FR2764291A1 - New 2-amino:propyl-5-naphthyl-1,3-dioxan derivatives - Google Patents
New 2-amino:propyl-5-naphthyl-1,3-dioxan derivatives Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
Description
1î 27642911î 2764291
Dérivés de 5-naphtalén-l-yl-l,3-dioxane, leur préparation et 5-Naphthalen-1-yl-1, 3-dioxane derivatives, their preparation and
leur application en thérapeutique.their application in therapy.
La présente invention a pour objet des composés de formule générale (I) R The subject of the present invention is compounds of general formula (I) R
OO
(I) dans laquelle Y représente un groupe hydroxy, un groupe (ClC4)alcoxy, ou un groupe de formule générale NR4R5 dans laquelle R4 et R5, indépendamment l'un de l'autre, représentent chacun un atome d'hydrogène ou un groupe (C1-C4)alkyle, et R, et R2 forment, avec l'atome d'azote et l'atome de carbone qui les relient, un cycle pyrrolidine, un cycle pipéridine ou (I) in which Y represents a hydroxy group, a (ClC4) alkoxy group, or a group of general formula NR4R5 in which R4 and R5, independently of each other, each represent a hydrogen atom or a group (C1-C4) alkyl, and R, and R2 form, with the nitrogen atom and the carbon atom which connect them, a pyrrolidine ring, a piperidine ring or
un cycle 1,2,3,4-tétrahydroisoquinoléine. a 1,2,3,4-tetrahydroisoquinoline cycle.
Les composés de l'invention peuvent exister sous forme de stéréoisomères cis ou trans ou de mélanges de tels isomères; par aileurs, et du fait de l'atome de cerbone asymétrique en The compounds of the invention may exist in the form of cis or trans stereoisomers or mixtures of such isomers; by wingers, and due to the asymmetric cerbone atom in
c du groupe -C(O)Y, ils peuvent exister sous forme d'énantio- c of the group -C (O) Y, they can exist in the form of enantio-
mères purs ou de mélanges d'énantiomères. pure mothers or mixtures of enantiomers.
Ils peuvent également exister à l'état de bases libres ou de They can also exist in the form of free bases or
sels d'addition à des acides.addition salts with acids.
Les composés selon l'invention peuvent être préparés par un The compounds according to the invention can be prepared by a
procédé illustré par le schéma qui suit. process illustrated by the diagram which follows.
On fait réagir le 2-(6-méthoxynaphtalén-l-yl)propane-1,3-diol de formule (II) avec le 2-(3-chloropropyl)-l,3-dioxolane de formule (III), en milieu acide et dans un solvant aprotique, The 2- (6-methoxynaphthalen-1-yl) propane-1,3-diol of formula (II) is reacted with 2- (3-chloropropyl) -1, 3-dioxolane of formula (III), in medium acid and in an aprotic solvent,
pour obtenir le 2-(3-chloropropyl)-5-(6-méthoxynaphtalén-1- to obtain 2- (3-chloropropyl) -5- (6-methoxynaphthalen-1-
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Schéma OH OH A r(II) H3C-. 1 Cl (III) Cl oiO Diagram OH OH A r (II) H3C-. 1 Cl (III) Cl oiO
1 5 0' 01 5 0 '0
(IV)(IV)
H3C'- /-H3C'- / -
H3C.,N 3H3C., N 3
RiRi
HN R2HN R2
R1 251 As (V)R1 251 As (V)
1-N R21-N R2
(i)(i)
H3C,- 0H3C, - 0
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yl)-l,3-dioxolane de formule (IV), et finalement on fait yl) -l, 3-dioxolane of formula (IV), and finally we do
réagir cet dernier avec une amine de formule générale (V), dans laquelle Y, R1 et R2 sont tels que définis ci-dessus, en présence d'une base organique ou minérale, dans un solvant 5 aprotique, par exemple le N,N-diméthylformamide, à une tempé- reacting the latter with an amine of general formula (V), in which Y, R1 and R2 are as defined above, in the presence of an organic or inorganic base, in an aprotic solvent, for example N, N -dimethylformamide, at a temperature-
rature de 20 à 110 C.stripping from 20 to 110 C.
Le 2-(6-méthoxynaphtalén-1-yl)propane-1,3-diol de formule (II) est décrit dans la demande de brevet EP-0 461 958. Le 2-(3-chloropropyl)-l, 3-dioxolane est disponible dans le commerce. Les amines de formule générale (V) sont disponibles 2- (6-methoxynaphthalen-1-yl) propane-1,3-diol of formula (II) is described in patent application EP-0 461 958. 2- (3-chloropropyl) -1,3 dioxolane is commercially available. The amines of general formula (V) are available
dans le commerce ou décrites dans la littérature. commercially or described in the literature.
Les exemples suivants illustrent la préparation de quelques composés selon l'invention. Les microanalyses élémentaires et les spectres IR et RMN confirment les structures des composés obtenus. Les numéros des composés indiqués entre parenthèses dans les titres correspondent à ceux du tableau donné plus loin. Dans les noms des composés, le tiret "-" fait partie du mot, et le tiret" "_ ne sert que pour la coupure en fin de ligne; il est à supprimer en l'absence de coupure, et ne The following examples illustrate the preparation of some compounds according to the invention. Elementary microanalyses and IR and NMR spectra confirm the structures of the compounds obtained. The numbers of the compounds indicated in parentheses in the titles correspond to those of the table given below. In compound names, the dash "-" is part of the word, and the dash "" _ is only used for breaking at the end of the line; it must be deleted in the absence of a cut, and
doit être remplacé ni par un tiret normal ni par un espace. must be replaced neither by a normal dash nor by a space.
Exemple 1 (Composé N 1).Example 1 (Compound N 1).
Oxalate de 1-[3-[5-(6-Méthoxynaphtalén-l-yl)-l,3-dioxan-2- 1- [3- [5- (6-Methoxynaphthalen-l-yl) -l, 3-dioxan-2- oxalate
yl]propyl]-L-prolinate d'éthyle.yl] propyl] -L-ethyl prolinate.
1.1. 2-(3-chloropropyl)-5-(6-méthoxynaphtalén-1-yl)-1,3- 1.1. 2- (3-chloropropyl) -5- (6-methoxynaphthalen-1-yl) -1.3-
dioxane. Dans un ballon de 500 ml contenant 150 ml de toluène on dioxane. In a 500 ml flask containing 150 ml of toluene,
introduit 5 g (21,5 mmoles) de 2-(6-méthoxynaphtalén-1- introduced 5 g (21.5 mmol) of 2- (6-methoxynaphthalen-1-
yl)propane-l,3-diol, 3,7 ml (28,05 mmoles) de 2-(3-chloro_ propyl)-l,3dioxolane, puis 40 ml d'éther chlorhydrique, et on chauffe le mélange au reflux pendant 6 h. On le laisse refroidir, on ajoute 100 ml d'une solution aqueuse d'hydrogénocarbonate de sodium à 5% et on l'extrait avec deux fois 100 ml d'acétate d'éthyle. On lave la phase organique à l'eau, on la sèche sur sulfate de magnésium, on la filtre, on évapore le solvant sous pression réduite et on yl) propane-1,3-diol, 3.7 ml (28.05 mmol) of 2- (3-chloro_ propyl) -l, 3dioxolane, then 40 ml of hydrochloric ether, and the mixture is heated to reflux for 6 a.m. It is allowed to cool, 100 ml of a 5% aqueous sodium hydrogencarbonate solution are added and it is extracted with twice 100 ml of ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, filtered, the solvent is evaporated off under reduced pressure and
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purifie le résidu par chromatographie sur colonne de gel de silice en éluant avec un mélange 9/1 d'éther de pétrole et d'acétate d'éthyle. On obtient 3,2 g de solide blanc que l'on purifies the residue by chromatography on a column of silica gel, eluting with a 9/1 mixture of petroleum ether and ethyl acetate. 3.2 g of white solid are obtained, which
utilise tel quel dans l'étape suivante. use as is in the next step.
1.2 Oxalate de 1-[3-[5-(6-Méthoxynaphtalén-l-yl)-1,3- 1.2 Oxalate of 1- [3- [5- (6-Methoxynaphthalen-1-yl) -1,3-
dioxan-2-yl]propyl]-L-prolinate d'éthyle. ethyl dioxan-2-yl] propyl] -L-prolinate.
Dans un ballon de 50 ml contenant 10 ml de N,N-diméthyl formamide on introduit 0,32 g (1 mmole) de 2-(3-chloropro_ pyl)-5-(6méthoxynaphtalén-l-yl)-l,3-dioxane, 0,22 g (1,2 mmoles) de L-prolinate d'éthyle, 0,3 g (2,2 mmoles) de carbonate de potassium, puis 0,29 g (2 mmoles) d'iodure de potassium, et on chauffe le mélange à 100 C pendant 4 h. On le laisse refroidir, on ajoute 50 ml d'eau et on l'extrait avec deux fois 70 ml d'acétate d'éthyle. On lave la phase organique à l'eau, on la sèche sur sulfate de magnésium, on la filtre, on évapore le solvant sous pression réduite et on purifie le résidu par chromatographie sur colonne de gel de silice en éluant avec un gradiant de dichlorométhane et de 0.32 g (1 mmol) of 2- (3-chloropro_ pyl) -5- (6methoxynaphthalen-1-yl) -1.3 is introduced into a 50 ml flask containing 10 ml of N, N-dimethyl formamide dioxane, 0.22 g (1.2 mmol) of ethyl L-prolinate, 0.3 g (2.2 mmol) of potassium carbonate, then 0.29 g (2 mmol) of potassium iodide, and the mixture is heated at 100 ° C. for 4 h. It is allowed to cool, 50 ml of water are added and it is extracted with twice 70 ml of ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, filtered, the solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a gradient of dichloromethane and of
méthanol de 99,5/0,5 à 99/1.methanol from 99.5 / 0.5 to 99/1.
On obtient 0,22 g (0,5 mmoles) de composé qu'on cristallise 0.22 g (0.5 mmol) of compound is obtained which is crystallized
sous forme d'oxalate dans l'acétate d'éthyle. as an oxalate in ethyl acetate.
Point de fusion: 116-118 C.Melting point: 116-118 C.
Exemple 2 (Composé N 2).Example 2 (Compound N 2).
1-[3-[5-(6-Méthoxynaphtalén-l-yl)-l,3-dioxan-2-yl]propyl]-L- 1- [3- [5- (6-Methoxynaphthalen-1-yl) -1, 3-dioxan-2-yl] propyl] -L-
prolinamide. Dans un ballon de 50 ml contenant 15 ml de N,N-diméthylform prolinamide. In a 50 ml flask containing 15 ml of N, N-dimethylform
amide on introduit 0,5 g (1,6 mmoles) de 2-(3-chloropropyl)- amide 0.5 g (1.6 mmol) of 2- (3-chloropropyl) is introduced -
-(6-méthoxynaphtalén-1-yl)-l,3-dioxane, 0,2 g (1,9 mmoles) de Lprolinamide, 0,2 g (1,6 mmoles) de carbonate de potas sium, puis 0,48 g (3,2 mmoles) d'iodure de potassium, et on - (6-methoxynaphthalen-1-yl) -1.3-dioxane, 0.2 g (1.9 mmol) of Lprolinamide, 0.2 g (1.6 mmol) of potassium carbonate sium, then 0.48 g (3.2 mmol) of potassium iodide, and
chauffe le mélange à 110 C pendant 3 h 30. heats the mixture to 110 C for 3 h 30.
On le laisse refroidir, on ajoute 60 ml d'eau et on l'extrait avec deux fois 80 ml d'acétate d'éthyle. On lave la phase organique à l'eau, on la sèche sur sulfate de magnesium, on la filtre, on évapore le solvant sous pression réduite et on purifie le résidu par chromatographie sur colonne de gel de It is allowed to cool, 60 ml of water are added and it is extracted with twice 80 ml of ethyl acetate. The organic phase is washed with water, dried over magnesium sulphate, filtered, the solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a gel column.
27642912764291
silice en éluant avec un gradiant de dichlorométhane et de méthanol de 99/1 à 97/3. On obtient 0,3 g de composé qu'on silica eluting with a gradient of dichloromethane and methanol from 99/1 to 97/3. We obtain 0.3 g of compound which
cristallise sous forme de base dans le propan-2-ol. crystallizes as base in propan-2-ol.
Point de fusion: 164-166 C.Melting point: 164-166 C.
Exemple 3 (Composé N 6).Example 3 (Compound N 6).
Oxalate de 2-[3-[5-(6-méthoxynaphtalén-l1-yl)-l,3-dioxan-2- 2- [3- [5- (6-methoxynaphthalen-111-yl) -l, 3-dioxan-2- oxalate
yl]propyl]-N-méthyl-l,2,3,4-tétrahydroisoquinoléine-3-carbox_ amide. yl] propyl] -N-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylamide.
3.1 N-Méthyl-1,2,3,4-tétrahydroisoquinoléine-3-carboxamide. 3.1 N-Methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide.
Dans un ballon de 100 ml contenant 25 ml d'une solution de méthylamine à 33% dans l'éthanol on introduit 1,75 g (8,5 mmoles) 1,2,3,4tétrahydroisoquinoléine-3-carboxylate d'éthyle et on laisse le mélange à 25 C pendant 20 h. On le concentre à sec sous pression réduite et on obtient 1,7 g de composé sous forme d'huile incolore que l'on utilise 1.75 g (8.5 mmol) 1,2,3,4tetrahydroisoquinoline-3-ethyl carboxylate are introduced into a 100 ml flask containing 25 ml of a 33% methylamine solution in ethanol. leave the mixture at 25 C for 20 h. It is concentrated to dryness under reduced pressure and 1.7 g of compound are obtained in the form of a colorless oil which is used
tel quel dans l'étape suivante.as is in the next step.
3.2 Oxalate de 2-[3-[5-(6-Méthoxynaphtalén-l-yl)-1,3- 3.2 2- [3- [5- (6-Methoxynaphthalen-1-yl) oxalate -1,3-
dioxan-2-yl]propyl]-N-méthyl-1,2,3,4- dioxan-2-yl] propyl] -N-methyl-1,2,3,4-
tétrahydroisoquinoléine-3-carboxamide. Dans un ballon de 100 ml contenant 20 ml d'acétonitrile on tetrahydroisoquinoline-3-carboxamide. In a 100 ml flask containing 20 ml of acetonitrile,
introduit 0,5 g (1,6 mmoles) de 2-(3-chloropropyl)-5-(6- introduced 0.5 g (1.6 mmol) of 2- (3-chloropropyl) -5- (6-
méthoxynaphtalén-1-yl)-1,3-dioxane, 0,3 g (1,6 mmoles) de N- methoxynaphthalen-1-yl) -1.3-dioxane, 0.3 g (1.6 mmol) of N-
méthyl-1,2,3,4-tétrahydroisoquinoléine-3-carboxamide, 0,2 g (1,6 mmoles) de carbonate de potassium, puis 0,23 g (1,5 mmoles) d'iodure de potassium, et on chauffe le mélange à C pendant 8 h. On le laisse refroidir, on ajoute 20 ml d'eau et on l'extrait avec deux fois 20 ml d'acétate d'éthyle. On lave la phase organique à l'eau, on la sèche sur sulfate de magnésium, on la filtre, on évapore le solvant sous pression réduite et on purifie le résidu par chromatographie sur colonne de gel de silice en éluant avec un mélange 98/2 de dichlorométhane et de méthanol. On obtient 0,12 g (0,25 mmoles) de composé qu'on cristallise sous forme d'oxalate dans l'éther diisopro_ pylique. methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide, 0.2 g (1.6 mmol) of potassium carbonate, then 0.23 g (1.5 mmol) of potassium iodide, and heats the mixture at C for 8 h. It is allowed to cool, 20 ml of water are added and it is extracted with twice 20 ml of ethyl acetate. The organic phase is washed with water, dried over magnesium sulphate, filtered, the solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a 98/2 mixture dichloromethane and methanol. 0.12 g (0.25 mmol) of compound is obtained which is crystallized in the form of an oxalate from diisopropyl ether.
Point de fusion: 88-90 C.Melting point: 88-90 C.
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Le tableau qui suit illustre les structures chimiques et les The following table illustrates the chemical structures and
propriétés physiques de quelques composés selon l'invention. Dans la colonne "R1NCHR2", "pyrrol", "piper" et "isoq" signifient que R1 et R2 forment, avec l'atome d'azote et 5 l'atome de carbone qui les relient, respectivement, un cycle pyrrolidine, un cycle pipéridine ou un cycle 1,2,3,4-tétra- physical properties of some compounds according to the invention. In the column "R1NCHR2", "pyrrol", "piper" and "isoq" mean that R1 and R2 form, with the nitrogen atom and the carbon atom which connect them, respectively, a pyrrolidine ring, a piperidine cycle or 1,2,3,4-tetra- cycle
hydroisoquinoléine. Dans la colonne "Sel", "-" désigne un composé à l'état de base, "fum." désigne un fumarate (ou (E)-2-butènedioate),10 "ox." désigne un oxalate (ou éthanedioate), et "HCl" désigne un chlorhydrate; le rapport molaire acide:base est indiqué hydroisoquinoline. In the "Salt" column, "-" denotes a compound in the basic state, "fum." denotes a fumarate (or (E) -2-butenedioate), 10 "ox." denotes an oxalate (or ethanedioate), and "HCl" denotes a hydrochloride; the acid: base molar ratio is indicated
entre parenthèses.in parentheses.
Dans la colonne "F ( C)", "(d)" désigne un point de fusion In the column "F (C)", "(d)" indicates a melting point
avec décomposition.with decomposition.
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TableauBoard
/ NyR2 O' Y/ NyR2 O 'Y
1W (I)1W (I)
H3C.o -o2 NO Y R1NCHR2 Config. Sel F (*C) i [a] 1 - OCH2CH3 pyrrol S ox. (1:1):116-118 -26 H3C.o -o2 NO Y R1NCHR2 Config. Salt F (* C) i [a] 1 - OCH2CH3 pyrrol S ox. (1: 1): 116-118 -26
2 -NH2 pyrrol S 164-166 n. d.2 -NH2 pyrrol S 164-166 n. d.
3 -NHCH3 pyrrol S 119-121 -303 -NHCH3 pyrrol S 119-121 -30
4 -OCH2CH3 piper RS ox. (1:1) 129-131 - 4 -OCH2CH3 piper RS ox. (1: 1) 129-131 -
-NHCH3 pyrrol RS - 99-101 --NHCH3 pyrrol RS - 99-101 -
6 -NHCH3 isoq RS ox. (1:) 88-90 -6 -NHCH3 isoq RS ox. (1 :) 88-90 -
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Les composés selon l'invention ont fait l'objet d'essais The compounds according to the invention were the subject of tests
pharmacologiques qui ont mis en évidence leur intérêt comme substances thérapeutiques. pharmacological studies which have shown their interest as therapeutic substances.
Propriétés antisodiques neuronales. L'entrée de calcium provoquée par un stimulus dépolarisant dans les synaptosomes corticaux du rat peut être mesurée à l'aide d'une sonde fluorescente, selon la méthode décrite par A. Deffois et coll. dans Neurosciences Letters (1996) 220 Neuronal antisodium properties. The entry of calcium caused by a depolarizing stimulus into the cortical synaptosomes of the rat can be measured using a fluorescent probe, according to the method described by A. Deffois et al. in Neurosciences Letters (1996) 220
117-120.117-120.
Les effets d'un agoniste des canaux sodiques comme la The effects of a sodium channel agonist like
veratridine (10 pM) sur l'augmentation des taux intracel- veratridine (10 pM) on the increase in intracel levels-
lulaires de calcium dans ce modèle sont inhibés par les composés de l'invention à des CI50 (concentrations inhibant Calcular cells in this model are inhibited by the compounds of the invention at IC50 (concentrations inhibiting
la réponse de 50%) de 0,3 à 10 MM. 50% response) from 0.3 to 10 MM.
Activité vis-à-vis des convulsions toniques induites chez la Activity vis-à-vis the tonic convulsions induced in the
souris par électrochoc supramaximal. mouse by supramaximal electroshock.
Le protocole de cet essai est décrit par E. A. Swinyard et J. H. Woodhead dans Antiepileptic Drugs, Raven Press, New The protocol for this trial is described by E. A. Swinyard and J. H. Woodhead in Antiepileptic Drugs, Raven Press, New
York, 111-126 (1982).York, 111-126 (1982).
min après administration intraveineuse du composé à tes- min after intravenous administration of the test compound
ter, on note le nombre de souris présentant des convulsions toniques (extensions des pattes antérieures et postérieures), immédiatement après application d'un courant électrique (0,4 s, 60 mA, 50 Hz) à l'aide d'un appareil Apelex ETC UNIT 7801TM. Les résultats sont exprimés par la DA50, dose qui protège 50% des animaux, calculée selon la méthode de J. T. Lichtfield et F. Wilcoxon (J. Pharm. Exp. Ther., 96, 99-113 (1949)), à l'aide du logiciel ProbitT, à partir de 3 ou 4 ter, we note the number of mice having tonic convulsions (extensions of the front and hind legs), immediately after application of an electric current (0.4 s, 60 mA, 50 Hz) using an Apelex device ETC UNIT 7801TM. The results are expressed by the DA50, a dose which protects 50% of the animals, calculated according to the method of JT Lichtfield and F. Wilcoxon (J. Pharm. Exp. Ther., 96, 99-113 (1949)), at. using ProbitT software, from 3 or 4
doses administrées chacune à un groupe de 8 souris. doses each administered to a group of 8 mice.
Les DA50 des composés les plus actifs sont de l'ordre de The DA50 of the most active compounds are of the order of
0,7 mg/kg.0.7 mg / kg.
Propriétés anti-ischémiques.Anti-ischemic properties.
Les composés ont été soumis au test de l'ischémie cérébrale Compounds were tested for cerebral ischemia
globale chez la souris.overall in mice.
L'ischémie est due à un arrêt cardiaque induit par une injection intraveineuse rapide de chlorure de magnésium. Dans The ischemia is due to cardiac arrest induced by a rapid intravenous injection of magnesium chloride. In
9 27642919 2764291
ce test on mesure le "temps de survie", c'est-à-dire this test we measure the "survival time", that is to say
l'intervalle entre le moment de l'injection de chlorure de magnésium et le dernier mouvement respiratoire observable de chaque souris. Ce dernier mouvement est considéré comme5 l'indice ultime d'une fonction du système nerveux central. the interval between the time of injection of magnesium chloride and the last observable respiratory movement of each mouse. This latter movement is considered to be the ultimate index of a function of the central nervous system.
L'arrêt respiratoire apparaît approximativement 19 secondes Respiratory arrest appears approximately 19 seconds
après l'injection de chlorure de magnésium. after injection of magnesium chloride.
Des souris mâles (Charles River CD1) sont étudiées par groupes de 10. Elles sont nourries et abreuvées ad libitum avant les essais. Le temps de survie est mesuré 10 minutes après l'administration intrapéritonéale des composés de l'invention. Les résultats sont donnés sous la forme de la différence entre le temps de survie mesuré dans un groupe de souris ayant reçu le composé et le temps de survie mesuré Male mice (Charles River CD1) are studied in groups of 10. They are fed and watered ad libitum before the tests. The survival time is measured 10 minutes after the intraperitoneal administration of the compounds of the invention. The results are given in the form of the difference between the survival time measured in a group of mice having received the compound and the survival time measured
dans un groupe de 10 souris ayant reçu le liquide véhicule. in a group of 10 mice having received the vehicle liquid.
Les rapports entre les modifications dans le terme de survie et la dose du composé sont enregistrés graphiquement selon The relationships between the modifications in the survival term and the dose of the compound are recorded graphically according to
une courbe semilogarithmique.a semilogarithmic curve.
Cette courbe permet le calcul de la "dose efficace 3 secondes" (DE3.,), c'est-à-dire la dose (en mg/kg) qui produit une augmentation de 3 secondes du temps de survie par rapport This curve allows the calculation of the "effective dose 3 seconds" (DE3.,), That is to say the dose (in mg / kg) which produces a 3 second increase in survival time compared to
au groupe témoin de 10 souris non traitées. to the control group of 10 untreated mice.
Une augmentation de 3 secondes du temps de survie est à la A 3 second increase in survival time is at the
fois significative statistiquement et reproductible. both statistically significant and reproducible.
Les DE3,. des composés de l'invention les plus actifs sont de The DE3 ,. the most active compounds of the invention are
l'ordre de 0,1 mg/kg par voie intraveineuse. around 0.1 mg / kg intravenously.
Les résultats des essais montrent que les composés selon l'invention ont des propriétés neuroprotectrices, et qu'ils peuvent donc être utilisés pour la préparation de médicaments utiles dans le traitement ou la prévention des désordres The results of the tests show that the compounds according to the invention have neuroprotective properties, and that they can therefore be used for the preparation of medicaments useful in the treatment or prevention of disorders.
cérébrovasculaires d'origine ischémique ou hypoxique (inf- cerebrovascular of ischemic or hypoxic origin (inf-
arctus cérébral, traumatisme crânien ou médullaires, arrêt cardiaque ou respiratoire, attaque ischémique transitoire, cerebral artery, head or spinal cord injury, cardiac or respiratory arrest, transient ischemic attack,
asphyxie périnatale), du glaucome, des maladies neurodégéné- perinatal asphyxia), glaucoma, neurodegenerative diseases
ratives progressives (démences séniles comme la maladie d'Alzheimer, démences vasculaires, maladie de Parkinson, maladie de Huntington, atrophie olivo-ponto-cérébelleuse, sclérose latérale amyotrophique, maladies neurodégénératives progressive ratives (senile dementias such as Alzheimer's disease, vascular dementias, Parkinson's disease, Huntington's disease, olivo-ponto-cerebellar atrophy, amyotrophic lateral sclerosis, neurodegenerative diseases
27642912764291
d'origine virale, etc), et dans la prévention des accidents ischémiques cérébraux associés à la chirurgie cardiaque et vasculaire et à la thérapie endovasculaire. Du fait de leurs propriétés anticonvulsivantes ils peuvent5 également être utilisés dans le traitement de l'épilepsie. Enfin, le traitement d'autres affections, telles que les neuropathies, les douleurs neurogènes (par exemple liées aux neuropathies ou à la crise migraineuse), la spasticité neuro- logique et les dyskinésies, peut également être envisagé.10 A cet effet ils peuvent être présentés sous toutes formes de compositions pharmaceutiques appropriées à l'administration entérale ou parentérale, telles que comprimés, dragées, gélules, capsules, suspensions ou solutions buvables ou15 injectables telles que sirops, ampoules, etc, associés à des of viral origin, etc.), and in the prevention of ischemic strokes associated with cardiac and vascular surgery and endovascular therapy. Due to their anticonvulsant properties they can also be used in the treatment of epilepsy. Finally, the treatment of other conditions, such as neuropathies, neurogenic pain (for example linked to neuropathies or migraine attack), neurological spasticity and dyskinesias, can also be considered.10 For this purpose they can be presented in all forms of pharmaceutical compositions suitable for enteral or parenteral administration, such as tablets, dragees, capsules, capsules, suspensions or oral or injectable solutions such as syrups, ampoules, etc., combined with
excipients convenables, et dosés pour permettre une adminis- suitable excipients, and dosed to allow administration
tration journalière de 1 à 1000 mg de substance active. daily ration of 1 to 1000 mg of active substance.
11i 276429111i 2764291
Claims (4)
Priority Applications (20)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9706947A FR2764291B1 (en) | 1997-06-05 | 1997-06-05 | 5-NAPHTALEN-1-YL-1,3-DIOXANE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| CN98807817A CN1265658A (en) | 1997-06-05 | 1998-06-03 | 5-naphthalen-1-yl-1,3-dioxane derivatives, preparation and therapeutic application |
| TR1999/03022T TR199903022T2 (en) | 1997-06-05 | 1998-06-03 | 5-Naphthalin-1-yl-1, 3-dioxane derivatives, preparations and therapeutic applications. |
| ARP980102585A AR012908A1 (en) | 1997-06-05 | 1998-06-03 | A COMPOUND DERIVED FROM 5-NAFTALEN-1-IL-1,3-DIOXANE IN THE FORM OF A PURE STEREOISOMER OR A MIXTURE OF STEREOISOMERS, A MEDICINAL PRODUCT CONSISTING OF SUCH A COMPOUND, AND A PHARMACEUTICAL COMPOSITION CONTAINING SUCH A COMPOUND |
| EP98928419A EP0986552A1 (en) | 1997-06-05 | 1998-06-03 | 5-naphthalen-1-yl-1,3-dioxane derivatives, preparation and therapeutic application |
| IL13324298A IL133242A0 (en) | 1997-06-05 | 1998-06-03 | 5-Naphthalene-1-yl-1,3-dioxane derivatives their preparation and their therapeutic application |
| KR1019997011436A KR20010013435A (en) | 1997-06-05 | 1998-06-03 | 5-naphthalen-1-yl-1,3-dioxane derivatives, preparation and therapeutic application |
| EEP199900560A EE9900560A (en) | 1997-06-05 | 1998-06-03 | 5-Naphthalen-1-yl-1,3-dioxane derivatives, their preparation and therapeutic use |
| CA002290695A CA2290695A1 (en) | 1997-06-05 | 1998-06-03 | 5-naphthalen-1-yl-1,3-dioxane derivatives, preparation and therapeutic application |
| AU80251/98A AU8025198A (en) | 1997-06-05 | 1998-06-03 | 5-naphthalen-1-yl-1,3-dioxane derivatives, preparation and therapeutic application |
| BR9810742-9A BR9810742A (en) | 1997-06-05 | 1998-06-03 | Derivatives of 5-naphthalen -1yl-1,3-dioxane, preparation and application in therapy |
| SK1661-99A SK166199A3 (en) | 1997-06-05 | 1998-06-03 | 5-naphthalen-1-yl-1,3-dioxane derivatives, preparation and therapeutic application |
| PL98337234A PL337234A1 (en) | 1997-06-05 | 1998-06-03 | Derivatives of 5-naphtalen-1-yl-1,3-dioxane, their production and therapeutic application |
| PCT/FR1998/001113 WO1998055474A1 (en) | 1997-06-05 | 1998-06-03 | 5-naphthalen-1-yl-1,3-dioxane derivatives, preparation and therapeutic application |
| JP50172399A JP2002502412A (en) | 1997-06-05 | 1998-06-03 | 5-Naphthalen-1-yl-1,3-dioxane derivative, production method and therapeutic use |
| HU0002166A HUP0002166A3 (en) | 1997-06-05 | 1998-06-03 | 5-naphthalen-1-yl-1,3-dioxane derivatives and pharmaceutical compositions thereof |
| CO98031750A CO4940480A1 (en) | 1997-06-05 | 1998-06-04 | DERIVATIVES OF 5-NAFTALEN-1-IL-1,3-DIOXANE AND ITS PREPARATION. |
| ZA984854A ZA984854B (en) | 1997-06-05 | 1998-06-04 | 5-Naphthalene-1-YL-1,3-Dioxane derivatives their preparation and their therapeutic application |
| BG103937A BG103937A (en) | 1997-06-05 | 1999-11-30 | 5-naphthalen-1-yl-1,3-dioxane derivatives, their preparation and application in therapy |
| NO995966A NO995966L (en) | 1997-06-05 | 1999-12-03 | 5-Naphthalen-1-yl-1,3-dioxane derivatives, their preparation and therapeutic use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9706947A FR2764291B1 (en) | 1997-06-05 | 1997-06-05 | 5-NAPHTALEN-1-YL-1,3-DIOXANE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| FR2764291A1 true FR2764291A1 (en) | 1998-12-11 |
| FR2764291B1 FR2764291B1 (en) | 1999-07-16 |
Family
ID=9507629
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FR9706947A Expired - Fee Related FR2764291B1 (en) | 1997-06-05 | 1997-06-05 | 5-NAPHTALEN-1-YL-1,3-DIOXANE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
Country Status (2)
| Country | Link |
|---|---|
| FR (1) | FR2764291B1 (en) |
| ZA (1) | ZA984854B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2714055A1 (en) * | 1993-12-22 | 1995-06-23 | Synthelabo | New anticonvulsive 1,3-dioxane derivs |
-
1997
- 1997-06-05 FR FR9706947A patent/FR2764291B1/en not_active Expired - Fee Related
-
1998
- 1998-06-04 ZA ZA984854A patent/ZA984854B/en unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2714055A1 (en) * | 1993-12-22 | 1995-06-23 | Synthelabo | New anticonvulsive 1,3-dioxane derivs |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2764291B1 (en) | 1999-07-16 |
| ZA984854B (en) | 1999-01-04 |
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