BE820242A - HETEROCYCLICAL DERIVATIVES OF SUBSTITUTED 1-ALKYL-4-PHENYLPIPERAZINE WITH PHARMACOLOGICAL ACTION AND METHOD OF MAKING THEM - Google Patents

HETEROCYCLICAL DERIVATIVES OF SUBSTITUTED 1-ALKYL-4-PHENYLPIPERAZINE WITH PHARMACOLOGICAL ACTION AND METHOD OF MAKING THEM

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Publication number
BE820242A
BE820242A BE2053876A BE2053876A BE820242A BE 820242 A BE820242 A BE 820242A BE 2053876 A BE2053876 A BE 2053876A BE 2053876 A BE2053876 A BE 2053876A BE 820242 A BE820242 A BE 820242A
Authority
BE
Belgium
Prior art keywords
emi
formula
derivatives
piperazine
viii
Prior art date
Application number
BE2053876A
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Dutch (nl)
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Publication of BE820242A publication Critical patent/BE820242A/en

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Classifications

    • 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
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/50—Ketonic radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Description

       

   <EMI ID=1.1> 

  
fenylpiperazine met farmakologische werking en werkwijze voor het maken ervan." 

  
De onderhavige uitvinding heeft betrekking op heterocyklische derivaten gesubstitueerde van 1-alkyl-4-fenylpiperazine met farmakologische werking en op de werkwijze voor het maken ervan.

  
Zoals men weet vergen de steeds sterkere uitbreiding van de kardiovaskulaire aandoeningen, te wijten aan het steeds veelvuldiger optreden van funktionele hypertensie, en de snelle verspreiding van aandoeningen in verband met allergische reakties

  
 <EMI ID=2.1> 

  
op de studie, het experimenteel onderzoek en het maken van nieuwe preparaten met betere therapeutische werking, waarvan nieuwe therapeutische effekten of ten minste toch een vlottere genezing bij de behandeling van de betrokken aandoeningen te verwachten is.

  
In het onderhavige verband werden bijzonder fraaie resultaten verkregen met heterocyklische derivaten van gesub-

  
 <EMI ID=3.1> 

  
en bijzonder doelmatige therapeutische werking als antihypertensiva hebben, dank zij hun vasodilaterend en alfa-inhiberend effekt en hun antihistaminische en antibradykinische werking.

  
De aanvraagster heeft immers op onverwachte wijze gevonden dat, volgens het hoofdobjekt van de onderhavige uitvinding, een aantal derivaten van gesubstitueerde l-alkyl-4-fenylpiperazine, die verder nauwkeurig zullen worden beschreven, bijzonder doelmatig zijn bij de behandeling van de storingen en afwijkingen in verband met de hoge bloeddruk en van de schadelijke gevolgen, veroorzaakt door histamine en bradykinine.

  
De uitvinding heeft dan ook als specifiek voorwerp een klasse van heterocyklische derivaten van gesubstitueerde l-alkyl4-fenylpiperazine, beantwoordend aan de volgende algemene formule:

  

 <EMI ID=4.1> 
 

  

 <EMI ID=5.1> 


  
welke derivaten een antihypertensieve, antihistaminische en antibradykinische werking hebben.

  
Van de voornoemde derivaten zijn vooral diegene bijzonder

  
 <EMI ID=6.1> 

  
getal n in de kombinaties volgens de onderstaande tabel I aanwezig zijn.

  
Tabel 1
 <EMI ID=7.1> 
  <EMI ID=8.1> 

  

 <EMI ID=9.1> 
 

  
Vervolg van tabel 1 
 <EMI ID=10.1> 
 Vervolg van Tabel 1
 <EMI ID=11.1> 
 Wat de werkwijzen voor het maken van de bedoelde heterocyklische derivaten van gesubstitueerde l-alkyl-4-fenylpiperazine volgens de uitvinding betreft, zijn verschillende werkschema's voorzien naar gelang het de volgende derivaten betreft:
(a) alkoholische derivaten,
(b) alkoxy-derivaten,
(c) pyridyl-, imidazolyl-en tetrahydroisochinolylderivaten.

  
Het basisprocédé waarvan de verschillende bedoelde werkschema's alleen varianten zijn, bestaat uit de volgende stadia:

  
(1) reaktie van broomacetylpyridine-hydrobromide met fenylpiperazine onder stikstof atmosfeer in methanol in aanwezigheid van triëthylamine;

  
(2) rechtstreekse reduktie van de in stadium (1) verkregen ketonen met NaBH4 tot de overeenkomstige alkoholen in een oplossing van alkohol in water ( derivaten a);

  
(3) Chlorering van de aldus verkregen alkoholen met SOC12 in trichloormethaan ( CHC13); en

  
(4) toevoeging van de aldus verkregen ongezuiverde chloorderivaten (3) aan een alkoholische oplossing met natriummethylaat of - ethylaat en afscheiding van de alkoxyderivaten (b) uit het reaktiemengsel door verdunning met water en extraktie met ether.

  
Wat de pyridyl-: imidazolyl- en tetrahydro-isochinolyl&#65533;

  
 <EMI ID=12.1> 

  
overeenkomstige heterocyklische chlooralkyl-derivaten te laten reageren met N-fenylpiperazine of met een van haar derivaten in

  
 <EMI ID=13.1> 

  
Wat in het bijzonder de pyridylethylderivaten (c) betreft kunnen deze verbindingen eveneens worden gemaakt volgens een alter- <EMI ID=14.1>  het voornoemde stadium (1) verkregen ketonische tussenverbin-

  
 <EMI ID=15.1> 

  
in diëthyleenglykol in aanwezigheid van natrium.

  
Wat in het bijzonder de .verbindingen volgens de bovenataande tabel I betreft, kunnen deze verbindingen volgens de volgende werkwijzen worden gemaakt*
(a) Alkoholische derivaten ( verbindingen 15,16,17,18,
19,20,21,22,23,24,25,32 en 33) .. 

  
Men laat broomacetylpyridine (II) reageren met fenylpiperazine of met een derivaat van fenylpiperazine (III) onder stikstof in methanol in aanwezigheid van triëthylamine volgens

  
 <EMI ID=16.1> 

  

 <EMI ID=17.1> 


  
waarna men de aldus verkregen ketoderivaten (VI) reduceert met

  
 <EMI ID=18.1> 

  
 <EMI ID=19.1> 

  

 <EMI ID=20.1> 
 

  
 <EMI ID=21.1> 

  
 <EMI ID=22.1> 
 <EMI ID=23.1> 
 <EMI ID=24.1> 

  
Men chloreert de alkoholderivaten (a) met SOC12 en voegt de aldus verkregen ongezuiverde chloorderivaten toe aan een alkoholische oplossing van natriummethylaat of-ethylaat. De reaktie verloopt volgens de onderstaande reaktievergelijking

  

 <EMI ID=25.1> 


  
 <EMI ID=26.1> 

  
volgende kombinaties:
 <EMI ID=27.1> 
 
 <EMI ID=28.1> 
(c) Pyridyl- , imidazolyl- en tetrahydro - isochinolylderivaten

  
Men verkrijgt deze verbindingen door de betrokken heterocykli sche chlooralkylderivaten te laten reageren met piperazine of

  
 <EMI ID=29.1> 

  
amine volgens de onderstaande reaktievergelijking:

  

 <EMI ID=30.1> 


  
waarin R, R2 en n aanwezig zijn in de ene of andere van de 

  
 <EMI ID=31.1> 

  

 <EMI ID=32.1> 
 

  

 <EMI ID=33.1> 


  
De voornoemde werkwijze is volgens de uitvinding bijzonder geschikt voor het maken van de verbindingen 1,3,5,6,7,8,9,10,
11,12, 13, 14, 34 en 35 ( zie boven)o

  
De pyridylethylderivaten ( verbindingen 2,3 en 4) kunnen eveneens worden verkregen door de overeenkomstige ketonderivaten
(VI) te laten reageren met hydrazine in aanwezigheid van natrium volgens de onderstaande reaktievergelijking:

  

 <EMI ID=34.1> 


  
waarin R, R2 en n aanwezig zijn in de ene of andere van de volgende kombinaties:

  

 <EMI ID=35.1> 


  
De uitvinding wordt hier verder toegelicht door de beschrijving van een aantal voorbeelden aangaande alle bovenvermelde voorkeurverbindingen,nl. de verbindingen 1-35 volgens de voorgaande tabel I, waarbij telkens de fysische eigenschappen, de brutoformule en het gevonden en berekend gehalte (%) van de verschillende samenstellende elementen worden aangegeven en ook de algemene synthesemethoden, onderverdeeld in vier groepen 1, 2,3 en 4 overeenkomstig de verschillende groepen van derivaten
(a) , (b) en (c), worden beschreven.

  
Voorbeeld 1

  

 <EMI ID=36.1> 


  
Men lost 28,1 g ( 0,1 mol) broom-3-acetylpyridinehydrobromide op in 500 ml methanol en voegt aan de aldus verkregen op-

  
 <EMI ID=37.1> 

  
N-fenylpiperazine, opgelost in 50 ml methanol, toe onder stikstof
(doorstroming van stikstof) terwijl het mengsel wordt geroerd en gekoeld.

  
De temperatuur wordt tijdens het mengen op 5-10*C gehouden

  
 <EMI ID=38.1> 

  
 <EMI ID=39.1> 

  
 <EMI ID=40.1> 

  
een oplossing van 7,5 g NaBH4 in 100 ml water indruppelen. Het reaktiemengsel wordt na het toevoegen 60 minuten op kamertemperatuur gehouden onder voortdurend roeren en daarna ingedampt tot een 

  
klein volume, aangezuurd met verdund zwavelzuur, behandeld met aktieve kool, gefiltreerd en alkalisch gemaakt met lithiumhydroxide. 

  
Het afgescheiden olieachtige produkt wordt met trichloormethaan geëxtraheerd; het trichloormethaan wordt gedroogd op Na2so4

  
en het oplosmiddel wordt verdampt. Het residu is een dikke olieachtige vloeistof, die kristalliseert bij rust.

  
 <EMI ID=41.1> 

  
 <EMI ID=42.1> 

  

 <EMI ID=43.1> 
 

  
De volgende verbindingen worden op gelijkaardige wijze  gemaakt. 

  

 <EMI ID=44.1> 


  
 <EMI ID=45.1> 

  

 <EMI ID=46.1> 


  
 <EMI ID=47.1> 

  

 <EMI ID=48.1> 


  
 <EMI ID=49.1> 

  

 <EMI ID=50.1> 


  
 <EMI ID=51.1>  

  
Brutoformule: C18H23N30

  

 <EMI ID=52.1> 


  
Molekuulgewicht: 297,40; smeltpunt: 81[deg.]C ; opbrengst:
52% ( omgekristalliseerd uit ligroine)

  
 <EMI ID=53.1> 

  

 <EMI ID=54.1> 


  
Molekuulgewicht: 297,40: smeltpunt: 142'C; opbrengst:
60% ( cmgekristalliseerd uit ligroine)

  
 <EMI ID=55.1> 

  

 <EMI ID=56.1> 


  
 <EMI ID=57.1> 
 <EMI ID=58.1> 
 <EMI ID=59.1>  
 <EMI ID=60.1> 
 Molekuulgewicht: 317,50; smeltpunt: 135-136'C; opbrengst:
56% ( omgekristalliseerd uit ethylacetaat)

  
 <EMI ID=61.1> 

  

 <EMI ID=62.1> 


  
Molekuulgewicht: 301,37; smeltpunt: 85-87[deg.]C; opbrengst:
57% (omgekristalliseerd uit ligroine)

  
 <EMI ID=63.1> 

  

 <EMI ID=64.1> 


  
Molekuulgewicht: 283,40; smeltpunt: 108[deg.]C; opbrengst: 
45% (omgekristalliseerd uit ligroine) 

  
 <EMI ID=65.1> 

  

 <EMI ID=66.1> 


  
 <EMI ID=67.1> 
 <EMI ID=68.1> 
 
 <EMI ID=69.1> 
 Voorbeeld 2

  

 <EMI ID=70.1> 


  
 <EMI ID=71.1> 

  
 <EMI ID=72.1> 

  
roeren langzaam een oplossing van 4,4 ml SOC12(0,06 mol) in 20 ml trichloormethaan toe. Men houdt het reaktiemengsel 30 minuten

  
op kamertemperatuur en laat vervolgens gedurende 3 uur bezinken. Na droogdampen wordt het residu opgelost in een minimale hoeveelheid methanol en wordt de aldus verkregen oplossing langzaam onder koelen toegevoegd aan een oplossing van natriummethylaat in methanol (3,5 g natrium in 75 ml methanol). 

  
Men laat gedurende 3 uren bezinken, verwijdert het oplos-  middel door verdamping , lost het residu op in 20 ml water en extraheert de aldus verkregen waterige oplossing tweemaal met ether, waarna men de etherische oplossing uitdampt en de olieachtige verdampingsrest destilleert sub vacuo. Men laat het destillaat rustig staan, zo dat het kan uitkristalliseren. 

  
Molekuulgewicht:297,40; smeltpunt: 69-70[deg.]C; opbrengst: 
42% ( omgekristalliseerd uit ethaan)

  
Brutoformule: C18H23N30

  

 <EMI ID=73.1> 


  
De volgende verbindingen worden op gelijkaardige wijze gemaakt.

  

 <EMI ID=74.1> 
 

  
 <EMI ID=75.1> 

  
opbrengst :46% 

  
 <EMI ID=76.1> 

  

 <EMI ID=77.1> 


  
 <EMI ID=78.1> 

  
HG; opbrengst: 50 %

  
 <EMI ID=79.1> 

  

 <EMI ID=80.1> 


  
 <EMI ID=81.1> 

  
opbrengst: 45 %

  
Brutoformule: C20H27N302

  

 <EMI ID=82.1> 


  
Molekuulgewicht: 331,80; kookpunt: 180[deg.]C bij 0,2 mm Hg; 
- *  opbrengst: 52% 

  
 <EMI ID=83.1> 
 <EMI ID=84.1> 
  <EMI ID=85.1> 

  
Hg; opbrengst: 42% 

  
 <EMI ID=86.1> 

  

 <EMI ID=87.1> 


  
Voorbeeld 3 

  

 <EMI ID=88.1> 


  
Voor het maken van de derivaten 2,3 en 4 moeten eerst de

  
 <EMI ID=89.1> 

  
vindt plaats door de reaktie te laten verlopen als in voorbeeld 1 

  
j  tot het punt waarbij het reaktiemengsel 4 uur onder roeren op  kamertemperatuur wordt gehouden. Op dit punt wordt het reaktiemengsel uitgedampt sub vacuo en wordt de verdampingsrest opgelost

  
in ether. Het oplosmiddel wordt uit de oplossing verdreven door verdamping en de olieachtige verdampingsrest kristalliseert bij

  
rust. De volgende verbindingen kunnen volgens deze werkwijze

  
worden geisoleerd:

  
 <EMI ID=90.1> 

  
Molekuulgewicht: 281,40; smeltpunt:103-104[deg.]C; opbrengst:
67% (omgekristalliseerd uit hexaan). 

  
Brutoformule: C17H19N30

  

 <EMI ID=91.1> 


  
Molekuulgewicht: 315,50; smeltpunt: 81-83[deg.]C; opbrengst:
70% (omgekristalliseerd uit hexaan).

  
 <EMI ID=92.1>  
 <EMI ID=93.1> 
 Molekuulgewicht: 311,40; smeltpunt: 98[deg.]C; opbrengst:
72% ( omgekristalliseerd uit hexaan)

  
 <EMI ID=94.1> 
 <EMI ID=95.1> 
- methyl-3'-pyridylketon en 75 ml N2N2 a 98% (0,15 mol) toe onder roeren aan een oplossing van 4,14 g (0,18 mol) natrium in 80 ml diëthyleenglykol, waarna men het mengsel gedurende 2 uren onder voortdurend roeren op 120-130[deg.]C houdt ter verwijdering van het overtollige water en de overtollige hydrazine.

  
Men houdt vervolgens de temperatuur gedurende 3 a 4 uren

  
op 180-190[deg.]C, verwijdert het oplosmiddel door verdamping sub

  
vacuo, lost de verdampingsrest op in water, extraheert de aldus verkregen oplossing met ether, dampt de etherische oplossing uit tot droog, lost de verdampingsrest op in een verdunde HC1-oplossing, extraheert de zure oplossing met trichloormethaan en ether, verdrijft de organische oplosmiddelen en maakt de zure oplossing alkalisch met een verdunde LiOH-oplossing na behandeling met aktieve kool.

  
Er slaat een olieachtig produkt neer, dat kristalliseert. Men destilleert sub vacuo bij 178-182[deg.]C en 0,2 mm Hg.

  
Molekuulgewicht: 297,70; smeltpunt: 59-60[deg.]C; opbrengst:

  
45 % ( omgekristalliseerd uit hexaan)

  
Brutoformule: C18H23N30
 <EMI ID=96.1> 
 
 <EMI ID=97.1> 
 De volgende verbindingen worden op gelijkaardige wijze verkregen, uitgaande van de overeenkomstige ketonen.

  

 <EMI ID=98.1> 


  
Molekuulgewicht: 267,40; smeltpunt: 66-67[deg.]C; opbrengst:
50 % (omgekristalliseerd uit hexaan).

  
Brutoformule: C17H21N3

  

 <EMI ID=99.1> 


  
Molekuulgewicht: 301,80; smeltpunt: 72[deg.]C; opbrengst:
53 % ( omgekristalliseerd uit hexaan).

  
 <EMI ID=100.1> 

  

 <EMI ID=101.1> 


  
Voorbeeld 4 

  

 <EMI ID=102.1> 


  
Aan 4,2 g (0,023 mol) 3-(2-chloorethyl) piridine.HCl in

  
 <EMI ID=103.1> 

  
amine en vervolgens 4,5 g (0,023 mol) o-methoxyfenylpiperazine toe. Men verwarmt het reaktiemengsel gedurende 8 uur op het waterbad en verwijdert vervolgens het oplosmiddel door verdamping sub vacuo. De verdampingsrest is een olieachtige vloeistof, die

  
 <EMI ID=104.1> 

  
een kristallijne neerslag.

  
 <EMI ID=105.1>   <EMI ID=106.1> 

  

 <EMI ID=107.1> 


  
De volgende verbindingen worden op gelijkaardige wijze gemaakt.

  

 <EMI ID=108.1> 


  
Molekuulgewicht: 253,30; smeltpunt: 74-76[deg.]C; opbrengst:
41 % (omgekristalliseerd uit ligrolne)

  
Brutoformule: C16H19N3

  

 <EMI ID=109.1> 


  
 <EMI ID=110.1> 

  
opbrengst: 40 %

  
Brutoformule: C18H23N3 

  

 <EMI ID=111.1> 


  
 <EMI ID=112.1> 

  
 <EMI ID=113.1> 

  
 <EMI ID=114.1> 

  

 <EMI ID=115.1> 


  
 <EMI ID=116.1>  
 <EMI ID=117.1> 
 <EMI ID=118.1> 

  
50 % (omgekristalliseerd uit hexaan) 

  
 <EMI ID=119.1> 

  

 <EMI ID=120.1> 


  
 <EMI ID=121.1> 

  
52 % (omgekristalliseerd uit hexaan)

  
Brutoformule: C21H27N3

  

 <EMI ID=122.1> 


  
De volgende verbindingen werden gemaakt volgens de werkwijze van voorbeeld 4, waarbij echter de reaktietemperatuur

  
 <EMI ID=123.1> 

  

 <EMI ID=124.1> 


  
 <EMI ID=125.1> 

  
 <EMI ID=126.1> 

  

 <EMI ID=127.1> 


  
 <EMI ID=128.1>  45 % (omgekristalliseerd uit isopropanol)

  
 <EMI ID=129.1> 

  

 <EMI ID=130.1> 


  
Molekuulgewicht: 272,30; smeltpunt: 163-165[deg.]C; opbrengst:
43 % (omgekristalliseerd uit isopropanol)

  
 <EMI ID=131.1> 

  

 <EMI ID=132.1> 


  
 <EMI ID=133.1> 

  
43 % ( omgekristalliseerd uit ethylacetaat)

  
 <EMI ID=134.1> 

  

 <EMI ID=135.1> 


  
Molekuulgewicht: 276,70; smeltpunt: 166-168[deg.]C; opbrengst:
40 % (omgekristalliseerd uit ethylacetaat)

  
 <EMI ID=136.1> 

  

 <EMI ID=137.1> 


  
 <EMI ID=138.1> 

  
45 % (omgekristalliseerd uit ethylacetaat) 

  
 <EMI ID=139.1> 

  
 <EMI ID=140.1>  

  

 <EMI ID=141.1> 


  
Molekuulgewicht: 272,30; smeltpunt: 124-126[deg.]C; opbrengst:
42 &#65533;

  
 <EMI ID=142.1> 

  

 <EMI ID=143.1> 


  
De uitvinding werd aldus beschreven en toegelicht aan de hand van een aantal typische uitvoeringswijzen. Dit betekent natuurlijk niet dat ze beperkt blijft tot de beschreven gevallen en het is zonder meer duidelijk dat ze eveneens betrekking heeft op alle wijzigingen, aanvullingen en aanpassingen ervan, natuurlijk op voorwaarde dat haar grenzen, bepaald door de onderstaande



   <EMI ID = 1.1>

  
phenylpiperazine with pharmacological action and method for making it. "

  
The present invention relates to heterocyclic derivatives substituted of 1-alkyl-4-phenylpiperazine with pharmacological action and to the method of making the same.

  
As is known, the increasing spread of cardiovascular disease due to the increasing occurrence of functional hypertension and the rapid spread of conditions associated with allergic reactions

  
 <EMI ID = 2.1>

  
on the study, the experimental research and the making of new preparations with better therapeutic effect, of which new therapeutic effects or at least a faster cure in the treatment of the disorders involved.

  
In the present context, particularly fine results were obtained with heterocyclic derivatives of sub-

  
 <EMI ID = 3.1>

  
and have particularly effective therapeutic activity as antihypertensive agents, due to their vasodilating and alpha-inhibiting effect and their antihistamine and antibradykinic activity.

  
Indeed, the Applicant has unexpectedly found that, according to the main object of the present invention, a number of derivatives of substituted 1-alkyl-4-phenylpiperazine, which will be further described in detail, are particularly effective in the treatment of the disturbances and aberrations in related to high blood pressure and the harmful effects caused by histamine and bradykinin.

  
Accordingly, the invention has as a specific article a class of heterocyclic derivatives of substituted 1-alkyl-4-phenylpiperazine, corresponding to the following general formula:

  

 <EMI ID = 4.1>
 

  

 <EMI ID = 5.1>


  
which derivatives have antihypertensive, antihistamine and antibradykinic activity.

  
Especially those of the aforementioned derivatives are special

  
 <EMI ID = 6.1>

  
number n in the combinations according to Table I below.

  
Table 1
 <EMI ID = 7.1>
  <EMI ID = 8.1>

  

 <EMI ID = 9.1>
 

  
Continued from Table 1
 <EMI ID = 10.1>
 Continued from Table 1
 <EMI ID = 11.1>
 As for the processes for making the intended heterocyclic derivatives of substituted 1-alkyl-4-phenylpiperazine according to the invention, different process schemes are provided depending on the following derivatives:
(a) alcoholic derivatives,
(b) alkoxy derivatives,
(c) pyridyl, imidazolyl and tetrahydroisoquinolyl derivatives.

  
The basic process of which the various workflows referred to are only variants consists of the following stages:

  
(1) reaction of bromoacetylpyridine hydrobromide with phenylpiperazine under nitrogen atmosphere in methanol in the presence of triethylamine;

  
(2) direct reduction of the ketones obtained in stage (1) with NaBH4 to the corresponding alcohols in an aqueous alcohol solution (derivatives a);

  
(3) Chlorination of the alcohols thus obtained with SOCl2 in trichloromethane (CHCl3); and

  
(4) addition of the crude chlorine derivatives (3) thus obtained to an alcoholic solution containing sodium methylate or ethylate and separation of the alkoxy derivatives (b) from the reaction mixture by dilution with water and extraction with ether.

  
As for the pyridyl: imidazolyl and tetrahydroisoquinolyl &#65533;

  
 <EMI ID = 12.1>

  
reacting corresponding heterocyclic chloralkyl derivatives with N-phenylpiperazine or with one of its derivatives in

  
 <EMI ID = 13.1>

  
In particular, as regards the pyridylethyl derivatives (c), these compounds can also be made according to an alter <EMI ID = 14.1> the above-mentioned stage (1) obtained ketonic intermediate.

  
 <EMI ID = 15.1>

  
in diethylene glycol in the presence of sodium.

  
In particular, as regards the compounds of Table I above, these compounds can be made by the following methods *
(a) Alcoholic derivatives (compounds 15,16,17,18,
19,20,21,22,23,24,25,32 and 33) ..

  
Bromoacetylpyridine (II) is reacted with phenylpiperazine or with a derivative of phenylpiperazine (III) under nitrogen in methanol in the presence of triethylamine according to

  
 <EMI ID = 16.1>

  

 <EMI ID = 17.1>


  
after which the keto derivatives (VI) thus obtained are reduced by

  
 <EMI ID = 18.1>

  
 <EMI ID = 19.1>

  

 <EMI ID = 20.1>
 

  
 <EMI ID = 21.1>

  
 <EMI ID = 22.1>
 <EMI ID = 23.1>
 <EMI ID = 24.1>

  
The alcohol derivatives (a) are chlorinated with SOCl2 and the crude chlorine derivatives thus obtained are added to an alcoholic solution of sodium methylate or ethylate. The reaction proceeds according to the reaction equation below

  

 <EMI ID = 25.1>


  
 <EMI ID = 26.1>

  
following combinations:
 <EMI ID = 27.1>
 
 <EMI ID = 28.1>
(c) Pyridyl, imidazolyl and tetrahydroisoquinolyl derivatives

  
These compounds are obtained by reacting the respective heterocyclic chloroalkyl derivatives with piperazine or

  
 <EMI ID = 29.1>

  
amine according to the reaction equation below:

  

 <EMI ID = 30.1>


  
wherein R1, R2 and n are present in one or the other of the

  
 <EMI ID = 31.1>

  

 <EMI ID = 32.1>
 

  

 <EMI ID = 33.1>


  
The aforementioned process is particularly suitable according to the invention for making the compounds 1,3,5,6,7,8,9,10,
11,12, 13, 14, 34 and 35 (see above) o

  
The pyridylethyl derivatives (compounds 2,3 and 4) can also be obtained by the corresponding ketone derivatives
(VI) react with hydrazine in the presence of sodium according to the following reaction equation:

  

 <EMI ID = 34.1>


  
wherein R, R2 and n are present in one or the other of the following combinations:

  

 <EMI ID = 35.1>


  
The invention is further illustrated here by the description of a number of examples regarding all the above-mentioned preferred compounds, viz. the compounds 1-35 according to the preceding Table I, where in each case the physical properties, the chemical formula and the found and calculated content (%) of the various constituent elements are indicated as well as the general synthesis methods, subdivided into four groups 1, 2,3 and 4 according to the different groups of derivatives
(a), (b) and (c) are described.

  
Example 1

  

 <EMI ID = 36.1>


  
28.1 g (0.1 mol) of bromo-3-acetylpyridine hydrobromide are dissolved in 500 ml of methanol and added to the solution thus obtained.

  
 <EMI ID = 37.1>

  
N-phenylpiperazine, dissolved in 50 ml methanol, under nitrogen
(nitrogen flow through) while stirring and cooling the mixture.

  
The temperature is kept at 5-10 ° C during mixing

  
 <EMI ID = 38.1>

  
 <EMI ID = 39.1>

  
 <EMI ID = 40.1>

  
drop in a solution of 7.5 g NaBH4 in 100 ml water. The reaction mixture is kept at room temperature for 60 minutes after the addition with continuous stirring and then evaporated to one

  
small volume, acidified with dilute sulfuric acid, treated with activated carbon, filtered and made alkaline with lithium hydroxide.

  
The separated oily product is extracted with trichloromethane; the trichloromethane is dried over Na2 SO4

  
and the solvent is evaporated. The residue is a thick oily liquid that crystallizes at rest.

  
 <EMI ID = 41.1>

  
 <EMI ID = 42.1>

  

 <EMI ID = 43.1>
 

  
The following connections are made in a similar manner.

  

 <EMI ID = 44.1>


  
 <EMI ID = 45.1>

  

 <EMI ID = 46.1>


  
 <EMI ID = 47.1>

  

 <EMI ID = 48.1>


  
 <EMI ID = 49.1>

  

 <EMI ID = 50.1>


  
 <EMI ID = 51.1>

  
Chemical formula: C18H23N30

  

 <EMI ID = 52.1>


  
Molecular weight: 297.40; melting point: 81 [deg.] C; yield:
52% (recrystallized from ligroin)

  
 <EMI ID = 53.1>

  

 <EMI ID = 54.1>


  
Molecular weight: 297.40: melting point: 142 ° C; yield:
60% (cm crystallized from ligroin)

  
 <EMI ID = 55.1>

  

 <EMI ID = 56.1>


  
 <EMI ID = 57.1>
 <EMI ID = 58.1>
 <EMI ID = 59.1>
 <EMI ID = 60.1>
 Molecular weight: 317.50; melting point: 135-136 ° C; yield:
56% (recrystallized from ethyl acetate)

  
 <EMI ID = 61.1>

  

 <EMI ID = 62.1>


  
Molecular weight: 301.37; melting point: 85-87 [deg.] C; yield:
57% (recrystallized from ligroin)

  
 <EMI ID = 63.1>

  

 <EMI ID = 64.1>


  
Molecular weight: 283.40; melting point: 108 [deg.] C; yield:
45% (recrystallized from ligroin)

  
 <EMI ID = 65.1>

  

 <EMI ID = 66.1>


  
 <EMI ID = 67.1>
 <EMI ID = 68.1>
 
 <EMI ID = 69.1>
 Example 2

  

 <EMI ID = 70.1>


  
 <EMI ID = 71.1>

  
 <EMI ID = 72.1>

  
stirring slowly to add a solution of 4.4 ml of SOCl2 (0.06 mol) in 20 ml of trichloromethane. The reaction mixture is held for 30 minutes

  
at room temperature and then allow to settle for 3 hours. After evaporation to dryness, the residue is dissolved in a minimal amount of methanol and the solution thus obtained is slowly added with cooling to a solution of sodium methylate in methanol (3.5 g sodium in 75 ml methanol).

  
It is allowed to settle for 3 hours, the solvent is removed by evaporation, the residue is dissolved in 20 ml of water and the aqueous solution thus obtained is extracted twice with ether, after which the ethereal solution is evaporated and the oily evaporation residue is distilled in vacuo. The distillate is allowed to stand quietly so that it can crystallize out.

  
Molecular weight: 297.40; melting point: 69-70 [deg.] C; yield:
42% (recrystallized from ethane)

  
Chemical formula: C18H23N30

  

 <EMI ID = 73.1>


  
The following connections are made in a similar manner.

  

 <EMI ID = 74.1>
 

  
 <EMI ID = 75.1>

  
yield: 46%

  
 <EMI ID = 76.1>

  

 <EMI ID = 77.1>


  
 <EMI ID = 78.1>

  
HG; yield: 50%

  
 <EMI ID = 79.1>

  

 <EMI ID = 80.1>


  
 <EMI ID = 81.1>

  
yield: 45%

  
Chemical formula: C20H27N302

  

 <EMI ID = 82.1>


  
Molecular weight: 331.80; boiling point: 180 [deg.] C at 0.2 mm Hg;
- * yield: 52%

  
 <EMI ID = 83.1>
 <EMI ID = 84.1>
  <EMI ID = 85.1>

  
Hg; yield: 42%

  
 <EMI ID = 86.1>

  

 <EMI ID = 87.1>


  
Example 3

  

 <EMI ID = 88.1>


  
To create derivatives 2, 3 and 4, the

  
 <EMI ID = 89.1>

  
takes place by allowing the reaction to proceed as in example 1

  
to the point where the reaction mixture is kept at room temperature with stirring for 4 hours. At this point the reaction mixture is evaporated in vacuo and the evaporation residue is dissolved

  
in ether. The solvent is removed from the solution by evaporation and the oily evaporation residue crystallizes on

  
peace. The following compounds can be made according to this method

  
are isolated:

  
 <EMI ID = 90.1>

  
Molecular weight: 281.40; melting point: 103-104 [deg.] C; yield:
67% (recrystallized from hexane).

  
Chemical formula: C17H19N30

  

 <EMI ID = 91.1>


  
Molecular weight: 315.50; melting point: 81-83 [deg.] C; yield:
70% (recrystallized from hexane).

  
 <EMI ID = 92.1>
 <EMI ID = 93.1>
 Molecular weight: 311.40; melting point: 98 [deg.] C; yield:
72% (recrystallized from hexane)

  
 <EMI ID = 94.1>
 <EMI ID = 95.1>
methyl 3'-pyridyl ketone and 75 ml of N2N2 at 98% (0.15 mol) with stirring to a solution of 4.14 g (0.18 mol) of sodium in 80 ml of diethylene glycol and the mixture stirred for 2 hours. with continued stirring at 120-130 [deg.] C to remove excess water and hydrazine.

  
The temperature is then maintained for 3 to 4 hours

  
at 180-190 [deg.] C, remove the solvent by evaporation sub

  
under vacuum, the evaporation residue dissolves in water, the solution thus obtained is extracted with ether, the ethereal solution evaporates to dryness, the evaporation residue dissolves in dilute HCl solution, extracts the acidic solution with trichloromethane and ether, expels the organic solvents and make the acidic solution alkaline with a dilute LiOH solution after treatment with activated carbon.

  
An oily product precipitates and crystallizes. It is distilled in vacuo at 178-182 [deg.] C and 0.2 mm Hg.

  
Molecular weight: 297.70; melting point: 59-60 [deg.] C; yield:

  
45% (recrystallized from hexane)

  
Chemical formula: C18H23N30
 <EMI ID = 96.1>
 
 <EMI ID = 97.1>
 The following compounds are similarly obtained from the corresponding ketones.

  

 <EMI ID = 98.1>


  
Molecular weight: 267.40; melting point: 66-67 [deg.] C; yield:
50% (recrystallized from hexane).

  
Chemical formula: C17H21N3

  

 <EMI ID = 99.1>


  
Molecular weight: 301.80; melting point: 72 [deg.] C; yield:
53% (recrystallized from hexane).

  
 <EMI ID = 100.1>

  

 <EMI ID = 101.1>


  
Example 4

  

 <EMI ID = 102.1>


  
To 4.2 g (0.023 mol) of 3- (2-chloroethyl) piridin.HCl in

  
 <EMI ID = 103.1>

  
amine and then 4.5 g (0.023 mol) of o-methoxyphenylpiperazine. The reaction mixture is heated on the water bath for 8 hours and then the solvent is removed by evaporation in vacuo. The evaporation residue is an oily liquid, which

  
 <EMI ID = 104.1>

  
a crystalline precipitate.

  
 <EMI ID = 105.1> <EMI ID = 106.1>

  

 <EMI ID = 107.1>


  
The following connections are made in a similar manner.

  

 <EMI ID = 108.1>


  
Molecular weight: 253.30; melting point: 74-76 [deg.] C; yield:
41% (recrystallized from ligrolne)

  
Chemical formula: C16H19N3

  

 <EMI ID = 109.1>


  
 <EMI ID = 110.1>

  
yield: 40%

  
Chemical formula: C18H23N3

  

 <EMI ID = 111.1>


  
 <EMI ID = 112.1>

  
 <EMI ID = 113.1>

  
 <EMI ID = 114.1>

  

 <EMI ID = 115.1>


  
 <EMI ID = 116.1>
 <EMI ID = 117.1>
 <EMI ID = 118.1>

  
50% (recrystallized from hexane)

  
 <EMI ID = 119.1>

  

 <EMI ID = 120.1>


  
 <EMI ID = 121.1>

  
52% (recrystallized from hexane)

  
Chemical formula: C21H27N3

  

 <EMI ID = 122.1>


  
The following compounds were made according to the procedure of Example 4, except for the reaction temperature

  
 <EMI ID = 123.1>

  

 <EMI ID = 124.1>


  
 <EMI ID = 125.1>

  
 <EMI ID = 126.1>

  

 <EMI ID = 127.1>


  
 <EMI ID = 128.1> 45% (recrystallized from isopropanol)

  
 <EMI ID = 129.1>

  

 <EMI ID = 130.1>


  
Molecular weight: 272.30; melting point: 163-165 [deg.] C; yield:
43% (recrystallized from isopropanol)

  
 <EMI ID = 131.1>

  

 <EMI ID = 132.1>


  
 <EMI ID = 133.1>

  
43% (recrystallized from ethyl acetate)

  
 <EMI ID = 134.1>

  

 <EMI ID = 135.1>


  
Molecular weight: 276.70; melting point: 166-168 [deg.] C; yield:
40% (recrystallized from ethyl acetate)

  
 <EMI ID = 136.1>

  

 <EMI ID = 137.1>


  
 <EMI ID = 138.1>

  
45% (recrystallized from ethyl acetate)

  
 <EMI ID = 139.1>

  
 <EMI ID = 140.1>

  

 <EMI ID = 141.1>


  
Molecular weight: 272.30; melting point: 124-126 [deg.] C; yield:
42 &#65533;

  
 <EMI ID = 142.1>

  

 <EMI ID = 143.1>


  
The invention has thus been described and illustrated by a number of typical embodiments. This, of course, does not mean that it is limited to the cases described and it is quite clear that it also covers all modifications, additions and adaptations thereof, provided, of course, that its limits, determined by the following

Claims (1)

conclusies, niet worden overschreden. conclusions, are not exceeded. E I S E N REQUIREMENTS 1.- Heterocyklische derivaten van gesubstitueerde 1-alkyl4-fenylpiperazine, beantwoordend aan de volgende algemene formule: <EMI ID=144.1> Heterocyclic derivatives of substituted 1-alkyl-4-phenylpiperazine, having the following general formula: <EMI ID = 144.1> waarin <EMI ID=145.1> <EMI ID=146.1> welke derivaten antihypertensieve eigenschappen hebben dank zij hun vasodilaterend en alfa-inhiberend effekt en hun antihistaminische en antibradykinische werking. in which <EMI ID = 145.1> <EMI ID = 146.1> which derivatives have antihypertensive properties due to their vasodilating and alpha-inhibiting effect and their antihistamine and antibradykinic effect. 2.--Heterocyklische alkoholderivaten van gesubstitueerde <EMI ID=147.1> 2. Heterocyclic alcohol derivatives of substituted <EMI ID = 147.1> <EMI ID=148.1> <EMI ID = 148.1> <EMI ID=149.1> <EMI ID = 149.1> 3.- Heterocyklische alkoxyderivaten van gesubstitueerde 1-alkyl-4-fenylpiperazine volgens eis 1, beantwoordend aan de 3.- Heterocyclic alkoxy derivatives of substituted 1-alkyl-4-phenylpiperazine according to requirement 1, meeting the <EMI ID=150.1> <EMI ID = 150.1> alkylradikaal en n = 1 alkyl radical and n = 1 <EMI ID=151.1> <EMI ID = 151.1> 4.- Heterocyklische pyridyl-, imidazolyl- en tetrahydroisochinolylderivaten van gesubstitueerde l-alkyl-4-fenylpiperazine volgens eis 1, beantwoordend aan de voornoemde algemene formule (I) 4.- Heterocyclic pyridyl, imidazolyl and tetrahydroisoquinolyl derivatives of substituted 1-alkyl-4-phenylpiperazine according to claim 1, corresponding to the aforementioned general formula (I) <EMI ID=152.1> <EMI ID = 152.1> <EMI ID=153.1> <EMI ID = 153.1> 5.- Werkwijze voor het maken van heterocyklische derivaten van gesubstitueerde l-alkyl-4-fenylpiperazine, beantwoordend aan de algemene formule (VIII) volgens eis 2, met het kenmerk dat ze de volgende stadia omvat: <EMI ID=154.1> Method for making heterocyclic derivatives of substituted 1-alkyl-4-phenylpiperazine, according to the general formula (VIII) according to requirement 2, characterized in that it comprises the following stages: <EMI ID = 154.1> (B) rechtstreekse reduktie van de in het stadium(A) ver- <EMI ID=155.1> (B) Direct reduction of the <EMI ID = 155.1> in stage (A) van alkohol in water. of alcohol in water. 6.- Werkwijze voor het maken van heterocyklische derivaten 6.- Process for making heterocyclic derivatives <EMI ID=156.1> <EMI ID = 156.1> mule (IX) volgens eis 3, met het kenmerk dat ze de volgende stadia omvat: mule (IX) according to requirement 3, characterized in that it comprises the following stages: (A) chlorering van de alkoholderivaten volgens eis 5 met SOC12 in trichloormethaan; en (B) toevoeging van de aldus verkregen ongezuiverde chloorderivaten aan een alkoholische oplossing van natriummethylaat of (A) chlorination of the alcohol derivatives according to requirement 5 with SOCl2 in trichloromethane; and (B) adding the crude chlorine derivatives thus obtained to an alcoholic solution of sodium methylate or -ethylaat, gevolgd door afscheiding van de aldus verkregen alkoxyderivaten uit het reaktiemengsel door verdunning met water en extraktie met ether. ethylate, followed by separation of the alkoxy derivatives thus obtained from the reaction mixture by dilution with water and extraction with ether. 7.- Werkwijze voor het maken van heterocyklische pyridylderivaten van gesubstitueerde 1-alkyl-4-fenylpiperazine, beantwoordend aan de algemene formule (VII) volgens eis 4, met het kenmerk dat men de ketonische tussen verbindingen, verkregen in stadium (A) van de werkwijze volgens eis 5, na afscheiding en zuivering laat reageren met hydrazine in diëthyleenglukol in aanwezigheid van natrium. Process for making heterocyclic pyridyl derivatives of substituted 1-alkyl-4-phenylpiperazine, corresponding to the general formula (VII) according to claim 4, characterized in that the ketonic intermediates obtained in stage (A) of the process according to claim 5, after separation and purification, is reacted with hydrazine in diethylene glucol in the presence of sodium. 8.- Werkwijze voor het maken van heterocyklische derivaten van gesubstitueerde l-alkyl-4-fenylpiperazine, beantwoordend aan 8.- Process for making heterocyclic derivatives of substituted 1-alkyl-4-phenylpiperazine according to de algemene formule (VIII), volgens eis 4, met het kenmerk dat the general formula (VIII), according to claim 4, characterized in that men een heterocyklisch chloro-alkylderivaat, beantwoordend aan a heterocyclic chloro-alkyl derivative corresponds to de volgende algemene formule (IV) R-(CH2)n -Cl, laat reageren met <EMI ID=157.1> the following general formula (IV) R- (CH2) n -Cl, react with <EMI ID = 157.1> gemene formule mean formula <EMI ID=158.1> <EMI ID = 158.1> waarin R, R2 en n dezelfde betekenis hebben als aangegeven in eis 1. wherein R1, R2 and n have the same meaning as indicated in requirement 1. <EMI ID=159.1> <EMI ID = 159.1> fenylpiperazine volgens formule (VIII) van eis 2, waarin R bèta - (C H5N-) en R2 = -H. phenylpiperazine of the formula (VIII) of claim 2, wherein R is beta - (CH5N-) and R2 = -H. <EMI ID=160.1> <EMI ID = 160.1> (o-methoxyfenyl)-piperazine volgens formule (VIII) van eis 2, (o-methoxyphenyl) -piperazine of formula (VIII) of requirement 2, <EMI ID=161.1> <EMI ID = 161.1> (m-methoxy-fenyl)-piperazine volgens formule (VIII) van eis 2, (m-methoxy-phenyl) -piperazine of formula (VIII) of claim 2, <EMI ID=162.1> <EMI ID = 162.1> <EMI ID=163.1> <EMI ID = 163.1> (p-methoxyfenyl)-piperazine volgens formule (VIII) van eis 2, (p-methoxyphenyl) piperazine of formula (VIII) of requirement 2, <EMI ID=164.1> <EMI ID = 164.1> <EMI ID=165.1> <EMI ID = 165.1> (o-toluyl)-piperazine volgens formule (VIII) van eis 2, waarin R = bèta - (C5H5N-) en R2 = o (-CH3). (o-toluyl) -piperazine of formula (VIII) of claim 2, wherein R = beta - (C5H5N-) and R2 = o (-CH3). <EMI ID=166.1> <EMI ID = 166.1> (m-toluyl)-piperazine volgens formule (VIII) van eis 2, waarin (m-toluyl) -piperazine of the formula (VIII) of claim 2, wherein <EMI ID=167.1> <EMI ID = 167.1> <EMI ID=168.1> <EMI ID = 168.1> (p-toluyl)-piperazine volgens formule VIII van eis 2, waarin (p-toluyl) -piperazine of formula VIII of claim 2, wherein <EMI ID=169.1> <EMI ID = 169.1> <EMI ID=170.1> <EMI ID = 170.1> (o-chlorofenyl) piperazine volgens formule VIII van eis 2, (o-chlorophenyl) piperazine according to formula VIII of requirement 2, <EMI ID=171.1> <EMI ID=172.1> <EMI ID = 171.1> <EMI ID = 172.1> (m-chlorofenyl)-piperazine volgens formule VIII van eis 2, waarin R = bèta-(C5H5N-) en R2 - m(-Cl). (m-chlorophenyl) -piperazine of formula VIII of claim 2, wherein R = beta- (C5H5N-) and R2 - m (-Cl). <EMI ID=173.1> <EMI ID = 173.1> (p-chlorofenyl)-piperazine volgens formule VIII van eis 2, waarin (p-chlorophenyl) -piperazine of formula VIII of claim 2, wherein <EMI ID=174.1> <EMI ID = 174.1> <EMI ID=175.1> <EMI ID = 175.1> fenylpiperazine volgens formule IX van eis 3, waarin R = bèta - phenylpiperazine according to formula IX of requirement 3, wherein R = beta - <EMI ID=176.1> <EMI ID = 176.1> <EMI ID=177.1> R = bèta -(C5H5N-) , X= -CH3 en R2 = o(-Cl). <EMI ID = 177.1> R = beta - (C5H5N-), X = -CH3 and R2 = o (-Cl). <EMI ID=178.1> <EMI ID = 178.1> (o-chlorofenyl)-piperazine volgens formule IX van eis 3, waarin (o-chlorophenyl) -piperazine of formula IX of claim 3, wherein <EMI ID=179.1> <EMI ID = 179.1> <EMI ID=180.1> <EMI ID = 180.1> fenyl)-piperazine volgens formule VII van eis 4, waarin R = bèta- (C5H5N-), n = 2 en R2 = o (-OCH3). i phenyl) -piperazine of formula VII of claim 4, wherein R = beta- (C5H5N-), n = 2 and R2 = o (-OCH3). i <EMI ID=181.1> <EMI ID = 181.1> piperazine volgens formule IX van eis 4, waarin R = bèta- (C5H5N-), n - 2 en R2 = -H. piperazine of formula IX of requirement 4, wherein R = beta- (C5H5N-), n-2 and R2 = -H. <EMI ID=182.1> <EMI ID = 182.1> chlorofenyl)- piperazine volgens formule VII van eis 4, waarin R = chlorophenyl) piperazine of formula VII of claim 4, wherein R = <EMI ID=183.1> <EMI ID = 183.1> <EMI ID=184.1> <EMI ID = 184.1> piperazine volgens formule VII van eis 4, waarin R = bèta-(C H N-), piperazine according to formula VII of claim 4, wherein R = beta- (CHN-), <EMI ID=185.1> <EMI ID = 185.1> <EMI ID=186.1> <EMI ID=187.1> <EMI ID=188.1> <EMI ID = 186.1> <EMI ID = 187.1> <EMI ID = 188.1> eis 4, waarin requirement 4, in which <EMI ID=189.1> <EMI ID = 189.1> <EMI ID=190.1> <EMI ID = 190.1> <EMI ID=191.1> <EMI ID = 191.1> <EMI ID=192.1> <EMI ID = 192.1> <EMI ID=193.1> <EMI ID = 193.1> <EMI ID=194.1> <EMI ID=195.1> <EMI ID=196.1> <EMI ID=197.1> <EMI ID=198.1> <EMI ID = 194.1> <EMI ID = 195.1> <EMI ID = 196.1> <EMI ID = 197.1> <EMI ID = 198.1> <EMI ID=199.1> <EMI ID = 199.1> <EMI ID=200.1> <EMI ID = 200.1> <EMI ID=201.1> <EMI ID = 201.1> toluyl)-piperazine volgens formule VII van eis 4, waarin toluyl) -piperazine of the formula VII of claim 4, wherein <EMI ID=202.1> <EMI ID = 202.1> <EMI ID=203.1> <EMI ID = 203.1> <EMI ID=204.1> <EMI ID = 204.1> <EMI ID=205.1> <EMI ID = 205.1> <EMI ID=206.1> <EMI ID = 206.1> 44:- Heterocyklische derivaten van gesubstitueerde lalkyl-4-fenylpiperazine met farmakologische werking en werkwijze 44: - Heterocyclic derivatives of substituted alkyl-4-phenylpiperazine with pharmacological action and method <EMI ID=207.1> <EMI ID = 207.1> hoofdzaak volgens de voorgaande beschrijving.. essentially according to the preceding description.
BE2053876A 1974-03-01 1974-09-24 HETEROCYCLICAL DERIVATIVES OF SUBSTITUTED 1-ALKYL-4-PHENYLPIPERAZINE WITH PHARMACOLOGICAL ACTION AND METHOD OF MAKING THEM BE820242A (en)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0289227A1 (en) * 1987-04-24 1988-11-02 Syntex Pharmaceuticals Ltd. Substituted imidazolyl-alkyl-piperazine and -diazepine derivatives
WO1996030343A1 (en) * 1995-03-29 1996-10-03 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US5856326A (en) * 1995-03-29 1999-01-05 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US6358956B1 (en) 1999-03-03 2002-03-19 Merck & Co., Inc. Inhibitors of prenyl-protein transferase
EP1988077A4 (en) * 2006-02-23 2009-09-02 Shionogi & Co Nirogenous heterocyclic derivatives substituted with cyclic groups
WO2011012075A1 (en) * 2009-07-29 2011-02-03 江苏恩华药业股份有限公司 Substituted phenyl piperazinyl aralkylone derivatives and its application for preparing analgesic drugs

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1200928B (en) * 1983-07-11 1989-01-27 Malesci Sas PROCEDURE FOR THE PREPARATION OF 1-PYRIDYL-ALCHIL-4-ARIL PIPERAZINE USEFUL FOR THEIR ANTI-HYPERTENSIVE ACTIVITY, THEIR SEPARATION IN THE RELATIVE OPTICAL ANTIPODES AND STEREOISOMER COMPOUNDS SO OBTAINED

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0289227A1 (en) * 1987-04-24 1988-11-02 Syntex Pharmaceuticals Ltd. Substituted imidazolyl-alkyl-piperazine and -diazepine derivatives
WO1996030343A1 (en) * 1995-03-29 1996-10-03 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US5856326A (en) * 1995-03-29 1999-01-05 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US6358956B1 (en) 1999-03-03 2002-03-19 Merck & Co., Inc. Inhibitors of prenyl-protein transferase
EP1988077A4 (en) * 2006-02-23 2009-09-02 Shionogi & Co Nirogenous heterocyclic derivatives substituted with cyclic groups
WO2011012075A1 (en) * 2009-07-29 2011-02-03 江苏恩华药业股份有限公司 Substituted phenyl piperazinyl aralkylone derivatives and its application for preparing analgesic drugs

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