DE2924681A1 - PHENYLPIPERAZINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THE SAME - Google Patents
PHENYLPIPERAZINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THE SAMEInfo
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- DE2924681A1 DE2924681A1 DE19792924681 DE2924681A DE2924681A1 DE 2924681 A1 DE2924681 A1 DE 2924681A1 DE 19792924681 DE19792924681 DE 19792924681 DE 2924681 A DE2924681 A DE 2924681A DE 2924681 A1 DE2924681 A1 DE 2924681A1
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- 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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- 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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- 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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- 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
BESCHREIBUNGDESCRIPTION
Die Erfindung betrifft Phenylpiperazinderivate, die Additionssalze dieser Verbindungen mit pharmazeutisch annehmbaren Säuren, ein Verfahren zu ihrer Herstellung und die therapeutische Anwendung dieser Verbindungen, insbesondere Arzneimittel, die diese Substanzen als Wirkstoffe enthalten.The invention relates to phenylpiperazine derivatives, the addition salts of these compounds with pharmaceutical acceptable acids, a process for their preparation and the therapeutic use of these compounds, especially drugs that contain these substances as active ingredients.
Die Erfindung betrifft insbesondere die Phenylpiperazinderivate der nachstehenden allgemeinen Formel IThe invention relates in particular to the phenylpiperazine derivatives of the general formula I below
2020th
in derin the
η 1,2 oder 3
undη 1,2 or 3
and
R eine Gruppe der allgemeinen FormelR is a group of the general formula
E1 E 1
/■*/ ■ *
3030th
in der
R1 und R„ jeweils Wasserstoffatome oderin the
R 1 and R "are each hydrogen atoms or
gemeinsam die Gruppe der Formel 35together the group of formula 35
909882/0751909882/0751
SYNTHELABO, SET 28SYNTHELABO, SET 28
C _C _
X eine Thiogruppe, eine Oxygruppe, eine Iminogruppe, eine Alkyliminogruppe oderX is a thio group, an oxy group, an imino group, an alkylimino group or
eine Methylengruppe und m 0 oder 1 darstellen; eine Gruppe der Formela methylene group and m represent 0 or 1; a group of the formula
O''
eine Tetrahydrofur-2-ylgruppe; eine Gruppe der Formel -CH2-SH; eine Gruppe der Formel
-CH2-S-Alkyl; eine Gruppe der Formel -CH„-O-Alkyl
oder eine Gruppe der Formel -CH2-S-CO-O''
a tetrahydrofur-2-yl group; a group of the formula -CH 2 -SH; a group of the formula -CH 2 -S-alkyl; a group of the formula -CH "-O-alkyl or a group of the formula -CH 2 -S-CO-
Alkyl;Alkyl;
worin die Alkylgruppen 1 bis 8 Kohlenstoffatome aufweisen,
bedeuten.wherein the alkyl groups have 1 to 8 carbon atoms,
mean.
Die Additionssalze der Verbindungen der allgemeinen Formel I mit pharmazeutisch annehmbaren Säuren sind ebenfalls Gegenstand der Erfindung.The addition salts of the compounds of general formula I with pharmaceutically acceptable acids are also Subject of the invention.
Erfindungsgemäß kann man die Verbindungen der allgemeinen Formel I dadurch herstellen, daß man m-Trifluormethylthio-phenylpiperazin der nachstehenden Formel IIAccording to the invention, the compounds of the general Formula I prepared by using m-trifluoromethylthio-phenylpiperazine of the formula II below
(/ V-N Vh (ID (/ VN Vh (ID
3030th
SCF3 SCF 3
' mit einer Verbindung der nachstehenden allgemeinen Formel III ' with a compound of the general formula III below
Y- (CH0) -R (III)Y- (CH 0 ) -R (III)
2 η2 η
SYNTHELABO, SET 28SYNTHELABO, SET 28
- 6- 6
in derin the
R und η die oben angegebenen Bedeutungen besitzen undR and η have the meanings given above and
Y für ein Anion des aktivierten Alkoholderivats, wie ein Halogenidion, eine Mesylation, ein Tosylation oder ein Halogenomethansulfonation Y for an anion of the activated alcohol derivative, such as a halide ion, a mesylation ion, a tosylate ion or a halogenomethanesulfonate ion
steht, umsetzt.stands, implements.
Diese Reaktion bewirkt man vorzugsweise bei einer Temperatur von 20 bis 150 °C in einem polaren oder nichtpolaren Lösungsmittel, wie einem benzolischen Kohlenwasserstoff, einem Hydroxylgruppen oder Ketongruppen aufweisenden Lösungsmittel, Dimethylformamid (DMF) oder Hexamethylphosphortriamid (HMPT).This reaction is preferably carried out at a temperature of 20 to 150 ° C in a polar or non-polar solvent, such as a benzene hydrocarbon, a solvent containing hydroxyl groups or ketone groups, dimethylformamide (DMF) or Hexamethylphosphoric triamide (HMPT).
Zur Herstellung der Verbindung, in der R für die Gruppe der Formel -CH„SH steht, kann man auch das Phenylpiperazin der obigen Formel II mit Äthylensulfid umsetzen.Phenylpiperazine can also be used to prepare the compound in which R represents the group of the formula —CH “SH of the above formula II with ethylene sulfide.
Man kann die Verbindungen der Formel I, in der R eine Tetrahydrofur-2-yl-Gruppe (-^x1 ) , eine Gruppe der Formel -CH2O-Alkyl oder eine Gruppe der Formel-CH2S-Alkyl darstellt, dadurch herstellen, daß man die Verbindung der nachstehenden Formel IVThe compounds of the formula I in which R is a tetrahydrofur-2-yl group (- ^ x 1 ), a group of the formula -CH 2 O-alkyl or a group of the formula -CH 2 S-alkyl, can thereby be obtained produce that the compound of the following formula IV
NH2 (IV)NH 2 (IV)
SCF3 SCF 3
mit einer Verbindung der nachstehenden allgemeinen Formel Vwith a compound of the general formula V below
HaI-CH0-CH0.»__HaI-CH 0 -CH 0. »__
2 J>N- (CH2) R (V) HaI-CH2-CH2 *-""" 2 J> N- (CH 2 ) R (V) Hal-CH 2 -CH 2 * - """
909882/0751909882/0751
SYNTHELABO, SET 28SYNTHELABO, SET 28
in der η und R die oben angegebenen Bedeutungen besitzen und Hai für ein Halogenatom steht, umsetzt.in which η and R have the meanings given above and Hal stands for a halogen atom.
Erfindungsgemäß kann man auch die Derivate der allgemeinen Formel I, in der R eine Gruppe der Formel -CH2-S-Alkyl oder der Formel -CH2-S-CO-Alkyl bedeutet, ausgehend von einer Verbindung der nachstehenden allgemeinen Formel IAccording to the invention, the derivatives of the general formula I in which R is a group of the formula -CH 2 -S-alkyl or the formula -CH 2 -S-CO-alkyl, starting from a compound of the general formula I below
in der η die oben angegebenen Bedeutungen besitzt, herstellen, indem man diese Verbindung mit einem entsprechenden Alkylhalogenid oder Acylhalogenid umsetzt.in the η has the meanings given above, produce by this compound with a corresponding Reacts alkyl halide or acyl halide.
Die Verbindungen der oben angegebenen Formelui sind in der Literatur beschrieben.The compounds of the formula given above are described in the literature.
Die folgenden Beispiele dienen der weiteren Erläuterung der Erfindung.The following examples serve to further illustrate the invention.
Die Analysen und die IR- und NMR-Spektren bestätigen die angegebenen Strukturen der erfindungsgemäßen Verbindungen. The analyzes and the IR and NMR spectra confirm the stated structures of the compounds according to the invention.
1- {2-/"4-(3-Trifluormethylthio-phenyl)-piperazin-1-yl/-äthyiy-2-pyridon und dessen Hydrochlorid.1- {2 - / "4- (3-trifluoromethylthio-phenyl) -piperazin-1-yl / -ethyiy-2-pyridone and its hydrochloride.
Formel I, η = 2, R = - N J) Formula I, η = 2, R = - N J)
SYNTHELABO, SET 28SYNTHELABO, SET 28
Q mm Q mm
Man erhitzt eine Mischung aus 18,36 g (0,07 Mol) 4-(3-Trifluormethylthio-phenyl)-piperazin, 11,8 g (0,075 Mol) 1-N-(ß-Chlor-äthyl}-pyridon-2, 58,8 ml Toluol, 17,25 g (0,1248 Mol) pulverförmiges Kaliumcarbonat und 0,35 Kaliumjodid unter Stickstoff zum Sieden am Rückfluß. Nach Ablauf von 16 Stunden filtriert man die Reaktionsmischung und dampft das Filtrat ein. Man nimmt mit Äther auf und extrahiert mit 1Oprozentiger Chlorwasserstoffsäure. Die wäßrige Phase wird mit einer Natriumhydroxidlösung auf einen pH-Wert von 9 bis 10 alkalisch gestellt.A mixture of 18.36 g (0.07 mol) of 4- (3-trifluoromethylthiophenyl) piperazine, 11.8 g, is heated (0.075 mol) 1-N- (β-chloro-ethyl} -pyridone-2, 58.8 ml toluene, 17.25 g (0.1248 mol) powdered potassium carbonate and 0.35 potassium iodide under nitrogen to reflux. Filtered after 16 hours the reaction mixture and evaporate the filtrate. Take up with ether and extract with 10 percent hydrochloric acid. The watery one The phase is made alkaline to a pH of 9 to 10 with a sodium hydroxide solution.
Man extrahiert das Produkt mit Äther und wäscht es bis zu einem pH-Wert von 7 bis 8 mit Wasser.The product is extracted with ether and washed with water to a pH of 7 to 8.
Man trocknet, filtriert und engt ein. Man erhält 24 g eines Öls, das man über 600 g Siliciumdioxid chromatographiert (wobei man mit einer Methanol/Chloroform-Mischung (0,5/9,5) eluiert). Man gewinnt 18,8 g eines braunen Öls, das man in Äther löst und mit 10,86 ml (0,0489 Mol) einer 4,5n Chlorwasserstofflösung in Äther versetzt. Man filtriert, wäscht mit Äther und kristallisiert aus Isopropylalkohol um. Man erhält ein weißes Pulver. Man setzt die Base mit Hilfe einer konzentrierten Ammoniaklösung frei und bildet aus der Base das Hydrochlorid durch Zugabe einer 4,18n Chlorwasserstoffsäurelösung in Äther. Man filtriert, wäscht mit Äther und trocknet im Exsikkator durch Erhitzen in Gegenwart von Kaliumhydroxid. Das erhaltene Produkt schmilzt bei 217 bis 218 0C.It is dried, filtered and concentrated. 24 g of an oil are obtained which is chromatographed on 600 g of silica (eluting with a methanol / chloroform mixture (0.5 / 9.5)). 18.8 g of a brown oil are obtained, which are dissolved in ether and treated with 10.86 ml (0.0489 mol) of a 4.5N hydrogen chloride solution in ether. It is filtered, washed with ether and recrystallized from isopropyl alcohol. A white powder is obtained. The base is released with the aid of a concentrated ammonia solution and the hydrochloride is formed from the base by adding a 4.18N hydrochloric acid solution in ether. It is filtered, washed with ether and dried in a desiccator by heating in the presence of potassium hydroxide. The product obtained melts at 217 to 218 ° C.
1- j 2-£4-(3-Trifluormethylthio-phenyl)-piperazin-1-yl7~ äthyl j 3-methyl-benzimidazolidinon-21- j 2- £ 4- (3-trifluoromethylthio-phenyl) -piperazin-1-yl7-ethyl j 3-methyl-benzimidazolidinone-2
909882/0751909882/0751
SYNTHELABO, SET 28SYNTHELABO, SET 28
Formel 1: R1 und R2= ζ\ η = 2 X = N-CH3 m = 0Formula 1: R 1 and R 2 = ζ \ η = 2 X = N-CH 3 m = 0
2= ζ\ η = 2 X = N-CH3 2 = ζ \ η = 2 X = N-CH 3
Man erhitzt eine Mischung aus 10,5 g (0,04 Mol) 4-(3-Trifluormethylthio-phenyl)-piperazin, 12,16 g (0,088 MdI) pulverförmiges Kaliumcarbonat, 40 ml Toluol, 9,48 g ((0,045MoI) 1-(ß-Chloräthyl)-3-methyl-benzimidazolidinon-2 und 0,3 g Kaliumjodid unter Stickstoff zum Sieden am Rückfluß. Nach Ablauf von 16 Stunden ist die Reaktion praktisch vollständig abgelaufen. Man filtriert und dampft das Filtrat ein. Man nimmt das kristalline Produkt mit Äther auf und filtriert. Man erhält die Base, die bei 125 bis 127 0C schmilzt.A mixture of 10.5 g (0.04 mol) 4- (3-trifluoromethylthiophenyl) piperazine, 12.16 g (0.088 MdI) powdered potassium carbonate, 40 ml toluene, 9.48 g ((0.045 mol) is heated 1- (β-chloroethyl) -3-methyl-benzimidazolidinone-2 and 0.3 g of potassium iodide under nitrogen to reflux. After 16 hours the reaction is practically complete. The filtrate is filtered and evaporated takes the crystalline product with ether and filtered. this gives the base which melts at 125 to 127 0 C.
Man löst die Base in 400 ml Aceton und 50 ml Methylenchlorid. Man gibt 7 ml (0,0293 Mol) einer 4,18n Chlorwasserstofflösung in Äther zu. Das Hydrochlorid fällt langsam aus. Man rührt während 1 Stunde, filtriert und trocknet dann im Exsikkator während 8 Stunden bei 60 0C. Man erhält ein weißes Pulver. F = 260 bis 263 0C (Zersetzung).The base is dissolved in 400 ml of acetone and 50 ml of methylene chloride. 7 ml (0.0293 mol) of a 4.18N hydrogen chloride solution in ether are added. The hydrochloride slowly precipitates. The mixture is stirred for 1 hour, filtered and then dried in a desiccator for 8 hours at 60 ° C. A white powder is obtained. F = 260 to 263 0 C (decomposition).
1-(m-Trifluormethylthio-phenyl)-4-(tetrahydrofur-2-ylmethyl)-piperazin und dessen Hydrochlorid1- (m-Trifluoromethylthiophenyl) -4- (tetrahydrofur-2-ylmethyl) piperazine and its hydrochloride
Formel I: η = 1 R= I JFormula I: η = 1 R = I J
Man erhitzt eine Mischung aus 13,5 g (0,05 Mol) m-Trifluormethylthio-piperazin, 13,5 g (0,054 Mol) Tetrahydrofur-2-yl-methyl-tosylat und 13,5 ml Hexamethylphosphortriamid während 2 Stunden auf 120 0C. Man kühlt auf 10 0C ab und gibt 100 ml Wasser zu. Man trennt dieA mixture of 13.5 g (0.05 mol) of m-trifluoromethylthio-piperazine, 13.5 g (0.054 mol) tetrahydrofur-2-yl-methyl-tosylate and 13.5 ml of hexamethylphosphoric triamide during 2 hours at 120 0 C. It is cooled to 10 ° C. and 100 ml of water are added. One separates the
909882/0751909882/0751
SYNTHELABO, SET 28SYNTHELABO, SET 28
- 10 -- 10 -
wäßrige Phase von der ölphase und wäscht diese dreimal mit Wasser zur Entfernung des Hexamethylphosphortriamids. Man nimmt mit Chloroform auf, trennt die Wasserspuren ab und trocknet die Chloroformlösung über Magnesiumsulfat. Man gibt eine Lösung von Chlorwasserstoff in Äther zu und verdampft die Lösungsmittel. Man verreibt den beim Eindampfen erhaltenen Rückstand mit Äther und saugt den Niederschlag ab. Man stellt mit 2n Natriumhydroxidlösung alkalisch und extrahiert mit Chloroform. Man verdampft das Chloroform und bildet das Hydrochlorid aus dem beim Eindampfen zurückbleibenden öl. Man kristallisiert die Verbindung aus einer Isopropylalkohol/Äther-Mischung um. F = 210 0C.aqueous phase from the oil phase and washes it three times with water to remove the hexamethylphosphoric acid. It is taken up in chloroform, the traces of water are separated off and the chloroform solution is dried over magnesium sulfate. A solution of hydrogen chloride in ether is added and the solvents are evaporated off. The residue obtained on evaporation is triturated with ether and the precipitate is filtered off with suction. It is made alkaline with 2N sodium hydroxide solution and extracted with chloroform. The chloroform is evaporated and the hydrochloride is formed from the oil which remains after the evaporation. The compound is recrystallized from an isopropyl alcohol / ether mixture. F = 210 0 C.
1- (m-Trifluormethylthio-phenyl)-4-(2-mercaptoäthyl)-piperazin und dessen Hydrochlorid)1- (m-Trifluoromethylthiophenyl) -4- (2-mercaptoethyl) piperazine and its hydrochloride)
Formel I: η = 1 R= -CH0-SHFormula I: η = 1 R = -CH 0 -SH
In einem Erlenmeyer-Kolben gibt man zu einer Lösung von 15 g (0,0557 Mol) n-Trifluormethylthio-phenyl-piperazin und 2 ml Methanol tropfenweise bei 20 0C 3,84 g (0,064 Mol) Äthylensulfid. Man erhitzt nach und nach auf 55 0C und behält diese Temperatur während 1 1/2 Stun-0 den bei. Dann verdampft man das Lösungsmittel und rektifiziert in einer Kugelkolonne. Kp.= 200 0C/ 0,1 mm Hg.In an Erlenmeyer flask are added to a solution of 15 g (0.0557 mol) of n-trifluoromethylthio-phenyl-piperazine and 2 ml of methanol dropwise at 20 0 C. 3.84 g (0.064 mol) of ethylene sulfide. The mixture is gradually heated to 55 ° C. and this temperature is maintained for 1 1/2 hours. The solvent is then evaporated off and rectified in a spherical column. Bp = 200 ° C / 0.1 mm Hg.
Man bildet das Hydrochlorid durch Zugabe einer Lösung von Chlorwasserstoff in Äther zu der Lösung der Base in Äthylacetat. F = 141 0C.The hydrochloride is formed by adding a solution of hydrogen chloride in ether to the solution of the base in ethyl acetate. F = 141 0 C.
909B82/075909B82 / 075
SYNTHELABO, SET 28SYNTHELABO, SET 28
- 11 -- 11 -
1-(m-Trifluormethylthio-phenyl)-4-(2-methylthioäthyl)-piperazin und dessen Hydrochlorid1- (m-Trifluoromethylthio-phenyl) -4- (2-methylthioethyl) piperazine and its hydrochloride
Formel I: η = 1 R =-CH9-S-CH-.Formula I: η = 1 R = -CH 9 -S-CH-.
L -5JL - 5 y
Zu einer auf 5 0C abgekühlten Lösung von 4,8 g (0,015 Mol) 1-(m-Trifluormethylthio-phenyl)-4-(2-mercaptoäthyl)-piperazin in 40 ml Dimethylformamid gibt man portionsweise 0,84 g(0,0175 Mol) 50prozentiges Natriumhydrid. Nachdem die Wasserstofffreisetzung aufgehört hat, gibt man tropfenweise 2,16 g (0,0152 Mol) Methyljodid, das man in 20 ml Dimethylformamid gelöst hat, zu. Man läßt über Nacht stehen, gießt dann auf Eis und extrahiert zweimal mit Äther. Man trocknet die Ätherlösung über Magnesiumsulfat und dampft ein.To a solution, cooled to 5 ° C., of 4.8 g (0.015 mol) of 1- (m-trifluoromethylthio-phenyl) -4- (2-mercaptoethyl) piperazine in 40 ml of dimethylformamide is added in portions 0.84 g (0, 0175 moles) 50 percent sodium hydride. After the release of hydrogen has ceased, 2.16 g (0.0152 mol) of methyl iodide, which has been dissolved in 20 ml of dimethylformamide, are added dropwise. It is left to stand overnight, then poured onto ice and extracted twice with ether. The ether solution is dried over magnesium sulfate and evaporated.
Man bereitet das Hydrochlorid in Äthylacetat durch Zugabe der theoretischen Menge Chlorwasserstoff in Äthanol. F = 135 0C.The hydrochloride is prepared in ethyl acetate by adding the theoretical amount of hydrogen chloride in ethanol. F = 135 0 C.
In der nachstehenden Tabelle sind die Verbindungen der obigen Beispiele und weitere erfindungsgemäße Verbindungen angegeben, die in der beschriebenen Weise hergestellt worden sind.The table below shows the compounds of the above examples and others according to the invention Compounds indicated, which have been prepared in the manner described.
SYNTHELABO, SET 28SYNTHELABO, SET 28
- 12 Tabelle - 12 table
SCF.SCF.
•(CH2)n-R• (CH 2 ) n -R
Verbindung Nr.Connection no.
Schmelzpunkt des Hydrochlorids (0C)Melting point of the hydrochloride ( 0 C)
188 - 190 (Zersetzung 188 - 190 (decomposition
217 - 218 (Zersetzung 217 - 218 (decomposition
230 (Zersetzung)230 (decomposition)
178 - 180 (Zersetzung) 178 - 180 (decomposition)
224 - 227 (Zersetzung) 224 - 227 (decomposition)
196 - 199196-199
(Beispiel 1) (Example 1)
217 - 218217-218
909882/10751909882/10751
SYNTHELABO, SET 28SYNTHELABO, SET 28
Nr.link
No.
Hydrochlorids
(0C)Melting point of
Hydrochloride
( 0 C)
(Bei
spiel 28th
(At
game 2
setzung)260 - 263 (Zer
setting)
(Bei
spiel 3)9
(At
game 3)
(Bei
spiel 4)10
(At
game 4)
(Bei
spiel 5)11
(At
game 5)
9-09 8 8 2/07 59-09 8 8 2/07 5
SYNTHELABO, SET 28SYNTHELABO, SET 28
- 14 -- 14 -
Die erfindungsgemäßen Verbindungen entfalten eine interessante Wirkung auf das Zentralnervensystem und können daher in der Therapie angewandt werden.The compounds according to the invention have an interesting effect on the central nervous system and can therefore be used in therapy.
Diese Aktivität wurde mit Hilfe des 4-Platten-Tests verdeutlicht und gemessen (C. Aron, These de Medecine, Paris (1970), J. R. Boissier, P. Simon und C. Aron "Une nouvelle methode de determination des tranquillisants chez la souris", Eur. J. Pharmacol. 4 (1968), 145 - 151).This activity was illustrated and measured with the help of the 4-plate test (C. Aron, These de Medecine, Paris (1970), J. R. Boissier, P. Simon and C. Aron "Une nouvelle methode de determination des tranquillisants chez la souris ", Eur. J. Pharmacol. 4 (1968), 145-151).
Man verabreicht die Verbindungen in verschiedenen Dosierungen (1, 3 und 10 mg/kg) 60 Minuten vor der Untersuchung auf oralem Wege. Dann mißt man den Prozentsatz der Desinhibierung der Mäuse.The compounds are administered in various doses (1, 3 and 10 mg / kg) 60 minutes before the test by the oral route. The percentage disinhibition of the mice is then measured.
Bei einer Dosis von 1 mg/kg variiert der Prozentsatz von 35 bis 70, bei einer Dosis von 3 mg/kg variiert er von 80 bis 150 und bei einer Dosis von 10 mg/kg variiert er von 120 bis 300.At a dose of 1 mg / kg the percentage varies from 35 to 70, at a dose of 3 mg / kg it varies it ranges from 80 to 150 and at a dose of 10 mg / kg it varies from 120 to 300.
Bei den gleichen Dosierungen ist der Prozentsatz um so höher, je stärker die Wirkung der Verbindung ist.At the same dosages, the higher the effect of the compound, the higher the percentage.
Die akute Toxizität (DL™) wurde an der Maus entweder bei intraperitonealer Verabreichung nach 48 Stunden oder nach oraler Verabreichung während 7 Tagen untersucht. Der DLj. „-Wert bei intraperitonealer Verabreichung variiert von 75 bis 230 mg/kg, während der DLj, „-Wert; bei oraler Verabreichung im Bereich von 250 bis 1000 mg/kg liegt.The acute toxicity (DL ™) was assessed on the mouse either when administered intraperitoneally after 48 hours or after oral administration for 7 days. The DLj. "Value when administered intraperitoneally varies from 75 to 230 mg / kg, while the DLj, "value; when administered orally in the range of 250 to 1000 mg / kg.
Die erfindungsgemäßen Verbindungen besitzen psychotrope Eigenschaften, so daß man sie zur Behandlung von verschiedenen Angstzuständen und Depressionszu-The compounds according to the invention are psychotropic Properties so that they can be used in the treatment of various anxiety and depression
SYNTHELABO, SET 28SYNTHELABO, SET 28
- 15 -- 15 -
ständen einsetzen kann.
5can use stands.
5
Sie können auf oralem oder parenteralem Wege mit irgendeinem geeigneten Bindemittel, Trägermaterial und/oder Hilfsstoff in beliebiger Verabreichungsform gegeben werden, beispielsweise in Form von Gelkügelchen, Tabletten, Kapseln, Dragees, injizierbaren Lösungen und dergleichen.They can be administered orally or parenterally with any suitable vehicle, carrier and / or adjuvant can be given in any form of administration, for example in the form of gel beads, Tablets, capsules, dragees, injectable solutions and the like.
Die tägliche Dosierung kann sich von 5 bis 200 mg erstrecken.The daily dosage can range from 5 to 200 mg.
Gegenstand der Erfindung sind daher auch Arzneimittel, die die erfindungsgemäßen Verbindungen der allgemeinen Formel I oder deren Additionssalze mit pharmazeutisch annehmbaren Säuren in Kombination mit üblichen, pharmazeutisch annehmbaren Bindemitteln, Trägermaterialien und/oder Hilfsstoffen enthalten.The invention therefore also relates to medicaments which contain the compounds according to the invention of the general Formula I or their addition salts with pharmaceutically acceptable acids in combination with customary, contain pharmaceutically acceptable binders, carrier materials and / or auxiliaries.
Claims (5)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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 |
| FR7818351A FR2429212A1 (en) | 1978-06-20 | 1978-06-20 | PHENYLPIPERAZINE DERIVATIVES AND THEIR THERAPEUTIC APPLICATION |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE2924681A1 true DE2924681A1 (en) | 1980-01-10 |
Family
ID=26220635
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19792924681 Withdrawn DE2924681A1 (en) | 1978-06-20 | 1979-06-19 | PHENYLPIPERAZINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THE SAME |
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 |
|---|---|---|---|---|
| US4367335A (en) * | 1981-08-03 | 1983-01-04 | Mead Johnson & Company | Thiazolidinylalkylene piperazine derivatives |
| US4456756A (en) * | 1981-08-03 | 1984-06-26 | Mead Johnson & Company | Spirothiazolidinyl 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 |
| 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 |
| 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 |
| 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 |
| ZA918221B (en) * | 1990-10-23 | 1992-06-24 | Akzo Nv | 4-(4-or 6-(trifluoromethyl-2-pyridinyl))-1-piperazinyl-alkyl 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 |
| EP0913397B1 (en) * | 1997-10-22 | 2006-07-05 | Council of Scientific and Industrial Research | A proces for the synthesis of 1-(4-Arylpiperazine-1-y1)-3-(2-oxypyrrolidin/piperidin-1-yl)propanes as therapeutic agents for hypertension, ischemia, cardiovascular and other adrenergic receptors related disorders |
| 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 |
| UA78974C2 (en) | 2001-10-20 | 2007-05-10 | Boehringer Ingelheim Pharma | Use of flibanserin for treating disorders of sexual desire |
| US10675280B2 (en) | 2001-10-20 | 2020-06-09 | Sprout Pharmaceuticals, Inc. | Treating sexual desire disorders with flibanserin |
| PL1912650T3 (en) | 2005-08-03 | 2018-01-31 | Sprout Pharmaceuticals Inc | Use of flibanserin in the treatment of obesity |
| CA2626134C (en) | 2005-10-29 | 2013-12-24 | Boehringer Ingelheim International Gmbh | Benzimidazolone derivatives for the treatment of premenstrual and other female sexual disorders |
| JP2009541443A (en) | 2006-06-30 | 2009-11-26 | 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 | Flibanserin for the treatment of urinary incontinence and related diseases |
| JP5793828B2 (en) | 2006-08-14 | 2015-10-14 | 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 | Formulation of flibanserin and method for producing the same |
| 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 |
| EP2056797A2 (en) | 2006-08-25 | 2009-05-13 | Boehringer Ingelheim International GmbH | Controlled release system and method for manufacturing the same |
| CL2008002693A1 (en) | 2007-09-12 | 2009-10-16 | Boehringer Ingelheim Int | Use of flibanserin for the treatment of selected vasomotor symptoms of hot flashes, night sweats, mood swings, and irritability |
| 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 AU AU48112/79A patent/AU521110B2/en not_active Ceased
- 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 IL IL57569A patent/IL57569A0/en unknown
- 1979-06-18 PT PT69775A patent/PT69775A/en unknown
- 1979-06-18 IT IT23695/79A patent/IT1121588B/en active
- 1979-06-18 LU LU81396A patent/LU81396A1/en unknown
- 1979-06-18 ES ES481632A patent/ES481632A1/en not_active Expired
- 1979-06-18 GR GR59368A patent/GR67646B/el unknown
- 1979-06-18 NZ NZ190758A patent/NZ190758A/en unknown
- 1979-06-18 NO NO792020A patent/NO792020L/en unknown
- 1979-06-19 NL NL7904755A patent/NL7904755A/en not_active Application Discontinuation
- 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 GB GB7921307A patent/GB2023594B/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| GB2023594B (en) | 1982-10-13 |
| AU4811279A (en) | 1980-02-07 |
| LU81396A1 (en) | 1981-02-03 |
| GR67646B (en) | 1981-09-01 |
| NO792020L (en) | 1979-12-21 |
| AU521110B2 (en) | 1982-03-18 |
| IT7923695A0 (en) | 1979-06-18 |
| ES481632A1 (en) | 1980-02-16 |
| NZ190758A (en) | 1980-10-24 |
| GB2023594A (en) | 1980-01-03 |
| IT1121588B (en) | 1986-04-02 |
| FI791926A (en) | 1979-12-21 |
| SE7905402L (en) | 1979-12-21 |
| PT69775A (en) | 1979-07-01 |
| NL7904755A (en) | 1979-12-27 |
| IL57569A0 (en) | 1979-10-31 |
| DK251079A (en) | 1979-12-21 |
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