HK1012246B - Pharmaceutical compositions of an imidazolyl-akenoic acid salt and their use as angiotensin ii antagonists - Google Patents

Description

The present invention relates to pharmaceutical compositions comprising an imidazolyl-alkenoic acid angiotensin II receptor antagonist. The pharmaceutical compositions are useful in regulating hypertension induced or exacerbated by angiotensin II, and in the treatment of congestive heart failure, renal failure, and glaucoma.

BACKGROUND OF THE INVENTION

The class of peptide pressor 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 essential hypertension, congestive heart failure and in some forms of renal disease. In addition to a direct action on arteries and arterioles, angiotensin II (AII), being one of the most potent endogenous vasoconstrictors known, exerts stimulation on the release of aldosterone from the adrenal cortex. Therefore, the renin-angiotensin system, by virtue of its participation in the control of renal sodium handling, plays an important role in cardiovascular hemeostasis.

Interruption of the renin-angiotensin system with converting enzyme inhibitors, such as captopril, has proved to be 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 towards inhibition of the renin-angiotensin system would block the action of AII at the receptor. Compelling - evidence suggests that AII also contributes to renal vasoconstriction and sodium retention that is characteristic of a number of disorders such as heart failure, cirrhosis and complications of pregnancy (Hollenberg, N.K., (1984), J. Cardiovas. Pharmacol., 6, S176). In addition, recent animal studies suggest that inhibition of the renin-angiotensin system may be beneficial in halting or slowing the progression of chronic renal failure (Anderson, S., et al., (1985), J. Clin. Invest., 76, 612). Also, a recent patent application (South African Patent Application No. 87/01,653) claims that AII antagonists are useful as agents for reducing and controlling elevated intraocular pressure, especially glaucoma, in mammals.

The pharmaceutical compositions of this invention inhibit, block and antagonize the action of the hormone AII, and are therefore useful in regulating and moderating angiotensin induced hypertension, congestive heart failure, renal failure and other disorders attributed to the actions of AII. When the pharmaceutical compositions of this invention are administered to mammals, the elevated blood pressure due to AII is reduced and other manifestations based on AII intercession are minimized and controlled. The pharmaceutical compositions of this invention are also expected to exhibit diuretic activity.

Recognition of the importance of blocking and inhibiting the actions of AII has stimulated other efforts to synthesize antagonists of AII. The following references have disclosed imidazole derivatives which are described as having AII blocking activity and 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. Specifically, the disclosure includes 1-benzyl-2-n-butyl-5-chloroimidazole-4-acetic acid and 1-benzyl-2-phenyl-5-chloroimidazole-4-propanoic acid.

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

Carini et al. in EP 253,310 disclose certain imidazolylpropenoic acids. 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)imidazol-5-yl]propenoate.

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

EP403159 discloses imidazolyl-alkenoic acids as angiotension II receptor antagonists, including the compound (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid, and pharmaceutically acceptable salts thereof.

DESCRIPTION OF THE INVENTION

The present invention provides a pharmaceutical composition which comprises (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid methanesulfonate and a pharmaceutically acceptable carrier, in solid dosage form adapted for oral administration.

Also included in the present invention is the use of the composition defined above in the manufacture of a medicament for the treatment of diseases in which angiotensin II receptor antagonism is a factor. The use of the composition defined above in the manufacture of a medicament for the treatment of hypertension, congestive heart failure, glaucoma, and renal failure is also included in this invention.

(E)-3-[2-n-Butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid methanesulfonate is prepared by procedures described herein and illustrated by the examples. Reagents, protecting groups and functionality on the imidazole and other fragments of the molecule must be consistent with the proposed chemical transformations. 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 to the art (J. Org. Chem. 45:4038, 1980) or is synthesized by known procedures. For example, imidazole is converted to 2-n-butylimidazole by reacting imidazole with triethylorthoformate and p-toluenesulfonic acid to give 1-diethoxyorthoamide imidazole and then treating with n-butyl lithium to give the 2-lithium derivative of the orthoamide and alkylating with n-butyl iodide in a suitable solvent, such as tetrahydrofuran (THF).

The 1-substituted benzyl group is incorporated onto the 2-n-butylimidazole by known procedures, for example, by reaction with a substituted 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 a metal hydride, preferably sodium hydride at a reaction temperature of about 25°C to about 100°C, preferably at about 50°C. The resulting 1-substituted-benzyl-2-n-butylimidazole is hydroxymethylated in the 5-position, for example, by reacting with formaldehyde in the presence of sodium acetate in acetic acid to provide the 1-substituted-benzyl-2-n-butyl-5-hydroxymethylimidazole intermediate.

Alternatively, the above prepared 5-hydroxymethyl-imidazole intermediate is prepared by reacting an 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 acetic anhydride to give 1-acetyl-5-acetoxymethyl-2-n-butylimidazole. The diacetate intermediate is N-alkylated, for example, using 2-chlorobenzyl triflate or 4-carbomethoxybenzyl triflate, and the resulting 1-substituted-2-n-butyl-5-acetoxymethyl-imidazole is treated with aqueous base, such as 10% sodium hydroxide solution, to give the 5-hydroxymethylimidazole intermediate described previously.

The hydroxymethyl group of the hereinbefore prepared intermediate is oxidized to an aldehyde by treatment with a suitable reagent, such as anhydrous chromic acid-silica gel in tetrahydrofuran or, preferably, with activated manganese dioxide, in a suitable solvent, such as benzene or toluene, or preferably methylene chloride, at a temperature of about 25°C to about 140°C, preferably at about 25°C. The imidazol-5-carboxaldehyde is reacted with an appropriate phosphonate, such as trimethyl-3-(2-thienyl)-2-phosphonoproprionate. The phosphonates are prepared, for example, from 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 reaction temperature of about 25°C to about 110°C, preferably at about 55°C, to provide the appropriate phosphonate. The reaction of the imidazol-5-carboxaldehyde with the phosphonates is performed 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, ether, dioxane, tetrahydrofuran, or preferably glyme, at a reaction temperature of 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-substituted-2-n-butyl-5-CH=C[(2-thienyl)methyl]-(COOalkyl)-imidazoles. These isomers are readily separated by chromatography over silica gel in suitable solvent systems, preferably hexane in ethyl acetate mixtures. The esters are hydrolyzed to the corresponding acid compounds using base, such as potassium hydroxide, lithium hydroxide or sodium hydroxide, in a suitable solvent system, such as, for example, aqueous alcohols or diglyme.

Alternatively, the 1-substituted-2-n-butylimidazol-5-carboxaldehyde is prepared by the following procedure. Starting 2-n-butylimidazol-5-carboxaldehyde is reacted with an N-alkylating protecting reagent, such as chloromethyl pivalate (POM-Cl), in the presence of a base, such as potassium carbonate, in a suitable solvent, such as dimethylformamide, 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 least hindered nitrogen atom of the imidazole nucleus. The 1-substituted-benzyl group is incorporated onto the imidazole by N-alkylation of the above prepared aldehyde with a halomethylbenzene compound, such as methyl 4-bromomethylbenzoate, at a temperature of about 80°C to about 125°C, preferably at about 100°C. The protecting group on the 3-nitrogen of the imidazole ring is removed by base hydrolysis, for example using a biphasic mixture of ethyl acetate and aqueous sodium carbonate, to give a 1-substituted-n-butylimidazole-5-carboxaldehyde compound. (E)-3-[2-n-Butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid methanesulfonate can be prepared from this 5-carboxaldehyde compound by the methods described above.

Alternately, the 2-n-butylimidazole starting material is reacted-with trimethylsilylethoxy-methyl(SEM) chloride to give 1-(trimethylsilyl)-ethoxymethyl-2-n-butylimidazole. The reaction is carried out, for example, in the presence of sodium hydride in a solvent such as dimethylformamide. The 5-tributyltin derivative is prepared by lithiation with, for example, butyllithium in a suitable solvent, preferably diethyl ether, followed by treatment of the lithio imidazole derivative with a tributyltin halide, preferably tri-n-butyltin chloride, at about -10°C to about 35°C, preferably at about 25°C. The 1-SEM-2-n-butyl-5-tributyltinimidazole is coupled with an α,β-unsaturated acid ester having a leaving group on the β-position, such as a halide or trifluoromethanesulfonyloxy group, for example, BrCR⁴=C[(2-thienyl)methyl](COOalkyl), in the presence of a phosphine ligand, such as bis(diphenylphosphino)propane, 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 50°C to about 150°C, preferably at about 120°C. Both the (E) and (Z) olefinic isomers are prepared by this procedure, and the isomeric esters are readily separated by chromatography over silica gel. The 1-SEM group from the (E) and (Z) isomers is hydrolyzed with acid, for example, aqueous hydrochloric, in a suitable alcoholic solvent, such as methanol or ethanol, and the 1-unsubstituted imidazole derivative is converted to the 1-t-butoxycarbonyl (t-BOC) imidazole with di-t-butyl dicarbonate (Hoppe-Seyler's Z. Physiol. Chem., (1976), 357, 1651). The t-BOC ester is alkylated and hydrolyzed with, for example, 2-chlorobenzyl triflate or 4-carbomethoxybenzyl triflate, in the presence of a suitable base, preferably diisopropylethylamine, in a suitable solvent, preferably methylene chloride, to afford the 1-substituted-imidazole derivative (ester). The (E) and (Z) isomers are hydrolyzed to the (E) and (Z) acids by the method described above.

(E)-3-[2-n-Butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid methanesulfonate is also prepared by the following procedure. The 1-substituted-2-n-butyl-imidazole-5-carboxaldehyde, prepared as described above, is reacted with a substituted half-acid, half-ester derivative of a 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 about 80°C to about 110°C, preferably at about 100°C. The resulting 1-substituted-2-n-butyl-5-CH=C(R⁵)COOalkylimidazole is hydrolyzed to the corresponding compound by alkaline hydrolysis as described above.

Alternately, (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid methanesulfonate is prepared as follows. The 1-substituted-2-n-butyl-imidazol-5-carboxaldehyde prepared hereinabove is treated with the lithium derivative of a substituted ethyl or methyl ester. This lithio derivative is prepared from the reaction of lithium diisopropylamide in a suitable solvent, preferably tetrahydrofuran, with an acid ester, such as ROOC-CH₂-CH₂-(2-thienyl), to generate the α-lithio derivative at about -78°C to about -10°C, preferably at about -78°C, which is then treated with the imidazol-carboxaldehyde. The intermediate β-hydroxy group of the imidazole ester is converted to 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-diazo-bicyclo[5.4.0]undec-7-ene, at about 50 to about 110°C, preferably at about 80°C, to afford 3-(imidazol-5-yl)-2-(2-thienyl)methyl-2-propenoic acid ester. The (E) isomer is the predominate olefinic isomer. The acid is prepared from the esters by the method described above.

(E)-3-[2-n-Butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid methanesulfonate is formed from the compound in which the substituent in the 1-position of the imidazole ring is substituted by CO₂C₁-C₄alkyl using basic hydrolysis, such as aqueous sodium or potassium hydroxide in methanol or ethanol, or using acidic hydrolysis, such as aqueous hydrochloric acid.

The methanesulfonate acid addition salt is formed with methanesulfonic acid by methods known in the art. For example, the base is reacted with the acid in an aqueous miscible solvent such as ethanol with isolation of the salt by removing the solvent or in an aqueous immiscible solvent when the acid is soluble therein, such as ethyl ether or chloroform, with the desired salt separating directly or isolated by removing the solvent.

Angiotensin II antagonist activity of (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid methanesulfonate is assessed by in vitro and in vivo methods. In vitro antagonist activity is determined by the ability of the compound to compete with ¹²⁵I-angiotensin II for binding to vascular angiotensin II receptors and by 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 compound to inhibit the pressor response to exogenous angiotensin II in conscious rats and to lower blood pressure in a rat model of renin dependent hypertension.

Binding

The radioligand binding assay is a modification of a method previously described in detail (Gunther et al., Circ. Res. 47:278, 1980). A particular fraction from rat mesenteric arteries is incubated in Tris buffer with 80 pM of ¹²⁵I-angiotensin II with or without angiotensin II antagonists for 1 hour at 25°C. The incubation is terminated by rapid filtration and receptor bound ¹²⁵I-angiotensin II trapped on the filter is quantitated with a gamma counter. The potency of angiotensin II antagonists is expressed as the IC₅₀ which is the concentration of antagonist needed to displace 50% of the total specifically bound angiotensin II.

Aorta

The ability of the compound to antagonize angiotensin II induced vasoconstriction is examined in the rabbit aorta. Ring segments are cut from the rabbit thoracic aorta and suspended in organ baths containing physiological salt solution. The ring segments are mounted over metal supports and attached to force displacement transducers which are connected to a recorder. Cumulative concentration response curves to angiotensin II are performed in the absence of antagonist or following a 30-minute incubation with antagonist. Antagonist disassociation constants (K_B) are calculated by the dose ratio method using the mean effective concentrations.

Inhibition of pressor response to angiotensin II in conscious rats

Rats are prepared with indwelling femoral arterial and venous catheters and a stomach tube (Gellai et al., Kidney Int. 15:419, 1979). Two to three days following surgery the rats are placed in a restrainer 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 time points prior to and following the administration of (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid methanesulfonate intravenously or orally at doses of 0.1 to 300 mg/kg. The dose of compound needed to produce 50% inhibition of the control response to angiotensin II (IC₅₀) is used to estimate the potency of the compound.

Antihypertensive activity

The antihypertensive activity of (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid methanesulfonate is measured by its ability to reduce mean arterial pressure in conscious rats made renin-dependent hypertensive by ligation of the left renal artery (Cangiano et al., J. Pharmacol. Exp. Ther. 208:310, 1979). Renal artery ligated rats are prepared with indwelling catheters as described above. Seven to eight days following renal artery ligation, the time at which plasma renin levels are highest, the conscious rats are placed in restrainers and mean arterial pressure is continuously recorded prior to and following the administration of the compound intravenously or orally. The dose of compound needed to reduce mean arterial pressure by 30 mm Hg (IC₃₀) is used as an estimate of potency.

The intraocular pressure lowering effects employed in this invention may be measured by the procedure described by Watkins, et al., J. Ocular Pharmacol., 1 (2):161-168 (1985).

(E)-3-[2-n-Butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid methanesulfonate is incorporated into convenient dosage forms, such as capsules or tablets. Solid pharmaceutical carriers are employed. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Similarly, the carrier or diluent may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies widely but, preferably, will be from about 25 mg to about 1 g per dosage unit.

The pharmaceutical preparations are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing and filling the ingredients, as appropriate, to give the desired oral products.

Doses of (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid methanesulfonate in a pharmaceutical dosage unit as described above will be an efficacious, nontoxic quantity selected from the range of .01 - 200 mg/kg of active compound, preferably 1 - 100 mg/kg. The selected dose is administered to a human patient in need of angiotensin II receptor antagonism from 1-6 times daily, orally. Oral dosage units for human administration preferably contain from 1 to 500 mg of active compound. Oral administration, at higher dosages, however, also can be used when safe and convenient for the patient.

No unacceptable toxicological effects are expected when (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid methanesulfonate is administered in accordance with the present invention.

The following examples illustrate preparation of (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid methanesulfonate and pharmaceutical compositions of this invention. Example 1 illustrates procedures used in the preparation of (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid methanesulfonate.

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

A mixture of valeramidine methyl ether hydrochloride (250 g, 1.66 mol) and dihydroxyacetone (150 g, 0.83 mol) dissolved in liquid ammonia was allowed to stand overnight at room temperature in a pressure vessel, and then heated at 65°C for 4 hours at 2585.625 kPa (375 psi). The ammonia was allowed to evaporate, and the residue was dissolved in methanol (3L). The resulting slurry was refluxed with added acetonitrile (1L). The solution was decanted from the solid ammonium chloride while hot. This procedure was repeated, and the combined acetonitrile extracts were treated with charcoal, filtered hot and the filtrate was concentrated in vacuum to give the dark oil, 2-n-butyl-5-hydroxymethylimidazole (253 g, 1.63 mol, 98%).

This crude alcohol (253 g) was treated with acetic anhydride (400 mL) at -15°C and then was allowed to warm to ambient temperature with stirring, and then stirred an additional 19 hours. The acetic anhydride was evaporated at reduced pressure, the residue taken up in methylene chloride, and the organic phase was washed with 5% sodium bicarbonate solution and water. The extract was dried over sodium sulfate and concentrated to give 323 g (83%) of 1-acetyl-4-acetoxymethyl-2-n-butylimidazole.

This diacetate was N-alkylated by the following procedure. To a solution of triflic anhydride (120 mL, 0.71 mol) in methylene chloride (200 mL) at -78°C under argon was added a solution of diisopropyl ethylamine (128 mL, 0.73 mol) and 2-chlorobenzyl alcohol (104 g, 0.72 mol) in methylene chloride (350 mL) over a period of 20 minutes. After being stirred an additional 20 minutes at -78°C, this solution was then treated with 1-acetyl-4-acetoxymethyl-2-n-butylimidazole (146 g, 0.61 mol) dissolved in methylene chloride (300 mL) over a 20=minute interval. The mixture was then stirred at ambient temperature for 18 hours and the solvents were evaporated, the residual 2-n-butyl-5-acetoxymethyl-1-(2-chlorophenyl)methyl-1H-imidazole was used without purification for the hydrolysis of 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 was heated on a steam bath for 4 hours. After cooling, methylene chloride was added, the organic phase was separated, washed with water, dried and concentrated. The residue was dissolved in ether, cooled, and seeded to give the crude product. Recrystallization from ethyl acetate gave 176 g of 2-n-butyl-1-(2-chlorophenyl)methyl-5-hydroxymethyl-1H-imidazole; mp 86-88°C.

(ii) 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-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 manganese dioxide (27 g) in methylene chloride (325 mL). The suspension was stirred at room temperature for 17 hours. The solids were filtered and the filtrate concentrated and flash chromatographed over silica gel with 6:4 hexane/ethyl acetate to afford 4.16 g (78%) of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde, as an oil. NMR and IR were consistent with the structure.

(iii) (E)-3-[2-n-butyl-1-{(2-chloropheny)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-thiophenemethanol (2.28 g, 0.02 mol) in carbon tetrachloride (25 mL) was added triphenylphosphine (6.81 g, 0.026 mol), and the solution was refluxed for 3 hours. The cooled reaction mixture was diluted with hexane (60 mL), chilled and filtered. The concentrated filtrate (4.6 g) was flash chromatographed over silica gel with 7:3 hexane/ethyl acetate to provide 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) under argon was treated dropwise 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 2-chloromethyl-thiophene (1.5 g, 11.3 mmol) was added, and the mixture was stirred at 65°C for 18 hours. The reaction 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 an oil. This was chromatographed over silica gel 4:1 ethylacetate/hexane to afford 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

To a suspension of sodium hydride (69 mg, 2.87 mmol) in glyme (5 mL) was added dropwise a solution of trimethyl 3-(2-thienyl)-2-phosphonopropionate in glyme (3 mL) under an atmosphere of argon. When the gas evolution had subsided, the mixture was heated to 50°C for 15 minutes. A solution of 2-n-butyl-1-(2-chlorophenyl)-methyl-1H-imidazol-5-carboxaldehyde (0.53 g, 1.92 mmol) in glyme (3 mL) was added, and the mixture was stirred at 60-65°C for 5 hours. The cooled reaction 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 was entirely consistent with the trans or E form of the 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]-2-(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 a solid precipitated. The mixture was diluted with water, cooled and filtered to provide 309 mg of solid. A 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; mp 177-179°C.

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

To a solution of diisopropylamine (1.96 g, 0.0194 mol) in dry tetrahydrofuran (40 mL) held at -78°C under argon was added n-butyl lithium (7.3 mL, 0.0183 mol of 2.5 M in toluene), and the mixture was stirred for 10 minutes. Then, methyl 3-(2-thienyl)propanoate (2.83 g, 0.0166 mol) in tetrahydrofuran (2 mL) was added, and the mixture was stirred for 30 minutes at -78°C. A solution of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-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 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. This was flash chromatographed over 70 g of silica gel with 4:1 ethyl acetate/hexane to provide 4.03 g (81%) of methyl 3-[2-n-butyl-1-(2-chlorophenyl)-methyl-1H-imidazol-5-yl]-3-hydroxy-2-(2-thienyl)methyl-propanoate.

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

A solution of methyl 3-[2-n-butyl-1-(2-chloro-phenyl)methyl-1H-imidazol-5-yl]-3-hydroxy-2-(2-thienyl)-methylpropanoate (4.03 g, 9.02 mmol) in methylene chloride (100 mL) was treated with 4-dimethyl-aminopyridine (0.386g, 3.16 mmol). Then acetic anhydride (8.5 mL, 9.02 mmol) was 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

A 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 1,8-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 was added. After filtration, the filtrate was concentrated to 6.29 g of an oil that 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 whose 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

Basic hydrolysis of this ester (2.88 g, 6.71 mmol) according to Method A (c) gave 2.59 g (93%) of (E)-3-[2-n-butyl-1-[(2-chlorophenyl)methyl]-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid; mp 175-177°C that was identical to the product from 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) By the procedure of Example 1 [(i), (ii) and (iii) Method B] using 4-carbomethoxybenzyl alcohol in place of 2-chlorobenzyl alcohol, the title compound was prepared; mp 250-253°C. (ii) Preparation of Monomethanesulfonate

The title compound, 3600 g, was added to 2-propanol (54 L) in a 20-gallon, glass-lined reactor. The stirred suspension was cooled to approximately 8°C. Methanesulfonic acid (2448 g) was added rapidly to the vigorously stirred suspension. The starting material dissolved quickly to give a clear solution within two minutes. A slight exotherm to approximately 11°C was observed. A fine, white solid began to precipitate from the solution within an additional three minutes. The suspension was stirred at a temperature of 3°C for 5.5 hours and the solid was collected by centrifugation. After washing with 10 L of 2-propanol, the product was dried under vacuum at 45°C to a constant weight of 4.21 kg (94% yield, uncorrected for assay).

The crude product (4.20 kg) was charged as a solid to 12.6 L of stirred, glacial acetic acid in a 10-gallon, glass-lined reactor. The slurry was heated to 80°C, giving a homogeneous solution: The solution was filtered warm 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 with slow cooling to 25°C in a separate 10-gallon, glass-lined reactor. Precipitation of a solid began 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 additions. The suspension was stirred for an additional 18 hours to allow complete precipitation. The solid product. was collected by centrifugation and washed with 10 L of ethyl acetate. After drying to a constant weight under vacuum at 40°C, a recovery of 3.80 kg of product; mp 251-252°C (90.4%, uncorrected for assay) was obtained.

Example 3

An oral dosage form for administering (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid methanesulfonate is produced by screening, mixing and filling into hard gelatin capsules the ingredients in proportions, for example, as shown below.

Ingredients	Amounts
(E)-3-[2-n-butyl-1-{(4-carboxy-phenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid methanesulfonate	100 mg
magnesium stearate	10 mg
lactose	100 mg

Example 4

The sucrose calcium sulfate dihydrate and (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid methanesulfonate are mixed and granulated with a 10% gelatin solution. The wet granules are screened, dried, mixed with the starch, talc and stearic acid, screened and compressed into a tablet.

Claims (8)

1. A pharmaceutical composition which comprises (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid methanesulfonate and a pharmaceutically acceptable carrier, in solid dosage form adapted for oral administration.
2. The composition according to claim 1 in unit dose form comprising from 1 to 500mg of (E)-3-[2-n-butyl-1{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid methanesulfonate as active ingredient.
3. The composition according to claim 1 or 2 in the form of a tablet or capsule.
4. The use of the composition of claims 1 to 3 in the manufacture of a medicament for the treatment of diseases in which angiotensin II receptor antagonism is a factor.
5. The use of the composition of claims 1 to 3 in the manufacture of a medicament for the treatment of hypertension.
6. The use of the composition of claims 1 to 3 in the manufacture of a medicament for the treatment of congestive heart failure.
7. The use of the composition of claims 1 to 3 in the manufacture of a medicament for the treatment of renal failure.
8. A process for preparing a pharmaceutical composition in solid dosage form adapted for oral administration, which comprises bringing into association(E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid methanesulfonate and a pharmaceutically acceptable carrier.