DK169966B1 - Process for preparing a 2-guanidinothiazole derivative - Google Patents
Process for preparing a 2-guanidinothiazole derivative Download PDFInfo
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- DK169966B1 DK169966B1 DK587287A DK587287A DK169966B1 DK 169966 B1 DK169966 B1 DK 169966B1 DK 587287 A DK587287 A DK 587287A DK 587287 A DK587287 A DK 587287A DK 169966 B1 DK169966 B1 DK 169966B1
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- thiourea
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/28—Radicals substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/50—Nitrogen atoms bound to hetero atoms
Description
DK 169966 B1DK 169966 B1
Den foreliggende opfindelse angår en særlig fremgangsmåde til fremstilling af et 2-guanidinotiazol-The present invention relates to a particular process for the preparation of a 2-guanidinothiazole
derivat med formlen Iderivative of formula I
N—/NHN / NH
5 H2N [i ftVc^ i5 H2N [i ftVc ^ i
HjN '"S^ ^ UHHjN '"S ^^ UH
eller salte deraf.or salts thereof.
Dette derivat er et vigtigt mellemprodukt til 10 fremstilling af famotidin (N-sulfamyl-3-(2-guanidinotia-zol-4-ylmetyltio)-propionamidin), der har vist sig at være et fremragende lægemiddel til behandling af mavesår og tolvfingertarmssår.This derivative is an important intermediate for the preparation of famotidine (N-sulfamyl-3- (2-guanidinothiazol-4-ylmethylthio) propionamidine), which has been found to be an excellent drug for treating gastric and duodenal ulcers.
Forbindelsen fremstillet ifølge opfindelsen er 15 kendt fra litteraturen.The compound of the invention is known from the literature.
I henhold til forfatterne af europæisk patentskrift nr. 87.274 blev isotiourinstoffet med formlen I vundet i et udbytte på over 90% ved omsætning af en forbindelse med den almene formel IIIAccording to the authors of European Patent Specification No. 87,274, the isothiourea of formula I was obtained in a yield of more than 90% by reacting a compound of general formula III
2020
h2n N·—1 Xh2n N · —1 X
// ) 111 A / * hx//) 111 A / * hx
H2N VH2N V
hvor X er et halogenatom, med tiourinstof i alkohol.where X is a halogen atom, with thiourea in alcohol.
25 En ulempe ved denne fremgangsmåde ligger imidler tid i,at den som udgangsmateriale anvendte klormetylfor-bindelse er et allergent stof som irriterer hud og slimhinder.A disadvantage of this method, however, lies in the fact that the chloromethyl compound used as a starting material is an allergic substance which irritates skin and mucous membranes.
Det isotiourinstof der var vundet på den ovenfor 30·beskrevne måde blev omsat med 3-klorpropionitril i nærværelse af natriumhydroxid i en vandig alkohol under afkøling til frembringelse af nitrilen i et udbytte på 89,8%. Denne proces er besværlig og kræver meget tid og meget arbejde fordi produktet må isoleres ved hjælp af 35 ekstraktion, azeotrop tørring og omkrystallisation fra en opløsningsmiddelblanding.The isothiourea recovered in the manner described above was reacted with 3-chloropropionitrile in the presence of sodium hydroxide in an aqueous alcohol with cooling to give the nitrile in 89.8% yield. This process is cumbersome and requires a lot of time and effort because the product must be isolated by extraction, azeotropic drying and recrystallization from a solvent mixture.
2 DK 169966 B12 DK 169966 B1
Forskere hos Yamanouchi Co. forsøgte at eliminere ulemperne ved de foran beskrevne metoder ved at udvikle en anden proces som er beskrevet i europæisk patentansøgning nr. 128.736. Dikloracetone blev kondenseret med amidi-5 notiourinstof under 0°C i flere dage til dannelse af tia- *Researchers at Yamanouchi Co. sought to eliminate the disadvantages of the methods described above by developing another process described in European Patent Application No. 128,736. Dichloroacetone was condensed with amide-5 notiourea below 0 ° C for several days to give thia-
zolinet med den almene formel IVthe zoline of the general formula IV
44
OHOH
H2] / \H2] / \
10 · HC1 VI10 · HC1 VI
h2n i et udbytte på 96,4%. Det på denne måde vundne tiazo-lin blev opvarmet med tiourinstof i alkohol til frembringelse af 15 en forbindelse med formlen I i et udbytte på 75,0% (83,8% beregnet ud fra tiourinstof).h2n in a yield of 96.4%. The thiazole thus obtained was heated with thiourea in alcohol to give a compound of formula I in a yield of 75.0% (83.8% calculated from thiourea).
Den vigtigste ulempe ved den netop beskrevne fremgangsmåde består i at den teknologiske fremgangsmåde er besværlig og langtrukken, at ringslutningen for-20 drer afkøling i hele reaktionsperioden og at den således vundne tiazolinforbindelse med formel IV er ganske ustabil. Ifølge nærværende opfinderes undersøgelser er dette tiazolinderivat særdeles ustabilt ved stuetemperatur.The main disadvantage of the process just described is that the technological process is cumbersome and long-lasting, that the ring closure improves cooling throughout the reaction period and that the thiazoline compound of formula IV thus obtained is quite unstable. According to the present inventors studies, this thiazoline derivative is extremely unstable at room temperature.
Den som mellemprodukt anvendte hudirriterende 25 klormetylforbindelse med formel IV, hvor X er et kloratom, blev første gang beskrevet i belgisk patentskrift nr.The intermediate skin irritant chloromethyl compound of formula IV, wherein X is a chlorine atom, was first described in Belgian patent no.
866.156, ifølge hvilket dikloracetone blev omsat med ami-dinotiourinstof ved omrøring i acetoneopløsning gennem en nat ved stuetemperatur. Det udbytte af den rene klor-30 metylforbindelse, der opnåedes ved omkrystallisation fra alkohol, blev imidlertid ikke anført. Ifølge nærværende opfinderes bestemmelser er dette udbytte under 80%. Der kendes ikke andre fremstillingsmåder fra lit- * teraturen, og ej heller kendes der ækvivalenter til el-35 ler varianter af den ovenfor beskrevne proces. *866,156, according to which dichloroacetone was reacted with amine dinothiourea by stirring in acetone solution through a night at room temperature. However, the yield of the pure chloromethyl compound obtained by recrystallization from alcohol was not stated. According to the present inventors, this yield is below 80%. No other modes of preparation are known from the literature, nor are any equivalents to or variants of the process described above. *
Det er formålet med den foreliggende opfindelse at tilvejebringe en fremgangsmåde ved hvilken mellempro 3 DK 169966 B1 duktet med formlen I for famotidin kan fremstilles i et enkelt trin således at isolering af de andre mellemprodukter, der har ubehagelige egenskaber, bliver unødvendig.It is the object of the present invention to provide a process by which the intermediate product of formula I for famotidine can be prepared in a single step so that isolation of the other intermediates having unpleasant properties becomes unnecessary.
Opfindelsen er baseret på den iagttagelse at S-5 alkylering udført ved omsætning af en dihalogenacetone-forbindelse med amidinotiourinforbindelsen med formlen IIThe invention is based on the observation that S-5 alkylation carried out by reacting a dihaloacetone compound with the amidinothiourine compound of formula II
H0N NH~ l i 2 L I ii 10 og den påfølgende ringslutning kan gennemføres selektivt ved anvendelse af jodidkatalysator i et opløsningsmiddel og resulterer i adskillelse af halogenmetylfor-bindelsen med den almene formel III i krystallinsk til-15 stand fra reaktionsblandingen. Efter tilsætning af vand og tiourinstof kan denne forbindelse omdannes til det ønskede produkt, dvs. forbindelsen med formlen I der udskiller sig i ren krystallinsk tilstand fra reaktionsblandingen.Honey NH-1 in 2 L II in 10 and the subsequent cyclization can be selectively carried out using iodide catalyst in a solvent and result in separation of the halo methyl compound of the general formula III in crystalline state from the reaction mixture. After addition of water and thiourea, this compound can be converted into the desired product, i.e. the compound of formula I which separates in the pure crystalline state from the reaction mixture.
20 Nye og overraskende træk indgår også i ovennævn te erkendelse. Det kunne nemlig ikke forventes at der ville opnås en sådan grad af selektivitet både i ringslutningen og i S-alkyleringen ved anvendelse af en jodidkatalysator i et acetonemedium. Dette er vel under-25 støttet af den kendsgerning at uden en jodid-katalysa-tor ved omsætningen af dikloracetone med amidinotiourin-stof efterfulgt af omsætningen med tiourinstof, blev de opnåede udbytter 25-35% lavere end udbyttet af reaktionen baseret på nærværende opfinderes erkendelse, skønt den 30 eneste forskel bestod i katalysen.20 New and surprising features are also included in the above recognition. Namely, it would not be expected that such a degree of selectivity would be obtained both in the cyclization and in the S-alkylation using an iodide catalyst in an acetone medium. This is well supported by the fact that without an iodide catalyst in the reaction of dichloroacetone with amidinothiourine substance followed by the reaction with thiourea, the yields obtained were 25-35% lower than the yield of the reaction based on the recognition of the present inventor. , although the only difference was in the catalysis.
Desuden blev dens selektivitets forøgende rolle af jodid-katalysen også verificeret i tilfælde af 2-ami-no-4-klormetyltiazol-hydroklorid med formlen VIn addition, its selectivity-enhancing role of the iodide catalysis was also verified in the case of 2-amino-4-chloromethylthiazole hydrochloride of formula V
35 j?35 j?
/ . HC1 V/. HC1 V
h2n 4 DK 169966 B1h2n 4 DK 169966 B1
en forbindelse der er kendt fra litteraturen. Ved omsætning af tiourinstof med dikloracetone i molforholdet Ί:1 opnåede man forbindelsen med formel V i et udbytte på 58,5%, og den følgende omsætningen med tiourinstof 5 resulterede i en forbindelse med formlen VIa compound known from literature. By reaction of thiourea with dichloroacetone in the molar ratio Ί: 1 the compound of formula V was obtained in a yield of 58.5% and the following reaction with thiourea 5 resulted in a compound of formula VI
NH-I 2 w S NH »'*NH-I 2 w S NH »'*
/1 -2 HCI/ 1 -2 HCl
H-NH-N
10 2 i et udbytte på 22,2% (J. Am. Chem. Soc. 2156, 1946).In a yield of 22.2% (J. Am. Chem. Soc. 2156, 1946).
I modsætning til disse udbytter vandtes forbindelsen med formel V i et udbytte på 86% ved anvendelse af den jodid-katalyse som er opfundet som resultat af nærvæ-15 rende opfinderes forsøg.In contrast to these yields, the compound of formula V was obtained in an 86% yield using the iodide catalysis invented as a result of the present inventors' experiments.
Det er også kendt at ringslutning af forbindelsen med formlen II indebærer mindst tre elementære trin.It is also known that cyclization of the compound of formula II involves at least three elemental steps.
Eftersom det kan forventes at det første trin, dvs. S-alkyleringen, kun accelereres af jodid-katalysen, er 20 det også overraskende at man foruden forøgelsen af selektiviteten opnår at hele tiazoldannelsen accelereres.Since it can be expected that the first step, i.e. The S-alkylation, accelerated only by the iodide catalysis, is also surprising that, in addition to the increase in selectivity, the entire thiazole formation is accelerated.
Den foreliggende opfindelse angår således en særlig fremgangsmåde til fremstilling af et 2-guanidino-tiazolderivat med formlen I eller salte deraf, og frem-25 gangsmåden er ejendommelig ved, at man ringslutter ami-dinotiourinstof med formlen IIThe present invention thus relates to a particular process for the preparation of a 2-guanidino-thiazole derivative of formula I or salts thereof, and the method is characterized by cyclizing aminodiothiourea of formula II
H-N NH- k 1H-N NH- k 1
30 H2N IIH2N II
med en 1,3-dihalogenacetone i et opløsningsmiddel, fortrinsvis acetone, i nærværelse af en jodid-katalysator som er opløselig i nævnte opløsningsmiddel, fortrinsvis natriumjodid og uden isolering omsætter det herved vund-55 ne halogenderivat med formlen III *with a 1,3-dihaloacetone in a solvent, preferably acetone, in the presence of an iodide catalyst which is soluble in said solvent, preferably sodium iodide, and without isolation, it thereby converts the halogen derivative of formula III *
-HX-HX
5 DK 169966 B1 hvor X er et halogenatom, med tiourinstof i nærværelse af vand.5 X 169966 B1 where X is a halogen atom, with thiourea in the presence of water.
I en foretrukket udførelsesform for fremgangsmåden ifølge opfindelsen bruges jodidkatalysatoren i en mængde 5 på 1-10 mol%, fortrinsvis 4-6 mol%.In a preferred embodiment of the process of the invention, the iodide catalyst is used in an amount of 5 to 1-10 mole percent, preferably 4-6 mole percent.
Ved fremgangsmåden ifølge opfindelsen dannes forbindelsen med formlen I ved en temperatur mellem 20°C og 60°C.In the process of the invention, the compound of formula I is formed at a temperature between 20 ° C and 60 ° C.
Ved fremgangsmåden ifølge opfindelsen sættes ami-10 dinotiourinstoffet med formel II portionsvis til vedkommende dihalogenacetoneforbindelse, fortrinsvis di-kloracetone, i et opløsningsmiddel og fortrinsvis i acetone som tillige indeholder natriumjodid. Der sættes vand og tiourinstof til den herved dannede krystalsu-15 spension, og efter kogning og afkøling filtreres den vundne forbindelse med formel I, vaskes med vandig acetone og tørres.In the process of the invention, the amino dinothiourea of formula II is added portionwise to the dihalogenacetone compound, preferably dichloroacetone, in a solvent and preferably in acetone which also contains sodium iodide. Water and thiourea are added to the resulting crystal suspension, and after boiling and cooling, the compound of formula I obtained is filtered, washed with aqueous acetone and dried.
Fordelene ved fremgangsmåden ifølge opfindelsen kan summarisk anføres som følger.The advantages of the method according to the invention can be summarized as follows.
20 a) På grund af jodidkatalysen bliver det unød vendigt at gennemføre en ringslutning som varer flere dage ved en temperatur under 0°C såvel som isolering af de ustabile mellemprodukter.(A) Because of the iodide catalysis, it becomes unnecessary to carry out a ring closure lasting several days at a temperature below 0 ° C as well as isolation of the unstable intermediates.
b) Det fremkomne hudirriterende produkt med for-25 mel III kan omdannes videre i samme beholder uden isolering.b) The resulting skin irritant product of Formula III can be further converted into the same container without isolation.
c) Det anvendte opløsningsmiddelsystem sikrer fra-skillelse af forbindelsen med formel I og dens salte i ren tilstand, mens forureningerne bliver i moder- 30 luden.c) The solvent system used ensures separation of the compound of formula I and its salts in the pure state while the contaminants remain in the mother liquor.
d) På grund af den ringe arbejdstid der behøves og de fortrinlige udbytter, er fremgangsmåden ifølge opfindelsen yderst nyttig til industriel udnyttelse. Apparatudnyttelsen er også meget fordelagtig: 240 kg af 35 forbindelsen med formlen I kan fremstilles i et arbejds- 3 rumfang på 1 m .d) Due to the low working time needed and the excellent yields, the process according to the invention is extremely useful for industrial utilization. The apparatus utilization is also very advantageous: 240 kg of the compound of formula I can be produced in a working volume of 1 m.
Fremgangsmåden ifølge opfindelsen belyses udførligt ved de følgende eksempler.The process of the invention is elucidated by the following examples.
Eksempel 6 DK 169966 B1 S-(2-Guanidinotiazol-4-ylmetyl)-isotiourinstof-dihydro-kloridmonohydrat 5a) 11,8 g (0,1 mol) amidinotiourinstof sættes til t en omrørt opløsning indeholdende 12,7 g (0,1 mol) 1,3-dikloracetone og 0,75 g (0,005 mol) natriumjodid i 92 ml ^ acetone i løbet af 2 timer. Efter omrøring i yderligere 2 timer tilsættes der 9,2 g vand og der dannes en opløs-10 ning efter kogning i kort tid. Til denne opløsning sættes der 7,6 g (0,1 mol) tiourinstof hvorefter blandingen koges i 1 time. Reaktionsblandingen indeholdende det olieagtige reaktionsprodukt henstår til afkøling under omrøring. Den herved dannede krystalsuspension 15 afkøles til 0°C, filtreres, vaskes to gange med acetone og tørres til frembringelse af den i overskriften angivne forbindelse med smp. 209-213°C (sønderdeling) i et udbytte på 27,86 g (85%) med et indhold af det virksomme stof på 98%, bestemt ved potentiometrisk titre-20 ring.Example 6 DK 169966 B1 S- (2-Guanidinothiazol-4-ylmethyl) isothiourea dihydrochloride monohydrate 5a) 11.8 g (0.1 mole) of amidinothiourea is added to a stirred solution containing 12.7 g (0.1 mole) of 1,3-dichloroacetone and 0.75 g (0.005 mole) of sodium iodide in 92 ml of acetone over 2 hours. After stirring for a further 2 hours, 9.2 g of water are added and a solution is formed after boiling for a short time. To this solution is added 7.6 g (0.1 mole) of thiourea and the mixture is boiled for 1 hour. The reaction mixture containing the oily reaction product is allowed to cool under stirring. The resulting crystal suspension 15 is cooled to 0 ° C, filtered, washed twice with acetone and dried to give the title compound with m.p. 209-213 ° C (dec.) In a yield of 27.86 g (85%) with a content of the active substance of 98%, as determined by potentiometric titration.
b) 35,4 g (0,3 mol) amidinotiourinstof sættes portionsvis til en omrørt opløsning indeholdende 38,1 g (0,3 mol) 1,3-dikloracetone og 2,25 (0,015 mol) natrium- 25 jodid i 240 ml acetone ved 30-36°C i løbet af 1 time.b) 35.4 g (0.3 mole) of amidinothiourea are added portionwise to a stirred solution containing 38.1 g (0.3 mole) of 1,3-dichloroacetone and 2.25 (0.015 mole) of sodium iodide in 240 ml. acetone at 30-36 ° C over 1 hour.
Den herved dannede krystalsuspension omrøres ved samme temperatur i yderligere 1 time hvorpå blandingen, efter tilsætning af 30 ml vand og 24 g (0,315 mol) tiourinstof, tilbagesvales under omrøring i 1 time. Blandingen 30 henstår til afkøling ved stuetemperatur og det krystallinske produkt filtreres og vaskes med 2 x 40 ml 90%s acetone til frembringelse af det i overskriften angivne produkt med smp. 210-214°C (sønderdeling) i et udbytte 1 på 88,02 g (89,7%) med et indhold af den ønskede forbin-35 delse på 98,2%, bestemt ved potentiometrisk titrering. * c) 127,0 kg (500 mol) 1,3-dikloracetone i opløsning i 50 vægt% acetone pumpes ind i en reaktor på 1000 1.The resulting crystal suspension is stirred at the same temperature for an additional 1 hour, after which the mixture, after addition of 30 ml of water and 24 g (0.315 mole) of thiourea, is refluxed with stirring for 1 hour. The mixture 30 is allowed to cool at room temperature and the crystalline product is filtered and washed with 2 x 40 ml of 90% s acetone to give the title product with m.p. 210-214 ° C (dec.) In a yield 1 of 88.02 g (89.7%) with a content of the desired compound of 98.2% as determined by potentiometric titration. c) 127.0 kg (500 mole) of 1,3-dichloroacetone in solution in 50% by weight acetone is pumped into a 1000 I reactor.
Efter tilsætning af 257 kg acetone og 3,75 kg (25 mol)After the addition of 257 kg of acetone and 3.75 kg (25 moles)
Claims (2)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU465886 | 1986-11-12 | ||
| HU864658A HU195959B (en) | 1986-11-12 | 1986-11-12 | Process for producing 2-guanidino-thiazole derivatives |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK587287D0 DK587287D0 (en) | 1987-11-10 |
| DK587287A DK587287A (en) | 1988-05-13 |
| DK169966B1 true DK169966B1 (en) | 1995-04-18 |
Family
ID=10968597
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK587287A DK169966B1 (en) | 1986-11-12 | 1987-11-10 | Process for preparing a 2-guanidinothiazole derivative |
Country Status (14)
| Country | Link |
|---|---|
| KR (1) | KR900006556B1 (en) |
| AR (1) | AR243874A1 (en) |
| AT (1) | AT389510B (en) |
| CA (1) | CA1323032C (en) |
| CS (1) | CS268693B2 (en) |
| DK (1) | DK169966B1 (en) |
| ES (1) | ES2005441A6 (en) |
| FI (1) | FI84912C (en) |
| GR (1) | GR871696B (en) |
| HU (1) | HU195959B (en) |
| NO (1) | NO167387C (en) |
| PT (1) | PT86113B (en) |
| SU (1) | SU1678205A3 (en) |
| YU (1) | YU46086B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5856500A (en) * | 1997-03-11 | 1999-01-05 | Albemarle Corporation | Synthesis of thiazole derivatives |
| US5731442A (en) * | 1997-03-11 | 1998-03-24 | Albemarle Corporation | Synthesis of thiazole derivatives |
-
1986
- 1986-11-12 HU HU864658A patent/HU195959B/en unknown
-
1987
- 1987-10-20 AT AT0277087A patent/AT389510B/en not_active IP Right Cessation
- 1987-10-21 CA CA000549936A patent/CA1323032C/en not_active Expired - Fee Related
- 1987-11-04 GR GR871696A patent/GR871696B/en unknown
- 1987-11-10 DK DK587287A patent/DK169966B1/en not_active IP Right Cessation
- 1987-11-10 AR AR87309242A patent/AR243874A1/en active
- 1987-11-11 NO NO874698A patent/NO167387C/en not_active IP Right Cessation
- 1987-11-11 PT PT86113A patent/PT86113B/en unknown
- 1987-11-12 ES ES8703223A patent/ES2005441A6/en not_active Expired
- 1987-11-12 FI FI875003A patent/FI84912C/en not_active IP Right Cessation
- 1987-11-12 SU SU874203655A patent/SU1678205A3/en active
- 1987-11-12 YU YU204987A patent/YU46086B/en unknown
- 1987-11-12 CS CS878101A patent/CS268693B2/en not_active IP Right Cessation
- 1987-11-19 KR KR1019870013045A patent/KR900006556B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| PT86113A (en) | 1987-12-01 |
| ES2005441A6 (en) | 1989-03-01 |
| AR243874A1 (en) | 1993-09-30 |
| NO874698D0 (en) | 1987-11-11 |
| NO167387B (en) | 1991-07-22 |
| NO874698L (en) | 1988-05-13 |
| YU204987A (en) | 1988-10-31 |
| PT86113B (en) | 1990-08-31 |
| DK587287A (en) | 1988-05-13 |
| FI875003A (en) | 1988-06-13 |
| SU1678205A3 (en) | 1991-09-15 |
| AT389510B (en) | 1989-12-27 |
| GR871696B (en) | 1987-12-08 |
| ATA277087A (en) | 1989-05-15 |
| FI875003A0 (en) | 1987-11-12 |
| DK587287D0 (en) | 1987-11-10 |
| FI84912C (en) | 1992-02-10 |
| YU46086B (en) | 1992-12-21 |
| CA1323032C (en) | 1993-10-12 |
| NO167387C (en) | 1991-10-30 |
| FI84912B (en) | 1991-10-31 |
| KR890008120A (en) | 1989-07-08 |
| HU195959B (en) | 1988-08-29 |
| CS268693B2 (en) | 1990-04-11 |
| CS810187A2 (en) | 1989-07-12 |
| KR900006556B1 (en) | 1990-09-13 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| B1 | Patent granted (law 1993) | ||
| PUP | Patent expired |