WO1997022341A1 - Endothelin receptor antagonists - Google Patents

Endothelin receptor antagonists 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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Prior art keywords
methoxy
compound
butyl
imidazol
subject
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PCT/US1996/020739
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French (fr)
Inventor
Juan Ignacio Luengo
Jia-Ning Xiang
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Smithkline Beecham Corporation
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Publication date
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to JP9523085A priority Critical patent/JP2000502104A/en
Priority to EP96945082A priority patent/EP0868180A4/en
Priority to US08/952,796 priority patent/US6258596B1/en
Publication of WO1997022341A1 publication Critical patent/WO1997022341A1/en

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    • 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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Abstract

Novel N-phenyl imidazole derivatives, pharmaceutical compositions containing these compounds and their use as endothelin receptor antagonists are described.

Description

ENDOTHELIN RECEPTOR ANTAGONISTS
FIELD OF INVENTION
The present invention relates to novel N-phenyl imidazole derivatives, pharmaceutical compositions contaiiiing these compounds and their use as endothelin receptor antagonists.
Endothelin (ET) 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.
In vivo, 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. These findings suggest that 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. Studies have shown that in vivo, 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 Lϋscher, Circ. 83: 701, 1991) heart failure, proliferation of vascular smooth muscle cells, (Takagi. Biochem & Biophvs. Res. Commuπ.: 168: 537-543, 1990, Bobek e aL, Am. J. Phvsiol. 258:408-C415, 1990) and atherosclerosis, (Nakaki et al.. Biochem. & Biophvs. Res. Co mun. 158: 880-881, 1989, and Leπnan et al.. New Eng. J. of Med. 325: 997-1001, 1991). Increased levels of endothelin have been shown after coronary balloon angioplasty (Kadel et al.. No. 2491 Circ. 82: 627, 1990).
Further, 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. 34 and ARDS (Adult Respiratory Distress Syndrome), Sanai et aj., Supra, p. 112. 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. 1991 p 127); Sepsis (Weitzberg et al.. Circ. Shock 33: 222-227, 1991; Pittet et al.. Ann. Surg. 213: 262-264, 1991), Cyclosporin-induced renal failure or hypertension (Eur. J. Pharmacol.. 180: 1 1- 192, 1990. Kidnev Int. 37: 1487-1491, 1990) and endotoxin shock and other endotoxin induced diseases (Biochem. Biophvs. Res. Commun.. 161: 1220-1227, 1989, Acta Phvsiol. Scand. 137: 317-318, 1989) and iiiilammatory skin diseases. (Clin Res. 41:451 and 484, 1993).
Endothelin has also been implicated in preclampsia of pregnancy. Clark et ah, Am. J. Obstet. Gvnecol. March 1992, p. 962-968; Kamor et al.. N. Eng. J. of Med.. Nov 22, 1990, p. 1486-1487; Dekker et al.. Eur J. Ob. and Gvn. and Rep. Bio. 40 (1991) 215-220; Schiff e Am. J. Ostet. Gvnecol. Feb 1992, p. 624-628; diabetes mellitus, Takahashi et al.. Diabetologia (1990 33:306-310; and acute vascular rejection following kidney transplant, Watschinger et al.. Transplantation Vol. 52, No. 4, pp. 743-746.
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.
Thus, 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.
SUMMARY OF THE INVENTION
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-iι dazol-5-yl]-2-[(2-memoxy^,5-memyleneo oxyphenylmethyl]-2-propenoic acid; (E)-3-[2-Butyl- 1 -[2-(2carboxybenzylmethylether)-4-methoxyphenyl]- 1H- irrήdazol-5-yl]-2-[(2-memoxy-4,5-memylenedioxyphenylmethyl]-2-propenoic acid; (E)-3-[[2-Butyl- 1 -[2-[( 1 , 1 -dioxo-2H- 1 ,2,4-benzothiadiazin)3-yl)]methoxy-4- methoxyjphenyl]- 1 H-imidazol-5-yl]-2-(2-methoxy-4,5- methylenedioxyphenyl)methyl]-2-propenoic acid; (E)-3-[2-Butyl-l-[2- [[[(phenyls fonylammo)carbonyl]me ylamino]methyl]-4-methoxyphenyl]- 1 H- imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenylmethyl]-2-propenoic acid; and (E)-3-[2-Butyl- 1 -[2-(2-carboxyphenoxymethyl)-4-methoxyphenyl]- 1H- imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenylmethyl]-2-propenoic acid; 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.
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. DETAILED DESCRIPTION OF THE LNVENΗON
The compounds of this invention are:
(E)-3-[[2-Butyl- 1 -[2-[(2-hydroxymethylphenyl)methoxy-4-methoxy]phenyl]- 1H- imidazol-5-yl]-2-(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid;
Figure imgf000007_0001
(E)-3-[2-Butyl-l-[2-[N-(phenylsulfonyl)]methylenecarbamoyl]-4-methoxyphenyl]- lH-imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenylmethyl]-2-propenoic acid;
Figure imgf000007_0002
(Ε)-3-[2-Butyl-l-[2-(2carboxyberιzyhιe ylemer)-4-me oxyphenyl]-lH-imidazol- 5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenylmethyl]-2-propenoic acid;
Figure imgf000008_0001
(E)-3- [[2-Butyl- 1 - [2-[( 1 , 1 -dioxo-2H- 1 ,2,4-benzothiadiazin)3-y l)]methoxy-4- me oxy]phenyl]-lH-imidazol-5-yl]-2-(2-methoxy-4,5- methylenedioxyphenyl)methyl]-2-propenoic acid;
Figure imgf000008_0002
(E)-3-[2-Butyl- 1 -[2-[[[(phenylsulfonylarnmo)carbonyl]memylamino]methyl]-4- memoxyρhenyl]-lH-imidazol-5-yl]-2-[(2-methoxy-4,5- methy lenedioxypheny lmethyl] -2-propenoic acid; and (E)-3-[2-Butyl-l-[2-(2-carboxyphenoxymemyl)-4-memoxyphenyl]-lH-iιnidazol-5- yl]-2-[(2-methoxy-4,5-methylenedioxyphenylmethyl]-2-propenoic acid; and pharmaceutically acceptable salts thereof.
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. In order to use 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.
Compounds of the invention and their pharmaceutically acceptable salts which are active when given orally can be formulated as syrups, tablets, capsules and lozenges. 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. Where the 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. Where the 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. Where the 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.
Typical 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.
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.
Preferably 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.
No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the present invention.
The biological activity of the compounds of the invention are demonstrated by the following tests:
I. Binding Assay
A) Membrane Preparation
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) rl25τrET-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. After the incubation, the reactions were stopped with 3.0 ml cold buffer containing 50 mM Tris and 10 mM MgCl2, pH 7.5. Membrane bound radioactivity was separated from free ligand by filtering through Whatman GF/C filter paper and washing the filters 5 times with 3 ml of cold buffer using a Brandel cell harvester. Filter papers were counted in a gamma counter with an efficiency of 75%.
TJ. In Vitro Vascular Smooth Muscle Activity
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;
MgSO 1.2; CaCl2, 2.5; NaHCO3, 25.0; and dextrose, 11.0. 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
Figure imgf000013_0001
(EV3-F 2-Butyl- 1 -r2-(2-hvdroxymethylphenyl)methoxy-4-methoxy1phenyl- 1 H- imida7.ol-5-vn-2-r(2-methoxy-4.5-methylenedioxyphenyl methyl]-2-propenoic acid
a) 2.4-Dimethoxynitrobenzene
To a solution of sodium methoxide in methanol (freshly prepared by adding 50.0 g (2.17 mol) of sodium, in portions, to 1.5 1 of methanol at 0 °C) was added 2,4- dichloro-nitrobenzene (95.0 g, 0.495 mol) in methanol (100 ml). After refluxing for 3 days, the reaction mixture was cooled in an ice bath and filtered, the precipitate was washed with water and dried (Na2SO4). The title compound was collected as a yellow solid (83.0 g, 91%). b) 2-Hvdroxy-4-methoxynitrobenzene
To a solution of dimethoxynitrobenzene (30.0 g, 0.163 mol) in 99% methanesulfonic acid (300 ml) was added ^/-methionine (31.8 g, 0.212 mol) and the mixture was stirred at rt for 24 h. The solution was poured onto ice and stirred with water (1.51). The precipitate was filtered and washed with water. The title compound was collected as a yellow solid (23.1 g, 84%).
c) 2-Methoxymethoxy-4-methoxynitrobenzene
To a solution of hydroxynitrobenzene (21.2 g, 0.125 mol) in DMF (250 ml) was added sodium hydride (4.5 g, 0.188 mol) at 0°C under argon. The mixture was allowed to stir at 0°C for 1 h, then bromomethyl methy lether (22 ml, 0.150 mol) was added. After stirring for 18 h at rt the reaction was quenched with water. The mixture was extracted with ethyl acetate (3 x 30 ml) and the combined organic extracts were washed with brine and dried (Na2SO4). Removal ofthe solvent under reduce pressure gave the title compound as a brown oil (23.4 g, 88%).
d) 2-Methoxymethoxy-4-methoxy aniline
To a solution of nitrobenzene (10.0 g, 0.047 mol) in ethanol (50 ml) was added 10% Pd C (1.0 g) and the mixture was shaken under hydrogen atmosphere at 55 mm Hg for 24 h at rt. The mixture was filtered through a pad of Celite and the filtrate was dried (Na2SO4). Removal ofthe solvent afforded the title compound as a brown oil (8.2 g, 95%).
e) 1-Methoxypentaimidate hydrochloride
To a solution of valeronitrile (72.3 g, 0.872 mol) in methanol (75 ml) was bubbled through gaseous HCl until saturation. The solution was then placed in the freezer for three days. The precipitate was filtered and was rinsed several times with ether. The title compound was collected as a white solid (130.0 g, 99%).
f) 1 -Methoxypentaimidate
To a suspension of the HCl salt (16.5 g, 0.108 mol) in anhydrous ether (50 ml) was added triethylamine (15.5 ml, 0.110 mol). The mixture stirred at rt for 18 h under argon and then the precipitate was filtered. The filtrate was concentrated to 80% dryness and the crude product was used in the next reaction without further purification.
g) N-(2-Methoxymethoxy-4-methoxyphenyl)-pentanamidine
To a solution of 1 -methoxypentaimidate (11.3 g, 0.109 mol) in dichloromethane (20 ml) was added freshly prepared 2-methoxymethoxy-4-methoxy aniline ( 10.0 g,
0.055 mol) of Example 1(d) and 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,
85%).
h) 2-Butyl- 1 -(2-methoxymethoxy-4-rnethoxyphenyl)- 1 H-imidazol-5- carboxaldehvde
To a solution of N-(2-Methoxyme oxy-4-methoxyphenyl)-pentanamidine (5.10 g, 0.019 mol) in iso-propanol (50 ml) was added triethylamine (3.20 ml, 0.0230 mol), acetic acid (1.4 ml, 0.025 mol) and 2-bromo-l,3-dicarboxaldehyde propane (3.20 g, 0.0211 mol), respectively. The mixture was stirred at reflux for 5 h and then cooled to room temperature. After filtration and concentration, The crude residue was dissolved in ethyl acetate and washed with 10% sodium bicarbonate solution, water, dried (Na2SO_ι). After removing the solvent under reduced pressure, flash chromatography ofthe residue (silica gel, 25% ethyl acetate/hexane) afforded the title compound as a dark yellow oil (3.85 g, 63%).
i ) 1 -Methoxy- 3.4-methylenedioxybenzene
To a solution of sesamol (10.0 g, 0.072 mol) in DMF (50 ml) was added sodium hydride (2.08 g, 0.087 mol) at rt under argon. After stirring for 1 h the rnixture was treated with Iodomethane (13.5 ml, 0.216 mol) and stirred for another 18 h. Upon the removal of the solvent the residue was extracted with ethyl acetate and washed with water, dried (Na2SO4) and concentrated to afford the title compound as a dark brown oil (10.5 g, 96%).
j) 2-Methoxy-4.5-methylenedioxy benzaldehyde
To a solution of phosphorous oxychloride (3.0 ml, 0.033 mol) in DMF (10 ml) was added a solution of l-methoxy-3,4-methylenedioxybenzene ( 2.0 g, 0.013 mol) in DMF (2 ml) at 0 °C. After stirring at 60 °C for 18 h the mixture was cooled to 0 °C and then poured into water (500 ml). The precipitate was filtered and dried. The title compound was collected as a yellow sohd (2.20 g, 92%).
k Diethyl 2-(4.5-methylenedioxy-l-methoxybenzyliden)-malonate
A solution of the 2-methoxy-4,5-methylenedioxy benzaldehyde (16.0 g, 0.089 mol), diethyl malonate (15.0 ml, 0.090 mol), piperidine (4.4 ml, 0.044 mol) and acetic acid (2.5 ml, 0.045 mol) in benzene (75 ml) stirred at reflux, equipped with a Dean-Stark apparatus, for 24 h. Upon removal of the solvent the crude residue was extracted with ethyl acetate and washed with 10% sodium carbonate solution, water, dried (Na2SO_t). After removing the solvent, flash chromatography of the residue (silica gel, 25% ethyl acetate/hexane) provided the title compound as a yellow solid (26.0 g, 91%). 1) Diethyl 2-(4.5-methylenedioxy- 1 -methoxybenzylVmalonate
To a solution of the diethyl 2-(4,5-methylenedioxy-l-methoxybenylidene)-malonate (23.4 g, 0.073 mol) in ethanol (100 ml) was added sodium borohydride (2.8 g, 0.073 mol) and the mixture was stirred at rt for 5 h. The reaction was quenched with water and extracted with ethyl acetate (3x200 mL). The combined organic extracts were dried (Na2SO4) and evaporated to afford the title compound as an oil ( 20.3 g, 86%).
m Ethyl hydrogen 2-(4.5-methylenedioxy-l-memoxybenyl)-malonate
To a solution of the diethyl 2-(4,5-methylenedioxy-l-methoxybenyl)-malonate (20.0 g, 0.066 mol) of in ethanol (50 ml) was added a solution of potassium hydroxide (3.5 g, 0.066 mol) in water (25 ml). The solution stirred at reflux for 6 h. After concentrating the aqueous layer was washed with ether and acidified with concentrated HCl to pH 1 and extracted with ethyl acetate. The organic extracts were dried (Na2SO4) and concentrated to afford the title compound as a yellow solid (17.3 g, 89%).
n) Ethyl-(Ε)-3-r2-butyl-l-(2-(methoxymethoxy)-4-methoxyphenyl')l-lH-imidazol- 5-vn-2-r(2-methoxy-4.5-methylenedioxy)phenylmethyll-2-propenoate
A solution of l-(2-methoxymethoxy-4-methoxyphenyl)-lH-imidazol-5- carboxaldehyde ( 1.00 g, 2.976 mmol) of Example 3(b), ethyl hydrogen 2-(4,5- methylenedioxy-l-methoxybenzyl)-malonate (2.64 g, 8.930 mmol), piperidine(0.15 ml, 1.488 mmol) and acetic acid (0.085 ml, 1.488 mmol) in benzene (50 ml) was equipped with a Dean-Stark apparatus, and stirred at reflux for 24 h. The solvent was removed and the crude residue was extracted with ethyl acetate and washed with 10% sodium carbonate solution, water, dried (Na2SO4). After removing the solvent flash chromatography ofthe residue (silica gel, 50% ethyl acetate/hexane) yielded the title compound as a brown oil (1.03 g, 63%). Anal. (C3oH36N2θg) calcd: C, 65.18; H, 6.58; N, 5.07. found: C, 64.85; H, 6.20; N, 4.93.
o) Ethyl-(E 3-r2-butyl- 1 -(2-hvdroxy-4-methoxyphenvni- 1 H-imidazol-5-yl1-2-r(2- methoxy-4.5-methylenedioxyphenyl)methyIl-2-propenoate
To a solution of the ethyl-(E)-3-[2-butyl-l-(2-(methoxymethoxy)-4- methoxyphenyl)]-lH-imidazol-5-yl]-2-[(2-methoxy-4,5- methylenedioxy)phenylmethyl]-2-proρenoate (1.00 g, 1.811 mmol) in ethanol (25 ml) was added a catalytic amount of concentrated HCl . After stirring at reflux for 5 h the solvent was removed and the residue was extracted with ethyl acetate and washed with sodium bicarbonate (satd.), dried (Na2SO4). After removing the solvent flash chromatography of the residue (silica gel, 50% ethyl acetate/hexane) gave the title compound as a brown oil (0.856 g, 93%). Anal. (C28H32N2O7) calcd: C, 66.10; H, 6.36; N, 5.51. found: C, 65.92; H, 6.01; N, 5.12.
p) Ethyl (E)-3-r2-butyl- l-r2-(2-hvdroxymethylphenyl)methoxy-4-methoxylphenyl- lH- imidazol-5-yl1-2-f(2-methoxy-4.5-methylenedioxyphenyl)methyll-2-propenoate
To a solution of ethyl (E)-3-[2-butyl-l-(2-hydroxy-4-methoxyphenyl]-lH- imidazol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoate (0.380g, 0.776 mmol) and 2-hydroxymethylbenzyl bromide (0.190g, 0.931 mmol) in DMF (10 mL) was added sodium hydride (0.024g, 0.996 mmol) and the mixture was allowed to stir at room temperature for 18 h under an argon atmosphere. The reaction was quenched with water and extracted with ethyl acetate. The organic extracts were washed with water, brine and dried (Na2SO ). Purification was completed by flash chromatography (silica gel, 50% ethyl acetate/hexane) afforded the title compound as an oil (0.402 g, 83%): 1H NMR (250 MHz, CDC13) 7.49 (m, IH), 6.70 (s, IH), 6.52 (s, IH), 6.42 (s, IH), 5.78 (s, 2H), 5.10 (d, 2H), 4.51 (s, 2H), 4.10 (q, 2H), 3.82 (s, 3H), 3.80 (s, 3H), 2.38 (t, 2H), 1.50 (hextet, 2H), 1.18 (sextet, 2H), 0.75 (t, 3H).
q. (E)-3-r2-Butyl-l-r2-(2-hvdroxymethylphenyl)methoxy-4-methoχy]phenyl-lH- imidazol-5-yl1-2-r(2-methoxy-4.5-methylenedioxyphenvI)methyl1-2-propenoic acid
To a solution of ethyl (E)-3-[2-butyl-l-[2-(2-hydroxymethylphenyl)methoxy-4- methoxy Jpheny 1- 1 H-imidazol-5 -yl]-2- [(2-methoxy-4 ,5 - methylenedioxyphenyl)methyl]-2-propenoate (0.500g, 0.920 mmol) in methanol (10 mL) was added sodium hydroxide (0.065g, 1.170 mmol) in water (5 mL). The reaction was allowed to stir at reflux for 5 h. The organic solvent was removed and the aqueous layer was washed with ether. The aqueous layer was acidified by concentrated ΗC1 and extracted with ethyl acetate. The combined organic extracts were dried (Na SO4) and evaporated to afford a white sohd. Crystallization from methanol yielded the title compound as a white solid (0.486 g, 88%): 1H NMR (400 MHz, CD3OD) 7.49 (s, IH), 7.41 (d, IH), 7.38- 7.08 (m, 3H), 7.00 (s, IH), 6.82 (d, IH), 6.61 (s, IH), 6.42 (s, IH), 5.79 (s, 2H), 4.58 (s, 2H), 3.91 (s, 3H), 3.85- 3.60 (m, 5H), 2.73 (t, 2H), 1.58 (hextet, 2H), 1.20 (sextet, 2H), 0.80 (t, 3H); MS (ESI) m/e 601.2 [M+HJ+; m.p.: 165- 170 C; Anal. (Cs^^Os) calcd.: C, 67.92; H, 6.05; N, 4.66. found: C, 67.63; H, 5.90; N, 4.60.
EXAMPLE 2
Figure imgf000020_0001
(ΕV3-r2-Butyl-l-r2-rN-(phenylsulfonyπ]methylenecarbamoyl1-4-methoxyphenyll- lH-in idazol-5-yll-2-r(2-methoxy-4.5-methylenedioxyphenylmethyl1-2-propenoic Acid
a) 2-Nitro-5-methoxybenzaldehyde To a solution of 2-nitro-5-hydroxybenzaldehyde ( 16.19 g, 0.097 mol, prepared by the procedure of Hornig, J. Amer. Chem. Soc, 1952, 74, 4572) in DMF (50 mL) was added sodium hydride (2.79 g, 0.116 mol) at room temperature under argon. After stirring for 30 min the mixture was treated with iodomethane (41.25 g, 0.29 mol) and stirred for another 18 h. The reaction mixture was suspended between water and ethyl acetate and the organic layer was washed with water, brine, dried (MgSOJ, filtered and concentrated to afford the title compound as a tan sohd (15.35 g, 87%): Η NMR (400 MHz, CDCL.) δ 10.5 (s, IH), 8.18 (d, IH), 7.33 (d, IH), 7.15 (dd, IH), 3.98 (s, 3H); MS(ESI) m/e 182 [M+H].
b) 2-Nitro-5-methoxybenzaldehyde ethylene acetal
A solution of 2-nitro-5-methoxybenzaldehyde (15.34 g, 0.085 mol), p- toluenesulfonic acid monohydrate (0.902 g, 0.0047 mol), benzene (400 mL), and ethylene glycol (91 mL), equipped with a Dean-Stark apparatus, was stirred and refluxed overnight under argon. The reaction was cooled to room temperature and poured with vigorous stirring into 1 L of 10% KjCO3. The organic layer was washed with 10% potassium carbonate (2x500 mL) and brine (500 ml containing 50 ml of 10% KjCOj), dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound as an orange oil (16.81 g, 88%): Η NMR (250 MHz, CDCL) δ 8.05 (d, IH), 7.3 (d, IH), 7.43 (dd, IH), 6.58 (s, IH), 4.05 (m, 4H), 3.9 (s, 3H); MS(ESI) m/e 226 [M+H].
c) 2-Amino-5 methoxybenzaldehyde ethylene acetal
To a solution of 2-nitro-5-methoxybenzaldehyde ethylene acetal (10.03 g, 0.045 mol) and sodium acetate (326 mg, 50% 7„ of PtO2 load) in ethyl acetate (75 mL) was added platinum oxide (652 mg, 6.5% 7„) and the mixture was stirred ovemight at room temperature under a balloon of hydrogen. The mixture was filtered through a pad of celite and the filtrate was dried over anhydrous sodium sulfate, concentrated to a brownish oil, and flash chromatographed (silica gel, Et,O) to afford the title compound as a yellow oil (5.89 g, 68%): Η NMR (400 MHz, CDCL,) δ 6.95 (d, IH), 6.78 (dd, IH), 6.65 (d, IH), 5.85 (s, IH), 4.15-4.05 (m, 4H), 3.91 (b s, 2H), 3.77 (s, 3H); MS(ESI) m/e 196 [M+H].
d) N-(2-(2- 1 ,3-ethylenedioxy)-4-methoxyphenyl)pentanamidine The titie compound was prepared from 2-amino-5-methoxybenzaldehyde ethylene acetal by the procedure described in Example 1(g) as a colorless oil (5.06g, 60%): lH NMR (400 MHz, CDCL,) δ 7.15 (d, IH), 6.88 (dd, IH), 6.75 (d, IH), 5.85 (s, IH), 4.12 (m, 2H), 4.0 (m, 2H), 3.82 (s, 3H), 2.32 (t, 2H), 1.7 (m, 2H), 1.45 (m, 2H), 0.95 (t, 3H); MS(ESI) m/e 279 [M+H].
e) 2-Butyl- 1-(2-(2- 1 ,3-ethylenedioxy)-4-methoxyphenyl)- lH-imidazol-5- carboxaldehyde
The title compound was prepared from N-(2-(2-l,3-ethylenedioxy)-4- methoxyphenyl)-pentanamidine by the procedure described in Example 1(h) as an orange oil (5.39 g, 90%): Η NMR (400 MHz, CDC13) δ 9.48 (s, IH), 7.85 (s,lH), 7.22 (d,lH), 7.12 (d, IH), 7.03 (dd, IH), 5.36 (s,lH), 3.90 (s,3H), 3.88-3.80 (m,4H), 2.52 (dt, IH), 2.40 (dt, IH), 1.7 (m. 2H), 1.3 (m,2H), 0.87 (t,3H); MS(ESI) m/e 331 [M+H}.
f) Ethyl (E)-3-[2-butyl- 1 -(2-(2- 1 ,3-ethylenedioxy)-4-methoxyphenyl)]- lH-imidazol- 5-yl]-2-[(2-methoxy-4,5-methylenedioxy)phenylmethyl]-2-propenoate
The title compound was prepared from 2-butyl- l-(2-(2-l, 3-ethylenedioxy )-4- methoxyphenyl)-lH-imidazol-5-carboxaldehyde by the procedure described in Example l(n) as a yellow solid (4.67 g, 63%): Η NMR (400 MHz, CDCl,).δ 7.25 (d, IH, J=3Hz), 7.14 (s, IH), 7.13 (s, IH), 7.09 (d, IH, J=9Hz), 7.03 (dd, IH, J=9Hz, 3Hz), 6.55 (s, IH), 6.46 (s, IH), 5.84 (m, 2H), 5.23 (s, IH), 4.13 (q, 2H), 3.94 (m, 2H), 3.91 (s, 3H), 3.9-3.8 (m, 4H), 3.84 (s, 3H), 2.5 (dt, IH), 2.3 (dt, IH), 1.65 (m, 2H), 1.3 (m, 2H), 1.15 (t, 3H), 0.85 (t, 3H); MS(ESI) m/e 565 [M+H].
g) Ethyl (E)-3- [2-butyl- 1 -(2-formyl-4-methoxyphenyl)]- 1 H-imidazol-5-yl]-2- [(2- ethoxy-4,5-methylenedioxyphcnyl)methyl]-2-propenoate
The compound ofExample 2(f) (2.24 g, 3.96 mmol) was dissolved in 88% formic acid (31.0 mL) and stirred overnight at rt. The reaction was neutralized by slow, dropwise addition of 10% NaHCO3, extracted into EtOAc, washed with water and brine, dried (Na-SO , and concentrated to give the title compound as a yellow oil (1.92 g, 93%): 'H NMR (400 Mhz, CDCL) δ 9.4 (s, IH), 7.57 (d, IH), 7.33 (dd, IH), 7.25 (s, IH), 7.22 (d,lH), 7.1 (s, IH), 6.57 (s, IH), 6.45 (s, IH), 5.89 (s, 2H), 4.12 (q, 2H), 3.98 (s, 3H), 3.85 (s, 3H), 3.84 (m, 2H), 2.43 (m, 2H), 1.6 (m, 2H), 1.25 (m, 2H), 1.18 (t, 3H), 0.82 (t, 3H); MS(ESI) m/e 521 [M+H].
h) Ethyl (E)-3- [2-butyl- l-(2-hydroxymethyl-4-methoxyphenyl)]- lH-imidazol-5-yl]- 2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoate
To a solution of ethyl (E)-3-[2-butyl-l-(2-formyl-4-methoxyphenyl)]-lH- iιrn^azol-5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoate (1.00 g, 1.93 mmol) in ethanol (25 mL) was added sodium borohydride (0.146 g, 3.86 mmol) and the mixture was stirred at room temperature for 1.0 h. The reaction was quenched with 5% HCl , extracted into EtOAc, washed with water and brine, dried (Na.SO4), and concentrated to afford the title compound as a white sohd (0.96 g, 96%): Η NMR (400 Mhz, CDCL) δ 7.27 (d, IH), 7.18 (s, IH), 7.09 (d,lH), 7.08 (s, IH), 6.95 (dd,lH), 6.57 (s, IH), 6.44 (s, IH), 5.85 (s, 2H), 4.2 (dd, 2H), 4.1 (q, 2H), 3.9 (s, 3H), 3.82 (s,3H), 3.8 (m,2H), 3.0 (br s, IH), 2.39 (m, 2H), 1.55 (m, 2H), 1.25 (m, 2H), 1.16 (t, 3H), 0.81 (t, 3H);MS(ESD m/e 523 [M+H].
i) Ethyl (E)-3-[2-butyl-l-[2-[N-(phenylsulfonyl)]methylenecarbamoyI]-4- methoxyphenyl]-lH-imidazol-5-yl]-2-[(2-methoxy-4,5- methylenedioxyphenyl)methyl]-2-propenoate To a solution of compound of Example 2(h) (0.216 g, 0.413 mmol) in benzene (2.0 mL) was added a solution of benzenesulfonyl isocyanate (0.227 g, 1.24 mmol) in benzene (0.5 mL) and the mixture was stirred at room temperature under argon for 1.0 h. The reaction was concentrated and the residue was suspended between EtOAc and water, dried over anhydrous sodium sulfate, concentrated and purified by flash chromatography (silica gel, 4%MeOH:CHCl3) to afford the title compound as a white foam (0.25 g, 86%): Η NMR (400 Mhz, CDCL,) δ 7 98 (m, 2H), 7.61 (m, IH), 7.52 (m,2H), 7.22 (s, IH), 7.16 (s, IH), 7.07 (d, 2H), 7.06 (d, IH), 7.00 (dd, IH), 6.54 (s, IH), 6.45 (s, IH) 5.87 (s, 2H), 4.80 (d, IH, J=12Hz), 4.56 (d, IH, J=12Hz), 4.18 (m, 2H), 3.85 (s, 3H), 3.83 (m, 2H), 3.81 (s, 3H), 2.3 (t, 2H), 1.48 (m, 2H), 1.20 (t, 3H), 1.18 (m, 2H), 0.77 (t, 3H); MS(ESI) m/e 706 [M+H].
j) (E)-3-[2-Butyl- l-[2-[N-(phenylsulfonyl)]methylenecarbamoyl]-4- meu^oxyphenyl]-lH-imidazol-5-yl]-2-[(2-methoxy-4,5- methylenedioxyphenylmethyl]-2-propenoic acid
The title compound was prepared from ethyl (E)-3-[2-butyl-l-[2-[N- (phenylsulfonyl)]methylenecarbamoyl]-4-memoxyphenyl]-lH-imidazol-5-yl]-2-[(2- methoxy-4,5-methylenedioxyphenylmethyl]-2-propenoic acid by the procedure described in Example l(q) as a pale yellow sohd (0.130 g, 56%): LH NMR (400 Mhz, CDCL) δ 7.91 (d, 2H), 7.57 (m, IH), 7.46 (m, 2H), 7.22 (s, IH), 7.15 (s, IH), 7.09 (d, IH), 7.01 (d, IH), 6.98 (dd, IH), 6.50 (s, IH), 6.44 (s, IH), 5.80 (d, 2H), 4.63 (q, 2H), 3.83 (s, 3H), 3.79 (m, 2H), 3.76 (s, 3H), 2.45 (m, IH), 2.22 (m, IH), 1.46 (m, 2H), 1.16 (m, 2H), 0.75 (t,3H); MS(ESI) m/e 678 [M+H].; mp: 108-110°C.
EXAMPLE 3
Figure imgf000024_0001
(E)-3-r2-Butyl-l-[2-(2-carboxybenzylmethyl etherl-4-methoxyphenyll-lH-imidazol- 5-vn-2f(2-methoxy-4.5-methylenedioxyphenylmethvn-2-propenoic Acid
a) Ethyl (E)-3- [2-butyl- l-[2-(2-carboxybenzylmethyl ether)^-methoxyphenyl]-lH- imidazol-5-yl]-2[(2-methoxy-4,5-methylenedioxyphenylmethyl]-2-propenoate
To a solution of ethyl (E)-3-[2-butyl-l-(2-hydroxymethyl-4- methoxyphenyl)]-lH-imidazol-5-yl]-2-[(2-methoxy-4,5- methylenedioxyphenylmethyl]-2-propenoate (0.1227 g, 0.235 mmol) (Example 2h) in dimethylformamide (1.0 mL) was added methyl-2-(bromomethyl) benzoate (0.081 g, 0.353 mmol) and sodium hydride (0.0085 g, 0.353 mmol) and the mixture was stirred at room temperature for 1.0 h. The reaction was quenched with water, extracted with EtOAc, washed with water and brine, dried (Na-SO , and purified by flash chromatography (silica gel 50/50 hexanes/EtOAc) to afford the title compound as a yellow sohd (0.070 g, 45%): Η NMR (250 MHz, CDCL) δ 7.92 (d, IH), 7.57(m, IH), 7.45 (m, IH). 7.31 (d, IH), 7.26 (d, IH), 7.15 (s, IH), 7.09 (d, IH), 7.08 (s, IH), 6.98 (dd, IH), 6.55 (s, IH), 6.40 (s,lH), 5.83 (s, 2H), 4.81 (dd, 2H), 4.20 (q, 2H), 4.10 (q, 2H), 3.90 (s, 3H), 3.85 (s, 3H),3.83 (s,3H), 3.80 (m, 2H), 2.38 (m, 2H), 1.6 (m, 2H), 1.25 (m, 2H), 1.15 (t.3H)), 0.8 (t, 3H); MS(ESI) m/e 671 [M+H].
b) (E)-3-[2-Butyl-l-[2-(2-carboxybenzylmethylether)-4-methoxyphenyl]-lH- irmdazol-5-yl]-2-[(2-methoxy-4,5-methyIenedioxyphenylmethyl]-2-propenic acid
The titie compound was prepared from ethyl-(E)-3-[2-butyl-l-[2-(2- carboxybenzylmethylether)-4-methoxyphenyl]-lH-imidazol-5-yl]-2-[(2-methoxy- 4,5-methylenedioxyphenylmethyl]-2-propenoate by the procedure described in Example l(q) as a yellow sohd (0.051 g, 82%): Η NMR (400 Mhz, CDCL) δ 4.89 (d, IH), J=13Hz), 4.68 (d, IH, J=13Hz), 4.23 (d, IH, J=13Hz), 4.10 (d, IH, J=13Hz), 3.82 (s, 3H), 3.76 (s, 3H), 0.76 (t, 3H); MS(ESI) m/e 629 [M+H]; mp 128- 130°C.
EXAMPLE 4
Figure imgf000025_0001
(Ε -3-rr2-But^l-l-I2-r(l.l-dioxo-2H-1.2.4-benzothiadiazin)3-vnimethoxy-4- methoxy1phenvIl-lH-imidazol-5-yl]-2-(2-methoxy-4.5- methylenedioxyphenv rnethvIl-2-propenoic Acid
a) o-Choroacetylaminobenzenesulfonamide 97/22341 PCI7US96/20739
The procedure by Raffa et al., II Farmaco, Ed. Sci, 1962, 17, 532 for the synthesis of 1,2,4-benzothiadiazine- 1,1 -dioxides was used: a solution of o- aminobenzenesulfonamide (1.7 g, 10 mmol) in DMF (5 mL) was treated with dropwise with chloroacetyl chloride (1.7 g, 15 mmol) in diethyl ether (10 mL) in the presence of MgO (0.2 g) at 10- 12 CC and the mixture stirred at that temperature for 30 min. The organic phase was decanted and the residue treated with 5% aqueous sodium bicarbonate to pH 7.5. The mixture was extracted with ethyl acetate and the organic layer washed with water, dried over anhydrous sodium sulfate and evaporated to yield the title compound (1.1 g, 44%): mp 137-138 °C.
b) 3-Chloromethyl-2H- 1 ,2,4-benzothiadiazine- 1 , 1 -dioxide
A mixture of compound of example 4(a) (170 mg, 0.7 mmol) and sodium hydroxide (100 mg, 2.5 mmol) in methanol (10 mL) was stirred for 15 min at room temperature. The mixture was diluted with water and acidified with hydrochloride acid to provide the title compound as a white crystalline material (100 mg): mp
230 °C; lU NMR (400 MHz, DMSO-α^) δ 7.83 (d, J = 7.9 Hz, 1 H), 7.71 (t, J = 7.8 Hz, 1 H), 7.49 (t, J = 7.8 Hz, 1 H), 7.40 (d, J = 8.0 Hz, 1 H), 4.51 (s, 2 H).
c) Ethyl (E)-3- [[2-Butyl- 1 -[2-[( 1 , 1 -dioxo-2H- 1 ,2,4-benzothiadiazin)3-yl)]methoxy- 4-methoxy]phenyl]- lH-imidazol-5-yl]-2-(2-methoxy-4,5- methylenedioxyphenyl)methyl]-2-propenoate
To a solution of ethyl (E)-3-[[2 -butyl- l-(2-hydroxy-4-methoxy)phenyl]-lH- imidazol-5-yl]-2-(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoate (254 mg, 0.1 mmol) and 3-chloromethyl-2H-l,2,4-benzothiadiazine- 1,1 -dioxide (345 mg, 1.5 mmol) in DMF (8 mL) was added tetrabutylammonium iodide (625 mg, 1.69 mmol) and potassium carbonate (345 mg, 2.5 mmol) and the resulting mixture was heated at 70 °C for 2.5 h. The reaction was then diluted with water, extracted with ethyl acetate and the organic layer washed with water, dried over anhydrous sodium sulfate and evaporated. Purification of the resulting oil by column chromatography (sihca gel, 80:20 hexane ethyl acetate provided the title compound (240 mg, 68%): *H NMR (400 MHz, CDC13) δ 7.90 (d, J = 7.9 Hz, 1 H), 6.67 (d, J= 2.4 Hz, 1 H), 6.39 (s, 1 H), 6.32 (s, 1 H), 5.64 (s, 1 H), 5.57 (s, 1 H), 4.82 (d, J = 12.5 Hz, 1 H), , 4.78 (d, J= 12.5 Hz, 1 H), 4.13 (q, J= 7.0 Hz, 1 H), 3.94 (s, 3 H), 3.82 (s, 2H), 3.78 (s, 3 H). 2.42 (t, J = 7.6 Hz, 2 H), 1.18 (q, J = 7.0 Hz, 3 H), 0.76 (q, J = 7.3 Hz, 3 H).
d) (E)-3-[[2-Butyl- 1 -[2-[( 1 , 1 -dioxo-2H- 1 ,2,4-benzothiadiazin)3-yl)]methoxy-4- methoxyjphenyl]- lH-imidazol-5-yl]-2-(2-methoxy-4,5- methylenedioxyphenyl)methyl]-2-propenoic Acid
A solution of compound ofExample 4(c) (240 mg, 0.33 mmol) and potassium hydroxide (252 mg, 4.5 mmol) in 10: 1 methanol/water (22 mL) was refluxed for 5 h under argon. The mixture was diluted with water, washed with ether and the aqueous layer was acidified with hydrochloride acid, and extracted with ethyl acetate. Evaporation of the solvent followed by recrystallization afforded the title compound (157 mg): mp 263-264 °C. Anal. Calcd for C3 H3 N4θ9S» 1.25 H2O: C, 58.56; H, 5.28; N, 8.04. Found: C, 58.44; H, 5.20; N, 7.79.
EXAMPLE 5
πEV3-r2-Butyl-l-12-rrr(phenylsulfonylamino carbonvIlmethylarninolmethyl1-4- methoxyphenyl]- lH-imidazol-5-yll-2-f(2-methoxy-4.5- methylenedioxyphenylmethyn-2-propenoic Acid mp 225-227 °C
EXAMPLE 6
(EV3-12-Bu l-l-r2-(2-carboxyphenoxymethyl -methoxyphenyll-lH-irnidazol-5- yll-2-r(2-methoxy-4.5-methylenedioxyphenylmethyl]-2-propenoic Acid mp >285 °C EXAMPLE 7 Formulations for pharmaceutical use incorporating compounds of the present invention can be prepared in various forms and with numerous excipients. Examples of such formulations are given below.
Inhalant Formulation
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.
Tablets/Ingredients Per Tablet
1. Active ingredient 40 mg
(Cpd of the invention)
2. Corn Starch 20 mg
33.. AAllggiinniicc aacciidd 20 mg
4. Sodium Alginate 20 mg
5. Mg stearate 1,3 m.g 2.3 mg
Procedure for tablets:
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 aάrninistration 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.

Claims

CLAIMS:
1. A compound which is chosen from the group consisting of:
(E)-3-[[2-Butyl-l-[2-[(2-hydroxymethylphenyl)methoxy-4-methoxy]phenyl]-lH- imidazoI-5-yl]-2-(2-methoxy-4,5-methylenedioxyphenyl)methyl]-2-propenoic acid;
(E)-3-[2-Butyl-l-[2-[N-(phenylsulfonyl)]methylenecarbamoyl]-4-methoxyphenyl]- lH-in3id^-Zθl-5-yI]-2-[(2-methoxy-4,5-methylenedioxyphenylmethyl]-2-propenoic acid;
(E)-3-[2-Butyl-l-[2-(2carboxyberizylmethylether)-4-methoxyphenyl]-lH-imidazol- 5-yl]-2-[(2-methoxy-4,5-methylenedioxyphenylmethyl]-2-propenoic acid;
(E)-3-[[2-Butyl- 1 -[2-[( 1 , 1 -dioxo-2H- 1 ,2,4-rjenzothiadiazin)3-yl)]methoxy-4- methoxy]phenyI]-lH-imidazol-5-yl]-2-(2-methoxy-4,5- methylenedioxyphenyl)methyl]-2-propenoic acid;
(E)-3-[2-Butyl-l-[2-[[[(phenylsulfonylaπc no)carbonyl]methylamino]methyl]-4- methoxyphenyl]- lH-imidazol-5-yl]-2-[(2-methoxy-4,5- methylenedioxyphenylmethyl]-2-propenoic acid; and
(E)-3-[2-Butyl- 1 -[2-(2-carboxyphenoxymethyl)-4-methoxyphenyI]- 1 H-imidazol-5- yl]-2-[(2-methoxy-4,5-methylenedioxyphenylmethyl]-2-propenoic acid.
2. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
3. A compound of claim 1 for use as an endothelin receptor antagonist.
4. A method of treatment of diseases caused by an excess of endothelin comprising administering to a subject in need thereof, an effective amount of an endothelin receptor antagonist of Claim 1.
5. A method of treating hypertension, renal failure or cerebrovascular disease which comprises administering to a subject in need thereof, an effective amount of a compound of Claim 1.
6. A method for the prophylaxis and treatment of radiocontrast induced renal failure which comprises administering to a subject in need thereof, an effective amount of a compound of Claim 1.
7. A method of treatment of benign prostatic hypertrophy which comprises administering to a subject in need thereof, an effective amount of a compound of Claim 1.
8. A method of treatment of congestive heart failure which comprises administering to a subject in need thereof, an effective amount of a compound of Claim 1.
9. A method of treatment of migraine which comprises administering to a subject in need thereof, an effective amount of a compound of Claim 1.
10. A method of preventing or treating restenosis which comprises administering to a subject in need thereof, an effective amount of a compound of
Claim 1.
11. A method of treatment of pulmonary hypertension which comprises administering to a subject in need thereof, an effective amount of a compound of Claim 1.
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