CH649549A5 - NAPHTYRIDINE DERIVATIVES, THEIR PREPARATION AND MEDICAMENTS CONTAINING THEM. - Google Patents
NAPHTYRIDINE DERIVATIVES, THEIR PREPARATION AND MEDICAMENTS CONTAINING THEM. Download PDFInfo
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- CH649549A5 CH649549A5 CH7460/81A CH746081A CH649549A5 CH 649549 A5 CH649549 A5 CH 649549A5 CH 7460/81 A CH7460/81 A CH 7460/81A CH 746081 A CH746081 A CH 746081A CH 649549 A5 CH649549 A5 CH 649549A5
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/16—Peri-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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Description
La présente invention concerne des dérivés de l'hexahydro-2,3,3a,4,5,6 lH-indolo-[3,2,l-de]-[naphtyridine-l,5], leurs sels d'addans laquelle Ri et R2 ont les significations mentionnées plus haut. The present invention relates to derivatives of hexahydro-2,3,3a, 4,5,6 lH-indolo- [3,2, l-de] - [naphthyridine-1,5], their salts of which Ri and R2 have the meanings mentioned above.
Les composés (II) ont déjà été décrits dans la littérature, notamment par Taborsky R.G. et coll., « J. Med. Chem.», 7 (2), 135-41 (1964), par Hahn G. et coll., «Ber.», 71B, 2163-75 (1938), dans le 40 brevet français N° 2434165 et par la titulaire dans le brevet suisse No 622795. The compounds (II) have already been described in the literature, in particular by Taborsky R.G. et al., "J. Med. Chem. ", 7 (2), 135-41 (1964), by Hahn G. et al.," Ber. ", 71B, 2163-75 (1938), in French patent No. 2434165 and by the owner in Swiss Patent No. 622795.
Le procédé de l'invention consiste en la réduction des composés (II) selon une méthode classique, par exemple par traitement du composé (II) à l'aide d'un hydrure, tel que l'hydrure double de li-45 thium et d'aluminium, en présence d'un acide de Lewis, tel que le chlorure d'aluminium. The process of the invention consists in the reduction of the compounds (II) according to a conventional method, for example by treatment of the compound (II) using a hydride, such as the double hydride of li-45 thium and aluminum, in the presence of a Lewis acid, such as aluminum chloride.
La réaction est effectuée à une température allant de —40 à +80° C, dans un solvant tel que l'éther anhydre. The reaction is carried out at a temperature ranging from -40 to + 80 ° C, in a solvent such as anhydrous ether.
Les exemples suivants illustrent la présente invention. The following examples illustrate the present invention.
so Les analyses et les spectres IR et RMN confirment la structure des composés. n / a IR and NMR spectra and analyzes confirm the structure of the compounds.
Exemple 1 Example 1
Hexahydro-2,3,3a,4,5,6 lH-indolo-[3,2,l-de]-[naphtyridine-l,5] 55 et son méthanesulfonate. Hexahydro-2,3,3a, 4,5,6 lH-indolo- [3,2, l-de] - [naphthyridine-1,5,5] and its methanesulfonate.
Dans un tricol de 11, on place 5,4 g (0,04 mol) de chlorure d'aluminium. On ajoute en un seul jet 50 ml d'éther anhydre. A la solution obtenue, on ajoute peu à peu 2,3 g (0,06 mol) d'hydrure double de lithium et d'aluminium. On agite la suspension obtenue pendant 6o 10 min. On y ajoute peu à peu une suspension de 5,3 g (0,02 mol) de chlorhydrated'hexahydro-l,2,3,3a,4,5, 6H-indolo-[3,2,l-de]-[naph-tyridine-l,5]-one-6 dans 70 ml de tétrahydrofuranne anhydre. On agite à température ambiante pendant 30 min. On refroidit ensuite dans un bain de glace et on ajoute lentement 10 ml d'eau. On agite 65 10 min, puis on ajoute successivement 10 ml de lessive de soude (d = 1,38), 150 ml d'acétate d'éthyle et 100 ml d'eau. On agite 15 min. La phase organique est décantée. La phase aqueuse est extraite avec 2 fois 60 ml d'acétate d'éthyle. Les extraits organiques réunis sont 5.4 g (0.04 mol) of aluminum chloride are placed in a three-necked flask of 11. 50 ml of anhydrous ether are added in a single jet. 2.3 g (0.06 mol) of lithium aluminum hydride are gradually added to the solution obtained. The suspension obtained is stirred for 6o 10 min. A suspension of 5.3 g (0.02 mol) of hydrochloric acid hexahydro-1,2,3,3a, 4,5, 6H-indolo- [3,2, l-de] - is gradually added thereto - [naph-tyridine-1,5] -one-6 in 70 ml of anhydrous tetrahydrofuran. The mixture is stirred at room temperature for 30 min. It is then cooled in an ice bath and 10 ml of water are slowly added. Stir 65 10 min, then add successively 10 ml of sodium hydroxide solution (d = 1.38), 150 ml of ethyl acetate and 100 ml of water. Stir 15 min. The organic phase is decanted. The aqueous phase is extracted with 2 times 60 ml of ethyl acetate. The combined organic extracts are
3 3
649549 649549
lavés à l'eau, séchés sur sulfate de sodium et évaporés au bain-marie sous vide. On obtient une huile qui est séchée par entraînement azéotropique au toluène. La base obtenue est pure en Chromatographie sur couche mince (ccm). Cette huile est solubilisée dans 80 ml d'éther anhydre. On ajoute une solution de 2 g (0,02 mol) d'acide méthanesulfonique dans 20 ml d'éthanol. washed with water, dried over sodium sulphate and evaporated in a water bath under vacuum. An oil is obtained which is dried by azeotropic entrainment with toluene. The base obtained is pure by thin layer chromatography (ccm). This oil is dissolved in 80 ml of anhydrous ether. A solution of 2 g (0.02 mol) of methanesulfonic acid in 20 ml of ethanol is added.
On agite 30 min à température ambiante. On filtre le précipité blanc obtenu. On le lave à l'éther et le sèche au dessiccateur. The mixture is stirred for 30 min at room temperature. The white precipitate obtained is filtered. It is washed with ether and dried in a desiccator.
Le sel est recristallisé dans 80 ml d'éthanol. F = 246-248° C. The salt is recrystallized from 80 ml of ethanol. Mp 246-248 ° C.
Exemple 2 Example 2
Chloro-10-hexahydro-2,3,3a,4,5,6 lH-indolo-[3,2,l-de]-[naphty-ridine-1,5] et son méthanesulfonate. Chloro-10-hexahydro-2,3,3a, 4,5,6 lH-indolo- [3,2, l-de] - [naphty-ridine-1,5] and its methanesulfonate.
Dans un ballon tricol de 500 cm3, on place 2,25 g (0,0168 mol) de chlorure d'aluminium anhydre, 25 ml d'éther anhydre et 0,96 g (0,0252 mol) d'hydrure double de lithium et d'aluminium. A cette suspension on ajoute sous agitation une suspension de 2,5 g (0,0084 mol) de chlorhydrate de chloro-10-hexahydro-l,2,3,3a,4,5 6H-indolo-[3,2,l-de]-[naphtyridine-l,5]-one-6 dans 60 ml de tétrahy-drofuranne anhydre. A la fin de l'introduction, on obtient une solution grise et on agite pendant 1/2 h. On contrôle par ccm la disparition complète du produit de départ. 2.25 g (0.0168 mol) of anhydrous aluminum chloride, 25 ml of anhydrous ether and 0.96 g (0.0252 mol) of double lithium hydride are placed in a 500 cm3 three-necked flask and aluminum. To this suspension is added with stirring a suspension of 2.5 g (0.0084 mol) of hydrochloride-10-hexahydro-1,2,3,3a, 4,5 6H-indolo- [3,2, l -de] - [naphthyridine-1.5] -one-6 in 60 ml of anhydrous tetrahy-drofuran. At the end of the introduction, a gray solution is obtained and the mixture is stirred for 1/2 h. The complete disappearance of the starting product is checked by cmc.
On détruit le complexe par addition lente de 5 ml d'eau puis par 15 ml de lessive de soude (d = 1,38). On dilue le milieu par 150 ml d'eau, puis on extrait 3 fois avec 70 ml d'acétate d'éthyle. On lave l'extrait à l'eau, puis on le sèche sur sulfate de sodium. On filtre. Au filtrat on ajoute 0,9 g (0,0093 mol) d'acide méthanesulfonique en solution dans 2 ml d'acétate d'éthyle. The complex is destroyed by the slow addition of 5 ml of water and then with 15 ml of sodium hydroxide solution (d = 1.38). The medium is diluted with 150 ml of water, then extracted 3 times with 70 ml of ethyl acetate. The extract is washed with water, then dried over sodium sulfate. We filter. To the filtrate is added 0.9 g (0.0093 mol) of methanesulfonic acid dissolved in 2 ml of ethyl acetate.
Le précipité formé est essoré. On le recristallise dans environ 50 ml de méthanol en présence de noir décolorant. On filtre à chaud. Le filtrat laisse déposer des cristaux. On essore et sèche. F = 275-278° C. The precipitate formed is drained. It is recrystallized from approximately 50 ml of methanol in the presence of bleaching black. We filter hot. The filtrate leaves crystals. We wring and dry. Mp 275-278 ° C.
Dans le tableau sont représentés les composés de l'invention qui ont été préparés à titre d'exemples selon la méthode décrite ci-dessus. The table shows the compounds of the invention which have been prepared by way of examples according to the method described above.
Tableau Board
R R
Composé Compound
Ri r2 Ri r2
Base ou sel Base or salt
F (°C) F (° C)
1 (ex. 1) 1 (ex. 1)
H H
H H
m.s. m.s.
246-248 246-248
2 2
CHj-10 CHj-10
H H
base based
122-123 122-123
3 3
ch3o-io ch3o-io
H H
m.s. m.s.
248-250 248-250
4 4
F-10 F-10
H H
HCl HCl
>300 > 300
5 (ex. 2) 5 (ex. 2)
Cl-10 Cl-10
H H
base m.s. base m.s.
142-143 275-278 142-143 275-278
6 6
H H
CH3 CH3
m.s. m.s.
>260 > 260
7 7
Cl-9 Cl-9
H H
m.s. m.s.
251-253 251-253
8 8
Br-10 Br-10
H H
m.s. m.s.
265 265
9 9
ch3o-9 ch3o-9
H H
m.s. m.s.
214-216 214-216
(m.s. = méthanesulfonate) (m.s. = methanesulfonate)
Les composés de l'invention ont fait l'objet d'une étude pharmacolo-gique. The compounds of the invention were the subject of a pharmacological study.
1. Toxicité 1. Toxicity
La dose létale 50 (DL50) des composés est déterminée chez des souris de souche CD1 par méthode graphique. La DL50 est de 120 à 500 mg/kg par voie i.p. The lethal dose 50 (LD50) of the compounds is determined in mice of CD1 strain by graphic method. The LD50 is 120 to 500 mg / kg i.p.
2. Hypoxie hypobare 2. Hypobaric hypoxia
Des souris de souche CD1 sont maintenues dans une atmosphère appauvrie en oxygène, par réalisation d'un vide partiel (190 mm de mercure correspondant à 5,25% d'oxygène). CD1 strain mice are maintained in an oxygen-depleted atmosphere, by carrying out a partial vacuum (190 mm of mercury corresponding to 5.25% of oxygen).
Le temps de survie des animaux est noté. Ce temps est augmenté par les agents capables de favoriser l'oxygénation tissulaire et en particulier cérébrale. Les composés étudiés sont administrés, à plusieurs doses, par voie intrapéritonéale, 10 min avant l'essai. Les pourcentages d'augmentation du temps de survie par rapport aux valeurs obtenues chez les animaux témoins sont calculés. La dose active moyenne (DAM), dose qui augmente le temps de survie de 100%, est déterminée graphiquement. La DAM est de 10 à 15 mg/kg. The survival time of the animals is noted. This time is increased by agents capable of promoting tissue and in particular cerebral oxygenation. The compounds studied are administered, in several doses, intraperitoneally, 10 min before the test. The percentages of increase in survival time compared to the values obtained in the control animals are calculated. The average active dose (AMD), which increases the survival time by 100%, is determined graphically. The AMD is 10 to 15 mg / kg.
3. Action sur la durée du sommeil induit par le 4-hydroxybutyrate de sodium 3. Action on the duration of sleep induced by sodium 4-hydroxybutyrate
Cette action a été déterminée par l'influence d'un composé sur la durée du sommeil induit par le 4-hydroxybutyrate de sodium (GHB) chez le rat curarisé. This action was determined by the influence of a compound on the duration of sleep induced by sodium 4-hydroxybutyrate (GHB) in the curarized rat.
Les animaux utilisés sont des rats mâles de souche Charles River de 200 + 20 g. Les animaux, curarisés par l'alloférine à raison de 1 mg/kg par voie i.p., sont placés sous respiration artificielle à l'aide d'un masque appliqué sur le museau (fréquence respiratoire = 50/min; volume respiratoire: 14 cm3). The animals used are male rats of the Charles River strain of 200 + 20 g. The animals, curarized by alloferin at a rate of 1 mg / kg by ip route, are placed under artificial respiration using a mask applied to the muzzle (respiratory rate = 50 / min; respiratory volume: 14 cm3) .
L'œsophage est préalablement ligaturé afin d'éviter l'entrée de l'air dans l'estomac. The esophagus is previously ligated to prevent the entry of air into the stomach.
Des électrodes corticales front-pariétales et occipitales permettent l'enregistrement de l'activité électrocorticographique sur un po-lygraphe Grass modèle 79 P à la vitesse de 6 mm/s. Front-parietal and occipital cortical electrodes allow the recording of electrocorticographic activity on a Grass model 79 P polygraph at the speed of 6 mm / s.
La préparation de l'animal est effectuée sous anesthésie locale (Xylocaine à 2%). Les rats sont maintenus tout au long de l'expérience à température constante (37,5° C). 10 min après la fin de la préparation du rat, une dose de 200 mg/kg de 4-hydroxybutyrate de sodium est injectée par voie intraveineuse au niveau de la queue. The preparation of the animal is carried out under local anesthesia (Xylocaine 2%). The rats are maintained throughout the experiment at constant temperature (37.5 ° C). 10 min after the end of the preparation of the rat, a dose of 200 mg / kg of sodium 4-hydroxybutyrate is injected intravenously into the tail.
Une dose de 10 mg/kg du composé à étudier est administrée par voie intrapéritonéale 3 min après l'administration du 4-hydroxybutyrate de sodium. A dose of 10 mg / kg of the compound to be studied is administered intraperitoneally 3 min after the administration of sodium 4-hydroxybutyrate.
L'évaluation des tracés s'effectue par périodes de 15 min durant 75 min après l'injection de GHB. Durant cette période d'analyse, la durée totale du sommeil est déterminée. Une série de 15 témoins permet de préciser la durée du sommeil GHB. The tracings are evaluated in 15 min periods for 75 min after the GHB injection. During this analysis period, the total duration of sleep is determined. A series of 15 controls makes it possible to specify the duration of GHB sleep.
L'analyse statistique des résultats est réalisée à l'aide du test U de Mann-Whitney. The statistical analysis of the results is carried out using the Mann-Whitney U test.
La diminution de la durée du sommeil est de 25 à 40%. The decrease in sleep time is 25 to 40%.
L'étude pharmacologique des composés de l'invention montre qu'ils sont actifs dans l'épreuve d'hypoxie hypobare chez la souris tout en n'étant que peu toxiques et qu'ils exercent une action significative éveillante dans le test du sommeil induit par le 4-hydroxybutyrate de sodium. The pharmacological study of the compounds of the invention shows that they are active in the test of hypobaric hypoxia in mice while being only slightly toxic and that they exert a significant awakening action in the test of induced sleep. with sodium 4-hydroxybutyrate.
Les composés de l'invention, possédant une activité antianoxique et une activité psychotrope, peuvent être utilisés en thérapeutique pour le traitement des troubles de la vigilance, en particulier pour lutter contre les troubles du comportement imputables à des dommages vasculaires cérébraux et à la sclérose cérébrale en gériatrie, ainsi que pour le traitement des absences dues à des traumatismes crâniens, pour le traitement des encéphalopathies métaboliques, et pour le traitement des états dépressifs. The compounds of the invention, having an antianoxic activity and a psychotropic activity, can be used in therapy for the treatment of disorders of alertness, in particular for combating behavioral disorders attributable to cerebrovascular damage and to cerebral sclerosis. in geriatrics, as well as for the treatment of absences due to head trauma, for the treatment of metabolic encephalopathies, and for the treatment of depressive states.
L'invention comprend, par conséquent, toutes compositions pharmaceutiques renfermant les composés et/ou leurs sels comme principes actifs, en association avec tous excipients appropriés à leur administration, en particulier par voie orale ou parentérale. The invention therefore includes all pharmaceutical compositions containing the compounds and / or their salts as active ingredients, in combination with any excipients suitable for their administration, in particular by oral or parenteral route.
Les voies d'administration peuvent être les voies orales et parentérale. The routes of administration can be the oral and parenteral routes.
La posologie quotidienne peut aller de 10 à 100 mg. Les unités de prise peuvent donc être dosées par exemple de 2 à 50 mg de substance active associée à des excipients usuels, et peuvent se présenter sous forme de comprimés, dragées, gélules, suspensions ou solutions buvables ou injectables, etc. The daily dosage can range from 10 to 100 mg. The dosage units can therefore be dosed for example from 2 to 50 mg of active substance associated with usual excipients, and can be in the form of tablets, dragees, capsules, suspensions or oral or injectable solutions, etc.
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50 50
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65 65
R R
Claims (14)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR8024717A FR2494693A1 (en) | 1980-11-21 | 1980-11-21 | DERIVATIVES OF HEXAHYDRO-2,3,3A, 4,5,6 1H-INDOLO (3,2,1-DE) (NAPHTHYRIDINE-1,5), THEIR PREPARATION AND THEIR THERAPEUTIC USE |
Publications (1)
Publication Number | Publication Date |
---|---|
CH649549A5 true CH649549A5 (en) | 1985-05-31 |
Family
ID=9248208
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CH7460/81A CH649549A5 (en) | 1980-11-21 | 1981-11-20 | NAPHTYRIDINE DERIVATIVES, THEIR PREPARATION AND MEDICAMENTS CONTAINING THEM. |
Country Status (22)
Country | Link |
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JP (1) | JPS57116070A (en) |
AT (1) | AT379594B (en) |
AU (1) | AU546924B2 (en) |
BE (1) | BE891204A (en) |
CA (1) | CA1162544A (en) |
CH (1) | CH649549A5 (en) |
DE (1) | DE3143179A1 (en) |
DK (1) | DK515681A (en) |
ES (1) | ES8207176A1 (en) |
FR (1) | FR2494693A1 (en) |
GB (1) | GB2087889B (en) |
GR (1) | GR78026B (en) |
IE (1) | IE52160B1 (en) |
IL (1) | IL64328A (en) |
IT (1) | IT1195292B (en) |
LU (1) | LU83775A1 (en) |
NL (1) | NL8105282A (en) |
NO (1) | NO813945L (en) |
NZ (1) | NZ199008A (en) |
PT (1) | PT74019B (en) |
SE (1) | SE8106918L (en) |
ZA (1) | ZA818082B (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
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FR2527210A1 (en) * | 1982-05-18 | 1983-11-25 | Synthelabo | ENANTIOMERS OF HEXAHYDRO-2,3,3A, 4,5,6 1H-INDOLO (3,2,1-DE) (NAPHTHYRIDINE-1,5), THEIR SEPARATION METHOD AND THEIR THERAPEUTIC APPLICATION |
JPH02180885A (en) * | 1988-09-01 | 1990-07-13 | Glaxo Group Ltd | Lactam derivative |
CN113214250B (en) * | 2021-04-28 | 2022-06-14 | 华南理工大学 | Synthetic method of fused hexahydro-1, 6-naphthyridine compound |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
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DD129791A5 (en) * | 1976-04-13 | 1978-02-08 | Synthelabo | PROCESS FOR THE PREPARATION OF NAPHTYRIDINE DERIVATIVES |
GB1550496A (en) * | 1976-12-31 | 1979-08-15 | Logeais Labor Jacques | 1,2,3,3a4,5-hexahydro-canthine derivatives a process for their preparation and their therapeutic applications |
-
1980
- 1980-11-21 FR FR8024717A patent/FR2494693A1/en active Granted
-
1981
- 1981-10-30 DE DE19813143179 patent/DE3143179A1/en not_active Withdrawn
- 1981-11-17 GR GR66585A patent/GR78026B/el unknown
- 1981-11-19 LU LU83775A patent/LU83775A1/en unknown
- 1981-11-20 NO NO813945A patent/NO813945L/en unknown
- 1981-11-20 IT IT25212/81A patent/IT1195292B/en active
- 1981-11-20 IE IE2722/81A patent/IE52160B1/en unknown
- 1981-11-20 ZA ZA818082A patent/ZA818082B/en unknown
- 1981-11-20 GB GB8135005A patent/GB2087889B/en not_active Expired
- 1981-11-20 AU AU77700/81A patent/AU546924B2/en not_active Ceased
- 1981-11-20 CH CH7460/81A patent/CH649549A5/en not_active IP Right Cessation
- 1981-11-20 PT PT74019A patent/PT74019B/en unknown
- 1981-11-20 AT AT0501381A patent/AT379594B/en not_active IP Right Cessation
- 1981-11-20 BE BE0/206615A patent/BE891204A/en not_active IP Right Cessation
- 1981-11-20 NZ NZ199008A patent/NZ199008A/en unknown
- 1981-11-20 CA CA000390531A patent/CA1162544A/en not_active Expired
- 1981-11-20 JP JP56187652A patent/JPS57116070A/en active Pending
- 1981-11-20 SE SE8106918A patent/SE8106918L/en not_active Application Discontinuation
- 1981-11-20 IL IL64328A patent/IL64328A/en unknown
- 1981-11-20 ES ES507317A patent/ES8207176A1/en not_active Expired
- 1981-11-20 DK DK515681A patent/DK515681A/en not_active Application Discontinuation
- 1981-11-23 NL NL8105282A patent/NL8105282A/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
NZ199008A (en) | 1984-07-31 |
PT74019B (en) | 1983-12-07 |
IL64328A (en) | 1985-02-28 |
SE8106918L (en) | 1982-05-22 |
ATA501381A (en) | 1985-06-15 |
AU7770081A (en) | 1982-05-27 |
DE3143179A1 (en) | 1982-06-24 |
JPS57116070A (en) | 1982-07-19 |
FR2494693A1 (en) | 1982-05-28 |
ES507317A0 (en) | 1982-09-01 |
FR2494693B1 (en) | 1983-03-04 |
NL8105282A (en) | 1982-06-16 |
AT379594B (en) | 1986-01-27 |
GB2087889A (en) | 1982-06-03 |
CA1162544A (en) | 1984-02-21 |
GR78026B (en) | 1984-09-26 |
ES8207176A1 (en) | 1982-09-01 |
GB2087889B (en) | 1984-01-25 |
IL64328A0 (en) | 1982-02-28 |
IT1195292B (en) | 1988-10-12 |
IT8125212A0 (en) | 1981-11-20 |
AU546924B2 (en) | 1985-09-26 |
IE812722L (en) | 1982-05-21 |
BE891204A (en) | 1982-05-21 |
IE52160B1 (en) | 1987-07-22 |
NO813945L (en) | 1982-05-24 |
DK515681A (en) | 1982-05-22 |
LU83775A1 (en) | 1983-09-01 |
ZA818082B (en) | 1982-10-27 |
PT74019A (en) | 1981-12-01 |
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