AP527A - The methanesulfonate salt of (E)-3-(2-n-butyl-1-((4-carboxypenyl) methyl) -1H- imidazol-5-yl)-2-(thienyl)methyl-2-propenoic acid and pharmaceutical compositions containing this compound. - Google Patents

The methanesulfonate salt of (E)-3-(2-n-butyl-1-((4-carboxypenyl) methyl) -1H- imidazol-5-yl)-2-(thienyl)methyl-2-propenoic acid and pharmaceutical compositions containing this compound. Download PDF

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AP527A
AP527A APAP/P/1995/000742A AP9500742A AP527A AP 527 A AP527 A AP 527A AP 9500742 A AP9500742 A AP 9500742A AP 527 A AP527 A AP 527A
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methyl
butyl
compound
compounds
thienyl
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Richard Mccullock Keenan
Joseph Weinstock
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Smithkline Beecham Corp
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    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
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    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract

A compound of the formula

Description

The present invert ion reiser to new imida?olylalkenoic acidr. which ar*·· jnqictonsir. II receptor antagonists and are useful in regulating hyperLenslur induced or exacerbated by angiotensin II, and in the treatment of congestive heart failure, ienai failure, and glaucoma. This invention also relates to pharmaceutical compositions containing tnese compounds and meth'ds tor using these compounds as antagonists of angi-ns in II, < as antihypertensive agents and as agents ftr treating congestive heart failure, renal failure, ar.d Glaucoma.
BACK2P.C TI.’D _ OF THE 1NYEN Τ1 ON The class of peptide pressor hormone know,, as angiotensin is responsible for a vasopressor action that is implicated in the etiology of hypertension in mat.
Znacpropriate activity of the renin-angiotensin systems appears to be a key element in essential hyperte: sion, congestive heart failure and ir. some forms of renal disease. In addition to a direct action on arte:ies and arterioles, angiotensin II (All), being one of the most potent endogenous vasoconstrictors known, exerts
C. stimulation on the release of aldosterone fr?m the adrenal cortex. Therefore, the renin-angiotensin s’--siem, by virtue of its participation in the control cf re m'.
sodium handling, plays an important role in cardiovascular homeostasis.
Interruption of the renin-angiotensin syscem with converting enzyme inhibitors, such as captopril, has proved to be clinically useful in the treatment cf hypertension and congestive heart failure (drains, 71.3., et al·., (1984), Federation Proc . 42, 1314,·. Tne most direct approach towards inhibition of the reninangiotensin system would block the action of AIT at the
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BAD ORIGINAL »·οpf>pr r, r- . c.-2 1 i no ev i d- ?:' sοo-s *_ s thee All n 1 ' cοn L f i b'j'n’.'j t- ο ί' «ι ci . vα s < ’ n s t. l i o*_'; ι; ί n<.i n d . o ni retention that is characteristic of a number cf dis·- rde. s such as heart failure, cirrhosis and comp . ϊcations of pregnancy (Hollenberg, N.Z ., C 364), j, Cardiovas.
Pharmacol., p, 5176). In addition, r ecent animal stucieo suggest ι I ml ι 11 h i b i l i <: ι: ->( the rer hi-uiigiotensin system may be beneficial in halting or slowing the progression of chronic renal failure (Andersen, S., et al., (1985),
J. Cl in. Invest., ip, 612) . Also, a recent patent application (South African Patent Application No. 87/01,653) claims that All antagonists are useful as agents for reducing and controlling elevated intraocula. pressure, especially glaucoma, in mammals.
The compounds of this invention inhioit, block srd antagonize the action of the hormone ATI, and c-.re therefore useful in regulating and moderating angiotensin induced hypertension, congestive heart failure, renal failure and other disorders attributed to the actions cf
All. When compounds of this invention are administered to mammals, the elevated blood pressure due to All is reduced and other manifestations based on AIT intercession are minimized and controlled. Compounds of this invention are also expected to ex): io it diuretic activity.
Recognition of the importance of blocking and inhibiting the actions of All has stimulated other efforts to synthesize antagonists of All. The following references have disclosed imidazole derivatives which are described as having All blocking activitv and useful as hypotensive agents.
Furukawa et al., U.S. Patent 4,340,598 discloses imidazol-5-yl-acetic acids arid imidazol-5-yl -propanoic acids. Specifically, the discloser includes l-benzyl-235 n-butyl-5-chloroimidazole-4-acetic acid and *-benzyl-2pheny1-5-chioroimidazole-4-propanoic acid.
Furukawa, et al., U.S. Patent 4,355,040 discloses substituted imidazole-5-acetic acid derivatives. A
BAD ORIGINAL A pound ui ·'' l : i cu 1 J y d i : i if, 1 - < 3' - z i i .1 o r<’ : e:, ? y ' , - s.
’ * - Li! I y I - 4 - rΉ !.- : ’ ί m i da .· - ] (---5-a cot i c ί ·' i d .
Car ini. et ai. in EP 253,330 disclose r-aitain in.idazolylpropencic acids. 'wo intermediates described in this patent are ethyl 3-[1-(4-nitrobenzyl)-2-butyl-4chioroimidazol-5-yiJprtpenoate and ethyl 3-[2-buty1-4old oro - 1 - (4-ur.i nobenzy 1 ) i m i da zo1 -5-y1]p ropenoate.
Also, Wareing, in PCT/EP 86/00297, discloses as intermediates certain imidazolyIpropenoate compounds. On page 62, Formula (CX) is ethyl 3-[1(-4-fluorophenyl)-4isopropyl-2-phenyl-lH-imidazol-5-yl]-2-propenoate.
The compounds of the present invention than are 15 blockers of angiotensin II receptors are:
(E) -3- [ 2-n-butyl-l - ( (4-carboyynaphth-l-yl ) methyl}lH-imidazol-5-yl)-2-(2-thienyl) methy1-2-propenoic acid and (E)-3-[2-n-butyl-l-((4-carboxynaphth-l-yl) methyl>20 1H-imidazoi-5-yl]-2-(2-thienyl)methyl-2-prcpenoic acid, ethyl ester;
or a pharmaceutreally acceptable salt thereof, and (E)-3-[2-n-butyl-l-{(4-carboxypenyl) methyl}-1Himidazol-5-yl]-2- (2-thienyl)methyl-2-propenoic acid methanesulfonate,
The invention also relates to pharmaceutical· compositions comprising a pharmaceutical carrier and an effective amount of a compound hereinabove named.
Also included in the present invention are methods 30 for antagonizing angiotensin II receptors which comprises administering to a subject in need thereof an effective amount of a compound hereinabove named. Methods of treating hypertension, congestive heart failure, glaucoma, and renal failure by administering these compounds are also included in this invention.
The compounds of this invention are prepared by procedures described herein and illustrated by the examples. Reagents, protecting groups and functionality
- 3 AP/P/ 94/0074’
BAD ORIGINAL r
C 25 c
on the imidazole and other f r -5gmer.t £ ·.· i the molecule· ”us be consistent with the prcrosed chemical transformations Steps in the synthesis must L·.· cc.r.p.-t isle with the functional groups and the orctecting groups on the imidazole and ather parts . f the molecule.
The starting material, 2-n-butylimidazole, is known to the art (J. Org. Chem. <15:4038, 1980) or is synthesized by known procedures. For example, imidazole is converted to 2-n-butylimidazole by reacting imidazole with triethylorthoformate and p-toluenesulfonic acid tj give 1-diethoxyorthoamide imidazole and then treating with n-butyi lithium to give the 2-lithium derivative of the orthoamide and alkylating with n-butyl iodide in :-. suitable solvent, such as tetrahydrofuran (THF).
The 1-substituted naphthyl or benzyl group is incorporated onto the 2-n-butylimidazole by known procedures, for example, by reaction with substituted naphthyl or benzyl halide, mesylate or acetate, such ac 2-chlorobenzyl bromide or 4-carbomethoxybenzyl bromide, in a suitable solvent, such as dimethylformamide (DMF), in the presence of a suitable acid acceptor, such as sodium alkylate, potassium cr sodium carbonate, or a metal hydride, preferably sodium hydride ao a reaction temperature of about 25°C to about 100°C, p:eferal!y at about 50°C. The resulting 1-substituted-naphchyl or benzyl-2-n-butylimidazole is hydroxymethylated in the 5 -position, for example, by reacting with formaldehyde in the presence of sodium acetate in acetic acid to provide the 1-substituted-naphthyl or-benzyl-2-n-butyl-5hydroxymethy1 imidazole intermediates .
Alternatively, the above prepared 5-hydroxymethylimidazole intermediates are prepared by reacting an imido ether, such as valeramidine methyl ether, with dihydroxyacetone in liquid ammonia under pressure to give 2-n-butyl-5-hydroxymethylimidazole. This intermediate is reacted with acetic anhydride to give l-atvtyl-5acetoxymethyl-2-n-butylimidazole. The diacetate intermediate is N-alkylated, for example, using 2- 4 BAD ORIGINAL
AP . Ο Ο 5 2 7 r
C 25 c
chlorobenzyl trif_ate or 4-c ;ibomethoxybenz7ί trif’.are, and the rpsultino 1-subs’' ix :t-?d-2-n-but y 1 -5acetoxymc-rhy 1 -imidazc 1 e is 'uzatea with aq->.ous base, such as 10% sodium hydroxide solution, to give the chydroxymethy1 imidazole intermediates describe! previous 1y.
The hydroxymethyl crzup of the hereinbefore prepared intermediate is oxidized to an aldehyde by treatment with a suitable reagent, such as anhydrous chromic aoid-siiica gel in tetrahydrofuran or, preferably, with activated manganese dioxide, in a suitable solvent, such as benzene or toluene, or preferably methylene chloride, at a temperature of about 25°C to about 140°C, preferably at about 25°C. The imidazol-5-carboxaidenydes ore reacteo with an appropriate phosphonate, such t rirret ::/1-3- (2thienyl)-2-phosphonoproprionate. The phosphenates are prepared, for example, from trialkyl phosphonoacet.ates byalkylation with an appropriate halide, mesylate or acetate in the presence of a suitable base, such as sodium hydride, in a suitable solvent, preferably glyme at a reaction temperature of about 25°C to about 110°C, preferably at abc.t” 55°C, to provide the apprο; eo -'·: e phosphorate. The reaction of the imidazol-5carboxaldehyaes with the phosphorates 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, preferabiy at about 25°C, to provide a variable mixture of trans and cis, e.g., (E) and (Z) , l-substituted-2-nbutyl-5-CH~C[ (2-thienyl)methyl 1 -(COOalkyl)-imidazoles. These isomers are readily separated by chromatography over silica gel in suitable solvent systems, preferably hexane in ethyl acetate mixtures. The esters hydrolyzed to the corresponding acid compounds using base, such as potassium hydroxide, lithium hydroxide cr sodium hydroxide, in a suitable solvent system, such as,
AP/PZ Q 4 / 0 f) 7 4 ?
BAD ORIGINAL (
(' 25 c
for example, aqueous aicc.-ols or diglyme-.
Al Let i. a- ive 1 y, the 1 - subs 11 t uie i-2-n-c.-r.v limidaz-.i5-carboxaldeb.ydes are prepared by the following procedure. Starting 2-n-butyl imi daz o 1 - 5-ca r bexa ldehy des are reacted with an N-alkyiating protecting reagent, such as chloromethyl pivalate (POM-CI), in the presence oi a base, such on potatsium carhonare, in a suitable solvnt, such as dimethylformamide, at a temperature of about 2 to about 50°C, preferably at about 25°C, to give Nalkylation (e.g., POM-derivation) on the least hindered nitrogen atom of the imidazole nucleus. The 1substituted-naphthyl or -benzyl group is incorporated onto the imidazole by N-alkyiation of the above prepared aldehyde with a halomethylbenzene compounds, such as methyl 4-brcmomethylbenzoate or methyl 4bromomethylnaphthalene-l-carboxylate, at a temperature ci about 80°C to about 125°C, preferably at about 100°C.
The protecting group on the 3-nitrogen of the imidazole ring is removed by base hydrolysis, for example using a biphasic mixture of ethyl acetate and am.ecus sodium carbonate, to give l-substituted-n-butylimidszoie-5carboxaldehyde compounds'. The compounds cf this invention can be prepared from these 5-carboxaldehyde compounds by the methods described above.
Alternately, the 2-n-butylimidazole starting materials are reacted with trimethylsiJylethoxymethyl(SEM) chloride to give 1-(trimethylsilyl)ethoxymethyl-2-n-butylimidazole. The reac'ucn is carried out, for example, in the presence of sodium hydride in a solvent such as dimethylformamide. 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 tri-nbutyltin chloride, at about -10°C to about 35°C, preferably at about 25°C. The l-SEM-2-n-butyl-5tributyltinimidazole is coupled with an a, β-ur.saturated acid ester having a leaving group on the β-position, su~h
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-σ
-σ er?
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(
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y group, for
i.u the (
( presence of a phosphine ligand, such as bis (diphenylphosphino)prepane, or triphenylphosphine and a palladium (TT) compound, or preferably tetrakis(triphenylphosphine)palladium(0), with or without a base, such as tributylamine, at a temperature of about 50°C to about 150°C, preferably at about 120°C. Both the (E) and (Z) olefinic isomers are prepared by this procedure, and the isomeric esters are readily separated by chromatography over silica gel. The 1-SEM group fro:,, 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 1unsubstituted imidazole derivatives are converted to the 1-t-butoxycarbonyl (t-BOC) imidazoles with di-c-butyl dicarbonate (Hoppe-Seyler's Z. Physiol, Them., (1916),
357. 1651). The t-BOC esters are alkylated and hydrolyzed with, for example, 2-chlorobenzyl triflate or 4-carbomethoxybenzyl triflate, in the presence of a suitable base, preferably diisopropylethylamine, in a suitable solvent, preferably methylene chloride, to afford the l-substituted-imidazole derivatives (esters). The (E) and (Z) isomers are hydrolyzed to the (E) and (Z) acids by the method described above.
The compounds of this invention are also prepared by the following procedure. The l-substituted-2-n-buty1imidazole-5-carboxaldehydes, prepared as described above, are reacted with a substituted half-acid, half-ester derivative of a malonate, such as ethyl 2-carboxy-3-(2thienyl)propionate, in the presence of a base, such as piperidine, in a suitable solvent, such as toluene, at a temperature of about 80°C to about 110°C, preferably at about 100°C. The resulting l-substituted-2-n-buty1-5CH=C(R^)coOalkylimidazoles are nydrolyzed to the corresponding compounds of the present invention by alkaline hydrolysis as described above.
Alternately, the compounds of this invention are
BAD ORIGINAL prepared as follows. The imidazo1-i-arbczaIdehydes prepared h treated with the lithi-m derivative c □ --.i-n-t v reinafco1.'^ are substituted ethyl cr methyl ester. These litnio der’vatives are 5 prepared from the reaction of iitnium diisopropylami.de or.
a suitable solvent, preferably tetrahydrofuran, with an acid ester, such as ROCC-CH^-CHp-(2-thieny1), to generate the α-lithio derivatives at about -78°C to about --1CCT, preferably at about -78°C, which are then treated with the imidazol-carboxaldehyde. The intermediate C-hydroxy group of the imidazole ester is converted to a mesylate or an acetate and the mesylate, or preferably tine acetate, is heated in a suitable solvent, suer, as toluene, with one to two equivalents of i,8-diazo15 bicyclo[5.4.0}undec-7-ere, at about 50 to about 110°C, preferably at about 80°C, tc afford 3-(imidazol-5-yl)-2(2-thienyl)methyl-2-propenoic acid esters. The (E) isomer is the predominate olefinic isomer. The =c;ds are prepared from the esters by the metnoo described above.
Compounds of the present invention in which the substituent in the 1-position of the imidazole ring is substituted by carboxy are formed from, the compounds in which this group is substituted by CC^C^~C^alkyl using basic hydrolysis, such as aqueous sodium or potassium hydroxide in methanol or ethanol, or using acidic hydrolysis, such as aqueous hydrochloric acid.
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, benzol;, ascorbic, pamoic, succinic, bismethylenesalicylic, <
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BAD ORIGINAL (' 25 (
AP.00527 t j rta r i c, palmitic, benzenesu.
5<1 ! i f/y J i c, ci naconic, g - y o ionic, hydrccr.
ethar.edisul fctic, aceti.0, propionic, ?, c ?: cc r. i c, aspartic, stearic, ic, p-amincbenzcic, qlt.j.iic, tic, hydrobromic, sulfuric, cyclohexyisulfamic, phosphoric and nitric acids.
Pharmaceutically acceptable case .iddition salts cf g compounds cf Ι·ϊΐΓπηΠ3 (Γ) in which R 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, butylamine, piperazine, meglumine, choline, diethanolamine, and tromethamine.
Angiotensin II antagonist activity of the compounds of Formula (I) is assessed by in vitt^ and in vivo methods. vitro antagonist activity is ietermined by rthe ability of the compounds to compete with ' “Iangiotensin 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 i.ats and to lower blood pressure in a rat model of renin dependent hypertension.
APfP/ 94/0074»
Binding
The radioligand binding assay is a modification of a method previously described in detail (Gunther et 4.,
Ci re. Res. 42:278, 1980). A particular fraction from rs_ mesenteric arteries is incubated in Tris buffer with 60 125 pM of I-angiotensin II with or without angiotensin II antagonists for 1 hour at 25°C. The incubation is
125 terminated by rapid filtration and receptor bound Iangiotensin II trapped on the filter is quantitated with a gamma counter. The potency of angiotensin II antagonists is expressed as the IC5Q which is the concentration of antagonist needed to displace 50% of the
BAD ORIGINAL total spe : f i ca 1J y bound angiotensin II. Exemplary cf ’ii·? IC θ of compounds of the i r; v ·- n t : . , (E isomers, ii about 0.1 nX to about 3Gmfh
AQJtLi
The ability of the compounds to antagonize angiotensin. 11 induced vasoconstriction is examined in the rabbit aorta. Ping segments are cut from the rabbit thoracic aorta and suspended in organ baths containin';
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 tc angiotensin II are performed in the absence of antagonist or following a 30-minute incubation with antagonist.
Antagonist disassociation constants (K_, are calculated
D by the dose ratio method using the mean effective concentrations. Exemplary of the KQ of compounds of the invention (E isomers) is about 0.1 nM to about 0.50n>'.
Inhibition of pressor response to angiotensin I.I in conscious rats
Rats are prepared with indwelling femoral arterial and venous catheters and a stomach tube (Geliai et al., 25 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 30 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 35 the control response to angiotensin II (iCcn) is used tc estimate the potency of the compounds.
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AP. Ο Ο 5 2 7 7 ' he corp'•'unds i s /ear. arterial £jiiJJiypiLLL£?nslv.e.. activity
The aru ihypet tensive «ci’'vit7 measured by their ability tc reduce pressure in conscious rats made renin-dependent 5 hypertensive by ligation of the left rena^ artery (Cangiano et al., J, Pharmacol. Exp. Thor, 2 Q £ :310,
79). Kenai att.ery ligated rats are prepared with indwelling catheters as described above. Se\en to eight days following renal artery ligation, the time at whith 10 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 orai.y. The dose of compound needed to reduce mean arterial 15 pressure by 30 mm Hg (IC^q) is used as an estimate cf potency .
The intraocular pressure lowering effects employed in this invention may be measured by the procedure described by Watkins, et al., J. Ocular Pharmacol., J (2):161-168 (1985).
The compounds of the instant invention 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.
Ί L U 0 / V 6 /d/dV
BAD ORIGINAL jp
- 11 For topical ophthaimelg:c administ rat' or., the pharmaceut ical compositions adapted in 'ii.de solutions, suspensions, ointments, and solid inserts. Typical pharmaceutically acceptable carriers are, for exams 1'.
water, mixtures of water arc water-miscible solvent.*· such as lower alkanols or vegetable oils, ano 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 aixali 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 th.a form of a solid insert. -For example, one may use a solrd 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 the present invention 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
- 12 bad original $
AP . Ο Ο 5 2 7 injection, cr continuously 'ey infusion. Oral dosage units for human administrat ion preferably contain from 1 to 500 mg of active compound. Prefe.-nhiy, hwer 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 ar. amount selected from 0.0001 to 0.1 (w/v%), preferably from
0.0001 to 0.01. As a topical dosage unit form, ar. amour?
of active compound from between 50 ng to 0.05 mg, preferably 50 ng to 5 mg, is applied to the human eye.
No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the present invention.
The method of this invention of antagonizing angiotensin II receptors in mammals, inducing humans, comprises administering to a subject in need of such antagonism an effective amount of a compound of the instant invention. The method of this invention of .
producing antihypertensive activity and the method of treating congestive heart failure, glaucoma, and rerai failure comprise administering a compound of the instant invention to a subject in need thereof an effactive amount to produce said activity.
Contemplated equivalents of the present invention compounds are compounds otherwise corresponding thereto wherein substituents have been added to any of the unsubstituted positions of these compounds provided such compounds have the pharmaceutical utility of compounds cf the instant invention.
The following examples illustrate preparation or compounds and pharmaceutical compositions cf this invention. The examples are not intended to limit the scope of this invention as defined here bn above and as claimed below.
C-.
r-c
C“ cr
O' a
BAD ORIGINAL
LL)..-3.- ί 2 ~n-Duly 1-1 - ί (2-chlorophenyl)::. l 1 i/l ί - Hi - imide z px5_-yl!r2~ (2-thler.yllr.ethyl-2-pr tpenoic Acid (i) 2-n-outyl-l-(2-chloro-pheny1) methyl-1Himidazole
Imidazole was converted to the 1-diethoxyorthoamide derivative by the method of Curtis and Browa, J. Cry. £h£UU, (1980), 20. Imidazole (12.8 g, 0.19 moi) and
118.4 g (0.8 mol) of triethylorthoformate were reacted in the presence of 1 g of p-toluenesulfonic acid to give 20.6 (61%), bp 65-70°C (0.1 mm) of 1-diethoxyorthoamide imidazole. This product (24.0 g, 0.14 mol) was disseised in dry tetrahydrofuran (250 mL), cooled co -40cC and nbutyi 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 iidide (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 acin. The combine! aqueous extracts were neutralized with sodium bi carbonate 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-nbutylimidazole.
2-n-Butylimidazole (9.7 g, 0.078 mol) was dissolved in methanol (50 mL) and added dropwise to a solution cf 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-chlorobenzy 1 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 concentrated to give
18.5 g of crude product which was chromatographed over silica gel with 2:1 ethyl acetate/hexane to provide 11.3 g (61%) of 2-n-butyl-l-(2-chlorophenyl)methyl-lH- 14 CMX
Cd
Cd cr c
r· <
BAD ORIGINAL S
AP . Ο Ο 5 2 7 imidazole as an oil. Thi.-. Layer chromatography cn r i , ·' c gel with 4:1 othiyl acet a i e / hexane gave an Rr value c f
0.59.
(ii) 2-n-butyl-l-(2-chiorophenyi)methyl-5hydroxymethy1-1H-im i dazole
Method 1
A mixture of 2-n-butyl-l-(2-chiorophenyl) methyl-1 .'-iimidazole (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 wae 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 cnloride.
The extract was washed, dried, and crncentrated. The crude product (117 g) was flash chromatographed over 650 g of silica gel with a gradient of etnyi acetate to 10% of methanol in ethyl acetate to give 8.3 g of starting material, 24.5 g of a mixture of starting material and product, and 44 g (41%; of 2-n-butyl-l-(2-cnlorophery ’ · methy 1-5-hydroxymethy 1-lH-imidazoIe; mp 86-88°C (from, ethyl acetate). Further elution provided the bis (4,5hydroxymethyl) derivative; mp 138-140°C (from ethyl ( acetate).
; C Method. ..2 j A mixture of valeramidine methyl ether hydrochloride
J (250 g, 1.66 mol) and dihydroxyacetone (150 g, 0.83 mol;
ί dissolved in liquid ammonia was allowed to stand ί 30 overnight at room temperature in a pressure vessel, and ; then heated at 65°C for 4 hours at 375 psi. The ammonia 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 ammonium chloride while hoc. 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,
V L 0 0 / V 6 /d/cfV bad original.
2-n-buty 1 - :-hyrirtxymethyj : m .ida?a Le (253 g, 1.33 sc'.,
3%) .
This crude alcchci (253 g) was t .-vat id with ace anhydride (400 n.L) at -15°C and then, was allowed tc to ambient temperature with stirring, and then stirred an additional 19 hours. The acetic anhydride was evaperated at reduced pressure, the residue taken up in me thy ± eu»? chloride, and the organic phase was washed with 5% sodium bicarbonate solution and water. The extract was dried 10 over sodium sulfate and concentrated to give 323 g (83%) of 1-acetyl-4-acetoxymethyi-2-n-butylimidazole .
This diacetate was N-alkylated by the following procedure. To a solution of tri flic anhydride (120 mL, 0.71 mol) in methylene chloride (20C mL) at -78°C undo15 argon was added a solution of diisopropyl ethyiamine (125 mL, 0.73 mol) and 2-chlorobenzyl alcohol (104 g, 0.“2 mol) in methylene chloride (350 mL) over a period of 20 minutes. After being stirred an additional 20 minutes at -78°C, this solution was then treated with l-acetyl-420 acetoxymethy1-2-n-buty1imidazoie (146 g, 0.61 mcl) dissolved in methylene chloride (300 mL) over a 20-?·: note interval. The mixture was then stirred at ambient temperature for 18 hours and the solvents were evaporated, The residual 2-n-butyl~5-acetoxymethyl-l·- (225 chlorophenyl·)methyl-lH-imidazole was used without purification for the hydrolysis of the acetate group.
A solution of crude 2-n-butyl-5-acetcxymethyl-l-(2chlorophenyl)methyl-lH-imidazole (250 g) in methanol (200 mL) was treated with 10% sodium hydroxide solution (720 30 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-nbutyl-l- (2-chlorophenyl)methyl-5-hydroxymethyl-1Himidazole; mp 86-88°C. This material was Identical in all respects to the product prepared by Method 1.
«« rc o
•<r cr
CL <
BAD ORIGINAL
AP . Ο Ο 5 2 7 (iii) 2-n-but y 1 - 1 - (2- c.h 2 ο: cphe.ny 1) r ·- ; hyl-lhimidazol-5-carbo xaIdehyde
A solution of 2-n-bulyl-1 -(2-chiorophenyl)methvl-5hydroxymethyl-1H-imidazole (5.4 g, 0.0194 mol) in toluene (25 mL) was aaced tc a suspension of activated manganese dioxide (27 y) in methylene chloride (325 mL). The suspension was stirred at room temperature for 17 hours. The solids were filtered and the filtrate concentrated and flash chromatographed over silica gel with 6:4 hexane/ethyl acetate to afford 4.16 g (78%) of 2-n-butyi1-(2-chlorophenyl) metnyl-lH-imidazol-5-carboxaldehyde, as an oil. NMR and IR were consistent with the structure.
(iv)
Method A (a) (E)-3-(2-n-butyl-l-{(2-chloropheny) methyl}-lHimidazol-5-yI]-2-(2-thienyl) mechyl-2-propenoic acid trimethyl 3- (2-thienyl)-2-phosphonopropionatc c
r c
c σ
d
S
To a solution of 2-thiophenemethanol (3.28 g, 0.02 mol) in carbon tetrachloride (25 mL, was added triphenyIphosphine (5.81 g, 0.026 mol), and the solution was refluxed for 3 hours. The cooled reaction mixt-re was diluted with hexane (60 mL), chilled and filtered.
The concentrated filtrate (4.6 g) was flash chromatographed over silica gel with 7:3 hexane/ethyl acetate to provide 2-chloromethylthiophene (1.52 g, 57%) as an oil.
A suspension of sodium hydride (0.271 g, 11.3 mmol) in dry glyme (40 mL) under argon was treated dropwise with trimethyl phosphonoacetate (1.87 g, 10.3 mmol) in glyme (5 mL). The resulting mixture wss stirred at room temperature for 1.5 hours. Then 2-chloromethyl-thiophene (1.5 g, 11.3 mmol) was added, and the mixture was stirred at 65°C for 18 hours. The reaction was par itioned between water and ethyl acetate, and the organic layer was washed with water and brine, dried with anhydrous magnesium sulfate and concentrated to 1.9 g of an oil.
BAD ORIGINAL
This was chromat/graphed over silica gel 4:1 et hy 1 acetat e/heua.ne to afford 600 r.g (26%i of trimechyi
3-(2-thienyi)-2-phcsphonopropiccate.
(b) methyl (E)-3-[2-n-buty1-1-{ (2chlor.phenyl) methyl)-lK-imidazol-5-yl-2-(2thienyl ) methyl-2-propenoate
To a suspension of sodium hydride (69 mg, 2.67 mmol) in glyme (5 mL) was added dropwise a solution of trimethyl 3-(2-thienyl)-2-phosphonopropionate in glyme (3 mL) under an atomsphere of argon. When the gas evolution had subsided, the mixture was heated to 50°C for 15 minutes. A solution of 2-n-butyl-l-(2-chiorcphenyl)methy 1 - 1H-imidazcl-5-carboxaldehyde (0.53 g, 1.92 m.moli in glyme (3 mL) was added, and the mixture was stirred at 60-65°C for 5 hours. The cooled reaction was partitioned between water and ethyl acetate, and the organic layer was washed with water, dried, concentrated and flash chromatographed over silica gel to give 336 mg (41%) of methyl (E)-3-[2-n-butyl-l-[(2-chlorophenyl)-methyl]-1Rimidazol-5-yl [-2-(2-thienyl) metny 1-2-propenoate as an ο^,Ι whose NMR was entirely consistent with the trans or E form of the olefin.
(c) (E)-3-[2-n-butyl-l-{ (2-chlorophenyi)rr.ethyl}-1Himidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid
A solution of methyl (E)-3-[2-n-butyl-l-[(2chlorophenyl) methyl]-lH-imidazol-5-yl]-2- (230 thienyl)methyl-2-prcpenoate (336 mg, C.783 mz.vl; in ethanol (10 mL) was treated with 10% sodium hydroxide solution (4 mL), and the solution was stirred for 3 nours at 25°C. The pK 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-chloropheny1) methyl ]-lH-imidazcl5-yl]-2- (2-thienyl)methyl-2-propenoic acid; mp 177-179’C.
- 18 'C rc c_
A OZP/ 0 /,
BAD ORIGINAL
AP.0 0 5 2 7 (a) methyl 3-[2-n-buty]-1-{(2-chlcrophcnyl'methyl}lH-imidazol-5-yl]-3-hydroxy-2-(2thi enyl)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
2.5 M in toluene), and the mixture was stirred for 10 minutes. Then, methyl 3-(2-thienyl)propanoate (2.83 g, 0.0166 mol) in tetrahydrofuran (2 mL) was added, and the mixture was stirred for 30 minutes at -78°C. A solution of 2-n-butyl-l-(2-chlorophenyl)methyl-lH-imidazol-jcarboxaldehyde (3 g, C.Cllx mol) in tetrahydrofuran (4 mL) was added, and the resulting mixture was stirrea 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 overanhydrous magnesium sulfate and concentrated to 6.f' g of crude product. This was flash chromatographed over 70 g of silica gel with 4:1 e-thyl acetate/hexane to provide 4.03 g (81%) of methyl 3-[2-n-butyi-l-(2-chlorophe.nyi ) methyl-lH-imidazol-5-yl]- 3-hydroxy-2-(2-thienyl)methylpropanoate.
(b) methyl 3-acetoxy-3-[2-n-butyl-l-(2chlorophenyl)methyl-lH-imidazoi-5-yi]-2-(2thienyl)methylpropanoate
A solution of methyl 3-[2-n-butyl-l-(2-chlorophenyl ) methyl- ΙΗ-imi da zol- 5- yl] -3 -hydroxy-2- (2-thienyl;methylpropanoate (4.03 g, 9,02 mmol) in methylene chloride <100 mL) was treated with 4-dimethylaminopyridine (0.386g, 3.16 mmol). Then acetic anhydride (8.5 mL, 9.02 mmol) was added dropwise to the stirred mixture. The mixture was stirred for 18 hours, water v35 mL) was added, the mixture was stirred for 1 hour and then diluted with ether and saturated sodium bicarbonate solution. The ether layer was washed with brine, dried
- 19 bad original
C ϋ 25 c
with anhyd-ous magnesium sulfate a.nd evaporated to cMve the t : t j 3-a?e'. <;xy derivative as an -il (4.37 g, 99t) (c) methyl (E)-3-[2-r.-butyl-l-((2-chlc.-ph^nyi.methyl} - IH-imi da zo 1-5-yi ] -2-- (2-thienyl) methyl2-propenoate
A mixture of methyl 3-acetcxy-3-[?-n-buty1 -1 - (2chlorophenyl)methyl-lH-imidazol-5-yl]-2~ (2-thienyl, methylpropanoate (4.36 q, 8.92 mmol) in dry toluene (80 mL) was treated with 1, 8-diazabicyclo[5.4.0]undec-7-e-v (DBU) (3.2 mL, 21.4 mmol), and the resulting solution was heated at 80°C under argon for 3 hours. The solvent was evaporated, the residue triturated with ether and activated charcoal was added. After filtration, the filtrate was concentrated to 6.29 g of an oil mat was chromatographed over silica gel with 65:35 hexane/ethy1 acetate to give 2.89 g (76%) of methyl (E)-3-f2-n-bJtyi1- [(2-chlorophenyl) methyl]-lH-imidazol-5-ylJ-2-(2thienyl)-methyl-2-propenoate whose NMR and TLC (50% ethyl acetate in hexane on silica gel) were identical tc the product prepared by Method A.
(d) (E,-3-[2-n-butyl-l-{ (2-chlorophenyl)methyl}-:';imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid
Basic hydrolysis of this ester (2.88 g, 6.73 mmol) according to Method A (iii) gave 2.59 g (93%) of (E)-'5[2-n-butyl-1-[ (2-chlorophenyl) methyl]-1H-imidazoI-5 -y1]2- (2-thienyl) methy i-2-propenoic acid; mp 175-17',oc that was identical to the product from Method A.
Example.. .2 (E) -3- f 2-n-Butyl-l-( (4-ca.rboxyphenyl) methyl l-ΙΗ- iml dazol5-yl) -2- (2-thienyl) methyl-_2--propenoic Acid (i) By the procedure of Example 1 [(ii) Method 2, (iii, and (iv) Method B] using 4-carbo.methoxybenzyl alcohol in place of 2-chlorobenzyl alcohol, the title compound was prepared; mp 250-253cC.
- 20 BAD ORIGINAL hptpi 94/007* io
AP . Ο Ο 5 2 7
The ti._e compound, 3 600 g, (54 L) in rallon, glass-lined reactc;.
.o 2-propa.no.. The stirred suspension was coo.ed to approximately 8CC.
Methanesulfonic acid (24^8 g) was added rapidly t· vigorously stirred suspension. The starting material dissolved quickly to give a clear solution within two minutes. A slight exotherm to approximately 11&C was observed. A fine, white solid began to precipitate from the solution within an additional three minutes. The suspension was stirred at a temperature of 3°C for 5.5 hours and the solid was collected by centrifugation.
After washing with 1C L of 2-propancl, .n? product was dried under vacuum at 45°C to a constant weight of 4.21 kg (94% yield, uncorrected for assay).
The crude product (4.20 kg) was charged as a solid to 12.6 L of stirred, glacial acetic acid ...n a 10-gaixon, glass-lined reactor. The slurry was heated to 80cC, giving a homogeneous solution. The solution was filtered warm through an in-line filter, and the reactor and filter linos were washed'with 4.2 L cf additional acetic acid. The combined acetic acid solutions -ere stirred with slow cooling to 25°C in a separate 10-gallon, glasslined reactor. Precipitation of a solid began to cccu..· at about 45°C. After 2.5 hours the suspension was diluted with 42 L of ethyl acetate, added in two equal portions with a one hour interval between additions. The suspension was stirred for an additional IS hours tc allow complete precipitation. The solid product was collected by centrifugation and washed wit?» 10 L of ethyi acetate. After drying to a constant weight under vacuum at 40°C, a recovery of 3.80 kg of product; mp 251-152^0 (90.4%, uncorrected for assay) was obtained.
ho
V /O/C.
bad original
- 21 Example 2.
An o.al dcsage form for administer'ng orally active Formula (I) compounds is produced by scree.nino, mixing and filling into hard gelatin capsules the ingredients .n proportions, for example, as shown below.
(E)-3-[2-n-butyl-l-{ (4carboxypenyl) methyl}-lH-imidazol5—yl]—2—(2-thienyl)methy1-2propenoic acid methanesulfonate magnesium stearate lactose
100 mg 1 0 mg
0 mo
The sucrose calcium sulfate dihydrate and orally 10 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 '•tcaric acid, screened and compressed into a tablet.
AP/P/ 94/0074?
(E)-3-[2-n-butyl-l-{ (4carboxypeny1) methyl}-lK-imidazol5-yl]-2-(2-thienyl) methy1-2-
propenoic acid methanesulfonate 75 mg
calcium sulfate dihydrate 100 mg
sucrose 15 mg
starch 8 mg
talc 4 mg
stearic acid 2 mg
Example .5 (E)-3-[2-n-butyl-l-{(4-carboxypenyl)methyl}-1Kimidazol-5-yl]-2-(2-thienyl) methyl-2-propencic acid methanesulfonate, ethylester, 50 mg, is dispersed in 25 mL of normal saline to prepare an injectable preparation, bad ORIGINAL 3
AP.00527
A tor. ical opthamological solution for administering Formula (1) compounds is produced by mixing under sterile conditions the ingredients in proportions, for example, as shown (E)-3-(2-n-butyl-l-((4carboxypenyl) methyl}-lH-imidazol-5ylJ-2 - (2-thienyl)methyl-2-propencic acid methanesulfonate dibasic sodium phosphate monobasic sodium phosphate chlorobutanol hydroxyprcpano1 methylcellulose sterile water
1.0 N sodium hydroxide
1.0
10.4
2.4 5.0 5.0
g. s. ad 1.OmL q.s.aa pH 7.4
It is to be understood that the invention us not limited to the embodiments illustrated hereafcove arid the right to the illustrated embodiments and all modifications coming within the scope of the following claims is reserved.
V L 0 0 / 7 6 ΙάΙάϋ

Claims (5)

  1. Whnί is c 1 a i med i s :
    A compound which is (L) -3-[2-n-buty1-1-{ idea rboxypenyl) methyl}-lH-imicazol-5-yl]-2-(2thienyi)methy1-2-propenoic acid methanesuifcrate .
  2. 2. A pharmaceutical oharmaceut i ca i carrier and composition oomprisLng the compound ol ci i:m
  3. 3. A ccropri ses effective method of treating hypertension which administering to a subject in need thereof .I'junt of the compound of claim I.
    Cd f^·
    C
    G
  4. 4. A method of treating congestive heart failure which comprises administering to a subject in need thereof an effective amount of the compound of ciaim 1..
    σ>
  5. 5. A method of treating renal failure comprises administering to a subject i. need effective amount of tne compound of claim 1.
    which
    L h e r e' > t a n
    BAD ORIGINAL
    AP.00527
    The Methanesulfonate salt of__(E)-3-I2-n-butyl-l-( (42-prcpenoic ac.id and pharmaceutical compositions contain:ng rc <t cr.
    useful in regulating hypertension and in the treatment of 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.
APAP/P/1995/000742A 1991-08-14 1992-08-14 The methanesulfonate salt of (E)-3-(2-n-butyl-1-((4-carboxypenyl) methyl) -1H- imidazol-5-yl)-2-(thienyl)methyl-2-propenoic acid and pharmaceutical compositions containing this compound. AP527A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US07/746,262 US5185351A (en) 1989-06-14 1991-08-14 Imidazolyl-alkenoic acids useful as angiotensin II receptor antagonists

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AP9500742A0 AP9500742A0 (en) 1995-07-31
AP527A true AP527A (en) 1996-09-06

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APAP/P/1992/000416A AP525A (en) 1991-08-14 1992-08-14 Imidazol-alkenoic acid and pharmaceutical compositions containing them.
APAP/P/1995/000742A AP527A (en) 1991-08-14 1992-08-14 The methanesulfonate salt of (E)-3-(2-n-butyl-1-((4-carboxypenyl) methyl) -1H- imidazol-5-yl)-2-(thienyl)methyl-2-propenoic acid and pharmaceutical compositions containing this compound.
APAP/P/1995/000741A AP526A (en) 1991-08-14 1992-08-14 The ethyl ester of (E)-3-[2-n-butyl-1-{(4-carboxynaphth-1-yl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl) methyl-2-propenoic acid and pharmaceutical compositions containing this compound.

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