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WO1994027597A1 - Acides imidazolyl-alcenoiques antagonistes du recepteur de l'angiotensine ii - Google Patents

Acides imidazolyl-alcenoiques antagonistes du recepteur de l'angiotensine ii Download PDF

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WO1994027597A1
WO1994027597A1 PCT/US1994/005762 US9405762W WO9427597A1 WO 1994027597 A1 WO1994027597 A1 WO 1994027597A1 US 9405762 W US9405762 W US 9405762W WO 9427597 A1 WO9427597 A1 WO 9427597A1
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alkyl
compound
phenyl
pharmaceutically acceptable
acceptable salt
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PCT/US1994/005762
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English (en)
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Joseph Weinstock
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Smithkline Beecham Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • compositions containing these compounds and methods for using these compounds as antagonists of angiotensin ⁇ , as antihypertensive agents and as agents for treating congestive heart failure, renal failure, and glaucoma.
  • renin-angiotensin system Inappropriate activity of the renin-angiotensin systems appears to be a key element in essential hypertension, congestive heart failure and in some forms of renal disease.
  • angiotensin II (All), 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.
  • R 1 is m is 0-4;
  • R 3 is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl, COOR 7 , CONR 7 R 7 ,
  • R 4 and R 5 are not selected from hydrogen and C 1-6 alkyl, and with each heteroaryl group being unsubstituted or substituted by C 1 -C 6 alkyl, C 1 -C 6 alkoxy, Cl, Br, F, I, CF 3 , NR 7 R 7 , CO 2 R 7 , SO 2 NHR 7 , SO 3 H, CONR 7 R 7 , OH, NO 2 , SC 1 -C 6 alkyl, SO 2 C 1 -C 6 alkyl,
  • Y is a single bond, O, S, or C 1 -C 6 alkyl which is straight or branched or optionally substituted by phenyl or benzyl, wherein each of the aryl groups is unsubstituted or substituted by halo, NO 2 , CF 3 , C 1 -C 6 alkyl, C 1 -C 6 -alkoxy, CN, or CO 2 R 7 ;
  • R 6 is -Z-COOR 8 or -Z-CONR 7 R 7 ;
  • each n independently is 1-3;
  • each R 10 independently is H or C 1 -C 6 alkyl
  • R 1 1 is H, C 1-6 alkyl, C n F 2n+1 , or -(CH) 0-2 phenyl which is unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C 1 -C 6 alkyl, NO 2 , CF 3 , CO 2 R 10 , tetrazolyl, C 1 -C 6 alkoxy, OH, SC 1 -C 6 alkyl, SO 2 NHR 10 ,
  • U is absent or present as Cl, Br, F, I, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or hydroxy;
  • R 16 is CN, CO 2 H, tetrazolyl, or
  • each R 17 is CBZ, BOC, CO-phenyl, COCH 2 CH 3 , COCH 3 , COCF 3 ,
  • R 19 is H, C 1 -C 6 alkyl, phenyl, CN, COR 10 , CO 2 R 10 , tetrazolyl or ;
  • R 22 is (CH 2 ) 0-2 pnenyl unsubstituted or substituted by one to five substituents selected from Cl, Br, I, F, C 1 -C 6 alkyl, C 1 -5 alkoxy, C 1-5 alkylthio, NO 2 , CF 3 , CO 2 R 7 , or OH;
  • each R 23 independently is -OCH 2 -phenyl unsubstituted or substituted by NHR 25 or OR 26 ;
  • R 24 is C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl
  • R 26 is C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl
  • each Q independently is -O-, -S-, or -N(R10)-;
  • V is CO 2 R 10 , tetrazolyl, or -NHSO 2 R 1 1 ;
  • each r independently is 0-3;
  • each t independently is 0-2;
  • one of R 4 and R 5 is hydrogen or C 1 -C 6 alky 1 and m is one.
  • X is a single bond
  • R 3 is hydrogen, chloro, fluoro, trifluoromethyl, C 1 -C 6 alkyl, or
  • R 6 is COOH, COOC 1-2 alkyl, or CONH 2 ; or a pharmaceutically acceptable salt thereof.
  • Particular compounds of the invention include, but are not limited to, the following:
  • the E isomers (trans stereochemistry of the R 6 group and imidazole group) are generally more active and, thus, are preferred over the Z isomers (cis).
  • alkyl, alkenyl, alkoxy and alkynyl mean carbon chains which are branched or unbranched with the length of the chain determined by the descriptor preceding the term.
  • Aryl as used herein, means phenyl, biphenyl, or naphthyl. Heteroaryl means 2- or 3-thienyl, 2- or 3-furanyl, 2-, 3- or 4-pyridyl, pyrazolyl, imidazolyl, pyrrolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, or tetrazolyl.
  • CBZ represents a benzyloxycarbonyl group
  • BOC represents a tert- butyloxycarbonyl group
  • the invention also relates to pharmaceutical compositions comprising a pharmaceutical carrier and an effective amount of a compound of Formula (I).
  • Also included in the present invention are methods for antagonizing angiotensin II receptors which comprises administering to a subject in need thereof an effective amount of a compound of Formula (I).
  • hypertension, congestive heart failure, glaucoma, and renal failure by administering these compounds are also included in this invention.
  • the compounds of Formula (I) are angiotension II receptor antagonists, they may also be of value in the treatment of left ventricular
  • these compounds may be expected to be useful in the primary and secondary prevention of infarction, in the prevention of atheroma progression and in the regression of antheroma, in the prevention of restinosis after angioplasty or bypass surgery and in the improvement of cognitive funtion.
  • This intermediate is reacted with acetic anhydride to give 1-acetyl-5-acetoxymethyl-2-R 2 -imidazole.
  • the diacetate intermediate is N-alkylated and the resulting 1-R 1 (CH 2 ) -2-R 2 -5-acetoxy- methylimidazole is treated with aqueous base, such as 10% sodium hydroxide solution, to give the 1-R 1 (CH 2 ) m -2-R 2 -5-hydroxymethyl-imidazole intermediate.
  • aqueous base such as 10% sodium hydroxide solution
  • the 2-R 2 S-imidazole compounds are prepared by the following procedure. Benzylamines, substituted by one to three substituents selected from halo, C 1 -6 alkyl, C 1 -6 alkoxy, CN, NO 2 , CF 3 , CO 2 C 1-6 alkyl,
  • SC 1 -6 alkyl, or SO 2 C 1 -6 alkyl are alkylated with a C 1 -6 alkyl chloroacetate, for example methyl chloroacetate, in the presence of a base, such as triethylamine, in a suitable solvent, such as dimethylformamide.
  • a base such as triethylamine
  • a suitable solvent such as dimethylformamide.
  • the resulting alkylaminoalkyl ester compounds are N-formulated with formic acid in the presence of a suitable solvent, such as xylenes, followed by C-formulation of the carbon alpha to both the amino and the ester groups.
  • the free thio group of the ester imidazole is reacted with a halo-R' compound, wherein R' is C 2-10 alkyl, C 3-10 alkenyl, C 3 -C 10 alkynyl, C 3 -C 6 cycloalkyl or an optionally substituted (CH 2 ) 0-8 phenyl, preferably propyl bromide, in the presence of a suitable base, such as sodium carbonate, in an appropriate solvent, such as ethyl acetate.
  • a suitable base such as sodium carbonate
  • the 1-R 1 (CH 2 ) m -2-R 2 X-imidazol-5-carboxaldehydes are reacted with appropriate phosphonates, which are prepared, for example, from trialkyl phosphonoacetates by alkylation with an appropriate halide, mesylate or acetate in the presence of a suitable base, such as sodium hydride, in a suitable solvent, preferably glyme at a reaction temperature of about 25°C to about 110°C, preferably at about 55°C, to provide the appropriate phosphonates.
  • a suitable base such as sodium hydride
  • a suitable base such as a metal alkoxide, lithium hydride or preferably sodium hydride
  • a suitable solvent such as ethanol, methanol, ether, dioxane, tetrahydrofuran, or preferably gly
  • esters are readily separated by chromatography over silica gel in suitable solvent systems, preferably hexane in ethyl acetate mixtures.
  • bases such as potassium hydroxide, lithium hydroxide or sodium hydroxide
  • 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.
  • the 1-R 1 (CH 2 ) m -2-R 2 X-imidazol-5-carboxaldehydes are prepared by the following procedure. Starting 2-R 2 X-imidazol-5-carboxaldehydes are reacted with an N-alkylating protecting reagent, such as chloromethyl pivalate
  • 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 1 CH 2 -2-R 2 X-imidazole-5-carboxaldehyde compounds.
  • the Formula (I) compounds can be prepared from these 5-carboxaldehyde compounds by the methods described above.
  • the 2-R 2 X-imidazole starting materials are reacted with trimethylsilylethoxymethyl(SEM) chloride to give l-(trimethylsilyl)ethoxymethyl2-R 2 X-imidazole.
  • SEM trimethylsilylethoxymethyl
  • the reaction is earned 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-n-butyltin chloride, at about -10°C to about 35°C, preferably at about 25°C.
  • a tributyltin halide preferably tri-n-butyltin chloride
  • a phosphine ligand such as bis(diphenyl-phosphino)propane, or triphenylphosphine and a pal
  • Both the (E) and (Z) olefinic isomers are prepared by this procedure, and the isomeric esters are readily separated by chromatography over silica gel.
  • the 1-SEM group from the (E) and (Z) isomers is hydrolyzed with acid, for example, aqueous hydrochloric, in a suitable alcoholic solvent, such as methanol or ethanol, and the 1 -unsubstituted imidazole derivatives are converted to the 1-t-butoxycarbonyl (t-BOC) imidazoles with di-t-butyl dicarbonate (HoppeSeyler's Z. Physiol. Chem., (1976), 357, 1651).
  • the t-BOC esters are hydrolyzed and N-alkylated to afford the 1-R 1 (CH 2 ) m -imidazole derivatives (esters).
  • the (E) and (Z) isomers are hydrolyzed to the (E) and (Z) acids by the method described above.
  • the 1-R 1 (CH 2 ) m -2-R 2 X-imidazole-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-(2-thienyl)propionate, in the presence of a base, such as piperidine, in a suitable solvent, such as toluene, at a temperature of about 80°C to about 110°C, preferably at about 100°C.
  • a base such as piperidine
  • a suitable solvent such as toluene
  • Compounds of Formula (I) are also prepared as follows.
  • the 1-R 1 - (CH 2 ) m -2-R 2 X-imidazol-5-carboxaldehydes are treated with the lithium derivative of a substituted ethyl or methyl ester.
  • These lithio derivatives are prepared from the reaction of lithium diisopropylamide in a suitable solvent, preferably
  • the intermediate ß-hydroxy group of the imidazole ester is converted to a mesylate or an acetate and the mesylate, or preferably the acetate, is heated in a suitable solvent, such as toluene, with one to two equivalents of l,8-diazo-bicyclo[5.4.0]undec-7-ene, at about 50 to about 110°C, preferably at about 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 olefinic isomer.
  • the acids are prepared from the esters by the method described above.
  • the acid compounds are prepared from the esters by base hydrolysis.
  • Formula (I) compounds which are substituted by hydroxy are formed from Formula (I) compounds which are substituted by C 1 -C 4 alkoxy using an ether-cleaving reagent, such as boron tribromide or hydrobromic acid.
  • an ether-cleaving reagent such as boron tribromide or hydrobromic acid.
  • Formula (I) compounds which are substituted by carboxy are formed from Formula (I) compounds which are substituted by CO 2 C 1 -C 4 alkyl using basic hydrolysis, such as aqueous sodium or potassium hydroxide in methanol or ethanol, or using acidic hydrolysis, such as aqueous hydrochloric acid.
  • basic hydrolysis such as aqueous sodium or potassium hydroxide in methanol or ethanol
  • acidic hydrolysis such as aqueous hydrochloric acid.
  • Formula (I) compounds which are substituted by a tetrazol-5-yl group are prepared from the correponding carboxy compounds.
  • Formula (I) acid compounds are reacted with a halogenating agent, such as thionyl chloride, in a suitable solvent, for example benzene, to give the corresponding acid halide compounds.
  • a halogenating agent such as thionyl chloride
  • suitable solvent for example benzene
  • 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.
  • 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 R 6 is -Z-CO 2 H are prepared from these Formula (I) tetrazole ester compounds by basic hydrolysis as described above.
  • R 1 (CH 2 ) m -halides or alcohols useful in the preparation of Formula (I) compounds are known in the art or can be made by analogy processes using standard procedures of organic chemistry.
  • R 1 -(CH 2 ) m -mesylate or acetate is employed in the process of incorporating the R 1 (CH 2 ) m -group onto the imidazole ring, then the mesylate or acetate is prepared from the corresponding alcohol in a reaction with
  • compositions of Formula (I) are formed with appropriate organic or inorganic acids by methods known in the art.
  • 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.
  • suitable acids are maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic,
  • Pharmaceutically acceptable base addition salts of compounds of Formula (I) in which R 8 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.
  • 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 vitro and in vivo methods.
  • In vitro antagonist activity is determined by the ability of the compounds to compete with 125 I-angiotensin II for binding to vascular angiotensin II receptors and by their ability to antagonize the contractile response to angiotensin II in the isolated rabbit aorta.
  • In vivo activity is evaluated by the efficacy of the compounds to inhibit the pressor response to exogenous angiotensin II in conscious rats and to lower blood pressure in a rat model of renin dependent hypertension.
  • the radioligand binding assay is a modification of a method previously described in detail (Gunther et al., Circ. Res. 47:278, 1980).
  • a particular fraction from rat mesenteric arteries is incubated in Tris buffer with 80 pM of 125 I-angiotensin II with or without angiotensin II antagonists for 1 hour at 25°C.
  • the incubation is terminated by rapid filtration and receptor bound 125 I-angiotensin II trapped on the filter is quantitated with a gamma counter.
  • the potency of angiotensin II antagonists is expressed as the IC 50 which is the concentration of antagonist needed to displace 50% of the total specifically bound angiotensin II.
  • Ring segments are cut from the rabbit thoracic aorta and suspended in organ baths containing physiological salt solution.
  • the ring segments are mounted over metal supports and attached to force displacement transducers which are connected to a recorder.
  • concentration response curves to angiotensin ⁇ are performed in the absence of antagonist or following a 30-minute incubation with antagonist.
  • Antagonist disassociation constants (K B ) are calculated by the dose ratio method using the mean effective concentrations.
  • Rats are prepared with indwelling femoral arterial and venous catheters and a stomach tube (Gellai et al., Kidney Int. 15:419, 1979). Two to three days following surgery the rats are placed in a restrainer and blood pressure is continuously monitored from the arterial catheter with a pressure transducer and recorded on a polygraph. The change in mean arterial pressure in response to intravenous injections of 250 mg/kg angiotensin II is compared at various time points prior to and following the administration of the compounds intravenously or orally at doses of 0.1 to 300 mg/kg. The dose of compound needed to produce 50% inhibition of the control response to angiotensin II (IC 50 ) is used to estimate the potency of the compounds.
  • IC 50 The dose of compound needed to produce 50% inhibition of the control response to angiotensin II
  • the antihypertensive activity of the compounds is measured by their ability to reduce mean arterial pressure in conscious rats made renin-dependent
  • 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
  • the intraocular pressure lowering effects employed in this invention may be measured by the procedure described by Watkins, et al., J. Ocular Pharmacol., 1
  • the compounds of Formula (I) are incorporated into convenient dosage forms, such as injectable preparations, or for orally active compounds, capsules or tablets.
  • Solid or liquid pharmaceutical carriers are employed.
  • Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • Liquid carriers include syrup, peanut oil, olive oil, saline, and water.
  • the carrier or diluent may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the amount of solid carrier varies widely but, preferably, will be from about 25 mg to about 1 g per dosage unit.
  • the 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.
  • the pharmaceutical preparation may also contain non-toxic auxiliary substances such as emulsifying, preserving, wetting, and bodying agents, as for example, polyethylene glycols; antibacterial components, such as quarternary ammonium compounds; buffering ingredients, such as alkali metal chloride; antioxidants, such as sodium metabisulfite; and other conventional ingredients, such as sorbitan monolaurate.
  • auxiliary substances such as emulsifying, preserving, wetting, and bodying agents, as for example, polyethylene glycols; antibacterial components, such as quarternary ammonium compounds; buffering ingredients, such as alkali metal chloride; antioxidants, such as sodium metabisulfite; and other conventional ingredients, such as sorbitan monolaurate.
  • suitable ophthalmic vehicles may be used as carrier media for the present purpose including conventional phosphate buffer vehicle systems.
  • the pharmaceutical preparation may also be in the form of a solid insert.
  • a solid water soluble polymer as the carrier for the medicament.
  • Solid water insoluble inserts such as those prepared from ethylene vinyl acetate copolymer, may also be utilized.
  • the pharmaceutical preparations are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingredients, as appropriate, to give the desired oral, parenteral, or topical products.
  • an amount of active compound from between 50 ng to 0.05 mg, preferably 50 ng to 5 mg, is applied to the human eye.
  • the compounds of this invention may be co-administered with other pharmaceutically active compounds, for example in combination, concurrently or sequentially. Conpressively the compounds of this invention and the other active compound or compounds are formulated in a pharmaceutical composition.
  • examples of compounds which may be included in pharmaceutical compositions with the compounds of Formula (I) are diuretics, particularly a thiazide diuretic, such as hydrochlorothiazide, or a loop diuretic, such as furosemide, a calcium channel blocker, particularly dihydropyridine antagonists, such as nifedipine, ⁇ -adrenoceptor blockers, such as propranolol, renin inhibitors, such as enalkinen, and angiotensin converting enzyme inhibitors, such as captopril or enalapril.
  • diuretics particularly a thiazide diuretic, such as hydrochlorothiazide, or a loop diuretic, such as furosemide, a calcium channel block
  • All receptor antagonist compounds of this invention can also be administered in combination with other antihypertensives and/or diuretics and/or angiotensin converting enzyme inhibitors and/or calcium channel blockers.
  • the compounds of this invention can be given in combination with such compounds as amiloride, atenolol, bendroflumethiazide, chlorothalidone,
  • chlorothiazide clonidine, cryptenamine acetates and cryptenamine tannates, deserpidine, diazoxide, guanethidene sulfate, hydralazine hydroahloride,
  • teprotide zofenopril calcium, diflusinal, diltizem, felodipine, nicardipine,
  • one of the angiotensin II antagonists of this invention effective clinically in the 2.5-250 milligrams per day range can be effectively combined at levels at the 0.5-250 milligrams per day range with the following compounds at the indicated per day dose range: hydrochlorothiazide (15-200 mg), chlorothiazide (125-2000 mg), ethacrynic acid (15-200 mg), amiloride (5-20 mg), furosemide (5-80 mg), propanolol (20-480 mg) timolol maleate (5-60 mg), methyldopa (65-2000 mg), felodipine (5-60 mg), nifedipine (5-60 mg), and nitrendipine (5-60 mg).
  • hydrochlorothiazide 15-200 mg
  • chlorothiazide 125-2000 mg
  • ethacrynic acid 15-200 mg
  • amiloride 5-20 mg
  • furosemide 5-80 mg
  • hydrochlorothiazide (15-200 mg) plus amiloride (5-20 mg) plus angiotnesin II antagonist of this invention (3-200 mg) or hydrochlorothiazide (15-200 mg) plus timolol maleate (5-60 mg) plus an angiotensin II antagonist of this invention (0.5-250 mg) of hydrochlorothiazide (15-200 mg) and nifedipine (5-60 mg) plus an angiotensin II antagonist of this invention (0.5-250 mg) areeffective combinations to control blood pressure in hypertensive patients.
  • these dose ranges can be adjusted on a unit basis as necessary to permit divided daily dosage and, the dose will vary depending on the nature and severity of the disease, weight of patient, special diets and other factors.
  • the method of this invention of antagonizing angiotensin II receptors in mammals, including humans, comprises administering to a subject in need of such antagonism an effective amount of a compound of Formula (I).
  • the method of this invention of producing antihypertensive activity and the method of treating congestive heart failure, glaucoma, and renal failure comprise administering a compound of Formula (I) to a subject in need thereof an effective amount to produce said activity.
  • Contemplated equivalents of Formula (I) compounds are compounds otherwise corresponding thereto wherein substituents have been added to any of the unsubstituted positions of the Formula (I) compounds provided such compounds have the pharmaceutical utility of Formula (I) compounds.
  • 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 layer with aqueous hydrochloric acid and with diethyl ether.
  • a solution of this half-acid, half-ester (1.05 g, 4.62 mmol) in 5 ml of toluene is added to a refluxing solution of 2-n-butyl-1-[(2-cyano-1,2,3,4-tetrahydronaphthalene-6-yl)methyl]imidazole-5-aldehyde (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, half -ester is added, and the solution is then refluxed for 17 hours.
  • Tetrahydrofuran (8 ml) is added slowly under argon with stirring to a mixture of ethyl (E)-3-[2-n-butyl-1- ⁇ 2-cyano-1,2,3,4-tetrahydronaphthalene-6- yl]methyl ⁇ -1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-pro ⁇ enoate (2.15 mmol) and aluminum chloride (4.33 mmol).
  • Sodium azide (1.28 g, 19.43 mmol) is added all at once, followed by a 1 ml tetrahydrofuran rinse, and the reaction is heated to 65°C for 22 hours, then cooled to room temperature.
  • reaction mixture is diluted with ethyl acetate (8 ml) and treated with 10% hydrochloric acid solution (8 ml) with vigorous stirring for 5 minutes.
  • the ethyl acetate layer is washed with water and brine.
  • the combined aqueous layers are extracted once with ethyl acetate.
  • R 1 (CH 2 ) m -bromide or -iodide group in place of 2-cyano-6-iodomethyl-1,2,3,4-tetrahydronaphthalene. (See the specification on pages 18-19 for the preparation of the R 1 -(CH 2 ) m -bromides or -iodides.)

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Abstract

Antagonistes du récepteur de l'angiotensine II, de formule (I), efficaces dans la régulation de l'hypertension et le traitement des insuffisances cardiaques, des insuffisances rénales et du glaucome; préparations pharmaceutiques comportant ces antagonistes; et méthodes d'utilisation de ces compositions en vue d'induire l'antagonisme du récepteur de l'angiotensine II chez les mammifères.
PCT/US1994/005762 1993-05-21 1994-05-20 Acides imidazolyl-alcenoiques antagonistes du recepteur de l'angiotensine ii WO1994027597A1 (fr)

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US08/065,732 1993-05-21
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US08/203,145 1994-02-28

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0885217A4 (fr) * 1996-02-01 1999-04-21 Smithkline Beecham Corp Antagonistes des recepteurs de l'endotheline
EP0841926A4 (fr) * 1995-08-02 1999-08-04 Smithkline Beecham Corp Antagonistes du recepteur d'endotheline
WO2000068226A1 (fr) * 1999-05-05 2000-11-16 Aventis Pharma Deutschland Gmbh 1(p-thienylbenzyl)-imidazoles comme agonistes des recepteurs de l'angiotensine (1-7), leur procede de production, leur utilisation, et preparations pharmaceutiques les contenant
WO2005033063A3 (fr) * 2003-10-01 2007-03-22 Procter & Gamble Antagonistes de l'hormone concentrant la melanine
US7652054B2 (en) 2001-05-31 2010-01-26 Vicore Pharma Ab Tricyclic compounds useful as angiotensin II agonists
EP2455388A1 (fr) 2010-11-23 2012-05-23 LanthioPep B.V. Nouveaux agonistes du récepteur 2 (AT2) de type angiotensine et leurs utilisations
WO2021023698A1 (fr) 2019-08-02 2021-02-11 Lanthiopep B.V Agonistes du récepteur de l'angiotensine 2 (at2) destinés à être utilisés dans le traitement du cancer
WO2021186180A1 (fr) * 2020-03-20 2021-09-23 Vicore Pharma Ab Carbamates d'imidazolyle thiophene sulfonyle destinés à être utilisés dans le traitement de maladies associées à l'angiotensine ii

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US5212198A (en) * 1990-05-10 1993-05-18 G. D. Searle & Co. Alkoxy-substituted dihydrobenzopyran-2-carboxylic acids and derivatives thereof

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US5073566A (en) * 1989-11-30 1991-12-17 Eli Lilly And Company Angiotensin ii antagonist 1,3-imidazoles and use thereas
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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0841926A4 (fr) * 1995-08-02 1999-08-04 Smithkline Beecham Corp Antagonistes du recepteur d'endotheline
EP0885217A4 (fr) * 1996-02-01 1999-04-21 Smithkline Beecham Corp Antagonistes des recepteurs de l'endotheline
WO2000068226A1 (fr) * 1999-05-05 2000-11-16 Aventis Pharma Deutschland Gmbh 1(p-thienylbenzyl)-imidazoles comme agonistes des recepteurs de l'angiotensine (1-7), leur procede de production, leur utilisation, et preparations pharmaceutiques les contenant
US6235766B1 (en) 1999-05-05 2001-05-22 Aventis Pharma Deutschland Gmbh 1-(p-thienylbenzyl)imidazoles as agonists of angiotensin (1-7) receptors, processes for their preparation, their use, and pharmaceutical preparations comprising them
AU775244B2 (en) * 1999-05-05 2004-07-22 Aventis Pharma Deutschland Gmbh 1-(p-thienylbenzyl)-imidazoles as angiotensin-(1-7) receptor agonists, method for the production and the utilization thereof and pharmaceutical preparations containing said compounds
US8124638B2 (en) 2001-05-31 2012-02-28 Vicore Pharma Ab Tricyclic compounds useful as angiotensin II agonists
US7652054B2 (en) 2001-05-31 2010-01-26 Vicore Pharma Ab Tricyclic compounds useful as angiotensin II agonists
US7304065B2 (en) 2003-10-01 2007-12-04 The Procter & Gamble Company Melanin concentrating hormone antagonists
WO2005033063A3 (fr) * 2003-10-01 2007-03-22 Procter & Gamble Antagonistes de l'hormone concentrant la melanine
EP2455388A1 (fr) 2010-11-23 2012-05-23 LanthioPep B.V. Nouveaux agonistes du récepteur 2 (AT2) de type angiotensine et leurs utilisations
WO2012070936A1 (fr) 2010-11-23 2012-05-31 Lanthiopep B.V. Nouveaux agonistes du récepteur de l'angiotensine de type 2 (at2) et leurs utilisations
US9290540B2 (en) 2010-11-23 2016-03-22 Lanthio Pep B.V. Angiotensin Type 2 (AT2) receptor agonists and uses thereof
US9707268B2 (en) 2010-11-23 2017-07-18 Lanthiopep B.V. Angiotensin type 2 (AT2) receptor agonists and uses thereof
US10214563B2 (en) 2010-11-23 2019-02-26 Lanthiopep B.V. Angiotensin type 2 (AT2) receptor agonists and uses thereof
WO2021023698A1 (fr) 2019-08-02 2021-02-11 Lanthiopep B.V Agonistes du récepteur de l'angiotensine 2 (at2) destinés à être utilisés dans le traitement du cancer
WO2021186180A1 (fr) * 2020-03-20 2021-09-23 Vicore Pharma Ab Carbamates d'imidazolyle thiophene sulfonyle destinés à être utilisés dans le traitement de maladies associées à l'angiotensine ii

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