WO1997022341A1 - Antagonistes du recepteur d'endotheline - Google Patents

Antagonistes du recepteur d'endotheline Download PDF

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Publication number
WO1997022341A1
WO1997022341A1 PCT/US1996/020739 US9620739W WO9722341A1 WO 1997022341 A1 WO1997022341 A1 WO 1997022341A1 US 9620739 W US9620739 W US 9620739W WO 9722341 A1 WO9722341 A1 WO 9722341A1
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WO
WIPO (PCT)
Prior art keywords
methoxy
compound
butyl
imidazol
subject
Prior art date
Application number
PCT/US1996/020739
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English (en)
Inventor
Juan Ignacio Luengo
Jia-Ning Xiang
Original Assignee
Smithkline Beecham Corporation
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 Corporation filed Critical Smithkline Beecham Corporation
Priority to JP9523085A priority Critical patent/JP2000502104A/ja
Priority to EP96945082A priority patent/EP0868180A4/fr
Priority to US08/952,796 priority patent/US6258596B1/en
Publication of WO1997022341A1 publication Critical patent/WO1997022341A1/fr

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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
    • C07D405/06—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
    • 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
    • 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
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • 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
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to novel N-phenyl imidazole derivatives, pharmaceutical compositions contaiiiing these compounds and their use as endothelin receptor antagonists.
  • Endothelin is a highly potent vasoconstrictor peptide syn esized and released by the vascular endothehum. Endothelin exists as three isoforms, ET-1, ET-2 and ET-3. [Unless otherwise stated "endothelin” shall mean any or all of e 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 hypertension, acute myocardial infarction, subarachnoid hemorrhage, atherosclerosis, and patients with uraemia undergoing dialysis.
  • 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 is involved in the regulation of renal function and is involved in a variety of renal disorders including acute renal failure, cyclosporine nephrotoxicity, radio contrast induced renal failure and chronic renal failure.
  • the cerebral vasculature is highly sensitive to both the vasodilator and vasoconstrictor effects of endothelin. Therefore, 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, Circ. Res.. 65: 1193-1200, 1989) coronary vasospasm (Fukuda e l.. Eur. J. Pharm. 165 : 301 -304, 1989 and L ⁇ scher, Circ. 83: 701, 1991) heart failure, proliferation of vascular smooth muscle cells, (Takagi. Biochem & Biophvs. Res. Commu ⁇ .: 168: 537-543, 1990, Bobek e aL, Am. J. Phvsiol.
  • 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, 1991).
  • Endothelin may play a role in the pathogenesis of interstitial pulmonary fibrosis and associated pulmonary hypertension, Glard et al.. Third International Conference on Endothelin, 1993, p.
  • ARDS Adult Respiratory Distress Syndrome
  • Endothelin has been associated with the induction of hemorrhagic and necrotic damage in the gastric mucosa (Whittle et al.. Br. J. Pharm. 95: 1011-1013, 1988); Raynaud's phenomenon, Cinniniello et al.. Lancet 337: 114-115, 1991); Crohn's Disease and ulcerative colitis, Munch e al.. Lancet. Vol. 339, p. 381; Migraine (Edmeads, Headache, Feb.
  • Endothelin stimulates bom bone resorption and anabolism and may have a role in the coupling of bone remodeling. Tatrai et al. Endocrinology. Vol. 131, p. 603-607.
  • Endothelin has been reported to stimulate the transport of sperm in the uterine cavity, Casey et al.. J. Clin. Endo and Metabolism. Vol. 74, No. 1, p. 223- 225, therefore endothelin antagonists may be useful as male contraceptives.
  • Endothelin modulates the ovarian/menstrual cycle, Kenegsberg, J. of Clin. Endo. and Met.. Vol. 74, No. 1, p. 12, and may also play a role in the regulation of penile vascular tone in man, Lau e al.. Asia Pacific J. of Pharm.. 1991, 6:287-292 and Tejada et al.. J. Amer. Phvsio. Soc. 1991, H1078-H1085. Endothelin also mediates a potent contraction of human prostatic smooth muscle, Langenstroer et al.. J. Urology. Vol. 149, p. 495-499.
  • endothelin receptor antagonists would offer a unique approach toward the pharmacotherapy of hypertension, renal failure, ischemia induced renal failure, sepsis-endotoxin induced renal failure, prophylaxis and/or treatment of radio- contrast induced renal failure, acute and chronic cyclosporin induced renal failure, cerebrovascular disease, myocardial ischemia, angina, heart failure, asthma, pulmonary hypertension, pulmonary hypertension secondary to intrinsic pulmonary disease, 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 for prevention of restenosis, diabetes, preclampsia of pregnancy, bone remodeling, kidney transplant, male contraceptives, infertility and priaprism and benign prostatic hypertrophy.
  • This invention comprises the compounds (E)-3-[[2-Butyl-l-[2-[(2- hydroxymethylphenyl)methoxy-4-methoxy]phenyl]- 1 H-imidazol-5-yl]-2-(2- methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid; (E)-3-[2-Butyl-l-[2-[N-(phenylsulfonyl)]methylenecarbamoyl]-4-methoxyphenyl]- lH-i ⁇ dazol-5-yl]-2-[(2-memoxy ⁇ ,5-memyleneo oxyphenylmethyl]-2-propenoic acid; (E)-3-[2-Butyl- 1 -[2-(2carboxybenzylmethylether)-4-methoxyphenyl]- 1H- irr ⁇ dazol-5-yl]-2-[(2-memoxy-4,5-memylenedioxyphenylmethyl]-2
  • This invention further constitutes a method for antagonizing endothelin receptors in an animal, including humans, which comprises adrninistering to an animal in need thereof an effective amount of a compound of the invention.
  • the compounds of this invention are:
  • the invention also comprises 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, benign prostatic hypertrophy, pulmonary hypertension, migraine, stroke, cerebrovascular vasospasm, myocardial ischemia, angina, heart failure, atherosclerosis, and as an adjunct in angioplasty for prevention of restenosis.
  • a compound of the invention or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals it is normally formulated in accordance wim standard pharmaceutical practice as a pharmaceutical composition.
  • Compounds ofthe invention and their pharmaceutically acceptable salts may be administered in a standard manner for the treatment of the indicated diseases, for example orally, parenterally, sub-lingually, transdermally, rectally, via inhalation or via buccal adn_unistration.
  • a syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with a flavouring or colouring agent.
  • a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with a flavouring or colouring agent.
  • 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.
  • composition is in the form of a capsule
  • any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell.
  • composition is in the form of a soft gelatin shell capsule any pharmaceutical carrier routinely used for preparing dispersions or 97/22341 PC17US96/20739
  • suspensions may be considered, for example aqueous gums, celluloses, silicates or oils and are incorporated in a soft gelatin capsule shell.
  • Typical parenteral compositions consist of a solution or suspension of the compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil, or sesame oil.
  • 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 dichlorodifluoromethane or tricblorofluoromethane.
  • a typical suppository formulation comprises a compound of the invention 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 Kg, and preferably from 1 mg to 100 mg/Kg, and each dosage unit for parenteral administration contains suitably from 0.1 mg to 100 mg, of a compound of the invention 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 the invention.
  • the daily dosage regimen for oral administration is suitably about 0.01 mg/Kg to 40 mg/Kg, of a compound of the invetnion 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 invetnion 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 HCl 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 MgCl2, pH 7.5; aliquotted with small vials and frozen in liquid nitrogen.
  • 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 supernatant was removed and centrifuged at 40,000 xg for 30 min. at 4°C. The resulting pellet was resuspended as explained above for cerebellum and kidney cortex. Approximately 10 mg of membrane protein was used for each tube in binding experiments. B) rl25 ⁇ rET-l Binding Protocol
  • [125rjrfT_- binding to membranes from rat cerebellum (2-5 mg protein/assay tube) or kidney cortex (3-8 mg protein/assay tube) were measured after 60 minutes incubation at 30°C in 50 mM Tris HCl, 10 mM MgCl2, 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.
  • [ ⁇ T]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 (rniUimolar): NaCl, 112.0; KCl, 4.7; KH2PO4, 1.2;
  • Tissue bath solutions are maintained at 37°C and aerated continuously with 95% O2/ 5% CO2. 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 response. Only one concentration-response curve to ET-1 is generated in each tissue. ET receptor antagonists are added to paired tissues 30 min prior to the initiation of the concentration-response to contractile agonists. ET-1 induced vascular contractions are expressed as a percentage of the response elicited by 60 mM KCl for each individual tissue which is determined at the beginning of each experiment. Data are expressed as the mean ⁇ S.E.M. Dissociation constants (K5) of competitive antagonists were determined by the standard method of Arunlakshana and Schild.
  • Example 1(d) 0.055 mol
  • the mixture was stirred at reflux for 3 days.
  • After removing the solvent flash chromatography of the residue (silica gel, 5% methanol/dichloromethane) afforded the title compound as a dark solid (11.7 g,
  • a compound ofthe invention (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 No. 4 in a suitable mixer/blender.
  • 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 conversion to wet granules.
  • Step 3 The wet mass is converted to granules by passing it through an oscillating granulator using a No. 8 mesh (2.38 mm) screen.
  • Step 4 The wet granules are then dried in an oven at 140°F (60°C) until dry.
  • Step 5 The dry granules are lubricated with ingredient No. 5.
  • Step 6 The lubricated granules are compressed on a suitable tablet press.
  • Parenteral Formulation A pharmaceutical composition for parenteral a ⁇ rninistration is prepared by dissolving an appropriate amount of a compound of the invention 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)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Urology & Nephrology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouveaux dérivés de N-phényle imidazole, des compositions pharmaceutiques contenant ces composés et leur utilisation en tant qu'antagonistes du récepteur d'endothéline.
PCT/US1996/020739 1995-05-22 1996-12-20 Antagonistes du recepteur d'endotheline WO1997022341A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP9523085A JP2000502104A (ja) 1995-12-21 1996-12-20 エンドセリン受容体アンタゴニスト
EP96945082A EP0868180A4 (fr) 1995-12-21 1996-12-20 Antagonistes du recepteur d'endotheline
US08/952,796 US6258596B1 (en) 1995-05-22 1996-12-20 Variants of apolipoprotein A-I

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US900995P 1995-12-21 1995-12-21
US60/009,009 1995-12-21

Publications (1)

Publication Number Publication Date
WO1997022341A1 true WO1997022341A1 (fr) 1997-06-26

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Application Number Title Priority Date Filing Date
PCT/US1996/020739 WO1997022341A1 (fr) 1995-05-22 1996-12-20 Antagonistes du recepteur d'endotheline

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EP (1) EP0868180A4 (fr)
JP (1) JP2000502104A (fr)
WO (1) WO1997022341A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003086390A1 (fr) * 2002-04-12 2003-10-23 Pfizer Japan Inc. Composes imidazole servant d'agents anti-inflammatoires et analgesiques
WO2009132889A1 (fr) * 2008-04-30 2009-11-05 Nestec S.A. Produits contenant des acides phénoliques décarboxylés dérivés des acides chlorogéniques du café, et utilisations associées

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4760150A (en) * 1986-04-28 1988-07-26 Hodogaya Chemical Co., Ltd. Bis(methylenedioxyphenyl)imidazoles
US5538991A (en) * 1994-09-14 1996-07-23 Merck & Co., Inc. Endothelin antagonists bearing 5-membered heterocyclic amides
US5559105A (en) * 1992-07-17 1996-09-24 Smithkline Beecham Corporation Endothelin receptor antagonists

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0403158A3 (fr) * 1989-06-14 1991-12-18 Smithkline Beecham Corporation Acides imidazolyl-alcénoiques
DE69034103T2 (de) * 1989-06-14 2004-07-15 Smithkline Beecham Corp. Imidazoalkensäure
EP0563238B1 (fr) * 1990-12-14 2002-05-22 Smithkline Beecham Corporation Acides imidazolyl-alcenoiques
DE69526738T2 (de) * 1994-09-02 2003-02-06 Smithkline Beecham Corp Endothelin-rezeptor-antagonisten

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4760150A (en) * 1986-04-28 1988-07-26 Hodogaya Chemical Co., Ltd. Bis(methylenedioxyphenyl)imidazoles
US5559105A (en) * 1992-07-17 1996-09-24 Smithkline Beecham Corporation Endothelin receptor antagonists
US5538991A (en) * 1994-09-14 1996-07-23 Merck & Co., Inc. Endothelin antagonists bearing 5-membered heterocyclic amides

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0868180A4 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003086390A1 (fr) * 2002-04-12 2003-10-23 Pfizer Japan Inc. Composes imidazole servant d'agents anti-inflammatoires et analgesiques
US6956050B2 (en) 2002-04-12 2005-10-18 Pfizer, Inc. Imidazole compounds as anti-inflammatory and analgesic agents
WO2009132889A1 (fr) * 2008-04-30 2009-11-05 Nestec S.A. Produits contenant des acides phénoliques décarboxylés dérivés des acides chlorogéniques du café, et utilisations associées

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Publication number Publication date
EP0868180A1 (fr) 1998-10-07
JP2000502104A (ja) 2000-02-22
EP0868180A4 (fr) 1999-08-04

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