EP0676959A1 - Antagonistes des recepteurs de l'endotheline - Google Patents

Antagonistes des recepteurs de l'endotheline

Info

Publication number
EP0676959A1
EP0676959A1 EP94904877A EP94904877A EP0676959A1 EP 0676959 A1 EP0676959 A1 EP 0676959A1 EP 94904877 A EP94904877 A EP 94904877A EP 94904877 A EP94904877 A EP 94904877A EP 0676959 A1 EP0676959 A1 EP 0676959A1
Authority
EP
European Patent Office
Prior art keywords
indole
alkyl
carboxylic acid
compound
hydrogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP94904877A
Other languages
German (de)
English (en)
Other versions
EP0676959A4 (fr
Inventor
John Duncan Elliott
Jack Dale Leber
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of EP0676959A1 publication Critical patent/EP0676959A1/fr
Publication of EP0676959A4 publication Critical patent/EP0676959A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—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
    • C07D405/02—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
    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—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
    • C07D405/02—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
    • 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

Definitions

  • the present invention relates to novel indole derivatives, pharmaceutical compositions containing these compounds and their use as endothelin receptor
  • Endothelin is a highly potent
  • vasoconstrictor peptide synthesized and released by the vascular endothelium exists as three
  • endothelin shall mean any or all of the isoforms of endothelin].
  • Endothelin has profound effects on the cardiovascular system, and in particular, the coronary, renal and cerebral circulation. Elevated or abnormal release of endothelin is associated with smooth muscle contraction which is involved in the pathogenesis of cardiovascular, cerebrovascular, respiratory and renal pathophysiology. Elevated levels of endothelin have been reported in plasma from patients with essential
  • endothelin has pronounced effects on blood pressure and cardiac output.
  • An intravenous bolus injection of ET (0.1 to 3 nmol/kg) in rats causes a transient, dose-related depressor response (lasting 0.5 to 2 minutes) followed by a sustained, dose-dependent rise in arterial blood pressure which can remain elevated for 2 to 3 hours following dosing. Doses above 3 nmol/kg in a rat often prove fatal.
  • Endothelin appears to produce a preferential effect in the renal vascular bed. It produces a marked, long-lasting decrease in renal blood flow, accompanied by a significant decrease in GFR, urine volume, urinary sodium and potassium excretion. Endothelin produces a sustained antinatriuretic effect, despite significant elevations in atrial natriuretic peptide. Endothelin also stimulates plasma renin activity.
  • ET may be an important mediator of cerebral vasospasm, a frequent and often fatal consequence of subarachnoid hemorrhage.
  • ET also exhibits direct central nervous system effects such as severe apnea and ischemic lesions which suggests that ET may contribute to the development of cerebral infarcts and neuronal death.
  • ET has also been implicated in myocardial ischemia (Nichols et al. Br. J. Pharm. 99: 597-601, 1989 and Clozel and Clozel, Cire. Res., 65: 1193-1200, 1989) coronary vasospasm (Fukuda et al., Eur. J. Pharm. 165: 301-304, 1989 and L ⁇ scher, Circ. 83: 701, 1991) heart failure, proliferation of vascular smooth muscle cells, (Takagi, B-iochem & Biophys . Res. Commun.; 168: 537-543, 1990, Bobek et al ., Am. J. Physiol.
  • endothelin has been found to be a potent constrictor of isolated mammalian airway tissue including human bronchus (Uchida et al., Eur J. of Pharm. 154: 227-228 1988, LaGente, Clin. Exp. Allergy 20: 343- 348, 1990; and Springall et al ., Lancet, 337: 697-701,
  • Kidney Int, 37: 1487-1491, 1990 and endotoxin shock and other endotoxin induced diseases (Biochem, Biophys, Res. Commun., 161: 1220-1227, 1989, Acta Physiol. Scand. 137: 317-318, 1989).
  • endothelin receptor antagonists would offer a unique approach toward the pharmacotherapy of hypertension, renal failure, cerebrovascular disease, myocardial ischemia, angina, heart failure, asthma, atherosclerosis, Raynaud's phenomenon, ulcers, sepsis, migraine, glaucoma, endotoxin shock, endotoxin induced multiple organ failure or disseminated intravascular coagulation, cyclosporin-induced renal failure and as an adjunct in angioplasty and prevention of restenosis.
  • This invention comprises indole derivatives represented by Formula (I) and pharmaceutical
  • compositions containing these compounds, and their use as endothelin receptor antagonists which are useful in the treatment of a variety of cardiovascular and renal diseases including but not limited to: hypertension, acute and chronic renal failure, cyclosporine induced nephrotoxicity, stroke, cerebrovascular vasospasm, myocardial ischemia, angina, heart failure and
  • This invention further constitutes a method for antagonizing endothelin receptors in an animal, including humans, which comprises administering to an animal in need thereof an effective amount of a compound of Formula (I).
  • R 1 is -X(CH 2 ) n Ar or -X(CH 2 ) n R 8 or
  • R 2 is hydrogen, Ar or (c) ;
  • P 1 is -X (CH 2 ) n R 8 ;
  • P 2 is -X (CH 2 ) n R 8 , or -XR 9 Y;
  • R 3 and R 5 are independently hydrogen, R 11 , OH, C 1-8 alkoxy, S(O) q R 11 , N(R 6 ) 2 , Br, F, I, Cl, CF 3 , NHCOR 6 , -R 11 CO 2 R 7 , -XR 9 -Y, XY or -X(CH 2 ) n R 8 wherein the methylene groups of -X(CH 2 ) n R 8 may be unsubstituted or substituted by one or more -(CH 2 ) n Ar groups;
  • R 4 is hydrogen, Ar, R 11 , OH, C 1-5 alkoxy,
  • R 6 is independently hydrogen or C 1-4 alkyl
  • R 7 is independently hydrogen, C 1-6 alkyl or (CH 2 ) n Ar;
  • R 8 is hydrogen, R 11 , CO 2 R7, CO 2 C(R7) 2 O(CO)XR 7 , -N(R 7 )SO 2 R 7 , PO 3 (R 7 ) 2 ; SO 2 NR 7 R 11 , CONR 7 SO 2 R 11 ,
  • R 9 is C 1-10 alkyl, C 2-10 alkenyl or phenyl all of which may be unsubstituted or substituted by one or more OH, N(R 6 ) 2 , COOH, halogen or XC 1- 5 alkyl;
  • R 10 is R 3 or R 4 ;
  • R 11 is C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl all of which may be unsubstituted or substituted by one or more OH, CH 2 OH, N(R 6 ) 2 or halogen;
  • X is (CH 2 ) n , O, NR 6 or S(O) q ;
  • Y is CH 3 or -X(CH 2 ) n Ar
  • Ar is:
  • B is -CH 2 - or -O-;
  • q is zero, one or two
  • n is an integer from 0 to six;
  • n 1, 2 or 3;
  • the dotted line indicates the optional presence of a double bond; or a pharmaceutically acceptable salt thereof; provided that when the optional double bond is present there is no P 1 or R 10 and further provided that X is not oxygen in the definition of R 1 .
  • alkyl, alkenyl, alkynyl and alkoxy groups may be straight or branched.
  • halogen is used to mean iodo, fluoro, chloro or bromo.
  • Alkyl groups may be substituted by one or more halogens up to
  • R 9 and R 11 may be monovalent or divalent depending on their position in order to conform with the general laws of chemistry.
  • the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active form. All of these compounds and diastereoisomers are contemplated to be within the scope of the present invention.
  • Preferred compounds are those wherein R 1 is X(CH 2 ) n Ar, (Ar is (a) or (b)), dihydrobenzofuranyl, benzodioxanyl, cyclohexyl, or C 1-4 alkyl; R 2 is (a), (b), C 1-4 alkyl, indolyl or hydrogen; R 3 and R 5 are
  • R 4 is hydrogen, OH, C 1-5 alkoxy, halogen, C 1-4 alkyl, N(R 6 ) 2 , NH(CO)CH 3 or S(O) p C 1-5 alkyl;
  • P 1 and P 2 are independently hydrogen, CO 2 H or tetrazole;
  • Ar is (a), (b), phenyl, or pyridyl; and
  • X is (CH 2 ) n or oxygen.
  • R 3 is hydrogen or -X(CH 2 ) n R 8 , R 11 CO 2 R 7 ; R 4 and R 5 are
  • a palladium (0) catalyst such as tetrakis (triphenylphosphine) palladium (0)
  • a solvent such as toluene/methanol
  • a base such as aqueous sodium carbonate
  • Aryl boronic acids of Formula (4) may be prepared by transmetallation of aryl halides of Formula (6):
  • Ar-Hal (6) wherein Hal is Cl, Br or I, with an alkyllithium, such as n-butyllithium in a solvent such as dry tetrahydrofuran at low temperature (-40°--78°C) followed by quenching with a trialkylborate, such as tri-isopropylborate, then treatment with an acid such as aqueous hydrochloric.
  • alkyllithium such as n-butyllithium in a solvent such as dry tetrahydrofuran at low temperature (-40°--78°C)
  • a trialkylborate such as tri-isopropylborate
  • R 2 -(CH 2 ) n -Hal (7) in a suitable solvent such as dimethylformamide or hexamethylphosphoramide in the presence of a suitable base such as sodium hydride affords compounds of Formula (8), n is not zero.
  • esters of Formula (8) Saponification of esters of Formula (8) with aqueous sodium hydroxide in a solvent such as ethanol or
  • compounds of Formula (5) may be obtained by coupling of compound of type (3) with an aryl stannane derivative of Formula (10):
  • Ar-SnX 3 (10) in the presence of a palladium (0) catalyst such as tetrakis (triphenylphosphine) palladium (0) in a solvent such as dioxan or dimethylformamide at approximately 100°C in the presence of anhydrous lithium chloride.
  • a palladium (0) catalyst such as tetrakis (triphenylphosphine) palladium (0) in a solvent such as dioxan or dimethylformamide at approximately 100°C in the presence of anhydrous lithium chloride.
  • Aryl stannanes of Formula (10) may be prepared by
  • n is not 0.
  • n is not zero, may be obtained by coupling of compound (12) with an aryl stannane derivative of Formula (10) in the presence of a palladium (0) catalyst such as
  • compounds of Formula (5) may be prepared by a process which comprises: alkylation of an ester of acetoacetic acid (13)
  • a suitable solvent such as acetonitrile and a base such as 1,8 diazabicyclo[5.4.0]undec-7-ene to afford compounds of Formula (15).
  • tetrahydrofuran may be used as the solvent and sodium hydride as the base for the alkylation.
  • pharmaceutically acceptable salts may be administered in a standard manner for the treatment of the indicated diseases, for example orally, parenterally, sublingually, transdermally, rectally, via inhalation or via buccal administration.
  • compositions which are active when given orally can be formulated as syrups, tablets, capsules and lozenges.
  • a syrup formulation will be formulated as
  • composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used.
  • examples of such carriers include magnesium stearate, terra alba, talc, gelatin, agar, pectin, acacia, stearic acid, starch, lactose and sucrose.
  • any routine encapsulation is suitable, for example using the
  • composition in the form of a soft gelatin shell capsule any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be
  • Typical parenteral compositions consist of a solution or suspension of the compound or salt in a sterile aqueous or non-aqueous carrier optionally
  • a parenterally acceptable oil for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil, or sesame oil.
  • compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as
  • a typical suppository formulation comprises a compound of Formula (1) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogues.
  • a binding and/or lubricating agent for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogues.
  • Typical transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
  • the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer to themselves a single dose.
  • Each dosage unit for oral administration contains suitably from 0.1 mg to 500 mg, and preferably from 1 mg to 100 mg, and each dosage unit for parenteral administration contains suitably from 0.1 mg to 100 mg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free acid.
  • Each dosage unit for intranasal administration contains suitably 1-400 mg and preferably 10 to 200 mg per person.
  • a topical formulation contains suitably 0.01 to 1.0% of a compound of Formula (I).
  • administration is suitably about 0.01 mg/Kg to 40 mg/Kg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free acid.
  • the daily dosage regimen for parenteral administration is suitably about 0.001 mg/Kg to 40 mg/Kg, of a compound of the Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free acid.
  • the daily dosage regimen for intranasal administration and oral inhalation is suitably about 10 to about 500 mg/person.
  • the active ingredient may be administered from 1 to 6 times a day, sufficient to exhibit the desired activity.
  • Rat cerebellum or kidney cortex were rapidly dissected and frozen immediately in liquid nitrogen or used fresh.
  • the tissues 1-2 g for cerebellum or 3-5 g for kidney cortex, were homogenized in 15 mis of buffer containing 20mM Tris HC1 and 5mM EDTA, pH 7.5 at 4°C using a motor-driven homogenizer.
  • the homogenates were filtered through cheesecloth and centrifuged at 20,000 x g for 10 minutes at 4°C. The supernatant was removed and centrifuged at 40,000 xg for 30 minutes at 4°C.
  • the resulting pellet was resuspended in a small volume of buffer containing 50 mM Tris, 10 mM MgCl 2 , pH 7.5;
  • the membranes were diluted to give 1 and 5 mg of protein for each tube for cerebellum and kidney cortex in the binding assay.
  • Freshly isolated rat mesenteric artery and collateral vascular bed were washed in ice cold saline (on ice) and lymph nodes were removed from along the major vessel. Then, the tissue was homogenized using a polytron in buffer containing 20 mM Tris and 5mM EDTA, pH 7.5 at 4°C in 15 ml volume for ⁇ 6 gm of mesenteric artery bed. The homogenate was strained through cheesecloth and centrifuged at 2,000 xg for 10 min. at 4°C. The
  • MgCl 2 MgCl 2 , 0.05% BSA, pH 7.5 buffer in a total volume of 100 ml.
  • Membrane protein was added to tubes containing either buffer or indicated concentration of compounds.
  • [ 125 I]ET-1 (2200 Ci/mmol) was diluted in the same buffer containing BSA to give a final concentration of 0.2-0.5 nM ET-1. Total and nonspecific binding were measured in the absence and presence of 100 nM unlabelled ET-1.
  • Rat aorta are cleaned of connective tissue and adherent fat, and cut into ring segments approximately 3 to 4 mm in length.
  • Vascular rings are suspended in organ bath chambers (10 ml) containing Krebs-bicarbonate solution of the following composition (millimolar):
  • Tissue bath solutions are maintained at 37°C and aerated continuously with 95% 0 2 / 5% CO 2 . Resting tensions of aorta are maintained at 1 g and allowed to equilibrate for 2 hrs., during which time the bathing solution is changed every 15 to 20 min. Isometric tensions are recorded on Beckman R-611 dynographs with Grass FT03 force-displacement transducer. Cumulative concentration-response curves to ET-1 or other contractile agonists are constructed by the method of step-wise addition of the agonist. ET-1 concentrations are increased only after the previous concentration produces a steady-state contractile
  • ET-1 induced vascular contractions are expressed as a percentage of the response elicited by 60 mM KC1 for each individual tissue which is determined at the beginning of each experiment. Data are expressed as the mean ⁇ S.E.M. Dissociation constants (K b ) of
  • EXAMPLE 3 3-(3,4-MethylenedioxyphenylAl-(4-methoxybenzyl)indole-2- carboxylic acid.
  • the title compound was prepared by alkylation of methyl 3-(2- carboethoxymethoxy-4-methoxyphenyl) indole-2-carboxylate (100 mg, 0.27 mmol) with 6-chloropiperonyl chloride (55 mg, 0.27 mmol) followed by saponification using methods previously described in example 2a then crystallized from EtOAc as the bis (dicyclohexylamine) salt (97 mg, 41%);
  • the title compound was prepared by alkylation of ethyl 5- benzyloxy-3-(3,4-methylenedioxyphenyl)indole-2- carboxylate with 2-carboethoxymethoxy-4-methoxybenzyl chloride followed by saponification using methods
  • EXAMPLE 7 1-(2-Carhoxymethoxy-4-methoxvbenzyl)-3-(3,4- methylenedioxyphenyl)-5-(prop-1-yloxy)indole-2-carboxylic acid. a) Ethyl 1-(2-carboethpxymethoxy-4-methoxybenzyl)-5- hvdroxy-3-(3,4-methylenedioxyphenyl)indole-2-carboxylate.
  • the title compound was prepared from ethyl 1-(2- carboethoxymethoxy-4-methoxybenzyl)-3-(3,4- methylenedioxyphenyl)-5-(prop-1-yloxy)indole-2- carboxylate (50 mg, 0.085 mmol) by the method given in example 3d (33mg, 73%); m.p. 190 - 191° C.
  • the title compound was prepared from ethyl 1-(2-carboethoxymethoxy-4-methoxybenzyl)-5-hydroxy-3- (3,4-methylenedioxyphenyl) indole-2-carboxylate (150mg, 0.26 mmol) and ethyl bromoacetate (55 mg, 0.33 mmol) by the method given in example 7b (119 mg, 69%).
  • incorporating compounds of the present invention can be prepared in various forms and with numerous excipients. Examples of such formulations are given below.
  • a compound of formula I (1 mg to 100 mg) is aerosolized from a metered dose inhaler to deliver the desired amount of drug per use.
  • Step 1 Blend ingredients No. 1, No. 2, No. 3 and
  • Step 2 Add sufficient water portion-wise to the blend from Step 1 with careful mixing after each addition. Such additions of water and mixing until the mass is of a consistency to permit its converion to wet granules.
  • Step 3 The wet mass is converted to granules by
  • Step 4 The wet granules are then dried in an oven at
  • Step 5 The dry granules are lubricated with
  • Step 6 The lubricated granules are compressed on a suitable tablet press.
  • a pharmaceutical composition for parenteral administration is prepared by dissolving an appropriate amount of a compound of formula I in polyethylene glycol with heating. This solution is then diluted with water for injections Ph Eur. (to 100 ml). The solution is then steriled by filtration through a 0.22 micron membrane filter and sealed in sterile containers.

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Health & Medical Sciences (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne des dérivés d'indole de formule (1) dans laquelle les substituants ont la notation ci-définie. Les composés sont utiles dans des procédés s'opposant aux effets des récepteurs de l'endothéline, de traitement de l'hypertension, de traitement de l'insuffisance rénale et de traitement de maladies cérébro-vasculaires. L'invention concerne également des compositions pharmaceutiques.
EP94904877A 1992-12-22 1993-12-21 Antagonistes des recepteurs de l'endotheline. Withdrawn EP0676959A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US99546692A 1992-12-22 1992-12-22
US995466 1992-12-22
PCT/US1993/012435 WO1994014434A1 (fr) 1992-12-22 1993-12-21 Antagonistes des recepteurs de l'endotheline

Publications (2)

Publication Number Publication Date
EP0676959A1 true EP0676959A1 (fr) 1995-10-18
EP0676959A4 EP0676959A4 (fr) 1996-01-03

Family

ID=25541843

Family Applications (1)

Application Number Title Priority Date Filing Date
EP94904877A Withdrawn EP0676959A4 (fr) 1992-12-22 1993-12-21 Antagonistes des recepteurs de l'endotheline.

Country Status (7)

Country Link
EP (1) EP0676959A4 (fr)
JP (1) JPH08504826A (fr)
CN (1) CN1096513A (fr)
AU (1) AU5873594A (fr)
MX (1) MX9400071A (fr)
WO (1) WO1994014434A1 (fr)
ZA (1) ZA939516B (fr)

Cited By (3)

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US7557135B2 (en) 2005-05-27 2009-07-07 Wyeth Inhibitors of cytosolic phospholipase A2
US7605156B2 (en) 2001-12-03 2009-10-20 Wyeth Methods for the use of inhibitors of cytosolic phospholipase A2
US7713964B2 (en) 2001-12-03 2010-05-11 Wyeth Llc Methods for treating asthmatic conditions

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JPH08504826A (ja) 1996-05-28
EP0676959A4 (fr) 1996-01-03
CN1096513A (zh) 1994-12-21
ZA939516B (en) 1994-06-06
WO1994014434A1 (fr) 1994-07-07
AU5873594A (en) 1994-07-19

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