IE53466B1 - Improved process for the preparation of 2,4-diamino-5-(3',4',5'-trimethoxy-benzyl)-pyrimidine - Google Patents
Improved process for the preparation of 2,4-diamino-5-(3',4',5'-trimethoxy-benzyl)-pyrimidineInfo
- Publication number
- IE53466B1 IE53466B1 IE1520/82A IE152082A IE53466B1 IE 53466 B1 IE53466 B1 IE 53466B1 IE 1520/82 A IE1520/82 A IE 1520/82A IE 152082 A IE152082 A IE 152082A IE 53466 B1 IE53466 B1 IE 53466B1
- Authority
- IE
- Ireland
- Prior art keywords
- general formula
- compound
- trimethoxy
- reacting
- guanidine
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 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 title claims abstract description 10
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims abstract description 34
- 150000001875 compounds Chemical class 0.000 claims abstract description 20
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims abstract description 17
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims abstract description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 9
- -1 ethylene glycol monoalkylether Chemical class 0.000 claims abstract description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000002955 isolation Methods 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 5
- 150000004703 alkoxides Chemical class 0.000 claims description 5
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims 1
- 230000000973 chemotherapeutic effect Effects 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 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 abstract 1
- 229910052783 alkali metal Inorganic materials 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 229960004198 guanidine Drugs 0.000 description 13
- OPHQOIGEOHXOGX-UHFFFAOYSA-N 3,4,5-trimethoxybenzaldehyde Chemical compound COC1=CC(C=O)=CC(OC)=C1OC OPHQOIGEOHXOGX-UHFFFAOYSA-N 0.000 description 11
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 11
- 229960001082 trimethoprim Drugs 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 5
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000007859 condensation product Substances 0.000 description 2
- 229940093476 ethylene glycol Drugs 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 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
- 239000013078 crystal Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229960000789 guanidine hydrochloride Drugs 0.000 description 1
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 125000002560 nitrile group Chemical group 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001701 trimethoxybenzyl group Chemical group 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
The invention relates to an improved process for the preparation of 2,4-diamino-5-(3',4',5'-trimethoxy-benzyl)-pyrimidine of the general formula I by reacting a compound of the general formula II (wherein R is an alkyl group having 1-4 carbon atoms) with guanidine, which comprises preparing the said compound of the general formula II by reacting alpha -(3,4,5-trimethoxy-benzal)- beta -methoxy-propionitrile of the formula III with ethylene glycol monoalkylether of the general formula IV HO-CH2-CH2-OR (IV> (wherein R as as stated above) in the presence of an alkali metal alkoxide at a temperature between 60 DEG and 90 DEG and reacting the compound of the general formula II thus obtained - if desired without isolation - with guanidine in the presence of an alkanol having 4-8 carbon atoms. The advantage of the process is that it is economical and can be carried out with high yields even on industrial scale and provides a product of high purity. The compound of the formula I obtained is a known chemotherapeutical drug.
Description
This invention relates to an improved process for ths preparation of 2,4-diamino-5-{3·,4’,5’-trimethoxybsnzyl)-pyrimidine by reacting a compound of the general formula II
(wherein R is an alkyl group having 1-4 carbon atoms) with guanidine.
The a/^-diamino-S-iS’ ,4’ ,5’-trimethoxy-benzyl)pyrimidine of the formula I
is a well known chemotherapeutical drug (referred to further onas Trimethoprim),
Several procedures are known for ths preparation of the compound of the formula I; some of the said processes take place via a-(3,4,5-trimethoxy-benzyl)-fl(substituted)-acrylic-nitriles.
According to Hungarian Patent No. 149,799 3,4,5-trimethoxy-benzaldehyde is condensed with fi-alkoxy-propionitrile. The yield of the condensation reaction is higher than 80 % and the condensation product thus
I
- 3 obtained consists of about 80 % of oc-(3,4,5-trimethoxybanzal)-fl-alkoxy-propionitrila and 20 % of
According to Hungarian patent No. 162,316 the above known process is rendered more economical by condensing
3,4,5-trimethoxy-benzaldehyde with a B-alkoxy-propionitrile, reacting the condensation product thus obtained with an the amine, isomerising'a-(3,4,5-trimethoxy-benzal)-fl-aminopropionitrile derivative thus obtained into the corresponding benzyl derivative and reacting the latter compound with guanidine. The total yield of Trimethoprim related to the 3,4.5-trimethoxy-benzaldehyde starting material is, however, moderate.
According to Hungarian patent No. 174,318 3,4,5-trimethoxy-benzaldehyde is reacted with a B-(2-alkoxyethoxy)-propionitrile. Thus a «-(3,4,5-trimethoxy-benzal)fl-(2-alkoxy-athoxy)-propionitrile of the general formula
Ila
S3466
is obtained (wherein R is as stated above) with a yield of above 80 %, which is then isolated, thoroughly purified, subjected to isomerisation at 90-95 °C in the presence of a base into the corresponding benzyl isomer of the general formula II which is than reacted with guanidine to give Trimethoprim with a yield of about 80 %. Thus the total yield of the laboratory scale Trimethoprim production is about 64-72 %,
Although tha above process is significantly more economical than the previously described methods, the industrial scale use thereof is mat with serious problems. In the reaction of 3,4,5-trimathoxy-benzaldehyde and fl-(2-alkoxy-ethoxy)-propionitrile water is formed which is distilled off at a high temperature of about 120 °C. At this high temperature hydrolyis of the «-(3,4,5-trimethoxy-benzal)-B-(2-alkoxy-ethoxy)-propionitrile with the water being present takes place.
According to our experiments the nitrile group hydrolyses and the corresponding carboxylic acid is formed in an amount of some per cents. This side reaction gives rise to the formation of tarry side products which comes particularly into prominence as the batch size is increased. Thus the laboratory scale total yield of 64-72 % decreases to about 50-55 % already when
- 5 the batch size is of about a 10 molar amount. It can be stated that the above known process is unsatisfactory from economic point of view.
The aim of the present invention is the elaboration 5 of an economical industrial scale process for the preparation of 2,4-diamino-5-(3’,4',5’-trimethoxy-benzyl)-pyrimidina.
It has been found that the o-(3,4,5-trimethoxybenzal)-B-methoxy-propionitrile of the formula III
(HI) can be trans-etherified into the corresponding benzal 15 isomer of the general formula Ila almost with.quantitative yields by reacting with an ethylene glycol monoalkyl-ether of the general formula IV ho-ch2-ch2-or (IV) (wherein R is as stated above) and the compound of the general formula Ila can be converted easily into the corresponding benzyl isomer of the general formula II almost by theoretical yields. The benzyl isomer of the general formula II is so pure that it can be reacted without isolation and purification with guanidine to give Trimethoprim.
According to the present invention there is provided a process for the preparation of 2,4-diamino-5-{3’,4’,5’53466
- 6 trimethoxy-benzyl)~pyrimidine of the general formula I by reacting a compound of the general formula II (wherein R is an alkyl group having 1-4 carbon atoms)'with guanidine, which comprises preparing the said compound of the general formula II by reacting «-(3,4,5-trimethoxybenzal)-B-methoxy-propionitiMle . of the formula III with an ethylene glycole monoalkylather of the general formula IV (wherein R is as stated above) in the presence of an alkali alkoxide at a temperature between 60 °C and 90 °C and reacting the compound of the general formula II thus, obtained - if desired without isolation - with guanidine in the presence of an alkanol having 4-8 carbon atoms.
As compound of the general formula IV preferably ethylene glycol monomethylether can be used. The compound of the general formula IV is preferably used in an excess and plays the role of the solvent,too.
As alkali alkoxide preferably sodium methylate can be used.
It is not necessary to isolate the benzal isomer of the general formula Ila obtained in the reaction of the oc-(3,4,5-trimethoxy-benzal)-D-methoxy-propionitrile of the formula III and the ethylene glycol monoalkylether of the general formula IV. Under the reaction conditions used at 60-90 °C - preferably at 80-90 °C - the benzyl isomer is quantitatively formed within a few hours. The benzyl isomer of the general formula II can be isolated or, if desired, reacted with guanidine without isolation.
The benzyl isomer of the general formula II is
- 7 reacted with guanidine in the presence of an alcohol having 4-8 carbon atoms. For this purpose preferably tertiary butanol or isobutanol can ba used. The reaction between the benzyl isomer and guanidine can be carried out in the presence of a further organic solvent (a.g. an other alcohol, such as methanol) in addition to the alcohol having 4-8 carbon atoms.
If according to a preferred embodiment of the process of the present invention the compound of the general formula II is reacted with guanidine without isolation, the ethyleneglycol monomethyl ether of the general formula IV is always present in the ring closure stage of the reaction, provided it was used in an excess in the preparation of the benzyl derivative.
It is preferred to add guanidine in the form of an acid addition salt - e.g. the hydrochloride - to the benzyl derivative and to sat free the guanidine from its acid addition salt in the reaction mixture with the aid of a base, preferably an alkali alkoxide.
The reaction of the benzyl isomer and guanidine is carried out preferably at 70-100 °C, advantageously at the boiling point of the reaction mixture.
The «-(3,4,5-trimethoxy-benzal)-B-methoxy-propionitrile of the formula III is prepared in a known manner by reacting 3,4,5-trimethoxy-banzaldehyda with B-methoxypropionitrila. The latter B-methoxy-propionitrile is prepared by reacting acrylic nitrile with methanol in alkaline medium.
- 8 The process of the present invention enables the economical industrial scale manufacture of Trimethoprim.
The drawbacks of the process according to Hungarian patent No. 174,318 are eliminated.
The total yield related to 3,4,5-trimethoxy-benzaldehyde is about 80 %. According to the process of the present invention Trimethoprim can be manufactured from tho compound of the formula XII by a one-step technology. The purity of the product obtained meets the therapeutical requirements.
Further details of the present invention are to be found in the Examples without limiting our invention to the said Examples.
Example 1
Preparation of the starting material
1,75 g. of potassium hydroxide are dissolved in 115 ml of methanol. To the solution 55 g of acrylic nitrile are added within 20 minutes at a temperature below 40 °C.
The mixture is stirred at 40 °C for an hour, whereupon
100 g. of 3,4,5-trimethoxy-benzaldehyde are added. Tha reaction mixture is stirred at 60 °C for 8 hours whereupon it is cooled to 30 °C, 55 ml of methanol and in portions 30 g. of potassium hydroxide are added. The suspension formed is stirred for 5 hours, cooled to 20 °C and 500 ml of water are added within 15 minutes. The product is crystallized at 5-10 °C, filtered, washed three times with 15 ml. of methanol and three times with 100 ml. of water
-9-.
each and dried. Thus 116 g. of o-(3,4,5-trimethoxybenzal)-B-methoxy-propionitrile are obtained, Mp.:
81-83 °C. Yield: 86 %.
Example 2
Preparation of 2f4-diamino-5-(3,,4,,5,-trimethoxybenzyl)-pyrimidine
A mixture of 100 g, of oc-(3,4,5-trimethoxy-benzal)-Bmethoxy-propionitrile, 100 ml. of anhydrous ethylene glycol monomethylether and 5 g. of sodium methoxide is stirred at 82-84 °C for 3 hours. The reaction mixture is cooled then to 30 °C,/160 ml. of isobutanol, 40 ml. of methanol,
g. of guanidine-hydrochloride and 50 g, of powdered sodium methoxide are added. The reaction mixture is stirred at 35-40 °C for an hour and at 90-92 °C for 7 hours. The crystal suspension is cooled to 20 °C, filtered and washed on the filter three times with 20 ml. of methanol each. The moist substance thus obtained is washed with 500 ml. of lukewarm water (30-35 °C) and dried. Thus 102.5 g. of the title compound are obtained, yield: 93.6 %, mp.: 198-201 °C.
Claims (3)
1. What we claim is: 1.Animproved process for the preparation of 2,4diamino-5-(3’,4’,5’-trimethoxy-benzyl)-pyrimidine of the general formula 1 by reacting a compound of the general formula II 15 (wherein R is an alkyl group having 1-4 carbon atoms) with guanidine, which comprises preparing,the said compound of the general formula II by reacting a-(3,4,5-trimethoxybenz»l)-fi-msthoxy-propionitrile of the formula III (III) with an athylena glycol monoalkylether of the general 25 formula IV ho-ch 2 -ch 2 -or (IV) (wherein R is as stated above) in the presence of an - 11 alkali alkoxide at a temperature between 60 °C and 90 °C and reacting the compound of the general formula II thus obtained - if desired without isolation - with guanidine in the presence of an alkanol having 4-8 carbon atoms.
2. ,A process according to claim 1, which comprises carrying out the reaction of the compounds of the formulae III (III) and IV ho-ch 2 -ch 2 -or (IV) at a temparature between 80 °C end 90 °C.
3.A process according to claim 1, which comprises using sodium methoxide ss alkali alkoxide.
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 |
|---|---|
| IE821520L IE821520L (en) | 1982-12-26 |
| IE53466B1 true IE53466B1 (en) | 1988-11-23 |
Family
ID=10956594
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE1520/82A IE53466B1 (en) | 1981-06-26 | 1982-06-25 | Improved process for the preparation of 2,4-diamino-5-(3',4',5'-trimethoxy-benzyl)-pyrimidine |
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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