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WO1994022830A1 - Composes chimiques - Google Patents

Composes chimiques Download PDF

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Publication number
WO1994022830A1
WO1994022830A1 PCT/US1994/003478 US9403478W WO9422830A1 WO 1994022830 A1 WO1994022830 A1 WO 1994022830A1 US 9403478 W US9403478 W US 9403478W WO 9422830 A1 WO9422830 A1 WO 9422830A1
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Prior art keywords
alkyl
phenyl
substimted
compound
formula
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PCT/US1994/003478
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English (en)
Inventor
Joseph Weinstock
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Filing date
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Publication of WO1994022830A1 publication Critical patent/WO1994022830A1/fr
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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

Definitions

  • the present invention relates to new chemical compounds which are angiotensin II receptor antagonists and are useful in regulating hypertension induced or exacerbated by angiotensin II, and in the treatment of congestive heart failure, renal failure, and glaucoma.
  • This invention also relates to pharmaceutical compositions containing these compounds and methods for using these compounds as antagonists of angiotensin II, as antihypertensive agents and as agents for treating congestive heart failure, renal failure, and glaucoma.
  • angiotensin The class of peptide pressor hormone known as angiotensin is responsible for a vasopressor action that is implicated in the etiology of hypertension in man. Inappropriate activity of the renin-angiotensin systems appears to be a key element in essential hypertension, congestive heart failure and in some forms of renal disease.
  • angiotensin II AII
  • AII angiotensin II
  • the reninangiotensin system by virtue of its participation in the control of renal sodium handling, plays an important role in cardiovascular hemeostasis.
  • the compounds of this invention inhibit, block and antagonize the action of the hormone AII, and are therefore useful in regulating and moderating angiotensin induced hypertension, congestive heart failure, renal failure and other disorders attributed to the actions of AII.
  • compounds of this invention are administered to mammals, the elevated blood pressure due to AII is reduced and other
  • U.S. Patent 4,340,598 discloses imidazol-5-yl-acetic acids and imidazol-5-yl-propanoic acids. Specifically, the discloser includes 1-benzyl-2- n-butyl-5-chloroimidazole-4-acetic acid and 1-benzyl-2-phenyl-5-chloroimidazole- 4-propanoic acid.
  • U.S. Patent 4,355,040 discloses substituted imidazole-5- acetic acid derivatives.
  • a compound specifically disclosed is 1-(2-chlorobenzyl)-2- n-butyl-4-chloroimidazole-5-acetic acid.
  • Carini et al. in EP 253,310 disclose certain imidazolylpropenoic acids.
  • Two intermediates described in this patent are ethyl 3-[1-(4-nitrobenzyl)-2-butyl-4- chloroimidazol-5-yl]propenoate and ethyl 3-[2-butyl-4-chloro-1-(4- aminobenzyl)imidazol-5-yl]propenoate.
  • Wareing in PCT/EP 86/00297, discloses as intermediates certain imidazolylpropenoate compounds.
  • Formula (CX) is ethyl 3-[1(-4- fluorophenyl)-4-isopropyl-2-phenyl-1H-imidazol-5-yl]-2-propenoate.
  • R 1 is phenyl or naphthyl, each of which is unsubstituted or substituted by one to three substituents selected from CL Br, F, I, C 1-6 alkyl, NO 2 , CF 3 ,
  • Q-CO 2 R' tetrazolyl, C 1-6 alkoxy, OH, SC 1-6 alkyl, SO 2 NHR', NHSO 2 R", SO 3 H, CONR'R', CN, SO 2 C 1-6 alkyl, NR"R', NR'COH, NR'COC 1-6 alkyl or
  • n 0-4;
  • a 1 is C or N when X is a covalent bond, or C when X is other than a covalent bond;
  • a 3 is CR 2 ,CR 4 N, or NR 15 ;
  • a 4 is CR 5 , CR 5 R 9 , or N;
  • a 5 is absent or present as CR 6 or N;
  • a 6 is CR 7 when A 5 is absent or CR 8 or N when A 5 is present;
  • one of A 2 or A 3 is CR 2 ;
  • each R' independently is H or C 1-6 alkyl
  • R is R', C m F 2m+1 , wherein m is 1-3, or phenyl which is unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C 1-6 alkyl, NO 2 , CF 3 , Q-CO 2 R', tetrazolyl, C 1-6 alkoxy, OH, SC 1-6 alkyl, SO 2 NHR', NHSO 2 R', SO 3 H, CONR'R', CN, SO 2 C 1-6 alkyl, NR'R', NR'COH, NR'COC 1-6 a-kyl or
  • R 3 is O, (H,H), or (H, C 1-4 alkyl);
  • R 4 is H, C 1-4 alkyl, Cl, Br, F, or I;
  • R 5 is H, C 1-4 alkyl, Cl, Br, F, or I;
  • R 6 is H or C 1-4 alkyl
  • R 7 is C 2-8 alkyl. SC 1-7 alkyl or OC 1-7 alkyl;
  • R 8 is H, C 2-8 alkyl, SC 1-7 alkyl, or OC 1-7 alkyl;
  • each R 9 independently is H or C 1-6 alkyl
  • R 10 is H or C 1-6 alkyl
  • R 1 1 is CO 2 R', CONR'R', tetrazolyl, or SO 2 NH 2 ;
  • R 12 is C 1 -C 6 alkyl, phenyl- Y-, biphenyl-Y-, naphthyl- Y-, 2- or 3-thienyl-Y-, - or 3-furanyl-Y-, 2-, 3- or 4-pyridyl-Y-, pyrazolyl-Y-, imidazolyl-Y-, pyrrolyl-Y-, triazolyl-Y-, oxazolyl-Y-, isoxazolyl-Y-, thiazolyl-Y-, or tetrazolyl- Y-, with each heteroaryl group being unsubstituted or substituted by C 1 -C 6 alkyl, C 1 -C 6 alkoxy, Cl, Br, F, I, CF 3 , NR'R', CO 2 R', SO 2 NHR', SO 3 H, CONR'R', OH, NO 2 , SC 1 - C 6 alkyl, SO 2 C 1 -C
  • Y is a single bond, O, S, or C 1 -C 6 alkyl which is straight or branched optionally substituted by phenyl or benzyl, wherein each phenyl or benzyl group is unsubstituted or substituted by Cl, Br, F, I, NO 2 , CF 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, CN, or CO 2 R';
  • X is a covalent bond, -O-, -S-, or -N(R 9 )-;
  • U is absent or present as -O-, -S-, or -N(R 9 )-;
  • V is -O-, -S-, or -N(R 9 )-;
  • R 13 is H, phenyl, or benzyl wherein each phenyl or benzyl group is unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C 1-6 alkyl, NO 2 , CF 3 , Q-CO 2 R', tetrazolyl, C 1-6 alkoxy, OH, SC 1-6 alkyl,
  • R 14 is Cl, Br, F, or I
  • R 15 is H, C 1-6 alkyl, -(CH 2 ) 1-2 C 3-6 cycloalkyl, -(CH 2 ) 1-2 CF 3 , or
  • Phenyl wherein the phenyl is unsubstituted or substituted by any accessible combination of up to three substituents selected from Cl, Br, F, I, CF 3 , or C 1-6 alkyl;
  • alkyl and alkoxy mean carbon chains which are branched or unbranched with the length of the chain determined by the descriptor preceding the term.
  • any accessible combination means any combination of substituents that is available by chemical synthesis and is stable.
  • Aryl as used herein, means phenyl, biphenyl, or naphthyl.
  • Heteroaryl means 2- or 3-thienyl-Y-, 2- or 3-furanyl-Y-, 2-, 3- or 4-pyridyl-Y-, pyrazolyl-Y-, imidazolyl-Y-, pyrrolyl-Y-, triazolyl-Y-, oxazolyl-Y-, isoxazolyl-Y-, thiazolyl-Y-, or tetrazolyl- Y-.
  • R 1 is phenyl or naphthyl, each of which is substituted by Q-CO 2 R', CONR'R',
  • Formula (I) compounds wherein R 2 is X in which the A 1 - A 6 ring and the CO 2 H group are trans to each other are preferred. These isomers are generally more active and, thus, are preferred over the corresponding cis isomers (the Z isomers).
  • a 1 - A 6 rings to which X is attached at A 1 are represented by the following:
  • the invention also relates to pharmaceutical compositions comprising a pharmaceutical carrier and an effective amount of a compound of Formula (I).
  • Also included in the present invention are methods for antagonizing angiotensin II receptors which comprises administering to a subject in need thereof an effective amount of a compound of Formula (I).
  • Methods of treating hypertension, congestive heart failure, glaucoma, and renal failure by administering these compounds are also included in this invention.
  • the compounds of Formula (I) are angiotension II receptor antagonists, they may also be of value in the treatment of left ventricular hypertrophy regression, diabetic nephropathy, diabetic retinopathy, macular degeneration, haemorrhagic stroke, angina, and anxiety. Additionally, these compounds may be expected to be useful in the primary and secondary prevention of infarction, in the prevention of atheroma progression and in the regression of antheroma, in the prevention of restinosis after angioplasty or bypass surgery and in the improvement of cognitive funtion.
  • Steps in the synthesis must be compatible with the functional groups and the protecting groups on the naphthalene and other parts of the molecule.
  • the compounds of Formula (I) or pharmaceutically acceptable salts thereof are prepared by a process which comprises: a) reacting a compound of the formula (II):
  • R 12 is as defined in Formula (I), in the presence of a base; or c) reacting a compound of the formula (V):
  • R 1 ' is R 1 as defined in claim 1, except that the substituents on the R 1 group do not include tetrazolyl-5-yl, OH, or CO 2 H
  • 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 glyme
  • the reaction between a compound of formula (II) and a compound of formula (IV) is performed in the presence of a base, such as piperidine, in a suitable solvent, such as toluene, at a temperature of about 80°C to about 110°C preferably at about 100°C.
  • a base such as piperidine
  • a suitable solvent such as toluene
  • Formula (V) compounds are prepared from formula (II) compounds.
  • the aldehyde group of formula (II) compounds are treated with the lithium derivative of a substimted ethyl or methyl ester.
  • These lithio derivatives are prepared from the reaction of lithium diisopropylamide in a suitable solvent, preferably
  • R 1 -(CH 2 ) n - group is incorporated onto the A 1 -A 6 ring by reaction with a
  • R 1 -(CH 2 ) n - halide mesylate or acetate, such as 4-carbomethoxybenzyl bromide or methyl 4-bromomethylnaphthalene-1 carboxylate, in the presence of a suitable acid acceptor, such as sodium alkylate, potassium or sodium carbonate, or a metal hydride, preferably sodium hydride, at a reaction temperature of about 25°C to about 100°C, preferably at about 50°C.
  • a suitable acid acceptor such as sodium alkylate, potassium or sodium carbonate
  • a metal hydride preferably sodium hydride
  • the various formula (II) aldehyde compounds, or the hydroxymetyl precussors thereof, may be prepared employing the methods detailed in the publications hereinbelow and reference should be made to such publications for their disclosure, which are incorporated herein by reference.
  • the hydroxymethyl precussors thereof may be oxidized to the formula (II) aldehyde compounds by treatment with a suitable reagent, such as anhydrous chromic acid-silica gel in tetrahydrofuran or, preferably, with activated magnese dioxide, in a suitable solvent, such as benzene, or, preferably, methylene chloride.
  • 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.
  • a suitable inorganic or organic acid in an aqueous miscible solvent such as ethanol
  • an aqueous immiscible solvent when the acid is soluble therein, such as ethyl ether or chloroform
  • suitable acids are maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic,
  • Pharmaceutically acceptable base addition salts of compounds of Formula (I) are prepared by known methods from organic and inorganic bases, including nontoxic alkali metal and alkaline earth bases, for example, calcium, lithium, sodium, and potassium hydroxide; ammonium hydroxide, and nontoxic organic bases, such as triethylamine, butylamine, piperazine, meglumine, choline, diethanolamine, and tromethamine.
  • nontoxic alkali metal and alkaline earth bases for example, calcium, lithium, sodium, and potassium hydroxide
  • ammonium hydroxide such as triethylamine, butylamine, piperazine, meglumine, choline, diethanolamine, and tromethamine.
  • Angiotensin II antagonist activity of the compounds of Formula (I) is assessed by in vivo and in vivo methods.
  • In vitro antagonist activity is determined by the ability of the compounds to compete with 125 I-angiotensin II for binding to vascular angiotensin II receptors and by their ability to antagonize the contractile response to angiotensin II in the isolated rabbit aorta.
  • In vivo activity is evaluated by the efficacy of the compounds to inhibit the pressor response to exogenous angiotensin II in conscious rats and to lower blood pressure in a rat model of renin dependent hypertension.
  • the radioligand binding assay is a modification of a method previously described in detail (Gunther et al., Circ. Res.42:278, 1980).
  • a particular fraction from rat mesenteric arteries is incubated in Tris buffer with 80 pM of 125 I- angiotensin II with or without angiotensin II antagonists for 1 hour at 25°C.
  • the incubation is terminated by rapid filtration and receptor bound 125 I-angiotensin II trapped on the filter is quantitated with a gamma counter.
  • the potency of angiotensin II antagonists is expressed as the 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. Cumulative
  • concentration response curves to angiotensin II are performed in the absence of antagonist or following a 30-minute incubation with antagonist.
  • Antagonist disassociation constants (Kg) are calculated by the dose ratio method using the mean effective concentrations. Inhibition of pressor response to
  • 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 following the administration of the compounds intravenously or orally. The dose of compound needed to reduce mean arterial pressure by 30 mm Hg (IC 30 ) is used as an estimate of potency.
  • the intraocular pressure lowering effects employed in this invention may be measured by the procedure described by Watkins, et al., J. Ocular Pharmacol..1 (2):161-168 (1985).
  • 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 compositions adapted include solutions, suspensions, ointments, and solid inserts.
  • Typical pharmaceutically acceptable carriers are, for example, water, mixtures of water and water-miscible solvents such as lower alkanols or vegetable oils, and water soluble ophthalmologically acceptable non-toxic polymers, for example, cellulose derivatives such as methyl cellulose.
  • the pharmaceutical preparation may also contain non-toxic auxiliary substances such as emulsifying, preserving, wetting, and bodying agents, as for example, polyethylene glycols; antibacterial components, such as quarternary ammonium compounds; buffering ingredients, such as alkali metal chloride; antioxidants, such as sodium metabisulfite; and other conventional ingredients, such as sorbitan monolaurate.
  • 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.
  • Doses of the compounds of Formula (I) in a pharmaceutical dosage unit as described above will be an efficacious, nontoxic quantity selected from the range of .01 - 200 mg/kg of active compound, preferably 1 - 100 mg/kg.
  • the selected dose is administered to a human patient in need of angiotensin II receptor antagonism from 1-6 times daily, orally, rectally, topically, by injection, or continuously by infusion.
  • Oral dosage units for human administration preferably contain from 1 to 500 mg of active compound.
  • lower dosages are used for parenteral administration.
  • Topical formulations contain the active compound in an amount selected from 0.0001 to 0.1 (w/v%), preferably from 0.0001 to 0.01.
  • an amount of active compound from between 50 ng to 0.05 mg, preferably 50 ng to 5 mg, is applied to the human eye.
  • the method of this invention of antagonizing angiotensin II receptors in mammals, including humans, comprises administering to a subject in need of such antagonism an effective amount of a compound of Formula (I).
  • the method of this invention of producing antihypertensive activity and the method of treating congestive heart failure, glaucoma, and renal failure comprise administering a compound of Formula (I) to a subject in need thereof an effective amount to produce said activity.
  • Contemplated equivalents of Formula (I) compounds are compounds otherwise corresponding thereto wherein substiments have been added to any of the unsubstituted positions of the Formula (I) compounds provided such compounds have the pharmaceutical utility of Formula (I) compounds.
  • Examples 2-8 in Table I are prepared following the proceure of Example 1, replacing 5-n-butyl-1-(4-carboxomethyoxphenyl)methyl]pyrrole-2-carboxaldehyde with the appropriate Formula (II) heterocyclic aldehyde compounds. (See the specification on page 10 for the preparation of these aldehydes).
  • Example 1 The procedure of Example 1 is followed replacing 5-n-butyl-1-(4- carboxomethoxphenyl)methyl]pyrrole-2-carboxaldehyde with 5-n-butyl-1-[(4- carbomethoxynaphthyl)methyl]pyrrole-2-carboxaldehyde, which is prepared by the methods disclosed in EP Publication No. 323 841, replacing t-butyl 4'- bromomethylbiphenyl-2-carboxylate with methyl 4-bromomethylnaphthalene-1- carboxylate (Can J. Chem., 52:2629 (1981)).
  • Examples 10-16 in Table II are prepared following the procedure of Example 9, replacing 5-n-butyl-1-(4-carboxomethyoxphenyl)methyl]pyrrole-2- carboxaldehyde with the appropriate Formula (II) heterocyclic aldehyde
  • An oral dosage form for administering orally active Formula (I) compounds is produced by screening, mixing and filling into hard gelatin capsules the ingredients in proportions, for example, as shown below. Ingredients Amounts
  • sucrose calcium sulfate dihydrate and orally active Formula (I) compounds are mixed and granulated with a 10% gelatin solution.
  • the wet granules are screened, dried, mixed with the starch, talc and stearic acid, screened and compressed into a tablet.
  • a topical opthamological solution for administering Formula (I) compounds is produced by mixing under sterile conditions the ingredients in proportions, for example, as shown below. Ingredients Amounts

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte à des antagonistes du récepteur de l'angiotensine II ayant la formule (I) et qui sont utiles dans le traitement de l'hypertension, de l'insuffisance cardiaque congestive, de l'insuffisance rénale et du glaucome, ainsi qu'à des compositions pharmaceutiques renfermant ces antagonistes, et à des procédés d'utilisation de ces composés afin d'obtenir un effet antagoniste du récepteur de l'angiotensine II chez les mammifères.
PCT/US1994/003478 1993-03-31 1994-03-30 Composes chimiques Ceased WO1994022830A1 (fr)

Applications Claiming Priority (2)

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US4073393A 1993-03-31 1993-03-31
US08/040,733 1993-03-31

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WO1994022830A1 true WO1994022830A1 (fr) 1994-10-13

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5958968A (en) * 1995-08-02 1999-09-28 Smithkline Beecham Corporation Endothelin receptor antagonists
US6545031B1 (en) 1995-08-02 2003-04-08 Smithkline Beecham Corporation Endothelin receptor antagonists
US7109228B2 (en) 2001-04-10 2006-09-19 Agouron Pharmaceuticals, Inc. Pyrazole derivatives
US7141585B2 (en) 2000-07-07 2006-11-28 Agouron Pharmaceuticals, Inc. Pyrazole derivatives
EP1503986B1 (fr) * 2001-12-21 2015-09-30 Cytokinetics, Inc. Compositions et methodes permettant de traiter l'insuffisance cardiaque

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4792567A (en) * 1987-06-09 1988-12-20 Fmc Corporation Acaricidal aryl arylthien-2-yl ethenes
US5053073A (en) * 1986-04-17 1991-10-01 Imperial Chemical Industries Plc Thiophene derivatives useful as fungicidal, insecticidal or plant growth regulating agents

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5053073A (en) * 1986-04-17 1991-10-01 Imperial Chemical Industries Plc Thiophene derivatives useful as fungicidal, insecticidal or plant growth regulating agents
US4792567A (en) * 1987-06-09 1988-12-20 Fmc Corporation Acaricidal aryl arylthien-2-yl ethenes

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5958968A (en) * 1995-08-02 1999-09-28 Smithkline Beecham Corporation Endothelin receptor antagonists
US5969151A (en) * 1995-08-02 1999-10-19 Smithkline Beecham Corporation Endothelin receptor antagonists
US6096897A (en) * 1995-08-02 2000-08-01 Smithkline Beecham Corporation Endothelin receptor antagonists
US6353116B1 (en) 1995-08-02 2002-03-05 Smithkline Beecham Corporation Endothelin receptor antagonists
US6482956B2 (en) 1995-08-02 2002-11-19 Smithkline Beecham Corporation Endothelin receptor antagonists
US6545031B1 (en) 1995-08-02 2003-04-08 Smithkline Beecham Corporation Endothelin receptor antagonists
US7141585B2 (en) 2000-07-07 2006-11-28 Agouron Pharmaceuticals, Inc. Pyrazole derivatives
US7109228B2 (en) 2001-04-10 2006-09-19 Agouron Pharmaceuticals, Inc. Pyrazole derivatives
US8063044B2 (en) 2001-04-10 2011-11-22 Pfizer Inc. Pyrazole derivatives
EP1503986B1 (fr) * 2001-12-21 2015-09-30 Cytokinetics, Inc. Compositions et methodes permettant de traiter l'insuffisance cardiaque

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