FR2576308A1 - Tetrahydroquinoline derivatives, their preparation and their therapeutic application - Google Patents

Tetrahydroquinoline derivatives, their preparation and their therapeutic application Download PDF

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FR2576308A1
FR2576308A1 FR8500679A FR8500679A FR2576308A1 FR 2576308 A1 FR2576308 A1 FR 2576308A1 FR 8500679 A FR8500679 A FR 8500679A FR 8500679 A FR8500679 A FR 8500679A FR 2576308 A1 FR2576308 A1 FR 2576308A1
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radical
ester
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Dennis Bigg
Michel Mangane
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Synthelabo SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

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Abstract

Tetrahydroquinoline derivatives in the form of racemates or enantiomers corresponding to the formula I in which: R' represents a linear or branched (C1-4)alkyl radical, a benzyl radical or an allyl radical; R'' represents a hydrogen atom or a linear or branched (C1-4)alkyl radical, as well as their addition salts with pharmaceutically acceptable acids. Therapeutic application.

Description

La présente invention a pour objet des dérivés de tétrahydroquinoléine, leur préparation et leu-r application en thérapeutique. The present invention relates to tetrahydroquinoline derivatives, their preparation and their therapeutic application.

Les composés de l'invention répondent à la formule (I) donnée en annexe, dans laquelle
R' représente un radical (Cl 4)alkyle droit ou ramifié, le radical benzyle ou le radical allyle,
R" représente un atome d'hydrogène ou un radical (C1,4) alkyle droit ou ramifié.The compounds of the invention correspond to the formula (I) given in the annex, in which
R 'represents a straight or branched (Cl 4) alkyl radical, the benzyl radical or the allyl radical,
R "represents a hydrogen atom or a straight or branched (C1, 4) alkyl radical.

Les composés de l'invention peuvent exister sous la forme de racémates ou d'énantiomères qui font partie de l'invention.The compounds of the invention may exist in the form of racemates or enantiomers which form part of the invention.

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 (I) peuvent être préparés selon le schéma réactionnel donné en-annexe.The compounds of the invention (I) can be prepared according to the reaction scheme given in the appendix.

Dans ce schéma R est un radical (C14)alkyle, en particulier méthyle ou éthyle, X et Y sont des groupes labiles, en particulier des atomes d'iode ou de brome.In this scheme R is a (C14) alkyl radical, in particular methyl or ethyl, X and Y are labile groups, in particular iodine or bromine atoms.

Les esters de départ (II), en particulier les esters méthylique et éthylique, sont décrits par R.F. Collines, JACS, 77, 4921 (1955).The starting esters (II), in particular the methyl and ethyl esters, are described by R. F. Collines, JACS, 77, 4921 (1955).

La réaction entre l'ester de départ (II) et le composé R'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'ioduré de sodium.The reaction between the starting ester (II) and the compound R'X is carried out in a solvent such as acetone, methyl ethyl ketone or dimethylformamide, at room temperature or at a higher temperature, in the presence of a base , such as potassium carbonate. The reaction may be catalyzed, for example, by the addition of sodium iodide.

L'alkylation éventuelle de l'ester (III) ainsi obtenu est effectuée par action d'un composé R"Y (Y étant un radical labile) sur le dérivé lithié préparé in situ au moyen de diisopropylamidure de lithium (butyllithium + diisopropylamine).The optional alkylation of the ester (III) thus obtained is carried out by the action of a compound R "Y (Y being a labile radical) on the lithiated derivative prepared in situ using lithium diisopropylamide (butyllithium + diisopropylamine).

La formation de l'imidazoline å partir de l'ester (III) ou de l'ester (IV) est effectuée par l'éthylènediamine en présence de triméthylaluminium.The formation of the imidazoline from the ester (III) or the ester (IV) is carried out by ethylenediamine in the presence of trimethylaluminium.

Les exemples suivants et le tableau illustrent l'invention.The following examples and the table illustrate the invention.

Les analyses et les spectres IR et RMN confirment la structure des composés obtenus selon l'invention.Analyzes and IR and NMR spectra confirm the structure of the compounds obtained according to the invention.

Exemple 1. (dihydro-4,5 1H-imidazolyl-2)-2 méthyl-l tétrahydro-1,2,3,4 quinoléine.Example 1. (4,5-Dihydro-1H-imidazol-2-yl) -2-methyl-1,2,3,4-tetrahydroquinoline.

1.1. méthyl-l tétrahydro-1,2,3,4 quinolyl-2 carboxylate d'éthyle.1.1. ethyl 1-ethyl-1,2,3,4-tetrahydro-2-quinolyl carboxylate.

Dans un ballon de 100 ml on introduit 6,15 g (0,03 mole) de tétrahydro-1,2,3,4 quinolyl-2 carboxylate d'éthyle, 6,47 g (0,045 mole) de carbonate de potassium, 2,24 ml (0,036 mole) d'iodure de méthyle et 50 ml de diméthylformamide.Into a 100 ml flask, 6.15 g (0.03 mol) of ethyl 1,2,3,4-tetrahydro-2-quinolyl carboxylate, 6.47 g (0.045 mol) of potassium carbonate, are introduced. 24 ml (0.036 mol) of methyl iodide and 50 ml of dimethylformamide.

On agite ce mélange à la température ambiante pendant 10 h.This mixture is stirred at ambient temperature for 10 hours.

On filtre les sels formés, les lave avec 100 ml d'acétate d'éthyle et évapore les solvants. On lave le résidu à l'eau; extrait le mélange tt l'éther, sèche, évapore l'éther et distille une huile. On obtient une huile. Eb0,03=175 C.The salts formed are filtered, washed with 100 ml of ethyl acetate and the solvents evaporated. The residue is washed with water; Extract the mixture and ether, dry, evaporate the ether and distil an oil. An oil is obtained. Eb0.03 = 175 ° C.

1.2. (dihydro-4,5 lH-imidazolyl-2)-2 méthyl-l tétrahydro-1,2,3,4 quinoléine.1.2. (4,5-dihydro-1H-imidazol-2-yl) -2-methyl-1,2,3,4-tetrahydroquinoline.

Dans un ballon tricol, on introduit, sous argon, 20 mi de toluène, 8 ml (0,027 mole) d'une solution de triméthylaluminium 9 25,2 % dans de l'hexane. On refroidit le mélange è l'aide de glace et on ajoute goutte ti goutte 1,82 ml (0,027 mole) d'éthylènediainine. In a three-necked flask, 20 ml of toluene, 8 ml (0.027 mol) of a 25.2% solution of trimethylaluminum in hexane are introduced under argon. The mixture was cooled with ice and 1.82 ml (0.027 mole) of ethylenediainine was added dropwise.

fln chauffe le mélange réactionnel à 60 C et on introduit 4 g (0,182 mole) de l'ester obtenu précédemment sous 1.1. The reaction mixture is heated to 60 ° C. and 4 g (0.182 mol) of the ester obtained above under 1.1 are introduced.

On porte le mélange à la température du reflux, distille 15ml du solvant et maintient l'ébullition pendant 3 h. Après refroidissement, on amène la température du mélange à -10 C, ajoute 12 ml d'eau et agite pendant 20 mn.The mixture is brought to reflux temperature, distilled 15 ml of the solvent and boils for 3 h. After cooling, the temperature of the mixture is brought to -10 ° C., 12 ml of water are added and the mixture is stirred for 20 minutes.

On verse la suspension dans 100 ml d'acétate d'éthyle, lave à l'eau, sèche et évapore.The suspension is poured into 100 ml of ethyl acetate, washed with water, dried and evaporated.

On obtient une huile que l'on transforme en fumarate qui se présente sous la forme de cristaux jaune pâle que l'on fait recristalliser dans de l'éthanol.An oil is obtained which is converted into fumarate which is in the form of pale yellow crystals which are recrystallized from ethanol.

F = 158-9 C. F = 158-9C.

Exemple 2 (dihydro-4,5 lH-imidazolyl-23-2 éthyl-2 méthyl-l tétrahydro-1,2,3,4 quinoléine.Example 2 (4,5-dihydro-1H-imidazolyl-23-2 ethyl-2-methyl-1-tetrahydro-1,2,3,4 quinoline.

2.1. méthyl-l tétrahydro-l,2,3,4 quinolyl-2 carboxylate de méthyle.2.1. Methyl-1 methyl tetrahydro-1,2,3,4-quinolyl-2-carboxylate.

Dans un ballon de 100 m1 on introduit 5,73 g (0,03 mole) de tétrahydro-1,2,3,4 quinolyl 2 carboxylate de méthyle, 6,47 g (0,045 mole) de carbonate de potassium, 2,24 mi (0,036 mole) d'iodure de méthyle et 50 mi de diméthylformaide.In a 100 ml flask, 5.73 g (0.03 mol) of methyl 1,2,3,4-tetrahydro-quinolyl 2-carboxylate, 6.47 g (0.045 mol) of potassium carbonate, 2.24 g are added. mi (0.036 moles) of methyl iodide and 50 ml of dimethylformamide.

On agite ce mélange à la température ambiante pendant 10 h.This mixture is stirred at ambient temperature for 10 hours.

On filtre les sels formés, les lave avec 100 ml d'acétate d'éthyle et évapore les solvants. On lave le résidu à l'eau; on extrait le mélange à l'éther, sèche, évapore l'éther et distille une huile. On obtient une huile jaune
Eb0,018=165 C.The salts formed are filtered, washed with 100 ml of ethyl acetate and the solvents evaporated. The residue is washed with water; the mixture is extracted with ether, dried, the ether evaporated and an oil distilled. We get a yellow oil
Eb0.018 = 165 ° C.

2.2. méthyl-1 éthyl-2 tétrahydro-1,2,3,4 quinolyl-2 carboxylate de méthyle.2.2. methyl-1-ethyl-2-methyl-1,2,3,4-tetrahydro-2-quinolyl carboxylate.

Dans un ballon tricol de 100 ml on introduit, sous argon, 2,5 ml (0,018 mole) de diisopropylamine et 15 mi de tétrahydrofuronne.In a 100 ml three-neck flask, 2.5 ml (0.018 mol) of diisopropylamine and 15 ml of tetrahydrofuron are introduced under argon.

On refroidit la soltuion à -78 C et y ajoute 12 ml (0,018 mole) d'une solution de butyllithium 1,6 M dans de l'hexane. On agite le mélange une heure. On introduit alors 3 g (0,015 mole) de l'ester obtenu sous 2.1. en solution dans 10 ml de THF.The solution is cooled to -78 ° C. and 12 ml (0.018 mole) of a solution of 1.6 M butyllithium in hexane are added thereto. The mixture is stirred one hour. 3 g (0.015 mol) of the ester obtained under 2.1 are then introduced. in solution in 10 ml of THF.

On agite la solution. 1 heure à -78 C et ajoute 11,7 g (0,076 mole) d'ioduré d'éthyle en solution dans 10 ml de
THF. On agite le mélange une heure à -78 C, le laisse revenir à la température ambiante, l'agite pendant une nuit et le décompose par de l'eau.The solution is stirred. 1 hour at -78 ° C. and 11.7 g (0.076 mole) of ethyl iodide in solution in 10 ml of
THF. The mixture is stirred for one hour at -78 ° C., allowed to come to room temperature, stirred overnight and decomposed with water.

On extrait à l'éther, sèche et évapore le solvant. Après distillation on obtient une huile jeune.Extracted with ether, dried and evaporated the solvent. After distillation, a young oil is obtained.

Eb0,06=175 C. Eb0.06 = 175C.

2.3. (dihydro-4,5 1H-imidazolyl-2)-2 éthyl-2 méthyl-l tStrahydro-1,2,3,4 quinoléine.2.3. (4,5-dihydro-1H-imidazol-2-yl) -2-ethyl-2-methyl-1-tetrahydro-1,2,3,4-quinoline.

Dans un ballon tricol de 100 ml, on introduit ; sous argon 20 ml de toluène, 6,5 ml (0,018 mole) d'une solution de triméthylaluminium à 25,2 % dans de l'hexane. On refroidit le mélange à 0 C et on ajoute goutte à goutte 1,2 ml (0,018 mole) d'éthylènediamine en solution dans 10 ml de toluène.In a three-necked flask of 100 ml, one introduces; under argon 20 ml of toluene, 6.5 ml (0.018 mole) of a 25.2% solution of trimethylaluminum in hexane. The mixture is cooled to 0 ° C. and 1.2 ml (0.018 mol) of ethylenediamine dissolved in 10 ml of toluene are added dropwise.

On chauffe le mélange réactionnel à 60Q0 et introduit alors 2,24 g (0,096 mole) de l'ester obtenu sous 2.2. en solution dans 10 ml de toluène.The reaction mixture is heated to 60 ° C. and 2.24 g (0.096 mol) of the ester obtained under 2.2 are then introduced. in solution in 10 ml of toluene.

Le mélange est porté au reflux pendant 8 heures. Après refroidissement, on amène la température à -10 C, ajoute 6 ml d'eau et 50 ml d'acétate d'éthyle, agite 20 mn, sèche au sulfate de sodium, filtre les sel-s et évapore les solvants.The mixture is refluxed for 8 hours. After cooling, the temperature is brought to -10 ° C., 6 ml of water and 50 ml of ethyl acetate are added, the mixture is stirred for 20 minutes, dried over sodium sulfate, the salts are filtered off and the solvents are evaporated off.

Le résidu est extrait au CH2Cl2. On lave à l'eau la phase organique, sèche et évapore le solvant. On obtient une huile que l'on transforme en fumarate : on obtient des cristaux blancs que l'on fait recristalliser ians un mélange éthanol/méthyléthylcétone 50/50. F=170-171 C. The residue is extracted with CH2Cl2. The organic phase is washed with water and dried and the solvent is evaporated off. An oil is obtained which is converted into fumarate: white crystals are obtained which are recrystallized from a 50/50 ethanol / methyl ethyl ketone mixture. F = 170-171C.

Tableau

Figure img00050001
Board
Figure img00050001

Figure img00050002
Figure img00050002

<tb> Composé <SEP> R' <SEP> R" <SEP> Sel <SEP> F( C)
<tb> <SEP> 1 <SEP> Me <SEP> H <SEP> fumarate <SEP> 158-9
<tb> <SEP> 2 <SEP> Et <SEP> H <SEP> fumarate <SEP> 141-2
<tb> <SEP> 3 <SEP> Pr <SEP> H <SEP> fumarate <SEP> 139-40
<tb> <SEP> 4 <SEP> Allyl <SEP> H <SEP> fumarate <SEP> 161-2
<tb> <SEP> 5 <SEP> CH2-C6H5 <SEP> H <SEP> fumarate <SEP> 182-3
<tb> <SEP> 6 <SEP> Me <SEP> Me <SEP> fumarate <SEP> 183-4
<tb> <SEP> 7 <SEP> Me <SEP> Et <SEP> fumarate <SEP> 170-1
<tb> <SEP> 8 <SEP> Me <SEP> Pr <SEP> fumarate <SEP> 164-5
<tb>
Les composés de l'invention ont été soumis à des essais
pharmacologiques qui ont montré leur intérêt en tant que JX 2-antagonistes.<tb> Compound <SEP> R '<SEP> R "<SEP> Salt <SEP> F (C)
<tb><SEP> 1 <SEP> Me <SEP> H <SEP> fumarate <SEP> 158-9
<tb><SEP> 2 <SEP> And <SEP> H <SEP> fumarate <SEP> 141-2
<tb><SEP> 3 <SEP> Pr <SEP> H <SEP> fumarate <SEP> 139-40
<tb><SEP> 4 <SEP> Allyl <SEP> H <SEP> fumarate <SEP> 161-2
<tb><SEP> 5 <SEP> CH2-C6H5 <SEP> H <SEP> fumarate <SEP> 182-3
<tb><SEP> 6 <SEP> Me <SEP> Me <SEP> fumarate <SEP> 183-4
<tb><SEP> 7 <SEP> Me <SEP> And <SEP> fumarate <SEP> 170-1
<tb><SEP> 8 <SEP> Me <SEP> Pr <SEP> fumarate <SEP> 164-5
<Tb>
The compounds of the invention have been subjected to tests
pharmacological studies that showed their interest as JX 2-antagonists.

A cet effet les composés ont été étudiés dans le test de
potentialité et de sélectivité des antagonistes à l'égard
des récepteurs &alpha;2 in vitro.For this purpose the compounds were studied in the test of
potentiality and selectivity of antagonists with regard to
receptors &alpha; 2 in vitro.

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 nM de prazosine et de 1 pM de
cocagne, selon la méthode décrite par G.M. Drew (European
Journal of Pharmacology, 42, (1977) 123-130).The determination of the pA2 value for effects
clonidine inhibitors, a well-known 2-agonist, has been
place on the rat vas deferens stimulated at a frequency of
0.1 Hz in the presence of 30 nM prazosin and 1 μM
cocagne, according to the method described by GM Drew (European
Journal of Pharmacology, 42, (1977) 123-130).

Les pA2 des composés de l'invention sont compris entre 6 et
9.The pA2 of the compounds of the invention are between 6 and
9.

Les composés de l'invention sont des 42-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, de
l'obésité et du diabète.The compounds of the invention are 42-antagonists
powerful ones that can be used for the treatment of
depression (either alone or in combination with a product
which inhibits the mechanisms of neuronal capture), the
treatment of hypotension, treatment of ileum
post-operative paralytic, the treatment of asthma,
obesity and diabetes.

Les compositions pharmaceutiques peuvent être sous forme
appropriée pour l'administrastion 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 can be in the form
appropriate for oral, rectal or
parenteral; for example in the form of capsules,
tablets, granules, capsules or liquid solutions, syrups or
oral suspensions, and contain 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.

Annexe 1

Figure img00070001

Schema
Annexe 2
Figure img00080001
Annex 1
Figure img00070001

Diagram
Annex 2
Figure img00080001

Claims (5)

R' représente un radical (C1 4)alkyle droit ou ramifié, le radical benzyle ou le radical allyle, R" représente un atome d'hydrogène ou un radical (C1 4) alkyle droit ou ramifié, ainsi que leurs sels d'addition aux acides pharmaceutiquement acceptables.R 'represents a radical (C1 4) straight or branched alkyl, the benzyl radical or the allyl radical, R "represents a hydrogen atom or a radical (C1 4) straight or branched alkyl, as well as their addition salts with pharmaceutically acceptable acids. dans laquelle in which
Figure img00090001
Figure img00090001
 Revendications 1. Dérivés de tétrahydroquinoléine sous la forme de racémates ou -d'énantiomères répondant à la formule (I) 1. Derivatives of tetrahydroquinoline in the form of racemates or of enantiomers corresponding to formula (I) 2. Dérivés selon la revendication, caractérisés par le fait que R' est un radical méthyle, éthyle, propyle, allyle ou benzyle et R" est H ou un radical méthyle, éthyle ou propyle.2. Derivatives according to the claim, characterized in that R 'is a methyl, ethyl, propyl, allyl or benzyl radical and R "is H or a methyl, ethyl or propyl radical. 3. Procédé de préparation des composés selon la revendication 1, procédé caractérisé en ce que l'on fait réagir un ester de formule (II)3. Process for the preparation of the compounds according to claim 1, characterized in that an ester of formula (II) is reacted
Figure img00090002
Figure img00090002
 avec un composé R'X (X étant un radical labile), on alkyle éventuellement l'ester (III)  with a compound R'X (X being a labile radical), the ester (III) is optionally alkylated
Figure img00100001
Figure img00100001
 avec un composé R"Y (Y étant un radical labile), puis on fait réagir l'ester (III) ou l'ester alkylé (IV) with a compound R "Y (Y being a labile radical), then reacting the ester (III) or the alkylated ester (IV)
Figure img00100002
Figure img00100002
 avec de l'éthylènediamine en présence de triméthylaluminium. with ethylenediamine in the presence of trimethylaluminum. 4. Médicament caractérisé en ce qu'il est constitué par un composé tel que spécifié dans la revendication 1 ou la revendication 2.4. Medicinal product characterized in that it consists of a compound as specified in claim 1 or claim 2. 5. Composition pharmaceutique caractérisée en ce qu'elle contient un composé tel que spécifié dans la revendication 1 ou la revendicatin 2 en association avec tout excipient approprié. 5. A pharmaceutical composition characterized in that it contains a compound as specified in claim 1 or claim 2 in combination with any suitable excipient.
FR8500679A 1985-01-18 1985-01-18 TETRAHYDROQUINOLEIN DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION Expired FR2576308B1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4125530A (en) * 1969-12-15 1978-11-14 Merck & Co., Inc. Trifluoromethylimidazoles and a method for their preparation
EP0041623A2 (en) * 1980-06-02 1981-12-16 American Cyanamid Company Substituted imidazolinyl nicotine acids, esters and salts and use thereof as herbicidal agents

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4125530A (en) * 1969-12-15 1978-11-14 Merck & Co., Inc. Trifluoromethylimidazoles and a method for their preparation
EP0041623A2 (en) * 1980-06-02 1981-12-16 American Cyanamid Company Substituted imidazolinyl nicotine acids, esters and salts and use thereof as herbicidal agents

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