FR2486801A1 - Compsn. contg. tetra:hydro-2-aza-carbazole derivs. - with anti-anoxia and psychotropic activities, used in treatment of cerebral sclerosis, depression and as a stimulant - Google Patents

Compsn. contg. tetra:hydro-2-aza-carbazole derivs. - with anti-anoxia and psychotropic activities, used in treatment of cerebral sclerosis, depression and as a stimulant Download PDF

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FR2486801A1
FR2486801A1 FR8000789A FR8000789A FR2486801A1 FR 2486801 A1 FR2486801 A1 FR 2486801A1 FR 8000789 A FR8000789 A FR 8000789A FR 8000789 A FR8000789 A FR 8000789A FR 2486801 A1 FR2486801 A1 FR 2486801A1
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sep
alkyl
radical
cooc2h5
alkoxycarbonyl
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FR2486801B1 (en
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Gabor Koletar
Jonathan Frost
Regis Dupont
Patrick Lardenois
Claude Morel
Henry Najer
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Synthelabo SA
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Synthelabo SA
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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

Abstract

Pharmaceutical compsns. contain a pyridoindole deriv. of formula (I) as racemate or optically active cpd., opt. as its pharmaceutically acceptable acid addition salt. (n is 0 or 1; R1 is H, halo, alkyl, alkoxy or trifluoromethyl; R2 is alkoxycarbonyl or CONHR5; R3 is H, alkyl or alkoxycarbonyl; R4 is H, acyl, alkyl or CONHR6; R5 and R6 are H, alkyl, cycloalkyl, benzyl or opt. substd. phenyl; 'Alkyl' and 'alkoxy' have 1-4C and cycloalkyl 3-6C). (B) (I) are new cpds. except (a) where n is zero and R2 is alkoxycarbonyl; (b) where R4 is CONHR6 and (c) where R1 is 6-chloro; R2 is ethoxycarbonyl and n is 1, and R3 and R4 are both H.. (I) protect test animals against hypobaric anoxia; are antidepressants and reduce sleeping time. They are useful for treating e.g. loss of awareness esp. when caused by damage to cerebral blood vessels and in geriatric cerebral sclerosis. The usual dose is 10-100 mg per day. (I) are of low toxicity (no figures given).

Description

La presente invention concerne des dérivés de l'indole, leur préparation et leur application en thérapeutique.The present invention relates to indole derivatives, their preparation and their therapeutic application.

Les composés de l'invention, sous la forme de racémates ou d'isomères optiquement actifs, répondent a la formule (I)

Figure img00010001
The compounds of the invention, in the form of optically active racemates or isomers, have the formula (I)
Figure img00010001

dans laquelle
n est 0 ou 1,
R1 représente un atome d'hydrogène ou d'halogène, un radical alkyle
ou alcoxy,
R2 représente un radical alcoxycarbonyle ou CONHR5 dans lequel R5
est un radical alkyle, cycloalkyle ou ben::yle,
R3 est un atome d'hydrogène, un radical alkyle, un radical alcoxy
carbonyle, un radical alcoxy-carbonylmethyle ou un radical alkyl
aminocarbonyl-méthyle,
R4 est soit un atome d'hydrogène, soit le radical méthyle, soit un ;radical acyle, soit un radical CONHR6 dans lequel R6 est un atome 'hydrogène, un radical alkyle, cycloalkyle, benzyle, phényle ou phényle substitué,
les. alkyles et alcoxy ayant de 1 a 4 atomes de carbone, les cycle
alkyles ayant de 3 a 6 atomes de carbone, 15 l'exception des composés pour lesquels
soit n=O R1=H, R2= COO (Et ou Me) R3=H ou CH3 et R4=H,
soit n=1 R1=H, R2= COOEt, R3=H OU CH3 et R4=H,
soit n=l R1=H, R2 CONHCH3 R3=H et R4=H
frelon l'invention, on peut préparer les composés(I) selon les
schémas réactionnels suivants
Schéma 1 R3 # H n = O ou 1

Figure img00020001
in which
n is 0 or 1,
R1 represents a hydrogen or halogen atom, an alkyl radical
or alkoxy,
R2 represents an alkoxycarbonyl radical or CONHR5 in which R5
is an alkyl, cycloalkyl or benylyl radical,
R3 is a hydrogen atom, an alkyl radical, an alkoxy radical
carbonyl, an alkoxycarbonylmethyl radical or an alkyl radical
aminocarbonyl-methyl,
R 4 is either a hydrogen atom, a methyl radical, an acyl radical or a radical CONHR 6 in which R 6 is a hydrogen atom, an alkyl, cycloalkyl, benzyl, phenyl or substituted phenyl radical,
the. alkyl and alkoxy having from 1 to 4 carbon atoms, the rings
alkyls having 3 to 6 carbon atoms, with the exception of compounds for which
let n = O R1 = H, R2 = COO (and where Me) R3 = H or CH3 and R4 = H,
let n = 1 R1 = H, R2 = COOEt, R3 = H OR CH3 and R4 = H,
let n = 1 R1 = H, R2 CONHCH3 R3 = H and R4 = H
According to the invention, the compounds (I) can be prepared according to
following reaction schemes
Scheme 1 R3 # H n = O or 1
Figure img00020001

Schéma 2 R3 = H n =1

Figure img00030001
Figure 2 R3 = H n = 1
Figure img00030001

La transformation de l'ester (I) en amide (I) où R2 =CONHR5 est
effectuée de la même manière que dans le schéma réactionnel (I)
de meme l'addition du radical R4 = CONHR5 sur les composés (I) où
R2 = COOalk ou CONHR5 est effectuée de la même manière que dans le: schéma 1. The conversion of the ester (I) to amide (I) where R2 = CONHR5 is
performed in the same manner as in the reaction scheme (I)
the addition of the radical R4 = CONHR5 to the compounds (I) where
R2 = COOalk or CONHR5 is performed in the same manner as in Scheme 1.

Les composés pour lesquels R3 = H et n = 0 sont obtenus selon le mode de préparation décrit par Z.J.Vejdélek et Coll., J.of.Med.and Pharm.Chem., Vol.3, n03 (1961) p.427-440 .
Les exemples suivants illustrent l'invention. Les microanalyses et les spectres IR et RMN confirment la structure des composés.The compounds for which R3 = H and n = 0 are obtained according to the method of preparation described by ZJVejdélek et al., J.of.Med.and Pharm.Chem., Vol.3, n03 (1961) p.427-440 .
The following examples illustrate the invention. Microanalyses and IR and NMR spectra confirm the structure of the compounds.

Exemple 1 Méthyl-6 tétrahydro-2,3,4,9 1H-pyrido[3,4-b] indole-1
acétate d'éthyle
[n=1 R1= CH3-6 R2 = COOC2H5 R3=H R4=H] 1. On met en suspension dans 250ml d'éthanol, 52,62g (0,25 mole) chlorhydrate de méthyl-5 tryptamine et on porte à reflux. On met en suspension dans 250ml d'ethanol, 57,75g d'éthoxycarbonyl-3 dioxo-1,12 éthoxy-l propane et on ajoute goutte à goutte en 10mn 25ml d'acide chlorhydrique concentré. On ajoute cette suspension à la suspensior de méthyl-5 tryptamine HCl maintenue a la température de reflux. On laisse refroidir pendant la nuit. On élimine le solvant par évaporation e - on dissout le résidu dans 400ml d'eau et on alcalinise avec de l'amoniaque.Après extraction avec de l'acétate d'éthyle, on obtient une huile que l'on chromatographie sur une colonne de silice. Après solution avec un mélange 8/2 de chloroforme et d'éthanol, on obtien une huile qui se solidifie par trituration avec de l'éther de pétr le. Example 1 6-Methyl-2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indole-1
ethyl acetate
[n = 1 R1 = CH3-6 R2 = COOC2H5 R3 = H R4 = H] 1. 52.62 g (0.25 mol) of methyl-5-tryptamine hydrochloride are suspended in 250 ml of ethanol and reflux. 57.75 g of 3-ethoxycarbonyl-1,1-dioxoethoxypropane are suspended in 250 ml of ethanol and 25 ml of concentrated hydrochloric acid are added dropwise over 10 ml. This suspension is added to the suspension of 5-methyltryptamine HCl maintained at reflux temperature. It is allowed to cool overnight. The solvent is removed by evaporation and the residue is dissolved in 400 ml of water and basified with ammonia. After extraction with ethyl acetate, an oil is obtained which is chromatographed on a column of silica. After solution with an 8/2 mixture of chloroform and ethanol, an oil is obtained which solidifies by trituration with petroleum ether.

Après recristallisation dans de l'hexane, le composé obtenu

Figure img00040001

fond à 102-1030C. After recrystallization from hexane, the compound obtained
Figure img00040001

background at 102-1030C.

12. On chauffe à reflux 45g du composé précédent dans 450ml d'une solution aqueuse à 10% de NaOH, pendant 20h. On ajoute, goutte à goutte, de l'acide chlorhydrique concentré (100ml), en 30mn, au mélange réactionnel refroidi. On filtre le solide obtenu et on le sèche sur P205. 45 g of the preceding compound are refluxed in 450 ml of a 10% aqueous solution of NaOH for 20 hours. Concentrated hydrochloric acid (100 ml) is added dropwise over 30 minutes to the cooled reaction mixture. The solid obtained is filtered and dried over P 2 O 5.

3. On chauffe au reflux 99,6g du solide brut précédemment obtenu dans un mélange de 250ml d'éthanol et de 20ml d'acide sulfurique concentré, pendant 9h. On laisse reposer la nuit. On élimine l'étha- nol par évaporation et on alcalinise le solide résiduel avec de l'ammoniaque. On extrait avec 3 fois 300ml d'acétate d'éthyle la solution basique. On évapore. On obtient une huile qui, par trituration avec de l'éther de pétrole, donne un solide blanc. On le filtre et le sèche.3. 99.6 g of the crude solid obtained above are heated under reflux in a mixture of 250 ml of ethanol and 20 ml of concentrated sulfuric acid for 9 hours. We let it rest at night. The ethanol was removed by evaporation and the residual solid was basified with ammonia. The basic solution is extracted with 300 ml of ethyl acetate (3 × 300 ml). We evaporate. An oil is obtained which, by trituration with petroleum ether, gives a white solid. It is filtered and dried.

Après recristallisation dans de l'hexane, le composé obtenu fond à 1030C.After recrystallization from hexane, the compound obtained melts at 10 ° C.

Exemple 2 Chloro-6 méthyl-1 tétrahydro-2,3,4,9 1H-pyrido [3,4-b]
indole-l-carboxylate de méthyle
[n=0 R1=Cl-6 R2= COOCH3 R3=CH3 R4=H]
On fait réagir 36,1g (0,156 mole) de chlorhydrate de chloro-5 tryptamine en solution dans 350ml de méthanol avec 20g de pyruvate de méthyle.On laisse une semaine sous agitation à la température ambiante. On chasse le méthanol au rotavapor. Le résidu est repris avec de l'acétate d'éthyle. On agite 15mn puis on filtre le précipite. On traite le précipité avec une solution saturée de bicarbonate de sodium et on extrait à l'acétate d'éthyle. On élimine un insoluble par filtration. On décante la solution organique, on la lave, sèche et évapore au bain-marie sous vide.Example 2 6-Chloro-1-methyl-2,3,4,9-tetrahydro-1H-pyrido [3,4-b]
methyl indole-1-carboxylate
[n = 0 R1 = Cl-6 R2 = COOCH3 R3 = CH3 R4 = H]
36.1 g (0.156 mole) of 5-chloro-tryptamine hydrochloride in solution in 350 ml of methanol are reacted with 20 g of methyl pyruvate. The mixture is stirred for one week at room temperature. Methanol is removed in the rotavapor. The residue is taken up with ethyl acetate. Stir 15 minutes and then filter the precipitate. The precipitate is treated with saturated sodium bicarbonate solution and extracted with ethyl acetate. An insoluble material is removed by filtration. The organic solution is decanted, washed, dried and evaporated in a vacuum bath.

Le résidu huileux cristallise après quelques jours. Après recrista ~ lisation dans du toluène le composé fond à 1480C.The oily residue crystallizes after a few days. After recrystallization from toluene, the compound melts at 14 ° C.

Exemple 3 Méthyl-1 méthylaminocarbonyl-2 tétrahydro-2,3,4,9
l-pyrido 3,4 -b]indole-l-acétate d'éthyle
n=1 R1=H R2=COOC2H5 R3=CH3 R4=CONHCH3 lon met en suspension 10,9g (0,04 mole) de méthyl-1 tétrahydro-2,3, ,9 1H-pyrido[3,4-b]indole-1-acétate d'éthyle dans 200ml de cyclohexane. Example 3 1-Methyl-2-methylaminocarbonyl 2,3,4,9-tetrahydro
1-pyrido 3,4-b] indole-1-ethyl acetate
n = 1 R1 = H R2 = COOC2H5 R3 = CH3 R4 = CONHCH3 10.9 g (0.04 mol) of methyl-1-tetrahydro-2,3,9,9H-pyrido [3,4-b] are suspended indole-1-ethyl acetate in 200 ml of cyclohexane.

On ajoute 3ml (0,04 mole)d'isocyanate de méthyle. On chauffe au reflux pendant 1 heure. On laisse refroidir une nuit au réfrigéra leur. On filtre le précipité. On recristallise le produit dans de 1 'éthanol. 3 ml (0.04 mol) of methyl isocyanate are added. Refluxed for 1 hour. It is allowed to cool overnight in refrigeration. The precipitate is filtered. The product is recrystallized from ethanol.

F=217 C
Exemple 4 Aminocarbonyl-2 tétrahydro-2,3,4,9 1H-pyrido[3,4-b]
indole-1-carboxylate d'éthyle
[n=o R1=H R2=COOC2H5 R3=H R4-CONH2]
On chauffe vers 600C 56,2g (0,2 mole) de tétrahydro-2,3,4,9 1Hpyrido[3,4-b]indole-1-carboxylate d'éthyle dans 1000ml d'eau.Mp = 217 ° C
Example 4 2-Aminocarbonyl-2,3,4,9-tetrahydro-1H-pyrido [3,4-b]
ethyl indole-1-carboxylate
[n = o R1 = H R2 = COOC2H5 R3 = H R4-CONH2]
56.2 g (0.2 mol) of ethyl 2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indole-1-carboxylate are heated to 600 ° C. in 1000 ml of water.

On ajoute en une seule fois une solution de 15,2g (0,234 mole) de cyanate de sodium pulvérulent dans 200ml d'eau.On agite 15mn puis refroidit vers LOOC. On décante la phase aqueuse réactionnelle, lave le compose avec de l'eau et le recristallise dans de l'éthanol.A solution of 15.2 g (0.234 mol) of powdered sodium cyanate in 200 ml of water is added all at once. The mixture is stirred for 15 minutes and then cooled to LOOC. The aqueous phase is decanted, the compound is washed with water and recrystallized from ethanol.

F=215-2170C.  Mp 215-2170C.

Exemple 5 Méthyl-1 méthylaminocarbonyl-1 tétrahydro-2,3,4,9
1H-pyrido[3,4-b]indole
[ n=0 R1=H R2=CONH CH3 R3=CH3 R4=H
On met 4,8g (0,02 mole) de méthyl-1 tétrahydro-2,3,4,9, 1H pyrido [3,4-b)] indole-1-carboxylate de méthyle en solution dans 100ml d'éthanol saturé de méthylamine. On laisse à 1 température ambiante pendant 48 heures. On élimine le solvant puis reprend le résidu par 20ml d'éthanol. On filtre et lave à l'éthanol
F= 230-2310C.Example 5 1-methyl-1-methylaminocarbonyl-2,3,4,9-tetrahydro
1H-pyrido [3,4-b] indole
[n = 0 R1 = H R2 = CONH CH3 R3 = CH3 R4 = H
4.8 g (0.02 mol) of methyl-1-methyl-2,3,4,9-tetrahydro-1H-pyrido [3,4-b)] indole-1-carboxylate are dissolved in 100 ml of saturated ethanol. of methylamine. It is left at room temperature for 48 hours. The solvent is removed and the residue is taken up in 20 ml of ethanol. Filter and wash with ethanol
F = 230-2310C.

Exemple 6 Fluoro-6 méthylaminocarbonyl-1 tétrahydro-2,3,4,9
lH-pyrido[3,4-b]indole [1 R1 = F-6 R2=CONHCH3 R3=H R4=H J
On place dans un autoclave 20g de fluoro-6 tétrahydro-2,3,4,9 1H-pyrido[3,4-b] inole-1-acétate d'éthyle (obtenu selon le procédé de l'exemple 1) et 500ml d'éthanol saturé de méthylamine.Example 6 6-Fluoro-1-methylaminocarbonyl-2,3,4,9-tetrahydro
1H-pyrido [3,4-b] indole [1 R 1 = F-6 R 2 = CONHCH 3 R 3 = H R 4 = H]
20 g of 6-fluoro-2,3,4,9-tetrahydro-1H-pyrido [3,4-b] inol-1-ethyl acetate (obtained according to the method of Example 1) and 500 ml are placed in an autoclave. of ethanol saturated with methylamine.

On chauffe à 1000C pendant 5 h. On chasse le solvant et obtient un solide blanc. On le recristallise dans de l'éthanol. The mixture is heated at 1000 ° C. for 5 hours. The solvent is removed and a white solid is obtained. It is recrystallized from ethanol.

F= 227 C. Mp = 227 C.

Exemple 7 Chloro-6 méthylaminocarbonyl-1 méthyl-1 acétyl-2
tétrahydro-2,3,4,9 1H-pyrido [3,4-b] indole
tn=l R1 = C1-6 R2= CONHCH3 R3=CH3 R4=COCH3]
On dissout 3g (0,0102 mole ) de chloro-6 méthylaminocarbonyl-1 méthyl-l tétrahydro-2,3,4,9 lH-pyrido 3-4-b indole dans 30ml j de pyridine. On ajoute 2ml d'anhydride acétique. On agite à la température ambiante pendant 48h. On évapore et chasse la pyridine
On reprend le résidu avec 20ml d'éthanol et on filtre le préci pité. Après recristallisation dans 1'éthanol le produit fond à 214 C. Example 7 1-Chloro-1-methylaminocarbonyl-1-methyl-2-acetyl
2,3,4,9-tetrahydro-1H-pyrido [3,4-b] indole
tn = 1 R1 = C1-6 R2 = CONHCH3 R3 = CH3 R4 = COCH3]
3 g (0.0102 moles) of 6-chloro-1-methylaminocarbonyl-1-methyl-2,3,4,9-tetrahydro-1H-pyrido-4-indol in 30 ml of pyridine are dissolved. 2 ml of acetic anhydride are added. Stirred at room temperature for 48 hours. Evaporate and flush the pyridine
The residue is taken up with 20 ml of ethanol and the precipitate is filtered off. After recrystallization from ethanol, the product melts at 214 ° C.

Les composés de l'invention préparés à titre d'exemples sont représentés dans le tableau suivant. The compounds of the invention prepared by way of example are shown in the following table.

TABLEAU

Figure img00080001

m.s = Méthane-sulfonate
Figure img00080002
BOARD
Figure img00080001

ms = Methanesulfonate
Figure img00080002

<tb> <SEP> Composé <SEP> R1 <SEP> R2 <SEP> R3 <SEP> R4 <SEP> n <SEP> F <SEP> ( C)
<tb> 1 <SEP> CH3-6 <SEP> COOC2H5 <SEP> H <SEP> H <SEP> 1 <SEP> 103
<tb> <SEP> 2 <SEP> CH3-6 <SEP> C00C2H5 <SEP> COOC2H5 <SEP> H <SEP> 1 <SEP> 102-103
<tb> <SEP> 3 <SEP> CH30-6 <SEP> COOC2H5 <SEP> H <SEP> H <SEP> 1 <SEP> 181 <SEP> (maléate <SEP>
<tb> <SEP> 4 <SEP> CH30-6 <SEP> COOC2H5 <SEP> COOC2H5 <SEP> H <SEP> 1 <SEP> 100
<tb> <SEP> IH <SEP> COOC2H5 <SEP> COOC2H5 <SEP> H <SEP> 1 <SEP> 80-82
<tb> <SEP> 6 <SEP> Cl-6 <SEP> COOC2H5 <SEP> CH3 <SEP> H <SEP> 1 <SEP> 104
<tb> 7 <SEP> Cl-6 <SEP> COOC2H5 <SEP> H <SEP> H <SEP> 1 <SEP> 240 <SEP> m.s
<tb> 8 <SEP> Cl-6 <SEP> COOC2H5 <SEP> COOC2H5 <SEP> H <SEP> 1 <SEP> 101
<tb> <SEP> 9 <SEP> H <SEP> COOC2H5 <SEP> CH2COOC2H5 <SEP> H <SEP> 1 <SEP> 89
<tb> <SEP> 10 <SEP> F-6 <SEP> COOC2H5 <SEP> H <SEP> H <SEP> 1 <SEP> 229-230 <SEP> m.s
<tb> 11 <SEP> F-6 <SEP> COOC2H5 <SEP> COOC2H5 <SEP> H <SEP> 1 <SEP> 197 <SEP> HCl <SEP>
<tb> <SEP> 12 <SEP> Cl-6 <SEP> COOCH3 <SEP> CH3 <SEP> H <SEP> 0 <SEP> 148
<tb> <SEP> 13 <SEP> H <SEP> COOC2H5 <SEP> H <SEP> CONH2 <SEP> 1 <SEP> huile
<tb> 14 <SEP> H <SEP> COOC2H5 <SEP> CH2COOC2H <SEP> CONHCH3 <SEP> 1 <SEP> 162
<tb> 15 <SEP> 15 <SEP> H <SEP> COOC2H5 <SEP> CH3 <SEP> CONHCH3 <SEP> 1 <SEP> 217
<tb>

Figure img00090001
<tb><SEP> Compound <SEP> R1 <SEP> R2 <SEP> R3 <SEP> R4 <SEP> n <SEP> F <SEP> (C)
<tb> 1 <SEP> CH3-6 <SEP> COOC2H5 <SEP> H <SEP> H <SEP> 1 <SEP> 103
<tb><SEP> 2 <SEP> CH3-6 <SEP> C00C2H5 <SEP> COOC2H5 <SEP> H <SEP> 1 <SEP> 102-103
<tb><SEP> 3 <SEP> CH30-6 <SEP> COOC2H5 <SEP> H <SEP> H <SEP> 1 <SEP> 181 <SEP> (maleate <SEP>
<tb><SEP> 4 <SEP> CH30-6 <SEP> COOC2H5 <SEP> COOC2H5 <SEP> H <SEP> 1 <SEP> 100
<tb><SEP> IH <SEP> COOC2H5 <SEP> COOC2H5 <SEP> H <SEP> 1 <SEP> 80-82
<tb><SEP> 6 <SEP> Cl-6 <SEP> COOC2H5 <SEP> CH3 <SEP> H <SEP> 1 <SEP> 104
<tb> 7 <SEP> Cl-6 <SEP> COOC2H5 <SEP> H <SEP> H <SEP> 1 <SEP> 240 <SEP> ms
<tb> 8 <SEP> Cl-6 <SEP> COOC2H5 <SEP> COOC2H5 <SEP> H <SEP> 1 <SEP> 101
<tb><SEP> 9 <SEP> H <SEP> COOC2H5 <SEP> CH2COOC2H5 <SEP> H <SEP> 1 <SEP> 89
<tb><SEP> 10 <SEP> F-6 <SEP> COOC2H5 <SEP> H <SEP> H <SEP> 1 <SEP> 229-230 <SEP> ms
<tb> 11 <SEP> F-6 <SEP> COOC2H5 <SEP> COOC2H5 <SEP> H <SEP> 1 <SEP> 197 <SEP> HCl <SEP>
<tb><SEP> 12 <SEP> C-6 <SEP> COOCH3 <SEP> CH3 <SEP> H <SEP> 0 <SEP> 148
<tb><SEP> 13 <SEP> H <SEP> COOC2H5 <SEP> H <SEP> CONH2 <SEP> 1 <SEP> Oil
<tb> 14 <SEP> H <SEP> COOC2H5 <SEP> CH2COOC2H <SEP> CONHCH3 <SEP> 1 <SEP> 162
<tb> 15 <SEP> 15 <SEP> H <SEP> COOC2H5 <SEP> CH3 <SEP> CONHCH3 <SEP> 1 <SEP> 217
<Tb>
Figure img00090001

<tb> <SEP> Composé <SEP> R1 <SEP> R2 <SEP> R3 <SEP> R4 <SEP> n <SEP> F <SEP> ( C)
<tb> <SEP> L <SEP> I
<tb> <SEP> 16 <SEP> H <SEP> COOC2H5 <SEP> H <SEP> CONH2 <SEP> 0 <SEP> 215-217
<tb> <SEP> 17 <SEP> H <SEP> COOC2H5 <SEP> H <SEP> CONHC2H5 <SEP> 0 <SEP> 190-192
<tb> <SEP> 18 <SEP> H <SEP> COOC2H5 <SEP> H <SEP> CONF.C3H7n <SEP> 0 <SEP> 170-175
<tb> <SEP> 19 <SEP> H <SEP> COOC2H5 <SEP> H <SEP> CONHC4Hgt <SEP> 0 <SEP> 209-210
<tb> <SEP> 20 <SEP> H <SEP> COOC2H5 <SEP> H <SEP> CONHCH3 <SEP> 0 <SEP> 158-162
<tb> <SEP> 21 <SEP> H <SEP> COOC2H5 <SEP> H <SEP> CONBC3H7i <SEP> 0 <SEP> 145-150
<tb> <SEP> 22 <SEP> H <SEP> COOC2H5 <SEP> H <SEP> CONHC6H5 <SEP> 0 <SEP> 164-168
<tb> <SEP> 23 <SEP> 23 <SEP> H <SEP> 1 <SEP> COOC2H5 <SEP> H <SEP> CONH <SEP> Q <SEP> C <SEP> 0 <SEP> 160
<tb> <SEP> 24 <SEP> H <SEP> COOC2H5 <SEP> H <SEP> CONHC4H9n <SEP> 0 <SEP> 140
<tb> <SEP> 25 <SEP> H <SEP> CONHCH3 <SEP> CH3 <SEP> H <SEP> 1 <SEP> 182
<tb> <SEP> 26 <SEP> C1-6 <SEP> CONHCH3 <SEP> CE3 <SEP> H <SEP> 1 <SEP> 212
<tb> <SEP> 27 <SEP> H <SEP> CONHCH3 <SEP> CH2COSHCH3 <SEP> H <SEP> 1 <SEP> 215
<tb> <SEP> 28 <SEP> H <SEP> coNHcH2q <SEP> 3 <SEP> H <SEP> H <SEP> 1 <SEP> 160
<tb> I29 <SEP> H <SEP> CONH <SEP> 4 <SEP> H <SEP> H <SEP> 1 <SEP> 166-168
<tb> <SEP> i
<tb> <SEP> 30 <SEP> F-6 <SEP> CONHCH3 <SEP> H <SEP> H <SEP> 1 <SEP> 227
<tb> <SEP> 31 <SEP> C1-6 <SEP> CONHCH3 <SEP> H <SEP> H <SEP> 1 <SEP> 232-233
<tb> <SEP> 32 <SEP> CH3-6 <SEP> CONHCH3 <SEP> H <SEP> H <SEP> 1 <SEP> 216
<tb> ! <SEP> 33 <SEP> CE <SEP> 0-6 <SEP> CONHCH3 <SEP> H <SEP> H-;<SEP> 1 <SEP> 190
<tb>

Figure img00100001
<tb><SEP> Compound <SEP> R1 <SEP> R2 <SEP> R3 <SEP> R4 <SEP> n <SEP> F <SEP> (C)
<tb><SEP> L <SEP> I
<tb><SEP> 16 <SEP> H <SEP> COOC2H5 <SEP> H <SEP> CONH2 <SEP> 0 <SEP> 215-217
<tb><SEP> 17 <SEP> H <SEP> COOC2H5 <SEP> H <SEP> CONHC2H5 <SEP> 0 <SEP> 190-192
<tb><SEP> 18 <SEP> H <SEP> COOC2H5 <SEP> H <SEP> CONF.C3H7n <SEP> 0 <SEP> 170-175
<tb><SEP> 19 <SEP> H <SEP> COOC2H5 <SEP> H <SEP> CONHC4Hgt <SEP> 0 <SEP> 209-210
<tb><SEP> 20 <SEP> H <SEP> COOC2H5 <SEP> H <SEP> CONHCH3 <SEP> 0 <SEP> 158-162
<tb><SEP> 21 <SEP> H <SEP> COOC2H5 <SEP> H <SEP> CONBC3H7i <SEP> 0 <SEP> 145-150
<tb><SEP> 22 <SEP> H <SEP> COOC2H5 <SEP> H <SEP> CONHC6H5 <SEP> 0 <SEP> 164-168
SEP><SEP> 23
<tb><SEP> 24 <SEP> H <SEP> COOC2H5 <SEP> H <SEP> CONHC4H9n <SEP> 0 <SEP> 140
<tb><SEP> 25 <SEP> H <SEP> CONHCH3 <SEP> CH3 <SEP> H <SEP> 1 <SEP> 182
<tb><SEP> 26 <SEP> C1-6 <SEP> CONHCH3 <SEQ> CE3 <SEP> H <SEP> 1 <SEP> 212
<tb><SEP> 27 <SEP> H <SEP> CONHCH3 <SEP> CH2COSHCH3 <SEP> H <SEP> 1 <SEP> 215
<tb><SEP> 28 <SEP> H <SEP> CoNHcH2q <SEP> 3 <SEP> H <SEP> H <SEP> 1 <SEP> 160
<tb> I29 <SEP> H <SEP> CONH <SEP> 4 <SEP> H <SEP> H <SEP> 1 <SEP> 166-168
<tb><SEP> i
<tb><SEP> 30 <SEP> F-6 <SEP> CONHCH3 <SEP> H <SEP> H <SEP> 1 <SEP> 227
<tb><SEP> 31 <SEP> C1-6 <SEP> CONHCH3 <SEP> H <SEP> H <SEP> 1 <SEP> 232-233
<tb><SEP> 32 <SEP> CH3-6 <SEP> CONHCH3 <SEP> H <SEP> H <SEP> 1 <SEP> 216
<tb>! <SEP> 33 <SEP> CE <SEP> 0-6 <SEP> CONHCH3 <SEP> H <SEP> H -; <SEP> 1 <SEP> 190
<Tb>
Figure img00100001

<tb> Composé <SEP> R1 <SEP> R2 <SEP> R3 <SEP> R4 <SEP> n <SEP> F <SEP> ( C)
<tb> 34 <SEP> H <SEP> CONHC2H4 <SEP> H <SEP> H <SEP> 1 <SEP> 148-149
<tb> 35 <SEP> H <SEP> CONHCH3 <SEP> CH3 <SEP> CH3 <SEP> 1 <SEP> 240
<tb> 36 <SEP> H <SEP> CONHCH3 <SEP> CH3 <SEP> .H <SEP> 0 <SEP> 230
<tb> 37 <SEP> H <SEP> CONHCH3 <SEP> CH3 <SEP> CH3 <SEP> 0 <SEP> 207
<tb> 38 <SEP> Cl-6 <SEP> CONHCH3 <SEP> CH3 <SEP> H <SEP> 0 <SEP> 230
<tb> 39 <SEP> F-6 <SEP> CONHCH3 <SEP> CH3 <SEP> H <SEP> 0 <SEP> 238
<tb> 40 <SEP> Cl-6 <SEP> CONHCH3 <SEP> CH3 <SEP> COCH3 <SEP> 1 <SEP> 214
<tb> 41 <SEP> Cl-6 <SEP> CONHCH3 <SEP> CH3 <SEP> COCH3 <SEP> 0 <SEP> 2
<tb>
Les composés de l'invention ont été soumis à divers essais phar
macologiques.<tb> Compound <SEP> R1 <SEP> R2 <SEP> R3 <SEP> R4 <SEP> n <SEP> F <SEP> (C)
<tb> 34 <SEP> H <SEP> CONHC2H4 <SEP> H <SEP> H <SEP> 1 <SEP> 148-149
<tb> 35 <SEP> H <SEP> CONHCH3 <SEP> CH3 <SEP> CH3 <SEP> 1 <SEP> 240
<tb> 36 <SEP> H <SEP> CONHCH3 <SEP> CH3 <SEP> .H <SEP> 0 <SEP> 230
<tb> 37 <SEP> H <SEP> CONHCH3 <SEP> CH3 <SEP> CH3 <SEP> 0 <SEP> 207
<tb> 38 <SEP> Cl-6 <SEP> CONHCH3 <SEP> CH3 <SEP> H <SEP> 0 <SEP> 230
<tb> 39 <SEP> F-6 <SEP> CONHCH3 <SEP> CH3 <SEP> H <SEP> 0 <SEP> 238
<tb> 40 <SEP> Cl-6 <SEP> CONHCH3 <SEP> CH3 <SEP> COCH3 <SEP> 1 <SEP> 214
<tb> 41 <SEP> Cl-6 <SEP> CONHCH3 <SEP> CH3 <SEP> COCH3 <SEP> 0 <SEP> 2
<Tb>
The compounds of the invention have been subjected to various phar tests
macologiques.

Les composés ont en effet été soumis au test de l'anoxie hypobare
chez la souris et au test de l'action sur la durée du sommeil
induit par le 4-hydroxy-butyrate de sodium chez le rat curarisé.The compounds have indeed been subjected to the hypobaric anoxia test
in the mouse and the test of action on the duration of sleep
induced by sodium 4-hydroxy-butyrate in curarized rats.

ANOXIE HYPOBARE
Des souris de souche CD1 sont maintenues dans une atmosphère ap-
pauvrie en oxygène, par réalisation d'un vide partiel (190 mm de
mercure correspondant à 5,25 % d'oxygène).HYPOBARE ANOXIA
CD1 strain mice are maintained in an approved atmosphere.
poor oxygen, by performing a partial vacuum (190 mm of
mercury corresponding to 5.25% oxygen).

Le temps de survie des animaux est noté. Ce temps est augmenté par les agents capables de favoriser l'oxygénation tissulaire et en particulier cérébrale. Les composés étudiés sont administrés à plusiers doses, par voie intrapéritonéale, 10 minutes avant
l'essai. Les pourcentages d'augmentation du temps de survie par
rapport aux valeurs obtenues chez les animaux témoins sont cal
culés. La dose active moyenne (DAM), dose qui augmente le temps
de survie de 100% est déterminée graphiquement.The survival time of the animals is noted. This time is increased by the agents capable of promoting tissue oxygenation and in particular cerebral oxygenation. The compounds studied are administered at several doses, intraperitoneally, 10 minutes before
test. Percentages of increase in survival time by
compared to the values obtained in the control animals are cal
culés. The average active dose (AMD), a dose that increases the time
100% survival is determined graphically.

La DAM des composés de l'invention varie de 13 à 26 mg/kg par voie i.p.  The DAM of the compounds of the invention ranges from 13 to 26 mg / kg i.p.

ACTION SUR LA DUREE DU " SOMMEIL
Cette action a été déterminée par l'influence des composés sur 1 I. -
durée du n sommeil " induit par le 4-hydroxy-butyrate de sodium
(GHB) chez le rat curarisé sous respiration artificielle dans le
quel l'activité électrocorticographique est enregistrée par des électrodes corticales.ACTION ON THE DURATION OF "SLEEP
This action was determined by the influence of the compounds on 1 I. -
duration of n sleep "induced by sodium 4-hydroxy-butyrate
(GHB) in the curarized rat under artificial respiration in the
which electrocorticographic activity is recorded by cortical electrodes.

Les composés de l'invention diminuent la durée totale du sommeil
de 20 à 35%.The compounds of the invention reduce the total duration of sleep
from 20 to 35%.

L'étude pharmacologique des composés de l'invention montre qu'ils
sont actifs dans l'épreuve d'anoxie hypobare chez la souris tout
en n'étant que peu toxiques et qu'ils exercent une action signi
ficative éveillante dans le test du " sommeil " induit par le
4-hydroxy-butyrate de sodium. The pharmacological study of the compounds of the invention shows that they
are active in the hypobaric anoxia test in the mouse while
being only slightly toxic and that they exert a significant
awakening fiction in the test of "sleep" induced by the
Sodium 4-hydroxy-butyrate.

Les composés de l'invention, possédant à la fois une activité anti
anoxique et une activité psychotrope, peuvent être utilisés en
thérapeutique pour le traitement des troubles de la vigilance, en
particulier pour lutter contre les troubles du comportement impu-:
tables à des dommages vasculaires cérébraux et à la sclérose céré-
brale en gériatrie , ainsi que pour le traitement des abscences dues à à des traumatismes crâniens, et le traitement des états dépressifs. The compounds of the invention possessing both anti-
anoxic and psychotropic activity, can be used in
therapy for the treatment of vigilance disorders, in
particular for the fight against impugned behavioral disorders:
to cerebrovascular damage and cerebral sclerosis.
in geriatrics, as well as for the treatment of absences due to head trauma, and the treatment of depressive states.

L'invention comprend par conséquent, toutes compositions pharmaceutiques, renfermant les composés et/ou leurs sels comme principes
actifs, en association avec tous excipients appropriés à leur admi
nistration, en particulier par voie orale ou parentérale.The invention therefore includes any pharmaceutical compositions containing the compounds and / or their salts as principles
active ingredients, in combination with any excipients appropriate to their
particularly oral or parenteral.

Les voies d'administration peuvent être les voies orale et parenté
rale.Routes of administration may be oral and parent
rale.

La posologie quotidienne peut aller de 10 à 1000 mg.  The daily dosage can range from 10 to 1000 mg.

Claims (1)

Revendication Claim Compositions pharmaceutiques caractérisées- en ce qu'elles contiennent un composé répondant à la formule (I) sous la forme de racémate ou d'isomère optiquement actif , ou sous la forme d'un sel pharmaceutiquement acceptable,Pharmaceutical compositions characterized in that they contain a compound corresponding to formula (I) in the form of racemate or optically active isomer, or in the form of a pharmaceutically acceptable salt,
Figure img00130001
Figure img00130001
 formule dans laquelle n est 0 ou 1, formula where n is 0 or 1, R1 représente un atome d'hydrogène ou d'halogène, un radical alkyle ou alcoxy,R1 represents a hydrogen or halogen atom, an alkyl or alkoxy radical, R2 représente un radical alcoxycarbonyle ou CONHR5 dans lequel R5 est un- radical alkyle, cycloalkyle ou benzyle,R2 represents an alkoxycarbonyl radical or CONHR5 in which R5 is an alkyl, cycloalkyl or benzyl radical, R3 est un atome d'hydrogène, un radical alkyle, un radical alcoxycarbonyle, un radical alcoxy-carbonylméthyle ou un radical alkylaminocarbonyl-méthyle,R3 is a hydrogen atom, an alkyl radical, an alkoxycarbonyl radical, an alkoxycarbonylmethyl radical or an alkylaminocarbonylmethyl radical, R4 est soit un atome d'hydrogène, soit le radical méthyle, soit un radical acyle, soit un radical CONHR6 dans lequel R6 est un atome d'hydrogène, un radical alkyle, cycloalkyle, benzyle, phényle ou phényle substitué, les alkyles et.alcoxy ayant de 1 à 4 atomes-de carbone, les cycloalkyles ayant de 3 à 6 atomes de carbone, à l'exception des composes pour lesquels soit n=O R1=H, R2 COO (Et ou Me) R3--H ou CH3 et R4=H, soit n=l R1=H, R2=COOEt, R3=H ou CH3 et R4=H, soit n=l R1=H R2 CONHCH3 R3=H et R4 = H R4 is either a hydrogen atom, a methyl radical, an acyl radical or a radical CONHR6 in which R6 is a hydrogen atom, an alkyl, cycloalkyl, benzyl, phenyl or substituted phenyl radical, alkyls and the like; alkoxy having from 1 to 4 carbon atoms, cycloalkyls having from 3 to 6 carbon atoms, with the exception of the compounds for which either n = O R1 = H, R2 COO (Et or Me) R3-H or CH3 and R4 = H, where n = 1 R1 = H, R2 = COOEt, R3 = H or CH3 and R4 = H, or n = 1 R1 = H R2 CONHCH3 R3 = H and R4 = H
FR8000789A 1979-04-26 1980-01-15 Compsn. contg. tetra:hydro-2-aza-carbazole derivs. - with anti-anoxia and psychotropic activities, used in treatment of cerebral sclerosis, depression and as a stimulant Granted FR2486801A1 (en)

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FR8000789A FR2486801A1 (en) 1979-04-26 1980-01-15 Compsn. contg. tetra:hydro-2-aza-carbazole derivs. - with anti-anoxia and psychotropic activities, used in treatment of cerebral sclerosis, depression and as a stimulant

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR7910654A FR2455044A1 (en) 1979-04-26 1979-04-26 PYRIDO-INDOLES AND THEIR APPLICATION IN THERAPEUTICS
FR8000789A FR2486801A1 (en) 1979-04-26 1980-01-15 Compsn. contg. tetra:hydro-2-aza-carbazole derivs. - with anti-anoxia and psychotropic activities, used in treatment of cerebral sclerosis, depression and as a stimulant

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FR2486801A1 true FR2486801A1 (en) 1982-01-22
FR2486801B1 FR2486801B1 (en) 1983-12-16

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