IE83863B1 - Imidazolyl-alkenoic acids - Google Patents

Description

The present invention relates to new imidazolyl—alkenoic acids which are angiotensin II receptor antagonists and are useful in regulating hypertension induced or exacerbated by angiotensin H, 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. I 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 fonns of renal disease. In addition to a direct action on arteries and arterioles, angiotensin II (AH), 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. intraocularipressure, especially glaucoma, in mammals.

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

Compounds of this invention are also expected to exhibit activity.

Recognition of the importance of blocking and inhibiting the actions of AH has stimulated other effons to synthesize antagonists of AH. The following references have disclosed imidazole derivatives which are described as having AH 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 l—benzyl-2— n—butylchloroimidazole—4—acetic acid and I—benzyl—2—phenyl—5—chloro~imidazole— —propanoic acid.

Furukawa, et al., US. Patent 4,355,040 discloses substituted imidazole~5~ acetic acid derivatives. A compound specifically disclosed is l—(2—chlorobenzyl)—2— n4butyl4-chloroimidazole—5—acetic acid.

Carini et al. in EP 253,310 disclose certain imidazolylpropenoic acids. Two intemiediates described in this patent are ethyl 3-[l—(4-nitrobenzyl)—2Abutyl4i chl0r0imidaZOl——5—yl]pr0pen0ate and ethyl 3-[Z—butyl—4—chloro-l-(4— aniinobenzyhimidazol—5—yl]propenoate.

Also, Wareing, in l’(.‘T/l:'P 86/00297, discloses as intermediates certain irnidazolylpropenoate compounds, ()n page 62, Formula (CX) is ethyl 3»—[l—(4« fluorophenyl)—4—isopropyl—2—phenyl—l H—i midazolyl]—2—pr0penoate.

DESCRHEION OE THE INVENTION The present invention relates to blockers of angiotensin II receptors represented by the following Fomiula (I): I ,CH2—R Rho /R 2 N T \R5 R ‘ X"<\ l in N 3 in which: , E . . T K 115 phciiyl ui1.~;uE>siitu(cd oi subsiiuited by one to three .\‘iihsti!m*iitx‘ xvivclcd R4 is hydrogen R5 is Ihicnylrnelhyl optionally substituted by inethyl or n1eih0xy;and W is C()OH m a pharmaceulieally acceptable salt thereof, The F, isomers (trans stereocheniisuy of the R6 group and imidazolc group) are generally more active and thus, are preferred over the Z isomers (cis).

As used herein, the terms alkyi, alkenyl, alkoxy and aikynyl mean carbon chains which are branched or unbranched with the length of the chain determined by the descriptor pre(:cdiiig the term.

Particular compounds of the inveneion include, bur are not limited to, the fellowing: EiliCll}'i)II1<:[h)’i '2—]7£'0pCll0iC acid, (I313 {Z n bury! I {(2—ChlOi()pilt:Ii)’i}IIlC(hyi}-I!f~iK11i(1;iZ,()i~5—)/H>243‘ {hicnyl)inclhyl 2 propcnoic acid, (ii) 3v[2—I1~bUl)/1+]-((2-Chl()IOphcn)/i)fI}€[h)/i,‘—lH-iIIli(ia/2()i—5—yi]~2‘(5 mci‘hyl—2~ thienyl)inc£hyl Z p[Up\'.I)()it‘ acid, -7_(_7_ thieriyl)incthyi—Zpmpcimic acid, (I€)—,$—[2 n—buIyl— I ~{(2—nitr0phenyl)inethyl}—IH—inndazoi—5—y[j—2 (Z— thienyi)methyl—2—pr0pcm)iL: acid, (li)A ’>~[2n~hutyl—l—{(2—cy21n0phenyl)methyl}— lH—iniid:1zol—5—y!]~'.Z (Zr ihicnyl)mcIhyl»-Zvprupenoic acid, (l".)—3—[Z—n«hutyli I ~ { (4—inethox)/-3—methylphenyl)mcthyl ) -T I H—iinid2iz0l—5 /yl]—2r (2~thie/nyl)meIhyl~Z—pr0pen0ic acid, (E)—3 —[2~n—butyI—l~{(2»chI0r0phcnyl)n1cthyl}—lH«imid2Lzol—5—yi](5«n1cth0xy~ ~thicnyl)methyl»2—propenoic acid, (E)—3—[2— n —butyl—1 — { (2,3—dichlorophenybinethyl }— III—imidaz:01—5—yl]~2~(2— thicny1)incthyl—2—propenoic acid, (13).? [2 ii hulyil {(4~c2u*boxyv2-Chlorophcnyl)im-my}}—!H—iinid2izoI—5—yH* [iiiciiy1}Iimiiy! P, pimpzsiinii a:ci .5 (l:) 5vlZ~n-butyl~ 1 ~ { (4e("2ll'lI()Xy*'; —chlorophenyl)metliyl} lll llllltlit/4t?l—5"yl]—Z —(_’2 thienyl)ntethyl»2-propenoit: acitl, i (l£)~$»[2 —n-hexyl~ l — { 4—ttarboxyphcnyl)methyl } v l ll—iniida'/,ol 5 »yl)~»2~(2— tliienyl)methyl-Zproprénoit‘ attitl, (li)—3—l2~nbutyl — l ~ { (4i<‘ai bomethoxyphenyl)methyl }w l ll~irnidazol—firylJ~2~(2- thienyl)methyl32 piopenoic acid, and (lj) a3—[2—n—butyl» l ~ { (2—ti ifluoiomethylphenyl)—rnethyl }~ 1 Himidazol-5—yl]—2-(2— thienyl)methyl—Z propenoie acid; or a phannaeeutically acceptable salt thereof.

The invention also relates to phannaceutical compositions comprising a pliarmaccutical carrier and an effective amount of a compound of Formula (I).

Also included in the present invention are methods for antagonizing an giotensin II receptors which comprises administering to a subject in need thereof an effective amount of a compound of Formula (I). methods producing iitlllli)/‘pCfI6[1SlVC activity and methods of treating congestive heart failure, glaucoma, and renal failure by administering these compounds are also included in this invention.

The following procedure is useful for the preparation of compounds of Formula (I) particularly where R1 is 2£hlor0phenyl, R2 is n—butyl, R3 is hydrogen, ehloro, or CF}, R4 is hydrogen, R5 is as described in Formula (I), R6 is (‘()()R8 and R8 is hydrogen, methyl, or ethyl.

The l-RlCH2—group is incorporated onto the 2—R2X~imidazole by known procedures, for example, by reaction with an RLCH2 halide, mesylate or acetate, such as 2-ehlorobenzyl bromide, in a suitable solvent, such as dimethylfonnamide (DMF), in the presence of a suitable acid aeceptor,vsuch as sodium alkylate, potassium or sodium carbonate, or a rnetrtl hydride, preferably sodium hydride at :3 l'\; ‘Jr Alternatively, the l—l are prepared by reacting an imido ether, R2-aC(:Nll)~0/alkyl, such as valerainidine methyl ether, with dihydroxyaeetone in liquid ammonia under pressure to give 2~R2~ —hydroxymethyliinidazole. This intermediate is reacted with acetic anhydiide to give l—aeetyl—5-acetoxymethyl-R2—imidazole. The diacetate intermediate is N— alkylated, for example, using 2—chlorobenzyl triflate and the resulting l~R1Cll2~2— R25Aacetoxymethylimjdazole is treated with aqueous base, such as 10% sodium hydroxide solution, to give the 1—R1CH2—2—R2—5—hydroxymethylirnidazole intermediate. T if ' 1 Alternatively, the 2-R lS—imida7.ole compounds are prepared by the following procedure. Benzylamines, substituted by one to three substituents selected from SO2C1_4all(yl, are alkylated with a C; fialkyl rhloroaeetate, for exarnple methyl chloroacetate. in the presence of a base, such as triethylamine, in a suitable solvent, such as dimethylfotmamide The resulting .‘ill<_ylaiiiinoall<}'l ester cmiipoiiiitls are: N formulated with lionnic acid in the presence of a suitable solvent, such as X}/lc‘1t'(:$. followed by (i‘.«f0rmulati0n of the carbon alpha to both the amino and the ester groups. Reaction of this intermediate with acidic tliiocyanate, preferably potassiurn thiocyanate, in an inert Organic solvent, such as C1_4all RCll2—2—inercapto~5ralkanoate ester imidazole compounds. The free thio group of the ester iinidazole is reacted with a halo R l0 compound, wherein R l0 is (73 malkyl, (73,1()all;ciiyl, C3 >Cmall (CHZ)0,gl’h, preferably propyl brornide, in the presence of a suitable base, such as sodium carbonate, in an appropriate solvent, such as ethyl acetate. The ester is reduced to the hydroxymethyl~imidazole intermediate by reduction with a suitable reagent, preferably diisobutyl aluminum hydride, in an appropriate solvent, such as tetrahydrofuran, at a temperature of —78°C to 25°C, preferably at less than — 10°C.

The hydroxymethyl group of the hereinbefore prepared intermediate is oxidized to an aldehyde by treatment with a suitable reagent, such as anhydrous chrornic aeid~siliea 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 25°C to l4()°(7, pieferigihly at 25°C. The {R lCll_7;lZ— {?’X~lIIlitlIlZ()l/S"C3l’l,70X{1ltlCll)'(l(3S are reacted with an appropriate pl1 as those listed in Table I (Examples 26). The phosphonates are prepared,-for example, from trialkyl phosphonoacetates by alkylation with an appropriate halide, mesylate or acetate in the presence ofa suitable base, such as sodium hydride, in a suitable solvent, preferably glyme at a reaction temperature of 25°C to l 10°C, preferably at 55°C, to provide, for example, the phosphonates listed in Table l. The reaction of the irnidazol-5»carboxaldehydes 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 10°C to 50°C, preferably at 25°C, to provide a variable mixture of trans and cis, e.g., (E) and _ (Z), 1—R1CH2—2-RZX-5—CH:C(R5)o(COOea1kyl)-imidazoles. These isomers are readily separated by chromatography over silica gel in suitable solvent systems, preferably hexane in ethyl acetate mixtures The esters are hycdolyzed to the acids, 1—R1—CH2~2~R2X—5—CH=C(R5)COOH—imidazoles, using bases , such as potassium hydroxide, lithium hydroxide or sodium hydroxide, in a suitable solvent system, such as, for example, aqueous alcohols or diglyme. The trans and cis structures of the acids are readily determined by NMR by the NOE protocol, as well as by the biological activities since, generally, the trans (E) isomeric acids are the more potent isomers.

Alternatively, the l—R1CH2—2—R2X-iniidazol—5—carboxaldehydes are prepared by the following procedure. Starting 2-RZX-irnidazol—4«carb0xaldehydes are reacted with an N—all(ylating protecting reagent, such as chloromethyl pivalate (POM—Cl), in the presence of a base, such as dimethylforrnamide, at a temperature of 20°C to 50°C, preferably at 25°C, to give N—all(ylation (e.g., POM-derivation) on the least hindered nitrogen atom of the imidazole nucleus. The I-RICHZ-group is incorporated onto the imidazole by N —alkylation of the above prepared aldehyde with a halomethylbenzene compounds, such as methyl 4—bromomethyl—3—chlorobenzoate, at a temperature of 80°C to l25°C, preferably at 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 1—R 1CH2— 2—R2X~imidazole-5—carboxaldehyde compounds. The Formula (I) compounds can be prepared from these Scarboxaldehyde compounds by the methods described above.

Compounds of Formula (I), wherein R6 is COOR8, R1, R2. R3, R4 and R5 dfiscfibfid in FOF H1013 (D are also prepared by the following procedure.

The 2-R2X—imidazole starting materials are reacted with trimethylsilylethoxyinethyl (SEM) chloride to give l—(trimethylsilyl) ethoxymethyl— 2—R2~imidazole.r The reaction is camed out, for example, in the presence of sodium hydride in a solvent such as dimethylformarnide, The 5-tributyltin derivatives are 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 tn'»N~butyltin chloride, at —10°C to 35°C, preferably at °C. The 1—SEMe2—R2-5—tributyltinimidazole is coupled with an oglieunsaturated acid ester having a leaving group on the f3—position, such as a halide or trifluoromethanesulfonyloxy group, for example, BICFR4-=C(R5)(COOalkyl), in the presence of a phosphine ligand, such as bis(diphenylphospl1ino)propane, or triphenylphosphine and a palladium (ll) compound, or preferably tetrakis(triphenylphosphine)-palladium(0), with or—withoutTaibase, such as tiibutylamine, at a temperature of 50°C to 150°C, preferably at 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 l—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 l-unsubstituted imidazole derivatives are convened to the l~t~butoxycarbonyl (t~B()(‘) imidazoles with di—t—butyl dicarbonate (Hoppe—Seyler's Z. Physiol. Chem., (1976), ;_l_5_7, 165 l ).

The t-BOC esters are alkylated and hydrolyzed with, for example, 2—chlorobenzyl-()- triflate in the presence of a suitable base, preferably diisopropylethylamine, in a suitable solvent, preferably methylene chloride, to afford the l-(2- chlorophenyl)methylimidazole derivatives (esters). The (E) and (Z) isomers are hydrolyzed to the (E) and (Z) acids by the method described above.

Compounds of Formula (I) are also prepared by the following procedure.

The 1—R1CH2—2—R2X—imidazole—5~carboxaldehydes, prepared as described above, are reacted with a substituted half-acid, h_alf~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 80°C to ll0°C, preferably at 100°C. The resulting LR1CH2—2-R2x—5-cH=c(R5)Coo alkylimidazoles are hydrolyzed to the corresponding Formula (I) acid compounds by alkaline hydrolysis as described above.

Compounds of Formula (I) in which R3 is H are prepared as follows.

The 1-Rl—Cll2-2—R2X—imidazol~5£arboxaldehydesare treated with the lithium derivatives of a substituted 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—Cll2—Y—(2— thienyl), to generate the or-lithio derivatives at —78°C to —l0°C, preferably at »78°C, which are then treated with the imidazol—carboxaldel1yde.i Thefiritermediate [3- hydroxy group of the irnidazol 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 50 to 110°C, preferably at 80°C, to afford ester compounds of Formula (I) such as 3-(imidazol—5- yl)~2—(2—thienyl)methyl—2~propenoic acid esters. The (E) isomer is the predominate olefmic isomer. The acids are prepared from the esters by the method described above. Compounds of Formula (I), wherein R1 is ichlorophenyl, R2 is n—butyl, R3 is H, R4 is H, R55 heterocyclic or a substituted heterocyclic group as described in Foniiula (1) and R6 is COOH, may be prepared by heating 1- RI—CH2—2—R2X-imidazol~5-carboxaldehydes at 50°C to 180°C, preferably at 140°C, with an appropriate substituted heterocyclic acetic acid and with acetic anhydride and potassium carbonate to provide unsaturated acids of formula (I) such as 3—[2~n— butyl-I~(2—chlorophenyl)methyl~1H~imidazolA5—yl]~2~R5—2—propenoic acid. The trans olefinic acid is the principal product.

Compounds of Formula (I) in which the R1 substituent is substituted by hydroxy are f0lTllCd from Formula (I) compounds in which the R1 group is substituted by C1'—C4alkoxy using an ethercleaving reagent, such as boron tribromide or hydrobromic acid. ‘ Compounds of Formula (I) in which the R1 substituent is substituted by carboxy are fomied from Formula (I) compounds in which the R1 group is substituted by CO2C1-C4all(yl using basic hydrolysis or ethanol, or using acidic hydrolysis, such as aqueous hydrochloric acid.

Compounds of Formula (I) in which the R1 substituent is substituted by a tetrazol—5—yl group are prepared from the corresponding carboxy compounds. For example, Formula (1) acid compounds are reacted with a halogenating agent, Such 33 thionyl chloride, in a suitable solvent, for example benzene, to give the corresponding acid halide compounds.

The acid halides are then converted to primary amide compounds in a reaction with concentrated ammonia. Subsequent dehydration of the amides with oxalyl chloride/dimethylfonnamide in acetonitrile/dimethylformamide yields and the nitrile compounds, which are the immediate precursors to the Formula (I) tetrazole compounds, Tetrazole formation is accomplished by reacting the nitriles with azide, preferably aluminum azide prepared in situ by the reaction of sodium azide with aluminum chloride, in a suitable solvent, for example tetrahydrofuran. The Formula (I) compounds in which R6 is —CO2H are prepared from these Formula (I) tetrazole ester compounds by basic hydrolysis as described above.

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. snccinic, bismethylene—salicyclic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicyclic, citric, gluconic, aspartic, stearic, palmitit‘, itaconic, glycolic, p—aminoben7,oic, glutamic, benzenesulfonic, hydrochloric, hydrobromic, sulfuric, cycl0hexyl—sulfamic, phosphoric and nitric acids Phamiaceutically acceptable base addition salts of compounds of Formula (I) in which R8 is H 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, butylarnine, piperazine, and (trihydroxymethyl)—methylamine.

Angiotensin 1] antagonist activity of the compounds of Fonnula (I) is .assessed by ip yigg and Q Lh/L) methods. Q Litrg antagonist activity is determined by the ability of the compounds to compete with 1251-angiotensin H for binding to vascular angiotensin [1 receptors and by their ability to antagonize the contractile response to angiotensin II in the isolated rabbit aorta. Q vivo activity is evaluated by the efficacy of the compounds to inhibit the pressor response to exogenous y , _ . . . -. .. , angiotensin II in conscious rats and to lower blood pressure in a rat model of renin; dependent hypertension. T g A __ g (T V 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 solutions 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 H are performed in the absence of antagonist or following a 30-minute incubation with antagonist. Antagonist disassociation constants (KB) are calculated by the dose ratio method using the mean effective concentrations. Exemplary of the KB of compounds of the invention (E isomers) is about 0.1 nM to about 30 ttM.

Inhibition of pressgr response to Rats are prepared with indwelling femoral arterial and venous catheters and a stomach tube (Gellai et al., Kidney Int. l5:4l9, 1979). Two to three days following surgery the rats are placed in a restrainer and blood pressuie is continuously monitored from the arterial catheter with a pressure transducer and recorded on a polygraph. The change in mean arterial pressure imtresponse 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 E "llhe dose of compound needed to produce 50% inhibition of the control response to angiotensin I] (IC-;()) is used to estimate the potencyjof the compounds. The lC5Q of (E)—3-[2—n-butylél—{(2-chlorophenyl)methyl}—lH— imidazol—5—yl]—2—(2—thienyl)methyl-2—propenoic acid is 3.60 mg/kg i.v. and 44.00 mg/kg orally.

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 (Cairgiano et al.', J. Pharmacol. Exp. ]‘he_r- 20_8:3l0, 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 (IC50) is used as an estimate of potency. The IC50 of (E)o3v[2An—but_vl~ l —{ (Z—chlor0phenyl)methyl }—lH-imidazol- Siyl]~Z—(2ithienyl)methylo2—propenoic acid is 1.80 mg/.kg iv. and 8.0 mg/kg orally.

The intraocular pressure lowering effects employed in this invention may be measured by the procedure described by Watkins, et al,, L_Qc_‘_ul1r_£llar_rna<_:o_l_, l (2):l61—1(>8(l985).

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 earners 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 camer 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. lioi topical ophtlialiiioioizitt adrninistration, the pharinacenticai compositioiis adapted include solutions. stispensions, ointments, and solid inserts. Typical pharmaceutically acceptable carriers are, for example, water, mixtures of water and water—miscible solvents such as lowtti alkanols or vegetable oils, and waterlsolnhlc ophthalmologically acceptable nontoxic polymers, for example, cellulose derivatives such as methyl cellulose The phannacetitical preparation may also contain nontoxic auxiliary substances such as emulsifying, preserving wetting, and bodying agents, as for example, polyethylene glycols; antibacterial Components, such as quaternary ammonium Compounds; buffering ingredients, such as alkali metal chloride; antioxidants, such as sodium iiietabisiilfite, and other conventional ingredients, such as sorbitan inonolauiate.

Additionally, suitable ophthalmic vehicles may be used as camiei media for the present purpose including conventional phosphate buffer -vfeliicle systems The phannaceutical preparation may also be in the fonn ofa 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 phamiaceutical preparations are made following conventional ttwtliiiitpies oi a phamiaceutical cheinist inxolving inixiniz, graiiiilatiiig, and coiiipressinyg wlicii necessary, for tablet torins, or iiiixiiip, tilliiig and dissolving the ingi‘edient.<, as appropriate, to give the (iC.\‘ll't‘ti oral, paiviiteral, or topical products.

Doses of the conipounds ol lioiiinila (I) in a pharmaceutical dosage unit as described above will be an etlicacioiis, nontoxic quantity selected from the range of 0.01 — 200 mg/kg of active compound, preferably I — 100 mg/kg. The selected dose is administered to a human patient in need of angiotensin II receptor antagonism from L6 times daily, orally, rectally, topically. by injection, or continuously by infusion. Oral dosage units for human administration preferably contain from l to 500 mg of active compound. l’referably, lower dosages are used for parenteral administration. Oral administration, at higher dosages, however, also can be used when safe and the active compound in an amount selected from 0.0001 to 0.1 (w/v%), preferably from 0.000] to 0.01. As a topical dosage unit form, an amount of active compound from between 50 iii: to 0.05 mg, preferably 50 rig to 5 pg, is applied to the human eye.

The method of this invention of antagonizing angiotensin 11 receptors in mammals, including humans, comprises administering toia subject in need of such antagonism an effective amount ofa compound of Formula (I). The method of this invention of producing antiliypci‘tt*iisivv activity and the method of treating congestive heart failure, glaucoma, and renal failure comprise administering a compound of Fonnula (1) to a subject in need thereof an effective amount to produce said activity. .

Contemplated equivalents of Formula (1) compounds are cornpounds otherwise corresponding thereto wherein substituents have been added to any of the unsubstituted positions of the Formula (1) compounds provided such compounds have the pharmaceutical utility of Formula (1) 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 described hereinabove and as claimed below. -2 2;grierryl )methyl~2— propgnoic Acid (i) 2—n-butyl-1—(2-ch1oro-phenyl)methy1-1H—irnidazole lmidazole was converted to the 1-diethoxyorthoamide derivative by the method of Curtis and Brown, ’ (1980), 45, 20. lmidazo1e(12.8 g, 0.19 mol) and .4 g (0.8 mol) of triethylorthoformate were reacted in the presence of 1 g of p— toluenesullionic acid to give 20.6 (61 %), bp 65~70"C (0.1 mm) of Ldiethoxyorthoainide rmidazole. This product (240 g, 0.14 mol) was dissolved in dry tetrahydrofuran (250 ml.), cooled to 40°C and n»butyl lithium (0.14 mol. 56.4 ml. of 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 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. A flash distillation on a Kugelrohr apparatus provided 14.8 g (85%) of 2—n—butylimidazole. —n4Butylimidazole (9.7 g, 0.078 mol) was dissolved in methanol (50 mL) and added dropwise to a solution of sodium methoxide (from 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 2- chlorobenzyl bromide (16.3 g, 0.079 mol) was added. The mixture was heated at 50°C for 17 hours under argon, poured onto ice water and the product was extracted into ethyl acetate. The extract was washed, dried, and concentratedsto give 18.5 g of crude product which was chromatographed over silica gel with 2:1 ethyl acetate/hexane to provide l L‘) g (61%) of 2—n ebutyl— l—(2—chlorophenyl)rnethyl—lll—irnidazole as an oil. Thin layer chromatography on silica gel with 4:1 ethyl acetate/hexane gave an Rf value of 0.59. (ii) 2«n—butyl— l—(2—chlorophcnyl)methyl—5~hydroxymethyl—1H-imidazole _l\_/lgtflgddl A mixture of 2—n—butyl—,l —(2—chlorophenyl)rnethyl-lH—in1idaéole (95.5 g, 0.384 mol), 37% formaldehyde (500 mL), sodium acetate (80 g) and acetic acid (60 mL) was heated to reflux for 40 hours under argon. The reaction 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 to 10% of methanol in ethyl acetate to give 8.3 g of starting material, 245 g of a mixture of starting material and product, and 44 g (41%) of 2-n—butyl(2—chlorophenyl)-methyl—5-hydroxymfletliyli1H:imidazole; mp 86- 88°C (from ethyl acetate). Further elution provided the his (4,5—hydroxymethyl) derivative; mp l38—l40°C (from ethyl acetate).

Method 2 A mixture of valerarnidine 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‘’(‘ for 4 hours at 375 psi. The arrunonia was allowed to evaporate, and the residue was dissolved in methanol (3L). The resulting slurry was refluxed with added acetonitrile (IL). The solution was decanted from the solid anunoriiurn 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, l.63 rnol, 98%).

This crude alcohol (253 g) was treated with acetic anhydride (400 mL) at «l5"(" and then was allowed to wann to ambient temperature with stining, 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 l—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 ethylarnine (128 111L, 0.73 mol) and 2- chlorobenzyl alcohol (104 g, 0.72 mol) in rrietliylene chloride (350 mL) over a period of minutes. After being stirred an additional 20 minutes at»—78°C, this solution was then treated with l—acetyl—4—acetoxyrnethyl—2—n—butylirnidazole (146 g, 0.61 mol) dissolved in metliyleiie chloride (300 ml) over a Ztlriiiiiute interval. The mixture was their stirred at aiiihient temperature for 18 liotiis and thesolvents were evaporated, The iesidiial 2 I!’ 1iutyl«5:acetoxyinethyl—1~(2-‘chlorophenyl)metliyl»1H»imidazole was used without pt1I'll51L‘.(l1lt'J1l im the hydrolysis of the acetate group. I, A solution ol crude 2—I'l~l)tl1yl~.1~(2—Cl1lt)f0pl]Cn)/1)1I1C1ll)'l-—111- iniida1.ole (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~biityl—1— (2—ch1oropheny1)methyl—5—hydr0xymethyl—1Hdniidazole; mp 86-88°C. This material was identical in all respects to the product prepared by Method 1. (iii) 2—nAbuty1« 1—(2~chloiophenyl)niet1iyl— 1H-imidazol-Searboxaldehyde A solution of2vn—butyl—l—(2—ctr1orophenyl)methyl—5—hydroxymethyl— 111 iniidazole (5.4 g, 0.0194 niol) 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 1'/' hours. The solids were filtered and the filtrate (‘0f1('t‘l"lll’.'i1t’.tl and ilasli chiuiuatogiaplied over Sllt\.d gel with 674 hexane/ethyl ;icet.'ite to Ztl5lUl\.1’1 ltw 5: (78%) of Z—ii—hutyl» l-(Z~cli1or*opht:iiylJmt-thyl—1H—irnid;izol—5~tiarhoxaldehyde as an oil NMR turd IR were eoiisisteiit with the striicture l\(/1et_hgd A (a) trimethyl 3—(Z—thieny1)—2—phosphonopropionate lo a solution of 2~thiophenemethanol (7. 28 g, 0.02 mol) in carbon tetrachloride (25 mL) was added triphenylphosphine ((7.81 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 chromatograplied over silica gel with 7:3 hexane/ethyl acetate to provide 2«Chlor0metliylthiopherie (1.52 57%) as an oil A suspension of sodium hydride (0.271 g, 11.3 inniol) in dry glyme (40m1.) under argon was treated dropwise with trimetliyl phosphonoacetate (1.87 g, 103 mmol) in glyme (5 mL). The resulting mixture was stirred at room temperature for 1.5 hours.

Then 2—cliloromethyl—thiopheiie (1.5 g, l 13 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 wzislied with water and brine, dried with anliyilroiis magnesium sulfate and concentrated to L9 g of an oil. This was chromatograplied over silica gel 4:1 ethylacetate/hexane to afford’800 mg (28%) of trimethyl 3-(2—thienyl) pliosphonopropionate. .: (b) n1ethyl (E)—3-[2—n-butyl—1-{(2—chlorophenyl)methyl }~ IH-imida7.ol—5—yl~2~(2v 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 tn'methyl 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«:hlorophenyl)methyl— IH-imidazol-Searboxaldehydc (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 withwater, dried, concentrated and flash chrornatographed over silica gel to give 336 mg (41%) of methyl (E)—3—[2—n—butyl-I-[(2—chlorophenyl)methyl]—lH—imidazol—5—yl[-2—(2—tl1ienyl)methyl~2— propenoate as an oil whose NMR was entirely consistent with the trans or E form of the olefin. (t‘) (E)~3—[2—n—butyl— l —((2—chl0rophenyl)methyl } ~ I H—imidazol—5~yl]—2—(2~ thienyl)methyl~Z—propenoic acid A solution of methyl (E)—3—[2—n-butyl—l—[(2—chlorophenyl)methyl]—lH—imidazol- ~yl]—2~(2-thienyl)methyl-2—propenoate (336 mg, 0.783 mmol) in ethanol (l0 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~ l -[(2—chlorophenyl)methyl]— 1H—imidazolyl]—2—(2-thienyl)methyl—2-propenoic acid; mp 177-179°C.

Method B (a) methyl 3~[2~n-*butyl~ l—{(2—chlorophenyl)methyl}- lll~imiElaz0lA5— 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 oi 2-n-butyl—l~(2— chlorophenyl)methyl—lH—imidazol-5—carboxaldehyde (3 g, 0.0] ll 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 sulfateand 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—l—(2—chlorophenyl)methyl—lH—imidazol—5—yl]—3-hydroxy—2-(2~ thienyl)methyl—propanoate. (b) methyl 3—acetoxy-3—[2—n—butyl—l—(24:hlorophenyl)methyl—lH—imidazol—5—yl]—2— (2~thienyl)methylpropanoate A solution of methyl 3—[2—n—butyl—l-(2—chlorophenyl)methyl—lH-imidazol'5~yl]~ 3—hydroxy~2—(2—thienyl)—methylpropanoate (4.03 g, 9.02 mmol) in methylene chloride (100 mL) was treated with 4—dimethylaminopyn’dine (O.386g, 3.16 mmol). Then acetic anhydiide (8.5 mL, 9.02 mmol) was added dropwise to mixture. The mixture was stirred for l8 hours, water (35 mL) was added, the mixture was stined 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-aeetoxy derivative as an oil (4.37 g, 99%). (4.) methyl (E)«3v[2—n—butyl«l~{(2~chlorophenyl)methyl)—lH—in1idazolyl}-2—(2~ thienyl)methyl~2vpropenoate A mixture of methyl 3vacetoxy—3«[2—n—butyl—l‘(ZAchlorophenyl)n1ethyl—lH— imidazol—5Ayl}—2—(2—thienyl)»n1ethylpropanoate (4.36 g, 8.92 mmol) in dry toluene (80 mL) was treated with l,8—diazabicyclo[5.4.0]undec~7+:ne (DBU) (3.2 mL, 2l.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-1A[(2—chl0rophenyl)—n1ethyl]—lH-imidazol-5—yl]-2—(2—thienyl)-methyl—2—propenoate wh_o_se 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 }— l H—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 (iii) gave 2.59 g (93%) of (E)—3—[2—n—butyl—1-[(2~chlorophenyf)methyl]—1H-imidazol—5—yl]~2— (2-thienyl)methyl—2—propenoic acid; mp l75~l77°C that was identical to the product from Method A. <«' (22) /‘ .. .\_ mp mc no; U I r-< Q ‘ \./ "U .4 ,_. U '( / V. 0 pm E‘ 0 -4 N 1 1| 6 .—. 42 K! I I I D 04 u a C N C -a 6 u ..

X .- (H10) Ctfifla Examgln '3 4 .-cccmoqcufixcuceobofizuua uo manna :. v-an cum -cocaoqzuaxcuceouofizuun um.ux. ~ .Hme¢xu ..«.< vocu.x cm -a u...a..u r "U c" .a vouqnoum n . -.~ you -ucauuu-m : I E . \ <1I:& fx; _ 0 2: u.o2-m..2 me 2: u.n.2:-~2 9.. Q. : miooo :2 :o 3: :o / :0 E -.1c:£-T~_U:08:_ 8:: m xaou E N. E K \UIU /2 KNOU\UlU /I am m nucnmuqou Zmeauu fl .NV .u. 3. u ._ .u.:c.u:oo. nIll..I1Il.l0.'1IIuI.oI .E...2 ..¥o.c3:< I||l..I'.|.| H 93:. _E_x_a_mi2.Lc_4 A (_E)fi—[2—n—Butyl~ 1 — { (2—chloro<6~fluoro—phenyl)methyl } ~ 1 iIi:ii1i:idazol—5—'\/l]—2~(2»thienyl)— 4 . methyl—2~prop<_:noic Acid (i) 2—n—butyl— l -(2-chloro—6—fluorophenyl)methyl~ lH—imidazole A solution of 2—n—butyliinidazole (3.75 g, 0.03 mol) in dry diniethylformamide (4 mL) was added to sodium hydride (0.95 g) in dimethylformarnide (18 mL). After the gas evolution subsided, the mixture was stirred one hour under argon and 2—chloro—6— fluorobenzylchloride (5.5. g, 0.031 mol) in dimethylfonnamide (7 mL) was added to produce an exothenn. The mixture was stirred for 17 hours at ambient temperature, diluted with ice water and extracted with ethyl acetate. The washed, dried, concentrated organic layer provided 7.63 (94%) of the title compound whose NMR was consistent with the structure. This material was used without further purification. (ii) 2—n—butyl— 1—(2—chloro—6—fluorophenyl)—methyl-IH-irnidazolcarboxaldehyde The procedures of Example l(ii—iii) were used. From 7.63 g of crude 2-n—butyl— -(2Jehloro-6—fluorophenyl)~methyl»1H-imidazole and proportional amounts of other reagents was obtained 2.8 g of 2-n—butyl-1—(2+:hloro—6-fluorophenyl)methyl- hydroxymethyl~lH—imidazole after chromatography over silica gel with 3% of methanol in methylene chloride; mp 106 l08"C (from ethyl acetate). This material was oxidized with manganese dioxide and worked up as described above to give 0.88 g (63%) of 2—n— butyl—2-(2—chlorofluorophenyl)inethyl-IH~imidazolcarboxaldehyde; mp 88—90°C (from ethyl acetate). (iii) (E)—3—[2—n—butyl- 1 ~ { (2£hloro—6—fluorophenyl)methyl }— I I{—in1idazol~5—yl]~2A(2— thienyl)methyl—2—propenoic acid The procedure of Example 1, Method A is used. 2-n—Butyl—l~(2£hloro-6— fluorophenyl)Amethyl— l H—imidazole—5carboxaldehyde, trimethyl 3—(2—thienyl)~2~ pliosphonopropionate, sodium hydride and glyme are held at 60°C for 1 hour to give, after chromatography over silica gel with 50% of hexane in ethyl acetate, methyl (E)—[2- n—butyl— l — { (2—chloro46‘fluorophenyl)methyl } « 1H-imidazol—5-yl](2-1hienyl)methyl~2~ propenoate and corresponding cis or (Z)—isomer. The (E)—isomer is hydrolyzed to afford (E)~3-[2—n—butyl~1~((2—chloro~6-fluorophenyl)methyl)—lH—imidazol—5—yl]—2-(2- thienyl)methyl—2—pr0penoic acid. (50 inL) held at 78°C under argon was added mbutyi lithiit"i'rni(l().2 mE., 25.6 rnmoi of 2.5 M in toluene), and the mixture was stirred for l0 mintites. 'l"hen, methyi it-(4~ p)’fld)/l)p£0pal)0é1i6 (4.22 g, 25.6 mmol) (prepared by reaction of 4—pyridine caiboxaldeliyde with triinetliyl phosphonoacetate in the presence of sodium hydride in ethylene glycol dimetliyl ether, followed by catalytic hydrogenation of the double bond with 10% pzilladiuiii on carbon at 3 zitinosphcre ofhydrogen in an ethyl ;lt‘.Cl£if(’ St)lUllt)n (98%) to provide the saturated ester) was added in tetrahydroftirzin (fit) trim and llllx‘ mixture was stirred for 30 minutes at 725°C. A solution of 2—n~hutyl— l ~(2«c:liloro— yl—Ill—iinidzizol—5—carboxz1ldeliyde (5.9 g, 21.3 mmol) in tetrahydroltiriin (lt) phenyl)meth ml,) was added and stiiiing was continued for 30 minutes at —78"(.,‘ The rerictioii wzix partitioned between xziturated antiitonium tihloride solution and ether. the t?tg_:HlltZ extract was washed with brine, dried over magnesium sulfate, concentrated and tlzzsli chroniatograplietl over silica gel with 5% methanol in ethyl acetate to provide 332 g (30%) of methyl 3-[2—n~butyl—l—(2«hlot‘ophenyl)—Inethyl~lll~imid;tzol—5 yl) 3 h TLC on silica gel with 5% methanol in ethyl acetate y(lroxy~ —(4—pyridyl)methyl—prop2inoate. showed a hoinogenous product with an Rf of 0.79. l3 (ii) methyl 3—2icetoxy~3~[2-n—btityl— l -(2—chlor0phenyl)inethyl— l H-iinid:i1.ol—5~yl (4~pyridyl)propano:tte A solution of methyl 3'[2~D"blllyl-1—(2-ChiiOfOpl1CIl)/l)‘lDC[llyl~H‘i-ilI1ltlitZ0l'5')’"‘ 3~'ll)’dI't)Xy*2'(4’]))'Tl(lyl)—Ii1C[hyl-pf()pZ1n0£1lC(3.252 g, 7.5 mmol) inetltylene Lilll0fl(lC (50 mL), 4«diiiietliylztiiiiiiopyiidiiie (L50 mg, l.3 mmol) and acetic zinhytliitie (7,: ml,, 75 niinol) ‘W225 stizactl sit Lillll‘-lt;l3l t<:s:ipt‘:’:ittti-t: tor I8 h.om:< Water (5 mL) was added, the mixture was stirred for 2 hours and then diluted 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 ethyl acetate showed essentially one spot material with an R f of 0.86. No starting material was detected. This material was not purified further. (iii) methyl (E)-3—[2—n-butyl—1-{(2éhl0rophenyl)—methyl}—lH~in1idazol—5«yl]—2—(4- pyridyl)methyl-2—propenoate A mixture of methyl 3—acetoxy-3—[2-n-butyl~1—(2£hlorophenyl)methyl-1H- imidazol—5-yl]—2~(4-pyridyl)-propenoate (7.5 mmol), toluene (50 mL) and l,8—diaza- bicyclo[5,4,0]—undec—7+:ne (DBU) (3.4 mL, 22.5 mmol) was 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. N MR showed that the trans or E isomer was the primary product. (iv) (E)—3-[2—n-butyl— l—{(2—chlorophenyl)methyl } - I H—imidazol—5—yl]-2—(4-pyridyl)v methyl—2—propenoie acid A solution of methyl (E)—3—[2-n—butyl—l-{ (2£hlor0phenyl)methyl}— IH—imidazol— Sayl]A2«(4~pyridyl)rnethylpropenoate (31 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 vacuum, 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 afford 0.48 g of (E)—3—[2—nAbuIyl~ l «{(2—ehlorophenyl)methyl} lH~ imidazol-5—yl]—2—(4—pyridyl)methyl-2—propenoic acid; mp l78«l82°C (d).

‘Examples 67 In Table H are listed other examples of alkenoic acids prepared by the methods described inpreparation l(i—iv). The starting materials and products are shown in Table .1: auCo2uouu..:_n J .:.:$.£e 33¢": lcilocacaoe .:u uuclufaigoua TE: :3) .3 32,: .36 xzaCooH3=oEu .3 £._::u«c 3 .caCC:m Z .3: 3:310 ouvczfiac-a one ._co_..m.;a8a c. uanfuzn 3:3 uS.fE: 3.. V 22 3 ntzra uuavopma . _ _ m W :1 29:70.": / \~:o. _. .v..Oou~:U~:U/ \ \ w :6 :6 W m .2U 902-..: .xolélVu~:u.. : .:o8~_G~: / \ :2 o me «Nam. muauoum . mm :mE:u .¢ .. xa : .22 /915 z\/\/\\ \ By the procedure of Example 1, using in place of 2»cliloroben7.yl bromide, the following: _ Zamethylbenzyl bromide, I ~methoxybenzyl bromide, and ~phenylbenzyl bromide; and using the phosphonopropionate of Example 1, (MeO)2P(())CH(CH2_2- thienyl)COOMe, the following products are obtained: (E)-3—[2—n—butyl— I — { (2-methylphenyl)methyl }— I H—imidazol-5—yl]—2~(2~ I0 thienyl)methylpropenoic acid, (E)—3-[2—n—butyl— 1 — { l4—methoxyphenyl)methyl } - lH—imidazol—5-yl]—2—(2—thienyl)rnethyl—2~propenoic acid. and Example 9 The following methyl ester of a propenoate are prepared as in Example 8 3 methyl (E)-3—[2—n—butyl— l -[(4—methoxyphenyl)—methyl]—I HAimidazol—S—~yl]A2—(2— thienyl)rnethyl—2—pr0penoate. f This is treated with boron tribromide in methylene chloride at room temperature for six hours and then the reaction mixture is condensed and treated with a mixture of ethyl acetate and water. The washed ethyl acetate layer gives on evaporation: (E)—3—[2~n~butylA 1 ~ [(4—hydroxyphenyl)methyl]— I H ~imidazol—5 —yl]—2—(2~ thienyl)methyl—2~propenoic acid.

Preparation 2 (E)-3—j2—Phenyl- I 4{(2£hlorophenyl)methyl }— lH—imidaz0l—5—yl1—2—L2—thienyl)methyl propenoic Acid By the procedure of Example l(ii) Method 2, using benzamidine methyl ether in place of valeramidine methyl ether, 2—phenylhydroxymethylimidazole is prepared and convened to 2—phenyl—1—(2—chlorophenyl)methyl—5~hydroxy—methyl~lll-imidazole. The ~hydroxymethyl group is oxidized using manganese dioxide by the procedure of Example 1 (iii). The resulting 2—phenyl—l,—(2—chlorophenyl)methyl-lH—imidazol-5— carboxaldehyde is used in the procedure of Example 2] with methyl 3—(2— thienynpropanoate to give the title compound.

Example 10 Prepared by the procedure ofpreparation Zusing the following amidine methyl ether: (‘2H5(7:NH(OCH3); the following product is obtained: .

(E)—3—[2—ethyl—1-{(Z—chlorophenyl)fiiethyl }— l ll~irr1idazol—5-yl]—2—(2— thienyl)methyl—2~propenoic acid.

Example 11 Ql3iT_5—[2—n~B1rtyl—1 —{(4—carboxmhenyl [methyl }— I H—imidazol—5—yl]—2—(2—thienyl)methyl- ' 2-2r0r>;n.gig@ (i) By the procedure of Example 1 [(ii) Method 2, (iii) and (iv) Mlethod B] using 44:arbomethoxybenzy1 alcohol in place of Zchlorobenzyl alcohol, the title compound was prepared; mp 25(}253°C. ‘I Example 12 1 E [—3—[2—n—Butvl— 1 — { (4—carboxv~2~chlorophenvl)methyl }— 1 H-imidazol—5—vl]—2-( 2- thienyl)methyl—2—propenoic Acid A suspension of 2—buty1imidazol-5~aldehyde (l6,92 g, 0.1 11 mol, prepared by manganese dioxide oxidation of the alcohol, prepared in Example 1, Method 2), chloromethyl pivalate (21.77 g, 0.145 mol), and potassium carbonate(20.07 g, 0.145 mol) in 200 ml of dimethylformamide was stirred at ambient temperature under argon for four days. The solids were removed by filtration and washed with ether. The combined filtrates were partitioned between diethyl ether and water. The ether phase was washed successively with water and brine, dried over magnesium sulfate and concentratedvunder vacuum to give 23.6 g of 2—n—butyl—l—pivalyloxyrnetlrylimidazole—5— aldehyde.

A mixture of ethyl 4—bromomethyl-3£hlorobenzoate (5.28 g, 0.020 mol, U.S.

Patent No. 4,837,333) and 2-n—butyl»1-pivaloyloxymethyl~imidazole—5—aldehyde (4.45 g, 0.0167 mol) was heated at 100°C under argon for 18 hours. Repeated trituration with ether gave 6.38 g of a crystalline salt. A suspension of this salt in 100 ml ofethyl acetate was stirred for 0.5 hours with 100 ml of 5% aqueous sodium carbonate. The layers were separated, the_ aqueous layer washed with ethyl acetate,"a_nd the combined organic layers washed with water, dried over magnesium sulfate and concentrated to give an oil. Chromatography of this oil over silica eluting gel with ethyl acetate/hexane (1:1) gave 1.02 g of 2-n—butyl—1—[(4~carboethoxy—2~chlorophenyl)~methyl]imidazole—5— aldehyde.

Ethyl 2~carboxy—3—(2—thienyl)propionate (14 g, 0.061 mol) was prepared by stirring a solution of diethyl 2—thienylmalonate (16.8 g, 0.0655 mol) and potassium hydroxide (4.41 g, 0.0786 mol) in 200 ml of ethanol under argon at room temperature for 12 days and then purifying by removing the solvent under vacuum, dissolving the reside in water, washing the aqueous layeriwith aqueous hydrochloric acid and with diethyl ether.

A solution of this half-acid, half~ester (L05 g, 4.62 mmol) in 5 ml ofltoluene was added to a refluxing solution of 2—n—butyl~1-[(4—carboethoxy—2—chlorophenyl)methyl]— imidazole—5~aldehyde (l.03g, 3.08 mmol) and piperidine (0.26 g, 3.08 mmol) in 60 ml of toluene. Twice, at 1 hour intervals, an additional 1 g of the half—acid, halfester was added, and the solution was then refluxed for 17 hours. Evaporation of the toluene and chromatography of the residue over silica gel using 2:3 ethyl aoetate—hexane for elution gave 0.339 g of the diester of the title product. This was hydrolyzed in 2:1 ethanol—water with 5 equivalents of potassium hydroxide for 18 hours and worked up in the usual trimmer to give 0.260 g of final product; mp 234—236°C. of this product was in accord with its structure.

Example 13 1131n—Butyl—l—{ (4-sulfonamidophenybmethyl }—lH—imidazol~5~yl l~2—(2— thienyl )methyl;2’«p_r9_penoic Acid The procedure of Example l2is followed using 4~ hromomethylbenzenesulfonamide (Braselton, et al., A_r1_al_. gs, L386 (l97o)) in place of methyl 4—bromomethyl—3vchlorobenzoate to give the title compound.

Example 14 Qi)_—3—] 2—n—Butyl— l — {(4—carboxy—2»nitrgjienylhnethyl }—1H—iniidazgLi5:ylj;2¢(;— thienyl)methylézapropenoic Acid The procedure of Example 12 was followed using methyl 4—br0m0methyl—3~ nitrobenzoate (prepared from 4—methyl—3—nitrobenzoic acid by esteiification with gaseous hydrochloric acid—methanol followed by methyl bromination with N- broinosuccinimide) to give the title cornpound, t Example 15 (E)—3 ~I2—n~Butvl— l —{ (4-carboxych1orophenyl)methyl }—lH—imidazol—5—vl]—2-(2- thienyl)methyl—2—pr0penoic Acid The procedure of Example 12 was followed using ethyl 4—bromomethyl~2~ chlorobenzoate (lJ.S. PatentNo. 4,837,333) in place of ethyl 4—brom0methylchloro— benzoate to give the title compound; 245—246"C. chlorobenzoate (prepared from 3£hl0ro4—methylbenzoic acid by estcrification with 2- methylpropene in the presence of Concentrated sulfuric acid, followed by methyl hromination with N ~bromosuccinimide) in place of ethyl 4—bromomethyl—3— chlorobenzoate to give ethyl (E)A3~[2—n—butyl—l -{ [2-chloro4—(carbo-ti butoxy)phenyl]methyl )—1H-imidazol—5-yl]-2—(2-thienyl)methyl—2—propenoate. The (- butyl ester is converted to the corresponding acid compound using tiifluoroacetic acid.

To a suspension of ethyl (E)—3~[2—n-butyl~l—{(2chloro4- carboxyphenyl)methyl}-1H—imidazolyl]—2{2—thienyl)—methyl—2_p[openoa¢c in benzene is added thionyl chloride. The resultant mixture is heated to 50°C for 90 minutes, then evaporated to an oily residue. The residue is taken up in hexane and evaporated again. The acid chloride is treated with concentrated ammonium hydroxide and then the reaction mixture is stirred for 16 hours at room temperature. The solid is filtered, washed with water, and dried at 50°C under vacuum to yield the primary amide derivative. ‘I To a solution of dimethylformamide in acetonitrile is added oxalyl chloride at 0°C under argon. After 3 minutes, a solution of the amide prepared above in dimethylformamide is added via a cannula. Five minutes later, pyridine is added; the reaction mixture is stirred for an additional 5 minutes at 0°C‘, then partitioned between ethyl acetate and 50% aqueous ammonium chloride. The ethyl acetate layer is washed with water and brine. The ethyl acetate extract is dried with anhydrous sodium sulfate and evaporated to give the corresponding nitrile derivative.

Tetrahydrofuran is added under argon with stining to a mixture of the nitrile prepared above and aluminum chloride. Sodium azide is added all at once, followed by a tetrahydrofuran rinse, and the reaction is heated to 65°C for 22 hours, then cooled to room temperature. The reaction mixture is diluted with ethyl acetate and treated with % hydrochloric acid solution with vigorous stirring for Sgminutes. The ethyl acetate layer is washed with water and brine. The ethyl acetate layer isdiied with anhydrous sodium sulfate and evaporated to give ethyl (E)—3—[2—n—butyl—l—{ [2—chloro4»(lH— tetrazol—5—yl)phenyl]methyl }— 1 H—imidazol—5 -yl]—2»(2-thienyl)methyl -2—propenoate.

The title propenoic acid compound is prepared from the above ethyl ester by basic hydrolysis using aqueous base in methanol.

Example 1] gEL[Z—n~Butyl~l—{(2—nitrophenyl)methyl)-lll—imidazol-5»yl]~2—(2~thienyl)mc(hy1-2_ p_ropenoic Acid The title compound was prepared following the procedure of Example 1 using 2— nitrobcnzyl bromide in place of 24:hloroben1.yl bromide; mp 205—206°C. nitrobenzyl alcohol in place of Zchlorobenzyl alcohol; mp l82—l84°C.

,EzLa21pl;9 (EH2-n-B UtYl- 1 —l (4—nitrophenyl )methyl} — l H ~imidazol—5-yl]-2—(2-thienyl)methyl—2- _ propenoic Acid The title compound was prepared following the procedure of Example 42 using 4—nitrobenzyl bromide in place of ethyl4~bromomethyl~3—chlorobenzoate; mp 198- 200"C. (;3)_-[2—n—Butyl— 14 (2—mfluoromethylphenyl)methyl 1- I Hiniidazoi-5—i_xL1.;.g; thienyl)methyl~2—propenoic Acid The title compound was prepared following the procedure of Example l using 2- trifluoromethylbenzyl alcohol in place of Zchlorobenzyl alcohol; mp 202—203°C.

Example 21 gljl-jg;n-Butyl— l -1 12,3—dichlorophenyl)methyl } — l H~imidazol—5—vll—2—(2~thienyl)methyl— Zpropenoic Acid The title compound was prepared following the procedure of Example 1 using ,3~dichlorobenzyl alcohol in place of Zchlorobenzyl alcohol; mp 184—185°C.

E):ax1u>.12;2Z (E4)-[2—n—Butyl— 1- {(3-methoxy—2—nitrophenyl)methyl [- l H-imidazol—5—yl]-2—(2— thien1l)methyl—2— ropenoic Acid The title compound was prepared following the procedure of Example 42 using —methoxy—2—nitrobenzyl bromide in place of ethyl 4~hromomethyl—3—chlorobenzoate; mp 'll3—2l5°C. l Z"(I.

The title compound was prepared following the procedure of Exzsriipltt I using 3- methoxybenzyl alcohol in place of '2.--chlorobenzyl alcohol; mp E70» l 7 l "(‘ alcohol and triflic anhydnde; mp l8(>—l87°C_ L‘l.X@JDl?_l.€LZ] Lgldlflfiflifl :1 ill; ;l1.Ydi0,X.}'I3_ll'?£1DLn,¢fllLl l: 1 H-imidalol ~5:)/ll&(Lthi£f!XlLm:‘3l!1fl:2J?£9R The title compound was prepared from the Z—methoxy compound prepared in Example 64 using boron trihromide in methylene chloride; l8l—l83°(' propionate In place of 34:2 tlucnylill plum;ihouoprt>pion.xte; mp l?'<./1» l 85 Vt‘.

\.J’-\ phosphonopropionate; mp 170--171°C, The title compound was prepared followiiig the procedure of Example 1, using caproylamidine methyl ether hydrochloride in place of valeramidine methyl ether hydrochloride and using 4~earb0niethoxybeii'I.yl 2llC0l}()l in place of 2~ehlorobenzyl alcoliol; mp 2lO——2l2°C. liydroehlonde and 2—nitrobenzyl alcohol in place of Zichlorobenzyl alcohol; mp 223°C Example 34 113112-n—Butyl— l— { (4—hydroxy—3—methylphenyl)methvl } —lH—imidazol—5—yl]~2~(2— thienyl)methyl—2 The title compound was prepared by demethylation of (E)—2—n~butyl-l—{ (4~ methoxy-3—methylphenyl)methyl }— lH—imidazol»5-yl]—2—(2—thienyl)methyl—2—propenoic acid, prepared in Example 62, using boron tribroniide in methylene chloride; mp 150 l5'Z"(T.

Example 35 g E )—3—| 2-n—Butyl1 14—carbomethoxmhenyhmethyl }— l H~imidazol-5—yl]—2—(2— thienyl zmethylgg-prognoicflgcg The title compound was prepared using 2-n-butyl—l—[(4- carbomethoxyphenyl)methyl]imidazole-S-aldehyde (prepared by the method described for the preparation of 2—n—butyl—l-[(4—carboethoxy—2-chlorophenyl)methyl]imidazole-5— aldehyde in Example 42) and t-butyl 3—(2—thienyl)—propanoate by the procedure of Example 1 (iv, Method B), except, instead of basic hydrolysis, tnfluoroacetic acid hydrolysis of the t—butyl ester was employed; mp 2l7—220°C.

Example 36 (Iii-3.—[2—n—Butyl— 1-I (4-cyanophenynmethyl I — l H—imidazol—5—yll—2—(2—thienyl) proignoic Acid The title compound was prepared using 2—n—butyl-[(4- ]imidazole—5—aldehyde (prepared by the method of Example 42 methyl cyan0phenyl)methyl describing the preparation of 2—n—butyl- l—[(4—carboethoxy—2~ chlorophenyl)methyl]imidazole—5-aldehyde) and methyl 34(2-thienyl)propanoate by the procedure of Example 1 (iv, Method B), except, instead of basic hydrolysis of the ester with sodium hydroxide, potassium carbonate hydrolysis was employed; mp l90—l92°C.

The title compound was prepared using the procedure of Example I replacirxg valerainidinc methyl ether hydrochloride with butymmidine methyl ether hydrochloride and replacing Z—chlorobenzyl alcohol with étcarbomethoxybenzyl alcohol; nip IZ5(l"(‘ (ti) Examglegfi ti‘/Ev)~;i_f_l;Z~El-Pl’()Jf)jl~l-E(2-ClXl0[0),)llCl1Vi){l.1€thYl la il’l—irr«_idazol—-5—»yll 2_;Q_—:_l_2Vigji_:ylj:_r_i_e_tl_i)d, ;2;11I‘9.£fl12ic_/icifi The title valeramidine methyl ether hydrochloride with butyramidine methyl ether hydrocliloridc‘, mp Z() hydrochloride; mp l6l—l63°(‘, with N,N/l)lt)Il)<{)$ll(tClnllnldtf). f;1,>g:nmI:~: 4,3 iii} :3 -t 2.-n,—,.B_utyLL J14: a.I,bgxy;Z,5;dLc.bJ2L0p!1cny l)£153LllXlL:l_H;£i!B£Q17»_CLl_;5;Yl L212: th_i_¢nyL>zn:tt/l1y1£:P,r9i1«:n 93;./\_; The title compound was prepared using the pmcctdure of lixainple 42 replacing ethyl 4-l')t"()H10l'IlC(l]yl~3~Cl}l()l"Ol’}{’flZ03(tt with methyl /t—bromi'in1etliyl 3,6 dichlorobenzoate (prepajed by oxidation of 2,5—di(:hlor<>~p~xylene with nitric acid, lollnwcd by esterification with methanol/hydrochluric acid, and methyl broinination lat 105:: Examgleftj The suciose. calcium sulfate dihydiate and oially active Fonnula (E) compounds zuc mixed and granulated with a lO% gelatin S0lUllUll. The wet granules are scicened, diicxl, nuxcd with the staxch, talc and stcanc acid, .\LCtCL‘.t1CLl and coiiipicsscd into a tablet. chlorophenyl)—methyl }— l H—imidazol—5— yl]v2-(2-thicnylhnethyl-2—propenoic acid 75 mg calcium sulfate dihydrate 100mg sturose [5 mg staich 8 mg talc 4 mg stcaric acid 2 mg Examgle 46 (lei) 3 g[2—n~Butyl- l—~{ (4Acarboxy—3chl0rophcnyl)methyl )» lll—llI1l(l11ZOl<5'yl] 2e {Zrtl2ieiiyl)1:;xtthyl—2—pmpt:noic acid, 50 mg, is dispczsctl in 25 I!1l.4.){ll\):EH&il saline (C :L:.‘i.‘.»lc.‘: pi’cpai;:ti<.>i‘i ii,‘ _l:>:vyLii3Lc_4,Z A topical opihaniologicai solution for admiiiisteiing F pmdiicitd by mixing under stciilc conditions the iiigrodicnts in proponion as shown below.

Iggrgdicnts (E) 3—{2.—n—bulyl—l—{2- chIiorophcny1)me!hyl }~1H—imidaz01~5- yl]72 -(2«thjeriy1)mcthyl~2—propcnoic acid dibasic sodium phosphate inoiiobasic sodium phosphate ciiiorobuianui hyokoxypropano! iiicthylceiiulosc Storiic water .0 N sodium hydioxidc ormiiia (1) compounds is fiigiounts (mg/mL) L0 :04 2:; so .0 q,s.ad l.0mL qsad pH 7.4 IS to be understood that the invention 28 nm Iiniitcd to the cinbodinicms lill!.K‘{I11ICd hcrca hove and the right to the iliuxiraiod embodiments and all iiiodific;itioii.< iriiiiiiiig within the scope of tho following clziiiiis is rcscrvcd , foi example,

Claims (10)

1.Claims: I. A Compound of the formula (I): cH,+z'; ‘ I - rv=c::. R“ "‘< l ‘ (I) — ” R’ in which: R, is phenyl unsubstituted or substituted by one to three substituents selected from chloro, fluoro, trifluoromethyl, nitro, methyl, hydroxy, sulfamido, carboxy, carboC.+C4alkoxy, carbamoyl, cyano, or tetrazol-5—yl wherein n is l-3: R; is Cg—Cgalkyl; X is a single bond; R; is hydrogen; R4 is hydrogen; R5 is thienylmethyl optionally substituted by methyl or methoxy; and Rf, is COOH; or a pharrnaceutically acceptable salt thereof, wherein the compound of formula (I) is the E (trans) isomer.

2. A Compound according to claim 1 which is: (E)-3—[2—n~butyl—1—{(4~carboxy-3—chlor0phenyl)methyl}—1H—imidazol—5—yl]-2~(2— thienyl)methyl—2—propenoic acid; (E)—3-[2—n—butyl—1—{(2—chlorophenyl)methyl}-1H—imidazolyl](2- thienyl)methyl—2—pr0pen0ic acid; ‘ (E)v3—[2-n-butyl—1~{(4—carboxy-2—chl0rophenly)rriethyl}-1H—imidazol—5~yl]-2—(2— thienyl)methylproperioic acid; I 50 (36 (1:).% [2 n huIyI~l~{(4~carbomcthoxyphcnyI)mclhyI}~]H»irmdaz01—5-y}}~2—(2~ Ihi:’1)}'J‘)z11L‘.tI1yIr2—pr0pcn0ic acid; (Ii)—,%(2rn——hcxyI~1—{(4—carboxyphcnyl)mclhyl}—IH-rrrxid:rz<>i~5«y!j-2—(LZ» *’ thicn)})mc{hyl—Z—pI0pCn0i(; acid; ‘ (ff{)—3—[Z—n«propy!—l~{(4~carboxyphcrryflrnelhyl}~1H~irnidam{~5—yIj—2—(2i thicrryI)rrrcthyl—2—pr0pcn0ic acid; (E)—3-[2-n»butyl—I-{(Z—nitr0phenyI)met!1yl}—IH—imidazoIA5ry)]—2—(2—c thicnyl)mcthy1—2—pr0pen0ic acid; (E)r3—[Z—rr—bu[yl~1-{(2—chl0r0phenyi)methyi}~lH«imidaz0l—54yI]~2~(3— lhrcrryl)mcthyl—2—pr0pen0ic acid; (}i)—3—[2—n»butyI-I-{(2-chlorophenyhmcthyl}~]H—jmidazoF~5 yl]—2~(5—mc!hyE—2— thicnylflnethyi—Z—propen0ic acid; A (E)-3~{2An—butyi—1~{(2—cyanopher2y£)mc{hy!}—1HiimidazoE-5T}/E}-T2-(2~ thrcny!)methyl—Z—pmpen0ic acid; shzcrry}}mcthy!—2»pr0p€:n0' 7 acid; {,‘7}— %r§.’—r7—Tr>rr?'/vi i—{(2—chI0rophc;zjv'i*;rm {E112-11)-i mrIhyI—2propcnuic acid, (19%-“v {Z n~buIyi !—{(2,3»dichIorophcrrylkncthyl}iIH—z1rnd;rzu}{'~yl}»2-(3~ [h!:'u'r\1!)I‘l]L"”i'\'l 2 propcrroic ;1crd;or (H73 [.2 n—butyl 1—{(.

3.Zi!rifluoromcthylphcnyl)mcIhyl}~IHwnidzzzol-5—yl]-2~»(2~ thicnyl)mcthyli2—»pr0pcn0ic acid; or 21 pharrrrucculically aCccpi;2bic 331$ thereof. ,

4. A ifornpourrd according to claim 1 or Z for nee. as; 2: rm-riktzmcni. J. A pharmaceutical conrpositmrr which cornprrses a compound according to cithcr mun I or claim 2 and a pharmaccutically accrzplablv carrier.

5. A process for preparing :1 compound of thc formula (I) or ;r pharrrmccmically zmieptablrs salt thereof as defined in claim 1 or claim 2, which pr‘0ccs;s corrrpriscst a. rc21ctrngaC()nlpOund of the formula (II): wherein R2, R3, and X are as defined in claim 1, and R1 as defined in claim 1, except that the substituents on the R’ group do not include tetrazol—5—yl, OH or COZH, with (C1—C4alkoxy)3P(O)CH(R5)—COOC1-Cgalkyl, wherein R5 is as defined in claim I, in the presence ofa base; or b. reacting a compound of the formula (III): I-C.H,OC : o I V , eR‘=ccooc,4:,an > 1: , , R’)( —‘<\ I R‘ (In) N R3 wherein R2, R3, R4, R5, and X are as defined in claim 1, with a compound of the formula (IV): (W). Hzosozcr, (IV) wherein W is CL, Br, F, l, C;—C4alkyl, nitro, CO;C1~C4alkyl, C,—C4alkoxy, SC,- Caalkyl, CN, SOZCI-Cyalkyl. SOZNHR7, NHSO2C,-C4alkyl, or C,,F;,,+1, n is 13, and R7 is hydrogen, C,_4alkyl, or (CH2)U_4phenyl; or C. reacting a compound of the formula (II) as hereinbefore defined with a compound of the formula (V): * coon R°-cH/ ‘V’ \cooc,4;,amys 1 38 wherein R5 is as defined in claim 1, in the presence ofa base; or ‘ d. reacting a compound of the formula (VI): 5 R”-<=,~z 3" — ~ N cH—— (‘3HCOOC,-C,alkyl R’x —-<\ l R‘ .1 (VI) N 3 I0 ‘ wherein R2, R3, R5, and x are as defined in claim 1, R" is R’ as defined in claim 1, except that the substituents on the RV group do not include tetrazol—S—yl, OH, or COZH and R” is COCH3 or SO2CH3- with a base; or e. reacting a compound of the formula (II) as hereinbefore defined with an 15 appropriate heterocyclic acetic acid in acetic anhydride in the presence of a base: A and thereafter where necessary: (i) for formula (1) compounds in which the R‘ group is substituted by hydroxy, deprotecting the formula (I) compounds in which 20 the R' group is substituted by C1—C4alkoxy; or (ii) for formula (1) compounds in which the R‘ group is substituted by carboxy, hydrolysing the formula (I) compounds in which the R1 group is substituted by CO2C,.4 alkyl: or (iii) for formula (1) compounds in which the R‘ group is substituted 25 by a tetrazol—5—yl group, treating the formula (1) compound in which the Rligroup is substituted by carboxy, with a halogenating agent, followed by conversion to the primary amide in a reaction with ammonia, dehydration with oxalylchloride/dimethylformamide and reaction with azide; or 30 (iv) for formula (1) compounds in which Rfiis —COOH, hydrolysing the formula (1) compounds in which R6 is ~COOC;—C6alkly; and thereafter optionally forming a pharmaceutically accerftable salt.

6. The use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof as defined in either claim 1 or claim 2 in the manufacture of a medicament for treatment of diseases in which angiotensin ll receptor antagonism is a factor.

7.K 7.

8.The use of a Compound of the formula (I) or a pharmaceutically acceptable salt thereof as defined in either claim 1 or claim 2 in the manufacture of a medicament for the treatment of hypertension, congestive heart failure or renal failure‘ 8‘ A compound of the Formula 1 or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 Or 2 substantially as hereinbefore described by viiay of Example.

9. A pharmaceutical composition according to claim 4substantially as hereinbefore described by way of Example.

10. A process according to claimS substantially as hereinbefore described by way of Example. ‘ — 3 ’ l 1. A compound of the Formula 1 or a pharmaceutically acceptable salt thereof as defined in claim 1 whenever prepared by a process as claimed in claim 5 or claim 10. Tomkins & Co. rem],/, 50 _ ,