CS244908B2 - Preparation method of 2,4-diamino-5-/3,4,5-trimethoxybenzyl/-pyramidine - Google Patents
Preparation method of 2,4-diamino-5-/3,4,5-trimethoxybenzyl/-pyramidine Download PDFInfo
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- CS244908B2 CS244908B2 CS824717A CS471782A CS244908B2 CS 244908 B2 CS244908 B2 CS 244908B2 CS 824717 A CS824717 A CS 824717A CS 471782 A CS471782 A CS 471782A CS 244908 B2 CS244908 B2 CS 244908B2
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- formula
- guanidine
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- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 125000005806 3,4,5-trimethoxybenzyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1C([H])([H])* 0.000 title description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims abstract description 30
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims abstract description 15
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 11
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 claims abstract description 11
- -1 ethylene glycol monoalkylether Chemical class 0.000 claims abstract description 8
- 238000002955 isolation Methods 0.000 claims abstract description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims abstract 10
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract 4
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract 3
- RMKSZKNEPFLURM-UHFFFAOYSA-N 2-(methoxymethyl)-3-(3,4,5-trimethoxyphenyl)prop-2-enenitrile Chemical compound COCC(C#N)=CC1=CC(OC)=C(OC)C(OC)=C1 RMKSZKNEPFLURM-UHFFFAOYSA-N 0.000 claims abstract 2
- OPHQOIGEOHXOGX-UHFFFAOYSA-N 3,4,5-trimethoxybenzaldehyde Chemical compound COC1=CC(C=O)=CC(OC)=C1OC OPHQOIGEOHXOGX-UHFFFAOYSA-N 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 229960001082 trimethoprim Drugs 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 3
- 239000011541 reaction mixture Substances 0.000 claims 3
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 claims 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims 2
- 239000002253 acid Substances 0.000 claims 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims 2
- 150000003839 salts Chemical class 0.000 claims 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims 1
- OOWFYDWAMOKVSF-UHFFFAOYSA-N 3-methoxypropanenitrile Chemical compound COCCC#N OOWFYDWAMOKVSF-UHFFFAOYSA-N 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims 1
- 239000002585 base Substances 0.000 claims 1
- 238000009835 boiling Methods 0.000 claims 1
- 238000001816 cooling Methods 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 239000003960 organic solvent Substances 0.000 claims 1
- 238000007363 ring formation reaction Methods 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
- 239000000725 suspension Substances 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 abstract 1
- 230000000973 chemotherapeutic effect Effects 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 4
- 239000007859 condensation product Substances 0.000 description 3
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 150000008360 acrylonitriles Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 125000002560 nitrile group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
- C07D239/49—Two nitrogen atoms with an aralkyl radical, or substituted aralkyl radical, attached in position 5, e.g. trimethoprim
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
Vynález se týká zlepšeného způsobu přípravy 2,4 diamino-5-(3‘,4‘,5‘-trimethoxyben- . zyljpyrimidinu reakcí sloučeniny obecného vzorce IIThe invention relates to an improved process for the preparation of 2,4 diamino-5- (3 ‘, 4‘, 5‘-trimethoxybenzyl) pyrimidine by reacting a compound of formula II
CNCN
CH,OCH, O
IAND
CH.~C z IICH. ~ C of II
CH-O-CH-CHO í ž· (I) kdeCH-O-CH-CHO 2 (I) wherein
R představuje alkylskupinu obsahující 1 až 4 atomy uhlíku, s guanidinem.R is C 1 -C 4 alkyl, with guanidine.
2,4-dinmino-5- (3',4‘,5‘-trimethoxybenzyl)pyrimidin vzorce I2,4-Dinmino-5- (3 ', 4', 5'-trimethoxybenzyl) pyrimidine of formula I
СЩ0 je dobře známou chemoterapeutickou látkou, označovanou dále jako Trimethoprim.S10 is a well known chemotherapeutic agent, hereinafter referred to as Trimethoprim.
Je známo několik způsobů přípravy sloučeniny vzorce I, přičemž některé z těchto postupů probíhají přes ^-(3,4,5^^^11(^benzyl )-/3-( substituované) akrylonitrily.Several methods for the preparation of a compound of formula I are known, some of which are carried out via 4- (3,4,5-dimethyl-11 (4-benzyl) - [3- (substituted) acrylonitriles).
Podle maďarského patentu č. 149 799 seAccording to Hungarian patent no
3,4,5-trimethoxyb2nzyldehyd kondenzuje s /З-alkoxypropionitrilem. Výtěžek kondenzační reakce je vyšší než 80 % a kondenzační produkt, který se takto získá, se skládá asi z 80 % a-(3,4,5-trime1^t^c^x^y^fc^e^r^2^al)-3-alk^c^- xypropionitrilu a 20 % a-(3,4,5-trimethoxybenzyl)-/--alkoxyakrylonitrilu. Kondenzační produkt se pak nechá reagovat s guanidinem. Reakce s guanidinem se vsak zúčastňuje pouze benzylderivát, zatímco benzalsloučenina se isomeruje na benzylderivát prakticky jen ve velmi malém rozsahu. Výtěžek Trimethoprimu proto nepřekračuje 28 proč, a celkový výtěžek vztažený na 3,4,5-trimethoxybenzaldehyd není vyšší než 20 až 24 %.3,4,5-trimethoxybenzyl aldehyde is condensed with N-alkoxypropionitrile. The yield of the condensation reaction is greater than 80%, and the condensation product thus obtained consists of about 80% of α- (3,4,5-trimethyl-3,4-trimethyl) -cyclohexylamine. a1) -3-alk-4-xypropionitrile and 20% of α- (3,4,5-trimethoxybenzyl) - N -alkoxyacrylonitrile. The condensation product is then reacted with guanidine. However, only the benzyl derivative is involved in the reaction with guanidine, whereas the benzalic compound is practically only isomerised to the benzyl derivative to a very small extent. Therefore, the yield of Trimethoprim does not exceed 28 why, and the total yield based on 3,4,5-trimethoxybenzaldehyde is not more than 20 to 24%.
Podle maďarského patentu č. 162 316 se shora uvedený známý postup ekonomizuje tím, že se kondenzuje 3,4,5--rimethoxybenzaldehyd s /-alkoxχpropi(cnitгilem, takto získaný kondenzační produkt se nechá reagovat s aminem, získaný derivát a-(3,4,n-trimethoxybenzal)-/--aminopгopionitrilu se iso merizuje na odpovídající benzylderivát, který se nechává reagovat s guanidinem. Celkový výtěžek Trimethoprimu vztažený naAccording to Hungarian Patent No. 162,316, the above known process is economized by condensing 3,4,5-rimethoxybenzaldehyde with .alpha.-alkoxy-propi (cnitgil), the thus obtained condensation product is reacted with an amine, the obtained derivative of α- (3, The 4, n-trimethoxybenzal-1-aminopogopionitrile is isolated to the corresponding benzyl derivative which is reacted with guanidine.
3,4,5-trimethoxybenzaldehydovou výchozí látku je však jen prostřední.However, the 3,4,5-trimethoxybenzaldehyde starting material is only intermediate.
Podle maďarského patentu č. 174 318 seAccording to Hungarian patent no
3,4,5-trimethoxybenzaldehyd nechává reagovat s ^-(2-alkoxyethoxy)propionitrilem. Tak se získá a-(3,4,5-trimethoxybenzal)-/3-(2-alkoxyethoxy Jpropionitril obecného vzorce Ila3,4,5-trimethoxybenzaldehyde is reacted with 4- (2-alkoxyethoxy) propionitrile. There was thus obtained .alpha .- (3,4,5-trimethoxybenzal) -3- (2-alkoxyethoxy) propionitrile of the formula IIIa.
kdewhere
R má shora uvedený význam, ve výtěžku nad 80 %, který se pak izoluje, důkladně vyčistí, podrobí isomerizaci při 90 až 95 °C v přítomnosti zásady na odpovídající benzylisomer obecného vzorce II, který se pak nechává reagovat s guanidinem. Výtěžek Trimethoprimu je v tomto případě asi 80 %. Celkový výtěžek výroby Trimethoprimu v laboratorním měřítku je asi 64 až 72 proč.R is as defined above, in a yield of over 80% which is then isolated, thoroughly purified, subjected to isomerization at 90 to 95 ° C in the presence of a base to the corresponding benzylisomer of formula II, which is then reacted with guanidine. The yield of Trimethoprim in this case is about 80%. The overall production yield of Trimethoprim on a laboratory scale is about 64-72 why.
Ačkoliv je shora uvedený postup podstatně ekonomičtější než dříve popsané metody, jeho provádění v průmyslovém měřítku se setkalo s vážnými potížemi. Při reakciAlthough the above process is considerably more economical than the previously described methods, its implementation on an industrial scale has encountered serious difficulties. In reaction
3,4,5-trimethoxybenzaldehydu a β- (2-alkoxyethoxy)propionitrilu vzniká voda, která se oddestilovává při vysoké teplotě asi 120 stupňů Celsia. Při této vysoké teplotě dochází к hydrolýze ar-( 3,4,5-trimethoxybenzal ) -β- (2-alkoxyethoxy) propionitrilu působením přítomné vody.3,4,5-trimethoxybenzaldehyde and β- (2-alkoxyethoxy) propionitrile produce water which is distilled off at a high temperature of about 120 degrees Celsius. At this high temperature, ar- (3,4,5-trimethoxybenzal) -β- (2-alkoxyethoxy) propionitrile is hydrolyzed by the presence of water.
Podle provedených pokusů se hydrolyzuje nitrilová skupina a vzniká v množství několika procent odpovídající karboxylová kyselina. Tato vedlejší reakce způsobu vznik dehtovitých vedlejších produktů, jejichž množství se značně zvyšuje se zvyšující se velikostí dávky. Celkový výtěžek v laboratorním měřítku 64 až 72 °/o, klesá na asi 50 až 55 % již při velikosti dávky asi 10 molů. Lze konstatovat, že shora uvedený známý postup je neuspokojivý z ekonomického hlediska.According to the experiments carried out, the nitrile group is hydrolyzed and the corresponding carboxylic acid is formed in several percent. This side reaction of the process results in tarry by-products, the amount of which is greatly increased with increasing batch size. The overall yield on a laboratory scale of 64-72% decreases to about 50-55% already at a batch size of about 10 moles. It can be stated that the above known process is unsatisfactory from an economic point of view.
Úkolem vynálezu je vyvinutí ekonomického způsobu přípravy 2,4-diamino-5-(3‘,4‘,5‘-trimethoxybenzyl) pyrimidinu v průmyslovém měřítku.SUMMARY OF THE INVENTION It is an object of the present invention to provide an economical process for the preparation of 2,4-diamino-5- (3 ‘, 4‘, 5‘-trimethoxybenzyl) pyrimidine on an industrial scale.
Zjistilo se, že a-(3,4,5-triinethoxybenzal)-/ϊ-methoxypropionitril vzorce IIIIt has been found that α- (3,4,5-triinethoxybenzal) - ϊ-methoxypropionitrile of formula III
se může transetherifikovat na odpovídající benzalisomer obecného vzorce Ila takřka v kvantitativním výtěžku reakcí s ethylenglykoimonoalkyletherem obecného vzorce IVcan be transetherified to the corresponding benzalisomer of formula IIIa in almost quantitative yield by reaction with an ethylene glycoimonoalkyl ether of formula IV
HO—CH2—CH2—OR (IV) kdeHO — CH 2 —CH 2 —OR (IV) wherein
R má shora uvedený význam, a sloučenina obecného vzorce Ila se může snadno převést na odpovídající benzylisomer obecného vzorce II téměř s teoretickým výtěžkem. Získaný benzylisomer obecného vzorce II je tak čistý, že se může nechat reagovat bez izolace a čištění s guanidinem za vzniku Trimethoprimu.R is as defined above, and the compound of formula IIa can be easily converted to the corresponding benzylisomer of formula II in almost theoretical yield. The benzylisomer of formula (II) obtained is so pure that it can be reacted without isolation and purification with guanidine to form Trimethoprim.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU811869A HU187370B (en) | 1981-06-26 | 1981-06-26 | Improved process for producing 2,4-diamino-5-bracket-3-comma above, 4-comma above,5-comma above-trimethoxy-benzyl-bracket closed-pyrimidine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CS471782A2 CS471782A2 (en) | 1985-09-17 |
| CS244908B2 true CS244908B2 (en) | 1986-08-14 |
Family
ID=10956594
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS824717A CS244908B2 (en) | 1981-06-26 | 1982-06-24 | Preparation method of 2,4-diamino-5-/3,4,5-trimethoxybenzyl/-pyramidine |
Country Status (21)
| Country | Link |
|---|---|
| JP (1) | JPS5838266A (en) |
| AT (1) | AT387961B (en) |
| AU (1) | AU547823B2 (en) |
| BE (1) | BE893611A (en) |
| CA (1) | CA1174679A (en) |
| CH (1) | CH648834A5 (en) |
| CS (1) | CS244908B2 (en) |
| DD (1) | DD202703A5 (en) |
| DK (1) | DK155434C (en) |
| ES (1) | ES513482A0 (en) |
| FI (1) | FI76790C (en) |
| FR (1) | FR2508450B1 (en) |
| GB (1) | GB2104508B (en) |
| GR (1) | GR76159B (en) |
| HU (1) | HU187370B (en) |
| IE (1) | IE53466B1 (en) |
| IL (1) | IL66132A (en) |
| IT (1) | IT1190889B (en) |
| SE (1) | SE451133B (en) |
| SU (1) | SU1145929A3 (en) |
| YU (1) | YU42774B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2602507B1 (en) * | 1986-08-08 | 1989-06-09 | Sanofi Pharma | PROCESS FOR THE PREPARATION OF 2,4-DIAMINO-BENZYL-5 PYRIMIDINES |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB743221A (en) * | 1953-05-26 | 1956-01-11 | Wellcome Found | Improvements in or relating to the manufacture of acrylonitriles |
| DE1303727B (en) * | 1959-09-03 | 1976-02-05 | Ausscheidung aus: 14 45 176 The Wellcome Foundation Ltd., London | Alpha-arylidene-substituted propioni-iriles |
| NL122146C (en) * | 1960-09-02 | |||
| US4033962A (en) * | 1975-06-26 | 1977-07-05 | Hoffman-La Roche Inc. | 2,4-Diamino-pyrimidine derivatives and processes |
| DE2635765C3 (en) * | 1976-08-09 | 1979-02-08 | Ludwig Heumann & Co Gmbh, 8500 Nuernberg | Process for the preparation of 2,4-EMamino-5- (3 ', 4'r5'-trimethoxybenzyl) -pyrimidine |
| US4115650A (en) * | 1976-11-17 | 1978-09-19 | Hoffmann-La Roche Inc. | Process for preparing 2,4-diamino-5-(substituted benzyl)-pyrimidines |
| DE2730467A1 (en) * | 1977-07-06 | 1979-01-18 | Basf Ag | BENZYLPYRIMIDINE, METHOD FOR THE PRODUCTION THEREOF, AND MEDICINAL PRODUCTS CONTAINING THE SAME |
-
1981
- 1981-06-26 HU HU811869A patent/HU187370B/en not_active IP Right Cessation
-
1982
- 1982-06-23 SE SE8203914A patent/SE451133B/en not_active IP Right Cessation
- 1982-06-23 BE BE1/10544A patent/BE893611A/en not_active IP Right Cessation
- 1982-06-24 IT IT22035/82A patent/IT1190889B/en active
- 1982-06-24 SU SU823456294A patent/SU1145929A3/en active
- 1982-06-24 GR GR68560A patent/GR76159B/el unknown
- 1982-06-24 IL IL66132A patent/IL66132A/en unknown
- 1982-06-24 AT AT0244982A patent/AT387961B/en not_active IP Right Cessation
- 1982-06-24 GB GB08218310A patent/GB2104508B/en not_active Expired
- 1982-06-24 FI FI822268A patent/FI76790C/en not_active IP Right Cessation
- 1982-06-24 CS CS824717A patent/CS244908B2/en unknown
- 1982-06-25 DD DD82241097A patent/DD202703A5/en not_active IP Right Cessation
- 1982-06-25 YU YU1385/82A patent/YU42774B/en unknown
- 1982-06-25 AU AU85346/82A patent/AU547823B2/en not_active Ceased
- 1982-06-25 DK DK288082A patent/DK155434C/en not_active IP Right Cessation
- 1982-06-25 CA CA000406060A patent/CA1174679A/en not_active Expired
- 1982-06-25 ES ES513482A patent/ES513482A0/en active Granted
- 1982-06-25 CH CH3908/82A patent/CH648834A5/en not_active IP Right Cessation
- 1982-06-25 FR FR8211151A patent/FR2508450B1/en not_active Expired
- 1982-06-25 JP JP57109647A patent/JPS5838266A/en active Pending
- 1982-06-25 IE IE1520/82A patent/IE53466B1/en not_active IP Right Cessation
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