WO1994008986A1 - Enantiomeric cis-3-(4,6-dihydroxychroman-3-yl-methyl)benzoic acids - Google Patents

Enantiomeric cis-3-(4,6-dihydroxychroman-3-yl-methyl)benzoic acids Download PDF

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Publication number
WO1994008986A1
WO1994008986A1 PCT/US1993/006061 US9306061W WO9408986A1 WO 1994008986 A1 WO1994008986 A1 WO 1994008986A1 US 9306061 W US9306061 W US 9306061W WO 9408986 A1 WO9408986 A1 WO 9408986A1
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Prior art keywords
dihydroxychroman
compound
salt
benzoic acid
formula
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PCT/US1993/006061
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French (fr)
Inventor
Charles W. Murtiashaw, Iii
Brian C. Vanderplas
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Pfizer, Inc.
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Application filed by Pfizer, Inc. filed Critical Pfizer, Inc.
Priority to PL93308473A priority Critical patent/PL308473A1/en
Priority to JP6509963A priority patent/JPH07507811A/en
Priority to AU46504/93A priority patent/AU4650493A/en
Priority to KR1019950701524A priority patent/KR950704291A/en
Priority to EP93916752A priority patent/EP0665839A1/en
Publication of WO1994008986A1 publication Critical patent/WO1994008986A1/en
Priority to NO951507A priority patent/NO951507L/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4

Definitions

  • This invention relates to c/s-3-(4,6-dihydroxychroman-3-ylmethyl)benzoic acids and processes for the preparation of such compounds.
  • the compounds are intermediates useful in the preparation of optically pufe enantiomers of c/s-3-(6- arylmethyloxy-4-hydroxy-chroman-3-ylmethyl)aniline sulfonamides.
  • the latter compounds are useful in the treatment of asthma, arthritis, psoriasis, ulcers, myocardial infarction and related diseases.
  • the present invention relates to the compound of the formula
  • the present invention also relates to the optically pure diasteriomeri salts of the compound of formula I with the compound of formula
  • the compound of formula I is prepared, according to the invention, by acidifying the diasteriomeric salt of the compound of formula I with the compound of formula III.
  • the diasteriomeric salt of the compound of formula I with the compound of formula III is prepared according to the invention, by treating the compound of formula
  • the present invention also relates to a novel method for preparing the compound of formula II by reducing the compound of formula
  • a reducing agent selected from diisobutylaluminum hydride and borohydride ion in the presence of Ce (III) ion.
  • the compound of formula I also referred to herein as (3R-c/s)-3-(4,6- dihydroxychroman-3-ylmethyl)benzoic acid, is a novel compound prepared by acidifying the diasteriomeric salt of the compound of formula I and the compound of formula III in the presence of a solvent for the free acid.
  • the acidification is effected using an acid with a pK a of about ⁇ 3 such as HCI, H 2 S0 4 , oxalic and citric acids.
  • the diasteriomeric salt of the compound of formula I and the compound of formula III is prepared by heating the compounds of formulae II and III in the presence of a non-solvent for said salt and recovered, after cooling to room temperature, by filtration.
  • Non-solvents for the diasteriomeric salt include ethanol and isopropanol.
  • the preferred non-solvent is ethanol.
  • the reaction is preferably carried out at a temperature between about 0°C and about 80°C, preferably at the reflux temperature of the non-solvent. Most preferably the reaction is effected at about 80°C.
  • the treatment of the compound of formula II with the compound of formula III is carried out over a period of about 30 minutes to about 3 hours, preferably about 1 hour.
  • the salt is purified by slurrying with the non-sumble at an elevated temperature followed by filtration at about room temperature.
  • the slurrying procedure is, preferably, effected two times.
  • the other cis enantiomer, i.e. (3S-c/s)-3-(4,6-dihydroxychroman-3- ylmethyl)benzoic acid may be prepared by substituting the (+) base for the compound of formula III.
  • the 3S- acid may be prepared by treating the filtrate from the preparation of the diasteriomeric salt of the compound of formula I with acid followed by said (+ ) base followed by the above-indicated treatment for the salts with the (-) base.
  • Racemic c/s-3-(4,6-dihydroxychroman-3-ylmethyl)benzoic acid (compound II) is prepared, according to the invention, by the novel process of treating the compound of formula IV with a solution of a reducing agent in tetrahydrofuran/methanol.
  • a reducing agent in tetrahydrofuran/methanol.
  • Preferred reducing agents are diisobutylaluminum hydride and borohydride in the presence of a Ce (III) salt.
  • a most preferred reducing agent is borohydride ion in the presence of a Ce(lll) salt.
  • the tetrahydrofuran and methanol may be present in a ratio of from about 3:1 to about 1 :2, preferably about 3:1.
  • the reduction may be effected at a temperature from about -78°C to about 60°C, preferably at about 0°C.
  • the sulfonamides, especially the trifluoromethanesulfonamides, of the compound of formula VI are useful in the treatment of asthma, arthritis, psoriasis, ulcers, myocardial infarction and related diseases.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrane Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

This invention relates to enantiomerically pure cis-3-(4,6-dihydroxychroman-3-ylmethyl)benzoic acids and processes for the preparation of such compounds. The compounds are intermediates useful in the preparation of optically pure enantiomers of cis-3-(6-arylmethyloxy-4-hydroxy-chroman-3-ylmethyl)aniline sulfonamides which are useful in the treatment of asthma, arthritis, psoriasis, ulcers, myocardial infarction and related diseases. More particularly it relates to (3R-cis)-3-(4,6-dihydroxychroman-3-ylmethyl)benzoic acid. It also relates to an improved process for the preparation of racemic cis-3-(4,6-dihydroxychroman-3-ylmethyl)benzoic acid.

Description

ENANTIOMERIC C/S-3-(4.6-DlHYDROXYCHROMAN-3-YL-METHYϋBENZOIC ACIDS
BACKGROUND OF THE INVENTION
This invention relates to c/s-3-(4,6-dihydroxychroman-3-ylmethyl)benzoic acids and processes for the preparation of such compounds. The compounds are intermediates useful in the preparation of optically pufe enantiomers of c/s-3-(6- arylmethyloxy-4-hydroxy-chroman-3-ylmethyl)aniline sulfonamides. The latter compounds are useful in the treatment of asthma, arthritis, psoriasis, ulcers, myocardial infarction and related diseases. More particularly it relates to (3R-c/s) - 3-(4,6- dihydroxychroman-3-ylmethyl)benzoic acid, processes for its preparation from racemic cis - 3-(4,6-dihydroxychroman-3-ylmethyl)benzoic acid and a novel process for the preparation of the racemic acid.
The use of the intermediates of this invention in preparing the c/s-3-(6- arylmethyloxy-4-hydroxy-chroman-3-ylmethyl)aniline sulfonamides is described in the patent application of Marfat, et al. (attorney docket number PC 8230) filed concurrently herewith. SUMMARY OF THE INVENTION
The present invention relates to the compound of the formula
O H
Figure imgf000003_0001
novel processes for its preparation and a novel process for the preparation of the compound of the formula 0 H
Figure imgf000004_0001
( r ac e m l c )
useful in the preparation of the compound of formula I.
The present invention also relates to the optically pure diasteriomeri salts of the compound of formula I with the compound of formula
Figure imgf000004_0002
The compound of formula I is prepared, according to the invention, by acidifying the diasteriomeric salt of the compound of formula I with the compound of formula III.
The diasteriomeric salt of the compound of formula I with the compound of formula III is prepared according to the invention, by treating the compound of formula
II with the compound of formula III in the presence of a non-solvent for said salt. The present invention also relates to a novel method for preparing the compound of formula II by reducing the compound of formula
Figure imgf000005_0001
with a reducing agent selected from diisobutylaluminum hydride and borohydride ion in the presence of Ce (III) ion.
The overall reaction to prepare the compound I from the compound of formula IV through the above intermediate steps for the preparation of the compound of formula II is also part of the invention.
DETAILED DESCRIPTION OF THE INVENTION The compound of formula I, also referred to herein as (3R-c/s)-3-(4,6- dihydroxychroman-3-ylmethyl)benzoic acid, is a novel compound prepared by acidifying the diasteriomeric salt of the compound of formula I and the compound of formula III in the presence of a solvent for the free acid.
The acidification is effected using an acid with a pKa of about < 3 such as HCI, H2S04, oxalic and citric acids.
The diasteriomeric salt of the compound of formula I and the compound of formula III is prepared by heating the compounds of formulae II and III in the presence of a non-solvent for said salt and recovered, after cooling to room temperature, by filtration.
Non-solvents for the diasteriomeric salt include ethanol and isopropanol. The preferred non-solvent is ethanol. The reaction is preferably carried out at a temperature between about 0°C and about 80°C, preferably at the reflux temperature of the non-solvent. Most preferably the reaction is effected at about 80°C.
The treatment of the compound of formula II with the compound of formula III is carried out over a period of about 30 minutes to about 3 hours, preferably about 1 hour.
The salt is purified by slurrying with the non-soivent at an elevated temperature followed by filtration at about room temperature. The slurrying procedure is, preferably, effected two times. If desired, the other cis enantiomer, i.e. (3S-c/s)-3-(4,6-dihydroxychroman-3- ylmethyl)benzoic acid may be prepared by substituting the (+) base for the compound of formula III. Alternatively, the 3S- acid may be prepared by treating the filtrate from the preparation of the diasteriomeric salt of the compound of formula I with acid followed by said (+ ) base followed by the above-indicated treatment for the salts with the (-) base.
Racemic c/s-3-(4,6-dihydroxychroman-3-ylmethyl)benzoic acid (compound II) is prepared, according to the invention, by the novel process of treating the compound of formula IV with a solution of a reducing agent in tetrahydrofuran/methanol. Preferred reducing agents are diisobutylaluminum hydride and borohydride in the presence of a Ce (III) salt. A most preferred reducing agent is borohydride ion in the presence of a Ce(lll) salt.
The tetrahydrofuran and methanol may be present in a ratio of from about 3:1 to about 1 :2, preferably about 3:1.
The reduction may be effected at a temperature from about -78°C to about 60°C, preferably at about 0°C.
In the practice of using the novel compound of formula I said compound is converted to the optically pure enantiomeric compound of formula
O H
Figure imgf000006_0001
through a Curtius rearrangement followed by hydrogenation. The phenolic hydroxyl group of the compound of formula V is then converted to the alkyl or aryl ether of formula
Figure imgf000007_0001
by treatment with an alkyl or aryl halide in the presence of a base followed by sulfonation of the amino group of the compound of formula VI. The sulfonamides, especially the trifluoromethanesulfonamides, of the compound of formula VI are useful in the treatment of asthma, arthritis, psoriasis, ulcers, myocardial infarction and related diseases.
The following Examples illustrate but do not limit the scope of this invention.
EXAMPLE 1 Racemic c/s-3-(4,6-dihvdroxychroman-3-ylmethyl)benzoic acid
To a solution of 3-(6-hydroxy-4-oxo-chroman-3-ylmethyl)benzoic acid (2.00 gm, 6.70 mmol) in 24 ml tetrahydrofuran was added 12 ml methanol followed by 1.50 gm CeCI3 (4.02 mmol). The resulting hazy solution was cooled to 0°C and treated with a total of 0.52 gm NaBH4, portionwise, over 55 minutes. 1N HCI was added to the reaction mixture which was then concentrated on a rotary evaporator, transferred to a separatory funnel and partitioned between water and ethyl acetate. The organic phase was washed twice with 1 N HCI, once with water and once with brine followed by drying over Na2SO4 and filtration. The filtrate was concentrated to a light brown oil which was evacuated to a tan foam, yielding 1.93 gm (96%). 1H NMR (dimethylsulfoxide-d6) δ 7.88 (m, 2H), 7.44 (m, 2H), 6.64 (m, 3H), 4.40 (s, 1 H), 3.91 (m, 2H), 3.30 (m, 1 H), 2.91 (m, 1 H), 2.61 (m, 1h); 13C NMR (dimethylsulfoxide-d6) δ 167.492, 150.473, 146,386, 140.452, 133.621 , 130.876, 129.907, 128.568, 127.058, 125.866, 116.361 , 116.021 , 115.941 , 64.246, 63.532, 31.858.
EXAMPLE 2 (-)-c s-N-Benzyl-2-(hydroxymethyl)cyclohexylamine salt of f-)-c/s-3-(4.6- dihvdroxychroman-3-ylmethyl)benzoic acid
To a solution of 1.766 gm (5.88 mmol) of racemic c/s-3-(4,6-dihydroxychroman-3- ylmethyl)benzoic acid (prepared in Example 1) in 10 ml absolute ethyl alcohol was added a solution of 1 .290 gm (5.88 mmol) (-)-c/s-N-benzyl-2-(hydroxymethyl)- cyclohexylamine in 9 ml ethyl alcohol. The resulting suspension was heated at reflux for 1 hour, cooled to room temperature, stirred for 1 hour and filtered. The resulting off- white solids (1.996 gm) were suspended in 20 ml absolute ethyl alcohol and heated at reflux for 3 hours followed by cooling to room temperature and stirring for an additional hour. Filtration yielded 1.295 gm of light gray solids which were again suspended in refluxing ethanol (15 ml) for 2 hours. After cooling the suspension was filtered to give 1.065 gm (63.2% of the available enantiomer) off-white solids, m.p. 216 - 218° C, [σ]D = +42.7° (c = 0.309, methanol). EXAMPLE 3
(3R-c/s)-3-(4.6-Dihydroxychroman-3-ylmethyl)benzoic acid A suspension of 1.061 gm (2.042 mmol) of the enantiomeric salt, prepared in Example 2, in water was adjusted to Ph 1 with 10% HCI and transferred to a separatory funnel charged with ethyl acetate. The organic layer was washed with twice with 1 N HCI, once with water and once with brine and thendried over Na2S04. Concentration on the rotary evaporator and evacuation under high vacuum yielded 0.604 gm of the title compound as a white foam, m.p. 85-95°C, [σ]D -= + 100° (c = 0.475, tetrahydrofuran).

Claims

1. An optically pure enantiomer of c/s-3-(4,6-dihydroxychroman-3-yl methyl)benzoic acid.
2. The compound of claim 1 consisting of ((3R-c/s)-3-(4,6- dihydroxychroman-3-yl methyl)benzoic acid.
3. A diastereomeric salt formed from the compound of formula I and the compound of formula III.
4. A process for preparing ((3R-c/s)-3-(4,6-dihydroxychroman-3-yl methyl)benzoic acid which comprises acidifying the diastereomeric salt of claim 3.
5. The process of claim 4 wherein said acidification is effected by means of an acid having a pKa < 3.
6. The process of claim 5 wherein said acid is HCI.
7. The process of claim 4 wherein said diastereomeric salt is prepared by treating racemic c/s-3-(4,6-dihydroxychroman-3-yl methyl)benzoic acid with (-)-c/s-N- benzyl-2-(hydroxymethyl)cyclohexylamine in the presence of a non-solvent for said salt.
8. The process of claim 7 wherein racemic c/s-3-(4,6-dihydroxychroman-3-yl methyl)benzoic acid is prepared by treating the compound of theformula
Figure imgf000009_0001
with a reducing agent selected from borohydride ion, in the presence of Ce (III) ion, or diisobutylaluminum hydride.
9. The process of claim 8 wherein said reducing agent is borohydride ion in the presence of a Ce (III) salt in 3:1 tetrahydrofuran:methanol.
10. The process of claim 8 wherein said reducing agent is diisobutylaluminum hydride.
11. The process of claim 9 wherein said reducing agent is sodium borohydride ion and said Ce(lll) salt is CeCI3.
12. The process of claim 4 for preparing (3R- c/'s)-3-(4,6-dihydroxychroman-3- yimethyl)benzoic acid comprising the steps of a) treating the compound of the formula
Figure imgf000010_0001
with a reducing agent to form racemic c s-3-(4,6-dihydroxychroman-3-yl methyl)benzoic acid wherein said redoing agent is selected from borohydride ion, in the presence of Ce (III) ion, or diisobutylaluminum hydride. ; b) treating said acid with (-)-c/s-N-benzyl-2-(hydroxymethyl)cyclohexylamine to form a diasteriomeric salt in the presence of a non-solvent for said salt; and c) treating the diasteriomeric salt with an acid to release the desired benzoic acid.
13. The process of claim 12 wherein said reducing agent is borohydride ion in the presence of a Ce (III) salt in 3:1 tetrahydrofuran:methanol.
14. The process of claim 12 wherein said reducing agent is diisobutylaluminum hydride.
15. The process of claim 13 wherein said reducing agent is sodium borohydride ion and said Ce(lll) salt is CeCI3.
PCT/US1993/006061 1992-10-21 1993-06-30 Enantiomeric cis-3-(4,6-dihydroxychroman-3-yl-methyl)benzoic acids WO1994008986A1 (en)

Priority Applications (6)

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PL93308473A PL308473A1 (en) 1992-10-21 1993-06-30 Enabntiomeric cis-3-(4,6-dihydoxychroman-3-yl methyl)bezoic acids
JP6509963A JPH07507811A (en) 1992-10-21 1993-06-30 Enantiomeric cis-3-(4,6-dihydroxychroman-3-yl-methyl)benzoic acid
AU46504/93A AU4650493A (en) 1992-10-21 1993-06-30 (Enantiomeric cis)-3-(4,6-dihydroxychroman-3-YL-methyl)benzoic acids
KR1019950701524A KR950704291A (en) 1992-10-21 1993-06-30 Enantiomeric cis-3- (4,6-dihydroxychroman-3-ylmethyl) benzoic acid (enantiomeric cis-3- (4,6-DIHYDROXYCHROMAN-3-YLMETHYL) BENZOIC ACIDS)
EP93916752A EP0665839A1 (en) 1992-10-21 1993-06-30 $i(ENANTIOMERIC CIS)-3-(4,6-DIHYDROXYCHROMAN-3-YLMETHYL)BENZOIC ACIDS
NO951507A NO951507L (en) 1992-10-21 1995-04-20 Enantiomeric cis-3- (4,6-dihydroxychromoman-3-yl-methyl) benzoic acids

Applications Claiming Priority (2)

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US96433692A 1992-10-21 1992-10-21
US07/964,336 1992-10-21

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998011085A1 (en) * 1996-09-16 1998-03-19 Pfizer Inc. Processes and intermediates for preparing substituted chromanol derivatives
WO2001034563A1 (en) * 1999-10-27 2001-05-17 Nobex Corporation Resolution of intermediates in the synthesis of substantially pure bicalutamide
US6479692B1 (en) 2001-05-02 2002-11-12 Nobex Corporation Methods of synthesizing acylanilides including bicalutamide and derivatives thereof
US6482848B2 (en) 2000-05-24 2002-11-19 Sugen Incorporated Prodrugs of 3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives
US7601855B2 (en) 2004-09-21 2009-10-13 Novogen Research Pty Ltd Substituted chroman derivatives, medicaments and use in therapy
US8080675B2 (en) 2004-09-21 2011-12-20 Marshall Edwards, Inc. Chroman derivatives, medicaments and use in therapy
US9663484B2 (en) 2010-11-01 2017-05-30 Mei Pharma, Inc. Isoflavonoid compounds and methods for the treatment of cancer
US10980774B2 (en) 2015-02-02 2021-04-20 Mei Pharma, Inc. Combination therapies

Citations (1)

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Publication number Priority date Publication date Assignee Title
US5059609A (en) * 1987-10-19 1991-10-22 Pfizer Inc. Substituted tetralins, chromans and related compounds in the treatment of asthma, arthritis and related diseases

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
US5059609A (en) * 1987-10-19 1991-10-22 Pfizer Inc. Substituted tetralins, chromans and related compounds in the treatment of asthma, arthritis and related diseases

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998011085A1 (en) * 1996-09-16 1998-03-19 Pfizer Inc. Processes and intermediates for preparing substituted chromanol derivatives
CN1108298C (en) * 1996-09-16 2003-05-14 辉瑞大药厂 Process for preparing substituted chromanol derivatives
WO2001034563A1 (en) * 1999-10-27 2001-05-17 Nobex Corporation Resolution of intermediates in the synthesis of substantially pure bicalutamide
US6593492B1 (en) 1999-10-27 2003-07-15 Nobex Corporation Resolution of intermediates in the synthesis of substantially pure bicalutamide
US6482848B2 (en) 2000-05-24 2002-11-19 Sugen Incorporated Prodrugs of 3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives
US6479692B1 (en) 2001-05-02 2002-11-12 Nobex Corporation Methods of synthesizing acylanilides including bicalutamide and derivatives thereof
US6812362B2 (en) 2001-05-02 2004-11-02 Nobex Corporation Methods of synthesizing acylanilides including bicalutamide and derivatives thereof
US8957109B2 (en) 2004-09-21 2015-02-17 Mei Pharma, Inc. Chroman derivatives, medicaments and use in therapy
US8080675B2 (en) 2004-09-21 2011-12-20 Marshall Edwards, Inc. Chroman derivatives, medicaments and use in therapy
US8084628B2 (en) 2004-09-21 2011-12-27 Marshall Edwards, Inc. Substituted chroman derivatives, medicaments and use in therapy
US8461361B2 (en) 2004-09-21 2013-06-11 Marshall Edwards, Inc. Chroman derivatives, medicaments and use in therapy
US8697891B2 (en) 2004-09-21 2014-04-15 Marshall Edwards, Inc. Substituted chroman derivatives, medicaments and use in therapy
US7601855B2 (en) 2004-09-21 2009-10-13 Novogen Research Pty Ltd Substituted chroman derivatives, medicaments and use in therapy
US9138478B2 (en) 2004-09-21 2015-09-22 Mei Pharma, Inc. Substituted chroman derivatives, medicaments and use in therapy
US9198895B2 (en) 2004-09-21 2015-12-01 Mei Pharma, Inc. Chroman derivatives, medicaments and use in therapy
US9381186B2 (en) 2004-09-21 2016-07-05 Mei Pharma, Inc. Substituted chroman derivatives, medicaments and use in therapy
US9663484B2 (en) 2010-11-01 2017-05-30 Mei Pharma, Inc. Isoflavonoid compounds and methods for the treatment of cancer
US9708283B2 (en) 2010-11-01 2017-07-18 Mei Pharma, Inc. Isoflavonoid compositions and methods for the treatment of cancer
US9981936B2 (en) 2010-11-01 2018-05-29 Mei Pharma, Inc. Isoflavonoid compositions and methods for the treatment of cancer
US10105346B2 (en) 2010-11-01 2018-10-23 Mei Pharma, Inc. Isoflavonoid compounds and methods for the treatment of cancer
US10369132B2 (en) 2010-11-01 2019-08-06 Mei Pharma, Inc. Isoflavonoid compositions and methods for the treatment of cancer
US10973799B2 (en) 2010-11-01 2021-04-13 Mei Pharma, Inc. Isoflavonoid compositions and methods for the treatment of cancer
US11583514B2 (en) 2010-11-01 2023-02-21 Mei Pharma, Inc. Isoflavonoid compounds and methods for the treatment of cancer
US11723893B2 (en) 2010-11-01 2023-08-15 Mei Pharma, Inc. Isoflavonoid compositions and methods for the treatment of cancer
US10980774B2 (en) 2015-02-02 2021-04-20 Mei Pharma, Inc. Combination therapies

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HUT65128A (en) 1994-04-28
MX9306526A (en) 1994-04-29
MY131378A (en) 2007-08-30
HU9302973D0 (en) 1993-12-28
AU4650493A (en) 1994-05-09
FI934624A0 (en) 1993-10-20
CN1090577A (en) 1994-08-10
JPH07507811A (en) 1995-08-31
KR950704291A (en) 1995-11-17
PL308473A1 (en) 1995-08-07
EP0665839A1 (en) 1995-08-09
CZ100895A3 (en) 1995-10-18
CA2146005A1 (en) 1994-04-28

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