EP0463119A1 - Verwendung von Substituierte 2-Aminotetraline zur Herstellung eines Arzneimittels um Appetitlosigkeit oder Gewichtsverlust einzuleiten. - Google Patents

Verwendung von Substituierte 2-Aminotetraline zur Herstellung eines Arzneimittels um Appetitlosigkeit oder Gewichtsverlust einzuleiten.

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Publication number
EP0463119A1
EP0463119A1 EP90911220A EP90911220A EP0463119A1 EP 0463119 A1 EP0463119 A1 EP 0463119A1 EP 90911220 A EP90911220 A EP 90911220A EP 90911220 A EP90911220 A EP 90911220A EP 0463119 A1 EP0463119 A1 EP 0463119A1
Authority
EP
European Patent Office
Prior art keywords
group
oxygen
compound
propyl
carbon atoms
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.)
Ceased
Application number
EP90911220A
Other languages
English (en)
French (fr)
Other versions
EP0463119A4 (en
Inventor
James V. Peck
Gevork Minaskanian
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.)
Whitby Research Inc
Original Assignee
Whitby Research Inc
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 Whitby Research Inc filed Critical Whitby Research Inc
Publication of EP0463119A1 publication Critical patent/EP0463119A1/de
Publication of EP0463119A4 publication Critical patent/EP0463119A4/en
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/64—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/16—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring not being further substituted
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/74—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
    • C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the invention relates generally to substituted 2-aminotetralins and to processes for preparing such compounds. More particularly, the invention relates to compounds for therapeutic use, in particular in treating disorders of the central nervous, cardiovascular and endocrine systems. The compounds of this invention are also useful for alleviating glaucoma, parkinsonism, and schizophrenia, and for inducing anorexia and weight loss in mammals.
  • R 1 and R 2 are saturated alkyl groups and n is 1 or 2 , are dopamine receptor agonists (McDermed et al., J. Med. Chem. 18 , 362 (1975); Feenstra et al., Arch. Pharmacol. 313, 213 (1980). Many structure-activity relationship studies have been conducted to find compounds with high dopamine-receptor stimulating activity. A survey is contained in Katerinopoulos, H. E., et al., "Structure-Activity Relationships for Dopamine Analogues," Drugs of the Future. Vol. 12, No. 3, 1987, 223-253.
  • D 2 receptor potency of dopamine agonists is at a maximum when one of the two N-substituents fits into a receptor niche which, because of size constraints maximally accommodates an n-propyl group Conversely, activity drops off when the propyl group is replaced by the smaller groups ethyl or methyl. When the compound contains no N-substituent at least as small as n-propyl, activity is small or non-existent.
  • R 2 , R 3 and R 4 are each selected from the group consisting of H and OA with the provision that at least one of R 2 , R 3 and R 4 is H, that R 2 and R 4 are not both OA;
  • A is H or is selected from the group consisting of hydrocarbyl radicals, for example lower alkyl radicals optionally substituted with aromatic residues (i.e. methyl, ethyl, propyl, benzyl, etc.), as well as and
  • R 5 is selected from the group consisting of alkyl and aromatic residues having between 1 and 12, preferably between 1 and 6, carbon atoms, for example alkyl, optionally sub ⁇ titued with aromatic residues, and aromatic residues optionally substituted with alkyl radicals; n is an integer between 1 and 4; R 6 is an alkyl chain comprising between 1 and 4 carbon atoms, X is selected from the group consisting of -CH 2 -, oxygen, sulfur, and nitrogen, with the provision that when X is not -CH 2 -, R 1 is selected from the group consisting of
  • Z is oxygen, nitrogen or sulfur
  • Y is selected from the group consisting of hydroxy, nitro, cyano, azido, amino, acylamino, carbpxyamido, trifluoromethyl, sulfate, sulfonamido, halogen, hydrocarbyl, and hetero atom-substituted hydrocarbyl radicals, wherein said heteroatoms are selected from the group consisting of halogen, nitrogen, oxygen, sulfur and phosphorus and said hydrocarbyl radicals comprise from 1 to 12 carbon atoms, and a is an integer of from zero to 3; and with the further provision that when X is -CH 2 -, R 1 is either or
  • R 8 is hydrogen, aryl, or R 6 ; and further wherein R 9 is aryl, R 6' -OH, -NH 2 , -OR 6 , or -N(R 6 ) 2 ; or R 1 is
  • B is oxygen, sulfur or two hydrogen atoms, and pharmaceutically acceptable salts thereof.
  • R 2 is OA and A is H.
  • the compounds in the present invention be an optically active compound or racemic mixture thereof having substantial affinity and selectivity for binding to dopamine D 2 receptors, e.g., in a human.
  • 2-(N-n-propyl,N-2-[phenyloxy]ethylamino)-5-hydroxytetralin is especially preferred for its high affinity and selectivity for binding to dopamine D 2 receptors.
  • R 2 , R 3 and R 4 are each selected from the group consisting of H and OA with the provision that at least one of R 2 R 3 and R 4 is H, that R 2 and R 4 are not both OA;
  • A is H or is selected from the group consisting of hydrocarbyl radicals, for example lower alkyl radicals, optionally substituted with aromatic residues (i.e. methyl, ethyl, propyl, benzyl, etc.),
  • R 5 is selected from the group consisting of alkyl and a tic residues having between 1 and 12, preferably between 1 and 6, carbon atoms, for example alkyl residues optionally substituted with aromatic residues and aromatic residues optionally substituted with alkyl radicals; n is an integer between 1 or 4; R 6 is an alkyl chain comprising between 1 and 4 carbon atoms; X is selected from the group consisting of -CH 2 -, oxygen, sulfur, and nitrogen, with the provision that when X is not -CH 2 -, R is selected from the group consisting of
  • Z is oxygen, nitrogen or sulfur
  • Y is selected from the group consisting of hydroxy, nitro, cyano, azido, amino, acylamino, carboxyamido, trifluoromethyl, sulfate, sulfonamido, halogen, hydrocarbyl and hetero atom-substituted hydrocarbyl radicals, wherein said heteroatoms are selected from the group consisting of halogen, nitrogen, oxygen, sulfur and phosphorus and said hydrocarbyl radicals comprise from 1 to 12, preferably 1 to 6, carbon atoms, and a is an integer of from zero to 3, for instance zero to 2; and with the further provision that when X is -CH 2 -, R 1 is either
  • R 8 is hydrogen, aryl, or R 6 ; and further wherein R 9 is aryl, R 6 , -OH, -NH 2, -OR 6 , or -N(R 6 ) 2 ;
  • B is oxygen, sulfur or two hydrogen atoms, and pharmaceutically acceptable salts thereof.
  • R 2 is OA and A is H.
  • A is preferably H or is selected from the group consisting of phenyl and alkyl radicals having from 1 to 12 carbon atoms, and more preferably R 5 is an alkyl or aryl radical that would serve to extend the activity of the compound in the body, for example phenyl, methyl, t-butyl, o-methylphenyl, o-, m- or p-methoxyphenyl, p-isopropylphenyl or nonyl.
  • R The more preferred groups represented by R are thienyl, phenyl, hydroxyphenyl, furanyl and naphthalenyl, e.g., 2-thienyl, 3-thienyl, 3 -hydroxyphenyl, 4-hydroxyphenyl, etc.
  • n 2
  • X oxygen or -CH 2 - and R 2 is OA; and most preferably A is H and R 6 is propyl.
  • the compounds herein be an optically active or racemic mixtures capable of binding selectively to one or more dopamine D 2 receptors, e.g., in a human.
  • 2-(N-n-propyl,N-2-[phenyloxy] ethylamino)-5-hydroxytetralin is an especially preferred compound because of its high affinity and selectivity for binding to D 2 dopamine receptors.
  • the compounds herein will be useful in the treatment of disorders of the central nervous, cardiovascular, and endocrine systems. In particular it is believed that the compounds herein are useful in the treatment of such conditions in humans as elevated intraocular pressure, schizophrenia and parkinsonism, and for inducing anorexia and weight loss in humans and other mammals.
  • Y comprises no more than 5 carbon atoms and a is an integer from 0 to 2.
  • Specific preferred compounds of this group include:
  • R 1 is phenyl and/or substituted phenyl and is selected from the group of radicals represented by the formula:
  • Example 2 The product of Example 2 was also obtained by dissolving the product of Example 1 in dry dichloromethane and adding a solution of boron tribromide in dichloromethane dropwise at room temperture under nitrogen. After completion, the reaction was poured into a beaker containing NH 4 OH and ice and stirred for 0.5 h. The organic layer was separated, and the product was purified as in Example 2.
  • Example 1 phenoxyacetic acid can be replaced by 3-phenoxy-propionic acid.
  • Example 1 phenoxyacetic acid was replaced by (1-naphthoxy)-acetic acid.
  • the resulting oil was sujbected to flash chromatography (silica; pet ether) and the product was isolated; characteristic peak of NMR (300 MHz, CDCl 3 ); ⁇ 8.3-6.7 (m,10H), 4.2(m, 2H), 3.85(s, 3H), 1.0(t, 3H).
  • Example 6 The product of Example 6 was used as the starting material in Example 2. The resulting oil was subjected to flash chromatography and the isolated product showed characteristic peaks at : NMR (CDCl 3 ) ⁇ 8.3-6.6 (m, 10H), 4.2(m, 2H), 0.9(t,3H).
  • Example 1 phenoxyacetic acid was replaced by phthalide-3-acetic acid. The resulting oil was subjected to flash chromatography and the isolated product showed distinct peaks at: NMR (CDCl 3 ) ⁇ 8.0-6.7(m, 7H) , 5.7(m, 1H), 3.8(s, 3H), 0.9 (t, 3H).
  • NMR CDCl 3
  • Example 8 The product of Example 8 was used as the starting material for Example 3.
  • the resulting oil after purification showed distinct peaks at: NMR(CDC1 3 ) ⁇ 7.9-6.6(m, 7H), 5.7(m, 1H), 0.95(t, 3H).
  • Example 1 phenoxyacetic acid was replaced by diphenylactic acid.
  • the purified product showed characteristic peaks at: NMR(CDCl 3 ) ⁇ 7.8-6.65(m, 13H), 4.1(t, 1H), 3.8(s, 3H), 3.2(d, 2H), 0.7(t, 3H).
  • Example 1 phenoxyacetic acid was replaced by 3,3-diphenylpropionic acid.
  • the purified product showed distinct peaks at: NMR(CDCl 3 ) ⁇ 7.4-7.2 (m, 11H), 6.65(m, 2H), 4.05(t,lH), 3.8(s, 3H), 0.9(s, 3H).
  • Example 13 The product of Example 13 was used as starting material for Example 3.
  • the isolated product showed distinct peaks at: NMR(CDCl 3 ) ⁇ 7.4-7.0(m, 1H) , 6.7-6.5(m, 2H), 4.0(t, 1H), 0.9(t, 3H).
  • Example 1 phenoxyacetic acid was replaced by DL-2-phenoxypropionic acid.
  • the purified product showed distinct peaks at: NMR(CDCl 3 ) ⁇ 7.3-6.65 (m, 8H) , 4.45(m, 1H), 3.8(S, 3H) , 0.9(t, 3H) .
  • Example 15 The product of Example 15 was used as starting material for Example 2. The isolated product showed characteristic peaks at: NMR(CDCl 3 ) ⁇ 7.3-6.65(m, 8H) , 4.45(m, 1H), 0.9 (t, 3H). EXAMPLE 17
  • Example 1 phenoxyacetic acid was replaced by 3,3,3-lriphenylpropionic acid.
  • the purified product showed characteristic peaks at : NMR(CDCl 3 ) ⁇ 7.4-6.65(m, 18H), 3.8(s, 3H), 0.9(t, 3H).
  • Example 17 The product of Example 17 was used as starting material in Example 3. After purification the product showed distinct peaks at: NMR(CDCl 3 ) ⁇ 7.4-6.65(m, 18H), 0.9(t, 3H).
  • pehnoxyacetic acid can be replaced by triphenylacetic acid.
  • Example 19 The product of Example 19 can be used as the starting material for Example 3.
  • Example 2 phenoxyacetic acid can be replaced by ⁇ -methoxyphenlyacetic acid.
  • Example 21 The product of Example 21 can be used as the starting material for Example 2.
  • Example 1 phenoxyactic acid can be replaced by 1-indancarboxylic acid.
  • Example 23 The product of Example 23 can be used as the starting material for Example 3.
  • Example 1 phenoxyacetic acid can be replaced by 1,2,3,4-tetrahydro-2-naphthoic acid.
  • EXAMPLE 26
  • Example 25 The product of Example 25 can be used as the starting material for Example 3.
  • phenoxyacetic acid can be replaced by 3,5-dimethylphenoxyacetic acid.
  • Example 27 The product of Example 27 can be used as the starting material for Example 3.
  • the bovine caudate nuclei assay was employed. Bovine brains were obtained fresh from a local slaughterhouse. The caudate nuclei were dissected out and homogenized in Buffer A (50 mM Tris; 1 mM Na 2 -EDTA; 5 mM KCl; 1 mM MgCl 2 ; 2 mM CaCl 2 ; pH 7.4) using a Brinkman Polytron. The homogenate was centrifuged at 40,000 ⁇ g for 20 minutes and washed once. The pellett was resuspended in Buffer A, incubated at 37°C for 15 minutes, then centrifuged. The pellet was washed once more, resuspended to a protein concentration of 5-10 mg/ml in Buffer A and frozen at -70°C until used.
  • Buffer A 50 mM Tris; 1 mM Na 2 -EDTA; 5 mM KCl; 1 mM MgCl 2 ; 2 mM Ca
  • the rat cerebral cortex assay was employed. Male Sprague Dawley rats were killed by decapitation and the brains removed. The cerebral cortices were homogenized in 50 mM Tris; 2mM MgCl 2 (pH 7.4), and centrifuged at 40,000 ⁇ g for 10 minutes. The pellet was washed once, resuspended in Tris/MgCl 2 and incubated with 8 units/ml adenosine deaminase at 37 °C for 30 minutes. The homogenate was centrifuged, washed once, resuspended to a protein concentration of 5-10 mg/ml and frozen at -70°C until use.
  • radioligands were used as radioligands for each of the receptors tested: [ 3 H]-Spiperone 21-24 Ci/mmol for D 2 receptors, [ 3 H]-SCH23390 75-85 Ci/mmol for D 1 receptors, and [ 3 H]-Para aminoclonidine 48-52 Ci/mmol for ⁇ 2 -adrenergic receptors.
  • the radioligands were incubated with various concentrations of competing drug and the appropriate membrane source for periods of ' time as follows: 75 minutes at room temperature for D 2 receptors, 15 minutes at 37°C for D 1 receptors, or 30 minutes at room temperature for ⁇ 2 receptors.
  • D 2 1 ⁇ M butaclamol
  • D 1 1 ⁇ M SCH23390
  • ⁇ 2 1 ⁇ M yohimbine
  • the D 2 assays contained 30 nM Kotaserin in order to block the binding of 3 H-spiperone to 5HT 2 receptors.
  • the assays were terminated by filtration using a 24-port Brandell cell harvester over filters that had been previously soaked in 0.1% polyethyleneimine, and the filters were washed three times by filtration of cold buffer.
  • the filters were then placed in 5 ml scintillation vials to which 4 ml of Beckman Ready-Protein was then added, and each vial was counted for 2 minutes in a Beckman 3801 scintillation counter calibrated for conversion of cpm to dpm. Binding data were analyzed using the Ligand program of Munson and Rodbard (1980). The results are presented as K i values if the data were best fitted to a one-site model, or as K H and K L values if a two-site model produced the better fit.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP19900911220 1989-07-05 1990-07-02 Substituted 2-aminotetralins Ceased EP0463119A4 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US37558389A 1989-07-05 1989-07-05
US375583 1989-07-05

Publications (2)

Publication Number Publication Date
EP0463119A1 true EP0463119A1 (de) 1992-01-02
EP0463119A4 EP0463119A4 (en) 1992-01-22

Family

ID=23481446

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19900911220 Ceased EP0463119A4 (en) 1989-07-05 1990-07-02 Substituted 2-aminotetralins

Country Status (4)

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EP (1) EP0463119A4 (de)
AU (1) AU6072090A (de)
CA (1) CA2065450A1 (de)
WO (1) WO1991000727A1 (de)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5382596A (en) * 1993-08-05 1995-01-17 Whitby Research, Inc. Substituted 2-aminotetralins
IT1271411B (it) * 1993-09-14 1997-05-28 Zambon Spa Derivati del 2-ammino-1,2,3,4-tetraidro-naftalene attivi sul sistema cardiovascolare
SV2001000202A (es) * 1999-10-20 2001-10-16 Warner Lambert Co Uso de (-)-5-ceto-2-n,n-d1-n-propilamino-tetrahidrotetralina para el tratamiento del mal de parkinson
SE0001438D0 (sv) * 2000-04-18 2000-04-18 Axon Chemicals Bv New chemical compounds and their use in therapy
US7829587B2 (en) 2008-01-09 2010-11-09 Allergan, Inc. Substituted 2-aminotetralin derivatives as selective alpha 2B agonist

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US3930022A (en) * 1972-07-03 1975-12-30 Squibb & Sons Inc Certain tetrahydronaphthalenes used in the treatment of cardiac arrhythmia
US4267373A (en) * 1972-07-03 1981-05-12 E. R. Squibb & Sons, Inc. 5,6,7,8-Tetrahydronaphthalene hypotensive agents
CA1017359A (en) * 1972-07-03 1977-09-13 Frederic P. Hauck Substituted cyclic polymethylene phenols
US4314082A (en) * 1978-07-14 1982-02-02 American Hospital Supply Corporation Derivatives of 2-amino-6,7-dihydroxytetrahydro naphthalene (ADTN)
DE3062971D1 (en) * 1979-09-14 1983-06-09 Sandoz Ag Derivatives of tetraline, their preparation and medicaments containing these compounds
US4882352A (en) * 1986-07-28 1989-11-21 Nelson Research & Development Co. Method for treating schizophrenia
US4657925A (en) * 1984-08-13 1987-04-14 Nelson Research & Development Co. Method and compositions for reducing the intraocular pressure of mammals
US4743618A (en) * 1983-01-03 1988-05-10 Nelson Research & Development Co. Substituted 2-aminotetralins
US4885308A (en) * 1984-08-13 1989-12-05 Nelson Research & Development Co. Method and compositions for treatment of parkinsonism syndrome in mammals

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
No further relevant documents have been disclosed. *
See also references of WO9100727A1 *

Also Published As

Publication number Publication date
AU6072090A (en) 1991-02-06
WO1991000727A1 (en) 1991-01-24
EP0463119A4 (en) 1992-01-22
CA2065450A1 (en) 1991-01-06

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