WO1994022830A1 - Chemical compounds - Google Patents

Abstract

Angiotensin II receptor antagonists having formula (I) which are useful in the treatment of hypertension, congestive heart failure, renal failure, and glaucoma, pharmaceutical compositions including these antagonists, and methods of using these compounds to produce angiotensin II receptor antagonism in mammals.

Description

CHEMICAL COMPOUNDS

The present invention relates to new chemical compounds which are angiotensin II receptor antagonists and are useful in regulating hypertension induced or exacerbated by angiotensin II, and in the treatment of congestive heart failure, renal failure, and glaucoma. This invention also relates to pharmaceutical compositions containing these compounds and methods for using these compounds as antagonists of angiotensin II, as antihypertensive agents and as agents for treating 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 reninangiotensin 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 reninangiotensin system would block the action of AII at the receptor. Compelling evidence suggests that All 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 compounds 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 compounds of this invention are administered to mammals, the elevated blood pressure due to AII is reduced and other

manifestations based on All intercession are minimized and controlled. Compounds of this invention are also expected to exhibit diuretic activity.

Recognition of the importance of blocking and inhibiting the actions of All has stimulated other efforts to synthesize antagonists of AII. The following references have disclosed imidazole derivatives which are described as having All 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 discloser 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.

DESCRIPTION OF THE INVENTION

The compounds of the present invention that are Mockers of angiotensin II receptors are represented by the following Formula (I):

wherein: R¹ is phenyl or naphthyl, each of which is unsubstituted or substituted by one to three substituents selected from CL Br, F, I, C_1-6alkyl, NO₂, CF₃,

Q-CO₂R', tetrazolyl, C_1-6alkoxy, OH, SC_1-6 alkyl, SO₂NHR', NHSO₂R", SO₃H, CONR'R', CN, SO₂C_1-6alkyl, NR"R', NR'COH, NR'COC_1-6alkyl or

NR'CO-phenyl;

n is 0-4;

A¹ is C or N when X is a covalent bond, or C when X is other than a covalent bond;

A² is CR², CR¹⁴, or C=R³;

A³ is CR²,CR⁴ N, or NR¹⁵;

A⁴ is CR⁵, CR⁵R⁹, or N;

A⁵ is absent or present as CR⁶ or N;

A⁶ is CR⁷ when A⁵ is absent or CR⁸ or N when A⁵ is present;

with the proviso that:

(1) one of A² or A³ is CR²; and

(2) at least one, but not more than three of A¹, A³, A⁴, A⁵ and A⁶ are N;

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

R is R', C_mF_2m+1, wherein m is 1-3, or phenyl which is unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C_1-6alkyl, NO₂, CF₃, Q-CO₂R', tetrazolyl, C_1-6alkoxy, OH, SC_1-6alkyl, SO₂NHR', NHSO₂R', SO₃H, CONR'R', CN, SO₂C_1-6alkyl, NR'R', NR'COH, NR'COC_1-6a-kyl or

NR'CO-phenyl;

R² is

R³ is O, (H,H), or (H, C_1-4alkyl);

R⁴ is H, C_1-4alkyl, Cl, Br, F, or I;

R⁵ is H, C_1-4alkyl, Cl, Br, F, or I;

R⁶ is H or C_1-4alkyl;

R⁷ is C_2-8alkyl. SC_1-7alkyl or OC_1-7alkyl;

R⁸ is H, C_2-8alkyl, SC_1-7alkyl, or OC_1-7alkyl;

each R⁹ independently is H or C_1-6alkyl;

R¹⁰ is H or C_1-6alkyl;

R¹1 is CO₂R', CONR'R', tetrazolyl, or SO₂NH₂;

R¹² is C₁-C₆alkyl, phenyl- Y-, biphenyl-Y-, naphthyl- Y-, 2- or 3-thienyl-Y-, - or 3-furanyl-Y-, 2-, 3- or 4-pyridyl-Y-, pyrazolyl-Y-, imidazolyl-Y-, pyrrolyl-Y-, triazolyl-Y-, oxazolyl-Y-, isoxazolyl-Y-, thiazolyl-Y-, or tetrazolyl- Y-, with each heteroaryl group being unsubstituted or substituted by C₁-C₆alkyl, C₁-C₆alkoxy, Cl, Br, F, I, CF₃, NR'R', CO₂R', SO₂NHR', SO₃H, CONR'R', OH, NO₂, SC₁- C₆alkyl, SO₂ C₁-C₆alkyl, NR'COH, or N R'CO C₁-C₆alkyl and with each aryl group being unsubstituted or substituted by C₁-C₆alkyl, C₁-C₆alkoxy, Cl, Br, F, I, CF₃, NR'R', CO₂R', SO₂NHR', SO₃H, CONR'R', OH, NO₂, S C₁-C₆alkyl,

SO₂ C₁-C₆alkyl, NR'COH, or NR'CO C₁-C₆alkyl or with each aryl group being substituted by methylenedioxy, phenoxy, or phenyl;

Y is a single bond, O, S, or C₁-C₆alkyl which is straight or branched optionally substituted by phenyl or benzyl, wherein each phenyl or benzyl group is unsubstituted or substituted by Cl, Br, F, I, NO₂, CF₃, C₁-C₆alkyl, C₁-C₆alkoxy, CN, or CO₂R';

Q is -CH=CH-, -(CH₂)_0-4-. -X-(CH₂)_1-2-U-(CH₂)_1-2-, or -V-CH(R¹³)-;

X is a covalent bond, -O-, -S-, or -N(R⁹)-;

U is absent or present as -O-, -S-, or -N(R⁹)-;

V is -O-, -S-, or -N(R⁹)-;

R¹³ is H, phenyl, or benzyl wherein each phenyl or benzyl group is unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C_1-6alkyl, NO₂, CF₃, Q-CO₂R', tetrazolyl, C_1-6alkoxy, OH, SC_1-6alkyl,

SO₂NHR", NHSO₂R", SO₃H, CONR'R', CN, SC₂C_1-6alkyl, NR'R', NR'COH, NR'COC_1-6alkyl or NR'CO-phenyl;

R¹⁴ is Cl, Br, F, or I; and

R¹⁵ is H, C_1-6alkyl, -(CH₂)_1-2C_3-6cycloalkyl, -(CH₂)_1-2CF₃, or

-(CH₂)_0-2Phenyl, wherein the phenyl is unsubstituted or substituted by any accessible combination of up to three substituents selected from Cl, Br, F, I, CF₃, or C_1-6alkyl;

or a pharmaceutically acceptable salt thereof.

As used herein, the terms alkyl and alkoxy mean carbon chains which are branched or unbranched with the length of the chain determined by the descriptor preceding the term. The phrase "any accessible combination" means any combination of substituents that is available by chemical synthesis and is stable.

Aryl, as used herein, means phenyl, biphenyl, or naphthyl. Heteroaryl means 2- or 3-thienyl-Y-, 2- or 3-furanyl-Y-, 2-, 3- or 4-pyridyl-Y-, pyrazolyl-Y-, imidazolyl-Y-, pyrrolyl-Y-, triazolyl-Y-, oxazolyl-Y-, isoxazolyl-Y-, thiazolyl-Y-, or tetrazolyl- Y-.

As used herein, ---. indicates a single or double bond, wherein the A¹-A⁶ ring contains two or three double bonds. Presently preferred Formula (I) compounds are those compounds wherein

R¹ is phenyl or naphthyl, each of which is substituted by Q-CO₂R', CONR'R',

NHSO₂R", or tetrazolyl. The most preferred substituent on the R¹ phenyl or naphthyl is 4-CO₂H. Also, Formula (I) compounds wherein n is one are most preferred.

Another preferred embodiment are Formula (I) compounds wherein R² is X

in which the A¹ - A⁶ ring and the CO₂H group are trans to each other (the E isomers). These isomers are generally more active and, thus, are preferred over the corresponding cis isomers (the Z isomers).

The most preferred A¹ - A⁶ rings to which X is attached at A¹ are represented by the following:

The 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 which comprises administering to a subject in need thereof an effective amount of a compound of Formula (I). Methods of treating hypertension, congestive heart failure, glaucoma, and renal failure by administering these compounds are also included in this invention.

Because the compounds of Formula (I) are angiotension II receptor antagonists, they may also be of value in the treatment of left ventricular hypertrophy regression, diabetic nephropathy, diabetic retinopathy, macular degeneration, haemorrhagic stroke, angina, and anxiety. Additionally, these compounds may be expected to be useful in the primary and secondary prevention of infarction, in the prevention of atheroma progression and in the regression of antheroma, in the prevention of restinosis after angioplasty or bypass surgery and in the improvement of cognitive funtion.

The compounds of this invention are prepared by procedures described herein and illustrated by the examples. Reagents, protecting groups and

functionality on the A¹ - A⁶ ring 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 naphthalene and other parts of the molecule.

The compounds of Formula (I) or pharmaceutically acceptable salts thereof are prepared by a process which comprises: a) reacting a compound of the formula (II):

wherein A¹, A⁴, A⁵, A⁶, and n are as defined in Formula (I), R¹' is R¹ as defined in claim 1, except that the substituents on the R* group do not include tetrazol-5-yl, OH, or CO₂H, and D¹ is C or CH substimted by CHO and D² is CR⁴, N, or NR¹⁵ wherein R⁴ and R¹⁵ are as defined in Formula (I), or D¹ is CR¹⁴ or C=R³ and D² is C substimted by CHO, wherein R¹⁴ and R³ are as defined in Formula (I), with a compound of formula (HI):

(C_1-4alkoxy)₂P(O)CH(R¹²)-CO₂C_1-6alkyl (HI) wherein R¹² is as defined in Formula (I), in the presence of a base; or b) reacting a compound of the formula (II) as hereinbefore defined with a compound of the formula (IV):

wherein R¹² is as defined in Formula (I), in the presence of a base; or c) reacting a compound of the formula (V):

wherein A¹, A⁴, A⁵, A⁶, and n are as defined in Formula (I), R¹' is R¹ as defined in claim 1, except that the substituents on the R¹ group do not include tetrazolyl-5-yl, OH, or CO₂H, and D³ is C or CH substimted by -CH(OR¹⁶)-CH(R¹²)-CO₂C_1-6alkyl and D⁴ is CR⁴, N, or NR¹⁵ wherein R⁴ and R¹⁵ are as defined in Formula (I), or D³ is CR¹⁴ or C=R³ and D⁴ is C substituted by -CH(OR¹⁶)-CH(R¹²)-CO₂C_1-6alkyl , wherein R¹⁴ and R³ are as defined in Formula (I), and R¹⁶ is COCH₃ or SO₂CH₃, with a base; and thereafter where necessary:

(i) for Formula (I) compounds in which the R¹ group is substimted by hydroxy, deprotecting the Formula (I) compounds in which the R* group is substimted by C_1-4 alkoxy; or

(ii) for Formula (I) compounds in which the R¹ group is substimted by carboxy, hydrolyzing the Formula (I) compounds in which the R¹ group is substimted by CO₂ C_1-4alkyl; or

(iii) for Formula (I) compounds in which R¹ group is substimted by a tetrazol-5-yl group, treating the Formula (I) compound in which the R* group is substituted by carboxy, with a halogenating agent, followed by conversion to the priary amide in a reaction with ammonia, dehydration with oxalylchloride/dimethylformamide and reaction with azide; or

(iv) for Formula (I) compounds in which R¹¹ is CO₂H, hydrolyzing the

Formula (I) compounds in which R¹¹ is CO₂C_1-6alkyl; or

(v) for Formula (I) compounds in which R¹¹ is CONR'R' wherein R' is as defined in Formula (I) treating the Formula (I) compounds in which R¹¹ is CO₂H with a halogenating agent, followed by reaction with a R', R'- substimted amine; or

(vi) for Formula (I) compounds in which R^ is tetrazolyl, treating the Formula (I) compounds in which R¹¹ is CONH₂ with oxalyl

chloride/dimethylformamide, followed by reaction with azide;

and thereafter optionally forming a pharmaceutically acceptable salt.

The reaction between a compound of formula (II) and a compound of formula (HI) 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), -CH=C(R 12 )-

(CO₂C_1-6alkyl)-substituted Formula (I) compounds. 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 acids using base, such as potassium hydroxide, lithium hydroxide or sodium hydroxide, in a suitable solvent system, such as, for example, aqueous alcohol or diglyme.

The reaction between a compound of formula (II) and a compound of formula (IV) is performed 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 -CH=C(R¹²)CO₂C_1-6alkyl-substituted Formula (I) . compounds are hydrolyzed to the corresponding Formula (I) acid compounds by alkaline hydrolysis as described above.

The reaction between a compound of formula (V) and a base, such as one to two equivalents of 1,8-diazabicyclo[5.4.0]undec-7-ene, is carried out in a suitable solvent, such as toluene, at about 50°C to about 110°C, preferably at about 80°C, to afford the Formula (I) vinyl ester compounds. The corresponding carboxylic acids are prepared from the esters by the method detailed above.

Formula (V) compounds are prepared from formula (II) compounds. The aldehyde group of formula (II) compounds are treated with the lithium derivative of a substimted ethyl or methyl ester. These lithio derivatives are prepared from the reaction of lithium diisopropylamide in a suitable solvent, preferably

tetrahydrofuran, with an acid ester, such as ROOC-CH₂-Y-(2-thienyl), to generate the α-lithio derivatives at about -78°C, which are then treated with the Formula (II) aldehyde. The intermediate β-hydroxy group of the imidazole ester is converted to a mesylate or an acetate, for example, by reacting the alcohol with methanesulfonyl chloride in pyridine at 0°C to 25°C or by reacting the alcohol with acetic anhydride, to give Formula (V) compounds.

Formula (II) compounds are known in the art or can be made by analogy processes using standard procedures of organic chemistry. For example, the

R¹-(CH₂)_n- group is incorporated onto the A¹-A⁶ ring by reaction with a

R¹-(CH₂)_n- halide, mesylate or acetate, such as 4-carbomethoxybenzyl bromide or methyl 4-bromomethylnaphthalene-1 carboxylate, 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 various formula (II) aldehyde compounds, or the hydroxymetyl precussors thereof, may be prepared employing the methods detailed in the publications hereinbelow and reference should be made to such publications for their disclosure, which are incorporated herein by reference. The hydroxymethyl precussors thereof may be oxidized to the formula (II) aldehyde compounds by treatment with a suitable reagent, such as anhydrous chromic acid-silica gel in tetrahydrofuran or, preferably, with activated magnese dioxide, in a suitable solvent, such as benzene, or, preferably, methylene chloride.

Methods for preparing pyrroles of formula (II) which are the precussors to formula (1) and (2) compounds, respectively, are detailed in EP Publication No. 323 841.

Methods for preparing aminopyrimidines and aminopyridines of formula (II) which are precussors to formula (3) and (4) compounds, respectively, are detailed in EP Publication No. 475206.

Methods for preparing oxypyridines of formula (II) which are precussors to formula (5) compounds are detailed in EP Publication No. 453 210.

Methods for preparing dihydropyrimidines of formula (II) which are precussors to formula (6) and (7) compounds are detailed in EP Publication No. 481 448.

Methods for preparing pyrazoles of formula (II) which are precussors to formula (8) compounds are detailed in PCT Publication No. WO 91/15479.

It should be appreciated by those skilled in the art that the A¹ - A⁶ ring substimted by a R¹-(CH₂)_n-group and a substimted acrylic acid group are prepared by processes analogous to those detailed in U.S. Patent No.5,185,351. Reference should be made to such patent for its disclosure, which is incorporated herein by reference. Pharmaceutically acceptable acid addition salts of compounds of Formula (I) are formed with appropriate organic or inorganic acids by methods known in the art. For example, the base is reacted with a suitable inorganic or organic 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. Representative examples of suitable acids are maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic,

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. Pharmaceutically acceptable base addition salts of compounds of Formula (I) are prepared by known methods from organic and inorganic bases, including nontoxic alkali metal and alkaline earth bases, for example, calcium, lithium, sodium, and potassium hydroxide; ammonium hydroxide, and nontoxic organic bases, such as triethylamine, butylamine, piperazine, meglumine, choline, diethanolamine, and tromethamine.

Angiotensin II antagonist activity of the compounds of Formula (I) is assessed by in vivo and in vivo methods. In vitro antagonist activity is determined by the ability of the compounds to compete with ¹²⁵ I-angiotensin II for binding to vascular angiotensin II receptors and by their ability to antagonize the contractile response to angiotensin II in the isolated rabbit aorta. In vivo activity is evaluated by the efficacy of the compounds 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.42:278, 1980). A particular fraction from rat mesenteric arteries is incubated in Tris buffer with 80 pM of 125 I- angiotensin II with or without angiotensin II antagonists for 1 hour at 25°C. The incubation is terminated by rapid filtration and receptor bound 125 I-angiotensin II trapped on the filter is quantitated with a gamma counter. The potency of angiotensin II antagonists is expressed as the IC₅₀ which is the concentration of antagonist needed to displace 50% of the total specifically bound angiotensin II.

Aorta

The ability of the compounds to antagonize angiotensin II induced vasoconstriction is examined in the rabbit aorta. Ring segments are cut from the rabbit thoracic aorta and suspended in organ baths containing physiological salt solution. The ring segments are mounted over metal supports and attached to force displacement transducers which are connected to a recorder. Cumulative

concentration response curves to angiotensin II are performed in the absence of antagonist or following a 30-minute incubation with antagonist. Antagonist disassociation constants (Kg) 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 the compounds 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 compounds.

Antihypertensive activity

The antihypertensive activity of the compounds is measured by their 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 compounds 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).

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, acacia, magnesium stearate, and stearic acid. Liquid carriers include syrup, peanut oil, olive oil, saline, and water. 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. 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 an ampoule, or an aqueous or nonaqueous liquid suspension.

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

Additionally, suitable ophthalmic vehicles may be used as carrier media for the present purpose including conventional phosphate buffer vehicle systems.

The pharmaceutical preparation may also be in the form of a solid insert. For example, one may use a solid water soluble polymer as the carrier for the medicament. Solid water insoluble inserts, such as those prepared from ethylene vinyl acetate copolymer, may also be utilized.

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

Doses of the compounds of Formula (I) 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, rectally, topically, by injection, or continuously by infusion. Oral dosage units for human administration preferably contain from 1 to 500 mg of active compound. Preferably, lower dosages are used for parenteral administration. Oral administration, at higher dosages, however, also can be used when safe and convenient for the patient. Topical formulations 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 form, an amount of active compound from between 50 ng to 0.05 mg, preferably 50 ng to 5 mg, is applied to the human eye.

The method of this invention of 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 this invention of producing antihypertensive activity and the method of treating congestive heart failure, glaucoma, and renal failure comprise administering a compound of Formula (I) to a subject in need thereof an effective amount to produce said activity.

Contemplated equivalents of Formula (I) compounds are compounds otherwise corresponding thereto wherein substiments have been added to any of the unsubstituted positions of the Formula (I) compounds provided such compounds have the pharmaceutical utility of Formula (I) compounds.

The following examples illustrate preparation of compounds and

pharmaceutical compositions of this invention. The examples are not intended to limit the scope of this invention as defined hereinabove and as claimed below.

Example 1

(E)-5-n-Butyl-1-[(4-carboxyphenyl)methyllpyrrole-2-(2-thienyl)methyl-2-propenoic

Acid

Method A

(i) methyl (E)-5-n-butyl-1-[(4-carboxyphenyl)methyl]pyrrole-2-(2- thienyl)methyl-2-propenoate

To a suspension of sodium hydride (69 mg, 2.87 mmol) in glyme (5 mL) is added drop wise a solution of trimethyl 3-(2-thienyl)-2-phosphonopropionate (U.S. Patent No. 5,185,351) in glyme (3 mL) under an atmosphere of argon. When the gas evolution has subsided, the mixture is heated to 50°C for 15 minutes. A solution of 5-n-butyl-1-(4-carboxomethoxphenyl)methyl]pyrrole-2-carboxaldehyde (1.92 mmol, prepared in an analogous manner to that disclosed in EP Publication No. 323 841, replacing t-butyl 4'-bromomethylbiphenyl-2-carboxylate with 4- carbomethoxybenzyl bromide) in glyme (3 mL) is added, and the mixture is stirred at 60-65°C for 5 hours. The cooled reaction is partitioned between water and ethyl acetate, and the organic layer is washed with water, dried, concentrated and flash chromatographed over silica gel to give methyl (E)-5-n-butyl-1-[(4- carboxyphenyl)methyl]pyrrole-2-(2-thienyl)methyl-2-propenoate.

(ii) (E)-5-n-butyl-1-[(4-carboxyphenyl)methyl]pyrrole-2-(2-thienyl)methyl-2- propenoic acid

A solution of methyl (E)-5-n-butyl-1-[(4-carboxyphenyl)methyl]-pyrrole-2- (2-thienyl)methyl-2-propenoate (0.783 mmol) in ethanol (10 mL) is treated with 10% sodium hydroxide solution (4 mL), and the solution is stirred for 3 hours at 25°C. The pH is adjusted to 5 and a solid precipitates. The mixture is diluted with water, cooled and filtered to provide (E)-5-n-butyl-1-[(4-carboxyphenyl)- methyl]pyrrole-2-(2-thienyl)methyl-2-propenoic acid

Method B

(i) methyl 5-n-butyl-1-[(4-carboxyphenyl)methyl]pyrrole-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 is added n-butyl lithium (7.3 mL, 0.0183 mol of 2.5 M in toluene), and the mixture is stirred for 10 minutes. Then, methyl 3-(2-thienyl)propanoate (2.83 g, 0.0166 mol) in tetrahydrofuran (2 mL) is added, and the mixture is stirred for 30 minutes at -78°C. A solution of methyl (E)-5-n-butyl-1-[(4-carboxyphenyl)methyl]pyrrole-2-(2-thienyl)methyl-2- propenoate (0.0111 mol) in tetrahydrofuran (4 mL) is added, and the resulting mixture is stirred at -78°C for 30 minutes. The reaction is partitioned between saturated ammonium chloride solution and ether, the organic extract is washed with brine, dried over anhydrous magnesium sulfate and concentrated to give methyl 5-n- butyl-1-[(4-carboxypheny)lmethyl]pyrrole-3-hydroxy-2-(2-thienyl)- methylpropanoate.

(ii) methyl 5-n-butyl-1-[(4-carboxyphenyl)methyl]pyrrole-3-acetoxy-2-(2- thienyl)methylpropanoate

A solution of methyl 5-n-butyl-1-[(4-carboxyphenyl)methyl]pyrrole-3- hydroxy-2-(2-thienyl)methylpropanoate (9.02 mmol) in methylene chloride (100 mL) is treated with 4-dimethylaminopyridine (0.386g, 3.16 mmol). Then acetic anhydride (8.5 mL, 9.02 mmol) is added dropwise to the stirred mixture. The mixture is stirred for 18 hours, water (35 mL) is added, the mixture is stirred for 1 hour and then diluted with ether and saturated sodium bicarbonate solution. The ether layer is washed with brine, dried with anhydrous magnesium sulfate and evaporated to give the title 3-acetoxy derivative. (iii) methyl (E)-5-n-butyl-1-[(4-carboxyphenyl)methyl]pyrrole-2-(2- thienyl)methyl-2-propenoate A mixture of methyl methyl 5-n-butyl-1-[(4-carboxyphenyl)methyl]pyrrole- 3-acetoxy-2-(2-thienyl)methylpropanoate (8.92 mmol) in dry toluene (80 mL) is treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (3.2 mL, 21.4 mmol), and the resulting solution is heated at 80°C under argon for 3 hours. The solvent is evaporated, the residue triturated with ether and activated charcoal is added. After filtration, the filtrate is concentrated to give methyl (E)-5-n-butyl-1-[(4- carboxyphenyl)methyl]pyrrole-2-(2-thienyl)methyl-2-propenoate.

(iv) (E)-5-n-butyl-1-[(4-carboxyphenyl)methyl]pyrrole-2-(2-thienyl)methyl-2- propenoic acid

Basic hydrolysis of the above ester (6.71 mmol) according to Method A (ii) gives (E)-5-n-butyl-1-[(4-carboxyphenyl)methyl]pyrrole-2-(2-thienyl)methyl-2- propenoic acid.

Examples 2-8

Examples 2-8 in Table I are prepared following the proceure of Example 1, replacing 5-n-butyl-1-(4-carboxomethyoxphenyl)methyl]pyrrole-2-carboxaldehyde with the appropriate Formula (II) heterocyclic aldehyde compounds. (See the specification on page 10 for the preparation of these aldehydes).

Example 9

(E)5-n-Butyl-1-[(4-carboxynaphthyl)methyl]pyrrole-2-(2-thienyl)methyl-2- propenoic Acid

The procedure of Example 1 is followed replacing 5-n-butyl-1-(4- carboxomethoxphenyl)methyl]pyrrole-2-carboxaldehyde with 5-n-butyl-1-[(4- carbomethoxynaphthyl)methyl]pyrrole-2-carboxaldehyde, which is prepared by the methods disclosed in EP Publication No. 323 841, replacing t-butyl 4'- bromomethylbiphenyl-2-carboxylate with methyl 4-bromomethylnaphthalene-1- carboxylate (Can J. Chem., 52:2629 (1981)).

Examples 10-16

Examples 10-16 in Table II are prepared following the procedure of Example 9, replacing 5-n-butyl-1-(4-carboxomethyoxphenyl)methyl]pyrrole-2- carboxaldehyde with the appropriate Formula (II) heterocyclic aldehyde

compounds

Example 17

An oral dosage form for administering orally active Formula (I) compounds is produced by screening, mixing and filling into hard gelatin capsules the ingredients in proportions, for example, as shown below. Ingredients Amounts

(E)-5-n-butyl-1-[(4-carboxyphenyl)- methyl]pyrrole-2-(2-thienyl)methyl-2- propenoic acid 100mg

magnesium stearate 10 mg

lactose 100 mg

Example 18

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

Ingredients Amounts

(E)-5-n-butyl-1-[(4-carboxynaphthyl)- methyl]pyrrole-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 19

(E)-5-n-Butyl-1-[(4-carboxyphenyl)methyl]pyrrole-2-(2-thienyl)methyl-2- propenoic acid, 50 mg, is dispersed in 25 mL of normal saline to prepare an injectable preparation.

Example 20

A topical opthamological solution for administering Formula (I) compounds is produced by mixing under sterile conditions the ingredients in proportions, for example, as shown below. Ingredients Amounts

(m g/mL)

(E)-5-n-butyl-1-[(4-carboxynaphthyl)- methyl]pyrrole-2-(2-thienyl)methyl-2- propenoic acid 1.0

dibasic sodium phosphate 10.4

monobasic sodium phosphate 2.4

chlorobutanol 5.0

hydroxypropanol methylcellulose 5.0

sterile water q.s.ad 1.0mL

1.0 N sodium hydroxide q.s.ad pH 7.4

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

Claims

What is claimed is:

1. A compound of the formula:

wherein:

R¹ is phenyl or naphthyl, each of which is unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C_1-6alkyl, NO₂, CF₃,

Q-CO₂R', tetrazolyl, C_1-6alkoxy, OH, SC_1-6alkyl, SO₂NHR', NHSO₂R", SO₃H, CONR'R', CN, SO₂C_1-6alkyl, NR'R', NR'COH, NR'COC_1-6alkyl or

NR'CO-phenyl;

n is 0-4;

A¹ is C or N when X is a covalent bond, or C when X is other than a covalent bond;

A² is CR², CR¹⁴, or C=R³;

A³ is CR², CR⁴, N, or NR¹⁵;

A⁴ is CR⁵, CR⁵R⁹, or N;

A⁵ is absent or present as CR⁶ or N;

A⁶ is CR⁷ when A⁵ is absent or CR⁸ or N when A⁵ is present;

with the proviso that:

( 1 ) one of A² or A³ is CR²; and

(2) at least one, but not more than three of A¹, A³, A⁴, A⁵ and A⁶ are N;

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

R is R', C_mF2_m+1, wherein m is 1-3, or phenyl which is unsubstituted or substimted by one to three substiments selected from Cl, Br, F, I, C_1-6alkyl, NO₂, CF₃, Q-CO₂R', tetrazolyl, C_1-6alkoxy, OH, SC_1-6alkyl, SO₂NHR', NHSO₂R', SO₃H, CONR'R', CN, SO₂C_1-6alkyl, NR'R', NR'COH, NR'COC_1-6alkyl or NR'CO-phenyl;

R³ is O, (H,H), or (H, C_1-4alkyl);

R⁴ is H, C_1-4alkyl, Cl, Br, F, or I;

R⁵ is H, C_1-4alkyl, Cl, Br, F, or I;

R⁶ is H or C_1-4alkyl;

R⁷ is C_2-8alkyl, SC_1-7alkyl or OC_1-7alkyl;

R⁸ is H, C_2-8alkyl, SC_1-7alkyl, or OC_1-7alkyl;

each R⁹ independently is H or C_1-6alkyl;

R¹⁰ is H or C_1-6alkyl;

R¹¹ is CO₂R', CONR'R', tetrazolyl, or SO₂NH₂;

R¹² is C₁-C₆alkyl, phenyl-Y-, biphenyl-Y-, naphthyl-Y-, 2- or 3-thienyl-Y-, 2- or 3-furanyl-Y-, 2-, 3- or 4-pyridyl-Y-, pyrazolyl-Y-, imidazolyl-Y-, pyrrolyl-Y-, triazolyl-Y-, oxazolyl-Y-, isoxazolyl-Y-, thiazolyl-Y-, or tetrazolyl- Y-, with each heteroaryl group being unsubstimted or substimted by C₁-C₆alkyl, C₁-C₆alkoxy, Cl, Br, F, I, CF₃, NR'R', CO₂R', SO₂NHR', SO₃H, CONR'R', OH, NO₂, SC₁- C₆alkyl, SO₂C₁-C₆alkyl, NR'COH, or NR'COCi-Cόalkyl and with each aryl group being unsubstimted or substimted by C₁-C₆alkyl, C₁-C₆alkoxy, Cl, Br, F, I, CF₃, NR'R", CO₂R', SO₂NHR', SO₃H, CONR'R', OH, NO₂, SC₁-C₆alkyl,

SO₂C₁-C₆alkyl, NR'COH, or NR'COC₁-C₆alkyl or with each aryl group being substimted by methylenedioxy, phenoxy, or phenyl;

Y is a single bond, O, S, or C₁-C₆alkyl which is straight or branched optionally substimted by phenyl or benzyl, wherein each phenyl or benzyl group is unsubstimted or substimted by Cl, Br, F, I, NO₂, CF₃, C₁-C₆alkyl, C₁-C₆alkoxy, CN, or CO₂R';

Q is -CH=CH-, -(CH₂)0-4-, -X-(CH₂)_1-2-U-(CH₂)_1-2-, or -V-CH(R¹³)-; X is a covalent bond, -O-, -S-, or -N(R⁹)-;

U is absent or present as -O-, -S-, or -N(R⁹)-;

V is -O-, -S-, or -N(R⁹)-;

R¹³ is H, phenyl, or benzyl wherein each phenyl or benzyl group is unsubstimted or substimted by one to three substituents selected from Cl, Br, F, I, C_1-6alkyl, NO₂, CF₃, Q-CO₂R', tetrazolyl, C _1-6alkoxy, OH, SC_1-6alkyl,

SO₂NHR', NHSO₂R", SO₃H, CONR'R', CN, SO₂C_1-6alkyl, NR'R', NR'COH, NR'COC_1-6alkyl or NR'CO-phenyl;

R¹⁴ is Cl, Br, F, or I; and R¹⁵ is H, C_1-6alkyl, -(CH₂)_1-2C_3-6cycloalkyl, -(CH₂)_1-2CF₃, or -(CH₂)_0-2Phenyl, wherein the phenyl is unsubstituted or substimted by any accessible combination of up to three substiments selected from Cl, Br, F, I, CF₃, or C_{1 -6}alkyl;

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 wherein R¹ is phenyl or naphthyl, each of which is substimted by Q-CO₂R', CONR'R', NHSO₂R", or tetrazolyl.

3. The compound according to claim 2 wherein R¹ is phenyl or naphthyl, each of which is substimted by 4-CO₂H, and n is 1.

4 The compound according to claim 3 wherein R² is

in which the A¹ - A⁶ ring and the CO₂H group are trans to each

5. The compound according to claim 4 wherein A¹ - A⁶ and X are

6. The compound according to claim 4 wherein A¹ - A⁶ and X are

7. The compound according to claim 4 wherein A¹ - A⁶ and X are

8. The compound according to claim 4 wherein A¹ - A⁶ and X are

9. The compound according to claim 4 wherein A¹ - A⁶ and X are

10. The compound according to claim 4 wherein A¹ - A⁶ and X are

11. The compound according to claim 4 wherein A¹ - A⁶ and X are

12. The compound according to claim 4 wherein A¹ - A⁶ and X are

13. A pharmaceutical composition comprising a pharmaceutical carrier and a compound of claim 1.

14. A method of antagonizing angiotensin II receptors which comprises administering to a subject in need thereof an effective amount of a compound of claim 1.

15. A method of treating hypertension which comprises administering to a subject in need thereof an effective amount of a compound of claim 1.

16. A method of treating congestive heart failure which comprises administering to a subject in need thereof an effective amount of a compound of claim 1.

17. A method of treating renal failure which comprises adniinistering to a subject in need thereof an effective amount of a compound of claim 1.

18. A method of treating glaucoma which comprises administering to a subject in need thereof an effective amount of a compound of claim 1.