PT100491A - N- (HETEROARYL) -IMIDAZOLYL-ALCOHOLIC ACIDES, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND THEIR USE - Google Patents

Description

-3- 73 492 Ρ50015

The present invention relates to novel N- (heteroaryl) imidazolyl alkoic acids which are antagonists of the angiotensin II receptor and which are useful in the regulation of angiotensin II-induced or exacerbated hypertension and in the treatment of congestive heart failure, renal and glaucoma. The present invention also relates to pharmaceutical compositions containing these compounds and methods of using these compounds as angiotensin II antagonists, as antihypertensive agents and as agents for the treatment of congestive heart failure, renal and glaucoma.

BACKGROUND OF THE INVENTION The type of peptidic pressure hormone, known as angiotensin, is responsible for a vasopressor action that is implicated in the etiology of hypertension in man. Inappropriate activity of the renin-angiotensin systems appears to be a key element in primary hypertension, congestive heart failure, and some forms of renal disease. In addition, direct action on the arteries and arterioles, angiotensin II (AII), being one of the most potent endogenous vasoconstrictors known, stimulates the release of aldosterone from the adrenal cortex. Therefore, the renin-angiotensin system, by virtue of its participation in the control of renal sodium processing, plays an important role in cardiovascular hemeostasis. Discontinuation of the renin-angiotensin system with conversion enzyme inhibitors, such as captopril, has been shown to be clinically useful in the treatment of hypertension and congestive heart failure (Abrams, WB, et al. (1984), Federation Proc. 1314). The most direct approach to inhibition of the renin-angiotensin system would be to block the action of AII on the receptor. The evidence suggests that IIA also contributes to renal vasoconstriction and renal sodium retention, characteristics of a number of disorders such as heart failure, cirrhosis and complications of pregnancy (Hollenberg, NK, (1984), J. Cardiovas, Pharmacol., 6, S176). In addition, recent animal studies suggest that inhibition of the renin-angiotensin system may be beneficial in eliminating or slowing the progression of chronic renal failure (Anderson, S., et al., (1985), J. Clin. 612). Similarly a recent patent application (South African Patent Application No. 87/01653) states that IIA antagonists are useful as agents for the reduction and control of elevated intraocular pressure, especially glaucoma, in mammals.

The compounds of this invention inhibit, block and antagonize the action of the hormone AII and are therefore useful in the regulation and moderation of hypertension, congestive heart failure, angiotensin-induced renal failure and glaucoma and in the regulation of other disorders attributed to the actions of AII. When the compounds of the present invention are administered to mammals, elevated blood pressure due to AII is reduced and other manifestations based on the intervention of the AII are minimized and controlled. It is also expected that the compounds of the present invention exhibit diuretic activity. Recognition of the importance of blocking and inhibiting the actions of IIA stimulated further efforts to synthesize AII antagonists. The following references have disclosed imidazole derivatives which are described as having AII blocking activity and as being useful as hypotensive agents.

Furukawa et al., U.S. Patent 4,340,598 discloses imidazol-5-yl acetic acids and imidazol-5-yl-propanoic acids. The disclosure includes, in particular, 1-benzyl-2-n-butyl-5-chloroimidazol-4-acetic acid and 1-benzyl-2-phenyl-5-chloroimidazole-4-propanoic acid.

Furukawa et al., U.S. Patent 4,355,040 discloses substituted imidazol-5-acetic acid derivatives. A specifically disclosed compound is 1- (2-chlorobenzyl) -2-n-butyl-4-chloroimidazole-5-acetic acid. -5- 73 492 Ρ50015

Carini et al., In EP 253 310 discloses certain imidazolyl-propenoic acids. Two intermediates described in this patent are ethyl 3- [1- (4-nitrobenzyl) -2-butyl-4-chloro-imidazol-5-yl] propenoate and 3- [2-butyl-4-chloro- - (4-aminobenzyl) -imidazol-5-yl] propenoate.

Also, PCT / EP 86/00297 discloses as intermediates certain imidazolyl propenoate compounds. On p. 62, formula (CX) is ethyl 3- [1- (4-fluorophenyl) -4-isopropyl-2-phenyl-1H-imidazol-5-yl] -2-propenoate.

DESCRIPTION OF THE INVENTION

The compounds of the present invention, which are angiotensin II receptor blockers, are represented by the following Formula (I):

0) in which R 1 is Het, wherein Het is defined as a stable 5 to 7 membered monocyclic or 7 to 10 membered bicyclic heterocyclic ring which is 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 be optionally quaternized, and including any bicyclic group in which any of the heterocyclic rings defined above is fused to a benzene ring and wherein Het is unsubstituted or substituted by any stable stable combination of up to three substituents selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, Cl, Br, F, I, NR 7 R 7, A-CO 2 R 7, CO 2 NR 7 R 7, SO 3 NH, SO 2 NHR 7, OH, NO 2, W, SO 2 -C 1-4 alkyl, C 1 -C 6 alkyl; wherein W is C n F 2n + 1, wherein n is 1-3 and wherein A is -CH = CH-, - (CH 2) 1-4, -CH 2 CH (R 9) -, or -Q- (CH 2) "U" (ch2) 1-2 "> NH2 or N-C1 -C6 alkyl, U is absent or present as O, S, NH or N-C1 -C6 alkyl and R9 is hydrogen, phenyl or benzyl; m is 0-4; R 2 is C 2 -C 10 alkyl, C 3 -C 10 alkenyl, C 3 -C 10 alkynyl, C 3 -C 10 cycloalkyl, or (CH 2) g phenyl which is unsubstituted or substituted by one to three substituents selected from C 1 -C 6 alkyl, nitro, Cl, Br, F, I, hydroxy, C1-6 alkoxy, NR7 R7, CO2 R7, CN, CO2 R7 R7, W, tetrazol-5-yl, NR7, C1-6 alkylthio, NR7 COW, S-C1-6 alkyl, SO2 W, or SO2 C -C-Cal alkyl; X is a single bond, S, NR 7 or O; R 3 is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl, COOR 7, CONR 7 R 7, NO 2, W, CN, NR 7 R 7 or phenyl; R4 and R5 are independently hydrogen, C1 -C6 alkyl, 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- , each aryl or heteroaryl group being unsubstituted or substituted by C 1 -C 6 alkyl, C 1 -C 6 alkoxy, Cl, Br, F, I, NR 7 R 7, CO 2 R 7, SO 2 NHR 7, SO 3 H, COO R 7 R 7, OH, NO 2, C 1 -C 6 alkyl, SO 2 -C 1 -C 6 alkyl, NR 7 COOH, NR 7 COOH or NR 7 CO-C 1 -C 6 alkyl; Y is a single bond, O, S or C -C-C alquilo alkyl which is linear or branched or optionally substituted by phenyl or benzyl, wherein each phenyl or benzyl group is unsubstituted or substituted by halo, NO 2, CF 3, -C,, C alco alco alcoalkoxy, CN or CO₂R;; R6 is -Z-C00R8, -Z-COOR7R7 or -Z-tetrazol-5-yl; Z is a single bond, vinyl, -CH 2 O-CH 2 -, methylene optionally substituted by C 1 -C 6 -alkyl, one or two benzyl, thienylmethyl or furylmethyl groups or -C (O) NHCHR 9 -, wherein R 9 is H, C1-Cg, phenyl, benzyl, thienylmethyl or furylmethyl; W is C n F 2n + 1, wherein n is 1-3; each R 7 is independently hydrogen or C 1 -C 6 alkyl, and R 8 is hydrogen, C 1 -C 6 alkyl or 2-di (C 1 -C 6 alkyl) -aminopropoxy-2-oxoethyl ; or a pharmaceutically acceptable salt thereof.

Preferably, one of R4 and R5 is hydrogen or C1-4 alkyl,

Preferred Het R1 groups include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidinyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, 2,3 or 4-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, 2 or 3 tetrahydrofuryl, 2 or 3-thienyl, benzothienyl, benzoxazolyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulphone, benzofuranyl and oxadiazolyl, each R 1 group being unsubstituted or substituted by any combination stable heterocyclic ring of up to three substituents selected from the group consisting of C1 -C6 alkyl, C1 -C6 alkoxy, Cl, Br, F, I, NR 7 R 7, A-CO 2 R 7, CONR 7 R 7, SO 3 H, SO 2 NHR 7, OH, NO 2, W, SO 2 -C 1-6 alkyl, SO 2 W, S-C 1-6 alkyl, NR 7 COH, NR 7 COW or NR 7 CO- C^-C alquilo alkyl; wherein W is C n F 2n + 1, wherein n is 1-3 and wherein A is -CH = CH-, - (CH 2) 1-4, -Q-CH (R 9) -, or -Q- (CH 2) Wherein Q is O, S, NH, or N-C 1 -C 6 alkyl, U is absent or present as O, S, NH or N-C 1 -C 6 alkyl, and R 9 is hydrogen , phenyl or benzyl.

The most preferred compounds of this invention are represented by Formula (I) when: R 1 is 2 or 3-thienyl, 2 or 3-furyl or 2,3 or 4-pyridyl, each thienyl, furyl or pyridyl group being unsubstituted or substituted by CO 2 R 7 ; m is 0-2; X is a single bond or S; R 2 is C 2 -C 6 alkyl; R 49 is hydrogen, chloro, fluoro or trifluoromethyl; R1 is hydrogen or C1 -C6 alkyl; R5 is 2 or 3-thienyl-Y-, 2 or 3-furyl-Y- or 2,3-or 4-pyridyl-Y-, each thienyl, furyl or pyridyl group being unsubstituted or substituted by methyl or methoxy; Y is a single bond or C1 -C6 alkyl which is linear or branched; R6 is -Z-C00R8; Z is a single bond; and R8 is hydrogen or C1 -C6 alkyl; or a pharmaceutically acceptable salt thereof.

The E (trans stereochemistry of the COOR8 and imidazole groups) isomers are generally more active and thus are preferred to the Z (cis) isomers.

As used herein, the terms alkyl, alkenyl, alkoxy and alkynyl mean branched or unbranched carbon chains, wherein the chain length is determined by the general term preceding the term.

Particular compounds of the invention include, but are not limited to, the following: (E) -3- [2-n-butyl-1 - {(5-carboxy-2-thienyl) methyl} -1H- zol-5-yl] -2- (2-thienyl) methyl-2-propenoic acid; (E) -3- [2-n-butyl-1 - {(5-carboxy-3-thienyl) methyl} -1H-imidazol-5-yl] -2- (2-thienyl) methyl- -propionic acid; (E) -3- [2-n-butyl-1 - {(5-carboxy-2-furyl) methyl} -1H-imidazol-5-yl] -2- (2-thienyl) propenoic acid; and (E) -3- [2-n-butyl-1 - ((5-carboxy-2-pyridyl) methyl} -1H-imidazol-5-yl] -2- (2-thienyl) 2-propenoic acid; or a pharmaceutically acceptable salt thereof. The most preferred compounds of this invention are: (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. The present invention also relates to pharmaceutical compositions comprising a pharmaceutical carrier and an effective amount of a compound of Formula (I).

Also included in the present invention are methods for antagonizing angiotensin II receptors, comprising administering to a subject in need thereof, an effective amount of a compound of Formula (I). Methods of treating hypertension, congestive heart failure, renal insufficiency and glaucoma, by administration of these compounds are also included in the present invention. The present invention also relates to the use of a compound of formula (I) in the manufacture of a medicament for the treatment of diseases in which angiotensin II receptor antagonism is a factor, such as hypertension, congestive heart failure, glaucoma and insufficiency renal.

The compounds of this invention are prepared by the procedures described herein and illustrated by the examples. The reactants, protecting groups and functionality of the imidazole and other fragments of the molecule must be consistent with the proposed chemical transformations. The synthetic steps should be compatible with the functional groups and the protecting groups on the imidazole group and other parts of the molecule.

The starting materials, 2-R2X-imidazole, are known in the art (J. Org. Chem. 45: 4038, 1980), or are synthesized by known procedures. For example, the imidazole is converted to 2-n-butylimidazole by reacting the imidazole with triethyl orthoformate and p-toluenesulfonic acid to give imidazole 1-diethoxyorthoamide and subsequent treatment with n-butyllithium to give the 2- lithium of the orthoamide and alkylation with n-butyl iodide in a suitable solvent such as tetrahydrofuran (THF). The following procedure is useful in the preparation of compounds of formula (I) particularly when R1 is 2-thienyl, substituted by a carboxy; my M; R2 is n-butyl or n-propyl; X is a single bond or S; R 3 is hydrogen, chlorine or CF 3; R4 is hydrogen; R5 is 2-thienyl-methyl; R6 is COOR8 and R8 is hydrogen, methyl or ethyl. The 1-R 1 (CH 2) 1 group is incorporated into the 2-R 2 X imidazole by known procedures, for example by reaction with a halide, mesylate or acetate of R 1 - (CH 2) 1a such as 5-bromomethyl-2-carbomethoxythiophene, in a suitable solvent, such as dimethylformamide (DMF), in the presence of a suitable acid acceptor, such as sodium alkylate, sodium carbonate " or potassium metal hydride, preferably sodium hydride, at a reaction temperature of about 25 ° C to about 100 ° C, preferably at 50 ° C. The resulting 1-hydroxymethylated 1-R1 (CH2) m-2-R2 X-imidazole is hydroxymethylated in the 5-position, for example by reacting this compound with formaldehyde in the presence of sodium acetate in acetic acid to give the intermediates 1-R1CH2-2-R2X -5-hydroxymethylimidazole. The hydroxymethyl group is oxidized to an aldehyde by treatment with a suitable reagent, for example anhydrous silica gel chromic acid in tetrahydrofuran or, preferably, with activated manganese dioxide in a suitable solvent, such as benzene or toluene, or preferably of methylene at a temperature from about 25 ° C to about 140 ° C, preferably 25 ° C, to give 1-R1 (CH2) m-2-R2x-imidazole-5-carboxaldehydes.

Alternatively, the 1 - [(R *) m-2-R 2 -imidazole-5-carboxaldehydes are prepared by the following procedure. An imido ether, R2 -C (= NH) -O-alkyl, such as valeramidine-methyl ether is reacted with dihydroxyacetone in liquid ammonia under pressure to give 2-R2-5-hydroxymethylimidazole. The hydroxymethyl group is oxidized to the corresponding aldehyde as described above using for example manganese dioxide in a suitable solvent such as methylene chloride. The 2-R 2 -imidazole-5-carboxaldehydes are reacted with a N-alkylating, protective reagent, such as chloromethyl pivalate (MMP-Cl), in the presence of a base, such as potassium carbonate, in a suitable solvent, such as such as dimethylformamide, at a temperature from about 20 ° C to about 50 ° C, preferably at 25 ° C, to produce the N-alkylation (eg POM derivative) of at least one hindered nitrogen atom of the imidazole nucleus. The group 1 -R- * - (CH2) m is incorporated into the imidazole by N-alkylation of the above aldehyde prepared with, for example, a halomethylheteroaryl compound, such as 5-bromomethyl-2-carbomethoxythiophene, at a temperature from about 80 ° C to about 125 ° C, preferably at 100 ° C. The 3-nitrogen protecting group of the imidazole ring is removed by basic hydrolysis, using for example a biphasic mixture of ethyl acetate and aqueous sodium carbonate, to give 1-R1 (CH2) m-2-R2-imidazol- 5-carboxaldehydes.

Alternatively, the 1-R1 (CH2) m-2-R2-imidazole-5-carboxaldehydes are prepared from 2-R2-5-hydroxymethylimidazoles by the following procedure. The 5-hydroxymethyl intermediate is halogenated at the 4-position, using for example N-chlorosuccinimide, in a suitable solvent, such as tetrahydrofuran in 2-methoxyethane at a temperature of about 25Â ° C to about 60Â ° C, preferably 50Â ° C ;W. The 5-hydroxymethyl group of this intermediate is oxidized to give the 5-carboxyaldehyde using the methods described above. The resulting imidazole intermediate is selectively N-alkylated at the 1-position using, for example a halomethylheteroaryl compound, such as 5-bromomethyl-2-carbomethoxythiophene, in the presence of a base, such as potassium carbonate, in a suitable solvent, such as such as dimethylformamide. The halo group is removed by hydrogenolysis in the presence of a catalyst, such as palladium on carbon, to give 1-R1 (CH2) m-2-R2-5-hydroxymethylimidazoles. The 1-R1 (CH2) m-2-R2-imidazole-5-carboxaldehydes are prepared from 5-hydroxymethyl compounds by the method previously described.

The compounds of formula (I) are prepared from 1-R1 (CH2) m-2-R2X-imidazole-5-carboxyaldehydes in a reaction with an appropriately substituted phosphonate, such as 3- (2-thienyl) -2-phosphonopropionate trimethyl. The phosphonates are prepared from suitable trialkyl phosphonoacetates by alkylation with an appropriate halide, mesylate or acetate, in the presence of a suitable base, such as sodium hydride, in a suitable solvent, preferably glyme, at a temperature of reaction at 25 ° C to 110 ° C, preferably at 55 ° C, to give for example the phosphonates. The reaction of the imidazole-5-carboxaldehydes with the phosphonates is carried out in the presence of a suitable base, such as a metal alkoxide, lithium hydride or, preferably, sodium hydride, in a suitable solvent, such as ethanol, methanol, dioxane, tetrahydrofuran, or preferably glycol at a reaction temperature of about 10 ° C to about 50 ° C, preferably at 25 ° C, to provide a variable mixture of trans and cis, -2-R 2 X 5 -CH = C (R 5) - (COOalkyl) -imidazoles, (E) and (Z). These isomers are separated by chromatography on silica gel in suitable solvent systems, preferably hexane in ethyl acetate. The esters are hydrolyzed to the acids, using bases, such as potassium hydroxide, lithium hydroxide or sodium hydroxide, in a solvent such as, for example, sodium hydroxide. solvent system such as, for example, aqueous alcohols or diglyme. The trans and cis structures of the acids are readily determined by NMR by the NOE protocol, as well as by the biological activities since trans (E) isomeric acids are the most potent isomers.

The compounds of formula (I) are also prepared by the following procedure. The 2-R2X-imidazole starting materials are reacted with trimethylsilylethoxymethyl chloride (SEM) to give 1- (trimethylsilyl) ethoxymethyl-2-R2X-imidazole. The reaction is carried out, for example, in the presence of sodium hydride in a solvent, such as dimethylformamide. The 5-tributyl tin derivatives are prepared by lithiation with, for example, butyllithium in a suitable solvent, preferably diethyl ether, followed by treatment of the lithium imidazole derivative with a tributyltin halide, preferably tri-N-butyl chloride tin at a temperature of about -10Â ° to about 35Â ° C, preferably at 25Â ° C. The 1-SEM-2-R2X-5-tributyltin imidazole is coupled to an α, β-unsaturated acid ester having a leaving group in the 3 position, such as a halide or trifluoromethanesulfonyloxy group, for example Br CR 4 = C (R 5) (COOalkyl), in the presence of a phosphine ligand, such as bis (di-phenyl) -phenoxypropane or triphenylphosphine and a palladium (II) compound or, preferably, tetrakis triphenylphosphine) palladium (0), with or without a base such as tributylamine, at a temperature of about 50Â ° C to about 150Â ° C, preferably at 120Â ° C. Both the olefinic (E) and ( Z) are prepared by this procedure and the isomeric esters are separated by silica gel chromatography The 1-SEM group of the imidazoles of the (E) and (Z) isomers is hydrolyzed with acid, for example aqueous hydrochloric acid, in a suitable alcohol solvent , such as methanol or ethanol and the 1-unsubstituted imidazole derivatives are converted into 1-t-bu to-xycarbonyl- (t-BOC) -imidazoles with di-t-butyl dicarbonate (Hoppe-Seyler, Z. Physiol. Chem. (1976), 357, 1651). The t-BOC esters are alkylated and hydrolyzed with, for example, 2-thienylmethyl-O-triflate, in the presence of a suitable base, preferably diisopropylethylamine, in a suitable solvent, preferably methylene chloride, to give 1- (heteroaryl) methyl-imidazole (esters). The (E) and (Z) isomers are hydrolyzed to the acids (E) and (Z) by the method described above.

The compounds of formula (I) are also prepared by the following procedure. The 1-R - * - (CH2) m-2-R2X-imidazole-5-carboxaldehydes, prepared as described above, are reacted with a half acid, substituted ester ester of a malonate, such as -carboxy-3- (2-thienyl) propionate, in the presence of a base, such as piperidine, in an appropriate solvent, for example toluene or benzene, at a temperature from about 80 ° C to about 110 ° C. C, preferably at 80 ° C. The resulting 1-R1 (CH2) m-2-R2 X-5-CH = C (R5) COOalkylimidazoles are hydrolyzed to the corresponding acid compounds of formula (I) by alkaline hydrolysis as described above.

The compounds of formula (I) are also prepared by the following procedure. Prepared as described above, are converted to the corresponding alcohols with an organometallic derivative or Grignard reagent, preferably methyl lithium, in a solvent of the formula: ## STR1 ## wherein R 1, R 1, R 2, R 2, 73 492 5155, preferably tetrahydrofuran. The alcohol is oxidized, for example, by using manganese dioxide, to give the ketone. Olefinic esters are prepared from the ketone by reaction with appropriate phosphonates to give the (E) and / or (Z) isomers, which are readily separated. The acids are prepared from the esters by alkaline hydrolysis, as described above.

Additionally, the compounds of formula (I) are prepared as follows. The CH2) m-2-R2X-imidazole-5-carboxaldehydes are treated with the lithium derivative of a substituted ethyl or methyl ester. These lithium derivatives are prepared from the reaction of lithium diisopropylamide in a suitable solvent, preferably tetrahydrofuran, with an acid ester, such as ROOC-CH 2 -Y- (2-thienyl), to generate the α-lithium derivatives about -78 ° C to about -10 ° C, preferably -78 ° C, which are then treated with the imidazole-carboxaldehyde. The intermediate of the β-hydroxy group of the imidazole ester is converted into a mesylate or an acetate and the mesylate, or preferably the acetate, is heated in a suitable solvent, such as toluene, with one to two equivalents of 1,8-diazabicyclo [5,4,0] undec-7-ene, at about 50 ° C to about 110 ° C, preferably at 80 ° C, to give the ester compounds of formula (I), such as - (imidazol-5-yl) -2- (2-thienyl) methyl-2-propenoic acid. The (E) isomer is the predominant olefinic isomer. Acids are prepared from the esters by the method described above.

The compounds of Formula (I) wherein Y is a single bond is an aryl or a heteroaryl as described for formula (I) and R 6 is COOH may be prepared by heating 1-R 2 (CH 2) m -2- R2X-imidazole-5-carboxaldehydes at a temperature of about 50 ° C to about 180 ° C, preferably 140 ° C, with an appropriately substituted acetic acid, acetic anhydride and potassium carbonate to give the unsaturated acids of formula (I) such as 3- [2-n-butyl-1- (2-thienyl) methyl-1H-imidazol-5-yl] -2- (R) -2-propenoic acid. The trans olefinic acid is the major product. -15- 73 492 Ρ50015

Compounds of Formula (I) wherein R 6 is Z-COOR 8, wherein Z is an optionally substituted methylene group, are prepared by reduction of the trans or (E) isomers of 3- (imidazol-5-yl) - 2-propenoic acid (prepared as above) with a suitable hydride reagent, preferably diisobutylaluminium hydride, in a suitable solvent, such as tetrahydrofuran, to give the unsaturated alcohol compounds. These compounds are reacted with ethyl chloroformate, for example with a base, preferably triethylamine, in a suitable solvent, such as tetrahydrofuran, to give 5-EtOAc-COCH2 CR5 = CR4-imidazoles which are reacted with carbon mo presence of a phosphine ligand, preferably triphenylphosphine, with palladium (II) acetate, in a suitable solvent, preferably tetrahydrofuran, at a temperature of about 25øC to about 100øC, preferably at 40øC, for give the 5-EtOOCCH 2 CR 5 = CR 4 -imidazoles. The corresponding acids are prepared from these ethyl esters by basic hydrolysis as described above.

Compounds of Formula (I) wherein Z is -CH 2 COOR 8, having a further substitution on the α-carbon of the carboxylate group are prepared by converting 5-EtOOCH 2 CR 5 = CR 4 -imidazoles to the lithium derivative of an ester with a lithium dialkylamide, preferably diisopropylamide of lithium, and then treating with an alkylating agent, such as methyl halide, benzyl bromide or heterocyclic methyl halide to give the monoalkylated product compounds or the product dialkylated compounds. The acidic compounds are prepared from esters by basic hydrolysis.

Compounds of Formula (I) wherein R 6 is Z-COOR 8, wherein Z is -CH 2 O-CH 2 - are prepared from unsaturated alcohol compounds which have been obtained by reduction of the esters of propenoic acids of formula I). The alcohol is reacted with the appropriate hydride reagent, such as sodium hydride, in a suitable solvent, such as glyme, followed by reaction with an alkylating agent, such as methyl bromoacetate, to give methyl 5-MeO-CH 2 O-CH 2 CR 5 = CR4-imidazoles. The corresponding acids are 73 492 Ρ50015 * " Prepared by basic hydrolysis as described above.

Compounds of Formula (I) wherein R 6 is Z-COOR 8, wherein Z is C (O) NHCHR 9 are prepared from propenoic acid compounds of formula (I). These acids are reacted with the appropriately substituted amino acid such as glycinnamic ester hydrochloride or phenylalanine methyl ester hydrochloride in the presence of an amide forming reagent such as N-hydroxysuccinimide and dicyclohexylcarbodiimide in the presence of a base, e.g. for example triethylamine, in a suitable solvent, such as tetrahydrofuran, at a temperature from about 20Â ° C to about 50Â ° C, preferably at 35Â ° C. The S-C j jOCalkylalkyls are converted to their corresponding acids by basic hydrolysis as described above.

Compounds of Formula (I) wherein R 6 is Z-tetrazol-5-yl are prepared from the corresponding Z-COOH compounds. For example, the acid compounds of Formula (I) are reacted with a halogenating agent, such as thionyl chloride, in a suitable solvent, for example benzene, to give the corresponding acid halide compounds. The acid halides are then converted to primary amide compounds in a reaction with concentrated ammonia. Subsequent dehydration of the amides with oxalyl chloride / dimethylformamide in acetonitrile / dimethylformamide yields the nitrile compounds, which are the immediate precursors of the tetrazole compounds of formula (I). The formation of the tetrazole is effected by reaction of the nitriles with azide, preferably aluminum azide, prepared in situ by reaction of sodium azide with aluminum chloride, in a suitable solvent, for example tetrahydrofuran.

The compounds of Formula (I) wherein the R1 substituent is substituted with hydroxy are prepared from the compounds of Formula (I) wherein the R1 group is substituted with C1 -C4 alkoxy using a ethers, such as boron tribrometart or hydrobromic acid. -17- 73 492 Ρ50015

Compounds of Formula (I) wherein the R1 substituent is carboxy substituted are formed from compounds of Formula (I) wherein the R1 group is substituted with C1 -C4 alkyl, using basic hydrolysis, such as sodium hydroxide or potassium hydroxide in methanol or ethanol, or using acid hydrolysis, such as with aqueous hydrochloric acid.

Compounds of Formula (I) wherein the R1 substituent is substituted with CONR7 R7, are prepared from compounds of Formula (I) wherein the R3 group is substituted with carboxy. The carboxy compounds are reacted with a " halogenating agent such as thionyl chloride followed by reaction with an appropriately substituted amine NR 7 R 7 wherein R 7 is as defined for the compounds of formula (I).

The pharmaceutically acceptable acid addition salts of the compounds of Formula (I) are formed with appropriate inorganic or organic acids by methods known in the art. For example, the base is reacted with a suitable inorganic or organic acid in a water-miscible solvent, such as ethanol, with salt isolation by removal of the solvent, or in a water-immiscible solvent, when the acid is soluble therein, such as ethyl ether or chloroform, the desired salt being separated directly or being isolated by removal of the solvent. Representative examples of acids are maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylene-salicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic , p-aminobenzoic, glutamic, benzenesulfonic, hydrochloric, hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric acids.

The pharmaceutically acceptable base addition salts of the compounds of formula (I) wherein R8 is H, are prepared by known methods from organic and inorganic bases, including non-toxic alkali and alkaline earth metal bases, for example hydroxide of calcium, lithium, sodium and potassium; ammonium hydroxide and non-toxic organic bases such as triethylamine, butylamine, piperazine, meglumine, choline, diethanolamine and tromethamine. The angiotensin II antagonist activity of the compounds of Formula (I) is evaluated by in vitro and in vivo methods. In vitro antagonist activity is determined by the ability of the compounds to compete with125 I-angiotensin II on vascular receptor binding of angiotensin II and for its ability to antagonize the contractile response to angiotensin II in the isolated rabbit aorta. In vivo activity is evaluated by the efficacy of the compounds to inhibit the pancreatic response to exogenous angiotensin II in conscious rats and to lower blood pressure in a model in rats with renin-dependent hypertension.

Binding Radioligand binding assay is a modification of a method previously described in detail (Gunther et al., Cir. Res. 47: 278, 1980). A particular fraction of rat mesenteric arteries is incubated in 80æM Tris buffer of 125 I-angiotensin II, with or without angiotensin II antagonists, for 1 hour at 25øC. The incubation is terminated by rapid filtration and the 125 I-angiotensin II bound to the receptor retained in the filter is quantified with a gamma counter. The potency of angiotensin II antagonists is expressed as IC50, which is the antagonist concentration required to displace 50% of the total, specifically bound total angiotensin II. As an example of the IC 50 of compounds of the invention (E isomers) is about 1.0 nM to about 10 μ.

Aorta The ability of the compounds to antagonize angiotensin II-induced vasoconstriction is examined in the rabbit aorta. Rabbit thoracic aorta ring segments are cut and suspended in organ baths containing physiological saline solution. The annular segments are mounted on metal supports and connected to force the displacement of transducers which are connected to a register. The cumulative concentration response curves for angiotensin II are obtained in the absence of antagonist or after a 30 minute incubation with antagonist. The antagonist dissociation constants (KB) are calculated by the dose ratio method, using the mean effective concentrations. Typical for the KB of the compounds of the invention (E-isomers) is from about 0.1 nM to about 20 μ.

Inhibition of the pressor response to angiotensin II. in conscious rats

Rats are prepared with arterial and venous femoral catheters and a tube in the stomach (Gellai et al., Kidnev Int. 15: 419, 1979). Two to three days after surgery, the rats are placed in a movement restriction apparatus and blood pressure is continuously monitored from the arterial catheter with a pressure transducer and recorded on a polygraph. The change in mean arterial pressure in response to intravenous injections of 250 mg / kg angiotensin II is compared at various points in time before and after administration of the compounds intravenously or orally at doses of 0.1 to 300 mg / kg. The dose of compound required to produce a 50% inhibition of the control response to angiotensin II (IC 50) is used to evaluate the potency of the compounds.

Antihypertensive activity The antihypertensive activity of the compounds is measured by their ability to reduce mean blood pressure in conscious rats becoming renominant hypertensive by binding of the left renal artery (Cangiano et al., J. Pharmacol Exp. Ther 208: 310, 1979). Rats with the attached renal artery are prepared with internal catheters as described above. Seven to eight days after renal artery ligation, at which time plasma renin levels are maximal, conscious rats are placed in motion restriction devices. The mean arterial blood pressure is recorded continuously before and after intravenous or oral administration of the compounds. The dose of compound required to reduce mean blood pressure by 30 mm Hg (IC30) is used as a potency evaluator.

The intraocular pressure reduction effects employed in the present invention can be measured by the method described by Watkins, et al., J. Ocular Pharmacol., 1 (2): 161-168 (1985).

The compounds of Formula (I) are incorporated into convenient dosage forms, such as injectable preparations or, for orally active compounds, capsules or tablets. Solid or liquid pharmaceutical carriers are employed. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate and stearic acid. Liquid carriers include syrup, peanut oil, olive oil, saline and water. Likewise, the carrier or diluent may contain any sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier will vary widely, but will preferably be from about 25 mg to about 1 g per dosage unit. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid, such as a loop, or an aqueous or non-aqueous liquid suspension.

For topical ophthalmic administration, the adapted pharmaceutical compositions include solutions, suspensions, ointments and solid inserts. Typical pharmaceutically acceptable carriers are, for example, water, water miscible solvents and water soluble solvents, such as lower alkanol or vegetable oils and non-toxic, ophthalmologically acceptable water soluble polymers, for example cellulose derivatives such as methylcellulose . The pharmaceutical preparation may also contain non-toxic auxiliary substances such as emulsifying agents, preservatives, wetting agents and builders, for example polyethylene glycols, antibacterial components such as quaternary ammonium compounds; buffer ingredients such as alkali metal chloride; antioxidants such as sodium metabisulfite and other conventional ingredients such as sorbitan mono-laurate.

In addition, suitable ophthalmic vehicles may be used as carrier medium for the purpose in question, including conventional carrier systems of phosphate buffer. The pharmaceutical preparation may also be in the form of a solid insert. For example, a solid water soluble polymer may be used as the vehicle for the medicament. Solid water-insoluble inserts, such as those prepared from ethylene vinyl acetate copolymer, may also be used.

The pharmaceutical compositions are prepared following conventional pharmaceutical chemistry techniques involving mixing, granulating and compressing, when necessary, into tablet forms or blending, filling and dissolving the ingredients, as appropriate, to provide the desired oral, parenteral or topical products.

Dosages of the compounds of Formula (I) in a pharmaceutical dosage unit as described above will be an effective, non-toxic amount selected from the range of 0.1-200 mg / kg of active compound, preferably 1-100 mg / kg. The dose selected is administered to a human patient in need of angiotensin II receptor antagonism, 1-6 times per day, orally, rectally, topically, by injection or continuously by infusion. Oral dosage units for administration to humans preferably contain from 1 to 500 mg of active compound. Lower dosages are preferably used for parenteral administration. However, oral administration at higher doses may also be used when it is safe and convenient for the patient. Topical formulations contain the active compound in an amount selected from 0% to 0.1% (w / v%), preferably 0.0001 to 0.01. As the unit dosage form topically, an amount of active compound comprised between 50 ng and 0.05 mg, preferably between 50 ng and 5 μg, is applied to the human eye. The method of the present invention for antagonizing angiotensin II receptors in mammals, including humans, comprises administering to a subject in need of such antagonism an effective amount of a compound of Formula (I). The method of the present invention for producing antihypertensive activity and the method of treating congestive heart failure, glaucoma and renal insufficiency comprises administering the compound of Formula (X) to a subject in need of treatment in an amount effective for produce the required activity.

Suitable compounds of the formula (I) are those compounds which in any case correspond to them, to which substituents are added at any of the unsubstituted positions of the compounds of formula (I), provided that such compounds have the pharmaceutical utility of the compounds of formula (I).

The following examples illustrate the preparation of the compounds and pharmaceutical compositions of the present invention. The examples are not intended to limit the scope of the invention as described above and is claimed in the claims.

Example 1 (E) -3- [2-n-Butyl-1 - ((5-carboxy-2-thienyl) methyl] -1H-imidazol-5-yl] -2- (2-thienylmethyl- 2-propenoic acid (i) 2-n-butyl-1-pivalyloxymethylimidazole-5-carboxaldehyde

A mixture of valeramidinomethyl ether hydrochloride (250 g, 1.66 mol) and dihydroxyacetone (150 g, 0.83 mol) dissolved in liquid ammonia was dropped resting overnight at room temperature in a pressurized vessel and then heated at 65 " C for 4 hours at 375 psi (2.58 x 10 -3 kPa). The ammonia was allowed to evaporate and the residue was dissolved in methanol (3 L). The resulting slurry was refluxed with acetonitrile (11). 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 while hot and the filtrate was concentrated in vacuo to give the dark oil, 2-n-butyl-5-hydroxymethylimidazole (235 g, 1.63 mol, 98 (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 removed by filtration and the solvent was removed in vacuo. The crude 2-n-butylimidazole-5-carboxaldehyde was used without further purification (16.9 g).

A suspension of 2-butylimidazole-5-aldehyde (16.9 g, 0.111 mol), chloromethyl pivalate (21.77 g, 0.145 mol) and potassium carbonate (20.07 g, 0.145 mol) in 200 ml of dimethylformamide was stirred at room temperature under argon for four days. The solids were removed by filtration 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 in vacuo to give 23.6 g of 2-n-butyl-1-pivalyloxymethylimidazole-5-carboxaldehyde. (ii) 5-bromomethyl-2-carbomethoxythiophene

A solution of 5-methyl-2-thiophenecarboxylic acid (25 g, 0.176 mol) in 500 ml of methanol was saturated with hydrochloric acid gas 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 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. Then, N-bromosuccinimide (13.25 g, 0.074 mol) and dibenzoyl peroxide were 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 under vacuum to give 19 g of 5-bromomethyl-2-carbomethoxythiophene. ... (iii) 2-n-butyl-1 - [(5-carbomethoxy-2-thienyl) methyl] imidazole-5-carboxaldehyde

A mixture of 2-n-butyl-1-pivalyloxymethylimidazole-5-carboxaldehyde (5.0 g, 0.019 mol) and 5-bromomethyl-2-carbomethoxythiophene (4.86 g, 0.021 mol) was heated at 100 ° C under argon for 18 hours. Repeated trituration with ether gave 9.4 g of a crystalline salt. The suspension of this salt in 150 ml of ethyl acetate was stirred for 0.5 hour with 150 ml of 5% aqueous sodium carbonate. The layers were separated, the aqueous layer washed with ethyl acetate, and the combined organic layers were washed with water, dried over magnesium sulfate and concentrated to give an oil. Chromatography of this oil on 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 purified by removal of 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 ethyl 2-carboxy-3- (2-thienyl) propionate. (E) -3- [2-n-butyl-1 - {(5-carbomethoxy-2-thienyl) methyl} -1H-imidazol-5-yl] -2- (2-thienyl) 2-propenoate

A mixture of 2-n-butyl-1 - [(5-carbomethoxy-2-thienyl) methyl] imidazole-5-carboxaldehyde (0.5 g, 1.66 mmol), 2-carboxy-3- thienyl) propionate (1.14 g, 4.99 mmol), piperidine (0.155 g, 1.83 mmol), pyridine (0.5 mL) in 50 mL of benzene was refluxed for 18 h under argon in the presence of a Dean-Stark mousetrap. The crude product was flash chromatographed on silica gel eluting with ethyl acetate / hexane (1: 1) to provide 0.494 g (49%) of (E) -3- [2-n-butyl-1 - {(5 -carbomethoxy-2-thienyl) methyl} -1H-imidazol-5-yl] -2- (2-thienyl) methyl-2-propenoate. (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 (E) -3- [2-n-butyl-1 - {(5-carboxy-2-thienyl) methyl] -1H-imidazol-5-yl] -2- (2-thienyl) 2-propenoate (474 mg, 1.0 mmol) in ethanol (100 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 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 give 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). -26- 73 492 Ρ50015

Example 2 (E) -3- [2-n-Butyl-1 (5-carboxy-2-pyridyl) methyl] -1H-imidazol-5-yl] -2- (2-thienyl) methyl-2-propenoic acid ( i) 2-n-butyl-4-chloro-5-hydroxymethylimidazole To a solution of 2-n-butyl-5-hydroxymethylimidazole (25 g, 0.162 mol), prepared in example 1 (i) in 250 ml of tetrahydrofuran and 250 ml of 2-methoxyethane under argon was added portionwise to N-chlorosuccinimide (26 g, 0.195 mol). The reaction mixture was heated at 50-55 ° C for 2 hours. The solvents were removed in vacuo and the residue ????????? for 48 hours. The solid was filtered and then stirred with 100 ml of diethyl ether for 1 hour. The solid was collected to give 16 g (52%) of 2-n-butyl-4-chloro-5-hydroxymethylimidazole. (ii) 2-n-butyl-1 - [(5-carbomethoxy-2-pyridyl) methyl] -4-chloroimidazole-5-carboxaldehyde To a solution of 2-n-butyl-4-chloroimidazol- 5-carboxaldehyde (17.9 g, 9.6 mmol, prepared from 2-n-butyl-4-chloro-5-hydroxymethylimidazole by oxidation with manganese hydroxide) in 24 ml of dimethylformamide under argon was added potassium carbonate (1.59 g, 11.5 mmol). After stirring at room temperature for 10 minutes, 2-bromomethyl-5-carbomethoxypyridine (2.32 g, 10 mmol, prepared from 6-methylnicotinic acid, using the procedure of example 1 (ii)) was added. The reaction mixture was stirred at 70 ° C for 1.5 hours and then at room temperature for 18 hours. The reaction mixture was partitioned between water and ethyl acetate. The layers were separated and the organic extract was washed with water and brine and dried with magnesium sulfate. The solvent was removed in vacuo and the crude product was flash chromatographed on silica gel eluting with 30% ethyl acetate in hexane to give 2.14 g (67%) of 2-n-butyl-1- [ (5-carbomethoxy-2-pyridyl) methyl] -4-chloroimidazole-5-carboxaldehyde (iii) 2-n-butyl-1 - [(5-carbomethoxy-2-pyridyl) methyl] imidazole-5-carboxaldehyde

A mixture of 2-n-butyl-1 - [(5-carbomethoxy-2-pyridyl) methyl] -4-chloroimidazole-5-carboxaldehyde (1.6 g, 4.76 mmol), potassium acetate (0.47 g, 4.76 mmol) and 10% palladium on carbon (0.16 g) in 150 mL of methanol was hydrogenated at 193 kPa (28 psi) for 2 hours. The solids were filtered and the filtrate was concentrated under vacuum. The residue was dissolved in ethyl acetate and washed with 5% aqueous sodium carbonate solution and brine. The organic extract was dried over magnesium sulfate and concentrated in vacuo. The crude product (1.2 g) in 200 ml of methylene chloride was stirred with 3.0 g of manganese dioxide for 4 hours at room temperature. The solids were removed by filtration and the filtrate was concentrated to give 1.2 g of 2-n-butyl-1 - [(5-carbomethoxy-2-pyridyl) methyl] imidazole-5-carboxaldehyde. (iv) 3- [2-n-butyl-1 - {(5-carbomethoxy-2-pyridyl) methyl} -1H-imidazol-5-yl] -3-hydroxy-2- (2-thienyl) propanoate To a solution of diisopropylamine (0.53 g, 4.98 mmol) in dry tetrahydrofuran (20 mL), maintained at -78 ° C under argon, was added n-butyllithium (1.91 mL, , 78 mol of 2.5M in toluene). After stirring the reaction mixture for 30 minutes, methyl 3- (2-thienyl) propanoate (0.746 g, 4.38 mol) in tetrahydrofuran (5 ml) was added. The mixture was stirred for 30 minutes at -78 ° C. A solution of 2-n-butyl-1 - [(5-carbomethoxy-2-pyridyl) methyl-1H-imidazole-5-carboxaldehyde (1.2 g, 3.98 mmol) in tetrahydrofuran (5 mL) and the resulting mixture was stirred at -78 ° C for 20 minutes. The reaction was partitioned between saturated ammonium chloride solution and diethyl ether, the organic extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated to give 1.8 g of 3- [2-n-butyl-1- { (5-carbomethoxy-2-pyridyl) methyl} -1H-imidazol-5-yl] -3-hydroxy-2- (2-thienyl) methylpropanoate. (V) 3-Acetoxy-3- [2-n-butyl-1 - {(5-carbomethoxy-2-pyridyl) methyl] -1H-imidazol-5-yl] -3- hydroxy-2- (2-thienyl) methylpropanoate

A solution of methyl 3- [2-n-butyl-1 - {(5-carbomethoxy-2-pyridyl) methyl] -1H-imidazol-5-yl] -3-hydroxy- (2-thienyl) methylpropanoate methyl (1/8 g, 3.98 mmol) in methylene chloride (10 mL) was treated with 4-dimethylaminopyridine (0.194 g, 1.59 mmol). Acetic anhydride was then added dropwise to the stirred mixture. The mixture was stirred for 18 hours, water (25 ml) was added, the mixture was stirred for 1 hour and then diluted with diethyl ether and saturated with sodium bicarbonate solution. The ether layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated to give 1.99 g of 3-acetoxy-3- [2-n-butyl-1 - {(5-carbomethoxy-2-pyridyl) methyl} -1 H -imidazol-5-yl] -3-hydroxy-2- (2-thienyl) methylpropanoate. (vi) (E) -3- [2-n-butyl-1 - {(5-carbomethoxy-2-pyridyl) methyl} -1H-imidazol-5-yl] - (2-thienyl) methyl-2-propenoate of methyl

A mixture of 3-acetoxy-3- [2-n-butyl-1 - {(5-carbomethoxy-2-thienyl) methyl} -1H-imidazol-5-yl] -2- (2-thienyl) methylpropanoate (1.99 g, 3.88 mmol) in dry toluene (150 mL) was treated with 17 mL of 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU) and the resulting solution was heated at 80 ° C under argon for 1 hour. The solvent was evaporated, the residue triturated with diethyl ether, and activated charcoal was added. After filtration, the filtrate was concentrated to afford 6.29 g of an oil which was chromatographed over silica gel with hexane / ethyl acetate (1: 1) to give 0.43 g (24%) of (E) -3- [2- -n-butyl-1 - {(5-carbomethoxy-2-thienyl) methyl) -1H-imidazol-5-yl] -2- (2-thienyl) methyl-2-pro-penoate. (E) -3- [2-n-butyl-1 - ((5-carboxy-2-pyridyl) methyl) -1H-imidazol-5-yl] -2- (2-thienyl) methyl-2-propenoic acid The basic hydrolysis of the ester prepared above (0.43 g, 0.95%) as in Example 1 (vi) gave 0.278 g (70%) of (E ) -3- [2-n-butyl-1 - {(5-carboxy-2-pyridyl) methyl} -1H-imidazol-5-yl] -2- (2-thienyl) methyl-2-propenoic acid; mp 212-213 ° C.

Example 3 (E) -3- [2-n-Butyl-1- (5-carboxy-3-thienyl) methyl] -1H-imidazol-5-yl] -2- (2-thienyl) methyl-2-propenoic acid The title compound was prepared following the procedures described in example 1 (v-vi) using 2-n-butyl] -1 - [(5-carbomethoxy-3-thienyl) methyl] imidazole-5-carboxaldehyde (prepared by methods described in Example 2 (i-iii)) in place of 2-n-butyl-1 - [(5-carbomethoxy-2-thienyl) methyl] imidazole-5-carboxaldehyde; mp 133-135 ° C (d).

Example 4 (E) -3- (2-n-Butyl-1- (5-carboxy-2-furyl) methyl-1H-imidazol-5-yl] -2- (2-thienyl) methyl-2-propenoic acid The title compound was prepared following the procedures described in example 1 (v-vi) using 2-n-butyl-1 - [(5-carbomethoxy-2-furyl) methyl] imidazole-5-carboxaldehyde (prepared by the methods described in Example 2 (i-iii)) in place of 2-n-butyl] -1 - [(5-carbomethoxy-2-thienyl) methyl] imidazole-5-carboxaldehyde;

Example 5

An oral dosage form is provided for administration of the orally active compounds of Formula (I) by sieving, mixing and filling into hard gelatin capsules the ingredients in proportions, for example as shown below. -30- '' 73 492 Ρ50015

Ingredients Amounts 100 mg 10 mg 100 mg (E) -3- [2-n-Butyl-1 - {(5-carboxy-2-thienyl) methyl} -1H-imidazol-5-yl] -2- (2-thienyl) methyl-2-propenoic acid magnesium stearate lactose

Example 6

The sucrose, calcium sulfate, dihydrate and the orally active compounds of Formula (I) are mixed and granulated with a 10% solution of gelatin. The wet granules are sieved, dried, mixed with the starch, talc and stearic acid, sieved and compressed into tablets.

Ingredients Amounts (E) -3- [2-n-butyl-1 - {(5-carboxy-75 mg -3-thienyl) 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

To prepare an injectable composition, (E) -3- [2-n-butyl-1 - {(5-carboxy-2-thienyl) methyl} -1H-imidazol-5-yl] -2- ( 2-thienyl) methyl-2-propenoic acid, 50 mg, in 25 ml of normal saline.

Example 8

A topical ophthalmic composition for administration of the compounds of Formula (I) is produced by mixing, under sterile conditions, the ingredients in proportions, for example as shown below.

Ingredients

Amounts (ml / ml) 1.0 10.4 2.4 5.0 5.0 q.s. to 1.0 ml q.s. to pH 7.4 (E) -3- [2-n-Butyl-1 - {(5-carboxy-2-furyl) methyl} -1H-imidazol-5-yl] -2- (2-thienyl) ) methyl-2-propenoic acid sodium phosphate dibasic sodium phosphate monobasic chlorobutanol hydroxypropanol methylcellulose sterile water

1.0 N sodium hydroxide

It should be understood that the invention is not limited to the embodiments illustrated above and that the right to the illustrated embodiments and to all modifications within the scope of the appended claims is reserved.

Claims (18)

A compound having the formula: â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ- Wherein R 1 is Het, wherein Het is defined as a 5 to 7 membered monocyclic or 7 to 10 membered bicyclic heterocyclic ring which is 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 be optionally quaternized and any bicyclic group in which any of the heterocyclic rings defined above is fused to a benzene ring and wherein Het is unsubstituted or substituted by any stable stable combination of up to three substituents selected from the group consisting of C 1 -C 6 alkyl C C alco alcoalkyl, C C alco alcoalkyl, C Cg alcoalkyl, C Cg alcoalkyl, C C alco alcoalkyl, C C alco alcoalkyl, C C alco alcoalkyl, C C alco alcoalkyl, C C alco alcoalkyl, C C alco alcoalkyl, C C alco alcoalkyl, C C alco alcoalkyl, C C alco alcoalkyl, C C alco alcoalkyl, C C alco alcoalkyl, C C alco alcoalkyl, NR 7 COO or NR 7 CO- (C 1 -C 6) alkyl, wherein W is C n F 2 n + 1, wherein n is 1-3 and wherein A is -CH = (CH2) q-4, -Q-CH (R9) -, or -Q- (CH2) i-2, wherein Q is O, S, NH, or N-alkyl C 1 -C 6, U is absent or present as O, S, NH or N-C 1 -C 6 alkyl, and R 9 is hydrogen, phenyl or benzyl; m is 0-4; R 2 is C 2-10 alkyl, C 3-10 alkenyl, C 3-10 alkynyl, C 3-6 cycloalkyl, or (CH 2) o -phenyl, unsubstituted or substituted by one to three substituents selected from C 1 -C 6 alkyl, nitro, Cl, Br, F, hydroxy, C ^-C alco alkoxy, NR 7 R 7, CO 2 R 7, CN, COOR 7 R 7, W, tetrazol-5-yl, NR 7, CO-C 6 -C 8 alkyl, NR 7 CO, S-C 1-4 alkyl, SO 2 W, or SO 2 -C X is a single bond, S, NR 7 or O; -33- 73 492 Ρ50015 __ '. R 3 is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl, C 5 R 7, CONR 7 R 7, NO 2, W, CN, NR 7 R 7 or phenyl; R4 and R5 are independently hydrogen, C1 -C6 alkyl, 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 -, each aryl or heteroaryl group being unsubstituted or substituted by C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, Cl, Br, F, I, NR 7 R 7, CO 2 R 7, SO 2 NHR 7, SO 3 H, CONR 7 R 7, OH, NO 2, W, SO 2 W, S C1-6 alkyl, SO2 C1-6 alkyl, NR7 COOH, NR7 COW or NR7 CO-C1-6 alkyl; ... Y is a single bond, O, S or C 1 -C 6 alkyl which is linear or branched or optionally substituted by phenyl or benzyl, wherein each phenyl or benzyl group is unsubstituted or substituted by halo, NO 2, CF 3, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, CN or CO 2 R 7; R6 is -Z-C00R8, -Z-CO-NR7R7 or -Z-tetrazol-5-yl; Z is a single bond, vinyl, -CH 2 O-CH 2 -, methylene optionally substituted by C 1 -C 6 alkyl, one or two benzyl, thienylmethyl or furylmethyl groups or -C (O) NHCHR 9 -, wherein R 9 is H, C1-6 alkyl, phenyl, benzyl, thienylmethyl or furylmethyl; W is C n F 2n + 1, wherein n is 1-3; each R7 is independently hydrogen or C1 -C6 alkyl, and R8 is hydrogen, C1 -C6 alkyl or 2-di (C1 -C4) alkyl-amino-2-oxoethyl, or a pharmaceutically acceptable salt thereof. A compound according to claim 1, wherein R 1 is piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidinyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl , imidazolinyl, imidazolidinyl, imidazolidinyl, 2,3 or 4-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazolyl, benzopyranyl , benzothiazolyl, benzoxazolyl, 2 or 3-furyl, pyranyl, tetrahydrofuryl, tetrahydropyranyl, 2 or 3-thienyl, benzothienyl, benzoxazolyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulphone, benzofuranyl or oxadiazolyl , each R1 group being unsubstituted or substituted by any stable stable combination of up to three substituents selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, Cl, Br, F, I, NR 1 R 1, A-CO 2 R 1, SO 2 NHR 1, SO 3 H, CONR 1 R 1 / OH, NO 2, W, SO 2 W, , SO2-C1-6 alkyl, NR1 COH, NR1 COW or NR1 CO- (C1 -C6) alkyl; wherein W is C n F 2n + 1 / wherein n is 1-3 and wherein A is -CH = CH-, - (CH 2) q-4 -O-CH (R 9) -, or -Q- (CH 2) -O- (CH2) l-2-, wherein Q is 0, S ', NH, or N-C1-6 alkyl, U is absent or present as O, S, NH or N- And R 9 is hydrogen, phenyl or benzyl. A compound according to claim 2, wherein R 1 is 2 or 3-thienyl, 2 or 3-furyl or 2,3 or 4-pyridyl, each thienyl, furyl or pyridyl group being unsubstituted or substituted by CO 2 R 1 to be 0 -2. A compound according to claim 3, wherein X is a single bond or S, R 2 is C 2 -C 6 alkyl, R 3 is hydrogen, chloro, fluoro or trifluoromethyl and R 2 is hydrogen or C 1 -C 6 alkyl. A compound according to claim 4, wherein R 5 is 2 or 3-thienyl-Y-, 2 or 3-furyl-Y- or 2,3 or 4-pyridyl-Y-, each thienyl group, furyl or pyridyl unsubstituted or substituted by methyl or methoxy and Y is a single bond or C1-6 alkyl which is linear or branched. A compound according to claim 5, wherein R6 is -Z-C00R2, wherein Z is a single bond and R2 is hydrogen or C1 -C6 alkyl. A compound according to claim 6, characterized in that it is the E-isomer, wherein the COOR 2 group and the imidazole are transient to each other. A compound according to claim 7, characterized in that it is (E) -3- [2-n-butyl-1 - {(5-carboxy-2-thienyl) methyl} imidazol-5-yl] -2- (2-thienyl) methyl-2-propenoic acid or a pharmaceutically acceptable salt thereof. A compound according to claim 7, characterized in that: (E) -3- [2-n-butyl-1 - {(5-carboxy-3-thienyl) methyl} -1H-imidazol-5- yl] -2- (2-thienyl) methyl-2-propenoic acid? (E) -3- [2-n-butyl-1 - {(5-carboxy-2-furyl) methyl] -1H-imidazol-5-yl] -2- (2-thienyl) propenoic acid; or (E) -3- [2-n-butyl-1 - ((5-carboxy-2-pyridyl) methyl] -1H-imidazol-5-yl] -2- (2-thienyl) 2-propenoic acid; or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a pharmaceutical carrier and a compound of claim 1. A compound according to claim 1 for use in antagonizing angiotensin II receptor. A compound according to claim 1 for use in the treatment of hypertension. A compound according to claim 1 for use in the treatment of congestive heart failure. A compound according to claim 1 for use in the treatment of renal insufficiency. A compound according to claim 1 for use in the treatment of glaucoma. Use of a compound according to claim 1 in the preparation of a medicament for the antagonization of angiotensin II receptors. Use of a compound according to claim 1 in the preparation of a medicament for the treatment of hypertension. -36- 73 492 Ρ50015 Use of a compound according to claim 1 in the preparation of a medicament for the treatment of congestive heart failure. Use of a compound according to claim 1 in the preparation of a medicament for treating renal insufficiency. Use of a compound according to claim 1 in the preparation of a medicament for treating glaucoma. Lisbon, 15. MAI 1992 By SMITHKLINE BEECHAM CORPORATION = 0 OFFICIAL AGENT =