazolyl-Y-, thiazolyl-Y-, or tetrazolyl-Y-, with each aryl or heteroaryl group being unsubstituted or

substituted by C₁-C₆alkyl, C₁-C₆alkoxy, Cl, Br, F, I, NR⁷R⁷, CO₂R⁷, SO₂NHR⁷, SO₃H, CONR⁷R⁷, OH, NO₂, W, SO₂W, SC₁-C₆alkyl, SO₂C₁-C₆alkyl, NR⁷COH, NR⁷COW, or

NR⁷COC₁-C₆alkyl;

Y is a single bond, O, S, or C₁-C₆alkyl which is straight or branched or optionally substituted by phenyl or benzyl, wherein each phenyl or benzyl group is unsubstituted or substituted by halo, NO₂, CF₃,

C₁-C₆alkyl, C₁-C₆alkoxy, CN, or CO₂R⁷;

R⁶ is -Z-COOR⁸, -Z-CONR⁷R⁷, or -Z-tetrazol-5-yl; Z is a single bond, vinyl, -CH₂-O-CH₂-, methylene optionally substituted by C₁-C₆alkyl, one or two benzyl groups, thienylmethyl, or furylmethyl, or -C(O)NHCHR⁹-, wherein R⁹ is H, C₁-C₆alkyl, phenyl, benzyl,

thienylmethyl, or furylmethyl;

W is C_nF_2n+1, wherein n is 1-3;

each R⁷ independently is hydrogen, or C₁-C₆alkyl; and

R⁸ is hydrogen, C₁-C₆alkyl, or 2-di(C₁-C₆alkyl)-amino-2-oxoethyl; or a pharmaceutically acceptable salt thereof. The preferred compounds of this invention are represented by Formula (X) when:

R¹ is 2- or 3-thienyl, 2- or 3-furyl, or 2-, 3-, or pyridyl with each thienyl, furyl, or pyridyl group being unsubstituted or substituted by CO₂R⁷;

m is 0-2;

X is a single bond or S;

R² is C₂-C₈alkyl;

R³ is hydrogen, chloro, fluoro, or trifluoromethyl; R⁴ is hydrogen or C₁-C₆alkyl;

R⁵ is 2-, or 3-thienyl-Y-, 2-, or 3-furyl-Y-, or 2- or 3-, or 4-pyridyl-Y-, with each heteroaryl group being unsubstituted or substituted by methyl or methoxy;

Y is a single bond or C₁-C₆alkyl which is straight or branched;

R⁶ is -Z-COOR⁸;

Z is a single bond; and

R⁸ is hydrogen or C₁-C₆alkyl;

or a pharmaceutically acceptable salt thereof.

The most preferred compound of this invention is (E)-3-[2-n-butyl-1-{(5-carboxy-2-thienyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid or a pharmaceutically acceptable salt thereof.

Compounds of formula (X) are prepared as illustrated by Example 1.

Substituted imidazoles of the formula (XI):

in which: R¹ is adamantyl, phenyl, biphenyl, or naphthyl, with each phenyl, biphenyl, or naphthyl group being unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C₁-C₆alkyl, nitro, A-CO₂R⁷, tetrazol-5-yl, C₁- C₆alkoxy, hydroxy, SC₁-C₆alkyl, SO₂NHR⁷, NHSO₂R⁷, SO₃H,

CONR⁷R⁷, CN, SO₂C₁-C₆alkyl, NHSO₂R⁷, PO(OR⁷)₂, NR⁷R⁷,

NR⁷COH, NR⁷COC₁-C₆alkyl, NR⁷CON(R⁷)₂ , NR⁷COY, Y, or SO₂Y;

R² is C₂-C₁₀alkyl, C₃-C₁₀alkenyl, C₃-C₁₀alkenyl, C₃- C₆cycloalkyl, or (CH₂)_0-8phenyl unsubstituted or substituted by one to three substituents selected from C₁-C₆alkyl, nitro, Cl, Br, F, I, hydroxy, C₁-C₆alkoxy, NR⁷R⁷, CO₂R⁷, CN,

CONR⁷R⁷, Y, tetrazol-5-yl, NR⁷COC₁-C₆alkyl, NR⁷COY, SC₁- C₆alkγl, SO₂Y, or SO₂C₁-C₆alkyl;

X is a single bond, S, or O;

3

R is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl,

COOR⁷, CONR⁷R⁷, NO₂, Y, CN, NR⁷R⁷, or phenyl;

Y is C_mF_2m+1;

A is -(CH₂)_p-, -CH=CH-, -O(CH₂)_m-, or -S(CH₂)_m;

R⁴ is H, C₁-C₆alkyl, or -S (CH₂) _1-4CO₂R⁷;

t is 0 or 1;

R⁵ is -CHR⁶(CH₂)_qCO₂R⁷ or -(CH₂)_nR⁹;

R⁶ is hydrogen, CO₂R⁷, C₁-C₆alkyl, or -(CH₂)_nR⁸;

each m independently is 1-3;

each n independently is 0-3;

each p independently is 0-4;

each q independently is 0-2,

each R⁷ independently is hydrogen or C₁-C₆alkyl;

R⁸ is phenyl, naphthyl, 2- or 3-thienyl, 2- or 3-furyl,

2-, 3-, or 4-pyridyl, pyrimidyl, imidazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyrrolyl, oxazolyl, or isoxazolyl, with each R⁸ group being unsubstituted or

substituted by C₁-C₆alkyl, C₁-C₆alkoxy, Cl, Br, F, I, NR⁷R⁷,

CONR⁷R⁷, CO₂R⁷, SO₃H, SO₂NHR⁷, OH, NO₂, Y, SO^-Cgalkyl,

SO₂Y, SC₁-C₆alkyl, NR⁷COH, NR⁷COY, or NR⁷COC₁-C₆alkyl; and R⁹ is phenyl, naphthyl, 2- or 3-thienyl, 2- or 3-furyl, 2-, 3-, or 4-pyridyl, pyrimidyl, imidazolyl, thiazoiyl, triazolyl, tetrazolyl, pyrazolyl, pyrrolyl, oxazolyl, or isoxazolyl, with each R⁹ group being unsubstituted or substituted by C₁-C₆alkyl, C₁-C₆alkoxy, Cl, Br, F, I, NR⁷R⁷, CO₂R⁷, CONR⁷R⁷, SO₃H, SO₂NHR⁷, OH, NO₂, Y, SO₂C₁-C₆alkyl, SO₂Y, SC₁-C₆alkyl, NR⁷COH, NR⁷COY, or NR⁷COC₁-C₆alkyl;

or a pharmaceutically acceptable salt thereof.

Preferred compounds of this invention are represented by Formula (I) when:

R¹ is phenyl or naphthyl, with each phenyl or naphthyl group being unsubstituted or substituted by one to three substituents selected from Cl, Br, F, CF₃, NO₂, C₁-C₆alkyl, C₁-C₆alkoxy, hydroxy, A-CO₂R⁷, CONR⁷R⁷, or tetrazol-5-yl; each p independently is 0-2;

X is a single bond or S;

R² is C₂-C₈alkyl;

R³ is hydrogen, Cl, F, CF₃, or NO₂;

R⁵ is -CHR⁶(CH₂)_qCO₂R⁷ in which R⁶ is hydrogen, CO₂R⁷, C₁-C₆alkyl, or (CH₂)_nR⁸, wherein R⁸ is phenyl, naphthyl, 2- or 3-thienyl, or 2- or 3- furyl, with each R⁸ group being unsubstituted or substituted by C₁-C₆alkyl or C₁-C₆alkoxy;. or -(CH₂)_nR⁹ in which R⁹ is phenyl or 2-, 3-, or 4-pyridyl with each R⁹ group being substituted by CO₂R⁷, or R⁹ is imidazolyl; or a pharmaceutically acceptable salt thereof.

The most preferred compounds of this invention are:

S-[(2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl)methyl]-2-thio-3-(2-thienyl)propenoic acid,

S-[(2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl)methyl]thiosalicylic acid,

S-[(2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl)methyl]-2-mercaptonicotinic acid,

4-[(2-n-butyl-5-{[(2-carboxyphenyl)thio]methyl}-1H-imidazol-5-yl)methyl]-1-naphthalenecarboxylic acid;

or a pharmaceutically acceptable salt thereof. Compounds for formula (XI) are prepared as illustrated by Examples 2-4.

The above descriptions of classes of AII antagonists for use in the present invention were taken from pending patent applications. Certain of these applications have published and reference should be made to their full

disclosures, such publications being incorporated herein by reference. Furthermore, Examples 1-4 teach how to make compounds encompassed by the generic Formulae of (X) - (XI).

Certain AII antagonists employed in the invention may exist in isomeric form. This invention includes all such isomers both in pure form and admixture, including racemic mixtures and their pharmaceutically acceptable salts.

Angiotensin II antagonist activity is assessed by in vitro methods. In vitro antagonist activity is determined by the ability of the compounds to compete with ¹²⁵I- angiotensin. II for binding to vascular angiotensin II receptors and by their ability to antagonize the contractile response to angiotensin II in the isolated rabbit aorta.

For the purposes of the present invention the preferred All antagonists are compounds which are capable of inhibiting the action of AII by at least 50% at a concentration of 1μM or less, and especially preferred AII antagonists are

compounds which are capable of inhibiting the action of All by at least 50% at a concentration of 25nM or less when tested by the following standard methods.

Binding

The radioligand binding assay is a modification of a method previously described in detail (Gunther et al., Circ. Res. 47:278, 1980). A particular fraction from rat

mesenteric arteries is incubated in Tris buffer with 80 pM of ¹²⁵I-angiotensin II with or without angiotensin II antagonists for 1 hour at 25°C. The incubation is

terminated by rapid filtration and receptor bound ¹²⁵I- angiotensin II trapped on the filter is quantitated with a gamma counter. The potency of angiotensin II antagonists is expressed as the IC₅₀ which is the concentration of

antagonist needed to displace 50% of the total specifically bound angiotensin II.

Aorta

The ability of the compounds to antagonize angiotensin II induced vasoconstriction is examined in the rabbit aorta. Ring segments are cut from the rabbit thoracic aorta and suspended in organ baths containing physiological salt solution. The ring segments are mounted over metal supports and attached to force displacement transducers which are connected to a recorder. Cumulative concentration response curves to angiotensin II are performed in the absence of antagonist or following a 30-minute incubation with

antagonist. Antagonist dissociation constants (K_B) are calculated by the dose ratio method using the mean effective concentrations.

The in vivo anxiolytic activity of the instant

compounds is evaluated in the mouse using the black-white aversion test [Costall, et al., Pharmacol, Biochem. Behav, 32:777(1989)]. This test is based on mouse aversion for a brightly lit white area when compound to a dimly lit dark area which is simultaneously available. Active compounds cause a statistically significant increase in the time spent in the white section and a correspondingly reduced period in the black area. This behavior is similar to that caused by diazepam and is consistent with other compounds having anxiolytic activity. In the therapeutic use for the treatment of anxiety the AII receptor antagonizing compounds of this invention are incorporated into standard pharmaceutical compositions.

They can be administered orally, parenterally, rectally, topically or transdermally.

The compounds of the instant invention and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.

A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example, polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.

A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.

A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example,

pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueious gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.

The compounds of the instant invention and their

pharmaceutically acceptable salts which are active when administered parenterally (i.e. by injection of infusion) can be formulated as solutions or suspensions. A composition for parenteral administration will generally consist of a solution or suspension of the active ingredient in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.

Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to

administration.

A typical suppository composition conprises a compound of the instant invention or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent such as polymeric glycols, gelatins or coca butter or other low melting vegetable or synthetic waxes or fats.

A typical transdermal formulation comprises a

conventional aqueous or non-aqueous vehicle, for example, a cream, ointment lotion or paste or in the form of a

medicated plaster, patch or membrane.

For topical administration, the pharmaceutical

compositions adapted include solutions, suspensions, ointments, and solid inserts. Typical pharmaceutically acceptable carriers are, for example, water, mixtures of water and water-miscible solvents such as lower alkanols or vegetable oils, and water soluble ophthalmologically acceptable non-toxic polymers, for example, cellulose derivatives such as methyl cellulose. The pharmaceutical preparation may also contain non-toxic auxiliary substances such as emulsifying, preserving, wetting, and bodying agents, as for example, polyethylene glycols; antibacterial components such as quaternary ammonium compounds; buffering ingredients such as alkali metal chloride; antioxidants such as sodium metabisulfite; and other conventional ingredients such as sorbitan monolaurate.

Preferably the composition is in unit dose form. Doses of the compounds of the instant invention in a pharmaceutical dosage unit will be an efficacious, non-toxic quantity selected from the range of .01 - 200 mg/kg of active compound, preferably .1 - 100 mg/kg. The selected dose is administered to a human patient in need of treatment of anxiety induced by angiotensin II from 1-6 times daily, orally, rectally, topically, by injection, or continuously by infusion. Oral dosage units for human administration preferably contain from 10 to 500 mg of active compound.

Lower dosages are used generally for parenteral

administration. Oral administration is used when safe, effective, and convenient for the patient.

The following examples are intended to illustrate, but not to limit, the present invention. Examples 1-4 describe how to make certain compounds encompassed by the generic formulae of (X) - (XI). The remaining examples are directed to pharmaceutical compositions of this invention. The compounds included in these disclosed compositions are representative of the AII receptor antagonists included within the scope of the instant invention.

The procedures of Examples 1-4 are illustrative of the synthesis of compounds encompassed by generic formulae (X) and (XI). Substitution of starting materials by the

appropriate known reagents yields additional compounds within the scope of formulae (X) and (XI) . Reagents,

protecting groups, and functionality on the imidazole and other fragments of the molecule must be consistent with the proposed chemical transformations. Example 1

(E) -3- [2-n-Butyl-1 - { (5-carboxy-2-thienyl ) methyl }-1H-imidazol-5-yl ] -2- (2-thienyl ) methyl-2-propenoic Acid (i) 2-n-butyl-1-pivalyloxymethylimidazol-5- carboxaldehyde

A mixture of valeramidine methylether hydrochloride (250 g, 1.66 mol) and dihydroxyacetone (150 g, 0.83 mol) dissolved in liquid ammonia was allowed to stand

overnight at room temperature in a pressure vessel, and then heated at 65°C for 4 hours at 375 psi. The ammonia was allowed to evaporate, and the residue was dissolved in methanol (3L). The resulting slurry was refluxed with acetonitrile (1L). The solution was decanted from the solid ammonium chloride while hot. This procedure was repeated, and the combined acetonitrile extracts were treated with charcoal, filtered hot and the filtrate was concentrated in vacuo to give the dark oil, 2-n-butyl-5- hydroxymethylimidazole (235 g, 1.63.mol, 98%).

The 5-hydroxymethylimidazole (16.92 g, 0.111 mol) was dissolved in one liter of methylene chloride. To this solution was added 45 grams of manganese dioxide. After stirring at room temperature for four hours, the solids were filtered off and the solvent was removed in vacuo. The crude 2-n-butyl-imidazol-5-carboxaldehyde was used without further purification (16.9 g).

A suspension of 2-butylimidazol-5-aldehyde (16.9 g, 0.111 mol), chloromethyl pivalate (21.77 g, 0.145 mol), and potassium carbonate (20.07 g, 0.145) in 200 ml of dimethylformamide was stirred at ambient temperature under argon for four days. The solids were removed by filteration and washed with ether. The combined

filtrates were partitioned between diethyl ether and water. The ether phase was washed successively with water and brine, dried over magnesium sulfate and

concentrated under vaccum to give 23.6 g of 2-n-butyl-1-pivalyloxymethylimidazol-5-carboxaldehyde. (ii) 5-bromomethyl-2-carbomethoxythiophene

A solution of 5-methyl-2-thiophene carboxylic acid (25 g, 0.176 mol) in 500 ml of methanol was saturated with gaseous hydrochloric acid at 0°C. The reaction mixture was stirred at room temperature for 18 hours and then refluxed for 48 hours. The solvent was removed in vacuo and the crude methyl 5-methyl-2-thiophene

carboxylate was used without further purification.

The methyl ester prepared above (11.07 g, 0.071 mol) was dissolved in 200 ml of carbon tetrachloride under argon. N-bromosuccinimide (13.25 g, 0.074 mol) and dibenzoyl peroxide were then added. The reaction mixture was refluxed for 2 hours and allowed to stand at room temperature for 18 hours. The solids were collected and the filtrate was concentrated in vacuo to give 19 g of 5- bromomethyl-2-carbomethoxythiophene.

(iii) 2-n-butyl-1-[(5-carbomethoxy-2-thienyl)- methyl]imidazol-5-carboxaldehyde

A mixture of 2-n-butyl-1-pivalyloxymethylimidazol-5- carboxaldehyde (5.0 g, 0.019 mol) and 5-bromomethyl-2- carbomethoxy thiophene (4.86 g, 0.021 mol) was heated to 100°C under argon for 18 hours. Repeated trituration with ether gave 9.4 g of a crystalline salt. A

suspension of this salt in 150 ml of ethyl acetate was stirred for 0.5 hours with 150 ml of 5% aqueous sodium carbonate. The layers were separated, the aqueous layer washed with ethyl acetate, and the combined organic layers washed with water, dried over magnesium sulfate and concentrated to give an oil. Chromatography of this oil over silica gel eluting with ethyl acetate/hexane (1:1) gave 0.62 g of 2-n-butyl-1-[(5-carbomethoxy-2- thienyl)methyl]imidazol-5-carboxaldehyde.

(iv) ethyl 2-carboxy-3-(2-thienyl)propionate The title compound was prepared by stirring a solution of diethyl 2-thienylmalonate (16.8 g, 0.0655 mol) and potassium hydroxide (4.41 g, 0.0786 mol) in 200 ml of ethanol under argon at room temperature for 12 days and then purifying by removing the solvent under vacuum, dissolving the residue in water, washing the aqueous layer with aqueous hydrochloric acid and extracting the product with diethyl ether. The solvent was removed in vacuo to give 14 g of theyl 2-carboxy-3-(2-thienyl)-propionate.

(v) ethyl (E)-3-[2-n-butyl-1-{(5-carbomethoxy-2- thienyl)methyl}-1H-imidazol-5-yl]-2-(2- thienyl)methyl-2-propenoate A mixture of 2-n-butyl-1-[(5-carbomethoxy-2-thienyl)methyl]imidazol-5-carboxaldehyde (0.5 g, 1.66 mmol), ethyl 2-carboxy-3-(2-thienyl)propionate (1.14 g, 4.99 mmol), piperidine (0.155 g, 1.83 mmol), 0.5 ml of pyridine in 50 ml of benzene were refluxed for 18 hours under argon in the presence of a Dean-Stark trap. The crude product was flash chromatographed over silica gel eluting with ethyl acetate/hexane (1:1) to give 0.474 g (49%) of ethyl (E)-3-[2-n-butyl-1-{(5-carbomethoxy-2-thienyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoate.

(vi) (E)-3-[2-n-butyl-1-{(5-carboxy-2- thienyl)methyl}-1H-imidazol-5-yl]-2-(2- thienyl)methyl-2-propenoic acid A solution of ethyl (E)-3-[2-n-butyl-1-{(5-carboxy- 2-thienyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl- 2-propenoate (474 mg, 1.0 mmol) in ethanol (10 ml) was treated with 10% potassium hydroxide solution (5 ml) and the solution was stirred for 18 hours at 25°C. The ethanol was removed in vacuo and the reaction mixture was partitioned between water and diethyl ether. The aqueous layer was washed with diethyl ether (3X) and then the pH was adjusted to 4.5 with aqueous hydrochloric acid solution. The solid was collected to provide 0.35 g of crude product. Crystallization from methanol gave 0.31 g (72%) of (E)-3-[2-n-butyl-1-{(5-carboxy-2- thienyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2- propenoic acid; mp 239-240°C (d).

Example 2

S- [ (2-n-Bnt yl-1 - { (4-carboxyphenyl ) methyl }-1H-imidazol -5- yl) methyl]-D , L-2-thio-3- (2-thienvl) -propionic Acid

(i) 2-Bromo-3-(2-thienyl)propionic Acid

Thienylalanine (17.1 g, 0.1 mol) was added to a solution of 40.2 g (0.34 mol) of potassium bromide in 200 ml of 2.5 N sulfuric acid. Solid sodium nitrite (10.5 g, 0.15 mol) was added in portions over 45 minutes to the solution which was held at 0-4°C. The reaction mixture was stirred at 0-4°C for 1 hour, and then stirred at 25°C for 2 hours. The mixture was extracted with ether and the ether extract was washed with water and brine. The organic extract was dried and concentrated. The residue was dissolved in 20 ml of ether and the solution diluted with petroleum ether to the cloud point and then stored at -20°C for 18 hours. The insolubles were, removed by filtration and the solution concentrated to give 20.5 g (87%) of the product as an oil. The product was used in the next step without further purification. (ii) 2-Mercapto-3-(2-thienyl)propionic Acid

A solution of 7.05 g (0.03 mol) of the bromo acid in 45 ml of dimethylformamide under argon was treated with 8.91 g (0.0315 mol) of the cesium salt of thiobenzoic acid (J. Org. Chem. 51, 3664). The mixture stirred for 18 hours at ambient temperature. The reaction mixture was diluted with 135 ml of ether and washed with water. The ether was dried and then concentrated to give 5.46 g (62%) of an oil whose NMR was consistent with that expected for the 2-benzoylthio product. This oil (3.0 g) was dissolved in 41 ml of 1N ammonia and stirred for 18 hours under argon. After filtration, the pH was adjusted to 1 with 10% hydrochloric acid. The reaction mixture was extracted with ether and the ether extract was washed with water, dried with sodium sulfate, and concentrated to give the product as an oil.

(iii) 2-n-Bntyl-5-hydroxymethylimidazole A mixture of valeramidine methyl ether hydrochloride (250 g, 1.66 mol) and dihydroxyacetone (150 g, 0.83 mol) dissolved in liquid ammonia was allowed to stand

overnight at room temperature in a pressure vessel, and then heated at 65°C for 4 hours at 375 psi. The ammonia was allowed to evaporate, and the residue was dissolved in methanol (3L). The resulting slurry was refluxed with added acetonitrile (1L). The solution was decanted from the solid ammonium chloride while hot. This

procedure was repeated, and the combined acetonitrile extracts were treated with charcoal, filtered hot and the filtrate was concentrated in vacuum to give the dark oil, 2-n-butyl-5-hydroxy-methylimidazole (253 g, 1.63 mol, 98%). (iv) 2-n-Butyl-4-chloro-5-hydroxymethylimidazole

N-Chlorosuccinimide (54.68 g, 0.405 mol) was added in small portions over 15 minutes to a stirred solution of 2-n-butyl-5-hydroxymethylimidazole (50.00 g, 0.324 mol) in a mixture of 580 ml of tetrahydrofuran and 500 ml of 2-methoxyethanol heated in an oil bath at 40-50°C under argon. After 2.5 h the mixture was evaporated to dryness. The residue was suspended in 400 ml of water, stirred at 25°C for 1 h. A tan solid was collected by filtration, washed with water and air dried to give 51.95 g of a mixture consisting of 2-butyl-4-chloro-5- hydroxymethylimidazole and 2-butyl-4,5-dichloroimidazole. The dry powder was suspended in 150 ml of ether, stirred for 1 h at room temperature and then filtered to give 29.91 g (49%) of 2-n-butyl-4-chloro-5- hydroymethylimidazole; mp 150-153°C.

(v) 2-n-Butyl-4-chloro-5-imidazolecarboxaldehyde A stirred mixture of 2-n-butyl-4-chloro-5-hydroxymethylimidazole (15.00 g, 0.0795 mol) and

activated manganese dioxide (40.00 g) in 600 ml of

methylene chloride was refluxed for 24 h using a water separator. The mixture was filtered hot through a

Celite^® pad. The Celite^® pad was washed several times with hot methylene chloride. The washings were combined with the filtrate and concentrated in vacuo to give 12.81 g (86%) of the aldehyde as a white solid; mp 97-98°C. (vi) 2-n-Bυtyl-1-[(4-carbomethoxybiphenyl-5-yl)methyl]-4- chloro-5-imidazolecarboxaldehyde

A mixture of 2-n-butyl-4-chloro-5-imidazolecarboxaldehyde (2.46 g, 0.0132 mol) and anhydrous

potassium carbonate (2.73 g, 0.0198 mol) in 25 ml of dimethylformamide was stirred for 15 minutes at 25°C, then a solution of methyl 5-bromomethylphenyl-4- carboxylate (5.63 g, 0.0185 mol) in 5 ml of dimethylformamide was added all at once (rinsed in with 2×5 ml dimethylformamide). The mixture was heated in an oil bath at 105°C for 20 minutes under argon, cooled, and then filtered. The filter cake was washed with ether and combined with the filtrate. The combined organics were washed with four 50 ml portions of water and then brine. The dried (sodium sulfate) filtrate was evaporated in vacuo to give a syrup (6.97 g). The crude product was flash chromatographed [silica gel 60, 230-400 mesh, 776 g, column 9.5 cm O.D., 9:1 cyclohexane/ethyl acetate (2L) to 8:2 cyclohexane/ethyl acetate] to give 4.34 g (80%) of product as a syrup.

(vii) 2-n-Bυtyl-1-[(4-carbomethoxyphenynl)methyl]-5- imidazolecarboxaldehyde

A solution of 2-n-butyl-1-[(2-carbomethoxyphenyl)-methyl]-4-chloro-5-imidazolecarboxaldehyde (3.05 g,

0.00742 mol), anhydrous potassium acetate (0.66 g,

0.00742 mol) and 10% palladium on carbon (0.73 g) in 100 ml of methanol was hydrogenated at 35 psi for 45 minutes on a Parr shaker. The mixture was filtered through a Celite^® pad. The Celite^® pad was washed several times with methanol and the combined filtrates evaporated in vacuo to a syrup. The residue was partitioned in an ether/water mixture. The aqueous phase was adjusted to pH 8 with 5% aqueous sodium carbonate, extracted with ether, and the combined ether extracts were washed with water and brine. The dried (sodium sulfate) solution was evaporated to a syrup (2.72 g) consisting mostly of product and some alcohol.

The syrup was dissolved in 50 ml of methylene chloride, 2.5 g of activated manganese dioxide was added and mixture was refluxed for 3 h. The mixture was filtered through a Celite^® pad, the Celite^® pad washed several times with methylene chloride and the combined filtrates evaporated in vacuo to give 2.64 g (95%) of product, as a syrup. (viii) 2-n-Butyl-1-[(4-carbomethoxyphenyl)methyl]-5- chloromethyl-1H-imidazole

Method 1

2-n-Butyl-1-[(4-carbomethoxyphenyl)methyl]-1-H- imidazole-5-carboxaldehyde (6.07 g, 0.202 mol) dissolved in 50 ml of methanol was treated portionwise. with 0.483 g (0.0128 mol) of sodium borohydride. After several

minutes the pH of the mixture was brought to 7 with 10% hydrochloric acid. The mixture was concentrated under vacuum and water was added. The resulting crystals were collected by filtration, washed with water, and dried to give 5.90 g (97%) of the corresponding alcohol; mp 141-143°C. Method 7

2-n-Butyl-5-hydroxymethylimidazole (253 g) was treated with acetic anhydride (400 mL) at -15°C and then was allowed to warm to ambient temperature with stirring, and then stirred an additional 19 hours. The acetic anhydride was evaporated at reduced pressure, the residue taken up in methylene chloride, and the organic phase was washed with 5% sodium bicarbonate solution and water. The extract was dried over sodium sulfate and

concentrated to give 323 g (83%) of 1-acetyl-4- acetoxymethyl-2-n-butylimidazole.

This diacetate was N-alkylated by the following procedure. To a solution of triflic anhydride (120 mL, 0.71 mol) in methylene chloride (200 mL) at -78°C under argon was added a solution of diisopropyl ethylamine (128 mL, 0.73 mol) and 4-carbomethoxy alcohol (0.72 mol) in methylene chloride (350 mL) over a period of 20 minutes. After being stirred an additional 20 minutes at -78°C, this solution is then treated with 1-acetyl-4- acetoxymethyl-2-n-butylimidazole (146 g, 0.61 mol) dissolved in methylene chloride (300 mL) over a 20 minute interval. The mixture is then stirred at ambient

temperature for 18 hours and the solvents are evaporated. The residual 2-n-butyl-5-acetoxymethyl-1-(4- carbomethoxyphenyl)methyl-1H-imidazole is used without purification for the hydrolysis of the acetate group.

A crude 2-n-butyl-5-acetoxymethyl-1-(4-carboxymethoxy-phenyl)methyl-1H-imidazole is stirred in

methanol. After cooling, the methanol is removed in vacuo, methylene chloride is added, and the organic extract is washed with water, dried and concentrated to give 2-n-butyl-1-(4-carbomethoxyphenyl)-methyl-5-hydroxymethyl-1H-imidazole.

Thionyl chloride (7.5 ml) was added to 1.51 g

(0.00499 mol) of the alcohol and the mixture was heated on a steam bath for 45 minutes. Concentration under vacuum gave a syrup which was treated with 30 ml of ether. The ether then removed under vacuum. Repetition of the ether-evaporation cycle twice gave a solid which was taken up in 10 ml of methylene chloride and the solution added to ether to give 1.76 g (99%) of the chloromethyl imidazole hydrochloride; mp 151-153°C.

(ix) S-[(2-butyl-1-{(4-carbomethoxyphenγl)methyl}-1H- imidazol-5-yl)methyl]-D, L-2-thio-3-(2- thienyl)propionic Acid

A solution of 1.50 g (4.2 mmol) of the 5-chloromethylimidazole hydrochloride, 0.99 g (5.2 mmol) of 2- mercapto-3-(2-thienyl)propionic acid, and 4 ml of triethylamine in 10 ml of dimethylformamide was stirred at ambient temperature for 18 hours. The reaction mixture was diluted with water and extracted with ether. The aqueous layer was extracted with ethyl acetate, the ethyl acetate and then organic extract was dried over magnesium sulfate and concentrated. The residue was chromatographed (reverse phase C18 silica, 70% methanolwater) to give 0.355 g of an oil which was dissolved in 5% sodium bicarbonate. The aqueous layer was washed with ether and then the pH was adjusted to 4 with dilute hydrochloric acid. The product was extracted into ethyl acetate. The organic extract was dried over magnesium sulfate and concentrated to give 0.265 g of the title compound isolated as an oil.

(x) S-[(2-n-Bntyl-1-{(4-carboxyphenyl)methyl}-1H- imidazol-5-yl)methyl]-D,L-2-thio-3-(2- thienyl)propionic Acid The mono-acid compound hydrolyzed by stirring with 0.9 g of potassium hydroxide in a mixture of 4 ml of ethanol and 3 ml of water at 25°C for 18 h. The

hydrolysis mixture was evaporated to dryness, the residue was dissolved in water and the solution was extracted with ether. The orgainc extract was made acidic and the resulting solid was collected and washed with water to give a yellow solid; Anal. Caldc. for C₂₃H₂₅N₂O₄S·½H₂O: C, 59.08; H, 5.82; N, 6.00. Found: C, 59.02; H, 5.67; N, 5.92.

Example 3

S-[(2-n-Butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5- yl)methyl]thiosalicyclic Acid Following the procedure of Example 2 replacing 2- mercapto-3-(2-thienyl)propionic acid with methyl 2- mercaptobenzoate, S-[(2-n-butyl-1-{(4-carboxyphenyl)- methyl}-2-butyl-1H-imidazol-5-yl)methyl]thiosalicyclic acid was prepared; shrinks at 90°C.

Example 4

S-[(2-n-Butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5- yl)methyl]-2-mercaptonicotinic Acid

Following the procedure of Example 2 replacing 2-mercapto-3-(2-thienyl)propionic acid with methyl 2-mercaptonicotinate S-[(2-n-butyl-1-{(4-carboxyphenyl)-methyl}-1H-imidazol-5-yl)methyl]-2-mercaptonicotinic acid was prepared; mp 155-157°C.

Example 5

An oral dosage form for administering orally active formulae (I) - (XI) compounds is produced by screening, mixing and filling into hard gelatin capsules the

ingredients in proportions, for example, as shown below. Ingredients Amounts

(E)-3-[2-n-butyl-1-{(4-carboxy100 mg

phenyl)methyl}-1H-imidazol-5-yl]- 2-(2-thienyl)methyl-2-propenoic

acid methanesulfonate

magnesium stearate 10 mg

lactose 100 mg

Example 6

The sucrose calcium sulfate dihydrate and orally active formulae (I) - (XI) compounds are mixed and granulated with a 10% gelatin solution. The wet granules are screened, dried, mixed with the starch, talc and stearic acid, screened and compressed into a tablet.

Ingredients Amounts

(E)-3-[2-n-butyl-1-{(4-carboxy75 mg

chlorophenyl)methyl}-1H-imidazol- 5-yl]-2-(2-thienyl)methyl-2- propenoic acid

calcium sulfate dihydrate 100 mg

sucrose 15 mg

starch 8 mg

talc 4 mg

stearic acid 2 mg

Example 7

(E)-3-[2-n-Butyl-1-{(4-carboxynaphth-1-yl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid, 50 mg, is dispersed in 25 ml of normal saline to prepare an

injectable preparation.

It is to be understood that the invention is not limited to the embodiments illustrated hereabove and the right to the illustrated embodiments and all modifications coming within the scope of the following claims is reserved.

Claims

What is claimed is:

1. A method of treating anxiety which comprises administering to a subject in need thereof an effective amount of an angiotensin II antagonist of the formulae (I) (IX) :

Substituted imidazoles of the formula (I):

in which:

R¹ is adamantyl, phenyl, biphenyl, or naphthyl, with each aryl group being unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C₁-C₆-alkyl, nitro, A-CO₂R ⁷, tetrazol-5-yl, C₁-C₆alkoxy, hydroxy,

SC₁-C₆alkyl, SO₂NHR⁷, NHSO₂R⁷, SO₃H, CONR⁷R⁷, CN,

SO₂C₁ -C₆alkyl, NHSO₂R⁷, PO(OR⁷)₂, NR⁷R⁷, NR⁷COH,

NR⁷COC₁-C₆alkyl, NR⁷CON(R⁷)₂, NR⁷COW, W, SO₂W;

m is 0-4;

2

R is C₂-C₁₀alkyl, C₃-C₁₀alkenyl, C₃-C₁₀alkynyl,

C₃-C₈cycloalkyl, or (CH₂)_0-8phenyl unsubstituted or

substituted by one to three substituents selected from

C₁-C₆alkyl, nitro' Cl, Br, Ε, I, hydroxy, C₁-C₆alkoxy,

NR⁷R⁷, CO₂R⁷, CN, CONR⁷R⁷, W, tetrazol-5-yl,

NR⁷COC₁-C₆alkyl, NR⁷COW, SC₁-C₆alkyl, SO₂W, or SO₂C₁-C₈alkyl;

X is a single bond, S, NR , or 0;

3

R is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl,

COOR⁷, CONR⁷R⁷, NO₂, W, CN, NR⁷R⁷, or phenyl;

R ⁴ and R⁵ are independently hydrogen, C₁-C₆alkyl, thienyl-Y-, furyl-Y-, pyrazolyl-Y-, imidazolyl-Y-, pyrrolyl- Y-, triazolyl-Y-, oxazolyl-Y-, isoxazolyl-Y-, thiazolyl-Y-, pyridyl-Y-, or tetrazolyl-Y-, except that R ⁴ and R5 are not both selected from hydrogen and C₁-C₆alkyl and each

heterocyclic ring is unsubstituted or substituted by

C₁-C₆alkyl, C₁-C₆alkoxy, Cl, Br, F, I, NR⁷R⁷, CO₂R⁷,

SO₂NHR⁷, SO₃H, or CONR⁷R⁷, CH, NO₂, W, SO₂W, SC₁-C₆alkyl,

SO₂C₁-C₆alkyl, NR⁷COH, NR⁷COW, or NR⁷COC₁-C₆alkyl;

Y is a single bond, O, S, or C₁-C₆alkyl which is straight or branched or optionally substituted by phenyl or benzyl, wherein each of the aryl groups is unsubstituted or substituted by halo, NO₂, CF₃, C₁-C₆alkyl, C₁-C₆alkoxy, CN, or CO₂R⁷;

R⁶ is -Z-COOR⁸ or -Z-CONR⁷R⁷;

Z is a single bond, vinyl, -CH₂-O-CH₂-, methylene optionally substituted by C ₁-C₆alkyl, one or two benz-yl groups, thienylmethyl, or furylmethyl, or -C(O)NHCHR⁹-, wherein R⁹ is H, C₁-C₆alkyl, phenyl, benzyl, thienylmethyl, or furylmethyl;

W is C_nF_2n+1;

A is -(CH₂)_q-, -CH=CH-, -O(CH₂)_n-, or -S(CH₂)_n-;

each R⁷ independently is hydrogen, C₁-C₆alkyl, or

(CH₂) phenyl;

each n independently is 1-3;

each q independently is 0-4; and

p

R is hydrogen, C₁-C₆alkyl, or 2-di (C₁-C₆alkyl)-amino-2-oxoethyl; or a pharmaceutically acceptable salt thereof or Substituted imidazoles of the formula (II):

in which:

R¹ is adamantyl, phenyl, biphenyl, or naphthyl, with each aryl group being unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I,

C₁-C₆alkyl, nitro, A-CO₂R⁷, tetrazol-5-yl, C₁-C₆alkoxy, hydroxy, SC₁-C₆alkyl, SO₂NHR⁷, NHSO₂R⁷, SO₃H, CONR⁷R⁷, CN, SO₂C₁-C₆alkyl, NHSO₂R⁷, PO(OR⁷)₂, NR⁷R⁷, NR⁷COH,

NR⁷COC₁-C₆alkyl, NR⁷CON(R⁷)₂, NR⁷COW, W, SO₂W;

m is 0-4;

R² is C₂-C₁₀alkyl, C₃-C₁₀alkenyl, C₃-C₁₀alkynyl,

C₃-C₈cycloalkyl, or (CH₂)_0-8phenyl unsubstituted or substituted by one to three substituents selected from C₁-C₆alkyl, nitro, Cl, Br, F, I, hydroxy, C₁-C₆alkoxy,

NR⁷R⁷, CO₂R⁷, CN, CONR⁷R⁷, W, tetrazol-5-yl,

NR⁷COC₁-C₆alkyl, NR⁷COW, SC₁-C₆alkyl, SO₂W, or

SO₂C₁-C₆alkyl;

X is a single bond, S, NR⁷, or O;

R³ is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl,

COOR⁷, CONR⁷R⁷, NO-, W, CN, NR⁷R⁷, or phenyl;

R ⁴ and R⁵ are independently hydrogen, C₁-C₆alkyl, phenyl-Y-, naphthyl-Y-, or biphenyl-Y-, wherein the aryl groups are unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C₁-C₆alkoxy, hydroxy, CO₂R⁷, CN, NO₂, tetrazol-5-yl, SO.-H, CF₃,

CONR⁷R⁷, SO₂NHR⁷, C₁-C₆alkyl, or NR⁷R⁷, or by

methylenedioxy, phenoxy or phenyl, except that R ⁴ and R⁵ are not both selected from hydrogen;

Y is a single bond, 0, S, or C₁-C₆alkyl which is straight or branched or optionally substituted by phenyl or benzyl, wherein each of the aryl groups is

unsubstituted or substituted by halo, NO₂, CF₃,

C₁-C₄alkyl, C₁-C₄alkoxy, CN, or CO₂R⁷;

R⁶ is -Z-COOR⁸ or -Z-CONR⁷R⁷;

Z is a single bond, vinyl, -CH₂-O-CH₂-, methylene optionally substituted by C₁-C₄alkyl, one or two benzyl groups, thienylmethyl, or furylmethyl, or -C(O)NHCHR ⁹-, wherein R⁹ is H, C₁-C₄alkyl, phenyl, benzyl, thienylmethyl, or furylmethyl;

W is C_nF_2n+1;

A is -(CH₂)_q-, -CH=CH, -0(CH₂)_n-, or -S(CH₂)_n-;

each R⁷ independently is hydrogen, C₁-C₄alkyl, or

(CH₂)_qphenyl;

each n independently is 1-3;

each q independently is 0-4; and

R⁸ is hydrogen, C₁-C₆alkyl, or 2-di(C₁-C₆alkyl)-amino-2-oxoethyl; or

R⁵ and R⁶ are both hydrogen, R⁴ is -Z-COOR⁸ and Z is other than a single bond; or a pharmaceutically

acceptable salt thereof, or Substituted imidazoles of the formula (III):

in which:

R¹ is adamantyl, or phenyl, biphenyl, or naphthyl, with each aryl group being unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C₁-C₆alkyl, nitro, CO₂R⁷, C₁-C₆alkoxy, hydroxy, SC₁-C₆alkyl,

SO₂C₁-C₆alkyl, tetrazol-5-yl, SO₂NHR⁷, NHSO₂R⁷,

SO₃H, PO(OR⁷)₂, CONR⁷R⁷, CN, NR⁷R^?, NR⁷COH, NR⁷COC₁-C₆alkyl,

NR⁷CON(R⁷)₂, NR⁷COW, SO₂W, or W;

R is C₁-C₁₀alkyl, C₃-C₁₀alkenyl, (CH₂)_0-8-C_{3- 6}cycloalkyl, or (CH₂)_0-8Phenyl unsubstituted or substituted by one to three substituents selected from C₁-C₆alkyl, nitro, Cl, Br, F, I, hydroxy, C₁-C₆alkoxy, NR⁷R⁷, CO₂R⁷, CN,

CONR⁷R⁷, W, NR⁷COH, NR⁷COC₁-Cgalkyl, NR⁷COW, SO₂W, SO₂C₁- C₆alkyl, or SC₁-C₆alkyl;

X is a single bond, S, or O;

m is 0-4;

R³ is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl,

C₁-C₆alkyl, NR⁷R⁷, CO₂R⁷, CONR⁷R⁷, NO₂, CN, phenyl, or W;

R⁴ and R⁵ are each independently hydrogen, C₁-C₆alkyl, C₃-C₆Cycloalkyl, thienyl-Y-, furyl-Y-, pyrazolyl-Y-,

imidazolyl-Y-, thiazolyl-Y-, pyridyl-Y-, tetrazolyl-Y-, pyrrolyl-Y-, triazolyl-Y-, oxazolyl-Y-, isoxazolyl-Y-, or phenyl-Y-, with each aryl or heteroaryl group being

unsubstituted or substituted by C₁-C₆alkyl, C₁-C₆alkoxy, Cl, Br, F, I, NR⁷R⁷, CO₂R⁷, SO₂NHR⁷, SO₃H, OH, NO₂, CONR⁷R⁷, W, SO₂C₁-C₆alkyl, SO₂W, SC₁-C₆alkyl, NR⁷COH, NR⁷COW, or

NR⁷COC₁-C₆alkyl;

Y is C₁-C₆alkyl which is straight or branched or a single bond;

R⁶ is Z-tetrazol-5-yl;

Z is a single bond, vinyl, or methylene unsubstituted or substituted by C₁-C₄alkyl, one or two benzyl groups, thienylmethyl, or furylmethyl;

W is C_nF_2n+1, wherein n is 1-4; and each R⁷ independently is hydrogen or C₁-C₆alkyl;

or a pharmaceutically acceptable salt thereof, or

Substituted imidazoles of the formula (IV):

in which:

R is adamantyl, or phenyl, biphenyl, or naphthyl, with each aryl group being unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C₁-C₆alkyl, nitro, CO₂R⁷, C₁-C₆alkoxy, hydroxy, SC₁-C₆alkyl,

SO₂C₁-C₆alkyl, tetrazol-5-yl, SO-NHR⁷, NHSO₂R⁷, SO₃H,

PO(OR⁷)₂, CONR⁷R⁷, CN, NR⁷R⁷, NR⁷COH, NR⁷COC₁-C₆alkyl,

NR⁷CON(R⁷)₂, NR⁷COW, SO₂W, or W;

R¹ is C₂-C₁₀alkyl, C₃-C₁₀alkenyl, (CH₂)_{0- 8}C_3-6cycloalkyl, or (CH₂)_0-8phenyl unsubstituted or

substituted by one to three substituents selected from

C₁-C₆alkyl, nitro, Cl, Br, F, I, hydroxy, C₁-C₆alkoxy,

NR⁷R⁷, CO₂R⁷, CN, CONR⁷R⁷, W, NR⁷COH, NR⁷COC₁-C₆alkyl,

NR⁷COW, SC₁-C₆alkyl, SO₂C₁-C₆alkyl, or SO₂W;

R² is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl,

C₁-C₆alkyl, NR⁷R⁷, CO₂R⁷, CONR⁷R⁷, NO₂, CN, phenyl, or W;

X is a single bond, S, or 0;

₃

R is H, C_1-6alkyl, C_3-6alkenyl, COC_1-5alkyl, or

(CH₂)_0-3phenyl;

R⁴ is H, C_1-6alkyl, C_3-6alkenyl, or (CH₂)_0-3-phenyl;

R⁵ is CO₂R⁷, CONR⁷R⁷, or tetrazol-5-yl;

each n independently is 0-4;

R⁶ is phenyl, naphthyl, 2- or 3-thienyl, 2- or 3-furyl, 2-, 3-, or 4-pyridyl, pyrimidyl, imidazolyl, thiazolyl, triazolyl, triazolyl, tetrazolyl, pyrazolyl, pyrrolyl, oxazolyl, or isoxazolyl, with each aryl or heteroaryl group being unsubstituted or substituted by C_1-6alkyl, C_1-6alkoxy, Cl, Br, F, I, NR⁷R⁷, CO₂R⁷, CONR⁷R⁷, SO,H, SO₂NHR⁷, OH, NO₂ W, SO₂C₁-C₆alkyl, SO₂W, SC₁-C₆alkyl, NR⁷COH, NR⁷COW, or NR⁷COC₁-C₆alkyl;

W is C_mF_2m+1, wherein m is 1-4; and

each R⁷ independently is H or C_1-6alkyl;

or a pharmaceutically acceptable salt thereof, or

Substituted imidazoles of the formula (V):

in which:

R is adamantyl, or naphthyl, biphenyl, or phenyl, with each aryl group being unsubstituted or substituted by one to three substituents selected from halo, C_1-6alkyl,

C_1-6alkoxy, OH, CN, CO₂R ³, tetrazol-5-yl, SO₃H, SO₂NHR³, NO₂, W, SC_1-6alkyl, SO₂C_1-6alkyl, NHSO₂R³, PO(OR³)₂,

CONR³R³, NR³R³, NR³COH, NR³COC_1-6alkyl, NR³CON(R³)₂, NR³COW, or SO₂W;

R¹ is C_2-10alkyl, C_3-10alkenyl, (CH₂)_0-8C_3-6cycloalkyl, or (CH₂)_0-8phenyl unsubstituted or substituted by one to three substituents selected from C_1-6alkyl, C_1-6alkoxy, halo, OH, NO₂, NR³R³, W, CO₂R⁷, CN, CONR³R³, NR³COH,

tetrazol-5-yl, NR³COC_1-6alkyl, NR³COW, SC_1-6alkyl, SO₂W, or

SO₂C_1-6alkyl;

X is a single bond, S, NR³, or O; m is 0-4;

R² is H, C_1-6alkyl, halo, W, CHO, CH₂OH, CO₂R³,

CONR³R³, NO₂, CN, NR³R³, or phenyl;

each R independently is H or C, galkyl;

R⁴ is H, C_1-8alkyl, thienyl-Y-, furyl-Y-, pyrazolyl-Y-, imidazolyl-Y-, thiazolyl-Y-, pyridyl-Y-, tetrazolyl-Y-, pyrrolyl-Y-, triazolyl-Y-, oxazolyl-Y-, isoxazolyl-Y-, or phenyl-Y-, with each aryl or heteroaryl group being

unsubstituted or substituted by C_1-6alkyl, C_1-6alkoxy, halo, NR³R³, CO₂R³, OH, NO₂, SO₂NHR³, SO₃H, CONR³R , W, SO₂W, SC_{1- 6}alkyl, SO₂C_1-6alkyl, NR³COH, NR³COW, or NR⁷COC_1-6alkyl;

R⁵ is CO₂R³, CONR³R³, or tetrazol-5-yl;

W is C_qF_2q+1, wherein q is 1-4;

Y is a single bond or C1-6alkyl which is straight or branched; and

n is 0-5; or a pharmaceutically acceptable salt

thereof, or

Substituted imidazoles of the formula (VI):

in which:

R¹ is adamantyl, or phenyl, biphenyl, or naphthyl, with each aryl group being unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I,

C₁-C₆alkyl, nitro, CO₂R⁷, tetrazol-5-yl, C₁-C₆alkoxy, hydroxy, SC₁-C₆alkyl, SO₂NR⁷R⁷, NHSO₂R⁷, SO₃H, CONR⁷R⁷, CN, SO₂C₁-C₆alkyl, or C_nF_2n+1; R is C₂-C₁₀alkyl unsubstituted or substituted by

CO₂H, OH, or NR R⁷, C₃-C₁₀alkenyl, C₃-C₁₀alkynyl,

C₃-C₆cycloalkyl, or (CH₂)_0-8phenyl unsubstituted or

substituted by one to three substituents selected from C₁-C₆alkyl, nitro, Cl, Br, F, I, hydroxy, C₁ -C₆alkoxy,

NR⁷R⁷, CO₂R⁷, CN, or CONR⁷R⁷;

X is a single bond, S, or O;

R³ is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl,

COOR⁷, CONR⁷R⁷, NO₂, or C_nF_2n+1;

each n is 1-3;

m is 0-4;

R⁴ is CO₂R⁷, CONR⁷R⁷, or tetrazol-5-yl;

Y is a single bond or a carbonyl group;

R⁵ is hydrogen, C₁-C₆alkyl, C₃-C₆Cycloalkyl,

(CH₂) _0-4phenyl, or (CH₂) _0-3CH-diphenyl wherein each phenyl group independently is unsubstituted or substituted by one to three substituents selected from C₁-C₆alkyl, nitro, Cl,

Br, F, I, hydroxy, C₁-C₆alkyl, NR⁷R⁷, CO₂R⁷,or CONR⁷R⁷;

R is hydrogen or C. galkyl; and

each R independently is hydrogen, C₁-C₄alkyl, or

(CH₂)_0-4phenyl; or a pharmaceutically acceptable salt thereof, or

Substituted imidazoles of the formula (VII):

in which:

R is adamanfeylmethyl, or phenyl, biphenyl, or naphthyl. with each aryl group being unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I,

C_1-6alkyl, nitro, CO₂R⁸, tetrazol-5-yl, C_1-6alkoxy, hydroxy,

SC_1-4alkyl, SO2NHR⁸, NHSO₂R⁸, SO₃H, CONR⁸R⁸, CN,

SO₂C_1-4alkyl, or C_nF_2n+1, wherein n is 1-3;

R² is C_2-10alkyl, C_3-10alkenyl, C_3-10alkynyl,

C_3-6cycloalkyl, or (CH₂)_0-8-phenyl unsubstituted or

substituted by one to three substituents selected from

C_1-6alkyl, nitro, Cl, Br, F, I, hydroxy, C_1-6alkoxy, NR⁸R⁸, CO₂R⁸, CN, or CONR⁸R⁸;

X is a single bond, S, or O;

R³ is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl, CO₂R⁷,

CONR⁸R⁸, NO₂, or C_nF_2n+1, wherein n is 1-3;

q is 0 to 4;

m is 0 to 2;

R⁴ is H or C_1-6alkyl;

z is 0 to 1;

R⁵ is C_3-6alkyl, C_3-6alkenyl, phenyl-Y-, 2- or 3-thienyl-Y-, 2- or 3-furyl-Y-, 2-, 3-, or 4-pyridyl-Y-, tetrazolyl-Y-, triazolyl-Y-, imidazolyl-Y-, pyrazolyl-Y-, thiazolyl-Y-, pyrrolyl-Y-, or oxazolyl-Y-, with each aryl ring being unsubstitued or substi-tued by C_1-6alkyl, Cl, Br, F, I, C_1-6alkoxy, NR⁸R⁸, CO₂R⁸, or CONR⁸R⁸;

Y is a single bond or C_1-6alkyl which is branched or unbranched;

R⁶ is CO₂R⁸, CONR⁸R⁸, or tetrazol-5-yl;

R ⁷ is H, CO₂R⁸, or C_1-6alkyl; and

each R ⁸ independently is hydrogen, C_1-6alkyl, or

(CH₂)_0-4phenyl;

or a pharmaceutically acceptable salt thereof, or Substituted imidazoles of the formula (VIII):

in which:

R¹ is adamantylmethyl, or phenyl, biphenyl, or

naphthyl, with each aryl group being unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C₁-C₆alkyl, nitro, CO₂R⁵ C₁-C₆alkoxy, hydroxy, SC₁-C₆alkyl, SO₂C₁-C₆alkyl, tetrazol-5-yl, SO₂NHR⁵, NHSO₂R⁵ SO₃H, PO(OR⁵)₂ CONR⁵R⁵ CN, NR⁵R⁵, NR⁵COH, NR⁵COC₁-C₆alkyl, NR⁵CON(R⁵)₂, NR⁵COW, SO₂W, or W;

R² is C₂-C₁₀alkyl, C₃-C₁₀alkenyl, (CH₂)_0-8-

C₃-C₆cycloalkyl, or (CH₂)_o-8phenyl unsubstituted or

substituted by one to three substituents selected from

C₁-C₆alkyl, nitro, Cl, Br, F, I, hydroxy, C₁-C₆alkoxy, tetrazol-5-yl, NR⁵R⁵, CO₂R⁵, CN, CONR⁵R⁵, W, NR⁵COH,

NR⁵COC₁-C₆-alkyl, NR⁵COW, SO₂W, SO₂C₁-C₆alkyl, or

SC₁-C₆alkyl;

X is a single bond, S, NR⁵, or O;

n is 0-4;

R³ is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl,

C₁-C₆alkyl, NR⁵R⁵, CO₂R⁵, CONR⁵R⁵, NO₂, CN, phenyl, or W;

R ⁴ is CO₂R⁵, CONR⁵R⁵, or tetrazol-5-yl;

Z is hydrogen, Cl, Br, F, I, C₁-C₆alkyl, C₁-C₆alkoxy, hydroxy, CN, NO₂, CO₂R⁵, COR⁵R⁵, W, phenyl-Y-, naphthyl-Y-, thienyl-Y-, furyl-Y-, pyrozolyl-Y-, imidazolyl-Y-, thiazolyl-Y-, triazolyl-Y-, tetrazolyl-Y-, pyrrolyl-Y-, triazolyl-Y-, oxazolyl-Y-, or isoxazolyl-Y-, with each aryl or heteroaryl group being unsubstituted or substituted by C₁-C₆alkyl, C₁-C₆alkoxy, Cl, Br, F, I, CO₂R⁵, hydroxy, NO₂, CN, CONR⁵R⁵, or W;

Y is a single bond or C₁-C₆alkyl, which is straight or branched;

W is C_mF_2m+1, wherein m is 1-4,; and

each R5 independently is H or C₁-C₆alkyl; or a

pharmaceutically acceptable salt thereof, or

Substituted benzimidazoles of the formula (IX):

in which:

R¹ is -C(O)NH-CH(Y)-(CH₂)_n-aryl, -C(O)NH-CH(Y)- (CH₂)_n-heteroaryl, or phenyl unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I,

C_1-6alkyl,

C_1-6alkoxy, OH, CN, NO₂, CO₂R⁴, tetrazol-5-yl, CONR⁴R⁴,

SO₃H, C_mF_2m+1, SC_1-6alkyl, or SO₂C_1-6alkyl;

R² is hydrogen, C_2-10alkyl, C_3-10alkenyl, C_3-6-cycloalkyl, C_mF_2m+1 , or (CH₂) _0-8Phenyl unsubstituted or substituted by one to three substituents selected from

C_1-6alkyl, C_1-6alkoxy, Cl, Br, F, I, OH, NO₂, C_mF_2m+1,

CO₂R⁴, or NR⁴R⁴;

R³ is -(CH₂)_n-Y, -CH=CY-(CH₂)_n-aryl, -CH=CY-(CH₂)_n- heteroaryl, -(CH₂)_n-C(O)-NH-CH(Y)-(CH₂)_n-aryl, -(CH)₂)_n- C(O)-NH-CH(Y)-(CH₂)_nheteroaryl, -(CH₂)_m-NH-CH(Y)-(CH₂)_n- aryl or -(CH₂)_m-NH-CH(Y)-(CH₂)_n-heteroaryl, when R¹ is an optionally substituted phenyl group; or H when R¹ is

-C(O)NH-CH(Y)-(CH₂) -aryl or -C(O)NH-CH(Y)-(CH₂)_n- heteroaryl;

Y is CO₂R⁴ or tetrazol-5-yl;

X is Cl, Br, F, I, C_mF_2m+1, C_1-6alkyl, C_1-6alkoxy,

OH, O-phenyl, CO₂R⁴, tetrazol-5-yl, CN, or (CH₂)_0-4phenyl unsubstituted or substituted by Cl, Br, F, I, C_1-6alkyl,

C_1-6alkoxy, OH, C_mF_2m+1, CN, CO₂R⁴, NO₂, or NR⁴R⁴;

aryl is phenyl, biphenyl, or naphthyl wherein each aryl group is unsubstituted or substituted by C_1-6alkyl,

Cj-galkoxy, Cl, Br, F, I, OH, NO₂, CF₃, CO₂R⁴, or NR⁴R⁴; heteroaryl is 2- or 3-thienyl, 2-, or 3-furanyl, 2-,

3-, or 4- pyridyl, pyrimidyl, imidazolyl, thiazolyl, triazolyl, or tetrazolyl wherein each heteroaryl group is unsubstituted or substituted by C_1-6alkyl, C_1-6alkoxy,

Cl, Br, F, I, OH, NO₂, CF₃, CO₂R⁴, or NR⁴R⁴;

each m independently is 1-3;

each n independently is 0-2; and

each R⁴ independently is H or C_1-6alkyl; or a

pharmaceutically acceptable salt thereof, or

Substituted imidazoles of the formula (X):

(CH₂)_m-R

/^r

R²--XX--4 ->N-. >-*.3

^'N (X) in which:

R¹ is Het, wherein Het is defined as a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic ring, which is either saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group

consisting of N, O, S, wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quarternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring and wherein the Het is unsubstituted or substituted by any accessible stable combination of up to three substituents selected from the group consisting of C₁-C₆alkyl, C₁-C₆alkoxy, Cl, Br, F, I, NR⁷R⁷, A-CO₂R⁷, CONR⁷R⁷, SO₃H, SO₂NHR⁷, OH, NO₂, W, SO₂C₁-C₆alkyl, SO₂W, SC₁-C₆alkyl, NR⁷COW, or NR⁷COC₁-C₆alkyl, wherein W is C_nF_2n+1, in which n is 1-3 and wherein A is -CH=CH-, -(CH₂)_0-4-, -Q-CH(R⁹)-, or -Q-(CH₂)_1-2-U-(CH₂)_1-2-, in which Q is O, S, NH, or

NC_1-6alkyl, U is absent or present as O, S, NH, or

NC_1-6alkyl, and R⁹ is hydrogen, phenyl, or benzyl;

m is 0-4;

R² is C₂-C₁₀alkyl, C₃-C₁₀alkenyl, C₃-C₁₀alkenyl, C3-Cgcycloalkyl, or (CH₂)_0-8phenyl unsubstituted or substituted by one to three substituents selected from C_1-C₆alkyl, nitro, Cl, Br, F, I, hydroxy, C₁-C₆alkoxy, NR⁷R⁷, CO₂R⁷, CN, CONR⁷R⁷, W, tetrazol-5-yl,

NR⁷COC₁-C₆alkyl, NR⁷COW, SC_1-C₆alkyl, SO₂W, or

SO₂C_1-C₆alkyl;

X is a single bond, S, NR⁷, or O;

R³ is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl, COOR⁷, CONR⁷R⁷, NO₂, W, CN, NR⁷R⁷, or phenyl;

R⁴ and R⁵ are independently hydrogen, C₁-C₆alkyl, phenyl-Y-, biphenyl-Y-, naphthyl-Y-, 2- or 3-thienyl-Y-, 2- or 3-furyl-Y-, 2-, 3- or 4- pyridyl-Y-, pyrazolyl-Y-, imidazolyl-Y-, pyrrolyl-Y-, triazolyl-Y-, oxazolyl-Y-, isoxazolyl-Y-, thiazolyl-Y-, or tetrazolyl-Y-, with each aryl or heteroaryl group being unsubstituted or substituted by C₁-C₆alkyl, C₁-C₆alkoxy, Cl, Br, F, I, NR⁷R⁷, CO₂R⁷, SO₂NHR⁷, SO₃H, CONR⁷R⁷, OH, NO₂, W, SO₂W, SC₁-C₆alkyl, SO₂C₁-C₆alkyl, NR⁷COH, NR⁷COW, or

NR⁷COC₁-C₆alkyl;

Y is a single bond, O, S, or C₁-C₆alkyl which is straight or branched or optionally substituted by phenyl or benzyl, wherein each phenyl or benzyl group is

unsubstituted or substituted by halo, NO₂, CF₃,

C₁-C₆alkyl, C₁-C₆alkoxy, CN, or CO₂R⁷;

R⁶ is -Z-COOR⁸, -Z-CONR⁷R⁷, or -Z-tetrazol-5-yl;

Z is a single bond, vinyl, -CH₂-O-CH₂-, methylene optionally substituted by C₁-C₆alkyl, one or two benzyl groups, thienylmethyl, or furylmethyl, or -C(O)NHCHR⁹-, wherein R⁹ is H, C₁-C₆alkyl, phenyl, benzyl,

thienylmethyl, or furylmethyl;

W is C_nF_2n+1, wherein n is 1-3;

each R⁷ independently is hydrogen, or C₁-C₆alkyl;

and

R⁸ is hydrogen, C₁-C₆alkyl, or 2-di(C₁-C₆alkyl)- amino-2-oxoethyl; or a pharmaceutically acceptable salt thereof, or

Substituted imidazoles of the formula (XI):

in which:

R¹ is adamantyl, phenyl, biphenyl, or naphthyl, with each phenyl, biphenyl, or naphthyl group being unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C₁-C₆alkyl, nitro, A-CO₂R⁷, tetrazol-5-yl, C₁- C₆alkoxy, hydroxy, SC₁-C₆alkyl, SO₂NHR⁷, NHSO₂R⁷, SO₃H, CONR⁷R⁷, CN, SO₂C₁-C₆alkyl, NHSO₂R⁷, PO(OR⁷)₂, NR⁷R⁷,

NR⁷COH, NR⁷COC₁-C₆alkyl, NR⁷CON(R⁷)₂, NR⁷COY, Y, or SO₂Y;

R is C₂-C₁₀alkyl, C₃-C₁₀alkenyl, C₃-C₁₀alkenyl, C₃- C₆cycloalkyl, or (CH₂)_0-8phenyl unsubstituted or substituted by one to three substituents selected from C₁-C₆alkyl, nitro, Cl, Br, F, I, hydroxy, C₁-C₆alkoxy, NR ⁷R⁷, CO₂R⁷, CN,

CONR⁷R⁷, Y, tetrazol-5-yl, NR⁷COC₁-C₆alkyl, NR⁷COY, SC₁- C₆alkyl, SO₂Y, or SO₂C₁-C₆alkyl;

X is a single bond, S, or O;

R³ is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl,

COOR⁷, CONR⁷R⁷, NO₂, Y, CN, NR⁷R⁷, or phenyl;

Y is C_mF_2m+1;

A is -(CH₂)_p-, -CH=CH-, -O(CH₂)_m-, or -S(CH₂)_m;

R⁴ is H, C₁-C₆alkyl, or -S (CH₂)_1-4CO₂R⁷;

t is 0 or 1;

R⁵ is -CHR⁶(CH₂)_qCO₂R⁷ or -(CH₂)_nR⁹;

R^β is hydrogen, CO₂R⁷, C₁-C₆alkyl, or -(CH₂)_nR⁸;

each m independently is 1-3;

each n independently is 0-3;

each p independently is 0-4;

each q independently is 0-2;

each R⁷ independently is hydrogen or C₁-C₆alkyl;

R⁸ is phenyl, naphthyl, 2- or 3-thienyl, 2- or 3-furyl, 2-, 3-, or 4-pyridyl, pyrimidyl, imidazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyrrolyl, oxazolyl, or isoxazolyl, with each R⁸ group being unsubstituted or substituted by C₁-C₆alkyl, C₁-C₆alkoxy, Cl, Br, F, I, NR⁷R⁷, CONR⁷R⁷, CO₂R⁷, SO₃H, SO₂NHR⁷, OH, NO₂, Y, SO₂C₁-C₆alkyl, SO₂Y, SC₁-C₆alkyl, NR⁷COH, NR⁷COY, or NR⁷COC₁-C₆alkyl; and R⁹ is phenyl, naphthyl, 2- or 3-thienyl, 2- or 3-furyl, 2-, 3-, or 4-pyridyl, pyrimidyl, imidazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyrrolyl, oxazolyl, or isoxazolyl, with each R⁹ group being unsubstituted or substituted by C₁-C₆alkyl, C₁-C₆alkoxy, Cl, Br, F, I, NR⁷R⁷, CO₂R⁷, CONR⁷R⁷, SO₃H, SO₂NHR⁷, OH, NO₂, Y, SO₂C₁-C₆alkyl, SO₂Y, SC₁-C₆alkyl, NR⁷COH, NR⁷COY, or NR⁷COC₁-C₆alkyl;

or a pharmaceutically acceptable salt thereof. 2. A method of claim 1 wherein the compound is (E)-3- [2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2- (2-thienyl)methyl-2-propenoic acid or a pharmaceutically acceptable salt thereof. 3. A method of claim 1 wherein the compound is (E)-3- [2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazql-5-yl]-2- (2-thienyl)methyl-2-propenoic acid methanesulfonate.

4. A method of claim 1 wherein the compound is (E)-3- [2-n-butyl-1-{(4-carboxynaphth-1-yl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid or a

pharmaceutically acceptable salt thereof.