IE69386B1 - New 2-aminoaphthyridine derivatives their preparation and their use - Google Patents
New 2-aminoaphthyridine derivatives their preparation and their useInfo
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Abstract
New 2-aminonaphthyridine derivative of formula: <IMAGE> its optical isomers, its salts and its preparation. The product of formula (I) is particularly useful for preparing the automer of the product of formula: <IMAGE> which exhibits notable therapeutic properties.
Description
The present invention provides, as new compounds, the 2-aminonaphthyridine derivative of formula: and its optical isomers and salts.
The compound of formula (II) exhibits remarkable anxiolytic, hypnotic, anticonvulsant, antiepileptic and muscle-relaxant properties. It is described in US-A-4,960,779. It has been shown that, in the compound of formula (II), the active entity, or eutomer, is the dextrorotatory (+) isomer.
According to US-A-4,960,779, the separation of the optical isomers of the compound of formula (II) may be carried out by chiral phase chromatography. However, the industrial application of this process is not always convenient.
It has now been found that the product of formula 938 6 - 2 (I) , which has an asymmetric carbon atom and acidic and basic functional groups, is particularly advantageous for the preparation of the dextrorotatory isomer of the compound of formula (II) by formation of a salt with a chiral base followed by the cyclisation of the dextrorotatory isomer of the compound of formula (I) to form the dextrorotatory isomer of the compound of formula (II) According to the present invention, a racemic mixture of isomers of formula (I) may be obtained by opening of the pyrrolinone ring of a racemic mixture of isomers of formula (II) in basic medium. The product thus obtained is isolated, optionally separated into its optical isomers, and/or opt. .....—into a salt.
The openi e ring is carried out by means of an *) Generally ;ried out by stirring an aqueous-organic solution in ____pound of formula (II) in the presence of an excess of inorganic base, typically a hydroxide, carbonate or bicarbonate of an alkali or alkaline-earth metal. It is particularly advantageous to use sodium hydroxide as the inorganic base and to work in a water-pyridine mixture. It is also possible to carry out the reaction by using a water-dioxane mixture as a solvent.
According to a further feature of the invention, the new compound of formula (I) may also be obtained by reacting an inorganic base with a compound of formula: isolating the product thus obtained, optionally separating the product into its optical isomers and/or optionally converting the product into a salt.
Generally, at least two equivalents of the inorganic base (which is preferably sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate) are used while working in water or in an aqueous-organic medium at a temperature of between 0 and 50°C, preferably between 0 and 30°C. A pyridine-water mixture is preferably used as aqueous-organic medium.
The compound of formula (III) may be obtained by hydrolysis of a compound of formula: in which R represents a radical containing from medium. straight or branched chain alkyl 1 to 10 carbon atoms, in an acidic Generally, the hydrolysis is carried out by means of a strong inorganic acid such as concentrated sulphuric acid while working at a temperature of between 0 and 50°C, preferably approximately 20°C.
The compounds of formulae (III) and (IV) may be obtained under the conditions described in US-A-4,960,779.
The new compound of formula (I) may be purified by known methods such as by successive extractions in acidic and basic medium.
The compound of formula (I) in free acid form may be converted into an addition salt with an acid (e.g. hydrochloric, methanesulphonic, oxalic, maleic, fumaric acids) or into a salt with an inorganic base (e.g. sodium hydroxide or potassium hydroxide) or an organic base.
In order to prepare the eutomer of the compound of formula (II) , it is particularly advantageous to carry out, in succession, the following operations·. 1) formation of a salt with a chiral base or a chiral acid, 2) precipitation of one of the optical isomers, 3) release of the dextrorotatory optical isomer of formula (I), either from the precipitated salt or from the filtered mother liquors of the precipitated salt after optional formation of another salt with an appropriate chiral base or an appropriate chiral acid, and then 4) cyclisation of the dextrorotatory optical isomer of formula (I) to the dextrorotatory isomer of formula (II) under nonracemising conditions.
For example, it is thus possible to form a salt of the racemic product of formula (I) with (+)-ephedrine while working in an appropriate organic solvent such as ethanol. The salt of the dextrorotatory isomer of formula (I) and of (+)-ephedrine precipitates. The dextrorotatory isomer of formula (I) is then displaced from its salt by means of a strong acid, and is cyclised to the eutomer of the product of formula (II). According to an embodiment of the present invention the dextrorotatory isomer of the compound of formula (I) is cyclised to the dextrorotatory isomer of the compound of formula (II) by means of thionyl chloride while working in the presence of a condensation agent such as imidazole or pyridine in an organic solvent such as methylene chloride.
It is not necessary to separate the dextrorotatory isomer of formula (I) prior to the cyclisation to the dextrorotatory isomer of formula (II).
It is also possible to prepare a salt of the compound of formula (I) with cinchonine in an appropriate solvent such as ethanol. The salt of the laevorotatory isomer of formula (I) with cinchonine precipitates. The dextrorotatory isomer of formula (I), found mainly in the filtered mother liquors of the laevorotatory salt, is displaced from its (soluble) cinchonine salt and then converted into an insoluble salt with cinchonidine. The dextrorotatory isomer of formula (I) is then displaced from its (insoluble) cinchonidine salt and is cyclised to the eutomer of the product of formula (II) under the conditions - 6 described previously.
The invention further provides the dextrorotatory isomer of formula (ΪΙ) when obtained from a 2-aminonaphthyridine derivative of formula (I) as defined above.
The following Examples illustrate the present invention.
EXAMPLE 1 1400 cm3 of dioxane and 20 g of 2-(7-chloro~ l,8-naphthyridin-2-yl) -3-(5-methy 1-2-oxohexyl) 1-isoindolinone are introduced, at a temperature of approximately 20°C, into a stirred, 2 litre reactor. 244 cm3 of an N aqueous solution- of sodium hydroxide are added over 5 minutes. The mixture is left to react for 4 days at a temperature below 30°C.
The dioxane is removed by distillation under reduced pressure (40 mm of mercury; 5.3 kPa) at a temperature below 30°C. 100 cm3 of distilled water are added during the distillation.
An insoluble product is removed by filtration at 20°C. This product is washed with 3 times 50 cm3 of distilled water and is removed. The combined aqueous phases are acidified by addition, over 3 hours, of 48 cm3 of 5N hydrochloric acid at a temperature of 20°C. The pH of the suspension is then approximately 3.5.
After filtering the suspension, the precipitate is washed with 6 times 100 cm3 of distilled water and is then dried under reduced pressure (15 mm of mercury; 2.0 kPa) at 60°C for 16 hours. 14.3 g of 2-{l-[(7-chloro-l,8-naphthyridin2-vl)amino]-6-methyl-3-oxoheptyl}benzoic acid are thus obtained in the form of a white product whose retention time is 4.8 minutes by high performance liquid chromatography using a column 25 cm long and 0.46 cm in diameter with ’"Lichrospher O.D.S» 5 pm as the stationary phase and a mixture of 200 cm3 of pH 3, 25 mM phosphate buffer, 560 cm3 of acetonitrile and 240 cm3 of methanol, at a flow rate of 0.8 cm3/minute, as the mobile phase. 2—(7—Chloro—1,8-naphthyridin-2~yl)-3-(5-methyl2-oxohexyl)-1-isoindolinone can be prepared according to the method described in US-A-4,960,779.
EXAMPLE 2 g of 2-(7-chloro-l,8-naphthyridin-2-vl)-3-(5methyl-2-oxohexyl)-1-isoindolinone, 400 cm3 of pyridine and 60 cm3 of a 2N aqueous sodium hydroxide solution are introduced, at a temperature of approximately 20°C, into a stirred, 1 litre reactor. The mixture is left to react for 23 hours and the pyridine is then distilled under reduced pressure (15 mm of mercury; 2.0 kPa) at a temperature below 20°C. 500 cm3 of distilled water are added. An insoluble material is separated by filtration. The aqueous phase is acidified to pH = 3.8 by addition of 40 cm3 of 4N hydrochloric acid. The suspension is filtered, the precipitate is washed with 5 times 14 0 cm3 of distilled water and then dried for 16 hours under reduced pressure (15 mm of mercury; 2.0 kPa) at 60°C. 19.2 g of 2-{l-[(7-chloro-l,8-naphthyridin2~yl)amino]-6-methyl-3-oxoheptyl}benzoic acid are thus obtained in the form of a white product whose retention time by high performance liquid chromatography is 4.8 minutes under the conditions described in Example 1.
EXAMPLE 3 A suspension of 30 mg of 2-[2-(7-chloro1.8- naphthyridin~2~yl)-3-oxolisoindolinyl]-5-methyl3-oxoheptanoic acid in 4.7 cm3 of distilled water and 1.32 cm3 of a 0.1N aqueous sodium hydroxide solution is stirred at a temperature of approximately 20°C for 72 hours. An insoluble product is removed by filtration and the filtrate is acidified to a pH = 2 by addition of a 0.1N aqueous hydrochloric acid solution. The precipitate obtained is separated by filtration, washed with water and dried in air. 10 mg of 2-{l-[(7-chloro-l,8-naphthyridin2-yl)amino]-6-methyl-3-oxoheptyl}benzoic acid are thus obtained whose characteristics are identical to those of the product of Example 1. 2-[2-(7Chloro~l,8-naphthyridin"2-yl)~3~oxo~ l~isoindolinyl]"6-methyl-3--oxoheptanoic acid can be prepared in the following manner: A solution of 23 g of ethyl 2-[2~(7-chloro1.8- naphthyridin-2-vl)-3-oxo-l-isoindolinyl]-6-methvl~ 3-oxoheptanoate in 235 cm3 of 98% sulphuric acid is stirred for 20 hours at a temperature of approximately 20°C and is then poured into 1.5 kg of ice. The precipitate obtained is separated by filtration, washed with water to a pH = 6 and dried in air. The solid obtained is taken up in 3.8 litres of distilled water and 480 cm3 of a 0.1N aqueous sodium hydroxide solution. The insoluble product is separated by filtration, the filtrate is acidified to a pH = 3 by addition of a 0.1N aqueous hydrochloric acid solution. The precipitate obtained is separated by filtration, washed with distilled water and then with isopropyl ether and dried at 20°C under reduced pressure (0.07 kPa). 9.2 g of 2- [2-(7-chloro-l,8-naphthyridin-2-yl)-3-oxol~isoindolinyl]-6-methyl-3-oxoheptanoic acid, melting at 176°C, are thus obtained.
Ethyl 2-[2-(7-chloro-l,8-naphthyridin-2-yl)3- oxo-l-isoindolinyl]-6~methyl~3-oxoheptanoate can be obtained by the method described in US-A-4,960,779.
EXAMPLE 4 1) 1450 cm3 of 95 % (v/v) ethanol, 100 g of cinchonine and 145 g of 2~{[(7-chloro-l,8-naphthyridin~2~ yl)amino]-6-methyl-3-oxoheptyl}benzoic acid are introduced into a stirred, 2 litre reactor. The suspension is heated to 40°C and then cooled, over 3 hours 30 minutes, to 10°C. The suspension obtained is filtered. The precipitate is washed with 2 times 50 cm3 of ethanol at 10°C and then - a® ~ dri'Sd at 6a-C for 16 house miter EeffseeA pxssewax* (IS xs of nercosy; s.® Se»*). 99 »3 g ed ts® salt off eir^oaiag asd ®r 2-< 1-( (7-csXoso-lj, @-aaphthyridla-2-yl^ axise5~S-»ex^l~3" ©xefe*ptyljbaasaie acid ate tbt© obtained in the &®rss, off a «fe.it® product wtocs® cfearaoterietice ar® th* followings - optical xetatisas · +3,92.6* (e « 1 % Biathylea* chloride) - eaaatioaerio psrity s 98.5 t. 35Ό ear3! at S-aethylpyrrslidaae asd 50 g off the salt obtained previeasly at® iafetodSased into « etirred,, 2 litre reactor» 9® sa? off hyartcSxlorie acid are added, ever 30 Btiautes,, while eaiataiaing the teapesafagre at 20"C„ 'SS· aixfcare is left for 1 fcoex at ahi» tetperater» and then 660 ear3' off distilled water1 ar® added over X hour- The ewepeaeion obtained is filtered. The precipitate ie washed with 5 tinea 100 at? off water aad then dried at 6©’G ff«r 16 boar® Bader reduced pressure <15 ns off nereury,? 2.0 kPa), 28.6 g off (-)-£"6-«iet!ayl"3-o«c5£iieptyl> beiseic acid axe thus obtained in tb· ffoca off a white product wfecs· c&aracfcerietics .are the followings - optical rotation: £a^ - -227.«" - essantionerio purity? 99.6 i. <-0’0 ca s off aethylene Chloride, 20 g off the protest obtained previously and 21. s g off iaidascle ar® introduced at a ie^sritire off 20*c, into a stirred, X I. litre reactor. 7 cm3 of thionyl chloride are added, over 10 > minutes, using a syringe. The suspension is heated at reflux for 30 minutes, is then cooled to 20°C and washed j with 2 times 200 cm3 of distilled water. The washed solution is concentrated to half its volume and then 450 cm3 of absolute ethanol are added. Distillation at atmospheric pressure is continued until the temperature of the vapours is 78°C. 1 g of decolorising charcoal is added and the mixture is then held for 1 hour at 70°C. The suspension is filtered. The precipitate is washed with 50 cm3 of ethanol at 75°C. The filtrate and the wash are combined. After cooling over 2 hours to 15°C, the suspension is filtered. The precipitate is washed with 3 times 35 cm3 of ethanol and then dried at 60°C for 16 hours under reduced pressure (15 mm of mercury; 2.0 kPa). 16.7 g of (-)-2-(7-chloro-l, 8~naphthyridin--2-yl) 3-(5-methyl-2-oxohexyl)-1-isoindolinone are thus obtained in the form of a fluffy white product whose characteristics are the following: - optical rotation: [aJ20D = -132° (c = 1 : methylene chloride) - enantiomeric purity: 100 %. , 2) 1274.3 g of ethanolic liquors (corresponding to the filtrate of the cinchonine salt obtained previously with addition of the ethanol wash) are introduced into a 2 litre reactor. 260 cm3 of an N aqueous hydrochloric acid solution are added at 20°C. After stirring for 15 minutes, 650 cm3 of distilled water are added. The solution is concentrated under reduced pressure (25 mm of mercury; 3.3 < kPa) at a temperature below 30°C to remove the ethanol. The sus-pansion is then filtered. The precipitate is washed with 6 times 100 cm3 of water and then dried at 50°C for 16 hours under reduced pressure (15 mm of mercury; 2.0 kPa). 79.6 g of a white product mostly consisting of the dextrorotatory isomer of 2—{1—[(7-chloro-l,8naphthyridin-2-yl)amino]-6-methyl~3-oxoheptyl}benzoic acid are thus obtained, whose characteristics are the followings - optical rotations [α]ρ° = +160° (c = 1 ; methylene chloride) - enantiomeric purity: 73.2 %. 78.5 g of the product obtained previously, 54.3 g of cinchonidine and 700 cm3 of 95 % (v/v) ethanol are introduced into a 1 litre reactor. The solution is heated to reflux and then cooled over 3 hours to a temperature of 10°C. A product crystallises. The suspension is filtered.
The precipitate is washed with 2 times 50 cm3 of 95 % ethanol and then dried at 60°C for 16 hours under reduced pressure (15 mm of mercury; 2.0 kPa). 92.8 g of the cinchonidine salt of (+)-2-(1-((7chloro~l,8-naphthyridin~2~yl)amino]-6-methyl-3~ oxoheptyl}benzoic acid are thus obtained in the form of a white product whose characteristics are the following: ~ optical rotation: [a]o° = -137.7° (c = 1 ; methylene chloride) - enantiomeric purity: 100 %. g of the cinchonidine salt obtained previously are dissolved in 250 cm3 of N-methylpyrrolidone in a 1 litre reactor. 90 cm3 of N hydrochloric acid are added, over 30 minutes, while maintaining the temperature below 20°C. After stirring for 15 minutes at 20°C, 600 cm3 of distilled water are added over 1 hour. The suspension obtained is filtered. The precipitate obtained is washed with 5 times 100 cm3 of distilled water and then dried at 60°C for 16 hours under reduced pressure (15 mm of mercury ; 2.0 kPa). 29.7 g of (+)-2-{1-[(7-chloro-l,8-naphthvridin-2vl)amino]-6-methyl-3-oxoheptyl}benzoic acid are thus obtained in the form of a white product whose characteristics are the following: - optical rotation: [a]20D = 222.8° (c = 1 ; methylene chloride) - enantiomeric purity: 100 %. g of the dextrorotatory acid obtained previously and 21.8 g of imidazole are dissolved in 400 cm3 of methylene chloride in a 1 litre reactor. 7 cm3 of thionyl chloride are introduced, using a syringe, at a temperature of 20°C. The suspension is heated at reflux for 30 minutes and is then cooled to 20°C and is then washed 2 times with 200 cm3 of distilled water. The solution is concentrated, at atmospheric pressure, to half its volume and then 450 cm3 of absolute ethanol are added. The distillation of the methylene chloride is continued until the temperature of the vapour reaches 78°C. 1 g of decolorising charcoal is then added and the mixture is then left for one hour at 78°C. The suspension is filtered. The precipitate is washed with 50 cm3 of absolute ethanol at 75°C. The filtrate and the washes are combined and then cooled to 15°C over 2 hours. The suspension is filtered.
The precipitate is washed with 3 times 35 cm3 of absolute ethanol at 15°C and then dried at 60°C for 16 hours under reduced pressure (15 mm of mercury; 2.0 kPa). 16.8 g of (+)-2-(7-chloro-l,8-naphthyridin-2-yl)-3-(5-methyl2-oxohexyl)"l-isoindolinone are thus obtained in the form of a fluffy white product whose characteristics are the following: - optical rotation: [a]£° = +132° (c = 1; methylene chloride) - enantiomeric purity: 98.8%.
EXAMPLE 5 250 g of 2-{l-[(7-chloro-l,8-naphthyridin2-yl)amino]"6"methyl-3-oxoheptyl}benzoic acid, 97 g of (+)ephedrine and 875 cm3 of 95% (v/v) ethanol are introduced, at a temperature of approximately 20°C, into a 2 litre reactor. After dissolving the suspension at 40°C, the reaction mixture is cooled to approximately 2°C. The precipitate obtained is separated by filtration, washed with 2 times 125 cm3 of 95% (v/v) ethanol at 2°C and then dried for 16 hours at 60°C under reduced pressure (15 mm of mercury; 2.0 kPa). 156.6 g of the salt of (+)-ephedrine and 2-{l—[(7-chloro-l,8-naphthyridin-2-yl)amino]-6-methvl-3oxoheptyljbenzoic acid are thus obtained in the form of a white product whose characteristics are the following: - optical rotation: [α]β° = -64° (c = 1; methylene chloride) - enantiomeric purity: 100%. 2.75 g of the salt obtained previously and 5 cm3 of N-methylpyrrolidone are introduced into a 50 cm3 round bottom flask. 1.2 cm3 of concentrated hydrochloric acid and then, over 10 minutes, 15 cm3 of distilled water are added while maintaining the temperature at 20°C. The suspension obtained is filtered. The precipitate is washed with 5 times 10 cm3 of distilled water and then dried for 16 hours at 60°C under reduced pressure (15 mm of mercury; 2.0 kPa). 1.97 g of 2-{1-[(7-chloro-l,8-naphthyridin2-yl)amino]-6-methyl-3=oxoheptyl}benzoic acid are thus obtained in the form of a white product whose characteristics are the following: - optical rotation: [a]£° = +222.8° (c = 1; methylene chloride) - enantiomeric purity: 100%.
The product thus obtained is cyclised to (+)-2(7-chloro-l,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1isoindolinone under the conditions described previously in Example 4.
EXAMPLE 6 118.3 g of the salt of (+)-ephedrine and 2-(1[(7-chloro-l,8~naphthyridin-2-yl)amino]-6-mathy1-3oxoheptyl}benzoic acid and 1700 cm3 of methylene chloride are introduced into a 2.5 litre reactor. The organic solution is washed, at 20°C, with 400 cm3 of a 0.5N aqueous hydrochloric acid solution and then with 400 cm3 of distilled water. The organic phase is dehydrated by azeotropic distillation at 20°C under reduced pressure (250 mm of mercury; 33.3 kPa). The volume of the organic phase is adjusted to 1700 cm3 by addition of dry methylene chloride, 95.2 g of imidazole are then added and then, over 10 minutes, 25 cm3 of thionyl chloride. The suspension is heated at 40°C for 30 minutes, then cooled to 20°C and washed with 2 times 700 cm3 of distilled water. The methylene chloride is removed by distillation at atmospheric pressure while adding, to keep the volume constant, 2500 cm3 of absolute ethanol. When the temperature of the vapour reaches 78°C, the distillation is halted and 4 g of decolorising charcoal in suspension in 20 cm3 of absolute ethanol are then added. The mixture is left for 30 minutes at 78°C and then filtered while hot.
The decolorising charcoal is rinsed with 200 cm3 of ethanol at 77°C. The wash and the filtrate are combined and then cooled, at a rate of 20°C/hour, to a temperature of 10°C. The suspension is filtered. The precipitate is washed with 3 times 140 cm3 of absolute ethanol at 10°C and then dried at 60°C for 16 hours under reduced pressure (15 mm of mercury; 2.0 kPa). The slightly yellow product obtained (68.9 g) is recrystallised from 1400 cm3 of ethanol at reflux. After cooling to 1O°C, the suspension is filtered, The precipitate is washed with 3 times 100 cm3 of absolute ethanol at 10°C and then dried at 60°C for 16 hours under reduced pressure (15 mm of mercury; 2.0 kPa). 65.1 g of (+)-2-(7-chloro-l,8~naphthyridin-2-yl)-3-(5-methyl2-oxohexyl)-1-isoindolinone are thus obtained in the form of a fluffy white product whose characteristics are the following: - optical rotation: [α]β° = +132° (c = 1; methylene chloride) - enantiomeric purity: 100%.
Claims (7)
1. A 2-aminonaphthyridine derivative of formula: ci (I) and its optical isomers or a salt thereof.
2. A process for the preparation of a derivative as claimed in claim 1, which comprises reacting an inorganic base with a compound of formula: Cl (II) isolating the product thus obtained, optionally separating the product into its optical isomers, and/or optionally converting the product into a salt.
3. A process according to claim 2, substantially as described in Example 1 or 2.
4. A process for the preparation of a derivative as claimed in claim 1, which process comprises reacting an inorganic base with a compound of formula (HI) : ΐ. 4; isolating the product thus obtained, optionally separating the product into its optical isomers and/or optionally converting the product into a salt.
5. A process according to claim 4, substantially as described in Example 3.
6. A process for the preparation of the dextrorotatory isomer of a compound of formula: wherein the dextrorotatory isomer of the compound according to claim 1 is cyclized using thionyl chloride in the presence of a condensation agent in an organic solvent and the compound obtained isolated.
7. The dextrorotatory isomer of the compound of formula (II) as defined in claim 2, when obtained from a 2-aminonaphthyridine derivative of formula (I) as defined in claim 1.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9108827A FR2678931B1 (en) | 1991-07-12 | 1991-07-12 | NEW DERIVATIVE OF AMINO-2 NAPHTYRIDINE, ITS PREPARATION AND ITS USE. |
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| Publication Number | Publication Date |
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| IE922235A1 IE922235A1 (en) | 1993-01-13 |
| IE69386B1 true IE69386B1 (en) | 1996-09-18 |
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| EP (2) | EP0598765B1 (en) |
| JP (1) | JP2712114B2 (en) |
| KR (1) | KR100235376B1 (en) |
| AT (1) | ATE129499T1 (en) |
| AU (1) | AU669482B2 (en) |
| CA (1) | CA2112979C (en) |
| DE (1) | DE69205685T2 (en) |
| DK (1) | DK0598765T3 (en) |
| ES (1) | ES2079200T3 (en) |
| FR (1) | FR2678931B1 (en) |
| GR (1) | GR3017889T3 (en) |
| IE (1) | IE69386B1 (en) |
| IL (1) | IL102443A0 (en) |
| MA (1) | MA22586A1 (en) |
| MX (1) | MX9204056A (en) |
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| FR2678933B1 (en) * | 1991-07-12 | 1993-09-24 | Rhone Poulenc Rorer Sa | PROCESS FOR THE PREPARATION OF OPTICAL ISOMERS OF A DERIVATIVE OF AMINO-2 NAPHTYRIDINE. |
| FR2678934B1 (en) * | 1991-07-12 | 1995-01-13 | Rhone Poulenc Rorer Sa | PROCESS FOR THE PREPARATION OF THE DEXTROGYRE ISOMER OF AN ISOINDOLINONE DERIVATIVE. |
| FR2678932B1 (en) * | 1991-07-12 | 1993-09-24 | Rhone Poulenc Rorer Sa | PROCESS FOR THE PREPARATION OF OPTICAL ISOMERS OF A DERIVATIVE OF AMINO-2 NAPHTYRIDINE. |
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|---|---|---|---|---|
| FR2313060A1 (en) * | 1974-11-07 | 1976-12-31 | Rhone Poulenc Ind | Pyrrolidinone deriirrivs as tranquillizers - 1-Heterocyclyl-5(1-piperazinyl-carbonyloxy)-2(5H)-pyrrolidinone derivs prepd. from 5-aryloxycarbonyloxy cpds. and piperazine (OE060576) |
| FR2321290A1 (en) * | 1975-04-07 | 1977-03-18 | Rhone Poulenc Ind | 1,8-naphthyridine tranquillisers, e hypnotics, anti-epileptics etc. - 2-substd. by isoindoline, pyrrolo-(3,4-b)-pyrazines, pyrrolo-(3,4-b)-pyridine or oxathino-(1,4)(2,3-c)-pyrrole |
| FR2607503B1 (en) * | 1986-12-02 | 1989-02-24 | Rhone Poulenc Sante | NOVEL ISOINDOLINONE DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
-
1991
- 1991-07-12 FR FR9108827A patent/FR2678931B1/en not_active Expired - Fee Related
-
1992
- 1992-07-08 ZA ZA925100A patent/ZA925100B/en unknown
- 1992-07-08 IL IL102443A patent/IL102443A0/en unknown
- 1992-07-08 MA MA22870A patent/MA22586A1/en unknown
- 1992-07-09 NZ NZ243495A patent/NZ243495A/en not_active IP Right Cessation
- 1992-07-09 IE IE922235A patent/IE69386B1/en not_active IP Right Cessation
- 1992-07-10 JP JP5502046A patent/JP2712114B2/en not_active Expired - Lifetime
- 1992-07-10 KR KR1019940700065A patent/KR100235376B1/en not_active IP Right Cessation
- 1992-07-10 MX MX9204056A patent/MX9204056A/en unknown
- 1992-07-10 DE DE69205685T patent/DE69205685T2/en not_active Expired - Lifetime
- 1992-07-10 CA CA002112979A patent/CA2112979C/en not_active Expired - Lifetime
- 1992-07-10 AU AU23609/92A patent/AU669482B2/en not_active Expired
- 1992-07-10 EP EP92916431A patent/EP0598765B1/en not_active Expired - Lifetime
- 1992-07-10 AT AT92916431T patent/ATE129499T1/en active
- 1992-07-10 ES ES92916431T patent/ES2079200T3/en not_active Expired - Lifetime
- 1992-07-10 DK DK92916431.7T patent/DK0598765T3/en active
- 1992-07-10 WO PCT/FR1992/000669 patent/WO1993001190A1/en active IP Right Grant
- 1992-07-10 EP EP92402004A patent/EP0522969A1/en active Pending
-
1995
- 1995-10-26 GR GR950401392T patent/GR3017889T3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| MX9204056A (en) | 1993-01-01 |
| WO1993001190A1 (en) | 1993-01-21 |
| ES2079200T3 (en) | 1996-01-01 |
| CA2112979C (en) | 2003-09-30 |
| DE69205685T2 (en) | 1996-03-21 |
| EP0598765B1 (en) | 1995-10-25 |
| ATE129499T1 (en) | 1995-11-15 |
| DE69205685D1 (en) | 1995-11-30 |
| GR3017889T3 (en) | 1996-01-31 |
| FR2678931A1 (en) | 1993-01-15 |
| EP0598765A1 (en) | 1994-06-01 |
| KR100235376B1 (en) | 1999-12-15 |
| ZA925100B (en) | 1993-04-28 |
| AU2360992A (en) | 1993-02-11 |
| JP2712114B2 (en) | 1998-02-10 |
| IL102443A0 (en) | 1993-01-14 |
| IE922235A1 (en) | 1993-01-13 |
| JPH06509086A (en) | 1994-10-13 |
| CA2112979A1 (en) | 1993-01-21 |
| NZ243495A (en) | 1994-11-25 |
| AU669482B2 (en) | 1996-06-13 |
| DK0598765T3 (en) | 1995-12-04 |
| FR2678931B1 (en) | 1993-09-24 |
| MA22586A1 (en) | 1993-04-01 |
| EP0522969A1 (en) | 1993-01-13 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK9A | Patent expired |