LU81396A1 - PHENYLPIPERAZINE DERIVATIVES - Google Patents
PHENYLPIPERAZINE DERIVATIVES Download PDFInfo
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- LU81396A1 LU81396A1 LU81396A LU81396A LU81396A1 LU 81396 A1 LU81396 A1 LU 81396A1 LU 81396 A LU81396 A LU 81396A LU 81396 A LU81396 A LU 81396A LU 81396 A1 LU81396 A1 LU 81396A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/74—Oxygen atoms
- C07D211/76—Oxygen atoms attached in position 2 or 6
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—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
- 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D233/30—Oxygen or sulfur atoms
- C07D233/32—One oxygen atom
- C07D233/36—One oxygen atom with hydrocarbon radicals, substituted by nitrogen atoms, attached to ring nitrogen atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
- C07D235/26—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
- C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
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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
- C07D295/08—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
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/14—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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Description
- 1- î La présente invention concerne des dérivés de phénylpipérazine, * leurs sels d'addition à des acides pharmaceutiquement acceptables, leur préparation et leur application en thérapeutique.The present invention relates to phenylpiperazine derivatives, their addition salts with pharmaceutically acceptable acids, their preparation and their therapeutic use.
ii
SS
| Les composés de l'invention répondent à la formule 3 -(ch2>b-r I SCF3 dans laquelle i; n est 1, 2 ou 3 et r . R représente R, R_| The compounds of the invention correspond to the formula 3 - (ch2> b-r I SCF3 in which i; n is 1, 2 or 3 and r. R represents R, R_
I VYI VY
: - soit un radical -N (CH ) dans lequel yi R^ et R^ représentent chacun un atome d'hydrogène ou ensemble le groupe / \ ^ // X est un' radical thio,oxy,imino,alkylimino ou méthylène et: - either a radical -N (CH) in which yi R ^ and R ^ each represent a hydrogen atom or together the group / \ ^ // X is a 'thio, oxy, imino, alkylimino or methylene radical and
IJIJ
H m est 0 ou 1, I - « - p :j - soit le radical tétrahydrofuryle-2, soit le radical j - CH2“SH, soit un radical CH2-S-alkyle, soit un radical ] " CH -O-alkylesoit un radical CH_-S-CO-alkyle, |·- I _ les alkyles ayant de 1 à 8 atomes de carbone.H m is 0 or 1, I - "- p: j - either the tetrahydrofuryl-2 radical, or the j - CH2" SH radical, or a CH2-S-alkyl radical, or a] "CH -O-alkyl radical a CH_-S-CO-alkyl radical, | · - I _ alkyls having from 1 to 8 carbon atoms.
| Les sels d'addition que forment les composés (I) avec les acides \ | pharmaceutiquement acceptables font partie de l'invention.| The addition salts formed by the compounds (I) with the acids \ | pharmaceutically acceptable are part of the invention.
ί / i, i· l ' 2 -ί / i, i · l '2 -
Selon l'invention on peut préparer les composés (I) par réaction entre la m-trifluorométhylthio-phénylpipérazine (II)According to the invention, the compounds (I) can be prepared by reaction between the m-trifluoromethylthio-phenylpiperazine (II)
p-O Ip-O I
s6f3 et un composé (III) Y - (CH3)n_R (III), dans lequel R et n ont les significations données ci-dessus et Y représente un anion de dérivé activé d'alcool tel qu'un ion halogènure, mésylate, tosylate, halogêno-mëthanesulfonate.s6f3 and a compound (III) Y - (CH3) n_R (III), in which R and n have the meanings given above and Y represents an anion of activated alcohol derivative such as a halide, mesylate, tosylate ion , halogeno-methanesulfonate.
Cette réaction est effectuée à une température de 20 à 150°C dans un solvant polaire ou non tel qu'un hydrocarbure benzënique, un solvant hydroxylë ou cétonique, le dimëthylformamide (DMF) ou 1'hexaméthylphosphorotriamide (HMPT).This reaction is carried out at a temperature of 20 to 150 ° C. in a polar or non-polar solvent such as a benzene hydrocarbon, a hydroxyl or ketone solvent, dimethylformamide (DMF) or hexamethylphosphorotriamide (HMPT).
Pour préparer le composé dans lequel R est le radical CI^SH, on peut aussi faire réagir la phénylpipérazine (II) avec du sulfure d'éthylène.To prepare the compound in which R is the radical CI ^ SH, it is also possible to react the phenylpiperazine (II) with ethylene sulfide.
On peut aussi préparer les composés (I) dans lesquels R est <-1 CH20 alkyle ou CH^S alkyle, en faisant réagir le composé (IV) // V _NH2 avec un composé (V) de formule 'SCF, Hal-CH9-CH,·^ n-(ch2) rOne can also prepare the compounds (I) in which R is <-1 CH20 alkyl or CH ^ S alkyl, by reacting the compound (IV) // V _NH2 with a compound (V) of formula 'SCF, Hal-CH9 -CH, · ^ n- (ch2) r
Hal-CH2-CH2--^Hal-CH2-CH2 - ^
On peut selon l'invention obtenir les dérivés (I) dans lesquels R est un radical CH2~S-alkyle ou CH2-S-CO-alkyle à partir du composé (I) de formule ^ ^ -(CH2)n CH2 SH (I) scf3 par réaction avec un halogènure d'alkyle ou avec un halogènure / d'acyle corresDondant.It is possible according to the invention to obtain the derivatives (I) in which R is a CH2 ~ S-alkyl or CH2-S-CO-alkyl radical from the compound (I) of formula ^ ^ - (CH2) n CH2 SH ( I) scf3 by reaction with an alkyl halide or with a corresponding halide / acyl.
- Ί .- Ί.
Les composés (III) sont décrits dans la littérature.The compounds (III) are described in the literature.
Les exemples suivants illustrent la préparation des composés de 11 invention.The following examples illustrate the preparation of the compounds of 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.
fi Exemple 1 j £(Trif luorométhylthio-3 phênyl)-4 pipérazinyl-lj -2 ëthyli -1 pyridone-2 et son chlorhydrate.fi Example 1 j £ (Trifluoromethylthio-3 phenyl) -4 piperazinyl-1j -2 ethyli -1 pyridone-2 and its hydrochloride.
i n = 2 R = -n\ j-i n = 2 R = -n \ j-
Sous azote on porte à la température de reflux un mélange de j 18,36g (0,07 mole) de (trifluoromëthylthio-3 phényl)-4 pipërazine ; ' 11,8g (0,075 mole) de N-(p-chloro-éthyl)-1 pyridone-2, 58,8ml de ^ ' toluène, 17,25g (0,1248 mole) de carbonate de potassium pulvérisé et 0,35g d'iodure de potassium. Au bout de 16 heures on filtre puis évapore le filtrat. On reprend à l'éther et extrait à l'acide chlorhydrique 10%. La phase aqueuse est alcalinisëe â pH 9-10 par de la lessive de soude.Under nitrogen, a mixture of 18.36 g (0.07 mole) of (trifluoromethyl-3-phenyl) -4 pipërazine is brought to reflux temperature; '11.8 g (0.075 mole) of N- (p-chloro-ethyl) -1 pyridone-2, 58.8 ml of toluene, 17.25 g (0.1248 mole) of potassium carbonate pulverized and 0.35 g potassium iodide. After 16 hours, the filter is filtered and then the filtrate is evaporated. It is taken up in ether and extracted with 10% hydrochloric acid. The aqueous phase is basified to pH 9-10 with sodium hydroxide solution.
On extrait le produit à l'éther puis on le lave à LLeau jusqu'à pH 7-8.The product is extracted with ether and then washed with water to pH 7-8.
On sèche, filtre et concentre. On obtient 24g d'huile que l'on chromatographie sur 600g de silice (éluant MeOH 0,5/CHCl3 9,5).It is dried, filtered and concentrated. 24g of oil are obtained which is chromatographed on 600g of silica (eluent MeOH 0.5 / CHCl3 9.5).
On récupère 18,8g d'huile brune que l'on dissout dans de l'éther i et ajoute 10,86 ml (0,0489 mole) d'éther chlorhydrique 4,5 N.18.8 g of brown oil are recovered which is dissolved in ether i and 10.86 ml (0.0489 mol) of 4.5N hydrochloric ether are added.
!' On filtre, lave à l'éther et recristallise dans de 1 'isopropanol.! ' Filtered, washed with ether and recrystallized from isopropanol.
On obtient une poudre blanche. On libère la base à l'aide de ! NH^OH concentrée à partir de laquelle on obtient le chlorhydrate : à l'aide d'éther chlorhydrique 4,18N. On filtre, lave à l'éther : * . puis sèche au dessicateur chauffant en présence de potasse.A white powder is obtained. We release the base using! NH ^ OH concentrated from which the hydrochloride is obtained: using 4.18N hydrochloric ether. Filter, wash with ether: *. then dry in a heated desiccator in the presence of potash.
i ' Le produit obtenu fond à 217-218°C.i 'The product obtained melts at 217-218 ° C.
Exemple 2 < £(Trifluorométhylthio-3 phényl)-4 pipérazinyl-lj-2 éthylj-1 méthyl-3 benzimidazolidinone-2.Example 2 <£ (3-trifluoromethylthio-phenyl) -4 piperazinyl-1-2-ethyl-1-methyl-3 benzimidazolidinone-2.
et R2 = n=2 X=N-CH3 m=0 Jand R2 = n = 2 X = N-CH3 m = 0 J
/ / - 4 - !/ / - 4 -!
Sous azote on porte à la température de reflux le mélange suivant : 10,5g (0,04 mole) de (trifluorométhylthio-3 phényl)-4 pipérazine ; 12,16g (0,088 mole) de K2C03 pulvérisé ; 40 ml de toluène, 9,48g (0,045 mole) de (p-chloroêthyl)-1 mêthyl-3 benzi-midazolidinone-2 et 0,3g d'iodure de potassium. Au bout de 16h la réaction n'évolue pratiquement plus. On filtre puis évapore le filtrat. On reprend le produit cristallisé à l'éther et filtre. On obtient la base.Under nitrogen, the following mixture is brought to reflux temperature: 10.5 g (0.04 mole) of (3-trifluoromethylthio-phenyl) -4 piperazine; 12.16 g (0.088 mole) of K2CO3 sprayed; 40 ml of toluene, 9.48 g (0.045 mole) of (p-chloroethyl) -1 3-methyl-benzi-midazolidinone-2 and 0.3 g of potassium iodide. At the end of 16h the reaction hardly evolves any more. It is filtered and then the filtrate is evaporated. The product crystallized from ether is taken up and filtered. We get the basis.
F = 125-127°C.Mp 125-127 ° C.
On dissout la base dans 4 00ml d'acétone et 50ml de CE^C^· On y introduit 7ml (0,0293 mole) d'éther chlorhydrique 4,18R.The base is dissolved in 400 ml of acetone and 50 ml of CE ^ C ^ · 7 ml (0.0293 mole) of 4.18R hydrochloric ether are introduced.
Le chlorhydrate précipite doucement.On laisse agiter 1 heure puis filtre et sëche au dessicateur chauffant à 60°C pendant 8 heures.The hydrochloride precipitates gently, left to stir for 1 hour then filters and dries in a heated desiccator at 60 ° C for 8 hours.
On obtient une poudre blanche.A white powder is obtained.
F = 260-263°C (déc.)M = 260-263 ° C (dec.)
Exemple 3 (m-trifluorométhylthio-phényl)-1 (tétrahydrofuryl-2 méthyl)-4 pipérazine et son chlorhydrate, n = 1 R = -ÇExample 3 (m-trifluoromethylthio-phenyl) -1 (tetrahydrofuryl-2 methyl) -4 piperazine and its hydrochloride, n = 1 R = -Ç
On chauffe à 120°C durant 2 heures un mélange de 13,5g (0,05 mole) de m-trifluorométhylthio-pipérazine, 13,5g (0,054 mole) de tosylate de tétrahydrofuryl-2 méthyle et 13,5ml de HMPT. On refroidit à 10°C et on ajoute 100ml d'eau. On sépare l'eau de l'huile, puis on lave 3 fois à l'eau pour éliminer le HMPT. On reprend par du chloroforme, on sépare les traces d'eau et on sèche la solution , chloroformique sur du sulfate de magnésium. On ajoute de l'éther chlorhydrique et on évapore les solvants. On triture le résidu d'évaporation avec de l'éther, on essore le précipité. On alca-linise par NaOH 2N et on extrait au chloroforme.On évapore le chloroforme et on prépare le chlorhydrate à partir de l'huile restant de l'évaporation. On recristallise le composé dans un mélange iso-propanol/éther.A mixture of 13.5 g (0.05 mole) of m-trifluoromethylthio-piperazine, 13.5 g (0.054 mole) of 2-tetrahydrofuryl methyl tosylate and 13.5 ml of HMPT is heated at 120 ° C. for 2 hours. Cool to 10 ° C and add 100ml of water. The water is separated from the oil, then washed 3 times with water to remove the HMPT. It is taken up in chloroform, the traces of water are separated and the solution is dried, chloroformic over magnesium sulfate. Hydrochloric ether is added and the solvents are evaporated. The evaporation residue is triturated with ether, the precipitate is filtered off. It is alkalinized with 2N NaOH and extracted with chloroform. The chloroform is evaporated and the hydrochloride is prepared from the oil remaining from evaporation. The compound is recrystallized from an isopropanol / ether mixture.
F = 210°C.Mp 210 ° C.
AAT
/ ! - 5 - fi i \ i * î i ' Exemple 4 (m-trifluororoéthylthio-phényl)-1 (mercapto-2 éthyl) | -4 pipérazine et son chlorhydrate./! - 5 - fi i \ i * î i 'Example 4 (m-trifluororoethylthio-phenyl) -1 (2-mercapto ethyl) | -4 piperazine and its hydrochloride.
| [n = 1 R = Ch’2 SH] j Dans un erlenmeyer on ajoute goutte à goutte, à 20°C, 3,84g (j (0,064 mole) de sulfure d'éthylène à une solution de 15g (0,0557 I mole) de m-trifluoromëthylthic-phényl pipérazine et de 2ml de méthanol.| [n = 1 R = Ch'2 SH] j In an Erlenmeyer flask, 3.84 g (d (0.064 mole) of ethylene sulfide) are added dropwise at 20 ° C to a solution of 15 g (0.0557 I mole) of m-trifluoromethylthic-phenyl piperazine and 2 ml of methanol.
j On chauffe progressivement à 55°C et maintient cette température | 1 heure 30. On évapore le solvant et rectifie au tube à boules.j We gradually heat up to 55 ° C and maintain this temperature | 1 hour 30 minutes. The solvent is evaporated and rectified with a ball tube.
1 Eb = 200eC sous 0,1 mm de Hg.1 Eb = 200eC under 0.1 mm Hg.
-I-I
î On prépare le chlorhydrate par addition d'éther chlorhydrique à -i . une solution de la base dans de l'acétate d'éthyle. F = 141°C.The hydrochloride is prepared by adding hydrochloric ether at -i. a solution of the base in ethyl acetate. Mp = 141 ° C.
i -j \ Exemple 5 (m-trifluoromëthylthio-phényl)-1 (mëthylthio-2 i éthyl)-4 pipérazine et son chlorhydrate.i -j \ Example 5 (m-trifluoromethylthio-phenyl) -1 (2-methylthio-ethyl) -4 piperazine and its hydrochloride.
:j · [n - 1 R = CHj SCH2] jj A une solution refroidie à +5°C de 4,8g (0,015 mole) de (m-tri- fluorométhylthio-phényl)-1 (mercapto-2 éthyl)-4 pipérazine dans h |l ^ 40ml de D.M.F., on ajoute par portion 0,84g (0,0175mole) d'hydrurt [; de sodium à 50%. Lorsque le dégagement d'hydrogène a cessé, on y j: ajoute, goutte à goutte, 2,16g (0,0152 mole) d'iodure de méthyle !; fi en solution dans 20ml de DMF. On laisse en contact toute la nuit s jj On verse sur de la glace et extrait 2 fois à l'éther. On sèche i] la solution éthérëe sur sulfate de magnésium et on évapore.: j · [n - 1 R = CHj SCH2] jj To a solution cooled to + 5 ° C of 4.8g (0.015 mole) of (m-tri-fluoromethylthio-phenyl) -1 (2-mercapto ethyl) -4 piperazine in h | l ^ 40ml of DMF, 0.84 g (0.0175 mol) of hydrurt [is added per serving; 50% sodium. When the evolution of hydrogen has ceased, there is added: 2.16 g (0.0152 mol) of methyl iodide! fi in solution in 20ml of DMF. It is left in contact overnight s jj It is poured onto ice and extracted twice with ether. The ethereal solution is dried over magnesium sulfate and evaporated.
I On prépare le chlorhydrate dans de l'acétate d'éthyle en ajoutant P la quantité théorique d'éthanol chlorhydrique.I The hydrochloride is prepared in ethyl acetate by adding P the theoretical amount of hydrochloric ethanol.
HH
fi F = 135°C.fi F = 135 ° C.
| ’ .| ’.
I Dans le tableau suivant (I) sont représentés les composés de $ ;j l'invention préparés à titre d'exemples, iI In the following table (I) are represented the compounds of $; j the invention prepared by way of examples, i
5 /X5 / X
j '' !Î !| :· iîi!! Î! | : · Iî
- 6 -TABLEAU- 6 - TABLE
P—v_y— (cH2>n'RP — v_y— (cH2> n'R
SCF3SCF3
Composé n R Caractéristiques du chlorhydrate F(°C) - — 1 2 —N^^jO 188-190 (dec) 0Compound n R Characteristics of the hydrochloride F (° C) - - 1 2 —N ^^ jO 188-190 (dec) 0
II
2 2 -217-218 (dec) ___0__ 3 2 -'i 230 (dec) ___CT__ 4 2 N\/N CH3 178-180 (dec)2 2 -217-218 (dec) ___0__ 3 2 -'i 230 (dec) ___CT__ 4 2 N \ / N CH3 178-180 (dec)
IIII
___Q__ 5 3 224-227 (dec) 6 3 N ' 196-199 ___0__ 7 2 --R \ 217-218___Q__ 5 3 224-227 (dec) 6 3 N '196-199 ___0__ 7 2 --R \ 217-218
^ ^ X^ ^ X
8 2 _N'^'N_CH3 260-263 (dec) (ex 2) j—!—18 2 _N '^' N_CH3 260-263 (dec) (ex 2) j -! - 1
/ _ _ _ , - 7 - ’ Composé n R Caractéristiques du chlorhydrate F (°C) 9 1 210 (ex 3) — .5 £ 10 1 -CH2 SH 141 | (ex 4) j 11 1 -CH-jSCH-. 135 J ' (ex 5) i ! ! j | 12 1 -CH2 0CH3 151 ! ---- t t ί· ' 13 1 -CHo-S-C0CH-. 168 Ü 14 1 -CH2-0-C4H9 140 ;Î ____________________________________ i /(/x !' ί i*./ _ _ _, - 7 - ’Compound n R Characteristics of hydrochloride F (° C) 9 1 210 (ex 3) - .5 £ 10 1 -CH2 SH 141 | (ex 4) j 11 1 -CH-jSCH-. 135 I (ex 5) i! ! j | 12 1 -CH2 0CH3 151! ---- t t ί · '13 1 -CHo-S-C0CH-. 168 Ü 14 1 -CH2-0-C4H9 140; Î ____________________________________ i / (/ x! 'Ί i *.
ii jj ij !j j.ii jj ij! j j.
LL
j.j.
r t i t t , . *1 ‘ 8r t i t t,. * 1 ‘8
Les composés de l'invention sont actifs en thérapeutique dans le domaine du système nerveux çentral.The compounds of the invention are active in therapy in the field of the central nervous system.
Cette activité a été démontrée et mesurée par le test des 4 plaques (Aron C. Thèse de Médecine - Paris 1970) ; Boissier J.R., Simon P. et Aron C. - Une nouvelle méthode de détermination des tranquillisants chez la souris. Eur. J. Pharmacol. 1968,4^ , 145-151).This activity has been demonstrated and measured by the 4-plate test (Aron C. Thèse de Médecine - Paris 1970); Boissier J.R., Simon P. and Aron C. - A new method for determining tranquilizers in mice. Eur. J. Pharmacol. 1968,4 ^, 145-151).
Les composés sont administrés à plusieurs doses (1,3 et 10 mg/kg) par voie orale, 60 minutes avant le test. On mesure le pourcentage de désinhibition chez la souris.The compounds are administered in several doses (1.3 and 10 mg / kg) orally, 60 minutes before the test. The percentage of inhibition is measured in mice.
A la dose de lmg/kg le pourcentage varie de 35 à 70 ; à la dose de 3 mg/kg, il varie de 80 à 150 et à la dose de 10 mg/kg, il va de 120 à 300.At the dose of 1 mg / kg the percentage varies from 35 to 70; at a dose of 3 mg / kg, it varies from 80 to 150 and at a dose of 10 mg / kg, it ranges from 120 to 300.
Aux memes doses, plus le pourcentage est élevé plus l'activité du composé est grande.At the same doses, the higher the percentage the greater the activity of the compound.
La toxicité aiguë (DL50) est déterminée sur la souris soit par voie i.p. après 48 heures, soit par voie orale pendant 7 jours La DL50 par voie i.p. varie de 75 à 230 mg/kg. La DL50 par voie orale varie de 250 à 1000 mg/kg.Acute toxicity (LD50) is determined in mice either i.p. after 48 hours, orally for 7 days The LD50 i.p. ranges from 75 to 230 mg / kg. The oral LD50 ranges from 250 to 1000 mg / kg.
Les composés de l'invention possèdent des propriétés psychotropes qui permettent de les utiliser pour le traitement des divers états de l'anxiété et de la dépression.The compounds of the invention have psychotropic properties which make it possible to use them for the treatment of various states of anxiety and depression.
Ils peuvent être administrés par voie orale ou parentérale avec tout excipient approprié, sous toute forme d'administration appropriée : gélules, comprimés, capsules, dragées, solutés injectables ...They can be administered orally or parenterally with any suitable excipient, in any form of appropriate administration: capsules, tablets, capsules, dragees, injectable solutions ...
La posologie quotidienne peut aller de 5 à 200mg.The daily dosage can range from 5 to 200mg.
/* / // * / /
Claims (5)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7818351A FR2429212A1 (en) | 1978-06-20 | 1978-06-20 | PHENYLPIPERAZINE DERIVATIVES AND THEIR THERAPEUTIC APPLICATION |
| FR7818351 | 1978-06-20 | ||
| FR7818352A FR2429216A1 (en) | 1978-06-20 | 1978-06-20 | CNS-active substd. alkyl-meta:tri:fluoro:methyl:thio:phenyl-piperazine - with psychotropic properties, useful in treatment of anxiety and depression |
| FR7818352 | 1978-06-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| LU81396A1 true LU81396A1 (en) | 1981-02-03 |
Family
ID=26220635
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| LU81396A LU81396A1 (en) | 1978-06-20 | 1979-06-18 | PHENYLPIPERAZINE DERIVATIVES |
Country Status (15)
| Country | Link |
|---|---|
| AU (1) | AU521110B2 (en) |
| DE (1) | DE2924681A1 (en) |
| DK (1) | DK251079A (en) |
| ES (1) | ES481632A1 (en) |
| FI (1) | FI791926A (en) |
| GB (1) | GB2023594B (en) |
| GR (1) | GR67646B (en) |
| IL (1) | IL57569A0 (en) |
| IT (1) | IT1121588B (en) |
| LU (1) | LU81396A1 (en) |
| NL (1) | NL7904755A (en) |
| NO (1) | NO792020L (en) |
| NZ (1) | NZ190758A (en) |
| PT (1) | PT69775A (en) |
| SE (1) | SE7905402L (en) |
Families Citing this family (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4456756A (en) * | 1981-08-03 | 1984-06-26 | Mead Johnson & Company | Spirothiazolidinyl piperazine derivatives |
| US4367335A (en) * | 1981-08-03 | 1983-01-04 | Mead Johnson & Company | Thiazolidinylalkylene piperazine derivatives |
| US4411901A (en) * | 1981-12-23 | 1983-10-25 | Mead Johnson & Company | Benzisothiazole and benzisoxazole piperazine derivatives |
| US4452799A (en) * | 1981-12-23 | 1984-06-05 | Mead Johnson & Company | Benzisothiazole and benzisoxazole piperazine derivatives |
| US4423049A (en) | 1981-12-28 | 1983-12-27 | Mead Johnson & Company | 2-[4-[(4,4-Dialkyl-2,6-piperidinedion-1-yl)butyl]-1-piperazinyl]pyrimidines |
| US4361565A (en) * | 1981-12-28 | 1982-11-30 | Mead Johnson & Company | 2-[4-[(4,4-Dialkyl-2,6-piperidinedion-1-yl)butyl]-1-piperazinyl]pyridines |
| US4668687A (en) * | 1984-07-23 | 1987-05-26 | Bristol-Myers Company | Psychogeriatric 1-(2-pyrimidinyl)piperazinyl derivatives of 1-pyrrolidin-2-ones |
| GB8427125D0 (en) * | 1984-10-26 | 1984-12-05 | Lundbeck & Co As H | Organic compounds |
| US5098904A (en) * | 1990-06-27 | 1992-03-24 | Bristol-Myers Squibb Company | Cerebral function enhancing pyrimidinyl derivatives |
| ES2084763T3 (en) * | 1990-10-23 | 1996-05-16 | Akzo Nobel Nv | 4- (4- O 6- (2-TRIFLUORMETHYL PIRIDINYL)) 1-PIPERAZINYLALKYL SUBSTITUTED LACTAMS. |
| CA2067475C (en) * | 1991-05-08 | 2000-10-10 | Yasuo Oshiro | Carbostyril derivatives and their use |
| IT1251144B (en) * | 1991-07-30 | 1995-05-04 | Boehringer Ingelheim Italia | BENZIMIDAZOLONE DERIVATIVES |
| DE69736291T2 (en) * | 1997-10-22 | 2006-11-23 | Council Of Scientific And Industrial Research | A process for the synthesis of 1- (4-arylpiperazin-1-yl) -3- (oxopyrrolidine / piperidin-1-yl) propanes as therapeutic agents in hypertension, ischemia, cardiovascular and other disorders associated with adrenergic receptors |
| EP0911330B1 (en) * | 1997-10-22 | 2007-12-12 | Council of Scientific & Industrial Research | 1-(4-Arylpiperazine-1-y1)-3-(2-oxopyrrolidin/piperidin-1-y1) propanes as therapeutic agents for hypertension, ischemia, cardiovascular and other adrenergic receptors related disorders |
| US7183410B2 (en) | 2001-08-02 | 2007-02-27 | Bidachem S.P.A. | Stable polymorph of flibanserin |
| US10675280B2 (en) | 2001-10-20 | 2020-06-09 | Sprout Pharmaceuticals, Inc. | Treating sexual desire disorders with flibanserin |
| UA78974C2 (en) | 2001-10-20 | 2007-05-10 | Boehringer Ingelheim Pharma | Use of flibanserin for treating disorders of sexual desire |
| US8227476B2 (en) | 2005-08-03 | 2012-07-24 | Sprout Pharmaceuticals, Inc. | Use of flibanserin in the treatment of obesity |
| JP2009513604A (en) | 2005-10-29 | 2009-04-02 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Benzimidazolone derivatives for the treatment of premenstrual disorders and other female sexual disorders |
| WO2008000760A1 (en) | 2006-06-30 | 2008-01-03 | Boehringer Ingelheim International Gmbh | Flibanserin for the treatment of urinary incontinence and related diseases |
| CL2007002214A1 (en) | 2006-08-14 | 2008-03-07 | Boehringer Ingelheim Int | PHARMACEUTICAL COMPOSITION IN THE FORM OF COMPRESSED, WHERE AT LEAST THE LENGTH OF THE COMPRESSED IN THE PREVIOUS STATE OF THE APPLICATION IS AT LEAST 7/12 OF THE PILOR DIAMETER OF THE PATIENT AND AFTER INGERING IT IN THE FOOD STATE, THE LENGTH OF THE COMP |
| KR20090042967A (en) | 2006-08-14 | 2009-05-04 | 베링거 인겔하임 인터내셔날 게엠베하 | Formulations of flibanserin and method for manufacturing the same |
| AR062321A1 (en) | 2006-08-25 | 2008-10-29 | Boehringer Ingelheim Int | CONTROLLED RELEASE SYSTEM AND METHOD TO MANUFACTURE |
| PE20091188A1 (en) | 2007-09-12 | 2009-08-31 | Boehringer Ingelheim Int | COMPOUND 1- [2- (4- (3-TRIFLUOROMETIL-PHENYL) PIPERAZIN-1-IL) ETHYL] -2,3-DIHYDRO-1H-BENZIMIDAZOL-2-ONA (FLIBANSERIN), ITS ADDITION SALTS AND PHARMACEUTICAL COMPOSITIONS THAT THEY CONTAIN |
| CA2686480A1 (en) | 2008-12-15 | 2010-06-15 | Boehringer Ingelheim International Gmbh | New salts |
| BRPI1003506B1 (en) | 2010-09-24 | 2019-12-03 | Ache Int Bvi Ltd | alkyl-piperazine-phenyl-4 (3h) quinazolinone compound and use of the alkyl-piperazine-phenyl-4 (3h) quinazolinone compound associated with 5-ht1a and 5-ht2a serotonergic receptors |
-
1979
- 1979-06-15 FI FI791926A patent/FI791926A/en not_active Application Discontinuation
- 1979-06-15 DK DK251079A patent/DK251079A/en not_active Application Discontinuation
- 1979-06-15 AU AU48112/79A patent/AU521110B2/en not_active Ceased
- 1979-06-15 IL IL57569A patent/IL57569A0/en unknown
- 1979-06-18 ES ES481632A patent/ES481632A1/en not_active Expired
- 1979-06-18 LU LU81396A patent/LU81396A1/en unknown
- 1979-06-18 IT IT23695/79A patent/IT1121588B/en active
- 1979-06-18 NO NO792020A patent/NO792020L/en unknown
- 1979-06-18 PT PT69775A patent/PT69775A/en unknown
- 1979-06-18 NZ NZ190758A patent/NZ190758A/en unknown
- 1979-06-18 GR GR59368A patent/GR67646B/el unknown
- 1979-06-19 GB GB7921307A patent/GB2023594B/en not_active Expired
- 1979-06-19 SE SE7905402A patent/SE7905402L/en not_active Application Discontinuation
- 1979-06-19 DE DE19792924681 patent/DE2924681A1/en not_active Withdrawn
- 1979-06-19 NL NL7904755A patent/NL7904755A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| NO792020L (en) | 1979-12-21 |
| IT1121588B (en) | 1986-04-02 |
| GB2023594A (en) | 1980-01-03 |
| NL7904755A (en) | 1979-12-27 |
| GB2023594B (en) | 1982-10-13 |
| IT7923695A0 (en) | 1979-06-18 |
| PT69775A (en) | 1979-07-01 |
| AU4811279A (en) | 1980-02-07 |
| ES481632A1 (en) | 1980-02-16 |
| DE2924681A1 (en) | 1980-01-10 |
| NZ190758A (en) | 1980-10-24 |
| GR67646B (en) | 1981-09-01 |
| FI791926A (en) | 1979-12-21 |
| SE7905402L (en) | 1979-12-21 |
| IL57569A0 (en) | 1979-10-31 |
| DK251079A (en) | 1979-12-21 |
| AU521110B2 (en) | 1982-03-18 |
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