NZ243492A - Process for the preparation of the dextrorotatory isomer of a 2-aminonaphthyridine derivative intermediate compound using (+) ephedrine - Google Patents
Process for the preparation of the dextrorotatory isomer of a 2-aminonaphthyridine derivative intermediate compound using (+) ephedrineInfo
- Publication number
- NZ243492A NZ243492A NZ243492A NZ24349292A NZ243492A NZ 243492 A NZ243492 A NZ 243492A NZ 243492 A NZ243492 A NZ 243492A NZ 24349292 A NZ24349292 A NZ 24349292A NZ 243492 A NZ243492 A NZ 243492A
- Authority
- NZ
- New Zealand
- Prior art keywords
- formula
- compound
- dextrorotatory isomer
- ephedrine
- dextrorotatory
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- 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
- A61P25/20—Hypnotics; Sedatives
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Biomedical Technology (AREA)
- Public Health (AREA)
- Pain & Pain Management (AREA)
- Anesthesiology (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
New Zealand Paient Spedficaiion for Paient Number £43492
24 3 4 9 2
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NEW ZEALAND
THE PATENTS ACT 1953 PATENTS FORM NO.5 COMPLETE SPECIFICATION
"PROCESS FOR THE PREPARATION OF THE DEXTROROTATORY ISOMER OF A 2-AMINONAPHTHYRIDINE DERIVATIVE"
WE, RHONE-POULENC RORER SA, a French body corporate of 20 Avenue Raymond Aron, F 9216 0 ANTONY, France hereby declare the invention for which we pray that a patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the following statement:-
(followed by page la)
N.Z. PATH If
-9 JUL 1932
RECEIVED
243492
- la -
The present invention provides a process for the preparation of the dextrorotatory isomer of the 2-aminonaphthyridine derivative of formula:
.COOH
(I)
which is useful for the preparation of the dextrorotatory isomer of the compound of formula:
(II)
which exhibits remarkable anxiolytic, hypnotic, anticonvulsant, antiepileptic and muscle-relaxant 20 properties.
It has been shown that, in the case of the product of formula (II) which, with analogous products, is the subject of United States Patent No. 4,960,779, the active entity or eutomer is the dextrorotatory (+) isomer. 25 According to United States Patent No. 4,960,779, the separation of the optical isomers of the compound of formula (II) may be carried out by chiral phase
2
chromatography. However, the industrial application of this process is not always convenient to implement.
According to the present invention, the
dextrorotatory isomer of the compound of formula (I) is prepared by forming a salt of the racemic compound of formula (I) with (+)-ephedrine, separating the salt of the dextrorotatory isomer, the releasing the dextrorotatory isomer of the compound of formula (I) from its salt. 10 The dextrorotatory isomer of the compound of formula (I) may then be converted into the dextrorotatory isomer of the compound of formula (II) by cyclisation.
This reaction is described and claimed in New Zealand patent application no. 243494 which is in the name of the 15 present applicants and which has the same priority date as the present application.
formula (I) can be cyclised to the eutomer of the product of formula (II) using thionyl chloride, optionally in the
presence of a condensing agent such as imidazole or pyridine in an organic solvent such as methylene chloride. It is not necessary to separate the dextrorotatory isomer of the compound of formula (I) prior to its cyclisation to the dextrorotatory compound of formula (II).
Preparation of the salt of the racemic compound of formula (I) with (+)-ephedrine may be carried out in an appropriate organic solvent such as ethanol. The salt of the dextrorotatory compound of formula (I) and of
The dextrorotatory isomer of the compound of
24 34 9 2
3
(+)-ephedrine precipitates. The pure dextrorotatory isomer of the compound of formula (I) may then be displaced from 5 its salt with a strong acid such as hydrochloric acid.
obtained by opening the pyrrolinone ring of a racemic compound of formula (II) in basic medium as described and claimed in the present applicants co-pending New Zealand 10 patent application 243495 which has the same priority date as the present application. Generally, the opening of the pyrrolinone ring is carried out with an inorganic base at a temperature of between 0 and 50°C and, preferably, of between 0 and 3 0°C.
Generally, the process is carried out by stirring an aqueous/organic solution of the compound of formula (II) in the presence of an excess of inorganic base which is a hydroxide, carbonate or bicarbonate of an alkali or alkaline-earth metal. It is particularly advantageous to 2 0 use sodium hydroxide as inorganic base and to work in a water-pyridine mixture. It is also possible to carry out the reaction in a water-dioxane mixture.
The racemic compound of formula (I) can also be obtained by action of an inorganic base on the compound of
The racemic compound of formula (I) can be
24 3 49
- 3a -
formula:
ci
(III)
This reaction is also described and claimed in 10 New Zealand patent application no. 243495.
Generally, at least two equivalents of the inorganic base, preferably sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, are used, and the reaction is effected in water or an aqueous 15 sorganic medium at a temperature of between 0 and 50°C,
/. i /. ft ri v: "I $
preferably between 0 and 30°C. A dioxane-water mixture is preferably used as aqueous organic medium.
The compound of formula (III) can be obtained by hydrolysis in acid medium of a compound of formula:
ROCO
(IV)
in which R represents an alkyl radical containing 1 to 10 carbon atoms in a straight or branched chain. Generally, the hydrolysis is carried out with a strong inorganic acid such as concentrated sulphuric acid while working at a temperature of between 0 and 50°C, preferably approximately 15 20°C.
The compounds of formulae (III) and (IV) can be obtained under the conditions described in United States Patent No. 4,960,779.
The following Examples illustrate the present
invention.
EXAMPLE 1
250 g of 2-{1-[(7-chloro-l,8-naphthyridin-2-yl)amino]-6-methyl-3-oxoheptyl}benzoic acid, 97 g of (+)-25 ephedrine and 875 cm3 of 95% (v/v) ethanol are introduced, at a temperature of approximately 20°C, into a 2 litre reactor. After dissolving the suspension at 40°C, the
F
/■
3 4 9
reaction mixture is cooled to approximately 2°C. The precipitate obtained is separated by filtration, washed with 2 times 125 cm3 of 95% (v/v) ethanol at 2°C and then dried for 16 hours at 60°C under reduced pressure (15 mm of 5 mercury; 2.0 kPa). 156.6 g of the salt of (+)-ephedrine and ( + )—2 — {1—[(7-chloro-l,8-naphthyridin-2-yl)amino]-6-methyl-3-oxoheptyl}benzoic acid are thus obtained in the form of a white product whose characteristics are the following: - optical rotation: [a]f)"=-64° (c=l; methylene chloride) 10 - enantiomeric purity: 100%.
of N-methylpyrrolidone are introduced into a 50 cm3 round bottom flask. 1.2 cm3 concentrated hydrochloric acid and then, over 10 minutes, 15 cm3 of distilled water are added 15 while maintaining the temperature at 20°C. The suspension obtained is filtered. The precipitate is washed with 5 times 10 cm3 of distilled water and then dried for 16 hours at 600C under reduced pressure (15 mm of mercury; 2.0 kPa).
2-yl)amino]-6-methyl-3-oxoheptyl}benzoic acid are thus obtained in the form of a white product whose characteristics are the following:
- optical rotation: [a]o-+222.8° (c=l; methylene chloride)
- enantiomeric purity: 100%.
2-{1-[ (7-chloro-l,8-naphthyridin-2-yl)amino]-
6-methyl-3-oxoheptyl}benzoic acid can be prepared according to one of the following methods:
2.7 5 g of the salt obtained previously and 5 cm'
1.97 g of (+)-2-{l-[(7-chloro-l,8-naphthyridin-
n / 7 /. Q 0
/> /.: i i- s, y* ;£«» ' i Ll. ;- 6 - ;1) 1400 cm3 of dioxane and 20 g of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)- ;1-isoindolinone are introduced, at a temperature of approximately 20°C, into a stirred, 2 litre reactor. 244 ;5 cm3 of a N aqueous solution of sodium hydroxide are added over 5 minutes. The mixture is left to react for 4 days at a temperature below 30°C. ;The dioxane is removed by distillation under reduced pressure (4 0 mm of mercury; 5.3 kPa) at a 10 temperature below 30°C. 100 cm3 of distilled water are added during the distillation. ;An insoluble product is removed by filtration at 20°C. This product is washed with 3 times 50 cm3 of distilled water and is removed. The combined aqueous phases 15 are acidified by addition, over 3 hours, of 48 cm' of 5N hydrochloric acid at a temperature of 20°C. The pH of the suspension is then approximately 3.5. ;After filtering the suspension, the precipitate is washed with 6 times 100 cm3 of distilled water and is 20 then dried under reduced pressure (15 mm of mercury; 2.0 kPa) at 60°C for 16 hours. ;14.3 g of 2-{1—[(7-chloro-l,8-naphthyridin- ;2-yl)amino]-6-methyl-3-oxoheptyl}benzoic acid are thus obtained in the form of a white product whose retention ;25 time is 4.8 minutes by high performance liquid chromatography using a column 25 cm long and 0.4 6 cm in diameter with "Lichrospher O.D.S. 5 fj.m" as the stationary ;- 7 - ;phase and a mixture of 200 cm3 of pH 3, 25 mM phosphate buffer, 560 cm3 of acetonitrile and 240 cm3 of methanol, at a flow rate of 0.8 cm3/minute, as mobile phase. ;2-(7-chloro-l,8-naphthyridin-2-yl)-3-(5-methyl-5 2-oxohexyl)-1-isoindolinone can be prepared according to the method described in United States Patent No. 4,960,779, ;2) 20 g of 2-(7-chloro-l,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone, 400 cm3 of pyridine and 60 cm3 of a 2N aqueous sodium hydroxide ;10 solution are introduced, at a temperature of approximately 20°C, into a stirred, 1 litre reactor. The mixture is left to react for 23 hours and the pyridine is then distilled under reduced pressure (15 mm of mercury) at a temperature below 20°C. 500 cm3 of distilled water are added. An 15 insoluble material is separated by filtration. The aqueous phase is acidified to pH = 3.8 by addition of 40 cm3 of 4N hydrochloric acid. The suspension is filtered, the precipitate is washed with 5 times 140 cm3 of distilled water and then dried for 16 hours under reduced pressure 20 (15 mm of mercury; 2.0 kPa) at 60°C. ;19.2 g of 2-{l-[(7-chloro-l,8-naphthyridin-2-yl)amino]-6-methyl-3-oxoheptyl}benzoic acid are thus obtained in the form of a white product whose retention time by high performance liquid chromatography is 4.8 25 minutes under the conditions described previously. ;3) A suspension of 30 mg of 2-[2-(7-chloro- ;1,8-naphthyridin-2-yl)-3-oxo-l-isoindolinyl]-6-methyl- ;o /, 7 A f* f\
Z 4 v) 4 9 £
3-oxoheptanoic acid in 4.7 cm3 of distilled water and 1.32 cm3 of a 0.1N aqueous sodium hydroxide solution is stirred at a temperature of approximately 2 0°C for 72 hours. An insoluble product is removed by filtration and 5 the filtrate is acidified to a pH = 2 by addition of a 0.1N aqueous hydrochloric acid solution. The precipitate obtained is separated by filtration, washed with water and dried in air. 10 mg of 2-{1-[(7-chloro-l,8-naphthyridin-
2-yl)amino]-6-methyl-3-oxoheptyl}benzoic acid are thus 10 obtained whose characteristics are identical to those of the product obtained previously.
2-[2-(7-chloro-l, 8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl]-6-methyl-3-oxoheptanoic acid can be prepared in the following manner:
A solution of 23 g of ethyl 2—[2—(7-chloro-
1,8-naphthyridin-2-yl)-3-oxo-l-isoindolinyl]-6-methyl-
3-oxoheptanoate in 235 cm3 of 98% sulphuric acid is stirred for 20 hours at a temperature of approximately 20°C and is then poured into 1.5 kg of ice. The precipitate obtained is
2 0 separated by filtration, washed with water to a pH = 6 and dried in air. The solid obtained is taken up in 3.8 litres of distilled water and 480 cm3 of a 0.1N aqueous sodium hydroxide solution. The insoluble product is separated by filtration, the filtrate is acidified to a pH = 3 by 25 addition of a 0.1N aqueous hydrochloric acid solution. The precipitate obtained is separated by filtration, washed with distilled water and then with isopropyl ether and
Ik 3 4 9
dried at 20°C under reduced pressure (0.07 kPa). 9.2 g of
2-[2-(7-chloro-l,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl]-6-methyl-3-oxoheptanoic acid, melting at 176°C, are thus obtained.
Ethyl 2 — [2 —(7-chloro-l,8-naphthyridin-2-yl)-
3-oxo-l-isoindolinyl]-6-methyl-3-oxoheptanoate can be obtained by the method described in United States Patent No. 4,960,779.
EXAMPLE 2
20 g of the dextrorotatory acid obtained under the conditions described in Example 1 and 21.8 g of imidazole are dissolved in 400 cm3 of methylene chloride in a 1 litre reactor. 7 cm3 of thionyl chloride are introduced, using a syringe, at a temperature of 20°C. The 15 suspension is heated at reflux for 30 minutes and is then cooled to 20°C and washed 2 times with 200 cm3 of distilled water. The solution is concentrated, at atmospheric pressure, to half its volume and then 450 cm3 of absolute ethanol are added. The distillation of the methylene 20 chloride is continued until the temperature of the vapours reaches 78°C. 1 g of decolorising charcoal is then added and the mixture is left for one hour at 78°C. The suspension is filtered. The precipitate is washed with 50 cm3 of absolute ethanol at 75°C. The filtrate and the 25 washes are combined and then cooled to 15°C over 2 hours. The suspension is filtered. The precipitate is washed with 3 times 35 cm3 of absolute ethanol at 15°C and then dried
2 4 /> 4 9
at 60°C for 16 hours under reduced pressure (15 mm of mercury; 2.0 kPa). 16.8 g of (+)-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone are thus obtained in the form of a fluffy 5 white product whose characteristics are the following:
- optical rotation: [q]d°=+132° (c=l; methylene chloride)
- enantiomeric purity: 98.8%.
EXAMPLE 3
118.3 g of the salt of (+)-ephedrine and (+)-2-10 {l-[(7-chloro-l,8-naphthyridin-2-yl)amino]-6-methyl-3-oxoheptyl}benzoic acid and 1700 cm3 of methylene chloride are introduced into a 2.5 litre reactor. The organic solution is washed, at 20°C, with 400 cm3 of a 0.5N aqueous hydrochloric acid solution and then 400 cm3 of distilled 15 water. The organic phase is dehydrated by azeotropic distillation at 20°C under reduced pressure (250 mm of mercury; 33.3 kPa). The volume of the organic phase is adjusted to 1700 cm3 by addition of dry methylene chloride, 95.2 g of imidazole are then added and then, over 10 20 minutes, 25 cm3 of thionyl chloride. The suspension is heated at 40°C for 30 minutes, then cooled to 20°C and washed with 2 times 700 cm3 of distilled water. The methylene chloride is removed by distillation at atmospheric pressure while adding, to keep the volume 25 constant, 2500 cm3 of absolute ethanol. When the temperature of the vapour reaches 78°C, the distillation is halted and 4 g of decolorising charcoal in suspension in
<•' ( ~7 [.
L '7 -J 4
cm3 of absolute ethanol are added. The mixture is left for 30 minutes at 78°C and then filtered while hot. The decolorising charcoal is rinsed with 200 cm3 of ethanol at 77°C. The wash and the filtrate are combined and then 5 cooled, at a rate of 20°C/hour, to a temperature of 10°C. The suspension is filtered. The precipitate is washed with 3 times 140 cm3 of absolute ethanol at 10°C and then dried at 60°C for 16 hours under reduced pressure (15 mm of mercury; 2.0 kPa). The slightly yellow product obtained 10 (68.9 g) is recrystallised from 1400 cm3 of ethanol at reflux. After cooling to 10°C, the suspension is filtered. The precipitate is washed with 3 times 100 cm3 of absolute ethanol at 10°C and then dried at 60°C for 16 hours under reduced pressure (15 mm of mercury; 2.0 kPa) . 65.1 g of 15 (+)-2-(7-chloro-l,8-naphthyridin-2-yl)-3-(5-methyl-
2-oxohexyl)-1-isoindolinone are thus obtained in the form of a fluffy white product whose characteristics are the following:
- optical rotation: [a]12)°=+132° (c=l; methylene chloride) 20 - enantiomeric purity: 100%.
*
24 3 49 2
Claims (9)
1. Process for the preparation of the dextrorotatory isomer of the compound of formula: which comprises forming a salt of the corresponding 5 racemic product with (+)-ephedrine, separating the salt of the dextrorotatory isomer, and releasing the dextrorotatory isomer from its salt.
2. Process according to claim 1, in which the salt of the dextrorotatory compound of formula (I) 10 with (+)-ephedrine is precipitated from an organic solvent.
3. A process according to claim 2 in which the organic solvent is ethanol.
4. Process according to claim 1, 2 or 3 in 15 which the release of the dextrorotatory isomer of the compound of formula (I) is carried out with a strong acid.
5. Process according to claim 4 in which the strong acid is hydrochloric acid. 20
6. Process according to claim 1 substantially as described in Example 1. 24 3 4 - 13 -
7. The dextrorotatory isomer of the compound of formula: when prepared by the process according to any one of claims 1 to 6.
8 . Use of the product according to claim 7 for the preparation of the dextrorotatory isomer of the compound of formula:
9. Use according to claim 8 substantially as described in Example 2 or 3. &.Js2fcr.A By the authorised events A J PARK & SON Do 7Z^
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9108828A FR2678932B1 (en) | 1991-07-12 | 1991-07-12 | PROCESS FOR THE PREPARATION OF OPTICAL ISOMERS OF A DERIVATIVE OF AMINO-2 NAPHTYRIDINE. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NZ243492A true NZ243492A (en) | 1995-03-28 |
Family
ID=9415046
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NZ243492A NZ243492A (en) | 1991-07-12 | 1992-07-09 | Process for the preparation of the dextrorotatory isomer of a 2-aminonaphthyridine derivative intermediate compound using (+) ephedrine |
Country Status (13)
| Country | Link |
|---|---|
| EP (2) | EP0595964A1 (en) |
| JP (1) | JPH06509085A (en) |
| KR (1) | KR100235375B1 (en) |
| AU (1) | AU657569B2 (en) |
| CA (1) | CA2112981C (en) |
| FR (1) | FR2678932B1 (en) |
| IE (1) | IE72508B1 (en) |
| IL (1) | IL102444A0 (en) |
| MA (1) | MA22587A1 (en) |
| MX (1) | MX9204057A (en) |
| NZ (1) | NZ243492A (en) |
| WO (1) | WO1993001189A1 (en) |
| ZA (1) | ZA925101B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2678934B1 (en) * | 1991-07-12 | 1995-01-13 | Rhone Poulenc Rorer Sa | PROCESS FOR THE PREPARATION OF THE DEXTROGYRE ISOMER OF AN ISOINDOLINONE DERIVATIVE. |
| FR2678933B1 (en) * | 1991-07-12 | 1993-09-24 | Rhone Poulenc Rorer Sa | PROCESS FOR THE PREPARATION OF OPTICAL ISOMERS OF A DERIVATIVE OF AMINO-2 NAPHTYRIDINE. |
| AU783516B2 (en) | 2001-04-30 | 2005-11-03 | Warner-Lambert Company | Methods, kits and compositions for using pyrrole derivatives |
| DK1490363T3 (en) | 2002-03-29 | 2006-05-15 | Indevus Pharmaceuticals Inc | Methods for Preparation of 2-7-Chloro-1,8-naphthyridin-2-yl) -3- (5-methyl-2-oxo-hexyl) 1-isoindolinone |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2313060A1 (en) * | 1974-11-07 | 1976-12-31 | Rhone Poulenc Ind | Pyrrolidinone deriirrivs as tranquillizers - 1-Heterocyclyl-5(1-piperazinyl-carbonyloxy)-2(5H)-pyrrolidinone derivs prepd. from 5-aryloxycarbonyloxy cpds. and piperazine (OE060576) |
| FR2321290A1 (en) * | 1975-04-07 | 1977-03-18 | Rhone Poulenc Ind | 1,8-naphthyridine tranquillisers, e hypnotics, anti-epileptics etc. - 2-substd. by isoindoline, pyrrolo-(3,4-b)-pyrazines, pyrrolo-(3,4-b)-pyridine or oxathino-(1,4)(2,3-c)-pyrrole |
| FR2607503B1 (en) * | 1986-12-02 | 1989-02-24 | Rhone Poulenc Sante | NOVEL ISOINDOLINONE DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| FR2678931B1 (en) * | 1991-07-12 | 1993-09-24 | Rhone Poulenc Rorer Sa | NEW DERIVATIVE OF AMINO-2 NAPHTYRIDINE, ITS PREPARATION AND ITS USE. |
| FR2678933B1 (en) * | 1991-07-12 | 1993-09-24 | Rhone Poulenc Rorer Sa | PROCESS FOR THE PREPARATION OF OPTICAL ISOMERS OF A DERIVATIVE OF AMINO-2 NAPHTYRIDINE. |
-
1991
- 1991-07-12 FR FR9108828A patent/FR2678932B1/en not_active Expired - Lifetime
-
1992
- 1992-07-08 IL IL102444A patent/IL102444A0/en unknown
- 1992-07-08 ZA ZA925101A patent/ZA925101B/en unknown
- 1992-07-08 MA MA22871A patent/MA22587A1/en unknown
- 1992-07-09 NZ NZ243492A patent/NZ243492A/en not_active IP Right Cessation
- 1992-07-09 IE IE922236A patent/IE72508B1/en not_active IP Right Cessation
- 1992-07-10 KR KR1019940700066A patent/KR100235375B1/en not_active IP Right Cessation
- 1992-07-10 JP JP5502045A patent/JPH06509085A/en active Pending
- 1992-07-10 MX MX9204057A patent/MX9204057A/en unknown
- 1992-07-10 WO PCT/FR1992/000668 patent/WO1993001189A1/en not_active Application Discontinuation
- 1992-07-10 CA CA002112981A patent/CA2112981C/en not_active Expired - Lifetime
- 1992-07-10 AU AU23608/92A patent/AU657569B2/en not_active Expired
- 1992-07-10 EP EP92916241A patent/EP0595964A1/en not_active Withdrawn
- 1992-07-10 EP EP92402005A patent/EP0522970A1/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| JPH06509085A (en) | 1994-10-13 |
| MA22587A1 (en) | 1993-04-01 |
| CA2112981A1 (en) | 1993-01-21 |
| KR100235375B1 (en) | 1999-12-15 |
| ZA925101B (en) | 1993-04-28 |
| AU2360892A (en) | 1993-02-11 |
| IE922236A1 (en) | 1993-01-13 |
| WO1993001189A1 (en) | 1993-01-21 |
| MX9204057A (en) | 1993-07-01 |
| FR2678932A1 (en) | 1993-01-15 |
| IE72508B1 (en) | 1997-04-23 |
| FR2678932B1 (en) | 1993-09-24 |
| CA2112981C (en) | 2004-03-30 |
| AU657569B2 (en) | 1995-03-16 |
| IL102444A0 (en) | 1993-01-14 |
| EP0595964A1 (en) | 1994-05-11 |
| EP0522970A1 (en) | 1993-01-13 |
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