NO792020L - PROCEDURE FOR THE PREPARATION OF PHARMACOLOGICALLY ACTIVE PHENYL PIPERAZINES - Google Patents

PROCEDURE FOR THE PREPARATION OF PHARMACOLOGICALLY ACTIVE PHENYL PIPERAZINES

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Publication number
NO792020L
NO792020L NO792020A NO792020A NO792020L NO 792020 L NO792020 L NO 792020L NO 792020 A NO792020 A NO 792020A NO 792020 A NO792020 A NO 792020A NO 792020 L NO792020 L NO 792020L
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alkyl
compound
reacted
preparation
stands
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NO792020A
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Norwegian (no)
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Henry Najer
Philippe Manoury
Jean-Pierre Kaplan
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Synthelabo
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Priority claimed from FR7818351A external-priority patent/FR2429212A1/en
Priority claimed from FR7818352A external-priority patent/FR2429216A1/en
Application filed by Synthelabo filed Critical Synthelabo
Publication of NO792020L publication Critical patent/NO792020L/en

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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
    • C—CHEMISTRY; METALLURGY
    • 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
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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
    • C—CHEMISTRY; METALLURGY
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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
    • 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
    • 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
    • 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

Foreliggende oppfinnelse vedrører en fremgangsmåte for fremstilling av terapeutisk aktive fenylpiperazinderivater med den generelle formel (I) The present invention relates to a method for the production of therapeutically active phenylpiperazine derivatives with the general formula (I)

hvori in which

n er 1, 2 eller 3, og n is 1, 2 or 3, and

R står for entenR stands for either

- et radikal - a radical

hvoriin which

og R2hver betyr et hydrogenatom eller R^og R2sammen betyr gruppen X er tio-oksy, imino, alkylimino eller metylen, og m er 0 eller 1, eller står for - et radikal eller står for and R2 each means a hydrogen atom or R^ and R2 together means the group X is thiooxy, imino, alkylimino or methylene, and m is 0 or 1, or represents - a radical or represents

- 2-tetrahydrofuryl, CH2~SH, Cl^-S-alkyl, CH2-0-alkyl, eller Cl^-S-CO-alkyl, hvori alkylgruppene har 1 - ,8 - 2-tetrahydrofuryl, CH2~SH, Cl^-S-alkyl, CH2-0-alkyl, or Cl^-S-CO-alkyl, in which the alkyl groups have 1 - .8

karbonatomer,carbon atoms,

samt deres addisjonssalter med farmasøytisk tålbare syrer, og det særegne ved fremgangsmåten i henhold til oppfinnelsen er at enten as well as their addition salts with pharmaceutically acceptable acids, and the distinctive feature of the method according to the invention is that either

a) omsettes m-trifluormetyltio-fenyl-piperazin (II) med formel a) m-trifluoromethylthio-phenyl-piperazine (II) is reacted with formula

med en forbindelse (III) with a compound (III)

R-(CH0) -Y (III) R-(CH0)-Y (III)

2. n 2. n

hvori R og n har den ovennevnte betydning og Y står for et anion av et aktivert alkoholderivat som halogenid, mesylat, tosylat, halogen-metansulfonat, eller in which R and n have the above meaning and Y stands for an anion of an activated alcohol derivative such as halide, mesylate, tosylate, halogen-methanesulfonate, or

b) for fremstilling av en forbindelse (I) hvori R er CI^SH omsettes fenylpiperazinet (II) med etylensulfid, eller c) for fremstilling av forbindelse (I) hvori R er CH„0-alkyl eller CH„S-alkyl, omsettes en forbindelse b) for the preparation of a compound (I) in which R is CI^SH, react the phenylpiperazine (II) with ethylene sulphide, or c) for the preparation of compound (I) in which R is CH„0-alkyl or CH„S-alkyl, react a connection

med en forbindelse with a connection

hvori R og n har den ovennevnte betydning og Hal står for et halogenatom, og om ønsket, for fremstilling av en forbindelse (I) hvori R er CH2~S-alkyl eller CH2-S-CO-alkyl, omsettes en erholdt forbindelse in which R and n have the above meaning and Hal represents a halogen atom, and if desired, for the preparation of a compound (I) in which R is CH2~S-alkyl or CH2-S-CO-alkyl, a compound obtained is reacted

hvori n har den ovennevnte betydning, med et tilsvarende alkyl-halogenid eller acylhalogenid. wherein n has the above meaning, with a corresponding alkyl halide or acyl halide.

Disse trekk ved fremgangsmåten i henhold til oppfinnelsen frem-går av patentkravet. These features of the method according to the invention appear in the patent claim.

Reaksjonen under a) gjennomføres fordelaktig ved en temperatur fra 20 - 150°C i et eventuelt polart løsningsmiddel som f.eks. et benzenhydrokarbon, et hydroksyholdig løsningsmiddel eller ketonisk løsningsmiddel, dimetylformamid (DMF) eller heksametyl-fosfortriamid (HMPT). The reaction under a) is advantageously carried out at a temperature of 20 - 150°C in a possible polar solvent such as e.g. a benzene hydrocarbon, a hydroxy solvent or ketone solvent, dimethylformamide (DMF) or hexamethylphosphorus triamide (HMPT).

Forbindelsene III er tidligere beskrevet i litteraturen.The compounds III have previously been described in the literature.

De følgende eksempler illustrerer fremgangsmåten og analyser og spektra IR og RMN bekrefter strukturen av forbindelsene. The following examples illustrate the procedure and analyzes and spectra IR and RMN confirm the structure of the compounds.

EKSEMPEL 1. EXAMPLE 1.

1- {2- [4-(3-trif luormetyltio-f enyl) -l-piperazinyl]-etylj -2-pyridon og dets hydroklorid. 1-{2-[4-(3-trifluoromethylthio-phenyl)-1-piperazinyl]-ethyl j -2-pyridone and its hydrochloride.

Under nitrogen bringes en blanding av 18,36 g (0,07 mol) 4-(3-trifluormetyltio-fenyl)-piperazin, videre 11,8 g (0,075 mol) av N-l-(3-klor-etyl)-2-pyridon, 58,8 ml toluen, 17,25 g (0,1248 mol) pulverisert kaliumkarbonat og 0,35 g kaliumjodid til tilbakeløps-temperaturen. Blandingen opptas i eter og ekstraheres med 10% saltsyre. Den vandige fase gjøres alkalisk til pH 9 - 10 ved hjelp av NaOH-løsning. Under nitrogen, a mixture of 18.36 g (0.07 mol) of 4-(3-trifluoromethylthio-phenyl)-piperazine, further 11.8 g (0.075 mol) of N-1-(3-chloro-ethyl)-2- pyridone, 58.8 ml toluene, 17.25 g (0.1248 mol) powdered potassium carbonate and 0.35 g potassium iodide to the reflux temperature. The mixture is taken up in ether and extracted with 10% hydrochloric acid. The aqueous phase is made alkaline to pH 9 - 10 using NaOH solution.

Produktet ekstraheres med eter og vaskes med vann til pH 7 - 8. The product is extracted with ether and washed with water to pH 7 - 8.

Produktet tørkes, filtreres og inndampes. Det oppnås 24 g olje som kromatograferes over 600 g silika (elueringsmiddel MeOH 0,5/CHCl^9,5). Det gjenvinnes 18,8 g av en brun olje som opp-løses i eter og tilsettes 10,86 ml (0,0489 mol) saltsur eter 4,5 N. Det filtreres, vaskes med eter og omkrystalliseres fra isopropanol. Det oppnås et hvitt pulver. Basen frigis ved hjelp av konsentrert NH^OH hvorfra man oppnår hydrokloridet ved hjelp av saltsur eter 4,18 N. Man filtrerer, vasker med eter og tørker i oppvarmet ekcikator i nærvær av kalium. The product is dried, filtered and evaporated. 24 g of oil is obtained which is chromatographed over 600 g of silica (eluent MeOH 0.5/CHCl^9.5). 18.8 g of a brown oil is recovered which is dissolved in ether and 10.86 ml (0.0489 mol) of hydrochloric acid ether 4.5 N is added. It is filtered, washed with ether and recrystallized from isopropanol. A white powder is obtained. The base is released using concentrated NH^OH from which the hydrochloride is obtained using hydrochloric acid ether 4.18 N. Filter, wash with ether and dry in a heated desiccator in the presence of potassium.

Det oppnådde produkt smelter ved 217 - 218°C.The product obtained melts at 217 - 218°C.

EKSEMPEL 2. EXAMPLE 2.

1- ^2- [4-(3-trifluormetyltio-fenyl)-1-piperazinyl]-etylj-3-metyl-2- benzimidazolidinon. 1-[2-[4-(3-trifluoromethylthio-phenyl)-1-piperazinyl]-ethyl]-3-methyl-2-benzimidazolidinone.

Under nitrogen bringes følgende blanding: 10,5 g (0,04 mol) 4-(3-trifluormetyltio-fenyl)-piperazin, 12,16 g (0,088 mol) pulverisert K2C03, 40 ml toluen, 9,48 g (0,045 mol) 1-(3-klor-etyl)-3-metyl-2-benzimidazolidinon og 0,3 g kaliumjodid til til-bakeløpstemperaturen. Etter omtrent 16 timer er reaksjonen omtrent opphørt og man filtrerer og inndamper filtratet. Det krystalliserte produkt opptas i eter og filtreres og man oppnår basen. Under nitrogen is brought the following mixture: 10.5 g (0.04 mol) 4-(3-trifluoromethylthio-phenyl)-piperazine, 12.16 g (0.088 mol) powdered K 2 CO 3 , 40 ml toluene, 9.48 g (0.045 mol ) 1-(3-chloro-ethyl)-3-methyl-2-benzimidazolidinone and 0.3 g of potassium iodide to the reflux temperature. After approximately 16 hours, the reaction has approximately ceased and the filtrate is filtered and evaporated. The crystallized product is taken up in ether and filtered and the base is obtained.

Smp. = 125 - 127°C. Temp. = 125 - 127°C.

Basen oppløses i 400 ml aceton og 50 ml CE^C^. Det innføresThe base is dissolved in 400 ml of acetone and 50 ml of CE^C^. It is introduced

7 ml (0,0293 mol) saltsur eter 4,18 N. Hydrokloridet utfelles sakte. Det omrøres i 1 time hvoretter det filtreres og tørkes i oppvarmet ekcikator ved 60°C i 8 timer. Det oppnås et hvitt pulver. 7 ml (0.0293 mol) hydrochloric acid ether 4.18 N. The hydrochloride precipitates slowly. It is stirred for 1 hour, after which it is filtered and dried in a heated desiccator at 60°C for 8 hours. A white powder is obtained.

Smp. = 260 - 263°C (spaltning).Temp. = 260 - 263°C (decomposition).

EKSEMPEL 3. EXAMPLE 3.

1-(m-trifluorometyltio-fenyl)-4-(2-tetrahydrofuryl-metyl)-piperazin og dets hydroklorid. 1-(m-trifluoromethylthio-phenyl)-4-(2-tetrahydrofuryl-methyl)-piperazine and its hydrochloride.

Til 120°C oppvarmes i 2 timer en blanding av 13,5 g (0,05 mol) m-trifluormetyltio-piperazin, 13,5 g (0,0 54 mol) av 2-tetrahydrofuryl-metyltosylat og 13,5 ml HMPT. Det avkjøles til 10°C og tilsettes 100 ml vann. Vannet separeres fra oljen hvoretter oljen vaskes tre ganger med vann for å fjerne HMPT. Oljen opp tas i kloroform, spor av vann fjernes og kloroformløsningen tørkes over magnesiumsulfat. Det tilsettes saltsur eter og løsningsmidlet avdampes. Resten behandles for avdampning med eter og bunnfallet avsuges på filter. Det gjøres alkalisk med 2N NaOH og ekstraheres med kloroform. Kloroform avdampes og hydrokloridet fremstilles ved å gå ut fra oljen som er tilbake fra inndampingen. Forbindelsen omkrystalliseres fra en blanding isopropanol/eter. A mixture of 13.5 g (0.05 mol) of m-trifluoromethylthiopiperazine, 13.5 g (0.0 54 mol) of 2-tetrahydrofuryl methyl tosylate and 13.5 ml of HMPT is heated to 120°C for 2 hours . It is cooled to 10°C and 100 ml of water is added. The water is separated from the oil after which the oil is washed three times with water to remove HMPT. The oil is taken up in chloroform, traces of water are removed and the chloroform solution is dried over magnesium sulphate. Hydrochloric ether is added and the solvent is evaporated. The residue is treated for evaporation with ether and the precipitate is sucked off on a filter. It is made alkaline with 2N NaOH and extracted with chloroform. Chloroform is evaporated and the hydrochloride is prepared by leaving the oil remaining from the evaporation. The compound is recrystallized from an isopropanol/ether mixture.

Smp. = 210°C.Temp. = 210°C.

EKSEMPEL 4. EXAMPLE 4.

1-(m-trifluormetyltio-fenyl)-4-(2-merkapto-etyl)-piperazin og dets hvdroklorid. 1-(m-trifluoromethylthio-phenyl)-4-(2-mercapto-ethyl)-piperazine and its hydrochloride.

I en erlenmeyerkolbe tilsettes dråpevis ved 20 C 3,84 g (0,064 mol) etylensulfid til en oppløsning av 15 g (0,0557 mol) m-trifluormetyltio-fenylpiperazin og 2 ml metanol. In an Erlenmeyer flask, 3.84 g (0.064 mol) of ethylene sulphide are added dropwise at 20 C to a solution of 15 g (0.0557 mol) of m-trifluoromethylthio-phenylpiperazine and 2 ml of methanol.

Det oppvarmes gradvis til 55°C og denne temperatur opprettholdes i 1 time og 3 0 minutter. Løsningsmidlet avdampes og det rektifi-seres med kulekjøler. It is gradually heated to 55°C and this temperature is maintained for 1 hour and 30 minutes. The solvent is evaporated and it is rectified with a ball cooler.

Kokepunkt = 2 00°C under 0,1 mm Hg.Boiling point = 2 00°C below 0.1 mm Hg.

Hydrokloridet fremstilles ved tilsetning av saltsur eter til en oppløsning av basen i etylacetat. Smp. = 141°C. The hydrochloride is prepared by adding hydrochloric acid ether to a solution of the base in ethyl acetate. Temp. = 141°C.

EKSEMPEL 5. EXAMPLE 5.

1-(m-trifluormetyltio-fenyl)-4-(2-metyltio-etyl)-piperazin og dets hydroklorid. 1-(m-trifluoromethylthio-phenyl)-4-(2-methylthio-ethyl)-piperazine and its hydrochloride.

Til en oppløsning avkjølt til +5°C av 4,8 g (0,015 mol) 1-(m-tri- luormetyltio-fenyl)-4-(2-merkapto-etyl)-piperazin i 40 mlDMF, tilsettes porsjonsvis 0,84 g (0,0175 mol) natriumhydrid 50%. Etter at utviklingen av hydrogen er opphørt tilsettes dråpevis 2,16 g (0,0152 mol) metyljodid i oppløsning i 20 ml DMF. Blandingen setter bort over natten, helles ut over is og ekstraheres 2 ganger med eter. Eterløsningen tørkes over magnesiumsulfat og inndampes. Hydrokloridet fremstilles fra etylacetat ved tilsetning av den teoretiske mengde etanolisk saltsyre. To a solution cooled to +5°C of 4.8 g (0.015 mol) 1-(m-triluormethylthio-phenyl)-4-(2-mercapto-ethyl)-piperazine in 40 ml DMF, add portionwise 0.84 g (0.0175 mol) sodium hydride 50%. After the evolution of hydrogen has ceased, 2.16 g (0.0152 mol) of methyl iodide in solution in 20 ml of DMF are added dropwise. The mixture is left overnight, poured over ice and extracted twice with ether. The ether solution is dried over magnesium sulfate and evaporated. The hydrochloride is prepared from ethyl acetate by adding the theoretical amount of ethanolic hydrochloric acid.

Smp. = 13 5°C.Temp. = 135°C.

I den etterfølgende tabell I er angitt eksempelvise forbindelser fremstilt i henhold til oppfinnelsen. De nye forbindelser fremviser terapeutisk aktivitet på det sentrale nervesystem påvist ved den såkalte fireplaters test (Aron C. Thése de Médecine - Paris 1970); Biossier J.R., In the following table I, exemplary compounds produced according to the invention are indicated. The new compounds exhibit therapeutic activity on the central nervous system as demonstrated by the so-called four-plate test (Aron C. Thése de Médecine - Paris 1970); Biossier J.R.,

Simon P. et Aron C. - Une nouvelle méthode de détermination des tranquillisants chez la souris. Eur. J. Pharmacol. 1968, Simon P. et Aron C. - Une nouvelle méthode de determination des tranquillisants chez la souris. Eur. J. Pharmacol. 1968,

4, 145 - 151). 4, 145 - 151).

Forbindelsene tilføres i flere doser (1,3 og 10 mg/kg) ved oral tilførsel 60 minutter før testen. Man måler den prosentvise stimulering av musene. The compounds are administered in several doses (1.3 and 10 mg/kg) by oral administration 60 minutes before the test. The percentage stimulation of the mice is measured.

Ved dosering 1 mg/kg varierer den prosentvise økning fra 35 til 70 og ved dosering 3 mg/kg varierer den fra 80 til 150 og ved dosering 10 mg/kg varierer den fra 120 til 300. At a dosage of 1 mg/kg the percentage increase varies from 35 to 70 and at a dosage of 3 mg/kg it varies from 80 to 150 and at a dosage of 10 mg/kg it varies from 120 to 300.

I de samme doser vil prosentandelen øke sterkere når aktiviteten av forbindelsen er stor. In the same doses, the percentage will increase more strongly when the activity of the compound is high.

Akutt giftighet (LD50) bestemmes i mus ved intraterritoneal til-førsel etter 48 timer, eller ved oral tilførsel i 7 døgn (LD50) ved intraterritoneal tilførsel varierer mellom 75 og 230 mg/kg og LD50 ved oral tilførsel varierer mellom 250 og 1000 mg/kg. Acute toxicity (LD50) is determined in mice by intraterritoneal administration after 48 hours, or by oral administration for 7 days (LD50) by intraterritoneal administration varies between 75 and 230 mg/kg and LD50 by oral administration varies between 250 and 1000 mg/kg kg.

Forbindelsene har psykotrope egenskaper som tillater at de kan anvendes for behandling av forskjellige tilstander med angst og depresjon. The compounds have psychotropic properties which allow them to be used for the treatment of various conditions of anxiety and depression.

De kan tilføres oralt eller parenteralt med alle passende til-setningsmidler, i enhver passende tilførselsform som geler, They can be administered orally or parenterally with any suitable additives, in any suitable delivery form such as gels,

tabletter, kapseler, dragéer, injiserbare oppløsninger, etc. tablets, capsules, dragées, injectable solutions, etc.

Total dose er fra 5 til 200 mg. Total dose is from 5 to 200 mg.

Claims (1)

Fremgangsmåte for fremstilling av terapeutisk aktive fenyl- piperazinderiva.ter med den generelle formel (I) Process for the production of therapeutically active phenyl- piperazine derivatives of the general formula (I) hvori n er 1, 2 eller 3, og R står for enten- et radikal hvori R., og R^ hver betyr et hydrogenatom eller R^ og R« sammen betyr gruppen in which n is 1, 2 or 3, and R stands for either radical in which R., and R.sub.1 each mean a hydrogen atom or R.sub.1 and R.sub.1 together mean the group X er tio-oksy, imino, alkylimino eller metylen, og m er 0 eller 1, eller står for - et radikal eller står for X is thiooxy, imino, alkylimino or methylene, and m is 0 or 1, or represents - a radical or stands for - 2-tetrahydrofuryl, CH2 -SH, CH2 -S-alkyl, CH2 -0-alkyl, eller CH2 -S-CO-alkyl, hvori alkylgruppene har 1-8 karbonatomer, samt deres addisjonssalter med farmasøytisk tålbare syrer, karakterisert ved at entena) omsettes m-trifluormetyltio-fenyl-piperazin (II) med formel med en forbindelse (III) - 2-tetrahydrofuryl, CH2 -SH, CH2 -S-alkyl, CH2 -O-alkyl, or CH2 -S-CO-alkyl, in which the alkyl groups have 1-8 carbon atoms, as well as their addition salts with pharmaceutically acceptable acids, characterized in that either) m-trifluoromethylthio-phenyl-piperazine (II) of formula is reacted with a compound (III) hvori R og n har den ovennevnte betydning og Y står for et anion av et aktivert alkoholderivat som halogenid, mesylat, tosylat, halogen-metansulfonat, eller b) for fremstilling av en forbindelse (I) hvori R er CH2 SH omsettes fenylpiperazinet (II) med etylensulfid, eller c) for fremstilling av forbindelser (I) hvori R er CH2 0-alkyl eller CH„S-alkyl, omsettes en forbindelse in which R and n have the above meaning and Y stands for an anion of an activated alcohol derivative such as halide, mesylate, tosylate, halogen-methanesulfonate, or b) to produce a compound (I) in which R is CH2 SH, the phenylpiperazine (II) is reacted with ethylene sulphide, or c) for the preparation of compounds (I) in which R is CH2 0-alkyl or CH„S-alkyl, a compound is reacted med en forbindelse (V) with a compound (V) hvori R og n har den ovennevnte betydning og Hal står for et halogenatom, og om ønsket, for fremstilling av en forbindelse (I) hvori R er CH2 -S-alkyl eller CH2~ S-CO-alkyl, omsettes en erholdt forbindelse (I) in which R and n have the above meaning and Hal stands for et halogen atom, and if desired, for the preparation of a compound (I) in which R is CH2 -S-alkyl or CH2~ S-CO-alkyl, a compound obtained (I) is reacted hvori n har den ovennevnte betydning, med et tilsvarende alkyl-halogenid eller acylhalogenid.wherein n has the above meaning, with a corresponding alkyl halide or acyl halide.
NO792020A 1978-06-20 1979-06-18 PROCEDURE FOR THE PREPARATION OF PHARMACOLOGICALLY ACTIVE PHENYL PIPERAZINES NO792020L (en)

Applications Claiming Priority (2)

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FR7818351A FR2429212A1 (en) 1978-06-20 1978-06-20 PHENYLPIPERAZINE DERIVATIVES AND THEIR THERAPEUTIC APPLICATION
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

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AU521110B2 (en) 1982-03-18
GB2023594A (en) 1980-01-03
PT69775A (en) 1979-07-01
IT7923695A0 (en) 1979-06-18
SE7905402L (en) 1979-12-21
NL7904755A (en) 1979-12-27
DK251079A (en) 1979-12-21
ES481632A1 (en) 1980-02-16
AU4811279A (en) 1980-02-07
FI791926A (en) 1979-12-21
DE2924681A1 (en) 1980-01-10
IL57569A0 (en) 1979-10-31
GR67646B (en) 1981-09-01
IT1121588B (en) 1986-04-02
NZ190758A (en) 1980-10-24
LU81396A1 (en) 1981-02-03

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