LU81562A1 - PHENYL-1 PIPERAZINE DERIVATIVES - Google Patents
PHENYL-1 PIPERAZINE DERIVATIVES Download PDFInfo
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- LU81562A1 LU81562A1 LU81562A LU81562A LU81562A1 LU 81562 A1 LU81562 A1 LU 81562A1 LU 81562 A LU81562 A LU 81562A LU 81562 A LU81562 A LU 81562A LU 81562 A1 LU81562 A1 LU 81562A1
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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
- C07D295/096—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 separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- C—CHEMISTRY; METALLURGY
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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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Description
-1--1-
La présente invention a pour objet des dérivés de phényl-1 piperazine, leurs sels d’addition aux acides pharmaceutiquement acceptables/ leur préparation et leur utilisation en thérapeutique.The present invention relates to 1-phenyl piperazine derivatives, their addition salts with pharmaceutically acceptable acids / their preparation and their use in therapy.
5 Les composés répondent à la formule (I) \ y —-r2 (i> 10 < dans laquelle R4 R. représente un radical S (O) R, , S(0) CF_ ou S0o—N"' X m j n j z v_ 15 dans lequel m est 0, 1 ou 2, n est 1 ou 2, Rgest un radical alkyle de 1 à 10 atomes de carbone et et Rg représentent H ou un radical alkyle de 1 à 4 atomes de carbone ou NR^Rg forment ensemble un hétérocycle pouvant lui-même contenir un autre hété-roatome, et 20 rePrésente un atome d'hydrogène, le radical CHj-C^-OH ou un radical CH2“CE2~0-CORg, CI^-C^-O-CONHRg ou CI^-C^-O-Rg dans lesquels Rg est un alkyle de 1 à 6 atomes de carbone,à l'exception du composé pour lequel R2 est K lorsque R^ est le radical S(0)m Rg dans lequel m=0 et Rg=CEg.5 The compounds correspond to the formula (I) \ y —-r2 (i> 10 <in which R4 R. represents a radical S (O) R,, S (0) CF_ or S0o — N "'X mjnjz v_ 15 in which m is 0, 1 or 2, n is 1 or 2, Rgest an alkyl radical of 1 to 10 carbon atoms and and Rg represent H or an alkyl radical of 1 to 4 carbon atoms or NR ^ Rg together form a heterocycle which itself may contain another hetero-atom, and represents a hydrogen atom, the radical CHj-C ^ -OH or a radical CH2 “CE2 ~ 0-CORg, CI ^ -C ^ -O-CONHRg or CI ^ -C ^ -O-Rg in which Rg is an alkyl of 1 to 6 carbon atoms, with the exception of the compound for which R2 is K when R ^ is the radical S (0) m Rg in which m = 0 and Rg = CEg.
Les sels d'addition des composés (I) aux acides pharmaceutique-= ment acceptables font partie de l'invention.The addition salts of the compounds (I) with pharmaceutically acceptable acids form part of the invention.
On peut préparer les composés de l'invention selon le schéma réactionnel suivant: ry™2+ W/ 2 X-CH,-CE,^ \_/ 2 V R1 X = halogène ou OH ou alkyl* SOg ou aryl-SOg ou les 2 x=0 U' 1 · -2-The compounds of the invention can be prepared according to the following reaction scheme: ry ™ 2 + W / 2 X-CH, -CE, ^ \ _ / 2 V R1 X = halogen or OH or alkyl * SOg or aryl-SOg or the 2 x = 0 U '1 · -2-
La cyclisation s'effectue en présence d'un solvant tel qu'un alcool ou en l'absence de solvant.The cyclization is carried out in the presence of a solvent such as an alcohol or in the absence of solvent.
On peut obtenir les composés (ï) dans lesquels R2 est autre que H, à partir du composé (I) correspondant dans lequel R2 5 est H, par réaction avec un composé R2Y ( Y=halogène ou alkyl-SO^ ou aryl-SO^ ).Compounds (ï) in which R2 is other than H can be obtained from the corresponding compound (I) in which R2 5 is H, by reaction with a compound R2Y (Y = halogen or alkyl-SO ^ or aryl-SO ^).
On peut aussi préparer les composés pour lesquels R2=CH2-CH2*-OR£ CK2_CH2”OCORç ou CE2“CH2-OCONHRg à partir du composé (I) dans 10 lequel R2= CH2-CH2-OK par réaction avec un acide ou un dérivé fonctionnel d'acide (halogénure,anhydride) ou avec un halogénure Rg Hal ou avec un isocyanate.One can also prepare the compounds for which R2 = CH2-CH2 * -OR £ CK2_CH2 ”OCORç or CE2“ CH2-OCONHRg from compound (I) in which R2 = CH2-CH2-OK by reaction with an acid or a functional acid derivative (halide, anhydride) or with a halide Rg Hal or with an isocyanate.
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15 On peut aussi préparer les composés (I) dans lesquels R-^SÎOJ^R^It is also possible to prepare the compounds (I) in which R- ^ SÎOJ ^ R ^
ou S(0) CF-, par oxydation des composés correspondants (I) dans n Oor S (0) CF-, by oxidation of the corresponding compounds (I) in n O
lesquels R^SR^ ou SCF^ *which R ^ SR ^ or SCF ^ *
On peut enfin obtenir les composés (I)dans lesquels R2 est 20 CH'2CH2OH à partir de la phénylpipérazine correspondante J~\Finally, the compounds (I) in which R2 is 20 CH'2CH2OH can be obtained from the corresponding phenylpiperazine J ~ \
\ /-N NH par reaction avec un composé XCH9CH90H\ / -N NH by reaction with a compound XCH9CH90H
(X = Hal,mésyle ou tosyle).(X = Hal, mesyle or tosyle).
Les exemples non limitatifs ci-dessous illustrent l'invention.The nonlimiting examples below illustrate the invention.
Les analyses et les spectres IR et RMN confirment la structure des composés.The analyzes and the IR and NMR spectra confirm the structure of the compounds.
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-3--3-
Exemple 1 (Trifluoromêthyl-sulfonyl-3 phényl) -1 pipérasinc? et son monochlorhydrate.Example 1 (Trifluoromethyl-3-sulfonylphenyl) -1 piperasinc? and its monohydrochloride.
[Ri = S02CP3 . R2 = Hj[Ri = S02CP3. R2 = Hj
Dans une fiole d'Erlenmeyer de 100ml/ équipée d'un réfrigérant à reflux et d'un agitateur magnétique, on met 13,5g de trifluoromë-5 thylsulfonyl-3 aniline et 10,7g de chlorhydrate de di-(chloro-2 éthyl)-amine. Ce mélange est chauffé pendant 32 heures à 150°. On ajoute en cours de réaction un excès de 3C% du chlorhydrate de 1'amine halogénée.In a 100 ml Erlenmeyer flask / equipped with a reflux condenser and a magnetic stirrer, 13.5 g of 3-trifluoromë-5 thylsulfonyl-aniline and 10.7 g of di- (2-chloroethyl) hydrochloride are put )-amine. This mixture is heated for 32 hours at 150 °. During the reaction, a 3% excess of the hydrochloride of the halogenated amine is added.
Quand toute l'aniline de départ a réagi, on reprend la masse réactionnelle par du chlorure de méthylène,on l'alcalinise à l'aide d'hydroxyde de sodium N, on décante, on lave avec de l'eau,sèche la solution organique sur sulfate de sodium et l'évapore à siccité ^ On isole ainsi la base désirée huileuse. Elle est reprise par du toluène, décolorée avec du noir animal à la température du reflux. 15 Après filtration â chaud on évapore le solvant et distille la base Le chlorhydrate est préparé par réaction de la base liquide avec d< l'acide chlorhydrique au sein d'éther. Le sel précipité est récris-tallisé dans un mélange d'acétone et d'éthanol absolu. Le chlorhydrate de (trifluorométhylsulfonyl-3 phényl)-1 pipérazine fond à 20 176°C.When all the starting aniline has reacted, the reaction mass is taken up in methylene chloride, it is made alkaline with sodium hydroxide N, it is decanted, washed with water, the solution is dried organic on sodium sulfate and evaporated to dryness. The desired oily base is thus isolated. It is taken up in toluene, discolored with animal black at the reflux temperature. After hot filtration, the solvent is evaporated off and the base is distilled off. The hydrochloride is prepared by reaction of the liquid base with hydrochloric acid in ether. The precipitated salt is recreated in a mixture of acetone and absolute ethanol. (3-Trifluoromethylsulfonylphenyl) -1 piperazine hydrochloride melts at 176 ° C.
Exemple 2 [(Octylsulfonyl-3 phényl)-4 pipérazinyl-lj -2 éthanol e1 son fumarate d'acide.Example 2 [(3-Octylsulfonylphenyl) -4 piperazinyl-1j -2 ethanol and its acid fumarate.
^ = so2-ch2-(ch2)6-ch3, r2= ch2-ch2-oh| 25 Dans une fiole d'Erlenmeyer de 250ml, équipée d'un réfrigérateur à reflux et d'un agitateur magnétique, on met 6,4g (0,018 mole) d'fc>ctylsulfonyl-3 phényl)-1 pipérazine, 2,3g de carbonate de sodium ,2,8g (1,6 ml= 0,022 mole) de bromhydrine du glycol, quelques cristaux d'iodure de sodium et 150ml d'éthanol.(La pipérazine 30 de départ est préparée de la même manière que dans l'exemple 1, la cyclisation étant effectuée dans du butanol).^ = so2-ch2- (ch2) 6-ch3, r2 = ch2-ch2-oh | 25 6.4 g (0.018 mole) of fc> 3-ctylsulfonylphenyl) -1 piperazine, 2.3 g of a 250 ml Erlenmeyer flask, equipped with a reflux refrigerator and a magnetic stirrer sodium carbonate, 2.8 g (1.6 ml = 0.022 mole) of glycol hydrobromine, a few crystals of sodium iodide and 150 ml of ethanol. (The starting piperazine 30 is prepared in the same way as in Example 1, the cyclization being carried out in butanol).
On porte ä la température du reflux de l'éthanol et maintient l'ëbi lition pendant 8 heures. Après cette période, on ajoute un excès de 80% de bromhydrine du glycol et de carbonate de sodium.The reflux of ethanol is brought to the temperature and maintained for 8 hours. After this period, an 80% excess of glycol hydrobromine and sodium carbonate is added.
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-4--4-
Quand toute la pipérazine a réagi, on évapore l’éthanol et repren» 1’huile, résiduelle par un mélange d’eau et d'éther, on décante, jlave la phase éthérée avec de l'eau, la sache sur sulfate de sodr {et la concentre à. siccitë.When all of the piperazine has reacted, the ethanol is evaporated and the residual oil is taken up again, with a mixture of water and ether, it is decanted, the ethereal phase is washed with water, it is known over soda sulfate {and concentrates it at. siccitë.
5 On isole ainsi le dérivé de pipérazino-êthanol huileux.The oily piperazino ethanol derivative is thus isolated.
Son fumarate acide est préparé par action de l'acide sur la base . sein d'acétone. Le sel cristallise lentement par addition d'un pe d'éther. Il est isolé par filtration, séché et recristallisë dans de l'acétone. Il fond à 113,6°C, * !0 ‘Its acid fumarate is prepared by the action of the acid on the base. acetone breast. The salt crystallizes slowly by adding a pe of ether. It is isolated by filtration, dried and recrystallized from acetone. It melts at 113.6 ° C, *! 0 ‘
Exemple 3 (Trifluoromêthyl-suifinvl-3 phényl)-1 pipérazine et son fumarate acide SOCF3 ? R2 = h] 15 Cn introduit 6,27g (0/03 mole) de trifluoromêthyl sulfinyl-3 anili: et 5,34g (0,03 mole) de chlorhydrate de di-(chloro-2 ëthyl)-amine dans une fiole d'Erlenmeyer de 50ml. On porte ce mélange à 170° e le maintient pendant 8 heures à cette température. Quand toute l'aniline de départ a réagi, on reprend la masse réactionnelle av 20 du chlorure de méthylène, on l'alcalinise à l'aide d'hydroxyde de sodium, on décante la couche organique et on la lave avec de l'ea on sèche cette phase organique sur du sulfate de sodium et on l'évapore à siccitë. On obtient ainsi la base désirée sous forme d'huile gui est reprise par du toluène et décolorée avec du noir 25 animal à la température du reflux. Après filtration, on évapore 1 solvant et distille la base.Example 3 (Trifluoromethyl-suifinvl-3 phenyl) -1 piperazine and its acid fumarate SOCF3? R2 = h] 15 Cn introduces 6.27g (0/03 mole) of trifluoromethyl-3-sulfinyl anili: and 5.34g (0.03 mole) of di- (2-chloroethyl) hydrochloride in a vial d '' 50ml Erlenmeyer flask. This mixture is brought to 170 ° and maintained for 8 hours at this temperature. When all the starting aniline has reacted, the reaction mass is taken up with methylene chloride, it is made alkaline with sodium hydroxide, the organic layer is decanted and washed with water. this organic phase is dried over sodium sulfate and evaporated to dryness. The desired base is thus obtained in the form of an oil which is taken up in toluene and discolored with animal black at reflux temperature. After filtration, 1 solvent is evaporated and the base is distilled.
Son fumarate acide est préparé par réaction de la base et d'acide fumarique au sein de l'éthanol. Le sel est filtré et recr 30 tallisé de l'éthanol.Its acid fumarate is prepared by reaction of the base and fumaric acid within ethanol. The salt is filtered and recrystallized from ethanol.
Lè fumarate acide de (trifluoromêthyl sulfinyl-3 phényl)-1 pipérazine fond à 176,2°C.The acid fumarate of (trifluoromethyl-3-sulfinylphenyl) -1 piperazine melts at 176.2 ° C.
-5--5-
Exemple 4 |(Trifluorométhyl-sulfinyl-3 phënyl)-4 pipérazinol -2 1 1 1 1 · *· t éthanol et son oxalate acide.Example 4 | (Trifluoromethyl-3-sulfinyl phenyl) -4 piperazinol -2 1 1 1 1 · * · t ethanol and its acid oxalate.
SOCF3 ; R2 = -CH2-CH20h] vSOCF3; R2 = -CH2-CH20h] v
Dans, une fiole d1 erlenneyer de 250 ml, on introduit I0''ç (0,0359 mol 5 de (trifluorométhylsulfinyl-3 phényl)-l pipérazine, 4/99g (2,83ml ou 0,039 mole) de bromhiydrine du glycol, 4,24g de carbonate de sodium, quelques cristaux d'iodure de sodium et 100ml d'éthanol.Into a 250 ml Erlenneyer flask, I0''ç (0.0359 mol 5 of (trifluoromethylsulfinyl-3 phenyl) -l piperazine, 4 / 99g (2.83ml or 0.039 mole) of glycol bromihydrin is introduced. , 24g of sodium carbonate, a few crystals of sodium iodide and 100ml of ethanol.
On porte à la température du reflux et maintient l'ébullition pendant 6 heures. Après évaporation à siccitâ, on reprend le '10 résidu huileux avec de l'eau et de l'éther. On décante la phase organique, la lave avec de l'eau r la sèche sur sulfate de sodium et on l'évapore à sec. · .The temperature is brought to reflux and the boiling is maintained for 6 hours. After evaporation to dryness, the oily residue is taken up with water and ether. The organic phase is decanted, washed with water and dried over sodium sulfate and evaporated to dryness. ·.
On a ainsi la base huileuse brute, 15 On prépare son oxalate en solubilisant la base dans la quantité minimale d'éthanol absolu, et ajoutant de l'acide oxalique. Le sel précipité est filtré, séché et recristallisé dans l'éthanol.The crude oily base is thus obtained. Its oxalate is prepared by dissolving the base in the minimum quantity of absolute ethanol, and adding oxalic acid. The precipitated salt is filtered, dried and recrystallized from ethanol.
L'oxalate acide de T(trifluoromêthy]sulfinyl-3 phényl)-4 ü 20 pipérazino^ -2 éthanol fond à 119e c.The acid oxalate of T (trifluoromethy] sulfinyl-3 phenyl) -4 to 20 piperazino ^ -2 ethanol melts at 119th c.
Exemple 5 forifluoromëthvl-sulfinvl-3 Phënvl)-4 pipérazinol -2 ’ acétoxy-l ëthane et. son oxalate acide Tr;l = SOCF3 ? R2 = CK2 CR2OCOCH31 25Example 5 forifluoromëthvl-sulfinvl-3 Phënvl) -4 piperazinol -2 ’acetoxy-l ethane and. its acid oxalate Tr; l = SOCF3? R2 = CK2 CR2OCOCH31 25
Dans une fiole d'Erlenmeyer delOO ml, équipée d'un réfrigérant ä reflux et d'un agitateur magnétique, on met 2g (0,062 mole de |(trifluorométhylsulfinyl-3 phênyl)-4 pipérazinoJ-2 éthanol 11,42 ml d'anhydride acétique et 1 ou 2 gouttes de chlorure d’acé-tyle,en solution dans 50ml de toluène anhydre. On maintient pendant 30 i heure à la température de 60°, puis on évapore à siccité, on reprend le résidu par de l'éther et on lave la phase organique avec une solution d'hydroxyde de sodium N. Après décantation, on sèche . sur sulfate de magnésium et évapore de nouveau.2g (0.062 mole of | (trifluoromethylsulfinyl-3 phenyl) -4 piperazinoJ-2 ethanol 11.42 ml of anhydride are placed in a 100 ml Erlenmeyer flask equipped with a reflux condenser and a magnetic stirrer acetic acid and 1 or 2 drops of acetyl chloride, dissolved in 50 ml of anhydrous toluene. It is maintained for 30 i hour at a temperature of 60 °, then evaporated to dryness, the residue is taken up in ether and the organic phase is washed with a sodium hydroxide solution N. After decantation, it is dried over magnesium sulfate and evaporated again.
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! ! -6- j L'ester obtenu est une huile que l'on transforme· en oxalate acide au sein de l'éthanol absolu. Par cristallisation dans un mélange d'éthanol* et de méthanol (80/20), on obtient l'oxalate acide de [(trifluorométhyl sulfinyl-3 phényl)-4 pipérazinoj -2 acëtoxy-1'êthane pur qui fond à 190° C.! ! -6- j The ester obtained is an oil which is transformed · into an acid oxalate in absolute ethanol. By crystallization from a mixture of ethanol * and methanol (80/20), the acid oxalate of [(trifluoromethyl sulfinyl-3 phenyl) -4 pipérazinoj -2 acétoxy-l'éthane pure which melts at 190 ° C is obtained .
5 Exemple 6 [(méthÿlthio-3 phényl)-4 piperazinyl-l])-2 éthanol et son chlorhydrate.-5 Example 6 [(3-methÿlthio-phenyl) -4 piperazinyl-1]) - 2 ethanol and its hydrochloride.
[R1=CH3S R2=CH2CH20HJ[R1 = CH3S R2 = CH2CH20HJ
Dans un erlenmeyer rodé de 250 ml, équipé d'un agitateur magnétique et d'un réfrigérant à reflux, on introduit 100ml d'éthanol, 10g 10 (0,048 mole) de (méthylthio-3 phényl) -1 pipérazine (préparée selon le brevet des E.U.A. 2,976,290), 5,5g de carbonate de sodium, quelques cristaux d'iodure de sodium, 3,7ml de bromhydrine du glyco! On porte à la température de reflux pendant 6 heures, puis on rajoute 3,7 ml de bromhydrine du glycol et 5,5 g de carbonate de sodii 15 On filtre l'insoluble après 4 heures de reflux ; on évapore à sec l'éthanol, on reprend le résidu d'évaporation par de l'eau et on l'alcalinise avec de la soude ; on extrait avec du chloroforme ; on lave à l'eau, on sèche sur sulfate de sodium et on évapore à sec . On obtient une huile qui est transformée directement en chlorhydrati 20 Préparation du sel. On solubilise la base dans un minimum d'alcool absolu, on ajoute goutte à goutte de l'éther chlorhydrique 4,6Ν,3θ1·ί 9,3ml. Le chlorhydrate précipite ; on le filtre, l'essore et le sèche avant de le recristalliser dans l'éthanol. On obtient le produit fondant à 147°C.100 ml of ethanol, 10 g 10 (0.048 mol) of (3-methylthio-phenyl) -1 piperazine (prepared according to the patent) are introduced into a 250 ml erlenmeyer flask fitted with a magnetic stirrer and a reflux condenser. USA 2,976,290), 5.5g of sodium carbonate, a few crystals of sodium iodide, 3.7ml of glyco hydrobromine! It is brought to reflux temperature for 6 hours, then 3.7 ml of glycol hydrobromine and 5.5 g of sodium carbonate are added. The insoluble material is filtered after 4 hours of reflux; the ethanol is evaporated to dryness, the evaporation residue is taken up in water and it is made alkaline with sodium hydroxide; extracted with chloroform; washed with water, dried over sodium sulfate and evaporated to dryness. An oil is obtained which is directly transformed into hydrochloride. Preparation of the salt. The base is solubilized in a minimum of absolute alcohol, hydrochloric ether 4.6Ν, 3θ1 · ί 9.3ml is added dropwise. The hydrochloride precipitates; it is filtered, wrung and dried before recrystallizing from ethanol. The product melting at 147 ° C. is obtained.
2525
Dans le tableau suivant (I) sont représentés les composés préparés à titre d'exemples.In the following table (I) are shown the compounds prepared by way of examples.
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i , -7-i, -7-
TABLEAU ITABLE I
Composés R2 F°CCompounds R2 F ° C
1 SC^H^n CI^-C^-OH Monochlorhydrate 114/3 2 SC^-CF^ CH2-CE2-OH Monochlorhydrate 193,4 3 (ex.l) S02~CF3 H Monochlorhydrate 176 , 4 SO2-CK2“(0Η2)g-CH^ H Fumarate acide - 161,5 5 (ex.2) S02-CH2" (CH2) g-CH^ C^-CKj-OH Fumarate acide 113,6 * 6 S02“CH3 CH2-CH2“OH Monochlorhydrate 247,2 7 (ex.3) SGCF3 H Fumarate acide 176,2 8 (ex.4) SOCF3 CH2CH2OH Oxalate acide 119 9 (ex.5) SOCF3 CK2CH2OCOCH3 Oxalate acide 190 10 (ex.6) SCH3 CK2CH2OH Chlorhydrate 1471 SC ^ H ^ n CI ^ -C ^ -OH Monohydrochloride 114/3 2 SC ^ -CF ^ CH2-CE2-OH Monohydrochloride 193.4 3 (ex.l) S02 ~ CF3 H Monohydrochloride 176, 4 SO2-CK2 “ (0Η2) g-CH ^ H Acid fumarate - 161.5 5 (ex.2) S02-CH2 "(CH2) g-CH ^ C ^ -CKj-OH Acid fumarate 113.6 * 6 S02“ CH3 CH2-CH2 “OH Monohydrochloride 247.2 7 (ex. 3) SGCF3 H Acid fumarate 176.2 8 (ex. 4) SOCF3 CH2CH2OH Acid oxalate 119 9 (ex. 5) SOCF3 CK2CH2OCOCH3 Acid oxalate 190 10 (ex. 6) SCH3 CK2CH2OH Hydrochloride 147
Les composés de l'invention ont été soumis à des essais pharmacologiques dans différents domaines, en particulier dans le domaine du système nerveux central et dans le domaine analgésique.The compounds of the invention have been subjected to pharmacological tests in various fields, in particular in the field of the central nervous system and in the analgesic field.
La toxicité aiguë des composés a été déterminée par voie orale chez la souris. La DL5Q varie de 150 à 700 mg/kgThe acute toxicity of the compounds was determined orally in mice. The LD5Q varies from 150 to 700 mg / kg
Les composés de l'invention sont des agents psychotropes. Leur activité a été mesurée à l'aide du test des 4 plaques (ARON C. Thèse de Médecine, Paris 1970 ; BOISSIER J.R.,SIMON P. et ARON C. European Jour.Pharmacol. 1968,4,145-151).The compounds of the invention are psychotropic agents. Their activity was measured using the 4-plate test (ARON C. Thèse de Médecine, Paris 1970; BOISSIER J.R., SIMON P. and ARON C. European Jour.Pharmacol. 1968,4,145-151).
-δ--δ-
Les composés de l'invention sont administrés à plusieurs doses par voie orale.The compounds of the invention are administered in several doses orally.
Les pourcentages de désinhibition sont mesurés chez la souris. Pour les composés de l'invention ces pourcentages varient de 40 à 100% à la dose de lmg/kg, de 120 à 200% à la dose de 3mg/kg 5 et de 140 à 270% à la dose de 10 mg/kg.The inhibition percentages are measured in mice. For the compounds of the invention these percentages vary from 40 to 100% at the dose of 1 mg / kg, from 120 to 200% at the dose of 3 mg / kg and from 140 to 270% at the dose of 10 mg / kg .
Les composés de '1invention possèdent des propriétés psychotrope: gui permettent de les utiliser pour le traitement de l'anxiété et de la dépression.The compounds of the invention have psychotropic properties which allow them to be used for the treatment of anxiety and depression.
10 Ils peuvent être administrés par voie orale, endorectale ou parentérale avec tout excipient approprié et sous toutes formes * * d'administration correspondant à ces voies : gélules, capsules, cachets, comprimés, dragées, solutions ou suspensions buvables, suppositoires, solutés injectables.10 They can be administered orally, endorectally or parenterally with any suitable excipient and in all forms * * of administration corresponding to these routes: capsules, capsules, cachets, tablets, dragees, oral solutions or suspensions, suppositories, injectable solutions.
1515
La posologie quotidienne peut aller de 5 à 200 mg.The daily dosage can range from 5 to 200 mg.
Par ailleurs les composés de l'invention ont été également soumi ä des essais pharmacologiques dans le domaine analgésique ; en particulier au test de l'injection intrapéritonéale d'acide acé-2q tique chez la souris de Koster et coll. (Fed.proc.1959,18,42) modifié par Peterfàlvi, Branceni et coll.(Med.Pharmacol.Exp. 1966,15,254) dans lequel pour l'un des composés la dose active 5 . est de 7mg/kg par voie orale; et au test de la plaque chauffante (Eddy et Leimbach) (J.Pharm.Exp.Therap.1953,107,386)dans lequel 25 les doses actives 50 sont de 50mg/kg à 30mn et de 100mg/kg à 60mn pour l'un des composés choisi à titre d'exemple.Furthermore, the compounds of the invention have also been subjected to pharmacological tests in the analgesic field; in particular to the test of the intraperitoneal injection of acé-2q tick in the mouse of Koster et al. (Fed.proc.1959,18,42) modified by Peterfàlvi, Branceni et al. (Med.Pharmacol.Exp. 1966,15,254) in which for one of the compounds the active dose 5. is 7 mg / kg orally; and the hot plate test (Eddy and Leimbach) (J. Pharmac. Exp. Therap. 1953,107,386) in which the active doses 50 are 50 mg / kg at 30 min and 100 mg / kg at 60 min for one compounds chosen by way of example.
Ces résultats montrent que les composés de l'invention possèdent une activité analgésique essentiellement périphérique. En effet la DAC Λ dans le test de Koster est faible alors que la DAcr» dans 30 50 50 le test de la plaque chauffante est plus élevée.These results show that the compounds of the invention have an essentially peripheral analgesic activity. Indeed the DAC Λ in the Koster test is low while the DAcr ”in 30 50 50 the test of the hot plate is higher.
Ils peuvent être utilisés pour les traitements de diverses algie telles que céphalées, névralgies, douleurs dentaires, algies rhumatismales et traumatiques, douleurs viscérales.They can be used for the treatment of various painful conditions such as headache, neuralgia, dental pain, rheumatic and traumatic pain, visceral pain.
(λ(λ
• I• I
-9“ *-9 “*
Les composés de l'invention peuvent à cet effet être présentés sous toute forme d'administration appropriée pour la voie orale, parentérale ou endorectale, par exemple sous la forme de comprimés, gélules, solutions injectables ou suppositoires .... avec un excipient approprié.The compounds of the invention can for this purpose be presented in any form of administration suitable for the oral, parenteral or endorectal route, for example in the form of tablets, capsules, injectable solutions or suppositories .... with an appropriate excipient .
La posologie quotidienne peut aller de 50mg à 1000mg.The daily dosage can range from 50mg to 1000mg.
/l/\ “ a 4/ l / \ “a 4
Claims (8)
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7822672 | 1978-08-01 | ||
| FR7822672A FR2432515A1 (en) | 1978-08-01 | 1978-08-01 | CNS-active 1-phenyl-piperazine cpds. - useful as analgesics and psychotropic agents |
| FR7833105A FR2442234A2 (en) | 1978-08-01 | 1978-11-23 | CNS-active 1-phenyl-piperazine cpds. - useful as analgesics and psychotropic agents |
| FR7833105 | 1978-11-23 | ||
| FR7916029A FR2459797A2 (en) | 1978-08-01 | 1979-06-22 | PHENYL-1 PIPERAZINE DERIVATIVES AND THEIR THERAPEUTIC APPLICATION |
| FR7916029 | 1979-06-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| LU81562A1 true LU81562A1 (en) | 1981-03-24 |
Family
ID=27250847
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| LU81562A LU81562A1 (en) | 1978-08-01 | 1979-07-30 | PHENYL-1 PIPERAZINE DERIVATIVES |
Country Status (18)
| Country | Link |
|---|---|
| JP (1) | JPS5522690A (en) |
| AU (1) | AU4930979A (en) |
| BE (1) | BE877994A (en) |
| DE (1) | DE2930440A1 (en) |
| DK (1) | DK321479A (en) |
| ES (1) | ES483003A1 (en) |
| FI (1) | FI792401A (en) |
| FR (1) | FR2459797A2 (en) |
| GB (1) | GB2027703A (en) |
| GR (1) | GR69703B (en) |
| IL (1) | IL57920A0 (en) |
| IT (1) | IT1123497B (en) |
| LU (1) | LU81562A1 (en) |
| NL (1) | NL7905810A (en) |
| NO (1) | NO792502L (en) |
| NZ (1) | NZ191140A (en) |
| PT (1) | PT70007A (en) |
| SE (1) | SE7906507L (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2582288B1 (en) * | 1985-05-21 | 1987-08-07 | Massonnet Henry | IMPROVED COMPACT BIN |
| SE9904723D0 (en) * | 1999-12-22 | 1999-12-22 | Carlsson A Research Ab | New modulators of dopamine neurotransmission II |
| SE9904724D0 (en) * | 1999-12-22 | 1999-12-22 | Carlsson A Research Ab | New modulators of dopamine neurotransmission I |
| USRE46117E1 (en) | 1999-12-22 | 2016-08-23 | Teva Pharmaceuticals International Gmbh | Modulators of dopamine neurotransmission |
| DE602005017784D1 (en) | 2004-06-08 | 2009-12-31 | Nsab, Filial Af Neurosearch Sweden Ab | NEW DISUBSTITUTED PHENYLPIPERIDINES AS MODULATORS OF DOPAMINE AND SEROTONINE NEUROTRANSMISSION |
| ATE469885T1 (en) | 2004-06-08 | 2010-06-15 | Nsab Af Neurosearch Sweden Ab | NEW DISUBSTITUTED PHENYLPIPERIDINE AND PIPERAZINE AS MODULATORS OF DOPAMINE NEUROTRANSMISSION |
| US7851629B2 (en) | 2004-06-08 | 2010-12-14 | Nsab, Filial Af Neurosearch Sweden Ab, Sverige | Disubstituted phenylpiperidines as modulators of dopamine and serotonin neurotransmission |
| CA2584831C (en) | 2004-10-13 | 2013-09-17 | Neurosearch Sweden Ab | Process for the synthesis of 4-(3-methanesulfonylphenyl)-1-n-propyl-piperidine |
| SE529246C2 (en) | 2005-10-13 | 2007-06-12 | Neurosearch Sweden Ab | New disubstituted phenyl-piperidines as modulators of dopamine neurotransmission |
| EP2787997A4 (en) | 2011-12-08 | 2015-05-27 | Ivax Int Gmbh | The hydrobromide salt of pridopidine |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH353743A (en) * | 1955-06-29 | 1961-04-30 | Parke Davis & Co | Method for preparing piperazines |
| US2976290A (en) * | 1959-04-24 | 1961-03-21 | Parke Davis & Co | Piperazine derivatives and methods for their production |
| FR2224464A1 (en) * | 1973-04-05 | 1974-10-31 | Synthelabo | N-Phenyl-N'-beta-hydroxy-ethyl piperazines - as analgesic and anti-inflammatory agents |
-
1979
- 1979-06-22 FR FR7916029A patent/FR2459797A2/en active Granted
- 1979-07-26 DE DE19792930440 patent/DE2930440A1/en not_active Withdrawn
- 1979-07-27 GB GB7926224A patent/GB2027703A/en not_active Withdrawn
- 1979-07-27 AU AU49309/79A patent/AU4930979A/en not_active Abandoned
- 1979-07-27 NZ NZ191140A patent/NZ191140A/en unknown
- 1979-07-27 NL NL7905810A patent/NL7905810A/en not_active Application Discontinuation
- 1979-07-27 IT IT24749/79A patent/IT1123497B/en active
- 1979-07-30 LU LU81562A patent/LU81562A1/en unknown
- 1979-07-30 NO NO792502A patent/NO792502L/en unknown
- 1979-07-30 IL IL57920A patent/IL57920A0/en unknown
- 1979-07-30 DK DK321479A patent/DK321479A/en not_active Application Discontinuation
- 1979-07-31 BE BE0/196538A patent/BE877994A/en unknown
- 1979-07-31 JP JP9858679A patent/JPS5522690A/en active Pending
- 1979-07-31 SE SE7906507A patent/SE7906507L/en not_active Application Discontinuation
- 1979-07-31 PT PT70007A patent/PT70007A/en unknown
- 1979-07-31 ES ES483003A patent/ES483003A1/en not_active Expired
- 1979-08-01 FI FI792401A patent/FI792401A/en not_active Application Discontinuation
-
1980
- 1980-07-27 GR GR59710A patent/GR69703B/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5522690A (en) | 1980-02-18 |
| IT1123497B (en) | 1986-04-30 |
| BE877994A (en) | 1980-01-31 |
| IL57920A0 (en) | 1979-11-30 |
| GR69703B (en) | 1982-07-09 |
| FR2459797B2 (en) | 1982-05-14 |
| NL7905810A (en) | 1980-02-05 |
| DK321479A (en) | 1980-02-02 |
| GB2027703A (en) | 1980-02-27 |
| DE2930440A1 (en) | 1980-02-28 |
| NZ191140A (en) | 1981-01-23 |
| IT7924749A0 (en) | 1979-07-27 |
| PT70007A (en) | 1979-08-01 |
| ES483003A1 (en) | 1980-04-16 |
| AU4930979A (en) | 1980-02-07 |
| NO792502L (en) | 1980-02-04 |
| FR2459797A2 (en) | 1981-01-16 |
| SE7906507L (en) | 1980-02-02 |
| FI792401A (en) | 1980-02-02 |
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