EP0559755A1 - Imidazoles 5-aryle substitues - Google Patents

Imidazoles 5-aryle substitues

Info

Publication number
EP0559755A1
EP0559755A1 EP92900730A EP92900730A EP0559755A1 EP 0559755 A1 EP0559755 A1 EP 0559755A1 EP 92900730 A EP92900730 A EP 92900730A EP 92900730 A EP92900730 A EP 92900730A EP 0559755 A1 EP0559755 A1 EP 0559755A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
compound
methyl
butyl
imidazol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP92900730A
Other languages
German (de)
English (en)
Other versions
EP0559755A4 (fr
Inventor
Richard Mcculloch Keenan
Tina Morgan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of EP0559755A1 publication Critical patent/EP0559755A1/fr
Publication of EP0559755A4 publication Critical patent/EP0559755A4/xx
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to new substituted 5-aryl imidazoles which are angiotensin II receptor antagonists and are useful in regulating hypertension induced or exacerbated by angiotensin II, and in the treatment of congestive heart failure, renal failure, and glaucoma.
  • This invention also relates to
  • compositions containing these compounds and methods for using these compounds as antagonists of angiotensin II, as antihypertensive agents and as agents for treating congestive heart failure, renal failure, and glaucoma.
  • angiotensin The class of peptide pressor hormone known as angiotensin is responsible for a vasopressor action that is implicated in the etiology of hypertension in man. Inappropriate activity of the renin-angiotensin systems appears to be a key element in essential hypertension, congestive heart failure and in some forms of renal disease.
  • angiotensin II AII
  • AII angiotensin II
  • the renin-angiotensin system by virtue of its participation in the control of renal sodium handling, plays an important role in cardiovascular hemeostasis.
  • AII antagonists are useful as agents for reducing and controlling elevated intraocular pressure, especially glaucoma, in mammals.
  • the compounds of this invention inhibit, block and antagonize the action of the hormone AII, and are
  • angiotensin induced hypertension congestive heart failure, renal failure and other disorders attributed to the actions of AII.
  • compounds of this invention are administered to mammals, the elevated blood pressure due to AII is reduced and other manifestations based en AII intercession are minimized and controlled.
  • Compounds of this invention are also expected to exhibit diuretic activity.
  • U.S. Patent 4,340,598 discloses imidazol-5-yl-acetic acids and imidazol-5-yl-propanoic acids. Specifically, the discloser includes 1-benzyl-2-n-butyl-5-chloroimidazole-4-acetic acid and 1-benzyl-2-phenyl-5-chloroimidazole-4-propanoic acid.
  • U.S. Patent 4,355,040 discloses substituted imidazole-5-acetic acid derivatives.
  • a compound specifically disclosed is 1-(2-chlorobenzyl)-2-n-butyl-4-chloroimidazole-5-acetic acid.
  • the disclosure includes 4-chloro-1-(4-methoxy-3-methylbenzy)-2-phenyl-imidazole-5-acetic acid.
  • Carin , et al., in EP 253 310 discloses certain 1-aralkyl-imidazoles. Examples include 2-n-butyl-5-chloro-1-(4-nitrobenzyl)imidazole-4-acetic acid and methyl 1-[2'-carboxybiphenyl-4-yl-methyl]-2-n-butyl-4-chloroimidazole-5-carboxylate.
  • R 1 is adamantylmethyl, or phenyl, biphenyl, or naphthyl, with each aryl group being unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C 1 -C 6 alkyl, nitro, CO 2 R 5 , C 1 -C 6 alkoxy, hydroxy, SC 1 -C 6 alkyl, SO 2 C 1 -C 6 alkyl, tetrazol-5-yl,
  • R 2 is C 2 -C- 10 alkyl, C 3 -C 10 alkenyl,
  • X is a single bond, S, NR 5 , or O;
  • n 0-4;
  • R 3 is hydrogen, Cl, Br, F, I , CHO, hydroxymethyl , C 1 -C 6 alkyl, NR 5 R 5 , CO 2 R 5 , CONR 5 R 5 , NO 2 , CN, phenyl, or W;
  • R 4 is CO 2 R 5 , CONR 5 R 5 , or tetrazol-5-yl
  • Z is hydrogen, Cl, Br, F, I, C 1 -C 6 alkyl
  • Y is a single bond or C 1 -C 6 alkyl, which is straight or branched;
  • W is C m F 2m+1 , wherein m is 1-4,;
  • each R independently is H or C 1 -C 6 alkyl
  • R 1 is phenyl unsubstituted or substitiuted by one to three substituents selected from chloro, fluoro, nitro, methyl, trifluoromethyl, methoxy, hydroxy, sulfonamido, sulfamyl, cyano, carboxy, carboC 1 -6 alkoxy, carbamoyl, or tetrazol-5-yl;
  • R 2 is C 2 -C 8 alkyl
  • X is a single bond or S
  • R 3 is hydrogen, chloro, fluoro, or trifluoromethyl
  • Z is hydrogen, Cl, Br, F, I, C 1 -C 4 akyl
  • alkyl, alkenyl, alkoxy, and alkynyl mean carbon chains which are branched or unbranched with the length of the chain determined by the discriptor preceding the term.
  • Particular compounds of the invention include, but are not limited to, the following:
  • the invention also relates to pharmaceutical compositions comprising a pharmaceutical carrier and an effective amount of a compound of Formula (I). Also included in the present invention are methods for antagonizing angiotensin II receptors which
  • imidazole is converted to 2-n-butylimidazole by reacting imidazole with triethylorthoformate and p-toluenesulfonic acid to give 1-diethoxyorthoamide imidazole and then treating with n-butyl lithium to give the 2-lithium derivative of the orthoamide and alkylating with n-butyl iodide in a suitable solvent, such as tetrahydrofuran (THF).
  • THF tetrahydrofuran
  • the 2-R 2 X-imidazole starting materials are reacted with trimethylsilylethoxymethyl (SEM) chloride to give 1- (trimethylsilyl)ethoxymethyl-2-R 2 X-imidazole.
  • SEM trimethylsilylethoxymethyl
  • the reaction is carried out, for example, in the presence of sodium hydride in a solvent such as dimethylformamide.
  • the 5-tributyltin derivatives are prepared by lithiation with, for example, butyllithium in a suitable solvent, preferably diethyl ether, followed by treatment of the lithio imidazole derivative with a tributyltin halide, preferably tri-N-butyltin chloride, at -10°C to 35°C, preferably at 25°C.
  • a tributyltin halide preferably tri-N-butyltin chloride
  • the 1-SEM-2-R 2 X-5-tributyltin-imidazole is coupled with an appropriately substituted benzoic acid ester having a leaving group, such as a halide or a trifluoromethane-sulfonyloxy group, for example, methyl 4-trifluoromethane-sulfonyloxybenzoate, in the presence of a phosphine ligand such as
  • t-BOC esters are alkylated and hydrolyzed with, for example, 2-chlorobenzyl-O-triflate in the presence of a suitable base, preferably diisopropylethylamine, in a suitable solvent, preferably methylene chloride, to afford the 1- (2-chlorophenyl)methylimidazole derivatives (esters).
  • the Formula (I) ester compounds are hydrolyzed to the corresponding Formula (I) carboxylic acid compounds, 1- R 1 (CH 2 ) n -2-R 2 X-5-benzo ⁇ c acid-imidazoles, using base, such as potassium hydroxide, lithium hydroxide, or sodium hydroxide, in a suitable solvent system, such as aqueous alcohols or diglyme.
  • base such as potassium hydroxide, lithium hydroxide, or sodium hydroxide
  • a suitable solvent system such as aqueous alcohols or diglyme.
  • substituent is substituted by hydroxy or the Z group is hydroxy are formed from Formula (I) compounds in which the R 1 group is substituted by C 1 -C 4 alkoxy cr the Z substituent is C 1 -C 4 alkoxy using an ether-cleaving reagent, such as boron tribromide or hydrobromic acid.
  • an ether-cleaving reagent such as boron tribromide or hydrobromic acid.
  • substituent is substituted by carboxy or the Z group is carboxy are formed from Formula (I) compounds in which the R 1 group is substituted by CO 2 C 1 -C 4 alkyl or the Z group is CO 2 C 1 -C 4 alkyl using basic hydrolysis, such as aqueous sodium or potassium hydroxide in methanol or ethanol, or using acidic hydrolysis, such as aqueous hydrochloric acid.
  • basic hydrolysis such as aqueous sodium or potassium hydroxide in methanol or ethanol
  • acidic hydrolysis such as aqueous hydrochloric acid.
  • azide preferably aluminum azide prepared in situ by the reaction of sodium azide with aluminum chloride, in a suitable solvent, for example tetrahydrofuran to give Formula (I) tetrazole compounds.
  • acids are maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, aspartic,
  • base addition salts of compounds of Formula (I) in which a carboxy group is present are prepared by known methods from organic and inorganic bases, including nontoxic alkali metal and alkaline earth bases, for example, calcium, lithium, sodium, and potassium hydroxide; ammonium hydroxide, and nontoxic organic bases, such as triethylamine,
  • Angiotensin II antagonist activity of the compounds of Formula (I) is assessed by in vitro and in vivo
  • in vitro antagonist activity is determined by the ability of the compounds to compete with 125 I-angiotensin II for binding to vascular angiotensin II receptors and by their ability to antagonize the
  • the radioligand binding assay is a modification of a method previously described in detail (Gunther et al., Circ. Res. 47:278, 1980). A particular fraction from rat mesente-ric arteries is incubated in Tris buffer with 80 pM of 125 I-angiotensm II with or without angiotensin
  • IC 50 is the concentration of antagonist needed to displace 50% of the total specifically bound angiotensin II.
  • IC 50 of compounds of the invention is about
  • angiotensin II induced vasoconstriction is examined in the rabbit aorta. Ring segments are cut from the rabbit thoracic aorta and suspended in organ baths containing physiological salt solution. The ring segments are mounted over metal supports and attached to force displacement transducers which are connected to a recorder. Cumulative concentration response curves to angiotensin II are performed in the absence of
  • Antagonist disassociation constants are calculated by the dose ratio method using the mean effective concentrations.
  • Exemplary of the K B of compounds of the invention is about 23.5 to about 100 ⁇ M.
  • Rats are prepared with indwelling femoral arterial and venous catheters and a stomach tube (Gellai et al., Kidney Int. 15:419, 1979). Two to three days following surgery the rats are placed in a restrainer and blood pressure is continuously monitored from the arterial catheter with a pressure transducer and recorded on a polygraph. The change in mean arterial pressure in response to intravenous injections of 250 mg/kg
  • angiotensin II is compared at various time points prior to and following the administration of the compounds intravenously or orally at doses of 0.1 to 300 mg/kg.
  • the dose of compound needed to produce 50% inhibition of the control response to angiotensin II (IC 50 ) is used to estimate the potency of the compounds.
  • the antihypertensive activity of the compounds is measured by their ability to reduce mean arterial pressure in conscious rats made renin-dependent
  • Renal artery ligated rats are prepared with indwelling catheters as described above. Seven to eight days following renal artery ligation, the time at which plasma renin levels are highest, the conscious rats are placed in restrainers and mean arterial pressure is continuously recorded prior to and following the
  • the intraocular pressure lowering effects employed in this invention may be measured by the procedure described by Watkins, et al., J. Ocular Pharmacol., 1 (2):161-168 (1985).
  • the compounds of Formula (I) are incorporated into convenient dosage forms, such as injectable
  • Solid or liquid pharmaceutical carriers are employed.
  • Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • Liquid carriers include syrup, peanut oil, olive oil, saline, and water.
  • the carrier or diluent may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the amount of solid carrier varies widely but, preferably, will be from about 25 mg to about 1 g per dosage unit.
  • the preparation When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid, such as an ampoule, or an aqueous or nonaqueous liquid suspension.
  • the pharmaceutical compositions adapted include solutions, suspensions, ointments, and solid inserts.
  • Typical pharmaceutically acceptable carriers are, for example, water, mixtures of water and water-miscible solvents such as lower alkanols or vegetable oils, and water soluble ophthalmologically acceptable non-toxic
  • the pharmaceutical preparation may also contain non-toxic auxiliary substances such as emulsifying, preserving, wetting, and bodying agents, as for example, polyethylene glycols; antibacterial components, such as quarternary ammonium compounds;
  • buffering ingredients such as alkali metal chloride; antioxidants, such as sodium metabisulfite; and other conventional ingredients, such as sorbitan monolaurate.
  • suitable ophthalmic vehicles may be used as carrier media for the present purpose including conventional phosphate buffer vehicle systems.
  • the pharmaceutical preparation may also be in the form of a solid insert.
  • a solid water soluble polymer as the carrier for the medicament.
  • Solid water insoluble inserts such as those prepared from ethylene vinyl acetate copolymer, may also be utilized.
  • the pharmaceutical preparations are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingredients, as appropriate, to give the desired oral, parenteral, or topical products.
  • pharmaceutical dosage unit as described above will be an efficacious, nontoxic quantity selected from the range of .01 - 200 mg/kg of active compound, preferably
  • the selected dose is administered to a human patient in need of angiotensin II receptor
  • Oral dosage units for human administration preferably contain from 1 to 500 mg of active compound.
  • Topical formulations contain the active compound in an amount selected from 0.0001 to 0.1
  • an amount of active compound from between 50 ng to 0.05 mg, preferably 50 ng to 5 ⁇ g, is applied to the human eye.
  • the method of this invention of antagonizing angiotensin II receptors in mammals, including humans, comprises administering to a subject in need of such antagonism an effective amount of a compound of Formula (I).
  • antihypertensive activity and the method of treating congestive heart failure, glaucoma, and renal failure comprise administering a compound of Formula (I) to a subject in need thereof an effective amount to produce said activity.
  • Contemplated equivalents of Formula (I) compounds are compounds otherwise corresponding thereto wherein substituents have been added to any of the unsubstituted positions of the Formula (I) compounds provided such compounds have the pharmaceutical utility of Formula (I) compounds.
  • hydrochloride salt of the title compound was prepared following the procedure of Example 1 replacing methyl 3-hydroxybenzoate with methyl 2-hydroxybenzoate; mp 224-226°C.
  • An oral dosage form for administering orally active Formula (I) compounds is produced by screening, mixing and filling into hard gelatin capsules the ingredients in proportions, for example, as shown below. Ingradient s Amounts
  • sucrose calcium sulfate dihydrate and orally active Formula (I) compounds are mixed and granulated with a 10% gelatin solution.
  • the wet granules are screened, dried, mixed with the starch, talc and stearic acid, screened and compressed into a tablet.
  • a topical opthamological solution for administering Formula (I) compounds is produced by mixing under sterile conditions the ingredients in proportions, for example, as shown below. Ingredients Amounts

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

Abstract

L'invention se rapporte à des antagonistes du récepteur de l'angiotensine II, qui sont représentés par la formule (1) et qui sont utiles pour lutter contre l'hypertension et pour traiter les défaillances cardiaques congestives, les défaillances rénales et le glaucome, ainsi qu'à des compositions pharmaceutiques contenant ces antagonistes et à des procédés d'utilisation de tels composés pour produire une action antagoniste contre le récepteur de l'angiotensine II chez les mammifères.
EP92900730A 1990-11-30 1991-11-12 Imidazoles 5-aryle substitues Withdrawn EP0559755A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US62118890A 1990-11-30 1990-11-30
US621188 1990-11-30

Publications (2)

Publication Number Publication Date
EP0559755A1 true EP0559755A1 (fr) 1993-09-15
EP0559755A4 EP0559755A4 (fr) 1994-04-27

Family

ID=24489109

Family Applications (1)

Application Number Title Priority Date Filing Date
EP92900730A Withdrawn EP0559755A1 (fr) 1990-11-30 1991-11-12 Imidazoles 5-aryle substitues

Country Status (4)

Country Link
EP (1) EP0559755A1 (fr)
JP (1) JPH06503562A (fr)
AU (1) AU9055391A (fr)
WO (1) WO1992009278A1 (fr)

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5338740A (en) * 1993-07-13 1994-08-16 Pfizer Inc. Angiotensin II receptor antagonists
SE9903028D0 (sv) 1999-08-27 1999-08-27 Astra Ab New use
US6596739B2 (en) 2000-03-29 2003-07-22 The Procter & Gamble Company N-(1-phenylethyl)-5-phenyl-imidazole-2-amine compounds, their compositions and uses
US6552033B1 (en) 2000-05-16 2003-04-22 The Procter & Gamble Co. Imidazo-containing heterocyclic compounds, their compositions and uses
US8969514B2 (en) 2007-06-04 2015-03-03 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
CN101772513B (zh) 2007-06-04 2013-11-13 协同医药品公司 有效用于胃肠功能紊乱、炎症、癌症和其他疾病治疗的鸟苷酸环化酶激动剂
JP2011522828A (ja) 2008-06-04 2011-08-04 シナジー ファーマシューティカルズ インコーポレイテッド 胃腸障害、炎症、癌、およびその他の障害の治療のために有用なグアニル酸シクラーゼのアゴニスト
EP2321341B1 (fr) 2008-07-16 2017-02-22 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres
US9616097B2 (en) 2010-09-15 2017-04-11 Synergy Pharmaceuticals, Inc. Formulations of guanylate cyclase C agonists and methods of use
JP2016514671A (ja) 2013-03-15 2016-05-23 シナジー ファーマシューティカルズ インコーポレイテッド グアニル酸シクラーゼのアゴニストおよびその使用
CA2905435A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
AU2014274812B2 (en) 2013-06-05 2018-09-27 Bausch Health Ireland Limited Ultra-pure agonists of guanylate cyclase C, method of making and using same

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1338238C (fr) * 1988-01-07 1996-04-09 David John Carini Imidazoles bloquant les recepteurs de l'angiotensine ii et combinaisons de ces imidazoles avec des diuretiques et des anti-inflammatoires non steroidiens

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
No further relevant documents disclosed *
See also references of WO9209278A1 *

Also Published As

Publication number Publication date
JPH06503562A (ja) 1994-04-21
AU9055391A (en) 1992-06-25
EP0559755A4 (fr) 1994-04-27
WO1992009278A1 (fr) 1992-06-11

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