CA1175823A - Process for preparing imidazobenzodiazepins and their salts - Google Patents
Process for preparing imidazobenzodiazepins and their saltsInfo
- Publication number
- CA1175823A CA1175823A CA000399537A CA399537A CA1175823A CA 1175823 A CA1175823 A CA 1175823A CA 000399537 A CA000399537 A CA 000399537A CA 399537 A CA399537 A CA 399537A CA 1175823 A CA1175823 A CA 1175823A
- Authority
- CA
- Canada
- Prior art keywords
- formula
- piperazin
- product
- alkyl
- radical
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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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)
Abstract
L'invention concerne un procédé pour préparer les produits (I): <IMG> (I) où R1 est hydrogène, halogène, nitro, CF3, R2 est hydrogène, halogène, R3 et R4 forment un 4-alcoyl pipérazin-1-yl, 4cycloalcoylalcoyl-pipérazin-1-yl, 4-phényl pipérazin-1-yl, pipéridino, ainsi que leurs sels avec les acides, procédé essentiellement caractérisé en ce que l'on traite un produit (II): <IMG> (II) par une amine (III): <IMG> (III) et, le cas échéant, salifie. Le procédé de l'invention permet d'obtenir les produits de formule (I) qui possèdent d'intéressantes propriétés sédatives, hypnotiques, anxiolytiques, tranquillisantes, anticonvulsivantes et myorelaxantes, en un nombre de stades inférieur à celui de l'art antérieur.The invention relates to a process for preparing the products (I): <IMG> (I) where R1 is hydrogen, halogen, nitro, CF3, R2 is hydrogen, halogen, R3 and R4 form a 4-alkyl piperazin-1-yl , 4cycloalcoylalcoyl-piperazin-1-yl, 4-phenyl piperazin-1-yl, piperidino, as well as their salts with acids, process essentially characterized in that a product (II) is treated: <IMG> (II) with an amine (III): <IMG> (III) and, if necessary, salifies. The process of the invention makes it possible to obtain the products of formula (I) which have interesting sedative, hypnotic, anxiolytic, tranquilizing, anticonvulsant and muscle relaxant properties, in a number of stages lower than that of the prior art.
Description
1 l~s823 La présente invention concerne un nouveau procédé
de préparation d'imidazobenzo-diazépines, ainsi que de leurs sels d'addition avec les acides.
L'invention a plus précisément pour objet un nou-veau procédé de préparation des produits de formule générale:
Rl--f ~N.
~ R2 dans laquelle Rl 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 lls sont liés un radical -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.
Dans la formule I et dans ce qui suit, ; - lorsque Rl représente un atome d'halog~ne, il s'agit de préérence d'un atome de fluor, de chlore ou de brome et plus particulièrement d'un atome de chlore;
- lorsque R2 représente un atome d'halogène, il s'agit de préférence d'un atome de fluor, de chlore ou de brome, et plus particulierement d'un atome de fluor ou de chlore; de plus, lorsque R2 est un atome d'halogène, il est, de préfé-rence, en position ortho;
- lorsque R3 et R4 représentent ensemble avec l'atome d'azote auquel ils sont liés un radical 4-alcoyl-pipérazin-l-yl, il s'agit de préférence d'un radical 4-méthyl-pipérazin-l-yl ~ ` -1 ~75823 4-éthyl-pipérazin-1-yl ou 4-propyl-pipérazin-1-yl et plus particulièrement du radical 4-methyl-piperazin-1-yl.
- lorsque R3 et R4 representent ensemble avec l'atome d'azote auquel ils sont liés un radical 4 - cyclo alcoyl alcoyl-pipérazin-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 cyclopentyle.
Parmi les radicaux 4 - cyclo alcoyl alcoyl-pipérazin-l-yl on retient plus particulièrement le radical 4 - cyclopropyl méthyl-pipérazin-l-yl.
Les sels d'addition avec les acides mineraux ou organiques peuvent être, par exemple, les sels formés avec les acides chlorhydrique, bromhydrique, iodhydrique, nitri-que, sulfurique, phosphorique, propionique, acétique, formi-que, benzoique, maléique, fumarique, succinique, tartrique, citrique, oxalique, glyoxylique, aspartique, alcanesulfoni-ques, tels que l'acide benzène sulfonique.
Les produits de formule générale (I) et leurs sels ainsi qu'un procédé de préparation de ceux-ci ont eté décrits dans le brevet français n2,300,569 de la demanderesse.
Ainsl qu'il est indiqué dans ce brevet, les produits de for-mule générale (I) possedent d'intéressantes proprietés séda-tives, hypnotiques, anxiolytiques, tranquillisantes, anti-convulsivantes et myorelaxantes.
Le nouveau procédé de l'invention permet de prépa-rer 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.
La présente demande a ainsi pour objet un nouveau procédé 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:
I ~ 75823 R ~ ~ ~II) ~- R
dans laquelle Rl et R2 ont la signification déja indiquée, avec une amine de formule:
alcO / R3 CH N ~III) alcO ~ \R4 dans laquelle alc représente un .radical alcoyle renfermant de 1 a 3 atomes de carbone, R3 et R4 ont la signification ; déja indiquée, au sein d'un solvant organique, pour obtenir le produit de formula I recherché, que l'on peut salifier le cas échéant.
Dans des conditions préférentielles de mise en oeuvre du procedé 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 méthy~
lane et en présence d'un amine telle que la triéthylamine.
Les sels d'addition avec les acides des produits de formule I peuvent etre préparés en faisant réagir lesdits produits de formule I avec une quantité stoéchiométrique d'un acide minéral ou organique. La réaction est effectuée de préference dans un solvant organique ou un mélange de solvants organiques tel que les alcools, par exemple le mé-thanol ou l'~thanol, les halogénures d'alcoyle, par exemplele chlorure de méthylene.
Comme indiqué dans le brevet français n 2.300.569, les prodults de formule II peuvent être pr~pares au départ d'un produit de formule:
. , -, ' .
, ~ I 75823 S R ~ - ~ (IV) dans laquelle Rl et R2 ont la signification déjà indiquée, par réaction avec la glycine, pour obtenir un produit de formule:
R~ ~NEI-CH -COOH
~R2 dans laquelle Rl et R2 ont la signification déja indiquée, que l'on déshydrate pour obtenir le produit de formule (II) recherche.
La déshydratation peut avantageusement être effec-tuée au moyen d'un carbodiimide tel que le dicyclohexyl car-bodiimide.
Les produits de formule (III) lorsqu'ils ne sont pas connus, peuvent etre préparés par réaction d'un produit de formule:
H N (VI) dans laquelle R3 et R4 ont la signification déja indiquée, avec un alcoylcétal du dimékhyl formamide. Un exemple d'une telle préparation figure dans la partie expérimentale.
~ J75823 Il va être donne maintenant a titre non limitatif un exemple de mise en oeuvre de l'invention.
Exemple: ~-nitro 1,2-dihydro 2-(N-methyl-piperazin-l-yl) methylène 6-(o-chlorophenyl) lH, 4H-imidazo tl,2-a~ L~,4J
benzodiazepine-l-one.
Stade A. 2-carboxymethylamino-7-nitro 5-1o-chlorophenyl~
3H-~lL~-benzodiaze~ine.
e__ _ ___________ ___ -Dans 3 litres d'eau demineralisee, on introduit 1,360 kg de glycine puis progressivement, 1,450 kg de bicarbonate de sodium. On agite 30 minutes a temperature ambiante, on introduit 15 litres d'éthanol puis, en 5 minutes environ, 3 kg de 7-nitro 1,3-dihydro 5-(o-chlorophényl)-2H-a, ~7-benzodiazépine 2-thione.
On porte au reflux pendant 1 heure 30, distille sous pression réduite, ajoute 15 litres d'eau demineralisee par 2 fois, puis 7,5 litres de chlorure de methylene et sépare les phases.
On réextrait la phase aqueuse par 3 fois 6 litres de chlorure de methylene puis lave les phases chloromethyle-niques à l'eau et reunit l'ensemble des phases aqueuses. Ony ajoute 18 litres de chlorure de methylene, puis, a 0, +5C, 1,3 litre d'acide chlorhydrique 22Be. On obtient une solution chlorométhylénique de 2-carboxyméthylamino 7-nitro 5-(o-chlorophényl) 3H-Ll~7 benzodiazépine que l'on utilise au stade suivant.
Stade_B. 8-nitro 1~2-dihydro 6-1o-chloro~henyl~ lHL4H-m_da_oa ~2-a~ ~ ~ ~benzod_a_e~ine-l-one.
A la solution chlorométhylénique de 2-carboxy méthylamino 7-nitro 5-(o-chlorophényl) 3H-Ll,~7-benzodiaze-pine obtenue ci-dessus, on ajoute a ~5C en 2 minutes environ la solution de 1,865 kg de dicyclohexylcarbodiimide dans 3 litres de chlorure de méthylane puis agite pendant 30 minutes.
On laisse une nuit au repos puis essore. On lave 1 l ~ s823 The present invention relates to a new process preparation of imidazobenzo-diazepines, as well as their addition salts with acids.
The invention more specifically relates to a new calf preparation process for products of general formula:
Rl - f ~ N.
~ R2 in which Rl represents a hydrogen atom, an atom halogen, a nitro radical or a trifluoromethyl radical, R2 represents a hydrogen atom or a halogen atom, R3 and R4 represent together with the nitrogen atom to which They are linked a radical -alkyl-piperazin-l-yl, 4-cyclo alkyl alkyl piperazin-1-yl, 4-phenyl-piperazin-1-yl or piperidino, as well as their addition salts with mineral or organic acids.
In Formula I and in the following, ; - when Rl represents a halogen atom, it is presence of a fluorine, chlorine or bromine atom and more particularly of a chlorine atom;
- when R2 represents a halogen atom, it is preferably a fluorine, chlorine or bromine atom, and more particularly of a fluorine or chlorine atom; of more, when R2 is a halogen atom, it is preferably rence, in ortho position;
- when R3 and R4 represent together with the nitrogen atom to which they are linked a 4-alkyl-piperazin-l-yl radical, it it is preferably a 4-methyl-piperazin-1-yl radical ~ `-1 ~ 75823 4-ethyl-piperazin-1-yl or 4-propyl-piperazin-1-yl and more particularly of the 4-methyl-piperazin-1-yl radical.
- when R3 and R4 represent together with the atom nitrogen to which they are linked a radical 4 - cyclo alkyl alkyl-piperazin-l-yl, it is preferably a radical cyclo alkyl comprising from 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl or cyclopentyl radicals.
Among the radicals 4 - cyclo alcoyl alcoyl-pipérazin-l-yl the radical 4 - cyclopropyl is more particularly retained methyl-piperazin-1-yl.
Addition salts with mineral acids or organic can be, for example, the salts formed with hydrochloric, hydrobromic, hydroiodic, nitri-that sulfuric, phosphoric, propionic, acetic, formi-that, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkanesulfoni-such as benzene sulfonic acid.
Products of general formula (I) and their salts as well as a process for their preparation have been described in the French patent n2,300,569 of the plaintiff.
As indicated in this patent, the products of general mule (I) have interesting sedative properties tives, hypnotics, anxiolytics, tranquilizers, anti convulsive and muscle relaxant.
The new process of the invention makes it possible to prepare the products of formula (I) with good yields in a lower number of stages than that of the methods described in the aforementioned French patent.
The present application thus relates to a new process for the preparation of products of general formula I, as well as their addition salts with mineral acids or organic, characterized in that one reacts a formula product:
I ~ 75823 R ~ ~ ~ II) ~ - R
in which Rl and R2 have the meaning already indicated, with an amine of formula:
alcO / R3 CH N ~ III) alcO ~ \ R4 in which alc represents an alkyl radical containing from 1 to 3 carbon atoms, R3 and R4 have the meaning ; already indicated, in an organic solvent, to obtain the desired product of formula I, which can be salified if applicable.
In preferential conditions of implementation work of the process of the invention, the reaction of the product of formula ~ II) with the product of formula ~ III) is carried out within an organic solvent such as methyl chloride ~
lane and in the presence of an amine such as triethylamine.
Addition salts with product acids of formula I can be prepared by reacting said products of formula I with a stoichiometric amount of a mineral or organic acid. The reaction is carried out preferably in an organic solvent or a mixture of organic solvents such as alcohols, for example thanol or ~ thanol, alkyl halides, for example methylene chloride.
As indicated in French Patent No. 2,300,569, the products of formula II can be prepared at the start of a product of formula:
. , -, '' .
, ~ I 75823 SR ~ - ~ (IV) in which R1 and R2 have the meaning already indicated, by reaction with glycine, to obtain a product of formula:
R ~ ~ NEI-CH -COOH
~ R2 in which Rl and R2 have the meaning already indicated, which is dehydrated to obtain the product of formula (II) research.
Dehydration can advantageously be carried out killed with a carbodiimide such as dicyclohexyl car-bodiimid.
The products of formula (III) when they are not not known, can be prepared by reaction of a product of formula:
HN (VI) in which R3 and R4 have the meaning already indicated, with an alkylketal of dimékhyl formamide. An example of a such preparation appears in the experimental part.
~ J75823 It will now be given without limitation an example of implementation of the invention.
Example: ~ -nitro 1,2-dihydro 2- (N-methyl-piperazin-l-yl) methylene 6- (o-chlorophenyl) 1H, 4H-imidazo tl, 2-a ~ L ~, 4J
benzodiazepine-l-one.
Stage A. 2-carboxymethylamino-7-nitro 5-1o-chlorophenyl ~
3H- ~ lL ~ -benzodiaze ~ ine.
e__ _ ___________ ___ -In 3 liters of demineralized water, we introduce 1.360 kg of glycine then gradually, 1.450 kg of sodium bicarbonate. Shake for 30 minutes at temperature ambient, 15 liters of ethanol are introduced and then, in 5 minutes approx. 3 kg of 7-nitro 1,3-dihydro 5- (o-chlorophenyl) -2H-a, ~ 7-benzodiazepine 2-thione.
The mixture is refluxed for 1 hour 30 minutes, distilled under reduced pressure, add 15 liters of demineralized water twice, then 7.5 liters of methylene chloride and separates the phases.
The aqueous phase is re-extracted by 3 times 6 liters methylene chloride and then wash the chloromethyl phases-nics with water and combines all of the aqueous phases. 18 liters of methylene chloride are added thereto, then, at 0, + 5C, 1.3 liters of hydrochloric acid 22Be. We get a chloromethylenic solution of 2-carboxymethylamino 7-nitro 5- (o-chlorophenyl) 3H-L1 ~ 7 benzodiazepine which is used to the next stage.
Stade_B. 8-nitro 1 ~ 2-dihydro 6-1o-chloro ~ henyl ~ lHL4H-m_da_oa ~ 2-a ~ ~ ~ ~ benzod_a_e ~ ine-l-one.
With chloromethylenic solution of 2-carboxy methylamino 7-nitro 5- (o-chlorophenyl) 3H-Ll, ~ 7-benzodiaze-pine obtained above, we add a ~ 5C in about 2 minutes the solution of 1.865 kg of dicyclohexylcarbodiimide in 3 liters of methylane chloride and then stirred for 30 minutes.
It is left to rest overnight and then wrung. We wash
2 fois par 3 litres de chlorure de methylene et recueille la , , , ' 1 ~7~5823 solution chlorométhylenique de 8-nitro 1,2-dihydro 6-(o-chloro-phenyl) lH,4H-imidazo LI,2-a7 Ll,~7 benzodiazepine l-one que l'on utilise au stade suivant.
Stade_C___~3-nitro lL2-dihydro 2-1N-methyl piperazin-l-yl me-hylene-6-(o-chlorophenylL-lHL4H--midaz-o- ~L--~z-L~' benzod1aze~ine-1-one.
A la solution chloromethylenique de 8-nitro 1,2-dihydro 6-(o-chlorophenyl) lH,4H-imidazo a,2-a~7 Ll,47benzo-diazepine-l-one obtenue ci-dessus, on ajoute en 5 minutes environ et à température ambiante, 650 g de triethylamine puis 2,4 kg d'une solution de dimethylcetal de la N-formyl N-méthyl piperazine dont la preparation est donnee ci-apres.
On agite pendant 1 heure 30 minutes, concentre a sec sous pression réduite et ajoute 6 litres d'ethanol. On distille en maintenant le niveau constant par addition d'ethanol jusqu'a obtention de vapeurs a 78C, puis refroidit a 0 + 2C, agite pendant 2 heures et essore. On lave avec de l'éthanol et recueille 4,260 kg de produit brut que l'on puriie par traitement au charbon actif puis par de l'ethanol.
On recueille finalement 3,362 kg de 8-nitro 1,2-dihydro 2-(N-méthyl pipérazin-l-yl) méthylene 6-(o-chlorophé-nyl) lH,4H-imidazoL~,2-a~ Ll, Y benzodiazépine-l-one.
Le produit obtenu est identique à celui decrit à
l'exemple 30 du brevet français précité.
La solution de diméthylcétal de la N-formyl N-méthyl pipérazine peut être préparée comme suit:
dans 2 kg de diméthylcetal de diméthylformamide, on introduit 3,3 kg de N-méthyl piperazine, porte au reflux pen-dant 15 heures.
On distille la N-methyl pipérazine non combinee sous pression réduite, agite pendant 1 heure sous pression réduite a 115-120C puis refroidit à 20C. On obtient 3,920 kg d'une solution brune de diméthylcetal de N-formyl N-methyl pipérazine.
.. 2 times per 3 liters of methylene chloride and collect the , , , '' 1 ~ 7 ~ 5823 chloromethylenic solution of 8-nitro 1,2-dihydro 6- (o-chloro-phenyl) 1H, 4H-imidazo LI, 2-a7 Ll, ~ 7 benzodiazepine l-one than we use in the next stage.
Stade_C ___ ~ 3-nitro lL2-dihydro 2-1N-methyl piperazin-l-yl me-hylene-6- (o-chlorophenylL-lHL4H - midaz-o- ~ L-- ~ zL ~ ' benzod1aze ~ ine-1-one.
With chloromethylenic solution of 8-nitro 1,2-dihydro 6- (o-chlorophenyl) 1H, 4H-imidazo a, 2-a ~ 7 Ll, 47benzo-diazepine-l-one obtained above, added in 5 minutes approximately and at room temperature, 650 g of triethylamine then 2.4 kg of a dimethyl ketal solution of N-formyl N-methyl piperazine, the preparation of which is given below.
Stirred for 1 hour 30 minutes, concentrated to dry under reduced pressure and add 6 liters of ethanol. We distills keeping the level constant by addition ethanol until vapors are obtained at 78C, then cools at 0 + 2C, stir for 2 hours and spin. We wash with ethanol and collects 4,260 kg of crude product which is puriie by treatment with activated carbon then with ethanol.
Finally collected 3.362 kg of 8-nitro 1,2-dihydro 2- (N-methyl piperazin-1-yl) methylene 6- (o-chlorophen-nyl) 1H, 4H-imidazoL ~, 2-a ~ L1, Y benzodiazepine-1-one.
The product obtained is identical to that described in Example 30 of the aforementioned French patent.
N-formyl N-methyl dimethylketal solution piperazine can be prepared as follows:
in 2 kg of dimethylformamide dimethyl ketal, introduced 3.3 kg of N-methyl piperazine, brought to reflux during at 3 p.m.
Unmixed N-methyl piperazine is distilled under reduced pressure, stirred for 1 hour under pressure reduced to 115-120C then cools to 20C. We get 3,920 kg of a brown solution of dimethyl ketal of N-formyl N-methyl piperazine.
..
Claims (4)
(I) dans laquelle R1 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 sont liés un radical 4-alcoyl-pipérazin-1-yl, 4-cyclo alcoyl alcoyl pipérazin-1-yl, 4-phényl-pipérazin-1-yl ou pipéridino, 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:
(II) dans laquelle R1 et R2 ont la signification précitée, avec une amine de formule:
(III) dans laquelle alc représenté un radical alcoyle renfermant de 1 à 3 atomes de carbone et R3 et R4 ont la signification déjà indiquée, au sein d'un solvant organique. 1. Process for the preparation of the products of formula general:
(I) in which R1 represents a hydrogen atom, an atom halogen, a nitro radical or a trifluoromethyl radical, R2 represents a hydrogen atom or a halogen atom, R3 and R4 represent together with the nitrogen atom to which they are linked a radical 4-alkyl-piperazin-1-yl, 4-cyclo alkyl alkyl piperazin-1-yl, 4-phenyl-piperazin-1-yl or piperidino, as well as their addition salts with mineral or organic acids, characterized in that reacts a product of formula:
(II) in which R1 and R2 have the abovementioned meaning, with an amine of formula:
(III) in which alc represents an alkyl radical containing from 1 to 3 carbon atoms and R3 and R4 have the meaning already indicated, in an organic solvent.
en ce qu'il comporte en outre une étape de salification du produit de formule générale (I) obtenu. 2. Method according to claim 1, characterized in that it further comprises a step of salification of the product of general formula (I) obtained.
en ce que la réaction du produit de formule (II) avec le produit de formule (III) est effectuée au sein du chlorure de méthylène et en présence d'une amine. 3. Method according to claim 1, characterized in that the reaction of the product of formula (II) with the product of formula (III) is carried out in chloride methylene and in the presence of an amine.
en ce que l'amine est la triéthylamine. 4. Method according to claim 3, characterized in that the amine is triethylamine.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR8106171A FR2502621B1 (en) | 1981-03-27 | 1981-03-27 | |
FR81-06171 | 1981-03-27 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1175823A true CA1175823A (en) | 1984-10-09 |
Family
ID=9256708
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA000399537A Expired CA1175823A (en) | 1981-03-27 | 1982-03-26 | Process for preparing imidazobenzodiazepins 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 |
CH651565A5 (en) | 1985-09-30 |
ZA821141B (en) | 1983-01-26 |
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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