FR2488892A2 - NOVEL 1- (3- (3,4,5-TRIMETHOXYPHENOXY) -2-HYDROXYPROPYL) -4-ARYL-PIPERAZINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THEIR USE AS A MEDICINAL PRODUCT - Google Patents
NOVEL 1- (3- (3,4,5-TRIMETHOXYPHENOXY) -2-HYDROXYPROPYL) -4-ARYL-PIPERAZINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THEIR USE AS A MEDICINAL PRODUCT Download PDFInfo
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/24—Ethers with hydroxy compounds containing no oxirane rings with polyhydroxy compounds
Abstract
CE SONT LES COMPOSES DE LA FORMULE ET LEURS SELS, QUE L'ON OBTIENT PAR LE PROCEDE INDIQUE DANS LE BREVET PRINCIPAL. CES SUBSTANCES ONT UNE ACTION ANXIOLYTIQUE-ANTIAGRESSIVE ET UN EFFET NEUROLEPTIQUE-TRANQUILLISANT. INDICATIONS: EXCITATIONS, TROUBLES PSYCHONEUROTIQUES. (CF DESSIN DANS BOPI) RH ET RACYLE, NOTAMMENT ALCANOYLE EN C-C; OU RALCANOYLE EN C-C OU THIENYLCARBONYLE ET RALKYLE EN C-C; OU R ET RTHIENYLCARBONYLE.THESE ARE THE COMPOUNDS OF THE FORMULA AND THEIR SALTS, OBTAINED BY THE PROCESS INDICATED IN THE MAIN PATENT. THESE SUBSTANCES HAVE ANXIOLYTIC-ANTI-AGGRESSIVE ACTION AND A NEUROLEPTIC-TRANQUILLIZING EFFECT. INDICATIONS: EXCITATIONS, PSYCHONEUROTIC DISORDERS. (CF DRAWING IN BOPI) RH AND RACYL, IN PARTICULAR C-C ALKANOYL; OR C-C RALCANOYL OR THIENYLCARBONYL AND C-C RALKYL; OR R AND RTHIENYLCARBONYL.
Description
Le brevet principal a pour objet des composés de formule générale
dans laquelle R1 est mis pour un atome d'hydrogène, un radical alcanoyle à 2w6 C, un radical alcénoyle à 3-6 C, un radical cyclo-alcoylcarbonyle à 3-6 C, un radical benzoyle, un radical alcoxybenzoyle à 1-4 C dans le groupe alcoxy, un radical nicotinoyle, un radical thiénylcarbonyle, un radical furylcarbonyle, un radical phénylacétyle ou un radical alcoxy-phénylacétyle à 1-4 C dans le groupe alcoxy, et R2 représente un radical phényle, naphtyle ou pyridyle éventuellement substitué par des radicaux
R3 et R4, les radicaux R3 et R4 pouvant etre semblables ou dif f érents et représentant un hydrogène, un hydroxyle, un fluor, un chlore, un brome, le groupe nitro, le groupe trifluorométhyle, des radicaux aloyles à 1-6 C, des radicaux alcoxy à 1-6 C, des radicaux alcoylthio à 1-6 C, des radicaux alcoylsulfonyles à 1-6 C, des radicaux alcanoyles à 2-6 C, le groupe amino, des groupes acylamino ou des groupes acyloxy, l'acyle contenu dans les deux groupes mentionnés en dernier lieu pouvant être un radical acyle défini pour R1. I1 a également pour objet les sels de ces composés.The main patent relates to compounds of general formula
wherein R 1 is hydrogen, alkanoyl at 2 to 6 C, alkenoyl at 3-6 C, cycloalkylcarbonyl at 3-6 C, benzoyl, 1-4 alkoxybenzoyl C in the alkoxy group, a nicotinoyl radical, a thienylcarbonyl radical, a furylcarbonyl radical, a phenylacetyl radical or a 1-4C alkoxyphenylacetyl radical in the alkoxy group, and R2 represents a phenyl, naphthyl or pyridyl radical optionally substituted by radicals
R3 and R4, the radicals R3 and R4 being similar or different and representing a hydrogen, a hydroxyl, a fluorine, a chlorine, a bromine, the nitro group, the trifluoromethyl group, radicals aloyles at 1-6 C, 1-6C alkoxy radicals, 1-6C alkylthio radicals, 1-6C alkylsulfonyl radicals, 2-6C alkanoyl radicals, the amino group, acylamino groups or acyloxy groups; acyl contained in the two last mentioned groups which may be an acyl radical defined for R1. It also relates to the salts of these compounds.
Le brevet principal concerne en outre un procédé de préparation de ces composés et de leurs sels, caractérisés en ce qu'on fait réagir un composé de formule
avec un composé de formule
with a compound of formula
Y et Z étant différents dans chaque cas et représentant un hydrogène ou le groupe -CH2-CH(OR1)-CH2-V, V étant un atome de chlore, de brome ou d'iode ou, dans le cas où R1 est un hydrogène, pouvant former avec ce groupe hydroxy le noyau oxyde d'éthylène, et en ce qu'on réduit éventuellement un ou deux groupes nitro en groupes amino et/ou on acyle les composés obtenus avec un acide ou un dérivé d'acide correspondant au radical R1. On obtient les sels par addition d'acides.Y and Z being different in each case and representing a hydrogen or the group -CH 2 -CH (OR 1) -CH 2 -V, V being a chlorine, bromine or iodine atom or, in the case where R 1 is a hydrogen , which can form with this hydroxyl group the ethylene oxide nucleus, and in that one or two nitro groups are optionally reduced to amino groups and / or the compounds obtained are acylated with an acid or an acid derivative corresponding to the radical; R1. The salts are obtained by addition of acids.
Ces composés ont une activité pharmacodynamique et possèdent par exemple une action anti-agressive marquée, ainsi que des propriétés neuroleptiques, leurs effets anti-convulsifs et hypnotiques n'existant que dans une faible mesure ou étant complètement absents. En outre, ils possèdent des effets anti-pyrétiques et anti-oedémateux. Ces composés sont donc dotés de propriétés pharmacodynamiques favorables et ils sont susceptibles d'être utilisés comme médicaments en médecine humaine, en médecine vétérinaire, ainsi que dans l'agriculture, isolément ou en mélange avec d'autres substances à activité pharmacologique. These compounds have a pharmacodynamic activity and have for example a marked anti-aggressive action, as well as neuroleptic properties, their anti-convulsive and hypnotic effects existing only to a small extent or being completely absent. In addition, they possess anti-pyretic and anti-oedematous effects. These compounds are therefore endowed with favorable pharmacodynamic properties and they are likely to be used as medicaments in human medicine, in veterinary medicine, as well as in agriculture, alone or as a mixture with other substances with pharmacological activity.
La présente invention se rapporte à des composés particu- liers, qui sont couverts par la formule (I) du brevet principal et qui répondent à la formule spécifique (V) ci-apres
dans laquelle R' représente un atome d'hydrogène et R' un reste acyle, notamment un reste alcanoyle en C2-C6, ou bien R' représente un reste alcanoyle en C2-C6 ou un reste thiénylcarbonyle et R" est un reste alkyle en C1-C6, ou bien R et R" sont chacun un reste thiénylcarbonyle. La présente invention concerne également les sels de ces composés de formule (V) obtenus par addition d'acides pharmacologiquement utilisables.The present invention relates to particular compounds, which are covered by the formula (I) of the main patent and which correspond to the specific formula (V) below.
in which R 'represents a hydrogen atom and R' an acyl residue, especially a C2-C6 alkanoyl radical, or R 'represents a C2-C6 alkanoyl radical or a thienylcarbonyl radical and R "is an alkyl radical of C1-C6, or R and R "are each a thienylcarbonyl residue. The present invention also relates to the salts of these compounds of formula (V) obtained by addition of pharmacologically usable acids.
Les composés de la formule (V) correspondent aux composés de la formule (I) du brevet principal, dans laquelle le radical
R2 est un radical phényle substitué.The compounds of formula (V) correspond to the compounds of formula (I) of the main patent, in which the radical
R2 is a substituted phenyl radical.
La préparation des composés de la formule (V) a lieu par le procédé indiqué dans le brevet principal, c'est-à-dire par réaction d'un composé de la formule (II) avec les composés correspondants de la formule (III) (Exemples ci-après 27, 28 et 29), ou par acylation des composés de base correspondants (omportant un groupe hydroxyle libre (Exemples 30, 31, 32 et 33 > . The preparation of the compounds of the formula (V) takes place by the process indicated in the main patent, that is by reaction of a compound of the formula (II) with the corresponding compounds of the formula (III) (Examples hereinafter 27, 28 and 29), or by acylation of the corresponding base compounds (with a free hydroxyl group (Examples 30, 31, 32 and 33).
EXEMPLE 27 (#)-1-[3-(3,4,5-triméthoxy-phénoxy)-2-hydroxy-propyl]-4 (2-acétoxy-phenyl)-pipérazine
On fait bouillir à reflux dans 150 ml d'isopropanol O,Q3 mole de 1-(2-acétoxy-phényl)-pipérazine (produit brut) et 7,2 g (0,03 mole) d'éther 3,4,5-triméthoxy-phénoxy-glycidylique, jusqu'à ce que la réaction soit complète selon le contrôle effectué par chromatographie en couche mince. Après séparation du solvant par distillation, on obtient le chlorhydrate par traitement avec de l'acide chlorhydrique isopropanolique et on purifie ce chlorhydrate par recristallisation dans l'isopropanol. The reaction mixture is refluxed in 150 ml of isopropanol. O, Q3 mole of 1- (2-acetoxy-phenyl) -piperazine (crude product) and 7.2 g (0.03 mole) of 3,4,5-ether. -trimethoxy-phenoxy-glycidyl, until the reaction is complete according to the control carried out by thin layer chromatography. After separation of the solvent by distillation, the hydrochloride is obtained by treatment with isopropanol hydrochloric acid and this hydrochloride is purified by recrystallization from isopropanol.
Point de fusion : 189 - 1910C. Rendement 18 %.Melting point: 189 - 1910C. Yield 18%.
La 1- 2-acétyloxy-phényl]-pipérazine mise en oeuvre comme substance de départ est obtenue comme suit
On fait chauffer à reflux dans 800 ml de xylène 192,8 g (1 mole) de 2-methoxrphenylpiperazine, 130 ml (1,1 mole) de chlorure de benzyle et 150 g (1,10 mole) de carbonate de potassium, jusqu'à ce que la réaction soit complète selon le contrôle effectué par chromatographie en couche mince.The 1-2-acetyloxy-phenyl] -piperazine used as starting substance is obtained as follows
192.8 g (1 mole) of 2-methoxrphenylpiperazine, 130 ml (1.1 moles) of benzyl chloride and 150 g (1.10 moles) of potassium carbonate are refluxed in 800 ml of xylene. the reaction is complete according to the control carried out by thin layer chromatography.
On filtre, on chasse le solvant sous vide et on transforme en chlorhydrate de la façon habituelle avec de l'acide chlorhydrique isopropanolique (rendement : 70 %}. Filtered, the solvent removed in vacuo and converted to the hydrochloride in the usual manner with isopropanol hydrochloric acid (yield: 70%).
On chauffe à reflux 60 g (0,2 mole) du chlorhydrate ainsi obtenu dans 800 ml d'acide bromhydrique aqueux à 63 %, jusqu'à ce que la séparation de l'éther soit complète (contrôle par chromatographie en couche mince). On chasse ensuite le solvant sous vide et on lave à l'éther le résidu cristallin obtenu (rendement : 70 t). A partir du dibromhydrate, on libère la base libre de la façon habituelle au moyen d'ammoniaque diluée, On refroidit à 5 C 10 g (0,029 mole) de la base libre ainsi obtenue et 15 mi de triéthylamine dans 50 ml de dioxanne et on y ajoute goutte à goutte, tout en mélangeant, 0,032 mole de chlorure d'acetyle à une température au plus de IOOC. Après avoir agité pendant une heure à 100C, on sépare par filtration sous vide le chlorhydrate de triéthylamine qui a précipité et on chasse le solvant par distillation sous vide. 60 g (0.2 mol) of the hydrochloride thus obtained are heated under reflux in 800 ml of aqueous hydrobromic acid at 63% until the separation of the ether is complete (control by thin layer chromatography). The solvent is then removed in vacuo and the crystalline residue obtained is washed with ether (yield: 70%). From the dihydrobromide, the free base is liberated in the usual manner by means of dilute ammonia. 10 g (0.029 mol) of the free base thus obtained and 15 ml of triethylamine in 50 ml of dioxane are cooled to 5 ° C. and 0.032 moles of acetyl chloride are added dropwise at a temperature of not more than 10 ° C. while mixing. After stirring for one hour at 100 ° C, the precipitated triethylamine hydrochloride was filtered off in vacuo and the solvent was distilled off in vacuo.
Dans la base libre huileuse obtenue, sans autre purification, on hydrogène le groupe benzyle comme suit : on dissout 0,04 mole de la base libre dans 150 ml de méthanol et on hydrogène, en présence de 2 g de palladium à 10 % sur charbon, à 500C et sous 5 bars. Lorsque l'absorption d'hydrogène est terminée, on sépare le catalyseur par filtration et on chasse le solvant sous vide.In the oily free base obtained, without further purification, the benzyl group is hydrogenated as follows: 0.04 mol of the free base is dissolved in 150 ml of methanol and hydrogenated in the presence of 2 g of 10% palladium on carbon. , at 500C and under 5 bar. When the hydrogen uptake is complete, the catalyst is filtered off and the solvent is removed in vacuo.
On peut faire réagir directement, sans autre purification, la 1- (2-acétoxy-phényl) -pipérazine obtenue.The 1- (2-acetoxy-phenyl) -piperazine obtained can be reacted directly without further purification.
En opérant comme décrit ci-dessus, on obtient les composés mentionnés dans le tableau 2,dans chaque cas à partir de 0,03 mole d'éther 3,4,5-triméthoxyphénoxyglycidylique et de 0,03 mole du dérivé de pipérazine correspondant. Le composé de pipérazine de départ est obtenu chaque fois de la même manière que le composé de départ de l'Exemple précédent, en utilisant chaque fois, dans l'étape d'acylation, à la place du chlorure d'acétyle, l'autre chlorure d'acide correspondant (chlorure de benzoyle chlorure de l'acide cyclohexanecarboxylique). Tableau 2
Composé de pipérazine R2 dans la for- Point de fusion Rendement en % Exemple de départ mule I (du chlorhydrate) de la théorie n
R1 = H
1-(2-Benzoyloxy- 2-Benzoyloxy-phényl 194 - 196 C 31 % 28
phényl)-pipérazine
1-(2-Cyclohexyl- 2-Cyclohexylcarbonyloxy- 151 - 152 C 22 % 29
carbonyloxy- phényl
phényl)-pipérazine
EXEMPLE 30 (#)-1-[3-(3,4,5-triméthoxy-phénoxy)-2-acétoxy-propyl]-4 (2-méthoxy-phényl)-pipérazine
Piperazine R2 compound in the melting point Yield in% Example of starting mule I (hydrochloride) of theory n
R1 = H
1- (2-Benzoyloxy-2-benzoyloxy-phenyl 194 - 196 C 31% 28
phenyl) -piperazine
1- (2-Cyclohexyl-2-cyclohexylcarbonyloxy-151-152 C 22% 29
carbonyloxyphenyl
phenyl) -piperazine
EXAMPLE 30 (#) - 1- [3- (3,4,5-trimethoxy-phenoxy) -2-acetoxy-propyl] -4 (2-methoxy-phenyl) -piperazine
On met en suspension dans 100 ml de xylène 10 g (0,023 mole) de (#)-1-[3-(3,4,5-triméthoxy-phénoxy)-2-hydroxy-propyl]- 4T(2-méthoxy-phénul)-pipérazine. On ajoute à la suspension 10 ml de triéthylamine et on y fait tomber ensuite lentement goutte à goutte et à la température ambiante 9 ml de chlorure d'acétyle. On abandonne 2 heures la solution à la température ambiante. On sépare ensuite par filtration le chlorhydrate de triéthylammonium et on chasse le solvant par distillation sous vide. On purifie le produit brut obtenu par chromatographie en colonne sèche sur gel de silice (agent d'élution chloroforme/ méthanol 98:2). On obtient le chlorhydrate de la manière habituelle par traitement avec de l'acide chlorhydrique isopropanolique et on le fait recristalliser dans l'isopropanol. Point de fusion du chlorhydrate 178 - 1790C. Rendement : 80 %. 10 g (0.023 mol) of (N) - 1- [3- (3,4,5-trimethoxy-phenoxy) -2-hydroxy-propyl] -4T (2-methoxy) -propylene glycol are suspended in 100 ml of xylene. phénul) -piperazine. 10 ml of triethylamine are added to the suspension and 9 ml of acetyl chloride are then slowly added dropwise at room temperature. The solution is left at room temperature for 2 hours. The triethylammonium hydrochloride is then filtered off and the solvent is distilled off in vacuo. The crude product obtained is purified by dry column chromatography on silica gel (chloroform / methanol eluent 98: 2). The hydrochloride is obtained in the usual manner by treatment with isopropanol hydrochloric acid and is recrystallized from isopropanol. Melting point of hydrochloride 178 - 1790C. Yield: 80%.
EXEMPLE 31 (Référence DEGUSSA du composé:15 077)
EXEMPLE 32 (Référence DEGUSSA du composé:15 076) (+)-1- 3-(3,4,5-trimethoxyvphenoxy)-2-(thienyl-(2)-carbonyloxy)- propyl]-4- (2-méthoxy-phényl) -pipérazine (D 15 077).
EXAMPLE 32 (DEGUSSA reference of the compound: 15 076) (+) - 1- 3- (3,4,5-trimethoxy-phenoxy) -2- (thienyl- (2) -carbonyloxy) -propyl] -4- (2-methoxy) phenyl) -piperazine (D 15 077).
On met en suspension dans 100 ml de xylène 15 g (0,0319 mole) de dichlorhydrate de (#)-1-[3-(3,4,5-triméthoxy-phénoxy)-2- hydroxy-propyl]-4-(2-méthoxyphényl)-pipérazine et 3,3 g de triéthylamine. Sous agitation, on ajoute goutte à goutte 4,7 g (0,0319 mole) de chlorure d'acide thiophène-2-carboxylique à la température ambiante. On continue d'agiter pendant 1 heure à la température ambiante. On separe ensuite par filtration le chlorhydrate de triéthylammonium qui a précipité et on concentre la solution sous pression réduite. On reprend le résidu par de l'éther et on le mélange avec de- l'acide chlorhydrique isopropanolique. On fait recristalliser ledit chlorhydrate obtenu dans l'isopropanol. 15 g (0.0319 mol) of (#) - 1- [3- (3,4,5-trimethoxy-phenoxy) -2-hydroxypropyl] dihydrochloride are suspended in 100 ml of xylene. (2-methoxyphenyl) -piperazine and 3.3 g of triethylamine. With stirring, 4.7 g (0.0319 mol) of thiophene-2-carboxylic acid chloride are added dropwise at room temperature. Stirring is continued for 1 hour at room temperature. The precipitated triethylammonium hydrochloride is then filtered off and the solution is concentrated under reduced pressure. The residue is taken up in ether and mixed with isopropanol hydrochloric acid. The hydrochloride obtained is recrystallized from isopropanol.
Point de fusion du dichlorhydrate 198 - 1990C (la substance contient 1 mole d'isopropanol comme solvant de cristallisation). Melting point of the dihydrochloride 198 - 1990C (the substance contains 1 mole of isopropanol as the crystallization solvent).
Rendement : 42 %. Yield: 42%.
La préparation du thiényl-(3)-composé correspondant (0 15 076) est effectuée de manière analogue. The corresponding thienyl (3) -composition (0 15 076) is prepared analogously.
Point de fusion du dichlorhydrate 193 - 1940C. Melting point of 193 - 1940C dihydrochloride.
Rendement : 48 %
EXEMPLE 33 (#)-1-[3-(3,4,5-triméthoxy-phénoxy)-2-(thiényl-(2)-carbonyloxy)- propyl]-4-[2-(thiényl-(2)-carbonyloxy)-phényl]-pipérazine
EXAMPLE 33 (#) - 1- [3- (3,4,5-trimethoxy-phenoxy) -2- (thienyl- (2) -carbonyloxy) -propyl] -4- [2- (thienyl- (2) - carbonyloxy) -phenyl] -piperazine
On met en suspension 7 g (0,0167 mole) de (#)-1-[3-(3,4 5-triméthoxy-phénoxy)-2-hydroxy propyl]-4-(2-hydroxy-phényl)pipérazine dans 100 ml de dioxanne et 4 ml de triéthylamine. 7 g (0.0167 moles) of (-) - 1- [3- (3,4-trimethoxy-phenoxy) -2-hydroxypropyl] -4- (2-hydroxy-phenyl) piperazine are suspended in 100 ml of dioxane and 4 ml of triethylamine.
On ajoute à cette suspension, sous agitation, à la température ambiante et par portions,5 g (0,034 mole) de chlorure de l'acide thiophène-2-carboxylique. lorsque l'addition est terminée, on agite encore pendant 6 heures, puis on laisse reposer à la température ambiante. On sépare par filtration le chlorhydrate de triéthylammonium qui s'est forme et on chasse le solvant par distillation sous vide. On reprend par 100 ml d'éther le produit huileux restant, on le mélange avec de l'acide chlorhydrique isopropanolique jusqu'à réaction acide et on essore par filtration sous vide le chlorhydrate qui a précipité. On fait recristalliser dans l'isopropanol pour purifier le produit. Rendement : 61 %.5 g (0.034 mol) of thiophene-2-carboxylic acid chloride are added to this suspension, with stirring, at room temperature and in portions. when the addition is complete, stirring is continued for 6 hours and then allowed to stand at room temperature. The resulting triethylammonium hydrochloride is filtered off and the solvent is distilled off in vacuo. The remaining oily product is taken up in 100 ml of ether, it is mixed with isopropanol hydrochloric acid until acidic reaction and the precipitated hydrochloride is filtered off with suction under vacuum. It is recrystallized from isopropanol to purify the product. Yield: 61%.
Point de fusion du chlorhydrate 221 - 2220C.Melting point of hydrochloride 221-2220C.
Le tableau 3 ci-après indique l'action antiagressive des composés aussi bien selon le brevet principal que selon la présente addition. Cette action antiagressive a été déterminée par l'épreuve de combativité chez la souris et elle est indiquée sous forme de la DE 50 (en mg/kg de poids corporel de la souris). Table 3 below indicates the antiagressive action of the compounds both according to the main patent and according to the present addition. This antiaggressive action was determined by the mouse combative test and is indicated as the ED 50 (in mg / kg body weight of the mouse).
La DE 50 est la dose pour laquelle la posture de combat typique fait défaut chez 50 % des couples de souris soumis à l'expérience.The ED 50 is the dose for which the typical fighting posture is lacking in 50% of the pairs of mice subjected to the experiment.
Plus la DE 50 est faible, plus est grande l'activité du composé.The lower the DE 50, the greater the activity of the compound.
Comme le montre le tableau 3 ci-après, les composés selon les nouveaux exemples 27 et 30 en particulier font partie des composés les plus efficaces parmi ceux donnés à titre d'exemples dans le brevet principal et dans la présente addition. Les composés selon les exemples 32 et 31 sont aussi très actifs comparativement aux autres composés. La présente- addition est importante, précisément compte tenu de la forte activité desdits composés.As shown in Table 3 below, the compounds according to the new Examples 27 and 30 in particular are among the most effective compounds among those given as examples in the main patent and in the present addition. The compounds of Examples 32 and 31 are also very active compared to other compounds. The present addition is important, precisely in view of the high activity of said compounds.
Toutes les indications générales données dans le brevet principal au sujet des composés de la formule (I > s'appliquent également aux composés de la formule (V) suivant la présente addition et, en particulier, les informations relatives aux formes pharmaceutiques et a leur préparation, aux modes d'application des substances actives ou des médicaments, aux doses à utiliser et aux indications thérapeutiques, qui sont notamment les suivantes : excitation, tension interne, angoisse, troubles psychoneurotiques,troubles du sommeil, psychoses, états dépres sifs. All the general indications given in the main patent concerning the compounds of the formula (I> also apply to the compounds of the formula (V) according to the present addition and, in particular, the information relating to the pharmaceutical forms and to their preparation , the methods of application of the active substances or drugs, the doses to be used and the therapeutic indications, which include the following: excitement, internal tension, anxiety, psychoneurotic disorders, sleep disorders, psychoses, severe depression.
Données sur l'effet pharmacologique
TABLEAU 3
Exemple n Référence DEGUSSA DE 50 (mg/kg)
du composé épreuve de combativité
1 13 112 1,4 2 13 116 # 70
3 13 113 28
4 13 294 16
5 13 310 31
6 13 292 # 30
7 13 098 5,5
8 13 099 # 54
9 13 453 19
10 13 615 14
11 13 341 30
12 13 324 12
13 13 211 13 14 13 210 # 40
15 13 291 -70
16 13 572 21
17 13 114 9 18 13 548 # 30
19 13 570 N 40
20 14 342 1,3
21 13 771 # 60
22 13 447 14
23 13 489 16
24 14 417 3,3
26 14 192 1,4
27 14 841 3,2
28 14 825 80
29 14 826 50
30 14 964 3,8
31 15 077 9,7
32 15 076 6,4
33 15 194 40 Data on the pharmacological effect
TABLE 3
Example n DEGUSSA reference DE 50 (mg / kg)
Combativeness test compound
1 13 112 1.4 2 13 116 # 70
3 13 113 28
4 13 294 16
5,310,331
6 13 292 # 30
7 13 098 5.5
8 13 099 # 54
9 13 453 19
10 13 615 14
11 13 341 30
12 13 324 12
13 13 211 13 14 13 210 # 40
15 13 291 -70
16 13 572 21
17 13 114 9 18 13 548 # 30
19 13 570 N 40
20 14 342 1.3
21 13 771 # 60
22 13 447 14
23 13 489 16
24 14 417 3.3
26 14 192 1.4
27 14 841 3.2
28 14 825 80
29 14 826 50
30 14 964 3.8
31 15,077 9.7
32 15,076 6.4
33 15 194 40
Claims (12)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8018458A FR2488892A2 (en) | 1977-04-04 | 1980-08-25 | NOVEL 1- (3- (3,4,5-TRIMETHOXYPHENOXY) -2-HYDROXYPROPYL) -4-ARYL-PIPERAZINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THEIR USE AS A MEDICINAL PRODUCT |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB14100/77A GB1583372A (en) | 1977-04-04 | 1977-04-04 | 1-(3-(3,4,5-trimethoxyphenoxy)-2-hydroxypropyl)-4-aryl piperazine derivatives |
| FR8018458A FR2488892A2 (en) | 1977-04-04 | 1980-08-25 | NOVEL 1- (3- (3,4,5-TRIMETHOXYPHENOXY) -2-HYDROXYPROPYL) -4-ARYL-PIPERAZINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THEIR USE AS A MEDICINAL PRODUCT |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| FR2488892A2 true FR2488892A2 (en) | 1982-02-26 |
| FR2488892B2 FR2488892B2 (en) | 1983-05-13 |
Family
ID=26221957
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FR8018458A Granted FR2488892A2 (en) | 1977-04-04 | 1980-08-25 | NOVEL 1- (3- (3,4,5-TRIMETHOXYPHENOXY) -2-HYDROXYPROPYL) -4-ARYL-PIPERAZINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THEIR USE AS A MEDICINAL PRODUCT |
Country Status (1)
| Country | Link |
|---|---|
| FR (1) | FR2488892A2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6358515B2 (en) * | 1997-01-30 | 2002-03-19 | Senju Pharmaceutical Co., Ltd. | Hydroquinone derivatives |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2189044A1 (en) * | 1972-06-17 | 1974-01-25 | Sumitomo Chemical Co | |
| FR2395264A1 (en) * | 1977-04-04 | 1979-01-19 | Degussa | NEW DERIVATIVES 1- (3- (3,4,5-TRIMETHOXYPHENOXY) -2-HYDROXYPROPYL) -4-ARYL-PIPERAZINIQUES, PROCESS FOR THEIR PREPARATION AND APPLICATION AS A MEDICINAL PRODUCT |
-
1980
- 1980-08-25 FR FR8018458A patent/FR2488892A2/en active Granted
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2189044A1 (en) * | 1972-06-17 | 1974-01-25 | Sumitomo Chemical Co | |
| FR2395264A1 (en) * | 1977-04-04 | 1979-01-19 | Degussa | NEW DERIVATIVES 1- (3- (3,4,5-TRIMETHOXYPHENOXY) -2-HYDROXYPROPYL) -4-ARYL-PIPERAZINIQUES, PROCESS FOR THEIR PREPARATION AND APPLICATION AS A MEDICINAL PRODUCT |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6358515B2 (en) * | 1997-01-30 | 2002-03-19 | Senju Pharmaceutical Co., Ltd. | Hydroquinone derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2488892B2 (en) | 1983-05-13 |
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