CH651565A5 - PROCESS FOR THE PREPARATION OF IMIDAZOBENZODIAZEPINES AND THEIR SALTS. - Google Patents
PROCESS FOR THE PREPARATION OF IMIDAZOBENZODIAZEPINES AND THEIR SALTS. Download PDFInfo
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- CH651565A5 CH651565A5 CH1896/82A CH189682A CH651565A5 CH 651565 A5 CH651565 A5 CH 651565A5 CH 1896/82 A CH1896/82 A CH 1896/82A CH 189682 A CH189682 A CH 189682A CH 651565 A5 CH651565 A5 CH 651565A5
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- Prior art keywords
- formula
- piperazin
- alkyl
- product
- radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
La présente invention concerne un nuveau procédé de préparation d'imidazobenzo-diazépines, ainsi que de leurs sels d'addition avec les acides. The present invention relates to a new process for the preparation of imidazobenzo-diazepines, as well as their addition salts with acids.
L'invention a plus précisément pour object un nouveau procédé de préparation des produits de formule générale: The object of the invention is more precisely a new process for preparing the products of general formula:
dans laquelle R] représente un atome d'hydrogène, un atome d'halogène, un radical nitro ou un radical trifluorométhyle, R2 représente un atome d'hydrogène ou un atome d'halogène, R3 et R4 représentent ensemble avec l'atome d'azote auquel ils 20 sont liés un radical 4-alcoyl-pipérazin-l-yl, 4-cyclo alcoyl alcoyl pipérazin-l-yl, 4-phényl-pipérazin-l-yl ou pipéridino, ainsi que de leurs sels d'addition avec les acides minéraux ou organiques. in which R] represents a hydrogen atom, a halogen atom, a nitro radical or a trifluoromethyl radical, R2 represents a hydrogen atom or a halogen atom, R3 and R4 together represent with the atom nitrogen to which they are linked a 4-alkyl-piperazin-1-yl radical, 4-cyclo alkyl alkyl alkyl piperazin-1-yl, 4-phenyl-piperazin-1-yl or piperidino, as well as their addition salts with mineral or organic acids.
Dans la formule I e dans ce qui suit, In formula I e in the following,
25 lorsque R] représente un atome d'halogène, il s'agit de préférence d'un atome de fluor, de chlore ou de brome et plus particulièrement d'un atome de chlore; When R] represents a halogen atom, it is preferably a fluorine, chlorine or bromine atom and more particularly a chlorine atom;
lorsque R2 représente un atom d'halogène, il s'agit de préférence d'un atome de fluor, de chlore ou de brome, et plus 30 particulièrement d'un atome de fluor ou de chlore; de plus, lorsque R2 est un atome d'halogène, il est, de préférence, en position ortho; when R2 represents a halogen atom, it is preferably a fluorine, chlorine or bromine atom, and more particularly a fluorine or chlorine atom; moreover, when R2 is a halogen atom, it is preferably in the ortho position;
lorsque R3 et R4 représentent ensemble avec l'atome d'azote auquel ils sont liés un radical 4-alcoyl-pipérazin-l-yl, il 35 s'agit de préférence d'un radical 4-ménthyl-pipérazin-l-yl 4-éthyl-pipérazin-l-yl ou 4-propyl-pipérazin-l-yl et plus particulièrement du radical 4-ménthyl-pipérazin-l-yl, when R3 and R4 together with the nitrogen atom to which they are bonded represent a 4-alkyl-piperazin-1-yl radical, it is preferably a 4-menthyl-piperazin-1-yl 4 radical -ethyl-piperazin-1-yl or 4-propyl-piperazin-1-yl and more particularly of the 4-menthyl-piperazin-1-yl radical,
lorsque R3 et R4 représentent ensemble avec l'atom d'azote auquel ils sont liés un radical 4-cyclo alcoyl alcoyl-pipê-40 razin-l-yl, il s'agit de préférence d'un radical cyclo alcoyl comportant de 3 à 6 atomes de carbone tel que les radicaux cyclopropyle, cyclobutyle ou cyclophentyle. Parmi les radicaux 4-cyclo alcoyl alcoyl-pipérazin-1-yl on retient plus particulièrement le radical 4-cyclopropyl méthyl-pipérazin-l-yl. when R3 and R4 together with the nitrogen atom to which they are linked represent a 4-cyclo alkyl-alkyl-pipê-40 razin-1-yl radical, it is preferably a cyclo alkyl radical comprising from 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl or cyclophentyl radicals. Among the 4-cycloalkylalkyl-piperazin-1-yl radicals, the 4-cyclopropyl methyl-piperazin-1-yl radical is more particularly retained.
Les sels d'addition avec les acides minéraux ou organiques peuvent être, par exemple, les sels formés avec les acides chlorhydrique, bromhydrique, iodhydrique, nitrique, sulfuri-que, phosphorique, propionique, acétique, formique, benzoi-que, maléique, fumarique, succinique, tartrique, citrique, 50 oxalique, glyoxylique, aspartique, alcanesulfoniques tels que l'acide méthane sulfonique et arylsufoniques, tels que l'acide benzène sulfonique. The addition salts with mineral or organic acids can be, for example, the salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, propionic, acetic, formic, benzoin, maleic, fumaric acids. , succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkanesulfonic such as methane sulfonic acid and arylsufonic, such as benzene sulfonic acid.
Les produits de formule générale (I) et leurs sels ainsi qu'un procédé de préparation de ceux-ci ont été décrits dans le 55 brevet français n° 2 300 569 déposé par la titulaire. Ainsi qu'il est indiqué dans ce brevet, les produits de formule générale (I) possèdent d'intéressantes propriétés sédatives, hypnotiques, anxiolytiques, tranquillisantes, anticonvulsivantes et myorelaxantes. The products of general formula (I) and their salts as well as a process for their preparation have been described in French patent No. 2,300,569 filed by the holder. As indicated in this patent, the products of general formula (I) have interesting sedative, hypnotic, anxiolytic, tranquilizing, anticonvulsant and muscle relaxant properties.
60 Le nouveau procédé de l'invention permet de préparer, les produits de la formule (I) avec de bons rendements en un nombre de stades inférieur à celui des procédés décrits dans le brevet français précité. The new process of the invention makes it possible to prepare the products of formula (I) with good yields in a number of stages lower than that of the processes described in the aforementioned French patent.
La présente invention a ainsi pour object un nouveau pro-65 cédé de préparation des produits de formule générale I, ainsi que de leurs sels d'addition avec les acides minéraux ou organiques, caractérisé en ce que l'on fait réagir un produit de • formule: The subject of the present invention is therefore a new process pro-65 for preparing the products of general formula I, as well as their addition salts with mineral or organic acids, characterized in that a product of • is reacted. formula:
45 45
3 3
651 565 651,565
La déshydratation peut avantageusement être effectuée au moyen d'un carbodiimide tel que le dicyclohexyl carbo-diimide. Dehydration can advantageously be carried out using a carbodiimide such as dicyclohexyl carbo-diimide.
Les produits de formule (III) lorsqu'ils ne sont pas con-(II) 5 nus' Peuvent être préparés par réaction d'un produit de formule: The products of formula (III) when they are not known (II) 5 Can be prepared by reaction of a product of formula:
dans laquelle R] et R2 ont la signification déjà indiquée, avec une amine de formule: in which R] and R2 have the meaning already indicated, with an amine of formula:
alcQ alcQ
alpo alpo
(III) (III)
dans laquelle aie représente un radical alcoyle renfermant de 1 à 3 atomes de carbone, R3 et R4 ont la signification déjà indiquée, au sein d'un solvant organique, pour obtenir le produit de formule I recherché, que l'on peut salifier le cas échéant. in which aie represents an alkyl radical containing from 1 to 3 carbon atoms, R3 and R4 have the meaning already indicated, within an organic solvent, to obtain the desired product of formula I, which can be salified in the case if necessary.
Dans des conditions préférentielles de mise en œuvre du procédé de l'invention, la réaction du produit de formule (II) avec le produit de formule (III) est effectuée au sein d'un solvant organique tel que le chlorure de méthylène et en présence d'une amine telle que la triéthylamine. Under preferential conditions for implementing the process of the invention, the reaction of the product of formula (II) with the product of formula (III) is carried out in an organic solvent such as methylene chloride and in the presence an amine such as triethylamine.
Les sels d'addition avec les acides des produits de formule I peuvent être préparés en faisant réagir les dits produits de formule I avec une quantité stoéchiométrique d'un acide minéral ou organique. La réaction est effectuée de préférence dans un solvant organique ou un mélange de solvants organiques tel que les alcools, par exemple le méthanol ou l'éthanol, les halogénures d'alcoyle, par exemple le chlorure de méthylène. The acid addition salts of the products of formula I can be prepared by reacting the said products of formula I with a stoichiometric amount of a mineral or organic acid. The reaction is preferably carried out in an organic solvent or a mixture of organic solvents such as alcohols, for example methanol or ethanol, alkyl halides, for example methylene chloride.
Comme indiqué dans le brevet français n° 2 300 569, les produits de formule II peuvent être préparés d'un produit de formule: As indicated in French Patent No. 2,300,569, the products of formula II can be prepared from a product of formula:
(IV) (IV)
dans laquelle R] et R2 ont la signification déjà indiquée, par réaction avec la glycine, pour obtenir un produit de formule: in which R] and R2 have the meaning already indicated, by reaction with glycine, to obtain a product of formula:
«H-CHg-COOH "H-CHg-COOH
(V) (V)
dans laquelle R] et R2 ont la signification déjà indiquée, que l'on déshydrate pour obtenir le produit de formule (II) recherché. in which R] and R2 have the meaning already indicated, which is dried to obtain the desired product of formula (II).
(VI) (VI)
dans laquelle R3 et R4 ont la signification déjà indiquée, avec un alcoylcétal du diméthyl formamide. Un exemple d'une 15 telle préparation figure dans la partie expérimentale. in which R3 and R4 have the meaning already indicated, with an alkyl ketal of dimethyl formamide. An example of such a preparation is given in the experimental part.
Il va être donné maintenant à titre non limitatif un exemple de mise en œuvre de l'invention. An example of implementation of the invention will now be given without implied limitation.
Exemple Example
2o8-nitro 1,2-dyhidro2-(N-ménthyl-pipérazin-l-yl) méthylène 2o8-nitro 1,2-dyhidro2- (N-menthyl-piperazin-1-yl) methylene
6-( o-chlorophènyl) 1H, 4H-imidazo [ 1,2-a] [1,4] benzodi-azépine-l-one. 6- (o-chlorophenyl) 1H, 4H-imidazo [1,2-a] [1,4] benzodi-azepine-1-one.
Stade A: 2-carboxyméthylamino-7-nitro 5-(o-chlorophènyl) 3H-[ 1,4]-benzodiazépine. Stage A: 2-carboxymethylamino-7-nitro 5- (o-chlorophenyl) 3H- [1,4] -benzodiazepine.
25 Dans 3 litres d'eau déminéralisée, on indroduit 1,360 kg de glycine puis progressivement, 1,459 kg de bicarbonate de sodium. On agite 30 minutes à température ambiante, on introduit 15 litres d'éthanol puis, en 5 minutes environ, 3 kg de 25 In 3 liters of demineralized water, 1.360 kg of glycine are introduced and then gradually, 1.459 kg of sodium bicarbonate. The mixture is stirred for 30 minutes at room temperature, 15 liters of ethanol are introduced and then, in approximately 5 minutes, 3 kg of
7-nitro 1,3-dihydro 5-(o-chlorophényl) -2H-[1,4]-benzodi-30 azépine 2-thione. 7-nitro 1,3-dihydro 5- (o-chlorophenyl) -2H- [1,4] -benzodi-30 azepine 2-thione.
On porte au reflux pendant 1 heure 30, distille sous pression réduite, ajoute 15 litres d'eau déminéralisée par 2 fois, puis 7,5 litres de chlorure de méthylène et sépare les phases. The mixture is refluxed for 1 hour 30 minutes, distilled under reduced pressure, 15 liters of demineralized water are added twice, then 7.5 liters of methylene chloride and the phases are separated.
On réextrait la phase aqueuse par 3 fois 6 litres de chlorure 35 de méthylène puis lave les phases chlorométhyléniques à l'eau et réunit l'ensemble des phases aqueuses. On y ajoute 18 litres de chlorure de méthylène, puis à 0°, -1- 5°C, 1,3 litre d'acide chlorhydrique 22° Be. On obtient une solution chlorométhy-lénique de 2-carboxyméthylamino 7-nitro 5-(o-chlôrophényl) 40 3H-[l,4]benzodiazépine que l'on utilise au stade suivant. The aqueous phase is re-extracted with 3 times 6 liters of methylene chloride and then the chloromethylenic phases are washed with water and all of the aqueous phases are combined. 18 liters of methylene chloride are added thereto, then at 0 °, -1- 5 ° C, 1.3 liters of 22 ° Be hydrochloric acid. A chloromethylenic solution of 2-carboxymethylamino 7-nitro 5- (o-chlorophenyl) 40 3H- [1,4] benzodiazepine is obtained which is used in the following stage.
Stade B: 8-nitro 1,2-dihydro 6-( o-chlorophènyl) 1H, 4H-imi-dazo [ 1,2-a] [ 1,4] benzodiazépine-l-one Stage B: 8-nitro 1,2-dihydro 6- (o-chlorophenyl) 1H, 4H-imi-dazo [1,2-a] [1,4] benzodiazepine-1-one
A la solution chlorométhylénique de 2-carboxy méthyl-45 amino 7-nitro 5-(o-chlorophényl) 3H-[1,4]-benzodiazépine obtenue ci-dessus, on ajoute à + 5 °C en 2 minutes environ la solution de 1,865 kg de dicyclohexylcarbodiimide dans 3 litres de chlorure de méthylène puis agite pendant 30 minutes. To the chloromethylenic solution of 2-carboxy methyl-45 amino 7-nitro 5- (o-chlorophenyl) 3H- [1,4] -benzodiazepine obtained above, the solution of + is added at + 5 ° C in about 2 minutes 1.865 kg of dicyclohexylcarbodiimide in 3 liters of methylene chloride and then stirred for 30 minutes.
On laisse une nuit au repos puis essore. On lave 2 fois par 50 3 litres de chlorure de méthylène et recueille la solution chlorométhylénique de 8-nitro 1,2-dihydro 6-(o-chlorophényl) IH, 4H-imidazo [1,2-a] [1,4] benzodiazépine 1-one que l'on utilise au stade suivant. It is left to rest overnight and then wrung. Wash 2 times with 50 3 liters of methylene chloride and collect the chloromethylenic solution of 8-nitro 1,2-dihydro 6- (o-chlorophenyl) IH, 4H-imidazo [1,2-a] [1,4] benzodiazepine 1-one which is used in the next stage.
55 Stade C: 8-nitro 1,2-dihydro 2-(N-méthyl pipérazin-l-yl) méthylène 6-(o-chlorophènyl) 1H, 4H-imidazo [1,2-a] [1, 4]benzodiazépine-l-one. 55 Stage C: 8-nitro 1,2-dihydro 2- (N-methyl piperazin-1-yl) methylene 6- (o-chlorophenyl) 1H, 4H-imidazo [1,2-a] [1, 4] benzodiazepine -l-one.
Ala solution chlorométhylénique de 8-nitro 1,2-dihydro 6-(o-chlorophényl) IH, 4H-imidazo [1,2-a] [1,4] benzodiazé-60 pine-1-one obtenue ci-dessus, on ajoute en 5 minutes environ et à température ambiante, 650 g de triéthylamine puis 2,4 kg d'une solution de diméthylcétai de la N-formyl N-méthyl pi-pérazine dont la préparation est donnée ci-après. Ala chloromethylenic solution of 8-nitro 1,2-dihydro 6- (o-chlorophenyl) IH, 4H-imidazo [1,2-a] [1,4] benzodiazé-60 pine-1-one obtained above, we add in approximately 5 minutes and at room temperature, 650 g of triethylamine then 2.4 kg of a solution of dimethyl ketai of N-formyl N-methyl pi-perazine, the preparation of which is given below.
On agite pendant 1 heure 30 minutes, concentre à sec sous 65 pression réduite et ajoute 6 litres d'éthanol. On distille en maintenant le niveau constant par addition d'éthanol jusqu'à obtention de vapeurs à 78 °C, puis refroidit à 0° -f 2 °C, agite pendant 2 heures et essore. On lave avec de l'éthanol et re- The mixture is stirred for 1 hour 30 minutes, concentrated to dryness under 65 reduced pressure and 6 liters of ethanol are added. It is distilled while keeping the level constant by adding ethanol until vapors are obtained at 78 ° C, then cooled to 0 ° -f 2 ° C, stirred for 2 hours and wrung. Wash with ethanol and re-
651565 651565
cueille 4,260 kg de produit brut que l'on purifie par traitement au charbon actif puis par de l'éthanol. picks 4.260 kg of crude product which is purified by treatment with activated carbon and then with ethanol.
On recueille finalement 3,362 kg de 8-nitro 1,2-dihydro 2-(N-méthyl pipérazin-l-yl) méthlène 6-(o-chlorophényl) 1H, 4H-imidazo [1,2-a] [1,4] benzodiazépine-1-one. Finally collected 3.362 kg of 8-nitro 1,2-dihydro 2- (N-methyl piperazin-1-yl) methlene 6- (o-chlorophenyl) 1H, 4H-imidazo [1,2-a] [1,4 ] benzodiazepine-1-one.
Le produit obtenu est identique à celui décrit à l'exemple 30 du brevet français précité. The product obtained is identical to that described in Example 30 of the aforementioned French patent.
La solution de diméthylcétai de la N-formyl N-méthyl pi-pérazine peut être préparée comme suit: The dimethyl ketai solution of N-formyl N-methyl pi-perazine can be prepared as follows:
dans 2 kg de diméthylcétai de diméthylformamide, on introduit 3,3 kg de N-méthyl pipérazine, porte au reflux pendant 15 heures. 3.3 kg of N-methyl piperazine, brought to reflux for 15 hours, are introduced into 2 kg of dimethylformamide dimethyl ketai.
On distille la N-méthyl pipérazine non combinée sous 5 pression réduite, agite pendant 1 heure sous pression réduite à 115-120 °C puis refroidit à 20 °C. On obtient 3,920 kg d'une solution brune de diméthylcétai de N-formyl N-méthyl pipérazine. The uncombined N-methyl piperazine is distilled under reduced pressure, stirred for 1 hour under reduced pressure at 115-120 ° C and then cooled to 20 ° C. 3.920 kg of a brown solution of dimethyl ketal of N-formyl N-methyl piperazine are obtained.
C VS
Claims (2)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8106171A FR2502621B1 (en) | 1981-03-27 | 1981-03-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH651565A5 true CH651565A5 (en) | 1985-09-30 |
Family
ID=9256708
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1896/82A CH651565A5 (en) | 1981-03-27 | 1982-03-26 | PROCESS FOR THE PREPARATION OF IMIDAZOBENZODIAZEPINES AND THEIR SALTS. |
Country Status (17)
| Country | Link |
|---|---|
| JP (1) | JPS57169483A (en) |
| AU (1) | AU549222B2 (en) |
| CA (1) | CA1175823A (en) |
| CH (1) | CH651565A5 (en) |
| DE (1) | DE3211243A1 (en) |
| DK (1) | DK153404C (en) |
| ES (1) | ES509284A0 (en) |
| FI (1) | FI71152C (en) |
| FR (1) | FR2502621B1 (en) |
| GB (1) | GB2095674B (en) |
| HU (1) | HU185092B (en) |
| IT (1) | IT1147917B (en) |
| MA (1) | MA19416A1 (en) |
| NL (1) | NL193246C (en) |
| PT (1) | PT74669B (en) |
| SE (2) | SE8200271L (en) |
| ZA (1) | ZA821141B (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3872090A (en) * | 1972-07-12 | 1975-03-18 | Boehringer Sohn Ingelheim | 3-(amino-methylene)-5-phenyl-1,4-benzodiazepin-2-ones |
| IL48888A (en) * | 1975-02-15 | 1979-03-12 | Roussel Uclaf | 2-aminomethylene-1,2-dihydro-6-phenyl-1h-imidazo(1,2-a)(1,4) benzodiazepin-1-ones, process for their preparation andpharmaceutical compositions incorporating them |
-
1981
- 1981-03-27 FR FR8106171A patent/FR2502621B1/fr not_active Expired
-
1982
- 1982-01-19 SE SE8200271D patent/SE8200271L/en not_active Application Discontinuation
- 1982-01-19 SE SE8200271A patent/SE448731B/en not_active IP Right Cessation
- 1982-02-03 ES ES509284A patent/ES509284A0/en active Granted
- 1982-02-22 ZA ZA821141A patent/ZA821141B/en unknown
- 1982-02-26 AU AU80947/82A patent/AU549222B2/en not_active Expired
- 1982-03-18 MA MA19621A patent/MA19416A1/en unknown
- 1982-03-19 IT IT48036/82A patent/IT1147917B/en active
- 1982-03-23 NL NL8201208A patent/NL193246C/en not_active IP Right Cessation
- 1982-03-24 JP JP57045728A patent/JPS57169483A/en active Pending
- 1982-03-25 FI FI821058A patent/FI71152C/en not_active IP Right Cessation
- 1982-03-26 DE DE19823211243 patent/DE3211243A1/en active Granted
- 1982-03-26 PT PT74669A patent/PT74669B/en unknown
- 1982-03-26 CA CA000399537A patent/CA1175823A/en not_active Expired
- 1982-03-26 CH CH1896/82A patent/CH651565A5/en not_active IP Right Cessation
- 1982-03-26 GB GB8208933A patent/GB2095674B/en not_active Expired
- 1982-03-26 DK DK138682A patent/DK153404C/en not_active IP Right Cessation
- 1982-03-26 HU HU82939A patent/HU185092B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| PT74669B (en) | 1985-01-08 |
| DE3211243C2 (en) | 1993-05-19 |
| FR2502621A1 (en) | 1982-10-01 |
| MA19416A1 (en) | 1982-10-01 |
| ES8302712A1 (en) | 1983-01-16 |
| AU549222B2 (en) | 1986-01-23 |
| DK153404B (en) | 1988-07-11 |
| IT8248036A0 (en) | 1982-03-19 |
| FI71152C (en) | 1986-11-24 |
| ES509284A0 (en) | 1983-01-16 |
| ZA821141B (en) | 1983-01-26 |
| CA1175823A (en) | 1984-10-09 |
| DE3211243A1 (en) | 1982-10-07 |
| FI821058L (en) | 1982-09-28 |
| HU185092B (en) | 1984-11-28 |
| GB2095674A (en) | 1982-10-06 |
| FR2502621B1 (en) | 1983-10-28 |
| NL8201208A (en) | 1982-10-18 |
| SE448731B (en) | 1987-03-16 |
| DK138682A (en) | 1982-09-28 |
| AU8094782A (en) | 1982-09-30 |
| FI821058A0 (en) | 1982-03-25 |
| SE8200271L (en) | 1982-09-28 |
| FI71152B (en) | 1986-08-14 |
| NL193246C (en) | 1999-04-02 |
| GB2095674B (en) | 1984-10-10 |
| DK153404C (en) | 1988-11-21 |
| IT1147917B (en) | 1986-11-26 |
| PT74669A (en) | 1982-04-01 |
| JPS57169483A (en) | 1982-10-19 |
| NL193246B (en) | 1998-12-01 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PFA | Name/firm changed |
Owner name: ROUSSEL-UCLAF TRANSFER- ROUSSEL UCLAF * ROUSSEL UC |
|
| PL | Patent ceased |