SI9200228A - Imidazolyl-alkenoic acids - Google Patents

Abstract

Angiotensin li receptor antagonists that are imidazolyl-alkenoic acids are useful for regulation hypertension and in the treatment of congestive failure heart, kidney and glaucoma failure, pharmaceutical compositions containing these anatagonists and methods use of these compounds to produce angiotensin II receptor antagonism in mammals.

Description

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

BACKGROUND OF THE INVENTION

The peptide pressor hormone class, known as angiotesin, is responsible for vasopressor function that is involved in the etiology of hypertension in humans. Inadequate functioning of renin-angiotensin systems appears to be a key element in essential hypertension, congestive heart failure and in some forms of kidney disease. In addition to direct action on the arteries and arterioles of angiotensin II (Ali), which is one of the best known effective potential endogenous vasoconstrictors, it stimulates the release of aldosterone from the adrenal cortex. Therefore, due to its involvement in the control of renal sodium regulation, the reninangiotensin system plays an important role in cardiovascular haemostasis.

Discontinuation of the renin-angiotensin system by conversion of enzyme inhibitors such as captopril has proven clinically useful in the treatment of hypertension and congestive heart failure (Abrams, W.B., et al., (1984), Federation Proc., 43,1314). The most direct approach to inhibiting the renin-angiotensin system would block the action of Ali at the receptor. Evidence suggests that Ali also contributes to renal vasoconstriction and sodium retention, which is characterized by many abnormalities such as heart failure, cirrhosis, and pregnancy complications (Hollenberg, NK, (1984), J. Cardiovas. Pharmacol., 6, S176 ). In addition, current animal studies suggest that inhibition of the renin-angiotensin system may be useful in delaying or slowing the progression of chronic renal failure (Anderson, S., et al., (1985), J. Ciin. Invest., 76, 612 ). Thus, a recent patent application (FOR patent application Nos. 87/01, 653) claims that AII antagonists are useful as a means of reducing and controlling elevated intraocular pressure, especially glaucoma, in mammals.

The compounds of this invention inhibit, block and antagonize the action of the hormone Ali and are therefore useful in the regulation and moderation of angiotensin-induced hypertension, congestive heart failure, renal failure and other abnormalities attributable to the action of Ali. If the compounds of this invention are administered to mammals, the elevated blood pressure due to Ali is reduced and other manifestations based on AII mediated are minimized and controlled. The compounds of this invention are therefore expected to have diuretic activity.

Recognizing the importance of blocking and inhibiting the action of AII, it encouraged other efforts to synthesize the AII antagonist. The following references describe imidazole derivatives that are said to contain AII blocking action and are useful as hypotensive agents.

In Furukawa et al., 4,340,598, imidazol-5-yl-acetic acids and imidazol-5-yl-propanoic acids and imidazol-5-yl-propanoic acids are described. The compounds specifically described are 1-benzyl-2-n-butyl-5-chloroimidazole-4-acetic acid and 1-benzyl-2-phenyl-5-chloroimidazole-4-propanoic acid.

In Furukawa et al., 4,355,040, substituted imidazole-5-acetic acid derivatives are described. The compound specifically described is 1- (2-chlorobenzyl) -2-n-butyl-4-chloroimidazole-5 acetic acid.

In Carini et al. EP 253,310 describes some imidazolylpropenoic acids. The two intermediates described in this patent are ethyl 3- [1- (4-nitrobenzyl) -2-butyl-4-chloroimidazol-5-yl] propenoate and ethyl 3- [2-butyl-4-chloro-1- (4- aminobenzyl) imidazol5-yl] propenoate.

Also in Wareing, in PCT / ep 86/00297, some imidazolylpropenoate compounds are described as intermediates. On page 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 that are angiotensin II receptor blockers are:

(E) -3- [2-n-Butyl-1 - {(4-carboxynaphth-1-yl) 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] ethyl ester 2 (2-thienyl) methyl-2-propenoic acids;

or a pharmaceutically acceptable salt and methanesulfonate of (E) -3- [2-n-butyl-1- {(4-carboxyphenylmethyl} -1H-imidazol-5-yl] 2 (2-thienyl) methyl-2-propenoic acid.

The invention also relates to pharmaceutical compositions containing pharmaceutical carriers and to an effective amount of a compound named above.

The present invention also encompasses methods for antagonizing angiotensin II receptors, comprising administering to the subject in need of therapy effective amounts of the above-named compound. The invention also encompasses methods of treating hypertension, congestive heart failure, glaucoma and renal failure by administering these compounds.

The compounds of this invention are prepared by the methods described in the present application and illustrated by examples. The reagents, protecting groups and functionality on imidazole and other fragments of the molecule must be consistent with the proposed chemical transformations. The steps in the synthesis must be compatible with the functional groups and the protecting groups on the imidazole and other parts of the molecule.

The starting material, 2-n-butylimidazole, is known in the art (J. Org. Chem. 45: 4038,1980) or synthesized by known methods. E.g. imidazole is converted to 2-n-butylimidazole by reaction of imidazole with triethylorthoformate and p-toluenesulfonic acid to give

1-diethoxythoroamide imidazole and then treated with n-butyl lithium to give the 2-lithium orthoamide derivative and alkylated with n-butyl iodide in a suitable solvent such as e.g. tetrahydrofuran (THF).

The 1-substituted naphthyl or benzyl group is incorporated into 2-n-butylimidazole by known methods, e.g. by reaction with subst. naphthyl or benzyl halide, mesylate or acetate such as 2-chlorobenzyl bromide or 4-carbomethoxybenzyl bromide in a suitable solvent such as dimethylformamide (DMF) in the presence of a suitable acid acceptor such as sodium alkylate, potassium or sodium carbonate or metal hydride , preferably sodium hydride, at a reaction temperature of from about 25 ° C to about 100 ° C, preferably about 50 ° C. The resulting 1-substituted-naphthyl or benzyl-2-n-butylimidazole is hydroxymethylated at position 5, e.g. by reaction with formaldehyde in the presence of sodium acetate in acetic acid to give 1-substitu-naphthyl or-benzyl-2-n-butyl-5-hydroxymethylimidazole intermediates.

Alternatively, the 5-hydroxymethyl-imidazole intermediates prepared above are prepared by reaction of imido ether, such as valeramidine methyl ether, with dihydroxyacetone in liquid ammonia under pressure to give 2-n-butyl-5-hydroxymethylimidazole. This intermediate is reacted with acet anhydride to give 1-acetyl-5-acetoxymethyl-2-butylimidazole. The diacetate intermediate is N-alkylated, e.g. using 2-chlorobenzyl triflate or 4-carbomethoxybesyl triflate, and the resulting 1-subst.-2-n-butyl-5-acetoxymethylimidazole is treated with an aqueous base such as 10% sodium hydroxide solution to obtain the previously described 5-hydroxymethylimidazole itermediate.

The hydroxymethyl group of the intermediate prepared above is oxidized to the aldehyde by treatment with a suitable reagent such as anhydrous chromic acid-silica gel in tetrahydrofuran, or preferably activated manganese dioxide, in a suitable solvent such as benzene or toluene, or preferably in methylene chloride, at a temperature of methylene chloride. from about 25 ° C to about 140 ° C, preferably at 25 ° C. Imidazole-5-carboxaldehyde is reacted with a suitable phosphonate such as trimethyl-3 - (- 2-thienyl) -2-phosphonopropionate. Phosphonates are prepared, e.g. from trialkyl phosphonoacetates by alkylation with a suitable halide, mesylate or acetate, in the presence of a suitable base such as sodium hydride, in a suitable solvent, preferably in glyme, at a reaction temperature of from about 25 ° C to about 110 ° C, preferably at about 55 ° C to provide suitable phosphonates. The reaction of imidazole-5-carboxaldehydes with phosphonates is carried out in the presence of a suitable base, such as metal alkoxide, lithium hydride, or preferably sodium hydride, in a suitable solvent such as ethanol, methanol, ether, dioxane, tetrahydrofuran, or preferably glyme, at the reaction temperature from about 10 ° C to about 50 ° C, preferably at about 25 ° C, to provide a variable mixture of trans and cis, e.g. (E) and (Z), 1-subst.-2-n-butyl-5CH = C [(2-thienyl) methyl] - (COOalkyl) -imidazoles. These isomers are easily separated by silica gel chromatography in suitable solvent systems, preferably in mixtures of hexane and ethyl acetate. The esters are hydrolyzed to the corresponding acidic compounds using a base such as potassium hydroxide, lithium hydroxide or sodium hydroxide in a suitable solvent system such as e.g. aqueous alcohols or diglyme.

Alternatively, l-subst.-2-n-butylimidazole-5-carboxaldehydes are prepared by the following procedure. The starting 2-n-butylimidazole-5-carboxyaldehyde is reacted with an N-alkylating protective reagent such as chloromethyl pivalate (P0M-C1) in the presence of a base such as potassium carbonate in a suitable solvent such as dimethylfomamide at a temperature of about 20 ° C to about 50 ° C, preferably at about 25 ° C, to give N-alkylation (e.g. POM derivation) on the last obstructed nitrogen atom of the imidazole nucleus.

The 1-substituted-naphthyl or -benzyl group is included on imidazole by N-alkylation of the above prepared aldehyde with halomethylbenzene compounds such as methyl

4-Bromomethylbenzoate or methyl 4-bromomethylnaphthalene-1-carboxylate, at a temperature of from about 80 ° C to about 125 ° C, preferably at about 100 ° C. Protective group at

The 3-nitrogen of the imidazole ring is removed by alkaline hydrolysis, e.g. using a two-phase mixture of ethyl acetate and aqueous sodium carbonate to give l -substimidazole-5-carboxaldehyde compounds. The compounds of this invention can be prepared from these 5-carboxaldehyde compounds by the methods described above.

Alternatively, the starting 2-n-butylimidazole materials are reacted with trimethylsilylethoxymethyl (SEM) chloride to give 1- (trimethylsilyl) -ethoxymethyl-2-n-butylimidazole. The reaction is carried out, e.g. in the presence of sodium hydride, in a solvent such as dimethylformamide. The 5-tributyltin derivatives are prepared by lithiation, e.g. with butyl lithium in a suitable solvent, preferably diethyl ether, and then by treating the lithio imidazole derivative with tributyltin halide, preferably with tri-n-butyltin chloride, from about -10 ° C to about 35 ° C, preferably at about 25 ° C. 1-SEM-2-n-butyl-5tributylquositerimidazole is attached to the ha, / 3-unsaturated acid ester having a leaving group at position β, such as a halide or trifluoromethanesulfonyloxy group, e.g. BrCR ⁴ = BrCR ⁴ = C [(2-thienyl) methyl] (COOalkyl) in the presence of a phosphine ligand such as bis (diphenylphosphino) propane, or triphenylphosphine and palladium (II) compound, or preferably tetrakis (triphenylphosphine) palladium (0) , with or without a base such as tributylamine, at a temperature of from about 50 ° C to about 150 ° C, preferably at about 120 ° C. Both, (E) and (Z), the olefin isomers are prepared by this process, and the isomeric esters are easily separated by chromatography over silica gel. The 1-SEM group of (E) and (Z) isomers is hydrolyzed with an acid, e.g. hydrogen chloride, in a suitable alcoholic solvent such as methanol or ethanol, and 1-unsubst. imidazole derivatives were converted to 1-tbutoxycarbonyl (t-BOC) imidazoles with di-t-butyl dicarbonate (Hoppe-Seyler's Z.

Physiol. Chem., (1976), 357, 1651). t-BOC esters are alkylated and hydrolyzed by e.g.

2-chlorobenzyl triflate or 4-carbomethoxybenzyl triflate, in the presence of a suitable base, preferably diisopropylethylamine, in a suitable solvent, preferably methylene chloride, to give l-substimidazole derivatives (esters). The (E) and (Z) isomers are hydrolyzed to (E) and (Z) acids by the method described above.

The compounds of the present invention are also prepared by the following procedure.

The 1-subst.-2-n-butyl-imidazole-5-carboxaldehyde prepared as described above is reacted with a substituted semi-acidic, semi-ester derivative of malonate, such as ethyl 2-carboxy-3- (2-thienyl ) propionate, in the presence of a base such as piperidine, in a suitable solvent such as toluene, at a temperature of from about 80 ° C to about 110 ° C, preferably at about 100 ° C. The resulting 1-subst.-2-n-butyl-5-CH = C (R ⁵ ) COOalkylimidazoles are hydrolyzed to the corresponding compounds of the present invention by alkaline hydrolysis as described above.

Alternatively, the compounds of the present invention are prepared as follows. The 1-subst.-2n-butyl-imidazole-5-carboxaldehyde prepared as indicated above is treated with a lithium derivative of substituted ethyl or methyl ester. These lithium derivatives are prepared by reacting lithium diisopropylamide in a suitable solvent, preferably tetrahydrofuran, with an acid ester such as ROOC-CH ₂ -CH ₂ - (2-thienyl) to give α-lithio derivatives at from about -78 ° C to about -10 ° C, preferably at about -78 ° C, which is then treated with imidazole-carboxaldehyde. The intermediate / 3-hydroxy group of the imidazole ester is converted to mesylate or acetate, and the mesylate or preferably acetate is heated in a suitable solvent, such as toluene, with one to two equivalents of 1.8-diazo-bicycle 5.4.0undec-7-one, at about 50 ° C to about 110 ° C, preferably at about 80 ° C, to give 3- (imidazol-5-yl) -2- (2-thienyl) methyl-2-propenoic acid esters. (E) The isomer is the predominant olefin isomer. Acids are prepared from esters by the method described above.

Compounds of the present invention in which the substituent at position 1 of the imidazole ring substituted with carboxy are obtained from compounds in which this group is substituted with C 1 -C 6 -alkyl using alkaline hydrolysis such as aqueous sodium or potassium hydroxide in methanol or ethanol, or using acid hydrolysis such as aqueous hydrochloric acid.

The pharmaceutically acceptable acid addition salts of the compounds of the invention are prepared with suitable organic or inorganic acids by known methods. E.g. the base is reacted with the addition of inorganic or organic acid in a water miscible solvent such as ethanol by isolating the salt by removing the solvent or in a water immiscible solvent when the acid in such solvent is soluble such as ethyl ether or chloroform, the desired salt being separated directly or isolated by solvent removal. Representative examples of suitable acids are maleic, fumam, benzoic, ascorbic, pamoic, succinic, bimethylene salicylic, methanesulfonic, ethandisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, aminobutyric , benzenesulfonic, hydrochloric, hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric acids.

Pharmaceutically acceptable base addition salts of the davits of the compounds of the invention in which R ⁸ is H, are prepared by known methods from organic and inorganic bases, including nontoxic alkali metal bases and alkaline earth, such as. calcium, lithium, sodium and potassium hydroxide; ammonium hydroxide and non-toxic organic bases such as triethylamine, butylamine, piperazine, meglumine, choline, diethanolamine and tromethamine.

The angiotensin II antagonistic activity of the compounds of the invention is determined by in vitro and in vivo methods. In vitro antagonistic activity is determined by the ability of the compounds to compete with ¹²⁵ I-angiotensin II for binding to vasculature angiotensin II receptors and by their ability to antagonize the contractile response to angiotensin (II) in the isolated rabbit aorta. In vivo function is evaluated by the efficacy of the compounds to inhibit the pressor response to exogenous angiotensin II in conscious rats and to reduce blood pressure in a rat model with renin-dependent hypertension.

Bind

An attempt at radioligand binding is a modification of the previously described method (Gunther et al., Circ. Res. 47: 278, 1980). A special fraction from rat mesenteric arteries was incubated in Tris buffer with 80 pM ¹²⁵ I-angiotensin II, with or without angiotensin II antagonists, for 1 hour at 25 ° C. Incubation was terminated by rapid filtration and the receptor-bound ¹²⁵ I-angiotensin II captured on the filter was quantified with a gamma counter. The potency of angiotensin II antagonists is expressed as IC ₅₀ , and is the concentration of the an8 antagonist required to displace 50% of all specifically bound angiotensin II. Exemplary IC _{50 of the} compounds of the invention (E isomers) is about 0.1 nM to about 30 mM.

The aorta

The ability of the compounds to antagonize angiotensin II-induced vasoconstriction is tested in the rabbit aorta. The ring segments were excised from the rabbit thoracic aorta and suspended in organic baths containing saline. The ring segments are loaded via metal supports and secured to force-shifting laptops connected to the binder. Cumulative angiotensin II concentration response curves are presented without antagonist, or after incubation for 30 minutes, with antagonist. Dissociation constants of the antagonist (K _B ) are calculated by the dose ratio method using average effective concentrations. Exemplary K _B compounds of the invention (E isomers) are from about 0.1 nM to about 0.50 nM.

Inhibition of pressor response to angiotensin II in conscious rats.

Rats were prepared by implanting a femoral arterial and venous catheter and gastric tube (Gellai et al., Kidnev Int. 15: 419, 1979). Two to three days after the operation, the rats were caged and blood pressure was continuously monitored from an arterial catheter with a pressure transducer and recorded on a polygraph. The change in mean arterial pressure in response to intravenous injection of 250 mg / kg angiotensin II is compared at different time points before and after administration of the compounds intravenously or orally at doses of 0.1 to 300 mg / kg. The dose of the compound required for 50% inhibition of the control response to angiotensin II (IC ₅₀ ) was used to determine the effectiveness of the compounds.

Antihypertensive activity

The antihypertensive activity of the compounds is measured by their ability to lower average arterial pressure in conscious rats that have been induced by renin-dependent hypertension by ligation of the left renal artery (Cangiano et al., J. Pharmacol. Exp. Ther. 208: 310,1079). Rats with tethered renal artery were prepared by implanting catheters as described above. Seven to eight days after the renal artery lining, during which time the renin plasma levels are highest, conscious rats are transferred to the cages and continuous average arterial pressure is recorded before and after administration of the compounds intravenously or orally. The dose of the compound required to lower the mean arterial pressure by 3999.66 Pa (30 mm Hg) (IC. ^) Was used as an estimate for efficacy.

The effects of intraocular pressure reduction used 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 the present invention are incorporated into suitable dosage forms, such as injectable preparations, or for oral active compounds into capsules or tablets. Solid or liquid pharmaceutical carriers are used. Solid carriers include starch, lactose, calcium sulfate dihydrate, terro albo, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Liquid carriers include syrup, peanut oil, olive oil, brine and water. Similarly, the carrier or diluent may include any prolonged-release material, such as glyceryl monostearate or glyceryl distearate, alone or with wax. The amount of solid carrier varies widely, but preferably should be from about 25 mg to about 1 g per dosage unit. If a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injection fluid such as an ampoule, or aqueous and non-aqueous liquid suspensions.

For topical ophthalmic administration, customized pharmaceutical compositions include solutions, suspensions, ointments and solid inclusions. Typical pharmaceutically acceptable carriers are e.g. water, mixtures of water and water miscible solvents such as lower alkanols or vegetable oils, and water-soluble ophthalmologically acceptable non-toxic polymers such as e.g. cellulose derivatives such as methyl cellulose. The pharmaceutical preparation may also contain non-toxic excipients such as emulsifying, preserving, wetting and thickening agents, such as e.g. polyethylene glycols; antibacterial components, which are quaternary ammonium compounds; buffering ingredients such as alkali chloride; antioxidants such as sodium metabisulphite; and other common ingredients such as sorbitan monolaurate.

Additionally, suitable ophthalmic carriers may be used as carrier media for the stated purpose, which include conventional phosphate buffer carrier systems.

The pharmaceutical preparation may also take the form of a solid inclusion. E.g. a solid water-soluble polymer can be used as a carrier for the drug. Solid water-soluble inclusions, such as those made from ethylene vinyl acetate copolymer, may also be used.

The pharmaceutical compositions are prepared according to conventional pharmaceutical techniques, which include mixing, granulating and compressing, where necessary, into tablet forms, or mixing, filling and dissolving ingredients as appropriate to obtain the desired oral, parenteral or topical products.

Doses of the compounds of the present invention, in the pharmaceutical dosage unit as described above, will be in an effective non-toxic amount selected from the range 0.01 - 200 mg / kg of the active compound, preferably 1-100 mg / kg. The selected dose is administered to a human patient in need of angiotensin II receptor antagonizing therapy, 1 - 6 times daily, orally, rectally, topically, by injection, or continuously by infusion. Oral dosage units for human administration preferably contain from 1 to 500 mg of the active compound. It is preferably used for parenteral administration of a lower dose. Oral administration at higher doses can, of course, also be used when it is safe and appropriate for the patient. Topical preparations contain the active compound in an amount selected from 0.0001 to 0.1 (w / v%), preferably from 0.0001 to 0.01. As a topical dosage unit, an amount of the active compound between 50 ng to 0.05 mg, preferably 50 ng to 5 mg, is administered to the human eye.

No unacceptable toxicological effects are expected when the compounds of the present invention are administered in accordance with the present invention.

The methods of this invention for antagonizing angiotensin II receptors in mammals, including humans, include administering to a subject in need of such antagonism an effective amount of a compound of the present invention. The method of this invention, the attainment of antihypertensive activity, and the method of treating congestive heart failure, glaucoma and renal failure, comprises administering the compound of the present invention to a subject in need of therapy in an effective amount to achieve said activity.

Equivalents of the compounds of the present invention are compounds which otherwise correspond to the latter, where substituents have been added to any unsubstituted position of these compounds, provided that such compounds have the pharmaceutical utility of the compounds of the present invention.

The following examples illustrate the preparation of the compounds and pharmaceutical compositions of the present invention. By way of example, it is not intended to limit the scope of the present invention as defined in the patent application above and as required below.

EXAMPLES

Example 1 (E) -3- [2-n-Butyl-1 - {(2-chlorophenyl) methyl} -1H-imidazol-5-yl] -2- (2-thienyl) methyl-2-propenoic acid (and 2-n-butyl-1- (2-chloro-phenyl) methyl-1H-imidazole

Imidazole is converted to the 1-diethoxythoroamide derivative by the method of Curtis and Brown, J. Org. Chem., (1980) 45, 20. Imidazole (12.8 g, 0.19 mol) and 118.4 g (0.8 mol) of triethylorthoformate are reacted in the presence of 1 g of p-toluenesulfonic acid to give 20. 6 g (61%), boiling point. 65-70 ° C (0.1 mm) 1-Diethoxythoroamide imidazole. This product (24.0 g, 0.14 mol) was dissolved in dry tetrahydrofuran (250 ml), cooled to -40 ° C and nbutyl lithium (0.14 mol, 56.4 ml 2.5 M in hexane) was added at -40 ° C to -35 ° C. After 15 minutes, n-butyl iodide (31.1 g, 0.169 mol) was added at -40 ° C and the reaction was stirred overnight at ambient temperature. The reaction mixture was partitioned between ether and 0.3 N hydrochloric acid, and the organic layer was repeatedly extracted with dilute hydrochloric acid. The combined aqueous extracts were neutralized with sodium bicarbonate solution, extracted with methylene chloride, dried over magnesium sulfate and concentrated. Flash distillation on a Kugelrohr apparatus yielded 14.8 g (85%) of 2-n-butylimidazole.

2-n-butylimidazole (9.7 g, 0.078 mol) was dissolved in methanol (50 ml) and added dropwise to a solution of sodium methoxide (sodium hydride (2.31 g, 0.0934 mol) in methanol (250 ml) ). After one hour, the solution was evaporated to dryness and the sodium salt was taken up in dry dimethylformamide (150 ml), and dry dimethylformamide (150 ml) and 2-chlorobenzyl bromide (16.3 g, 0.079 mol) were added. The mixture was heated at 50 ° C for 17 hours under argon, poured onto ice water and the product extracted into ethyl acetate. The extract was washed, dried and concentrated to give 18.5 g of crude product chromatographed over silica gel with 2: 1 ethyl acetate / hexane to give 11.9 g (61%) of 2-n-butyl-1 "( 2-chlorophenyl) methyl-1H-imidazole as an oil. Thin layer chromatography on silica gel with 4: 1 ethyl acetate / hexane gave an R _f value of 0.59.

(ii) 2-n-butyl-1- (2-chlorophenyl) methyl-5-hydroxymethyl-1H-imidazole

Method 1

Mixture of 2-n-butyl-1- (2-chlorophenyl) methyl-1H-imidazole (95.5 g, 0.384 mol), 37% formaldehyde (500 ml), sodium acetate (80 g) and acetic acid (60 ml) heated to reflux for 40 hours under argon. The reaction mixture was concentrated in vacuo and the residue was stirred with 500 ml of 20% sodium hydroxide solution for 4 hours, diluted with water and extracted with methylene chloride. The extract was washed, dried and concentrated. The crude product (117 g) was flash chromatographed over 600 g of silica gel with a gradient of ethyl acetate on 10% methanol in ethyl acetate to give 8.3 g of starting material, 24.5 g of a mixture of starting material and product, and 44 g (41%) 2-n-butyl-1 (2-chlorophenyl) -methyl-5-hydroxymethyl-1H-imidazole; m.p. 86-88 ° C (from ethyl acetate). Further dilution gave the bis (4,5-hydroxymethyl) derivative; m.p. 138-140 ° C (from ethyl acetate).

Method 2

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 at room temperature overnight in a pressure vessel and was then heated at 65 ° C 4 hours at 2585.5. 10 ³ Well. Allow the ammonia to evaporate and dissolve the residue in methanol (3 L). The resulting suspension was refluxed with acetonitrile (1 L) added. The solution is still hot decanted from solid ammonium chloride. This process was repeated several times and the combined acetonitrile extracts were treated with charcoal, hot filtered and the filtrate concentrated in vacuo to give 2-n-butyl-5-hydroxymethylimidazole (253 g, 1.63 mol, 98%) dark oil.

This crude alcohol (253 g) was treated with acetate anhydride (400 ml) at -15 ° C and then allowed to warm to ambient temperature with stirring and then stirred for 19 hours. The acetate anhydride is evaporated under reduced pressure, the residue is taken up in methylene chloride and the organic phase is 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-butyl imidazole.

This diacetate is N-alkylated by the following procedure. To a solution of triflate 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 2-chlorobenzyl alcohol (104 g, 0, 72 mol) in methylene chloride (350 ml) in 20 minutes. After stirring for an additional 20 minutes at -78 ° C, this solution was treated with 1-acetyl-4-acetoxymethyl-2-butylimidazole (146 g, 0.61 mol) dissolved in methylene chloride (300 ml) in 20 minutes interval. The mixture was then stirred at ambient temperature for 18 hours and the solvents were evaporated. The other 2-n-butyl-5-acetoxymethyl-1- (2-chlorophenyl) methyl-1H-imidazole was used without purification to hydrolyze the acetate group.

A solution of crude 2-n-butyl-5-acetoxymethyl-1- (2-chlorophenyl) methyl-1H-imidazole (250 g) in methanol (200 ml) was treated with 10% sodium hydroxide solution (700 ml) and the mixture warmed on the steam bath for 4 hours. After cooling, methylene chloride is added, the organic phase is separated, washed with water, dried and concentrated. The residue was dissolved in ether, cooled and split to give the crude product. Recrystallization from ethyl acetate yields 176 g of 2-n-butyl-1- (2-chlorophenyl) methyl-5-hydroxymethyl-imidazole; m.p. 86-88 ° C. This material is identical in all respects to the material prepared by Method 1.

(iii) 2-n-butyl-1- (2-chlorophenyl) methyl-1H-imidazole-5-carboxaldehyde

A solution of 2-n-butyl-1- (2-chlorophenyl) methyl-5-hydroxymethyl-1H-imidazole (5.4 g, 0.0194 mol) in toluene (25 ml) was added to a suspension of activated magnesium dioxide (27 g) and methylene chloride (325 ml). The suspension was stirred at room temperature for 17 hours. The solids were filtered off and the filtrate concentrated, and flash chromatography over silica gel with 6: 4 hexane / ethyl acetate gave 4.16 g (78%) of 2-n-butyl-1- (2-chlorophenyl) methylH-imidazole-5- carboxaldehyde as an oil. NMR and IR are consistent with the structure.

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

Method A

a) Trimethyl 3- (2-thienyl) -2-phosphonopropionate

To a solution of 2-thiophenmethanol (2.28 g, 0.02 mol) in carbon tetrachloride (25 ml) was added triphenylphosphine (6.81 g, 0.026 mol) and the solution refluxed for 3 hours. The cooled reaction mixture was diluted with hexane (60 ml), cooled and filtered. The concentrated filtrate (4.6 g) was flash chromatographed over silica gel with 7: 3 hexane / ethyl acetate to give 2-chloromethylthiophene (1.52 g, 57%) as an oil.

A suspension of sodium hydride (0.271 g, 11.3 mmol) in dry glyme (40 ml) was treated dropwise under argon with trimethyl phosphonoacetate (1.87 g, 10.3 mmol) in glyme (5 ml). The resulting mixture was stirred at room temperature for 1.5 hours. Then we add

2-chloromethyl-thiophene (1.5 g, 11.3 mmol) and the mixture was stirred at 65 ° C for 18 hours. The reaction mixture was partitioned between water and ethyl acetate, and the organic layer was washed with water and brine, dried with anhydrous magnesium sulfate and concentrated to 1.9 g of oil. This was chromatographed over silica gel with 4: 1 ethyl acetate / hexane to give 800 mg (28%) of trimethyl 3- (2-thienyl) -2-phosphonopropionate.

(b) Methyl (E) -3- [2-n-butyl-1- (2-chlorophenyl) methyl} -1H-imidazol-5-yl-2- (2-thienyl) methyl-2-propenoate

A solution of trimethyl 3- (2-thienyl) -2-phosphonopropionate in glyme (3 ml) was added dropwise to a suspension of sodium hydride (69 mg, 2.87 mmol) in glyme (5 ml) under argon. When the gas evolution is complete, the mixture is heated to 50 ° C for 15 minutes. A solution of 2-n-butyl-1- (2-chlorophenyl) methyl-1H-imidazole-5-carboxaldehyde (0.53 g, 1.92 mmol) in glyme (3 ml) was added and the mixture was stirred at 60-65 ° C 5 hours. The cooled reaction mixture was partitioned between water and ethyl acetate, and the organic layer was washed with water, dried, concentrated and flash chromatographed over silica gel to give 336 mg (41%) of methyl (E) -3- [2-n-butyl-1 - {2-chlorophenyl) methyl} -1H-imidazol-5-yl-2 (2-thienyl) -methyl-2-propenoate, as an oil whose NMR is fully consistent with the trans or E form of this olefin.

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

A solution of methyl (E) -3- [2-n-butyl-1 - [(2-chlorophenyl) methyl] -1H-imidazol-5-yl] -215 (2-thienyl) methyl-2-propenoate (336 mg, 0.783 mmol) in ethanol (10 ml) was treated with 10% sodium hydroxide solution (4 ml) and the solution was stirred for 3 hours at 25 ° C. The pH was adjusted to 5 and the solid precipitated. The mixture was diluted with water, cooled to give 309 mg of solids by filtration. Crystallization from ethyl acetate gave 195 mg (60%) of (E) -3- [2-n-butyl-1 - [(2-chlorophenyl) methyl] -1H-imidazol-5-yl] -2- (2- thienyl) methyl 2-propenoic acid, m.p. 177-179 ° C.

Method B (a) Methyl 3- [2-n-butyl-1 - {(2-chlorophenyl) methyl} -1H-imidazol-5-yl] -3-hydroxy-2- (2-thienylmethylpropanoate)

To a solution of diisopropylamine (1.96 g, 0.0194 mol) in dry tetrahydrofuran (40 ml,) maintained at -78 ° C under argon, n-butyl lithium (7.3 ml, 0.0183 mol 2.5 M in) was added. toluene) and the mixture was stirred for 10 minutes. Methyl 3- (2-thienyl) propanoate (2.83 g, 0.0166 mol) in tetrahydrofuran (2 ml) was then added and the mixture was stirred at -78 ° C for 30 minutes. A solution of 2-n-butyl-1- (2-chlorophenyl) methyl-1H-imidazole-5-carboxaldehyde (3 g, 0.0111 mol) in tetrahydrofuran (4 ml) was added and the resulting mixture was stirred at -78 ° C for 30 minutes . The reaction mixture was partitioned between saturated ammonium chloride solution and ether, the organic extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated to 6.67 g of crude product. Flash chromatography over 70 g of silica gel with 4: 1 ethyl acetate / hexane gave 4.03 g (81%) of methyl

3- [2-n-butyl-1 - {(2-chlorophenyl) methyl} -1H-imidazol-5-yl] -3-hydroxy-2- (2-thienyl) methylpropanoate.

(b) Methyl 3-acetoxy-3- [2-n-butyl-1- (2-chlorophenyl) methyl-1H-imidazol-5-yl] -2 (2-thienyl) methylpropanoate

Methyl 3- [2-n-butyl-1 - {(2-chlorophenyl) methyl} -1H-imidazol-5-yl] -3-hydroxy- (2-thienyl) methylpropanoate solution (4.03 g, 9.02) mmol) in methylene chloride (100 ml) was treated with 4-dimethyl-aminopyridine (0.386 g, 3.16 mmol). Acetic anhydride (8.5 ml, 9.02 mmol) was then added dropwise to the stirred mixture. The mixture was stirred for 18 hours, water (35 ml) was added, the mixture was stirred for 1 hour and then diluted with ether and saturated sodium bicarbonate solution. The ether layer was washed with brine, dried with anhydrous magnesium sulfate and evaporated to give the title 3-acetoxy derivative as an oil (4.37 g, 99%).

(c) Methyl (E); 3- [2-n-butyl-1- {(2-chlorophenyl) -methyl} -1H-imidazol-5-yl] -2 (2-thienyl) methyl-2-propenoate

Mixture of methyl 3-acetoxy-3- [2-n-butyl-1- (2-chlorophenyl) methyl-1H-imidazol-5-yl] -2- (2-thienyl) methylpropanoate (4.36 g, 8.92 mmol) in dry toluene (80 ml) was treated with 8-diazabicyclo [5.4.0] undec-7-ene (DBU) (3.2 ml, 21.4 mmol) and the resulting solution was heated at 80 ° C under argon for 3 hours. The solvent was evaporated, the residue triturated with ether and activated charcoal added. After filtration, the filtrate was concentrated to 6.29 g of oil, which was chromatographed over silica gel with 65:35 hexane / ethyl acetate to give 2.89 g (76%) of methyl (E) -3- [2-n-butyl- 1 - {(2-chlorophenyl) -methyl} -1H-imidazol-5-yl] -2 (2-thienyl) methyl-2-propenoate, NMR and TLC (50% ethyl acetate in hexane on silica gel) were identical to the product prepared by method A.

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

Alkaline hydrolysis of this ester (2.88 g, 6.71 mmol) according to method A (iii) gave 2.59 g (93%) (E) -3- [2 - n-butyl-l - {(2 -chlorophenyl) methyl} -1H-imidazol-5-yl] -2- (2-thienyl) methyl2-propenoic acid, m.p. 175-177 ° C, which is identical to the product of method A.

Example 2 (E) -3- [2-n-Butyl-1 - {(4-carboxyphenyl) methyl} -1H-imidazol-5-yl] -2 (2-thienyl) methyl-2-propenoic acid (i) Using the procedure of case (1) [(ii) method 2, (iii) and (iv) method Β], using

4-Carbomethoxybenzyl alcohol instead of 2-chlorobenzyl alcohol, the title compound was prepared; m.p. 250-253 ° C.

(ii) Preparation of monomethanesulfonate

The title compound (3600 g) was added to 2-propanol (54 L) in a 91 liter glass-coated reactor. The stirred suspension was cooled to about 8 ° C. Methanesulfonic acid (2448 g) was added rapidly to the stirred suspension. The starting material was quickly dissolved to give a clear solution in 2 minutes. A slight exotherm is observed up to about 11 ° C. Over the next three minutes, a fine white solid begins to precipitate from the solution. The suspension was stirred at 3 ° C for 5.5 hours and the solid was collected by centrifugation. After washing with 101 2-propanol, the product was dried under vacuum at 45 ° C to a constant mass of 4.21 kg (94% yield, uncorrected for the test).

The crude product (4.20 kg) was added as a solid in 12.6 l of mixed glacial acetic acid in

45.5 liter glass-coated reactor. The suspension was heated to 80 ° C to give a homogeneous solution. The solution was warmly filtered through an in-line filter, and the reactor and filter lines were washed with 4.2 l of additional acetic acid. The combined acetic acid solutions were stirred by slow cooling to 25 ° C in a separate, 45.5 liter glass-coated reactor. The precipitation of the solid begins to occur at about 45 ° C. After 2.5 hours, the suspension was diluted with 42 l of ethyl acetate added in two equal portions, with a one-hour interval between the two additions. The suspension was stirred for an additional 18 hours to allow complete precipitation. The solid was collected by centrifugation and washed with 10 l of ethyl acetate. After drying to a constant of mass under vacuum at 40 ° C, 3.80 kg of product is recovered; m.p. 251-252 ° C (90.4%, uncorrected for test).

Example 3 (E) -3-R2-n-Butyl-1 - {(2-chlorophenyl) methyl} -1H-imidazol-5-yl1-2 (4-pyridyl) methyl-2-propenoic acid (i) Methyl 3- [2-n-butyl-1- (2-chlorophenyl) methyl-1H-imidazol-5-yl] -hydroxy-2- (4-pyridyl) methylpropanoate

To a solution of diisopropylamine (3.58 ml, 25.6 mmol) in dry tetrahydrofuran (50 ml) maintained at -78 ° C under argon, was added n-butyl lithium (10.2 ml, 25.6 mmol 2.5 M in toluene), and the mixture was stirred for 10 minutes. Methyl 3- (4-pyridyl) propanoate (4.22 g, 25.6 mmol) was then added (prepared by reaction of 4-priridine carboxaldehyde with trimethyl phosphonoacetate in the presence of sodium hydride in ethylene glycol dimethyl ether, followed by double bond catalytic hydrogenation with 10% palladium on charcoal at 3.03975 bar of hydrogen in ethyl acetate solution (98%) to give a saturated ester) in tetrahydrofuran (40 ml) and stirred this mixture for 30 minutes at -78 ° C. A solution of 2-n-butyl-1- (2chloro-phenyl) methyl-1H-imidazole-5-carboxaldehyde (5.9 g, 21.3 mmol) in tetrahydrofuran (10 ml) was added and stirring was continued for 30 minutes at -78 ° C. The reaction mixture was partitioned between saturated ammonium chloride solution and ether, the organese extract was washed with brine, dried over magnesium sulfate, concentrated and flash chromatographed over silica gel with 5% methanol in ethyl acetate to give 3.32 g (30%) methyl 3- [2-n-butyl-1- (2-chlorophenyl) -methyl] -imidazol-5-yl] -3-hydroxy-2- (4-pyridyl) methyl-propanoate. TLC on silica gel with 5% methanol in ethyl acetate showed a homogeneous product with R _f 0.79.

(ii) Methyl 3-acetoxy-3- [2-n-butyl-1- (2-chlorophenyl) methyl-1H-imidazol-5-yl] -2 (4-pyridyl) propanoate

A solution of methyl 3- [2-n-butyl-1- (2-chlorophenyl) -methyl-1H-imidazol-5-yl] -3-hydroxy-2 (4-pyridyl) methyl-propanoate (3.32 g, 7 , 5 mmol), methylene chloride (50 ml),

4-Dimethylaminopyridine (150 mg, 1.3 mmol) and acetate anhydride (7.1 ml, 75 mmol) were stirred at ambient temperature for 18 hours. Water (5 ml) was added, the mixture was stirred for 2 hours and then dissolved with methylene chloride and 5% sodium bicarbonate solution. The organic phase was washed with 5% sodium bicarbonate solution and brine, dried and concentrated to give 4 g of the crude title compound. TLC on silica gel with 5% methanol in ethyl acetate shows essentially a one-point material with R _f 0.86. We do not detect any starting material. We do not clean this material further.

(iii) Methyl (E) -3- [2-n-butyl-1 - {(2-chlorophenyl) -methyl} -1H-imidazol-5-yl] -2 (4-pyridyl) methyl-2-propenoate

Mixture of methyl 3-acetoxy-3- [2-n-butyl-1- (2-chlorophenyl) methyl-1H-imidazol-5-yl] -2 (4-pyridyl) -propenoate (7.5 mmol), toluene ( 50 ml) and 1,8-diazabicyclo [5.4.0] -undec7-ene (DBU) (3.4 ml, 22.5 mmol) were heated at 90 ° C for 18 hours under argon. The cooled mixture was diluted with ether and washed with brine, dried and concentrated to 3.1 g (97%) of the title compound. NMR indicates that the primary products are the trans or E isomers.

(iv) (E) -3- [2-n-butyl-1 - {(2-chlorophenyl) methyl} -1H-imidazol-5-yl] -2- (4-pyridyl) methyl-2-propenoic acid

A solution of methyl (E) -3- [2-n-butyl-1 - {(2-chlorophenyl) methyl} -1H-imidazol-5-yl] -2 (4-pyridyl) -methyl-2-propenoate (3, 1 g, 7.3 mmol) in ethanol (16 ml) was treated with 10% sodium hydroxide solution and the mixture was stirred for 18 hours at 25 ° C. The solution was concentrated in vacuo, water was added, the pH was adjusted to 6.5 and the resulting solid was filtered, washed with water and crystallized from methanol / ether to give 0.48 g (E) -3- [2-n-butyl-1 - {(2-chlorophenyl) methyl} -1H-imidazol-5-yl] -2- (4-pyridyl) -methyl-2-propenoic acid, m.p. 178-182 ° C (d).

Example 4 (E) -3- [2-n-Butyl-1 - {(4-carboxynaphth-1-yl) methyl} -1H-imidazol-5-yl1-2- (2-thienyl) -methyl2-propenoic acid (i) 2-n-Butyl-5-hydroxymethyl-4-iodoimidazole

N-Iodosuccinimide (148.75 g, 0.661 mol) was added to a stirred solution of 2-n-butyl-4-hydroxymethylimidazole (100.78 g, 0.652 mol) in 500 ml abs. ethanol. After 20 minutes, warm the solution to 40-45 ° C for 45 minutes, dilute with 2.5 liters of water and cool. The crystalline product was collected by filtration, washed with water, and dried to give

174.5 g (95%) of crystals; m.p. 166-166.5 ° C.

(ii) 2-n-butyl-4-iodoimidazole-5-carboxaldehyde

A mixed mixture of 174.1 g (0.62 mol) of 2-n-butyl-5-hydroxymethyl-4-iodoimidazole and 360 g (4.14 mol) of manganese dioxide in 3 liters of methylene chloride was refluxed for 24 hours using traps to remove the water. The hot reaction mixture was filtered through Celite®, which was then washed with 4.5 liters of boiling methylene chloride. Concentrate the combined filtrates to dryness, dissolve the residue twice in 150 ml of methanol and concentrate the solution to dryness. Dissolve the residue in 130 ml of methanol and cool. After crystallization occurs, 700 ml of water are slowly added. The mixture was cooled, the solid was collected by filtration and washed with water to give 145.2 g (84%) of product; m.p. 104105 ° C.

(iii) Methyl 4 - [(2-n-butyl-5-formyl-4-iodo-1H-imidazol-1-yl) methyl] naphthalene-carboxylate

Suspension of 29.53 g (0.214 mol) of powdered potassium carbonate, 60.00 (0.214 mol)

2-n-butyl-4-iodoimidazole-5-carboxaldehyde and 65.68 g (0.235 mol) of methyl

Of 4-bromomethylnaphthalene-1-carboxylate (E.A. Dixon, A. Fischer, and F.P. Robinson, Can. J. Chem. 59, 2629 (1981)) was stirred in 600 ml of dimethylformamide for 5 hours under argon at

70 ° C. 6.56 g (0.0235 mol) of bromomethyl ester are added and the suspension is stirred for a further 15 hours at 70 ° C. The reaction mixture was poured into water and the resulting solid collected by filtration, washed with water and triturated several times with 250 ml of boiling methanol to give 86.8 g (85%) of the solid; m.p. 177.5-179 ° C.

(iv) Methyl 4 - {(2-n-butyl-5-formyl-1H-imidazol-1-yl) methyl] naphthalene-1-carboxylate

A suspension of 40.0 g (83.9 mmol) of methyl 4 - [(2-n-butyl-5-formyl-4-iodo-1H-imidazol-lyl) methyl] -naphthalene-1-carboxylate, 9.07 g ( 92.4 mmol) of potassium acetate, and 6.0 g of 10% palladium on charcoal in 1.2 liters of ethyl acetate were hydrogenated for two hours. The solid was removed by filtration and 8.0 g of 10% palladium on charcoal and 9.01 g (92.4 mmol) of potassium acetate were added. The reaction mixture was hydrogenated for a further 2 hours, the solids removed by filtration, and the solution concentrated to about 1/3 volume. The ethyl acetate solution was washed with aqueous sodium carbonate solution, dried over magnesium sulfate and concentrated in vacuo to give an oil which crystallized. Recrystallization from methylene chloride-hexane gave 25.77 g (87.6%) of colorless crystals; m.p. 95.5-97 ° C.

(v) Methyl (E) -3- [2-n-butyl-1 - {(4-carbomethoxy-naphth-1-yl) methyl} 1H-imidazol-5-yl] -2- (2-thienyl) methyl -2-propenoate

The title compound was prepared from 25.0 g of methyl 4 - [(2-butyl-5-formyl-1H-imidazol-lyl) methyl] naphthalene-1-carboxylate, according to the procedure of Example 3, to give 22.12 g (56% ) a product such as the hydrochloride salt; m.p. 217-218 ° C.

(vi) (E) -3- [2-n-butyl-1 - {(4-carboxynaphth-1-yl) methyl} -1H-imidazol-5-yl] -2 (2-thienyl) methylpropenoic acid

Suspension containing 14.46 g (26.14 mmol) methyl (E) -3- [2-n-butyl-1 - {(4-carbomethoxynaphth-1-yl) methyl} -1H-imidazol-5-yl ] -2- (2-Thienyl) methyl-2-propenoate, 8.38 g (2.09 mmol) of potassium hydroxide in a mixture of 165 ml of ethanol and 85 ml of water was stirred at ambient temperature for 18 hours. Concentration under vacuum and dilution with water gave 400 ml of a clear solution. Adjusting the pH to 4.03 with hydrochloric acid gives crystals from which, when recrystallized from methanol, 9.89 g (80%) of colorless crystals are obtained; m.p. 218-219 ° C as a partial hydrate.

Example 5

(E) -3- [2-n-Butyl-1 - {(4-carboxynaphth-1-yl) methyl} -1Himidazol-5-yl-2 - [(2-thienyl) methyl] -2-propenoyl ethyl ester acid

A solution of 5.0 g (14.27 mol) of methyl 4 - [(2-butyl-5-formyl-1H-imidazol-lyl) methyl] naphthalene-1-carboxylate in 60 ml of ethanol was treated with a solution of 2.0 g ( 50 mmol) of sodium hydroxide in 30 ml of water. After stirring for 18 hours at 25 ° C, the reaction mixture was concentrated in vacuo, diluted with water to 50 ml and adjusted to pH 3.5 with 12 N hydrochloric acid. Filtration of the cooled mixture afforded 4.71 g of white crystals; m.p. 183-184 ° C. Recrystallization from ethyl acetate gives a different crystalline form; m.p. 134-135 ° C.

To a solution of 27.2 g (0.119 mol) of ethyl 2-carboxy-3- (2-thienyl) propionate in 250 ml of benzene was added 4.71 g (14 mmol) of the above aldehyde-acid, 3.58 g (42 mmol) of piperidine and 10 ml of pyridine and the solution were refluxed for 18 hours, using a trap to remove water. Vacuum was removed under vacuum, toluene was added and volatiles were removed again. The residue is treated with 2.5% sodium bicarbonate solution and hexane, resulting in separation of the oil. Addition of ethyl acetate yields two phases. The aqueous phase was filtered, the pH adjusted to 3.86 with 12 N hydrochloric acid and extracted with ethyl acetate. This ethyl acetate solution was dried over magnesium sulfate and concentrated in vacuo to give gum, which was dissolved in ether and then acidified with ether HCl. Trituration of the resulting gum with ether yields 5.32 g of finely divided white crystals; m.p. 180-181.5 ° C, softening at 176 ° C (hydrochloride salt).

Example 6

The oral dosage form for administration of the orally active compounds of the invention is obtained by screening, mixing and stuffing the ingredients into hard gelatin capsules, in proportions such as e.g. shown below.

Ingridients

(E) -3- [2-n-Butyl-1 {(4-carboxyphenyl) methyl} -1H-imidazol5-yl] 2- (2-thienyl) methyl-2-propenoic acid methanesulfonate magnesium stearate lactose

Kdličina

100 mg 10 mg 100 mg

Example 7

The sucrose calcium sulfate dihydrate and orally active compounds of the invention are mixed and granulated with a 10% gelatin solution. The wet granules are sieved, dried, mixed with starch, talc and stearic acid, sieved and pressed into a tablet.

Ingredients Amount (E) -3- [2-n-Butyl-1 {(4-carboxynaphth-1-yl) methyl} -1Himidazol-5-yl] 2- (2-thienyl) methyl-2-propenoic acid 75 mg calcium sulfate dihydrate 100 mg sucrose 15 mg starch 8 mg talc 4 mg stearic acid 2 mg

Example 8

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

Example 9

A topical ophthalmic solution for administering the compounds of the invention is prepared by mixing the ingredients in proportions such as e.g. shown below, under sterile conditions.

Ingridients

Quantities (mg / ml)

(E) -3- [2-n-Butyl-1 - {(4 carboxyphenyl) methyl} -1H-imidazol-5yl] -2- (2-thienyl) methyl-2-propenoic acid methanesulfonate dibasic sodium phosphate monobasic sodium phosphate chlorobutanol hydroxypropanol methylcellulose sterile water

1.0 N sodium hydroxide

1.0

10.4

2.4 5.0 5.0

q.s. ad 1.0 ml q.s. ad pH 7.4

It is to be understood that the present invention is not limited to the embodiments presented hereinabove and the right to the embodiments presented and any modifications is reserved within the scope of the following claims.

For

SmithKline Beecham Corporation:

Claims (18)

A compound which is (E) -3- [2-n-butyl-1 - {(4-carboxynaphth-1-yl) methyl} -1Himidazol-5-yl] -2- (2-thienyl) methyl-2 -Proenoic acid or a pharmaceutically acceptable salt thereof. 2. A compound which is (E) -3- [2-n-butyl-1 - {(4-carboxynaphth-1-yl) methyl} -1Himidazol-5-yl] -2- (2-thienyl) methyl ethyl ester -2-propenoic acid or a pharmaceutically acceptable salt thereof. 3. A compound that is methanesulfonate (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. Pharmaceutical composition comprising a pharmaceutical carrier and a compound according to claim 1. Pharmaceutical composition comprising a pharmaceutical carrier and a compound according to claim 2. Pharmaceutical composition comprising a pharmaceutical carrier and a compound according to claim 3. Use of a compound according to claim 1 in the manufacture of a medicament for the treatment of a disease wherein the factor is angiotensin II receptor antagonism. Use of a compound according to claim 2 in the manufacture of a medicament for the treatment of a disease wherein the factor is angiotensin II receptor antagonism. Use of a compound according to claim 3 in the manufacture of a medicament for the treatment of a disease wherein the factor is angiotensin II receptor antagonism. Use of a compound of claim 1 in the manufacture of a medicament for the treatment of hypertension. Use of a compound according to claim 2 in the manufacture of a medicament for the treatment of hypertension. Use of a compound according to claim 3 in the manufacture of a medicament for the treatment of hypertension. Use of a compound according to claim 1 in the manufacture of a medicament for the treatment of congestive heart failure. Use of a compound according to claim 2 in the manufacture of a medicament for the treatment of congestive heart failure. Use of a compound according to claim 3 in the manufacture of a medicament for the treatment of congestive heart failure. Use of a compound according to claim 1 in the manufacture of a medicament for the treatment of kidney failure. Use of a compound according to claim 2 in the manufacture of a medicament for the treatment of kidney failure. Use of a compound according to claim 3 in the manufacture of a medicament for the treatment of kidney failure.