FR2554815A2 - Indole derivatives, their preparation and their application in therapeutics - Google Patents

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

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Publication number
FR2554815A2
FR2554815A2 FR8318121A FR8318121A FR2554815A2 FR 2554815 A2 FR2554815 A2 FR 2554815A2 FR 8318121 A FR8318121 A FR 8318121A FR 8318121 A FR8318121 A FR 8318121A FR 2554815 A2 FR2554815 A2 FR 2554815A2
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sep
formula
compound
radical
preparation
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FR8318121A
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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 FR8318121A priority Critical patent/FR2554815A2/en
Priority to DE8484401595T priority patent/DE3465993D1/en
Priority to EP84401595A priority patent/EP0141686B1/en
Priority to AT84401595T priority patent/ATE29494T1/en
Priority to KR1019840004683A priority patent/KR850001749A/en
Priority to NO843203A priority patent/NO843203L/en
Priority to ES535062A priority patent/ES8602771A1/en
Priority to CA000460777A priority patent/CA1236464A/en
Priority to HU843066A priority patent/HU192416B/en
Priority to FI843155A priority patent/FI843155A/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 FR2554815A2 publication Critical patent/FR2554815A2/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 derivatives, in the form of racemates or optically active isomers, corresponding to the formula: in which R is a straight or branched (C2-C6)alkyl radical, a (C3-C6)cycloalkyl(C1-C4)alkyl radical or a (C3-C6)alkenyl radical, and their pharmaceutically acceptable salts. Application in therapeutics.

Description

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

Les composés du brevet principal répondent à la formule

Figure img00010001

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

wherein is the benzyl or methyl radical.

Les composés du premier certificat d'addition répondent à la formule

Figure img00010002

dans laquelle est soit un radical phényle portant un ou plusieurs substituants choisis parmi les atomes-d'halogène et les radicaux méthyle, méthoxy et méthylènedioxy, soit un radical naphtyle.The compounds of the first certificate of addition satisfy the formula
Figure img00010002

wherein is a phenyl radical bearing one or more substituents selected from halogen atoms and methyl, methoxy and methylenedioxy radicals, or a naphthyl radical.

Les composés du présent certificat d'addition répondent h la formule (I)

Figure img00010003

dans laquelle R est un radical (C2-C6)alkyle droit ou ramifié, un radical (C3-C6)cycloalkyl-(Cl-C4)alkyle ou un radical (C3-C6) alcényle. The compounds of this certificate of addition have the formula (I)
Figure img00010003

wherein R is a straight or branched (C2-C6) alkyl radical, a (C3-C6) cycloalkyl- (C1-C4) alkyl radical or a (C3-C6) alkenyl radical.

Les composés peuvent exister, sous la forme de racémates ou d'isomères optiquement actifs. The compounds may exist in the form of racemates or optically active isomers.

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 etre préparés selon le schéma réactionnel suivant

Figure img00020001
The compounds of the invention may be prepared according to the following reaction scheme
Figure img00020001

R' = (C1-C4)aI kyle, plus particulièrement-éthyle. R '= (C1-C4) alkyl, more particularly ethyl.

L'ester éthylique de départ

Figure img00020002

est préparé selon la méthode décrite par E.J. Corey et al,
J. Amer. Chem. Soc., 92, 2476 (1970).The starting ethyl ester
Figure img00020002

is prepared according to the method described by EJ Corey et al,
J. Amer. Chem. Soc., 92, 2476 (1970).

La réaction entre l'ester de départ, par exemple le dihydro-2,3 lH-indolecarboxylate-2 d'éthyle, et le composë
RX (X=Br, C1-ou tout autre groupe labile) est effectuée dans un solvant tel que l'acétone, la méthyiéthylcétone ou le diméthylformamide, à la température ambiante ou à température plus élevée, en présence d'une base, telle que t2C03. La réaction peut être catalysée par exemple par
addition de NaI.The reaction between the starting ester, for example ethyl dihydro-2,3-H-indolecarboxylate-2, and the compound
RX (X = Br, C1-or any other leaving group) is carried out in a solvent such as acetone, methyl diethyl ketone or dimethylformamide, at room temperature or at a higher temperature, in the presence of a base, such as t2C03. The reaction can be catalyzed for example by
addition of NaI.

La réaction entre le P-l dihydro-2,3 lH-indolecarboxylate-2 d'allyle et l'éthylènediamine est effectuée en présence de triBéthylaluminium,
L'exemple suivant et le tableau illustrent l'invention. Les analyses et les spectres I@ et PtlN confirment la structure des composés.The reaction between allyl 2-dihydro-2,3-H-indolecarboxylate-2 and ethylenediamine is carried out in the presence of triethylaluminium,
The following example and the table illustrate the invention. Analyzes and spectra I @ and PtlN confirm the structure of the compounds.

Exemple tdihydro-4.5 lL!-imidazolyl-2)-2 n-hutyl-l dihydro-2,3 1H-indole.Example tdihydro-4,5-lL-imidazol-2-yl) -2-n-hutyl-1-dihydro-1H-indole.

1. On introduit dans un ballon 5,16 q (n,027 mole) de dihydro-2,3 111-indolecarboxylate-2 d'éthyle et 6,0 g (0,043 mole) de K2CO3 dans 50 ml de Dt1F. 1. To a flask was charged 5.16 g (n, 027 moles) of 2,3-dihydro-111-ethyl indolecarboxylate-2 and 6.0 g (0.043 moles) of K 2 CO 3 in 50 ml of DtlF.

Puis on ajoute 22,û g (0,12 mole) de iodobutane et on chauffe le mélange à 6000 pendant 9 heures tout en agitant.22.5 g (0.12 mol) of iodobutane are then added and the mixture is heated at 6000 for 9 hours while stirring.

On le verse ensuite sur un mélange d'eau et de glace, on l'extrait à l'éther, on lave, sèche et concentre la phase organique. On obtient une huile jaune qui, purifiée par chromatographie puis par distillation, présente un point d'ébullition de 1200C sous une pression de 0,7 Pa (0,005 mmElg) 2. A une solution de 1,55 g (0,0214 mole) de triméthylaluminium dans 15 ml de toluène, à 0-5 C, on ajoute une solution de 1,33 o (0,0221 mole) d'éthylènediamine dans 5 ml de toluène . On chauffe le mélange à 500C, et on ajoute 3,4 g (0,014 mole) de n-butyl-l dihydro-2,3 1H indolecarboxylate d'éthyle en solution dans 20 ml de toluène et on porte le tout au reflux pendant 24 heures.It is then poured into a mixture of water and ice, extracted with ether, washed, dried and concentrated in the organic phase. A yellow oil is obtained which, purified by chromatography and then by distillation, has a boiling point of 1200C under a pressure of 0.7 Pa (0.005 mmElg) 2. To a solution of 1.55 g (0.0214 mol) of trimethylaluminum in 15 ml of toluene, at 0-5 ° C, a solution of 1.33 o (0.0221 mol) of ethylenediamine in 5 ml of toluene is added. The mixture is heated to 500 ° C., and 3.4 g (0.014 mol) of n-butyl-1-dihydro-2,3H indolecarboxylate in solution in 20 ml of toluene are added and the mixture is refluxed for 24 hours. hours.

Ensuite on hydrolyse le mélange avec 20 ml d'eau, on sépare le précipité par filtration et on le rince à l'acétate d'éthyle, on réunit les phases organiques, on les lave à l'eau, on les sèche et on les concentre. On obtient une huile qui cristallise dans l'éther de pétrole en formant un solide blanc. The mixture is then hydrolysed with 20 ml of water, the precipitate is filtered off and rinsed with ethyl acetate, the organic phases are combined, washed with water, dried and treated. concentrated. An oil is obtained which crystallizes in petroleum ether to form a white solid.

On reprend ce solide blanc dans de l'éthanol et on le traite avec un équivalent d'acide fumarique. On concentre le mélange, on le triture dans l'acétone, et on recristallise le solide obtenu dans un mélange acétone/alcool isopropylique.This white solid is taken up in ethanol and treated with one equivalent of fumaric acid. The mixture is concentrated, triturated in acetone, and the solid obtained is recrystallized from an acetone / isopropyl alcohol mixture.

F = 111,5 - 113du. M.p.

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

TABLEAU

Figure img00050001
BOARD
Figure img00050001

<tb> Composé <SEP> R <SEP> sel <SEP> j <SEP> F(OCr
<tb> <SEP> 1
<tb> <SEP> 1 <SEP> n <SEP> C3H7 <SEP> fumarate <SEP> l30,5-132,5
<tb> <SEP> 2 <SEP> -n-C4lt9 <SEP> fumarate <SEP> 111,5-113
<tb> <SEP> 3 <SEP> j <SEP> -CH2 <SEP> - <SEP> fumarate <SEP> 172,5-175
<tb> <SEP> 4 <SEP> i <SEP> -i-CssHg <SEP> fumarate <SEP> 163,5-164,5
<tb> <SEP> 5 <SEP> | <SEP> -CH2CH=CH2 <SEP> fumarate <SEP> 128-130
<tb> <SEP> 6 <SEP> -CH2 <SEP> < <SEP> fumarate <SEP> 176-178
<tb> <SEP> 7 <SEP> -n-C <SEP> 6H13 <SEP> fumarate <SEP> 115-117
<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> R <SEP> salt <SEP> j <SEP> F (OCr
<tb><SEP> 1
<tb><SEP> 1 <SEP> n <SEP> C3H7 <SEQ> fumarate <SEP> l30.5-132.5
<tb><SEP> 2 <SEP> -n-C4lt9 <SEP> fumarate <SEP> 111,5-113
<tb><SEP> 3 <SEP><SEP> -CH2 <SEP> - <SEP> fumarate <SEP> 172.5-175
<tb><SEP> 4 <SEP> i <SEP> -i-CssHg <SEP> fumarate <SEP> 163.5-164.5
<tb><SEP> 5 <SEP> | <SEP> -CH2CH = CH2 <SEP> fumarate <SEP> 128-130
<tb><SEP> 6 <SEP> -CH2 <SEP><<SEP> fumarate <SEP> 176-178
<tb><SEP> 7 <SEP> -nC <SEP> 6H13 <SEP> fumarate <SEP> 115-117
<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 té étudiés dans le test de potentialité et de sélectivité des antagonistes à l'égard des récepteurs a2 in vitro.For this purpose, the compounds have been studied in the test for the potentiality and selectivity of α 2 -receptor antagonists in vitro.

La détermination de la valeur PA2 à l'égard des effets inhibiteurs de la clonidine, a2-ågoniste bien connu, a eu lieu sur le vas deferens du rat stimulé à une fréquence de 0,1 Hz en présence de 30 nM de prazosine et de 1 uM de cocainej selon la méthode décrit par S.M. Drew (European
Journal of Pharmacology, 42, (1977) 123-130).The determination of the PA2 value for clonidine inhibitory effects, a well-known a2-agonist, occurred on rat vas deferens stimulated at a frequency of 0.1 Hz in the presence of 30 nM prazosin and 1 μM cocainej according to the method described by SM Drew (European
Journal of Pharmacology, 42, (1977) 123-130).

Les pA2 des composés de l'invention sont compris ente 7 5 et 10.The pA2 of the compounds of the invention are included between 5 and 10.

Les composés de l'invention sont des 2-antagonistes puissants qui peuvent être utilisés pour le traitement de la dépression (soit seul, 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 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)

PevendicationsPevendications 1. Dérivés ce L'indole, sous la forme de racémates ou d'isomères optiquement actifs, répondant à la formule (I)1. Derivatives of indole, in the form of racemates or optically active isomers, corresponding to formula (I)
Figure img00070001
Figure img00070001
 dans laquelle n est un radical (C2-C6) alkyle droit ou ramifié, un radical (C3- 6 cyctoalkyî-(C1-C4) allyle ou un radical (C3-C6) alcényle.  wherein n is a straight or branched (C2-C6) alkyl radical, a (C3-C6-cycloalkyl) (C1-C4) allyl radical or a (C3-C6) alkenyl radical. ainsi que leurs sels pharmaceutiquement acceptables.as well as their pharmaceutically acceptable salts. 2. Procédé de préparation des composés selon la revendication 1, procédé caractérisé en ce que l'on fait réagir un ester de formule2. Process for the preparation of the compounds according to claim 1, characterized in that an ester of formula is reacted
Figure img00070002
Figure img00070002
 (où R' = (G1-C4)alkyîe), avec un composé de formule RX (où X = Br, C1 ou tout groupe labile et R a la signification donnée à la revendication 1), puis on fait réagir le composé obtenu (where R '= (G1-C4) alkyl), with a compound of formula RX (where X = Br, C1 or any leaving group and R has the meaning given in claim 1), then reacting the compound obtained
Figure img00070003
Figure img00070003
 avec de l'èthylènediamine en présence de triméthylaluminium. with ethylenediamine in the presence of trimethylaluminum. 3. Médicament caractérisé en ce qu'il est constitué d'un composé tel que spécifié dans la revendication 1.3. Medicinal product characterized in that it consists of a compound as specified in claim 1. 4. Composition pharmaceutique caractérisée en ce qu'elle contient un composé tel que spécifié dans la revendication 1 en association avec tout excipient approprié. 4. A pharmaceutical composition characterized in that it contains a compound as specified in claim 1 in combination with any suitable excipient.
FR8318121A 1983-08-11 1983-11-15 Indole derivatives, their preparation and their application in therapeutics Pending FR2554815A2 (en)

Priority Applications (17)

Application Number Priority Date Filing Date Title
FR8318121A FR2554815A2 (en) 1983-11-15 1983-11-15 Indole derivatives, their preparation and their application in therapeutics
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
AT84401595T ATE29494T1 (en) 1983-08-11 1984-07-30 INDOL DERIVATIVES, PROCESSES FOR THEIR PRODUCTION AND THEIR THERAPEUTIC USE.
KR1019840004683A KR850001749A (en) 1983-08-11 1984-08-07 Manufacturing method of indole derivative
NO843203A NO843203L (en) 1983-08-11 1984-08-10 PROCEDURE FOR THE PREPARATION OF INDOLIDATE DERIVATIVES
ES535062A ES8602771A1 (en) 1983-08-11 1984-08-10 Indole derivatives, their preparation and their therapeutical application.
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
FI843155A FI843155A (en) 1983-08-11 1984-08-10 FRAMSTAELLNING AV INDOLINDERIVAT OCH DERAS THERAPEUTIC TILLAEMPNING.
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
FR8318121A FR2554815A2 (en) 1983-11-15 1983-11-15 Indole derivatives, their preparation and their application in therapeutics

Publications (1)

Publication Number Publication Date
FR2554815A2 true FR2554815A2 (en) 1985-05-17

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FR8318121A Pending FR2554815A2 (en) 1983-08-11 1983-11-15 Indole derivatives, their preparation and their application in therapeutics

Country Status (1)

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FR (1) FR2554815A2 (en)

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