FR2506769A2 - Cyano:pentyl:phenyl-methoxymethyl-oxazolidinone - useful as antidepressant - Google Patents

Cyano:pentyl:phenyl-methoxymethyl-oxazolidinone - useful as antidepressant Download PDF

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FR2506769A2
FR2506769A2 FR8208858A FR8208858A FR2506769A2 FR 2506769 A2 FR2506769 A2 FR 2506769A2 FR 8208858 A FR8208858 A FR 8208858A FR 8208858 A FR8208858 A FR 8208858A FR 2506769 A2 FR2506769 A2 FR 2506769A2
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compound
formula
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oxazolidinone
methoxymethyl
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FR2506769B2 (en
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Jean-Francois Ancher
Guy Bourgery
Philippe Dostert
Colette Douzon
Patrick Guerret
Alain Lacour
Michel Langlois
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Synthelabo SA
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Delalande SA
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Priority claimed from IT8121838A external-priority patent/IT1226040B/en
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
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    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/14—Oxygen atoms

Abstract

3-(4-(5-cyanopentyl)phenyl-5 -methoxymethyl-2 -oxazolidinone of formula (I) is new. The intermediates 3-(4-(5-benzyloxypentyl) phenyl-5 -methoxymethyl-2 -oxazolidinone (II) is also new. (I) is prepd. by treating 3-(4-(5-hydroxypentyl)phenyl-5 -methoxymethyl-2 -oxazolidinone (III) with mesyl chloride in a basic medium and reacting the prod. with an alkali metal cyanide. (I) is an antidepressant with ca. 300 times the reserpine-antagonist activity of toloxatone and with low toxicity (LD50 above 1000 mg/kg, p.o., mouse).

Description

Le brevet principal nO 78 17388 a pour objet des dérivés répondant

Figure img00010001

dans laquelle le couple (A,, XO) prend notamment la valeur (oxygène, oxygène), ces dérivés présentant des activités intéressantes dans le domaine psychotrope eomme anti-dépresseurs potentiels.The main patent number 78 17388 relates to
Figure img00010001

in which the pair (A 1, X 0) in particular takes the value (oxygen, oxygen), these derivatives having interesting activities in the psychotropic field as potential anti-depressants.

Le présent troisième certificat d'addition concerne, quant a lui, un composé possèdant exactement la meme structure de base et les memes activités thérapeutiques que celles des dérivés de formule (Io). Ce composé répond plus précisément à la formule

Figure img00010002
The present third certificate of addition concerns, for its part, a compound having exactly the same basic structure and the same therapeutic activities as those of the derivatives of formula (Io). This compound responds more precisely to the formula
Figure img00010002

I1 est obtenu par une synthèse en deux étapes qui consiste à traiter le compose de formule

Figure img00010003

par le chlorure de mésyle, de préférence dans un solvant organique tel que le chlorure de méthylène, notamment a froid et en présence d'une base telle que la triéthylamine, puis a faire réagir sur le composé obtenu, le cyanure d'un métal alcalin tel que le potassium ou le sodium, de préférence dans un solvant organique tel que le DMSO.It is obtained by a two-step synthesis which consists of treating the compound of formula
Figure img00010003

mesyl chloride, preferably in an organic solvent such as methylene chloride, especially cold and in the presence of a base such as triethylamine, and then react on the compound obtained, the cyanide of an alkali metal such as potassium or sodium, preferably in an organic solvent such as DMSO.

Le composé de formule (II) est obtenu par débenzylation catalytique en milieu éthanolique et en présence de palladium sur charbon a 5 % du composé de formule

Figure img00010004

ce dernier étant obtenu par cyclisation par une solution a 10 Z de phosgène dans le dichloroéthane en présence de carbonate de potassium ou de triéthylamine, du composé de formule
Figure img00020001

lui-meme obtenu par condensation du méthoxy-3 epoxy-l,2 propane, en milieu alcoolique, avec l'aniline de formule
Figure img00020002
The compound of formula (II) is obtained by catalytic debenzylation in ethanolic medium and in the presence of 5% palladium on carbon of the compound of formula
Figure img00010004

the latter being obtained by cyclization with a 10% solution of phosgene in dichloroethane in the presence of potassium carbonate or triethylamine, of the compound of formula
Figure img00020001

itself obtained by condensation of 3-methoxy-1,2-propoxypropane, in an alcoholic medium, with the aniline of formula
Figure img00020002

L'aniline de formule (V) est, pour sa part, obtenue par réduction par le triéthylsylane (HSiEt3) en présence d'acide trifluoroacétique de la cétoaniline de formule

Figure img00020003
The aniline of formula (V) is, for its part, obtained by reduction with triethylsylan (HSiEt3) in the presence of trifluoroacetic acid of ketoaniline of formula
Figure img00020003

Cette dernière est obtenue par réduction par le fer en présence de chlorure d'ammonium à 10 % dans un mélange d'eau et d'é- thanol, du dérivé nitré de formule

Figure img00020004

obtenu par condensation du benzyloxy-4 n-butanal en présence de potasse, en milieu méthanolique ou THF, avec l'O(-phénylamino p-nitrobenzylester de l'acide diphénil phosphoreux.The latter is obtained by reduction with iron in the presence of 10% ammonium chloride in a mixture of water and ethanol, the nitro derivative of formula
Figure img00020004

obtained by condensation of 4-benzyloxy-butanal in the presence of potassium hydroxide, in methanolic medium or THF, with O-phenylamino-p-nitrobenzyl ester of diphenyl phosphorous acid.

Il est à noter qu'il est également possible d'obtenir le composé de formule (III) par cyclisation par la potasse éthanolique ou le méthylate de sodium en milieu méthanolique, du com- posé de formule

Figure img00030001
It should be noted that it is also possible to obtain the compound of formula (III) by cyclization with ethanolic potassium hydroxide or sodium methoxide in a methanolic medium, of the compound of formula
Figure img00030001

On donnera ci-après, a titre d'exemple, un mode de préparation du composé de formule (I) selon l'invention. An embodiment of the compound of formula (I) according to the invention will be given below as an example.

1ère étape : benzyl-oxy-5 para-nitrophényl"1 pentanone-1 (VII)
A une solution de 105 g d'αphénylamino paranitrobenzylester de l'acide diphénylphosphoreux dans 1200 ml de THF, refroidie à - 400 C, on ajoute une solution de 12,8 g de potasse dans 128 ml de méthanol, puis une solution de 40,6 g de benzyloxy-4 n-butanal dans 500 ml de THF en 30 minutes, et on laisse 2 heures à 400 C, puis 12 heures à température ambiante. Puis on évapore les solvants, reprend le résidu dans l'eau, extrait à l'acétate d'éthyle, évapore le solvant et triture dans de l'acide chlorhydrique concentré. On dilue à l'eau, extrait à l'é- ther, évapore le solvant et cristallise le résidu dans l'éther isopropylique.On obtient ainsi 23 g du composé attendu.1st step: benzyloxy-5-para-nitrophenyl-1-pentanone (VII)
To a solution of 105 g of phenylamino paranitrobenzyl ester of diphenylphosphorous acid in 1200 ml of THF, cooled to -400 ° C., a solution of 12.8 g of potassium hydroxide in 128 ml of methanol is added, followed by a solution of 40.6 g of benzyloxy-4 n-butanal in 500 ml of THF in 30 minutes, and left for 2 hours at 400 ° C., then 12 hours at room temperature. Then the solvents are evaporated, the residue is taken up in water, extracted with ethyl acetate, the solvent is evaporated and triturated in concentrated hydrochloric acid. It is diluted with water, extracted with ether, the solvent evaporated and the residue crystallized in isopropyl ether. 23 g of the expected compound are thus obtained.

. Rendement : 38 z
. Point de fusion : 750 C
. Formule brute : C18HlgN04
. Poids moléculaire : 313,34 2ème étape : benzyloxy-5 para-aminophenyl-1 pentanone-1 (VI)
On laisse agiter une heure à température ambiante un mélange de 23 g de composé de formule (VII) obtenu à l'étape précédente et de 23 g de fer en poudre dans 200 ml d'une solution aqueuse de chlorure d'ammonium à 10 % et 20 ml d'éthanol.. Yield: 38 z
. Melting point: 750 ° C
. Gross formula: C18HlgN04
. Molecular weight: 313.34 2nd step: 5-benzyloxy-1-aminophenylpentanone-1 (VI)
A mixture of 23 g of compound of formula (VII) obtained in the preceding step and 23 g of iron powder in 200 ml of a 10% aqueous solution of ammonium chloride is stirred for one hour at room temperature. and 20 ml of ethanol.

Puis on extrait au chlorure de méthylène, filtre, lave le filtrat à l'eau, le seche sur sulfate de sodium, filtre, évapore le filtrat et cristallise le résidu dans un mélange d'acétate d'éthyle et d'éther isopropylique. On obtient ainsi 18,6 g du composé attendu.It is then extracted with methylene chloride, filtered, the filtrate washed with water, dried over sodium sulfate, filtered, the filtrate evaporated and the residue crystallized from a mixture of ethyl acetate and isopropyl ether. 18.6 g of the expected compound are thus obtained.

. Point de fusion : 72" C Poids moléculaire : 283,36
. Formule brute : C18H21N02 3ème retape : benzyloxy-5 para-aminophenyl-1 pentane (V)
A un mélange de 16 g du composé de formule (VI) obtenu à l'étape précédente et de 21 g de triéthylsilane, on ajoute 30,1 ml d'acide trifluoroacétique et on laisse agiter 20 heures à température ambiante.Puis on dilue å l'eau, basifie a l'aide de soude concentrée, extrait au chlorure de méthylène, lave à l'eau, sèche sur sulfate de sodium, filtre, évapore lefiltrat et chromatographie le résidu sur une colonne de silice [éluant : mélange chlorure de méthylène (99) - méthanol (1)
On obtient ainsi 14 g du composé attendu qui se présente sous la forme d'une huile. (Rendement : 92 %)
Spectre de RMN, (CDC13) -T ppm = 7,3,s, et 6,8, m
(9 protons aromatiques) ; 4,5,s (-CH20) ;3,4,m
(O-CH2- et NH2) ; 2,5,m, et 1,5,m (-CH2-CH2-CS

Figure img00040001

4ème étape : para-(benzyloxy-5 n-pentyl) phénylamino-1 méthoxy-3
propanol-2 (IV)
A une solution portée aux reflux de 13,9 g du composé de formule (V) obtenu à l'étape précédente dans 80 ml d'éthanol, on ajoute en 4 heures une solution de 4,61 g de méthoxy-3 époxy-1,2 propane dans 80 ml d'éthanol. On laisse encore 5 heures au reflux, puis évapore le solvant et chromatographie le résidu sur une colonne de silice [éluant : chlorure de méthylène (98,9 Z) - méthanol (1 %) - ammoniaque (0,1 Z)j. On isole ainsi 11 g du composé attendu qui se présente sous la forme d'une huile.. Melting Point: 72 "C Molecular Weight: 283.36
. Crude formula: C18H21N02 3rd retape: 5-benzyloxy-1-para-aminophenyl pentane (V)
To a mixture of 16 g of the compound of formula (VI) obtained in the preceding step and 21 g of triethylsilane is added 30.1 ml of trifluoroacetic acid and stirred for 20 hours at room temperature.Then dilute å the water is basified with concentrated sodium hydroxide, extracted with methylene chloride, washed with water, dried over sodium sulphate, filtered, the filtrate is evaporated off and the residue is chromatographed on a silica column (eluent: mixture methylene (99) - methanol (1)
There is thus obtained 14 g of the expected compound which is in the form of an oil. (Yield: 92%)
NMR spectrum, (CDCl3) -T ppm = 7.3, s, and 6.8, m
(9 aromatic protons); 4.5, s (-CH 2 O); 3.4, m
(O-CH 2 - and NH 2); 2.5, m, and 1.5, m (-CH2-CH2-CS
Figure img00040001

4th step: para- (5-benzyloxy-n-pentyl) -phenylamino-1-methoxy-3
propanol-2 (IV)
To a solution refluxed with 13.9 g of the compound of formula (V) obtained in the preceding step in 80 ml of ethanol, a solution of 4.61 g of 3-methoxy-1-epoxy is added over 4 hours. , 2 propane in 80 ml of ethanol. After refluxing for a further 5 hours, the solvent is then evaporated off and the residue is chromatographed on a silica column (eluent: methylene chloride (98.9%) -methanol (1%) - ammonia (0.1%)). 11 g of the expected compound is thus isolated, which is in the form of an oil.

. Rendement : 61 Z ol Spectre de RMN (CDCl3) # ppm = 7,3,s, et 6,7,m (9 pro- tons aromatiques) ; 4,5,s (-CH20) ; 4,m

Figure img00040002

3,6 à 2,8,m (11 protons : NH, OCH2, OCH3, et
Figure img00040003

2,4,m
Figure img00040004

1,5,m ('CH2 -CH2-). . Yield: 61 Zn NMR Spectrum (CDCl 3) δ ppm = 7.3, s, and 6.7, m (9 aromatics); 4.5, s (-CH 2 O); 4, m
Figure img00040002

3.6 to 2.8, m (11 protons: NH, OCH 2, OCH 3, and
Figure img00040003

2.4, m
Figure img00040004

1.5 m (CH 2 CH 2 -).

Sème étape : para-(benzyloxy-5 n-pentyl) phényl-3 méthoxyméthyl-5
oxazolidinone-2 (III)
A une solution de 10,3 g du composé de formule (IV) obtenu à l'étape précédente et de 8,3 g de carbonate de potassium dans 150 ml de dichloréthane, on ajoute lentement, en maintenant la température à 200 C, 36 ml d'une solution à 10 Z de phosgène dans le dichloréthane, et on laisse agiter 15 minutes, puis on porte à 500 C pendant 5 heures. Puis on lave avec une solution de bicarbonate de sodium, à l'eau, sèche sur sulfate de sodium, filtre, évapore le filtrat et chromatographie le résidu sur une colonne de silice [éîuant : acétate d'éthyle (40 %) - hexane (60 %)j . On obtient ainsi 10,3 g du composé attendu qui se présente sous la forme d'une huile.Seventh step: para- (5-benzyloxy-n-pentyl) 3-phenoxymethyl-5-methyl
oxazolidinone-2 (III)
To a solution of 10.3 g of the compound of formula (IV) obtained in the preceding step and 8.3 g of potassium carbonate in 150 ml of dichloroethane is slowly added, while maintaining the temperature at 200.degree. ml of a 10% solution of phosgene in dichloroethane, and the mixture is stirred for 15 minutes and then heated at 500 ° C. for 5 hours. Then it is washed with sodium bicarbonate solution, with water, dried over sodium sulphate, filtered, the filtrate is evaporated and the residue is chromatographed on a column of silica [eluent: ethyl acetate (40%) - hexane ( 60%) j. There is thus obtained 10.3 g of the expected compound which is in the form of an oil.

Rendement : 89 z Spectre de RMN (CDC1 S ppm = 7,3,m (9 H aromati

Figure img00050001
Yield: 89 z NMR Spectrum (CDCl 3 S ppm = 7.3, m (9H aromati
Figure img00050001

6ème étape : para-(hydroxy-5 n pentyl-1) phényl-3 méthoxyméthyl-5
oxazolidinone-2 (II)
On hydrogènolyse à pression normale et température ambiante pendant 2 heures, en autoclave, une suspension de 10 g de composé de formule (III) obtenu à l'étape précédente et de 2 g de palladium sur charbon à 5 % dans 300 ml d'éthanol à 960. Puis on filtre, évapore le filtrat, et obtient une huile qui cristallise.Step 6: para- (5-hydroxy-1-pentyl) 3-phenyl-5-methoxymethyl
oxazolidinone-2 (II)
A suspension of 10 g of compound of formula (III) obtained in the preceding step and 2 g of 5% palladium on carbon in 300 ml of ethanol is hydrogenolyzed at normal pressure and at room temperature for 2 hours, in an autoclave. at 960. Then filter, evaporate the filtrate, and obtain an oil that crystallizes.

. Point de fusion : < 50 C
. Formule brute : C16R23NO3
. Poids moléculaire : 277,35
. Spectre de RMN (CDCl3) #ppm =
7,3,m (4 H aromatiques)

Figure img00050002
. Melting point: <50 ° C
. Gross formula: C16R23NO3
. Molecular weight: 277.35
. NMR spectrum (CDCl3) #ppm =
7.3 m (4 H aromatics)
Figure img00050002

1,5,m (CH2-CH2-CH2-) 7ème étape : Para- (cyano-5 n pentyl-1) phényl] -3 méthoxymEthyl-5
oxazolidinone-2 (I)
Numéro de code : 289
A une solution refroidie à 0 C de 5,7 g de compose de formule (II) obtenu à l'étape précédente et de 7 ml de triéthylamine dans 180 ml de chlorure de méthylène, on ajoute lentement 3,2 g de chlorure de mésyle.Puis on laisse agiter 1 heure à température ambiante, lave à l'eau, sèche sur sulfate de sodium, filtre et évapore le résidu (7,9 g) que l'on dissout dans 60 ml de D.M.S.O. et que l'on ajoute à une solution de 1,4 g de cyanure de potassium dans 70 ml de D.M.S.O. On porte le mélange 7 heures à 50-60 C, puis on dilue par l'eau, extrait au chlorure de méthylène, lave à liteau, sèche sur sulfate de sodium, filtre, évapore le filtrat et chromatographie le résidu sur une colonne de silice [éluants : hexane-acétate d'éthyle (60-40) et (50-50) . On obtient ainsi 5,6 g du composé attendu (huile).1.5, m (CH2-CH2-CH2-) 7th step: Para- (cyano-5-pentyl-1) phenyl] -3-methoxymethyl-5
oxazolidinone-2 (I)
Code number: 289
To a solution cooled to 0 ° C. of 5.7 g of the compound of formula (II) obtained in the preceding step and 7 ml of triethylamine in 180 ml of methylene chloride, 3.2 g of mesyl chloride are added slowly. Then it is stirred for 1 hour at room temperature, washed with water, dried over sodium sulfate, filtered and the residue evaporated (7.9 g) which is dissolved in 60 ml of DMSO and added. a solution of 1.4 g of potassium cyanide in 70 ml of DMSO is stirred for 7 hours at 50-60 ° C., then diluted with water, extracted with methylene chloride, washed with a slurry, dried over sulfate of sodium, filter, evaporate the filtrate and chromatograph the residue on a silica column [eluent: hexane-ethyl acetate (60-40) and (50-50). 5.6 g of the expected compound (oil) is thus obtained.

. Rendement : 96 z
. Spectre de RMN (CDC13) Xppm =
7,3,m : 4 H aromatiques 4,7,m : 1 H

Figure img00060001

3,8,d
Figure img00060002

3,5,d (J = 3 Hz) : -CH203,4,s : 2,4,m : CN-CH2- et
Figure img00060003
. Yield: 96 z
. NMR Spectrum (CDCl3) Xppm =
7.3, m: 4 aromatic H 4.7, m: 1 H
Figure img00060001

3.8, d
Figure img00060002

3.5, d (J = 3 Hz): -CH 2 O 3, s: 2.4, m: CN-CH 2 - and
Figure img00060003

1,5,m : (-CH2-CH2-CH2-) . Formule brute : C17H22N203 . Poids moléculaire : 302,36 .Analyse élémentaire

Figure img00060004
1.5, m: (-CH 2 -CH 2 -CH 2 -). Gross formula: C17H22N203. Molecular weight: 302.36. Elemental analysis
Figure img00060004

<tb> <SEP> C <SEP> H <SEP> N
<tb> Calculé <SEP> (%) <SEP> 67,53 <SEP> 7,33 <SEP> 9,27
<tb> Trouvé <SEP> (%) <SEP> 67,23 <SEP> 7,51 <SEP> 9,18
<tb>
Le composé de formule (I) a été étudié chez l'animal de laboratoire et a montré des activités dans le domaine psychotrope comme anti-dépresseur potentiel.<tb><SEP> C <SEP> H <SEP> N
<tb> Calculated <SEP> (%) <SEP> 67.53 <SEP> 7.33 <SEP> 9.27
<tb> Found <SEP> (%) <SEP> 67.23 <SEP> 7.51 <SEP> 9.18
<Tb>
The compound of formula (I) has been studied in laboratory animals and has shown activities in the psychotropic field as a potential anti-depressant.

Ces activités sont mises en évidence dans les tests suivants
Test A : potentialisation chez la souris des tremblements généralysés provoqués par une injection intrapéritonéale (200 mg/kg) de dl-5-hydroxytryptophane, selon le protocole décrit par GOURET C. et RAYNAUD G., dans J. Pharmacol. (Paris) (1974), 5, 231.These activities are highlighted in the following tests
Test A: Potentiation in mice of generalized tremor caused by an intraperitoneal injection (200 mg / kg) of dl-5-hydroxytryptophan, according to the protocol described by GOURET C. and RAYNAUD G., in J. Pharmacol. (Paris) (1974), 5, 231.

Test B : antagonisme vis-à-vis du ptosis observé une heure après une injection intraveineuse (2 mg/kg) de réserpine chez la souris selon le protocole décrit par GOURET C. et THOMAS J. Test B: antagonism towards ptosis observed one hour after an intravenous injection (2 mg / kg) of reserpine in the mouse according to the protocol described by GOURET C. and THOMAS J.

dans J. Pharmacol. (Paris), (1973), 4, 401.in J. Pharmacol. (Paris), (1973), 4, 401.

Les résultats obtenus dans ces deux tests avec le compo sé selon l'invention ainsi qu'avec une substance de référence, la TOLOXATONE, sont rassemblés dans le tableau ci-après. The results obtained in these two tests with the compound according to the invention as well as with a reference substance, TOLOXATONE, are summarized in the table below.

Tableau

Figure img00070001
Board
Figure img00070001

<SEP> Test <SEP> A <SEP> Test <SEP> B <SEP>
<tb> <SEP> Test <SEP> A <SEP> Test <SEP> B
<tb> Composé <SEP> testé <SEP> DE50 <SEP> (mg/kg/p.o.) <SEP> DE50 <SEP> (mg/kg/p.o.) <SEP>
<tb> <SEP> (I) <SEP> 0,15 <SEP> 0,2
<tb> <SEP> 50
<tb> <SEP> TOLOXATONE <SEP> 60 <SEP> 50
<tb>
On constatera d'après les résultats répertoriés dans ce tableau, que le composé selon l'invention est de loin plus actif que la TOLOXANE, composé de référence notoirement connu.<SEP> Test <SEP> A <SEP> Test <SEP> B <SEP>
<tb><SEP> Test <SEP> A <SEP> Test <SEP> B
<tb> Compound <SEP> tested <SEP> DE50 <SEP> (mg / kg / po) <SEP> DE50 <SEP> (mg / kg / po) <SEP>
<tb><SEP> (I) <SEP> 0.15 <SEP> 0.2
<tb><SEP> 50
<tb><SEP> TOLOXATONE <SEP> 60 <SEP> 50
<Tb>
It will be seen from the results listed in this table that the compound according to the invention is far more active than the well-known reference compound TOLOXANE.

On notera en outre que le composé de formule (I) selon 1 invention est très peu toxique puisque sa dose létale 50 (souris) est supérieure à 1000mg/kg/p.o.  Note further that the compound of formula (I) according to the invention is very low toxicity since its lethal dose 50 (mouse) is greater than 1000mg / kg / p.o.

Le composé objet du présent certificat d'addition constitue donc un médicament particulièrement indiqué pour le traitement des états dépressifs endogènes et exogènes. The compound that is the subject of this certificate of addition is therefore a drug that is particularly indicated for the treatment of endogenous and exogenous depressive states.

La présente invention concerne également des compositions pharmaceutiques comprenant le composé de formule (I) en association avec un support pharmaceutiquement acceptable. Ces compositions peuvent être administrées
- soit par voie orale sous forme de comprimés, de dragées ou de gélules, à une posologie de 50 à 500 mg/jour en moyenne de principe actif,
- soit sous forme de soluté injectable, à une posologie de 5 à 50 mg/jour de principe actif ; le solvant utilisé est constitué par des mélanges binaires ou ternaires contenant par exemple de l'eau, du polypropylène glycol, du polyéthylèneglycol 300 ou 400, ou tout autre solvant physiologique, les proportions relatives des différents constituants étant ajustées en fonction de la dose administrée. The present invention also relates to pharmaceutical compositions comprising the compound of formula (I) in combination with a pharmaceutically acceptable carrier. These compositions may be administered
- Orally in the form of tablets, dragees or capsules, at a dosage of 50 to 500 mg / day on average of active ingredient,
- In the form of injectable solution, at a dosage of 5 to 50 mg / day of active ingredient; the solvent used consists of binary or ternary mixtures containing, for example, water, polypropylene glycol, polyethylene glycol 300 or 400, or any other physiological solvent, the relative proportions of the various constituents being adjusted as a function of the dose administered.

Claims (5)

REVENDICATIONS 1. Nouvelle N-aryl oxazolidinone-2, caractérisée en ce qu'elle répond à la formule 1. New N-aryl oxazolidinone-2, characterized in that it corresponds to the formula
Figure img00090001
Figure img00090001
 2. Procédé de préparation du composé de formule (I) selon la revendication 1, caractérisé en ce qu'il consiste à traiter le composé de formule 2. Process for the preparation of the compound of formula (I) according to claim 1, characterized in that it consists in treating the compound of formula
Figure img00090002
Figure img00090002
 par le chlorure de mésyle en milieu basique, puis à faire réagir sur le produit ainsi obtenu un cyanure alcalin. by mesyl chloride in basic medium, and then to react on the product thus obtained an alkaline cyanide. 3. Médicament, notamment pour le traitement des états dépressifs endogènes et exogènes, cractérisé en ce qu'il est constitué par le composé objet de la revendication 1. 3. Medicament, especially for the treatment of endogenous and exogenous depressive states, characterized in that it consists of the compound of claim 1. 4. Composition pharmaceutique, caractérisé en ce qu'elle comprend le médicament selon la revendication 3 en association avec un support pharmaceutique acceptable. 4. Pharmaceutical composition, characterized in that it comprises the medicament according to claim 3 in association with an acceptable pharmaceutical carrier. 5. A titre d'intermédiaires de synthèse nouveaux, nécessaires à la préparationdu composé selon la revendication 1, le composé de formule (II) définie à la revendication 2 et le composé de formule 5. As novel synthesis intermediates necessary for the preparation of the compound according to claim 1, the compound of formula (II) defined in claim 2 and the compound of formula
Figure img00090003
Figure img00090003
FR8208858A 1978-06-09 1982-05-19 Cyano:pentyl:phenyl-methoxymethyl-oxazolidinone - useful as antidepressant Granted FR2506769A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR7817388A FR2428032A1 (en) 1978-06-09 1978-06-09 N-Aryl-azolidone cpds. - useful as psychotropic agents and antidepressants (NL 11.12.79)
IT8121838A IT1226040B (en) 1979-06-04 1981-05-20 3-Substd. phenyl-5-methoxymethyl oxazolidinone derivs.

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FR2506769A2 true FR2506769A2 (en) 1982-12-03
FR2506769B2 FR2506769B2 (en) 1984-01-20

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2653017A1 (en) * 1989-10-17 1991-04-19 Delalande Sa DERIVATIVES OF ARYL-3 OXAZOLIDINONE-2, THEIR PREPARATION PROCESS AND THEIR APPLICATION IN THERAPEUTICS.
FR2675504A1 (en) * 1991-04-16 1992-10-23 Delalande Sa ARYL-3 OXAZOLIDINONE DERIVATIVES, PROCESS FOR PREPARING THEM AND THEIR THERAPEUTIC USE
WO2001087837A1 (en) * 2000-05-18 2001-11-22 A/S Gea Farmaceutisk Fabrik Process and intermediates for the preparation of 1-(9h-carbazol-4-yloxy)-3-[2-(2-methoxy-phenoxy)-ethylamino]-propan-2-ol, carvedilol or acid addition salts thereof
WO2006008754A1 (en) * 2004-07-20 2006-01-26 Symed Labs Limited Novel intermediates for linezolid and related compounds
US7524954B2 (en) 2004-04-19 2009-04-28 Symed Labs Limited Process for the preparation of linezolid and related compounds
US7714128B2 (en) 2003-10-16 2010-05-11 Symed Labs Limited Crystalline form of linezolid

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2428032A1 (en) * 1978-06-09 1980-01-04 Delalande Sa N-Aryl-azolidone cpds. - useful as psychotropic agents and antidepressants (NL 11.12.79)
GB2076813A (en) * 1980-06-04 1981-12-09 Delalande Sa N-aryl 2-oxazolidinones

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2428032A1 (en) * 1978-06-09 1980-01-04 Delalande Sa N-Aryl-azolidone cpds. - useful as psychotropic agents and antidepressants (NL 11.12.79)
GB2076813A (en) * 1980-06-04 1981-12-09 Delalande Sa N-aryl 2-oxazolidinones

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2653017A1 (en) * 1989-10-17 1991-04-19 Delalande Sa DERIVATIVES OF ARYL-3 OXAZOLIDINONE-2, THEIR PREPARATION PROCESS AND THEIR APPLICATION IN THERAPEUTICS.
FR2675504A1 (en) * 1991-04-16 1992-10-23 Delalande Sa ARYL-3 OXAZOLIDINONE DERIVATIVES, PROCESS FOR PREPARING THEM AND THEIR THERAPEUTIC USE
EP0511031A1 (en) * 1991-04-16 1992-10-28 Synthelabo 3-Aryl-oxazolidinon derivatives, process for their preparation and their use in therapeutics
EP1375474A3 (en) * 2000-05-18 2004-10-06 A/S GEA Farmaceutisk Fabrik Intermediate for the preparation of carvedilol
DK174645B1 (en) * 2000-05-18 2003-08-04 Gea Farmaceutisk Fabrik As Process and intermediates for the preparation of 1- (9H-carbazol-4-yloxy) -3- [2- (2-methoxy-phenoxy) -ethylamino] -propan-2-ol, carvedilol and acid addition salts thereof
EP1375474A2 (en) * 2000-05-18 2004-01-02 A/S GEA Farmaceutisk Fabrik Intermediate for the preparation of carvedilol
WO2001087837A1 (en) * 2000-05-18 2001-11-22 A/S Gea Farmaceutisk Fabrik Process and intermediates for the preparation of 1-(9h-carbazol-4-yloxy)-3-[2-(2-methoxy-phenoxy)-ethylamino]-propan-2-ol, carvedilol or acid addition salts thereof
US7714128B2 (en) 2003-10-16 2010-05-11 Symed Labs Limited Crystalline form of linezolid
US7718799B2 (en) 2003-10-16 2010-05-18 Symed Labs Limited Crystalline form of linezolid
US7718800B2 (en) 2003-10-16 2010-05-18 Symed Labs Limited Crystalline form of linezolid
US7524954B2 (en) 2004-04-19 2009-04-28 Symed Labs Limited Process for the preparation of linezolid and related compounds
US7741480B2 (en) 2004-04-19 2010-06-22 Symed Labs Limited Process for the preparation of linezolid and related compounds
WO2006008754A1 (en) * 2004-07-20 2006-01-26 Symed Labs Limited Novel intermediates for linezolid and related compounds
US7429661B2 (en) 2004-07-20 2008-09-30 Symed Labs Limited Intermediates for linezolid and related compounds

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