FR2559482A2 - Indole derivatives, their preparation and their application in therapy - Google Patents

Indole derivatives, their preparation and their application in therapy Download PDF

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Publication number
FR2559482A2
FR2559482A2 FR8401998A FR8401998A FR2559482A2 FR 2559482 A2 FR2559482 A2 FR 2559482A2 FR 8401998 A FR8401998 A FR 8401998A FR 8401998 A FR8401998 A FR 8401998A FR 2559482 A2 FR2559482 A2 FR 2559482A2
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sep
formula
compound
compounds
alkyl
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French (fr)
Inventor
Dennis Bigg
Jacques Menin
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Synthelabo SA
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Synthelabo SA
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Priority to FR8401998A priority Critical patent/FR2559482A2/en
Priority to AT84401595T priority patent/ATE29494T1/en
Priority to DE8484401595T priority patent/DE3465993D1/en
Priority to EP84401595A priority patent/EP0141686B1/en
Priority to KR1019840004683A priority patent/KR850001749A/en
Priority to CA000460777A priority patent/CA1236464A/en
Priority to HU843066A priority patent/HU192416B/en
Priority to ES535062A priority patent/ES8602771A1/en
Priority to FI843155A priority patent/FI843155A/en
Priority to NO843203A priority patent/NO843203L/en
Priority to DK385984A priority patent/DK385984A/en
Priority to US06/639,323 priority patent/US4598086A/en
Priority to GR80101A priority patent/GR80101B/en
Priority to AU31802/84A priority patent/AU563559B2/en
Priority to NZ209174A priority patent/NZ209174A/en
Priority to PT79067A priority patent/PT79067B/en
Priority to IL72647A priority patent/IL72647A0/en
Publication of FR2559482A2 publication Critical patent/FR2559482A2/en
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D405/14—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 three or more hetero rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Indole derivative corresponding to the formula: in which R1 is a methyl, benzyl or allyl radical and R2 is a (C1-C4)alkyl or allyl radical, as well as their pharmaceutically acceptable salts. Application in therapy.

Description

Le présent certificat d'addition a pour objet des dérivés le l'indole, leur préparation et leur application en thérapeutique.This certificate of addition relates to indole derivatives, their preparation and their therapeutic application.

Les composés du brevet principal répondent à la formule

Figure img00010001

dans laquelle A est le radical benzyle ou méthyle.The compounds of the main patent meet the formula
Figure img00010001

wherein A is benzyl or methyl.

Les composés du premier certificat d'addition répondent è le formule

Figure img00010002

:çns laquelle est soit un radical phényle portant un ou plusieurs substiuants choisis parmi les atomes d'halogène et les radicaux @éthyle, méthoxy et méthylènedioxy, soit un radical nachtyle @@@ composés du deuxième certificat d'addition répondent à
formule
Figure img00010003

dans laquelle ss est un les @@@ (C2-C6)alkyle droit ou r@mif@é, un radical (C@@C@)@@ cloelkyl-(C1C4)alkyle ou un radical (c3-C6)alcényl@
Les composés du présent certificat d'addition répondent à la formule générale I
Figure img00020001

dans laquelle
R1 est un radical méthyle, benzyle ou allyle, et
R2 est un radical (Cl-C4)alkyle ou allyle.The compounds of the first certificate of addition answer to the formula
Figure img00010002

in which is either a phenyl radical bearing one or more substituents selected from halogen atoms and the radicals ethyl, methoxy and methylenedioxy, or a radical nachtyle compounds of the second certificate of addition satisfy
formula
Figure img00010003

wherein ss is a (C 1 -C 6) alkyl straight or fused alkyl, a (C 1 -C 6) alkyl cloelkyl- (C 1 -C 4) alkyl radical or a (C 3 -C 6) alkenyl radical;
The compounds of this certificate of addition have the general formula I
Figure img00020001

in which
R1 is a methyl, benzyl or allyl radical, and
R2 is a (C1-C4) alkyl or allyl radical.

Les composés peuvent exister, sous la forme de racémates ou d'énantiomères.The compounds may exist in the form of racemates or enantiomers.

Les sels pharmaceutiquement acceptables des composés (I) font partie de l'invention.The pharmaceutically acceptable salts of the compounds (I) form part of the invention.

Les composés de l'invention peuvent être préparés selon le schéma réactionnel suivant

Figure img00020002

dans lequel R' est un adical (C-C4!alkyle, en particulier éthyle, et X et Y son des groupes labiles, en particulier des atomes d'iode ou de brome.The compounds of the invention may be prepared according to the following reaction scheme
Figure img00020002

wherein R 'is a C 1 -C 4 alkyl, especially ethyl, and X and Y are labile groups, especially iodine or bromine atoms.

L'ester éthylique de départ (formule II) est préparé selon la méthode décrite par E.J. Corey et al, J. Arn. Chem. Soc.The starting ethyl ester (formula II) is prepared according to the method described by E.J. Corey et al., J. Arn. Chem. Soc.

92, 2476 (1970).92, 2476 (1970).

La réaction entre l'ester (II) de départ, par exemple le dihydro-2,3 lH-indolecarboxylate-2 d'éthyle, et le composé
R1 X est effectuée dans un solvant tel que l'acétone, la méthyléthylcétone ou le diméthylformamide, à la température
ambiante ou à température plus élevée, en présence d'une
base, telle que le carbonate de potassium. La réaction peut
être catalysée par exemple par addition d'iodure de sodium.The reaction between the starting ester (II), for example ethyl 2-dihydro-1H-indolecarboxylate, and the compound
R 1 X is carried out in a solvent such as acetone, methyl ethyl ketone or dimethylformamide, at room temperature
ambient temperature or at a higher temperature in the presence of
base, such as potassium carbonate. The reaction can
be catalysed for example by addition of sodium iodide.

L'alkylation ou l'alcénylation de l'ester (III) ainsi obtenu
est effectuée par action d'un halogénure R2Y sur le dérivé
lithié préparé in situ au moyen de diisopropylamidure de lithium (butyllithium + diisopropylamine).The alkylation or alkenylation of the ester (III) thus obtained
is carried out by the action of an R2Y halide on the derivative
lithiated prepared in situ using lithium diisopropylamide (butyllithium + diisopropylamine).

Enfin la formation de l'imidazoline à partir de l'ester (IV) ainsi obtenu est effectuée par l'éthylènediamine en présence de triméthylaluminium.Finally, the formation of imidazoline from the ester (IV) thus obtained is carried out with ethylenediamine in the presence of trimethylaluminium.

L'exemple suivant et le tableau illustrent l'invention. Les analyses et les spectres IR et RMN confirment la structure des composés obtenus selon l'invention.The following example and the table illustrate the invention. Analyzes and IR and NMR spectra confirm the structure of the compounds obtained according to the invention.

Exemple Diméthyl-1,2 (dihydro-4,5 lH-imidazolyl-2)-2 dihydro-2,3 lH-indole. EXAMPLE 1,2-Dimethyl-1,2-dihydro-1H-imidazol-2-yl dihydro-2,3H-indole.

1. Sous argon et à -78 C, on introudit dans un ballon 5 ml (0,036 mole) de diisopropylamine dans 30 ml de tétrahydrofuranne et 22,5 ml (Q,036 mole) de butyllithium à 1,6 M dans l'hexane. 1. Under argon and at -78 ° C., 5 ml (0.036 mol) of diisopropylamine in 30 ml of tetrahydrofuran and 22.5 ml (0.036 mol) of 1.6 M butyllithium in hexane are dissolved in a flask. .

On agite une heure à -780C, puis on introduit 6,2 g (0,030 mole) de méthyl-l dihydro-2,3 lH-indolecarboxylate-2 d'éthyle dissous dans 20 ml de tétrahydrofuranne, et on continue d'agiter pendant une heure à -780C. Enfin on ajoute 21,3 g, soit 9,3 ml (n,150 mole) de iodométhane, on agite encore une heure à -780C et on laisse revenir le mélange à la température ambiante.The mixture is stirred for 1 hour at -7 ° C. and then 6.2 g (0.030 mol) of ethyl-1-dihydro-2,3-H-indolecarboxylate-2 ethyl dissolved in 20 ml of tetrahydrofuran are added and the mixture is stirred for a further hour. one hour at -780C. Finally, 21.3 g, ie 9.3 ml (n, 150 moles) of iodomethane, are added, the mixture is stirred for a further hour at -780 ° C. and the mixture is allowed to return to room temperature.

On le verse alors sur un mélange d'eau et de glace, on l'extrait à l'éther, lave la phase organique à l'eau, la sèche et la concentre. On obtient une huile orange qu'on purifie par chromatographie sur silice en éluant avec un mélange 98/2 de cyclohexane/acétate d'éthyle.It is then poured into a mixture of water and ice, extracted with ether, the organic phase washed with water, dried and concentrated. An orange oil is obtained which is purified by chromatography on silica eluting with a 98/2 mixture of cyclohexane / ethyl acetate.

Après distillation l'huile obtenue a un point d'ébullition de ll0-115 C sous 0,67 Pa (0,005 mmHg).After distillation, the oil obtained has a boiling point of 110-115 ° C. at 0.005 mmHg.

2. Sous argon, à une solution de 1,34 g (0,0185 mmole) de triméthylaluminium (7,75 ml d'une solution à 25 Wi dans l'hexane) dans 15 ml de toluène on additionne, entre O et 5 C, au goutte à goutte et en l'espace de 30 minutes, une solution de 1,14 g, soit 1,3 ml (0,019 mole) d'éthylènediamine dans 5 ml de toluène, en maintenant la température entre O et 5 C. Puis on chauffe le mélange à 50 C et on ajoute, goutte à goutte, 2,6 g (0,012 mole) de l'huile précédemment obtenue en solution dans 20 ml de toluène. En fin d'addition, on chauffe à 80-900C, on distille l'hexane et on porte au reflux pendant 18 heures en suivant la réaction par chromatographie sur couche mince.2. Under argon, to a solution of 1.34 g (0.0185 mmol) of trimethylaluminum (7.75 ml of a solution of Wi in hexane) in 15 ml of toluene is added between 0 and 5 C., dropwise over a period of 30 minutes, a solution of 1.14 g, ie 1.3 ml (0.019 mol) of ethylenediamine in 5 ml of toluene, keeping the temperature between 0 and 5 ° C. The mixture is then heated to 50 ° C. and 2.6 g (0.012 mol) of the oil obtained in solution in 20 ml of toluene are added dropwise. At the end of the addition, the mixture is heated to 80.degree.-900.degree. C., the hexane is distilled and refluxed for 18 hours following the reaction by thin layer chromatography.

Il reste finalement une solution limpide jaune, que l'on hydrolyse par 20 ml d'eau, en refroidissant sur bain de glace. On filtre la solution blanchâtre obtenue, on l'extrait au chlorure de méthylène, on lave, sèche et concentre l'extrait. On obtient ainsi une huile orange que l'on reprend par de l'éther, et on verse cette solution dans une solution éthérée d'acide benzoique. lin solide blanc précipite, on le sépàre et on le recristallise dans de l'acétate d'éthyle. Le benzoate fond à 118,5-1205C.Finally, there remains a clear yellow solution, which is hydrolyzed with 20 ml of water, cooling on an ice bath. The whitish solution obtained is filtered, extracted with methylene chloride, washed, dried and the extract concentrated. An orange oil is thus obtained which is taken up in ether and this solution is poured into an ethereal solution of benzoic acid. The white solid precipitates, is separated and recrystallized from ethyl acetate. Benzoate melts at 118.5-1205C.

Le tableau suivant illustre d'autres composés de l'invention préparés à titre d'exemples. The following table illustrates other compounds of the invention prepared as examples.

Tableau

Figure img00050001
Board
Figure img00050001

Figure img00050002
Figure img00050002

<tb> Composé <SEP> P1 <SEP> R2 <SEP> Sel <SEP> F( C) <SEP>
<tb> <SEP> I <SEP> | <SEP> -CH3 <SEP> -CH3 <SEP> benzoate <SEP> 118,5-12Q <SEP>
<tb> <SEP> 2 <SEP> -CH3 <SEP> -CH2CH3 <SEP> fumarate <SEP> 129-130
<tb> <SEP> 3 <SEP> -CH3 <SEP> I <SEP> -CH2CH2CH3 <SEP> fumarate <SEP> 157-159
<tb> <SEP> 4 <SEP> -CH3 <SEP> -CH2CH=CH2 <SEP> fumarate <SEP> 177-179
<tb> <SEP> 5 <SEP> -CH2CH=CH2 <SEP> -CH3 <SEP> fumarate <SEP> 152-154
<tb> <SEP> 6 <SEP> -CH2-C6H5 <SEP> -CH2CH3 <SEP> fumarate <SEP> 164-166
<tb> <SEP> 7 <SEP> -CH2CH=CH2 <SEP> -CH2CH2CH3 <SEP> fumarate <SEP> 160,5-162
<tb> <SEP> 8 <SEP> -CH2-C6 <SEP> H <SEP> -CH3 <SEP> ' <SEP> fumarate <SEP> | <SEP> 183-186
<tb>
Les composés de l'invention ont été soumis à des essais pharmacologiques qui ont montré leur intérêt en tant que a2-antagonistes. <tb> Compound <SEP> P1 <SEP> R2 <SEP> Salt <SEP> F (C) <SEP>
<tb><SEP> I <SEP> | <SEP> -CH3 <SEP> -CH3 <SEP> Benzoate <SEP> 118.5-12Q <SEP>
<tb><SEP> 2 <SEP> -CH3 <SEP> -CH2CH3 <SEP> fumarate <SEP> 129-130
<tb><SEP> 3 <SEP> -CH3 <SEP> I <SEP> -CH2CH2CH3 <SEQ> fumarate <SEP> 157-159
<tb><SEP> 4 <SEP> -CH3 <SEP> -CH2CH = CH2 <SEP> fumarate <SEP> 177-179
<tb><SEP> 5 <SEP> -CH2CH = CH2 <SEP> -CH3 <SEP> fumarate <SEP> 152-154
<tb><SEP> 6 <SEP> -CH2-C6H5 <SEP> -CH2CH3 <SEP> fumarate <SEP> 164-166
<tb><SEP> 7 <SEP> -CH2CH = CH2 <SEP> -CH2CH2CH3 <SEP> fumarate <SEP> 160.5-162
<tb><SEP> 8 <SEP> -CH2-C6 <SEP> H <SEP> -CH3 <SEP>'<SEP> fumarate <SEP> | <SEP> 183-186
<Tb>
The compounds of the invention have been subjected to pharmacological tests which have shown their interest as α2-antagonists.

A cet effet les composés ont été étudiés dans le test de potentialité et de sélectivité des antagonistes à l'égard des récepteure &alpha;2 in vitro.For this purpose the compounds have been studied in the potency and selectivity assay of antagonists with respect to the in vitro receptor.

La détermination de la valeur pA2 à l'égard des effets inhibiteurs de la clonidine, 2-agoniste bien connu, a eu lieu sur le vas deferens du rat stimulé à une fréquence de 0,1 Hz en présence de 30 nil de prazosine et de 1 pM de cocalne, selon la méthode décrite par G.M. Drew (European
Journal of Pharacology, 42, (1977) 123-130).The determination of the pA2 value for the inhibitory effects of clonidine, a well-known 2-agonist, occurred on rat vas deferens stimulated at a frequency of 0.1 Hz in the presence of 30 μL of prazosin and 1 μM of cocalne, according to the method described by GM Drew (European
Journal of Pharacology, 42, (1977) 123-130).

Les pA2 des composés de l'invention sont compris entre 6 et 8.The pA2 of the compounds of the invention are between 6 and 8.

Les composés de l'invention sont des a2 -antagonistes puissants qui peuvent être utilisés pour le traitement de la dépression (soit seuls, soit en association avec un produit qui inhibe les mécanismes de captation neuronale), le traitement de l'hypotension, le traitement de l'ileum paralytique post-opératoire, le traitement de l'asthme et de l'obésité.The compounds of the invention are potent α 2 -antagonists that can be used for the treatment of depression (either alone or in combination with a product that inhibits neuronal uptake mechanisms), treatment of hypotension, treatment of the postoperative paralytic ileum, the treatment of asthma and obesity.

Les compositions pharmaceutiques peuvent être sous une forme appropriée pour l'administration par voie orale, rectale ou parentérale ; par exemple sous la forme de capsules, comprimés, granulés, gélules ou solutés liquides, sirops ou suspensions buvables, et contenir les excipients appropriés.The pharmaceutical compositions may be in a form suitable for oral, rectal or parenteral administration; for example in the form of liquid capsules, tablets, granules, capsules or solutes, syrups or oral suspensions, and containing the appropriate excipients.

La posologie quotidienne peut aller de 0,1 à 10 mg/kg p.o. The daily dosage can range from 0.1 to 10 mg / kg p.o.

Claims (4)

Revendicationsclaims 1. Composés, sous Forme de racémates ou d'énantiomères, répondant à la formule générale I1. Compounds, in the form of racemates or enantiomers, having the general formula I
Figure img00070001
Figure img00070001
 dans laquelle in which R1 est un radical méthyle, benzyle ou allyle, etR1 is a methyl, benzyl or allyl radical, and R2 est un radical (Cl-C4)alkyle ou allyle, ainsi que leurs sels pharmaceutiquement acceptables.R2 is a (C1-C4) alkyl or allyl radical, as well as their pharmaceutically acceptable salts. 2. Procédé de préparation des composés selon la revendication 1, caractérisé en ce qu'on fait réagir un ester de formule II 2. Process for the preparation of the compounds according to claim 1, characterized in that an ester of formula II is reacted
Figure img00070002
Figure img00070002
 dans laquelle R' est un groupe (C1-C4 )alkyle, avec un composé de formule R1 X, dans laquelle X est un groupe labile tel qu'un atome d'iode ou de brome, et R1 est tel que défini à la revendication 1, puis on fait réagir le composé obtenu, de formule III wherein R 'is (C1-C4) alkyl, with a compound of formula R1 X, wherein X is a leaving group such as iodine or bromine, and R1 is as defined in claim 1, then the resulting compound of formula III is reacted
Figure img00070003
Figure img00070003
 avec de l'éthylènediamine en présence de trimêthylaluminium.  with ethylenediamine in the presence of trimethylaluminum.
Figure img00080001
Figure img00080001
 <tb> avec le d'un compos de formule R2Y, dans laquelle Y est un groupe labile tel qu'un atome d'iode ou de brome et P 2 est tel que défini à la revendication 1, et enfin on fait réagir le composé obtenu, de formule IV, with a compound of formula R2Y, wherein Y is a leaving group such as an iodine or bromine atom and P 2 is as defined in claim 1, and finally the compound is reacted obtained, of formula IV, <tb> iisopropylamidue <SEP> de <SEP> lithium <SEP> suivi<tb> isopropylamide <SEP> of <SEP> lithium <SEP> followed <tb> <SEP> p<tb> <SEP> p <tb> <SEP> < <SEP> CO <SEP> R'<tb> <SEP> <<SEP> CO <SEP> R ' 3. Médicament caractérisé en ce qu'il est constitué d'un composé tel que défini à la revendication 1.3. Medicinal product characterized in that it consists of a compound as defined in claim 1. 4. Composition pharmaceutique, caractérisée en ce qu'elle contient un composé tel que défini à la revendication 1, en association avec tout excipient approprié. 4. Pharmaceutical composition, characterized in that it contains a compound as defined in claim 1, in association with any suitable excipient.
FR8401998A 1983-08-11 1984-02-09 Indole derivatives, their preparation and their application in therapy Pending FR2559482A2 (en)

Priority Applications (17)

Application Number Priority Date Filing Date Title
FR8401998A FR2559482A2 (en) 1984-02-09 1984-02-09 Indole derivatives, their preparation and their application in therapy
AT84401595T ATE29494T1 (en) 1983-08-11 1984-07-30 INDOL DERIVATIVES, PROCESSES FOR THEIR PRODUCTION AND THEIR THERAPEUTIC USE.
DE8484401595T DE3465993D1 (en) 1983-08-11 1984-07-30 Indole derivatives, their preparation and their therapeutical application
EP84401595A EP0141686B1 (en) 1983-08-11 1984-07-30 Indole derivatives, their preparation and their therapeutical application
KR1019840004683A KR850001749A (en) 1983-08-11 1984-08-07 Manufacturing method of indole derivative
CA000460777A CA1236464A (en) 1983-08-11 1984-08-10 Indole derivatives, their preparation and pharmaceutical compositions containing them
HU843066A HU192416B (en) 1983-08-11 1984-08-10 Process for preparing indole derivatives and pharmaceutical compositions containing sucg compounds
ES535062A ES8602771A1 (en) 1983-08-11 1984-08-10 Indole derivatives, their preparation and their therapeutical application.
FI843155A FI843155A (en) 1983-08-11 1984-08-10 FRAMSTAELLNING AV INDOLINDERIVAT OCH DERAS THERAPEUTIC TILLAEMPNING.
NO843203A NO843203L (en) 1983-08-11 1984-08-10 PROCEDURE FOR THE PREPARATION OF INDOLIDATE DERIVATIVES
DK385984A DK385984A (en) 1983-08-11 1984-08-10 CONTENT DERIVATIVES AND PROCEDURES FOR PREPARING THEREOF AND MEDICINE CONTAINING THESE RELATIONSHIPS
US06/639,323 US4598086A (en) 1983-08-11 1984-08-10 α2 antagonistic 2-(4,5-dihydro-2-1H-imidazolyl)-2,3-dihydro-1H-indoles
GR80101A GR80101B (en) 1983-08-11 1984-08-10 Method for the preparation of indole derivatives
AU31802/84A AU563559B2 (en) 1983-08-11 1984-08-10 Indoline derivatives
NZ209174A NZ209174A (en) 1983-08-11 1984-08-10 Indole derivatives and pharmaceutical compositions
PT79067A PT79067B (en) 1983-08-11 1984-08-10 PROCESS FOR THE PREPARATION OF INDOLE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
IL72647A IL72647A0 (en) 1983-08-11 1984-08-10 Indole derivatives,their preparation and pharmaceutical compositions containing them

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
FR8401998A FR2559482A2 (en) 1984-02-09 1984-02-09 Indole derivatives, their preparation and their application in therapy

Publications (1)

Publication Number Publication Date
FR2559482A2 true FR2559482A2 (en) 1985-08-16

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FR8401998A Pending FR2559482A2 (en) 1983-08-11 1984-02-09 Indole derivatives, their preparation and their application in therapy

Country Status (1)

Country Link
FR (1) FR2559482A2 (en)

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