WO1993011125A1 - Process for the preparation of a racemic 2-aminonaphthyridine derivative - Google Patents

Process for the preparation of a racemic 2-aminonaphthyridine derivative Download PDF

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WO1993011125A1
WO1993011125A1 PCT/FR1992/001122 FR9201122W WO9311125A1 WO 1993011125 A1 WO1993011125 A1 WO 1993011125A1 FR 9201122 W FR9201122 W FR 9201122W WO 9311125 A1 WO9311125 A1 WO 9311125A1
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formula
product
racemic
salt
preparation
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PCT/FR1992/001122
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French (fr)
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Marie-Thérèse David-Comte
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Rhone-Poulenc Rorer S.A.
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Priority to JP5509892A priority Critical patent/JPH07501535A/en
Priority to EP93901039A priority patent/EP0625152A1/en
Publication of WO1993011125A1 publication Critical patent/WO1993011125A1/en

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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
    • C07D471/02—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 two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a process for the preparation of a derivative of the racemic 2-amino-naphthyridine of formula:
  • the active entity or eutomer is the dextrorotatory isomer.
  • the dextrorotatory isomer of the product of formula (II) can also be obtained by cyclization of the dextrorotatory isomer of the product of formula (I) by means of thionyl chloride, optionally operating in the presence of a condensing agent such as imidazole or pyridine in an organic solvent such as methylene chloride.
  • a condensing agent such as imidazole or pyridine
  • the dextrorotatory isomer of the product of formula (I) can be obtained by resolution of the corresponding racemic by means of a chiral base. To this end, it is particularly advantageous to carry out the succession of the following operations: 1) formation of a salt with a chiral base or a chiral acid,
  • the dextrorotatory isomer of the product of formula (I) After displacement of its salt with cinchonine, the dextrorotatory isomer of the product of formula (I), which is mainly found in the filtration mother liquors of the levorotatory salt, is transformed into an insoluble salt with cinchonidine.
  • the dextrorotatory isomer of the product of formula (I) is displaced from its salt by means of a strong acid such as hydrochloric acid.
  • the product of racemic formula (I) can be obtained by opening the pyrrolidinone ring of a product of racemic formula (H) in basic medium.
  • the pyrrolidinone cycle is opened using a mineral base at a temperature between 0 and 50 ° C and, preferably, between 0 and 30 ° C.
  • the levorotatory isomer of the product of formula (II) is transformed into a racemic product of formula (I) by the action of a mineral base such as sodium hydroxide in a basic organic solvent such as pyridine at a temperature comprised between 0 and 50 ° C and preferably close to 20 ° C.
  • a mineral base such as sodium hydroxide
  • a basic organic solvent such as pyridine
  • the levorotatory isomer of the product of formula (Et) can be obtained by cyclization of the levorotatory isomer of the product of formula (I) by means of thionyl chloride in the presence of a condensing agent such as imidazole or pyridine by operating in an organic solvent such as methylene chloride.
  • the levorotatory isomer of the product of formula (I) can be obtained, for example, from the mother liquors of crystallization of the salt of the dextrorotatory isomer of the product of formula (I) with the (+) - ephedrine.
  • the levorotatory isomer of the product of formula (I) is obtained by displacement of its salt according to the usual methods after concentration of the ethanolic mother liquors of crystallization.
  • the chiral base used [(-) -é ⁇ hédrine] can also be recovered.
  • the suspension obtained is filtered.
  • the precipitate is washed with 5 times 525 cm3 of distilled water and then dried under reduced pressure (15 mm of mercury; 2 kPa) for 16 hours at 60 ° C.
  • the levorotatory isomer of [(7-chloro-naphthyridine-1,8 yl) -2] -2 (5-methyl-2-oxo-hexyl) -3 isoindolinone-1 can be obtained in the following way:
  • the organic phase is concentrated under atmospheric pressure to a volume of approximately 2200 cm3.
  • the product obtained is transformed into the levorotatory isomer of [(7-chloro-naphthyridine-1,8 yl-2) -2 (5-methyl-2-oxo-hexyl) -3 isoindolinone-1 using thionyl chloride (96.9 g) in the presence of imidazole (222.8 g).
  • the chloromethylenic phase (2614 g) is distilled under atmospheric pressure in the presence of 1000 cm3 of ethanol.
  • EXAMPLE 3 120 g of salt of ⁇ [(7-chloro-naphthyridin-1,8 yl-2) amino] -2 methyl-6-oxo-3 heptyl ⁇ -2 benzoic acid are dissolved with (+) - ephedrine in 2350 cm3 of methylene chloride. The organic phase is washed with 400 cm3 of 0.5N hydrochloric acid and then 400 cm3 of water. The combined aqueous phases are treated under the conditions of Example 2 to give an ethanolic solution of (+) - ephedrine which is used as it is in a new salification operation.

Abstract

Process for the preparation of a racemic 2-aminonaphthyridine derivative of formula (I) by means of a racemizing opening in a base medium of a levogyral isoindolinone derivative of formula (II).

Description

PROCEDE DE PREPARATION D'UN DERIVE DE L'AMINO-2 NAPHTYRIDINE RACEMIQUE PROCESS FOR THE PREPARATION OF A RACEMIC AMINO-2 NAPHTYRIDINE DERIVATIVE
La présente invention concerne un procédé de préparation d'un dérivé de l'amino-2 naphtyridine racémique de formule :The present invention relates to a process for the preparation of a derivative of the racemic 2-amino-naphthyridine of formula:
Figure imgf000003_0001
par ouverture racémisante en milieu basique de l'isomère lévogyre du produit de formule :
Figure imgf000003_0001
by racemizing opening in basic medium of the levorotatory isomer of the product of formula:
Figure imgf000003_0002
Figure imgf000003_0002
Dans le brevet américain US 4 960 779 ont été décrits le produit de formule (II) ainsi que des prodtiits analogues qui présentent des propriétés anxiolytiques, hypnotiques, anticonvulsivantes, antiépileptiques et myorelaxantes remarquables.In US Pat. No. 4,960,779, the product of formula (II) has been described, as well as analogous products which exhibit remarkable anxiolytic, hypnotic, anticonvulsant, antiepileptic and muscle relaxant properties.
Il a été montré que, en particulier pour le produit de formule (II), l'entité active ou eutomère est l'isomère dextrogyre.It has been shown that, in particular for the product of formula (II), the active entity or eutomer is the dextrorotatory isomer.
Selon le brevet américain US 4960 779, la séparation des isomères optiques du produit de formule (II) peut être effectuée par chromatographie sur phase chirale. Cependant, l'application industrielle de ce procédé n'est pas toujours commode.According to American patent US 4,960,779, the separation of the optical isomers of the product of formula (II) can be carried out by chromatography on a chiral phase. However, the industrial application of this process is not always convenient.
L'isomère dextrogyre du produit de formule (II) peut aussi être obtenu par cyclisation de l'isomère dextrogyre du produit de formule (I) au moyen de chlorure de thionyle en opérant éventuellement en présence d'un agent de condensation tel que l'imidazole ou la pyridine dans un solvant organique tel que le chlorure de méthylène.The dextrorotatory isomer of the product of formula (II) can also be obtained by cyclization of the dextrorotatory isomer of the product of formula (I) by means of thionyl chloride, optionally operating in the presence of a condensing agent such as imidazole or pyridine in an organic solvent such as methylene chloride.
L'isomère dextrogyre du produit de formule (I) peut être obtenu par dédoublement du racémique correspondant au moyen d'une base chirale. A cet effet, il est particulièrement avantageux d'effectuer la succession des opérations suivantes : 1) formation d'un sel avec une base chirale ou un acide chiral,The dextrorotatory isomer of the product of formula (I) can be obtained by resolution of the corresponding racemic by means of a chiral base. To this end, it is particularly advantageous to carry out the succession of the following operations: 1) formation of a salt with a chiral base or a chiral acid,
2) précipitation d'un des isomères optiques, puis2) precipitation of one of the optical isomers, then
3) libération de l'isomère dextrogyre du produit de formule (I), soit à partir du sel précipité, soit à partir des eaux-mères de filtration du sel précipité après formation éventuelle d'un autre sel avec une base chirale ou un acide chiral approprié.3) release of the dextrorotatory isomer of the product of formula (I), either from the precipitated salt, or from the filtration mother liquors of the precipitated salt after optional formation of another salt with a chiral base or an acid appropriate chiral.
Ainsi, il est possible de former un sel du produit de formule (I) racémique avec la (+)-éphédrine en opérant dans un solvant organique approprié tel que l'éthanol à 95 %. Le sel du produit de formule (I) dextrogyre est déplacé de son sel au moyen d'un acide fort tel que l'acide chlorhydrique. II est également possible de préparer un sel du produit de ormule (I) avec la cinchonine dans un solvant approprié tel que l'éthanol à 95 Ψo. Le sel du produit de formule (I) lévogyre avec la cinchonine précipite. Après déplacement de son sel avec la cinchonine, l'isomère dextrogyre du produit de formule (I), qui se trouve majoritairement dans les eaux-mères de filtration du sel lévogyre, est transformé en sel insoluble avec la cinchonidine. L'isomère dextrogyre du produit de formule (I) est déplacé de son sel au moyen d'un acide fort tel que l'acide chlorhydrique.Thus, it is possible to form a salt of the product of formula (I) racemic with (+) - ephedrine by operating in an appropriate organic solvent such as 95% ethanol. The salt of the product of formula (I) dextrorotatory is displaced from its salt by means of a strong acid such as hydrochloric acid. It is also possible to prepare a salt of the product of ormule (I) with cinchonine in a suitable solvent such as ethanol at 95 Ψo. The salt of the product of formula (I) levorotatory with cinchonine precipitates. After displacement of its salt with cinchonine, the dextrorotatory isomer of the product of formula (I), which is mainly found in the filtration mother liquors of the levorotatory salt, is transformed into an insoluble salt with cinchonidine. The dextrorotatory isomer of the product of formula (I) is displaced from its salt by means of a strong acid such as hydrochloric acid.
Le produit de formule (I) racémique peut être obtenu par ouverture du cycle pyrrolidinone d'un produit de formule (H) racémique en milieu basique.The product of racemic formula (I) can be obtained by opening the pyrrolidinone ring of a product of racemic formula (H) in basic medium.
Généralement l'ouverture du cycle pyrrolidinone est effectuée au moyen d'une base minérale à une température comprise entre 0 et 50°C et, de préférence, comprise entre 0 et 30°C.Generally, the pyrrolidinone cycle is opened using a mineral base at a temperature between 0 and 50 ° C and, preferably, between 0 and 30 ° C.
Il a maintenant été trouvé, et c'est ce qui fait l'objet de la présente invention, que l'isomère lévogyre du produit de formule (H), qui est quasiment inactif, peut être transformé en produit de formule (I) racémique qui, à son tour, peut être transformé en isomère dextrogyre du produit de formule (H) selon les procédés décrits précédemment.It has now been found, and this is the subject of the present invention, that the levorotatory isomer of the product of formula (H), which is practically inactive, can be transformed into a product of racemic formula (I) which, in turn, can be transformed into a dextrorotatory isomer of the product of formula (H) according to the methods described above.
Selon l'invention, l'isomère lévogyre du produit de formule (II) est transformé en produit de formule (I) racémique par action d'une base minérale telle que la soude dans un solvant organique basique tel que la pyridine à une température comprise entre 0 et 50°C et de préférence voisine de 20°C.According to the invention, the levorotatory isomer of the product of formula (II) is transformed into a racemic product of formula (I) by the action of a mineral base such as sodium hydroxide in a basic organic solvent such as pyridine at a temperature comprised between 0 and 50 ° C and preferably close to 20 ° C.
L'isomère lévogyre du produit de formule (Et) peut être obtenu par cyclisation de l'isomère lévogyre du produit de formule (I) au moyen de chlorure de thionyle en présence d'un agent de condensation tel que l'imidazole ou la pyridine en opérant dans un solvant organique tel que le chlorure de méthylène. L'isomère lévogyre du produit de formule (I) peut être obtenu, par exemple, à partir des eaux-mères de cristallisation du sel de l'isomère dextrogyre du produit de formule (I) avec la (+)-éphédrine. L'isomère lévogyre du produit de formule (I) est obtenu par déplacement de son sel selon les méthodes habituelles après concentration des eaux-mères éthanoliques de cristallisation. La base chirale utilisée [(- )-éρhédrine] peut aussi être récupérée.The levorotatory isomer of the product of formula (Et) can be obtained by cyclization of the levorotatory isomer of the product of formula (I) by means of thionyl chloride in the presence of a condensing agent such as imidazole or pyridine by operating in an organic solvent such as methylene chloride. The levorotatory isomer of the product of formula (I) can be obtained, for example, from the mother liquors of crystallization of the salt of the dextrorotatory isomer of the product of formula (I) with the (+) - ephedrine. The levorotatory isomer of the product of formula (I) is obtained by displacement of its salt according to the usual methods after concentration of the ethanolic mother liquors of crystallization. The chiral base used [(-) -éρhédrine] can also be recovered.
Les exemples suivants, donnés à titre non limitatif, montrent comment l'invention peut être mise en pratique.The following examples, given without limitation, show how the invention can be put into practice.
EXEMPLE 1 Dans un réacteur de 2 litres, on introduit, à une température voisine de 20°C,EXAMPLE 1 Into a 2 liter reactor, the following are introduced at a temperature in the region of 20 ° C.
75 g de l'isomère lévogyre de la [(chloro-7 naphtyridine-1,8 yl)-2]-2 (méthyl-5 oxo-2 hexyl)-3 isoindolinone-1 dont le titre énantiomérique est de 92,3 %, 1500 cm3 de pyridine et 225 cm3 de soude aqueuse 2N. On agite pendant 23 heures puis distille la pyridine sous pression réduite (15 mm de mercure ; 2 kPa) en maintenant la température du mélange réactionnel inférieure à 20°C. On ajoute alors 1875 cm3 d'eau distillée et sépare par filtration l'insoluble obtenu. La phase aqueuse est acidifiée jusqu'à pH = 3,8 par addition de 150 cm3 d'acide chlorhydrique 4N. La suspension obtenue est filtrée. Le précipité est lavé avec 5 fois 525 cm3 d'eau distillée puis séché sous pression réduite (15 mm de mercure ; 2 kPa) pendant 16 heures à 60°C.75 g of the levorotatory isomer of [(7-chloro-naphthyridin-1,8 yl) -2] -2 (5-methyl-2-oxo-hexyl) -3 isoindolinone-1 with an enantiomeric titer of 92.3% , 1500 cm3 of pyridine and 225 cm3 of 2N aqueous sodium hydroxide. The mixture is stirred for 23 hours and then the pyridine is distilled under reduced pressure (15 mm of mercury; 2 kPa) while keeping the temperature of the reaction mixture below 20 ° C. 1875 cm3 of distilled water are then added and the insoluble material obtained is filtered off. The aqueous phase is acidified to pH = 3.8 by adding 150 cm3 of 4N hydrochloric acid. The suspension obtained is filtered. The precipitate is washed with 5 times 525 cm3 of distilled water and then dried under reduced pressure (15 mm of mercury; 2 kPa) for 16 hours at 60 ° C.
On obtient ainsi 73,8 g d'acide {[(chloro-7 naphtyridine-1,8 yl-2) amino]-2 méthyl-6 oxo-3 heptyl}-2 benzoïque sous forme d'un produit beige dont le pouvoir rotatoire est nul.73.8 g of {[(chloro-7 naphthyridin-1,8 yl-2) amino] -2 methyl-6 oxo-3 heptyl} -2 benzoic acid are thus obtained in the form of a beige product, the power of which is rotary is zero.
L'isomère lévogyre de la [(chloro-7 naphtyridine-1,8 yl)-2]-2 (méthyl-5 oxo- 2 hexyl)-3 isoindolinone-1 peut être obtenu de la manière suivante :The levorotatory isomer of [(7-chloro-naphthyridine-1,8 yl) -2] -2 (5-methyl-2-oxo-hexyl) -3 isoindolinone-1 can be obtained in the following way:
1760 cm3 (1540 g) de filtrat éthanolique de salification de 362,6 g d'acide {[(chloro-7 naphtyridine-1,8 yl-2) amino]-2 méthyl-6 oxo-3 heptyl}-2 benzoïque avec 141 g de (- )-éphédrine sont concentrés sous pression atmosphérique jusqu'à un volume de 460 cm3. Au concentrât visqueux, on ajoute 500 cm3 de chlorure de méthylène. La solution organique est lavée avec 2 fois 800 cm3 d'eau distillée puis diluée par addition de 3500 cm3 de chlorure de méthylène. La phase organique est lavée avec 1040 cm3 d'acide chlorhydrique 0,5N puis avec 1000 cm3 d'eau déminéralisée. La phase organique est concentrée sous pression atmosphérique jusqu'à un volume d'environ 2200 cm3. Le produit obtenu est transformé en isomère lévogyre de la [(chloro-7 naphtyridine-1,8 yl-2)-2 (méthyl-5 oxo-2 hexyl)-3 isoindolinone-1 au moyen de chlorure de thionyle (96,9 g) en présence d'imidazole (222,8 g). On obtient ainsi 159,4 g d'isomère lévogyre de la [(chloro-7 naphtyridine-1,8 yl-2)-]-2 (méthyl-5 oxo- 2 hexyl)-3 isoindolinone sous forme d'un produit blanc dont le titre énantiomérique est de 92,3 %.1760 cm3 (1540 g) of ethanolic salification filtrate of 362.6 g of {[(7-chloro-naphthyridine-1,8 yl-2) amino] -2 methyl-6 oxo-3 heptyl} -2 benzoic acid with 141 g of (-) -ephedrine are concentrated under atmospheric pressure to a volume of 460 cm3. To the viscous concentrate, 500 cm 3 of methylene chloride are added. The organic solution is washed with 2 times 800 cm3 of distilled water and then diluted by adding 3500 cm3 of methylene chloride. The organic phase is washed with 1040 cm3 of 0.5N hydrochloric acid and then with 1000 cm3 of demineralized water. The organic phase is concentrated under atmospheric pressure to a volume of approximately 2200 cm3. The product obtained is transformed into the levorotatory isomer of [(7-chloro-naphthyridine-1,8 yl-2) -2 (5-methyl-2-oxo-hexyl) -3 isoindolinone-1 using thionyl chloride (96.9 g) in the presence of imidazole (222.8 g). 159.4 g of levorotatory isomer of [(chloro-7 naphthyridine-1,8 yl-2) -] - 2 (methyl-5-oxo-2 hexyl) -3 isoindolinone are thus obtained in the form of a white product whose enantiomeric titer is 92.3%.
EXE PLE 2PLE EXE 2
A partir du filtrat éthanolique (1760 cm3) de salification de l'acide {[(chloro-7 naphtyridine-1,8 yl-2) amino]-2 méthyl-6 oxo-3 heptyl}-2 benzoïque avec la (+)-éphédrine traité dans les conditions décrites dans l'exemple 1, on récupère 2224 g de phase aqueuse acide d'extraction du concentrât éthanolique dilué au chlorure de méthylène. La phase aqueuse est alcalinisée par addition de 50 cm3 de soude ION puis est extraite par 2 fois 1000 cm3 de chlorure de méthylène.From the ethanolic filtrate (1760 cm3) of salification of {[(7-chloro-naphthyridine-1,8 yl-2) amino] -2 methyl-6 oxo-3 heptyl} -2 benzoic acid with (+) -Ephedrine treated under the conditions described in Example 1, 2,224 g of acid aqueous phase are recovered to extract the ethanolic concentrate diluted with methylene chloride. The aqueous phase is made alkaline by adding 50 cm3 of ION sodium hydroxide solution and is then extracted with 2 times 1000 cm3 of methylene chloride.
La phase chlorométhylénique (2614 g) est distillée sous pression atmosphérique en présence de 1000 cm3 d'éthanol.The chloromethylenic phase (2614 g) is distilled under atmospheric pressure in the presence of 1000 cm3 of ethanol.
On récupère ainsi 526 g de solution éthanolique contenant 13,5 % (p/p) de (+)-éphédrine.526 g of ethanolic solution containing 13.5% (w / w) of (+) - ephedrine are thus recovered.
Le pouvoir rotatoire est de +43,4° (c = 5 % ; acide chlorhydrique IN).The rotary power is + 43.4 ° (c = 5%; hydrochloric acid IN).
EXEMPLE 3 On dissout 120 g de sel de l'acide {[(chloro-7 naphtyridine-1,8 yl-2) amino]-2 méthyl-6 oxo-3 heptyl}-2 benzoïque avec la (+)-éphédrine dans 2350 cm3 de chlorure de méthylène. La phase organique est lavée avec 400 cm3 d'acide chlorhydrique 0,5N puis 400 cm3 d'eau. Les phases aqueuses réunies sont traitées dans les conditions de l'exemple 2 pour donner une solution éthanolique de (+)- éphédrine qui est utilisée telle quelle dans une nouvelle opération de salification. EXAMPLE 3 120 g of salt of {[(7-chloro-naphthyridin-1,8 yl-2) amino] -2 methyl-6-oxo-3 heptyl} -2 benzoic acid are dissolved with (+) - ephedrine in 2350 cm3 of methylene chloride. The organic phase is washed with 400 cm3 of 0.5N hydrochloric acid and then 400 cm3 of water. The combined aqueous phases are treated under the conditions of Example 2 to give an ethanolic solution of (+) - ephedrine which is used as it is in a new salification operation.

Claims

REVENDICATIONS
1 - Procédé de préparation d'un dérivé de l'amino-2 naphtyridine racémique de formule :1 - Process for the preparation of a derivative of the racemic 2-amino-naphthyridine of formula:
Figure imgf000007_0001
par ouverture racémisante en milieu basique de l'isomère lévogyre du produit de formule :
Figure imgf000007_0001
by racemizing opening in basic medium of the levorotatory isomer of the product of formula:
Figure imgf000007_0002
Figure imgf000007_0002
2 - Procédé selon la revendication 1 caractérisé en ce que l'on opère en présence d'une base minérale dans un solvant organique basique.2 - Process according to claim 1 characterized in that one operates in the presence of a mineral base in a basic organic solvent.
10 3 - Procédé selon la revendication 2 caractérisé en ce que la base minérale est la soude.10 3 - Process according to claim 2 characterized in that the mineral base is sodium hydroxide.
4 - Procédé selon la revendication 2 caractérisé en ce que le solvant organique basique est la pyridine.4 - Process according to claim 2 characterized in that the basic organic solvent is pyridine.
5 - Procédé selon l'une des revendications 1 à 4 caractérisé en ce que l'on 15 opère à une température comprise entre 0 et 50°C.5 - Method according to one of claims 1 to 4 characterized in that one operates at a temperature between 0 and 50 ° C.
6 - Procédé selon l'une des revendications 1 à 5 caractérisé en ce que l'on6 - Method according to one of claims 1 to 5 characterized in that one
T opère à une température voisine de 20°C. T operates at a temperature in the region of 20 ° C.
PCT/FR1992/001122 1991-12-04 1992-12-02 Process for the preparation of a racemic 2-aminonaphthyridine derivative WO1993011125A1 (en)

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JP5509892A JPH07501535A (en) 1991-12-04 1992-12-02 Method for producing racemic 2-aminonaphthyridine derivatives
EP93901039A EP0625152A1 (en) 1991-12-04 1992-12-02 Process for the preparation of a racemic 2-aminonaphthyridine derivative

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FR9114983A FR2684673B1 (en) 1991-12-04 1991-12-04 PROCESS FOR THE PREPARATION OF A DERIVATIVE OF RACEMIC 2-AMINO NAPHTYRIDINE.

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US6949653B2 (en) 2002-03-29 2005-09-27 Indevus Pharmaceuticals, Inc. Methods for making 2-(7-chloro-1,8-naphthyridine-2-yl)-3-(5-methyl-2-oxo-hexyl)-1-isoindolinone
US7026332B2 (en) 2001-04-30 2006-04-11 Indevus Pharmaceuticals, Inc. Methods of treating obsessive-compulsive disorder

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US4960779A (en) * 1986-12-02 1990-10-02 Rhone-Poulenc Sante Pyrrole derivatives, and pharmaceutical compositions which contain them and pharmacological methods of use

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7026332B2 (en) 2001-04-30 2006-04-11 Indevus Pharmaceuticals, Inc. Methods of treating obsessive-compulsive disorder
US7553847B2 (en) 2001-04-30 2009-06-30 Indevus Pharmaceuticals, Inc. Use of pagoclone for the treatment of social anxiety disorder
US6949653B2 (en) 2002-03-29 2005-09-27 Indevus Pharmaceuticals, Inc. Methods for making 2-(7-chloro-1,8-naphthyridine-2-yl)-3-(5-methyl-2-oxo-hexyl)-1-isoindolinone
US7057047B2 (en) 2002-03-29 2006-06-06 Indevus Pharmaceuticals, Inc. Methods for making 2-(7-chloro-1,8-naphthyridine-2-yl)-3-(5-methyl-2oxo-hexyl)-1-isoidolinone
US7304158B2 (en) 2002-03-29 2007-12-04 Indevus Pharmaceuticals, Inc. Method for making 2-(7-chloro-1,8-naphthyridine-2-yl)-3-(5-methyl-2-oxo-hexyl)-1-isoindolinone)

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EP0625152A1 (en) 1994-11-23
FR2684673A1 (en) 1993-06-11
FR2684673B1 (en) 1994-01-21
CA2121690A1 (en) 1993-06-10
JPH07501535A (en) 1995-02-16

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