DE1809225A1 - New heterocyclic compounds and processes for their preparation - Google Patents

New heterocyclic compounds and processes for their preparation

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Publication number
DE1809225A1
DE1809225A1 DE19681809225 DE1809225A DE1809225A1 DE 1809225 A1 DE1809225 A1 DE 1809225A1 DE 19681809225 DE19681809225 DE 19681809225 DE 1809225 A DE1809225 A DE 1809225A DE 1809225 A1 DE1809225 A1 DE 1809225A1
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Germany
Prior art keywords
amino
piperazine
pyrimidinyl
original
het
Prior art date
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Application number
DE19681809225
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German (de)
Inventor
Roger Canevari
Michel Laubie
Gilbert Regnier
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Science Union et Cie
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Science Union et Cie
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Publication of DE1809225A1 publication Critical patent/DE1809225A1/en
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/22—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to two ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

H.WEICKMANN, mM.pinrS. DR.K.FINCKE F. A. WEICKMANN, „ηχ-οπεη. Β. HUBER PATENTANWÄLTE H. WEICKMANN, m M .pinr S. DR.K.FINCKE F. A. WEICKMANN, "ηχ-οπεη. Β. HUBER PATENT Attorneys

8 MtNCHEN 27, DEN 8 MONTHS 27 DEN

UOHI.STni.9SE 23UOHI.STni.9SE 23

BDF (0811) 48 39 31 /28BDF (0811) 48 39 31/28

_J_J

■'Soh/Gl■ 'Soh / Gl

SOIESfOB WiOI EO? 0IE9 S002ESE PEAHOAXSB EE EECJaERCHBSOIESfOB WiOI EO? 0IE 9 S002ESE PEAHOAXSB EE EECJaERCHB

5 ΡΗΑΜΗΕΙ0Η 5 0Η

hatarocycllsehe Verbindangöa ima ssu ihrer Hera tellurighatarocycllsehe connectionangöa ima ssu their hera tellurig

I)Ie -vorliiiaienae Srflnaung hai; neue heterooyoliscJxe Yerbingeii 4sx. allgemeine». Foxmel IiI) Ie -vorliiiaienae Srflnaung hai; new heterooyoliscJxe Yerbingeii 4sx. general ». Foxmel II

r~\r ~ \

He-t,He-t,

In dor Hefe einen in dm? 4-St©llung gebimdeneK.In dor yeast one in dm? 4-position GebimdeneK.

oinaa. Pyrazinyl-, ainen. S-Sriazinyl- cxlßr sinea C Real;, subeiJitiilert oder nichttmbfltituiort durch einen AXlcyl Rdst mit 1 - 4 C»»Atöjneat einen Alkoxyrest mit "t - 4 C-Atomen oder Amino bsw, oin^n- in. der 2-Stellimg geoinaa. Pyrazinyl, aines. S-Sriazinyl- cxlßr sinea C Real ;, subeiJitiilert or not tmbfltituiort by an AXlcyl Rdst with 1 - 4 C »» Atöjnea t an alkoxy group with "t - 4 C-Atoms or amino bsw, oin ^ n- in. The 2-Stellimg ge

älnylx®&'bf . mo3?.oöu.'batittii3i*t duarcb. älnylx® &'b f . mo3? .oöu.'batittii3i * t duarcb.

1098 17/22001098 17/2200

BAD ORIGINALBATH ORIGINAL

oxy oder öarbäthos:|i.ethe:s;y· bzw, di elites ti f.iii art at? roh Ith und Carboxy oder QarMthoxy, "eecleauetj sum Gegenstand. oxy or öarbäthos: | i.ethe: s; y · or, di elites ti f.iii art at? raw Ith and carboxy or QarMthoxy, "eecleauetj sum subject.

Die neuen Verbindungen, die Gegenstand äer Erfindung können durch Umsetzung eines Halogen-Derivates der allge meinen Formel IIϊThe new compounds that are the subject of the invention can by reacting a halogen derivative of the general my formula IIϊ

Eat -Z1 IIEat -Z 1 II

in der Z Cl oder Br und Het einen, wie oben definierten heterocyclischen Rest bedeutet, mit 1 —C33 »4""-Methyl©ntü·-·* oxybenzyl)-piperasin der Formel III in which Z is Cl or Br and Het is a heterocyclic radical as defined above, with 1 —C3 3 »4""- methyl (ntü · - · * oxybenzyl) piperasine of the formula III

IIIIII

hergestellt warden.manufactured.

Die Reaktion wird in einem polaren Lösungsmittel, wie Alkoholen mit hohem Siedepunkt, z.B. Butanol odsr Pentanol, einem Amid, wie Dimethylformamid oder in einem nichtpolaren lösungsmittel, besonders einem aromatischen Kohlenwasserstoff, z.B. Benzol, Toluol oder XyIoI9 durchgeführt, Ea ist vorteilhaft, bei einer Temperatur zwischen 80 und HO0O in Gegenwart eines Akzeptors für die Säure, die im Yerlauf der Reaktion gebildet wird, zu arbeitsn. Dieser Säureakzeptor kann ein A3.kali~ oder Erdalkalicarbonat oder -hydrogoncarbonate besonders Katriixm·=· oder Kaliumcarbonat, Calciumcarbonat oder eine tertiäre organische Base, wie Dimethylanilin9 Pyridin odor Triethylamin» sein. Man kann auch in gleicher Weise» falls gewünscht, diese Salze oder diese tertiären Basen durch einen Überschuss an monosubstituiertem Pip$razin ersetzen. The reaction is carried out in a polar solvent, such as alcohols with a high boiling point, for example butanol or pentanol, an amide, such as dimethylformamide, or in a non-polar solvent, especially an aromatic hydrocarbon, for example benzene, toluene or XyIoI 9 Temperature between 80 and HO 0 O in the presence of an acceptor for the acid that is formed in the course of the reaction to work. This acid acceptor can be a A3.kali ~ or alkaline earth metal or -hydrogoncarbonate particularly Katriixm · = · or potassium carbonate, calcium carbonate or a tertiary organic base such as dimethylaniline 9 pyridine odor triethylamine be ". In the same way, if desired, these salts or these tertiary bases can also be replaced by an excess of monosubstituted piperazine.

1098 17/22001098 17/2200

BAD ORiGiNALBAD ORiGiNAL

. ~ ..;!...;.ι;ii!!!,ii::ll!ιi.1^..■ι.|..:..■'?!:■■!:■■ ■■':■■■ ■■»*%■ . ~ ..; ! ...;. ι; ii ! ! ! , ii :: ll! ιi. 1 ^ .. ■ ι. | .. : .. ■ '?!: ■■!: ■■ ■■': ■■■ ■■ »*% ■

180922b180922b

3b ist "auch alE Ees Randteil dor B^findtm/:^ öle e veuen heterociycXis«hen Vex-Mada*!./··;^ eie schvaohe öindj salt SUutme· i:a Alirs AiMi1?.inn^:.j^JLgis asu 3b is "also alE Ees edge part dor B ^ findtm /: ^ öle e veuen heterociycXis« hen Vex-Mada *! ./ ··; ^ eie schvaohe öindj salt SUutme · i: a Alirs AiMi1? .Inn ^ :. j ^ JLgis asu

lsidtmgess. ^if aie Säuren in simmi fcaelgno'ä ittolr. a.« B. 'feöf-'er oder- mit W^ssex' iaisoh"baxlen Alkoliole:üs töM \</6:^,-3η. Als Saurem, dlo :cfe die Bildung äßr M-ß geoigxiui Kind, werösn aus ä.3r leihe dor Min ,'taraarmi;σ Ohlommassrstoi:Cßäa:?e? Bromv/ass-ir« r oder Piiosphorraä-are,-, üus derlsidtmgess. ^ if aie acids in simmi fcaelgno'ä ittolr. a. «B. 'feöf-'er or- with W ^ ssex'iaisoh" bax l en alcohols: ü s töM \ </ 6: ^, - 3η. As sour, dlo: cfe the formation according to M-ß geoigxiui Kind, werösn from ä.3r leihe dor Min, 'taraarmi; σ Ohlommassrstoi: Cßäa:? E ? Bromv / ass-ir «r or Piiosphorraä-are, -, üus der

Reilia der orgaiiißchen Säursas Essigsäure, Propion-s Reilia of the organic acid as acetic acid, propion- s

'-j, "BJe-'-j, "BJe-

X'ie 'neuen ¥e]?birjciingen köui?.en .gegelKmi'-nfalls durch pjriyei Jta?i.ißcha Methoden, wie Destillation., Kris^talliiaation, Ohromatographle oder dr?.rol.t oheisieolie? Mstliode?.is wie JSorsetzupg der Addiiionssaliie smrsh s3ka3 1a(;lie Mittel, ^sr^i nigt werden.'X'ie 'new ¥ e]? Birjciingen köui? .En .gegelKmi'-nfall by pjriyei Jta? I.ißcha methods, such as distillation., Kr ^ talliiaation, Ohromatographle or dr? .Rol.t oheisieolie? Mstliode? .I s like JSorsetzupg der Addiiionssaliie smrsh s3ka3 1a (; lie means, ^ sr ^ i nigt. '

Me nenon Yi?:-*'3induiigen der Br.fiiicliing liaDen interessante cJie usiu. tl).örapeutisoli<2 Eigenschaften iiüi! kon--Me nenon Yi?: - * '3induiigen the Br.fiiicliing liaDen interesting cJie usiu. tl) .örapeutisoli <2 properties iiüi! kon--

als periphere vaaoflilatorisclie und "broiiclia-- ™as peripheral vaaoflilatorisclie and "broiiclia-- ™

e Hittel ver\f©ndet ve Hittel ver \ f © ndet v

Trie atazte I!or;r:::.aität 'itfurd^ ar;. Mausen h&sJüL&wx, und. man hat ■'■J.i'iu DLUq. "bei inlrsperitcnaler 7f53?al)2isictfrsmg τοπ 50 Ms ^3'OO mg.ii'g mU i'.'wi oralem ^er.-ibreic-irang diener Yert.i».-dimgsn τοϊι "2Ou » 3000 ms/kg gsfrmde.u« Trie atazte I ! or r ::: .aität 'itfurd ^ ar; . Mausen h & s J üL & wx, and. one has ■ '■ J.i'iu DL U q. "at inlrsperitcnaler 7f53? al) 2 i sictfrsmg τοπ 50 Ms ^ 3'OO mg.ii'g mU i '.' wi oral ^ er.-ibreic-irang diener Yert.i» .- dimgsn τοϊι "2Ou» 3000 ms / kg gsfrmde.u «

Bei der Vexml^i^lommg von 3 ing/kg dui? reiten !"erb durch int^avor-iiic/p Psriuairm l>öin F^vilnchiju vrurde eino 'D rüsiierurag des "Blx'.fc'voj.'v.K'.T».·- ;m d^r Pfote·v dAt the Vexml ^ i ^ lommg of 3 ing / kg dui? riding! "erb through int ^ avor-iiic / p Psriuairm l> öin F ^ vilnchiju vrurde eino 'D rüsiierurag des"Blx'.fc'voj.'v.K'.T ». · -; md ^ r paw · v d

109 817/2200109 817/2200

8AD ORIGINAL8AD ORIGINAL

■düngen bewegt, festgestellt« Biss "foavwist @ino werte vasodilatorisoh® 'Wirkung,,■ fertilize in motion, determined «bite» foavwist @ino values vasodilatorisoh® 'effect ,,

Me bronöhadilatorisoh«? Wirkeamfcslt wurde ιϊ&οϊι der Metkode von Kcmastt und Rossler [Aroli,,. oxp« Path, -a. l^iarra, 19!Än 71 (1940) ] bestimmt,, Is wrcle-gefmiä©»,, das ε» die n@u@i?. Verbindungen imstande sind, den duxöli Histsaiin, Serotonin oder Acetyloholln verursaclii'en Bronohospasraen beim Meeröoiiweiiiohön entgegenauwirkea. Biese Spasrasm werden durch intravenös verabreicht® Bösen von 1-3 mg/kg zu !50 - 100 ^ gehonmit.Me bronöhadilatorisoh «? In effect, ιϊ & οϊι became the method of Kcmastt and Rossler [Aroli ,,. oxp "Path, -a. l ^ iarra, 19! Än 71 (1940)] determines ,, Is wrcle-gefmiä © »,, das ε» die n @ u @ i ?. Compounds are able to counteract the duxoli histsaiin, serotonin or acetyloholln cause bronohospasraen in the sea. These spasrasm are administered intravenously from 1-3 mg / kg to 50-100%.

Diese Eigenschaften erlauben die therapeutische Yerweiidung dieser Verbindungen„ besonders bei der Beliandluxig von pe:.?i~ pheren Kreislaufstörungen, z»B. Venen- oder Arterienent-Zündungenr sowie akuter oder chronischer Atmungsinsuffiziena, besondere von Bronchialasthma.These properties allow the therapeutic refinement of these compounds "particularly in the case of the luxury of peoples:.? I ~ peripheral circulatory disorders, eg. Venous or Arterienent ignitions r and acute or chronic Atmungsinsuffiziena, particularly bronchial asthma.

In diesen Fällen kümien 2-4 mal täglich 10 - 200 mg verabreicht werden. In these cases 10-200 mg should be administered 2-4 times a day.

Me Verbindungen können orals rektal oder parenteral Wk abreicht werden, wobei der aktive Bestandteil mit pharmakologischen S.rägerns wie destilliertem Wassor, Stärke, Talk, Laktose, Ithjloelluloae oder Kakaobutter vermischt oder an diese gebunden soixi kaim. Mo gewüEsohten pharmaseutisehen Verabreichungf-siOrmen können 3?ablettenp Xiragees, Kapseln, Suppositories in^iaierbars oder trinkbar® Lösungen sein.Me compounds can be administered orally or parenterally s rectally Wk are abreicht, wherein the active ingredient having pharmacological S.rägern s mixed or as distilled Wassor, starch, talc, lactose, cocoa butter Ithjloelluloae or bound to these soixi kaim. The usual pharmaceutical administration methods can be 3 tablets p xiragees, capsules, suppositories in liquid or drinkable solutions.

Die pharmazeutischen Jäusasamensetzungen, die eine Verbindung; • der allgemeinen Pormel I oder eines t-jeinor Salze, ve:cmischt mit oder gebunden an pharmazeutische OPräge-i', enthalten, bil den ebenfalls einen Tüll der Erfindimg.The pharmaceutical compositions of Jäusa, which are a compound; • the general Pormel I or a t-jeinor salts, ve: cmixed with or bound to pharmaceutical OPtrag-i ', contain, bil also a tulle of the invention.

1 09817/22001 09817/2200

SAO ORIGINALSAO ORIGINAL

Dia folgsadeit. Bsi Bid. sie ciiexum :-iur SU/X&atemng des rens siir Hsrs'mLliuig der si^Ci'Slide follow. Bsi Bid. she ciiexum: -iur SU / X & atemng des rens siir Hsrs'mLliuig the si ^ Ci '

p -wurden auf dör ife.iK'bjrak .laoli. Kollerp -were on dör ife.iK'bjrak .laoli. Rage

dem Ml&lthe Ml & l

Beispiel 1example 1

5»u einer Lösimg von 2! g 1 -(3' ,4"-Methylen«lioxybens!yl)-pi- pexazlid und 14? 9 g 2j,5-Diclilorpyrimiai2i i;a if30 cm Dimethylformamid (I)MF) g:Ll>t man 28 g Xaliuiiioar^cmat imd erhitzt die Miscirang ö Stunden, auf 13O0C, Hack Ablauf cliösar ZsIt werden die gebildeten Salse abfiltriert and das I)MF unter Draek abdestilliert. Dor warm*} Rückstand wird5 »u a solution of 2! g 1 - (3 ', 4 "-Methylene lioxybens! yl) -pipexazlid and 14.9 g 2j, 5-diclilorpyrimiai2i; a if 30 cm dimethylformamide (I) MF) g: Ll> t one 28 g Xaliuiiioar ^ CMAT IMD heats the Miscirang ö hours at 13O 0 C, Hack sequence are ZsIt cliösar filtered off and the formed salse I) MF *} residue distilled off under Draek. Dor is hot

mit 100 cw? siedendera. Wasser behandelt und unter starkem Rühren abgefcöhlt, wobei das Öl kristallisiert„ Man erhält 23 g weisser Kristalle mit einem Schmelsspmilnt you 99 - 1010O,with 100 cw? simmeringa. Water and treated abgefcöhlt with vigorous stirring, the oil crystallized "is obtained 23 g of white crystals with a Schmelsspmilnt you 99-101 0 O,

Shtsprechend dem Bölaplel 1 erhält wan. folgend.® Yerbindüngen$ According to the Bölaplel 1 gets wan. following.® Yerbindüngen $

a) 1 - { 4f -Oarbäthoxymo tho3£y-2»-pyrlmidinyl) · 4- (3!f, 4 "«-me thy» iendiosybenzyl)~piperai3in .aus 2~0hlor«»4"-carl)atho2{:ymethoxypyrimidin, Dienlorhydrat, .?„ 195 - 2000C.a) 1 - {4 f -Oarbäthoxymo tho3 £ y-2 »-pyrlmidinyl) 4- (3 ! f , 4" «-me thy» iendiosybenzyl) ~ piperai3ine .from 2 ~ chloro «» 4 "-carl) atho2 {: ymethoxypyrimidine, diene chlorohydrate,.? "195 - 200 0 C.

b ) 1 - ( 5»~0arbäthoxy-2 · -pyrimidine 1 )-4- C 3 ", 4 i?-»methyle;ad;i oxy-> beni2y.l)-plpera2;in aus 2-0hlor-5carbätho:icypyrira:Ldini freie Base, P. 104°C.b) 1 - (5 ~ 0arbethoxy-2 · -pyrimidine 1) -4- C 3 ", 4 i? -» methyle; ad; i oxy-> beni2y.l) -plpera2; in from 2-chloro-5carbetho : icypyrira: Ldin i free base, P. 104 ° C.

c) 1 - ( 4' ~Äthoxy-5~carbäthoxy-2' -pyrimidiiiyi ) -4- ( 3 ", 4 "-methy-c) 1 - (4 '~ ethoxy-5 ~ carbethoxy-2' -pyrimidiiiyi) -4- (3 " , 4" -methy-

109817/2200 8AOOR1G1NAL 109817/2200 8AOOR 1 G 1 NAL

1809 2 2b1809 2 2b

X ^»plperasin aus 2c •=OlLLor-4-ä'i;lio^;y-5->Qar"b(;)3qr" pyrimldin, Ohlorhydrat, F. 196 - .2000G,X ^ »plperasin from 2 c • = OlLLor-4-ä'i; lio ^; y-5- > Qar" b (;) 3qr "pyrimldin, Ohlorhydrat, F. 196 - .200 0 G,

Q) ι„(5«-Carboxyl5-pyrimidinyl)-4-(3",4n-(methylendioxyben£5yl)~plperaain aus 2~01ilor«»5~i3arboxypyrimld.1.M.j freie Base F. 254°C Q ) ι "(5" -Carboxyl 5 -pyrimidinyl) -4- (3 ", 4 n - (methylenedioxyben £ 5yl) ~ plperaain from 2 ~ 01ilor« »5 ~ i3arboxypyrimld.1.Mj free base mp 254 ° C

Beispiel 2Example 2

1 - C 48 -Pyrimiäiiiyl) ~4~ C 3 w y 4iä™ (me'b}.iyIend:Löxj])an;ä jl) -piperaa.tn erhält man nach dem Verfahren d©s Beispiel« 1 "beim' Arbei^an in Toluol unter Rückfluss in Ciegemtr&rt von KaliumcarT&onats ausgehend τοη 4-öhlorpyrimidin, Mehlorhydratj, J0192 » 198ö0 (Zersetzung).1 - C 4 8 -Pyrimiäiiiyl) ~ 4 ~ C 3 w y 4 iä ™ (me'b} .iyIend: Löxj]) an; ä jl) -piperaa.tn is obtained according to the procedure d © s example «1" when '^ elaboration in refluxing toluene in Ciegemtr & KaliumcarT rt of & onate s starting τοη 4-öhlorpyrimidin, Mehlorhydratj, J 0 192 »ö 198 0 (dec).

Entsprechend dem Beispiel 2. erhält, man folgende 1 - ( 2" ~Aniiuo«-4 ° -pyrimidinyl )~4~ C 3"'«4 "«methyl endioxybenayl) =» piperazin aus 2->Amino-4-"ßlilori>y2,>iiddinf' freie BaBe9 F. 1710O,According to Example 2, one obtains the following 1- (2 "~ aniiuo« -4 ° -pyrimidinyl) ~ 4 ~ C 3 "" 4 "« methylendioxybenayl) = »piperazine from 2->amino-4-" ßlilori > y2, > iiddin f 'free BaBe 9 F. 171 0 O,

Beispiel J-Example J-

1 - C 49,6' »Disnethoxy-2-S-triazinyl)»4- C 3 'S 4" ayl)-pipera!3in erhält man nach dem- Verfahren des Beispiels 1 beim Arbeiten mit Be"\sol unter Rückfluss in Gegenwart ύοϊι kaliumcarbonat, ausgehend von 2-Chlor-4p6£,diBietho3£y-S-triaziE.j, die frei® Base,'P. 1020G, Chlorhydrat, I\ 25O°O (Zersetauiig)«1- C 4 9 , 6 '»Disnethoxy-2-S-triazinyl)» 4- C 3' S 4 "ayl) -pipera! 3in is obtained by the process of Example 1 when working with Be" \ sol under reflux in the presence of ύοϊι potassium carbonate, starting from 2-chloro-4 p £ 6, diBietho3 £ yS-triaziE.j, the free® base, 'P. 102 0 G, chlorohydrate, I \ 25O ° O (decomposed) "

Entsprechend der Arbeitsweise deo Beispiele 3 erhält- man folgende Verbindungen!The following are obtained in accordance with the procedure of Example 3 Links!

109817/2200109817/2200

BAD ORIGINALBATH ORIGINAL

a) 1 - {65 -Ketbo J8iy-2 9-S.« tri asinyl) Q©r.»yl)-piperas:isi aus 2~Gl?lGi>=6"» kyclrat,, Γ« 230" O (Zersetsimg) e a) 1 - {6 5 -Ketbo J8iy-2 9 -S. «triasinyl) Q © r.» yl) -piperas: isi from 2 ~ Gl? lGi> = 6 "» kyclrat ,, Γ «230" O (Decomposition) e

"b) 1 ~ C 2s -S-TriaainyJL )-4- (5"»4 "-raaisa au3 2"b) 1 ~ C 2 s -S-TriaainyJL) -4- (5"»4" -raaisa au3 2

(3il fl 4 B-iaethylenäio3iy-( 3 il fl 4 B -iaethylenäio3iy-

Chlor-Chlorine-

y 1 )-pip€i 207-21 *ie0y 1) -pip € i 207-21 * i e 0

»yl)-plperaain aus?
P. 185 - 1900C0 »Yl) -plperaain from?
P. 185-190 0 C 0

freiefree

a) 1 - {4c, 6q -Siamino-2'-S-1;rIaz:liiyl)-4"C 3ft, 4 "--metliyientlioay*' benzyl5-pipemzi?*. aus 2~öiilor-4»6~dlispiiJio-S»-1;riajsin3 freie Base, P, 199 - 2050O1 a) 1 - {4 c , 6 q -Siamino-2'-S-1; rIaz: liiyl) -4 "C 3 ft , 4" -metliyientlioay * 'benzyl5-pipemzi? *. from 2 ~ oilor-4 »6 ~ dlispiiJio-S» -1; riajsin 3 free base, P, 199-205 0 O 1

Beispiel 4Example 4

ι a ( 4.c -»CiMnaEollnyl }«4- (3 H f 4 w«iQß erhält man nach dsm Terfatireii ß ten is Pi€E' in Crcgenwart τοπ. ICal. 4-Chlorcid-nsBoIin»ι a (4. c - "CiMnaEollnyl}" 4- (3 H f 4 w "iQß is obtained according to dsm Terfatireii ß ten is Pi € E 'in Crcgenwart τοπ. ICal. 4-Chlorcid-nsBoIin"

»plp-arassin. Beispiels '! "beim Arbeiis ausgehend
- 233cO.»Plp-arassin. Example '! "going out at work
- 233 c O.

2äatsi>2.*ecjie?2ö. öer Arbeitsweise d3ß lisi£!piö/.s 4 erhält man .folgande YsrMadiuigeaj2äatsi> 2. * ecjie? 2ö. A method of working d3ß lisi £! piö / .s 4 is obtained .followed by YsrMadiuigeaj

a 5 1 - (2s -ChisiaKolinjrl )-4- ( 3 " f 4 "--laeuliyleadiosij'benzyl )-pip« rasxn aus S-Ghlorclilnasolin, d.i'2 i'i.'eie Bane» P. 1410C3 a 5 1 - (2 s -ChisiaKolinjrl) -4- (3 " f 4"--laeuliyleadiosij'benzyl) -pip «rasxn from S-Ghlorclilnasolin, d.i'2 i'i.'eie Bane» P. 141 0 C 3

"b; 1>- { 2 »-He tSiyl-4' -eui"b; 1> - {2» -He tSiyl-4 '-eui

austhe end

3?.3 ?.

iaayl) -4- Ί 3i? ? 4 "-iaayl ) -4- Ί 3 i? ? 4 "-

Beispiel 5 Example 5

·".„( *:■ «/p^rr-a;!üij-l)^-·' ^",4H'-ine'(;h.vI.<-.;.-ii .f ;:'-s;ybi^s?7J i-p.f pe^'^ui· "." (*: ■ «/ p ^ rr-a;! Üij-l) ^ - · '^", 4 H ' -ine '(; h.vI. <- .; .- i i .f ;: '- s; ybi ^ s? 7J ip.f pe ^' ^ ui

1098 17/22001098 17/2200

BAD ORIGINALBATH ORIGINAL

180922b180922b

erliält man nach dem Verfahren des Beispiels. 1 beim Arbeiten in IMP in Gegenwart von K„00,, abgehend von 3-Clilorpyrazin, Dichlorhydrat, P. 228 - 234°Ccan be obtained by following the procedure in the example. 1 when working in IMP in the presence of K "00 ,, starting from 3-clilorpyrazine, Dichlorohydrate, P. 228-234 ° C

Entsprechend der Arbeitsweise des Beispiels 5 erhält man fol gende Verbindungen:In accordance with the procedure of Example 5, the following compounds are obtained:

a) 1-(2',5'-."Dimethyl-3'-pyrazinyl)-4-(3",4M-me1;hylendioxyben zyl)-piperazin aus 2,5-Dimethyl«-3-chlorpyra33in, *. 273 - 275°ö.a) 1- (2 ', 5' -. "Dimethyl-3'-pyrazinyl) -4- (3", 4 M -me1; hylenedioxybenzyl) piperazine from 2,5-dimethyl «-3-chloropyra33in, * . 273 - 275 ° ö.

b) 1-(5l-Methyl-3l-pyraziiiyl)~4-'(3n f4"--niethylendio3cybenzyl)-piperazin aus 3-Chlor-5-niethylpyrazin,":2)ichlorl'tydrat,- P. 254 - 2550Cb) 1- (5 l -Methyl-3 l -pyraziiiyl) ~ 4 - '(3 n f 4 "-niethylenedio3cybenzyl) -piperazine from 3-chloro-5-niethylpyrazine,": 2) chloro hydrate, - P 254-255 0 C

c) 1-C 2 · -Amino-3' -pyraziny!)-4- (3 ", 4K-Methylenciioxybenzyl )-piperazin aus 2-Amino~3-chlorpyra3inf ."Dichlorhydrat, Fo 225 - 228°ö.c) 1-C 2 · -amino-3'-pyraziny!) - 4- (3 ", 4 K -methyleneciioxybenzyl) -piperazine from 2-amino ~ 3-chloropyra3ine f ." dichlorohydrate, Fo 225-228 ° ö.

10981 7/2200
8AD10981 7/2200
8AD

Claims (1)

PatöntansprfioliöPatöntansprfioliö -1«, Heu© hetsrooycliooiie Varbinäuü^ai?. dar allgemeinen ?i mel I-1 ", hay © hetsrooycliooiie Varbinäuü ^ ai ?. dar general? i mel I 2 L JL CH2 -HT- F- H©t (I)2 L JL CH 2 -HT- F- H © t (I) wobei Het einen in der 4-*S teilung gebundenen Pyrimidinyl-, Pyrazinyl-, S-!Eriasinyl~ oder Chinazolinylrest, die gegebenenfalls durch ein oder zwei Alirylreste mit 1 - 5 C-Atomen, Alkoxyrest mit 1-4 Ö-Atomen odex· Amino substituiert sind, oder einen In der 2-Stellung gebitnäe- neu Pyrimidinylreat, der durch Haloge^i, Carboxy, Oarbäthorcy oder Carbäthosyaiethoxy monosubotituiert oder durch Atlioxy, Carboxy oder öarhätho^y dxsubstituiert iat bedeutet«.where Het has a pyrimidinyl, pyrazinyl, S-! Eriasinyl ~ or quinazolinyl radical bonded in the 4- * S division, which is optionally replaced by one or two aliryl radicals with 1 - 5 carbon atoms, alkoxy radicals with 1-4 O atoms or odex Amino are substituted, or a bitnäe- neu pyrimidinylreat in the 2-position, which means monosubotituted by halogen, carboxy, carbethoxy or carbethosyethoxy or substituted by oxy, carboxy or arhätho ^ y dxsubstituted «. !-{5}-Chlor~2'~pyrimidinyl)»4~C3i', 4"~)>ie b zyl5-piperazin.! - {5 } -Chlor ~ 2 '~ pyrimidinyl) »4 ~ C3 i ', 4"~)> ie b zyl5-piperazine. 3. 1-C21-Amino-45-pyrimidLnyl)-4-(3", 4.n-Di©thylenaio3sybeii- * zyl)-piperazin.,3. 1-C2 1 -amino-4 5 -pyrimidLnyl) -4- (3 ", 4. n -Di © thylenaio3sybeii- * zyl) -piperazin., 4. 1 - C 4' -Amino-2 · -S-- tri aainyl) « 4- C 3 " > 4 n-m$ fcb4. 1 - C 4 '-amino-2 · -S- triaainyl) «4- C 3 "> 4 n -m $ fcb 5. 1 - C 4" -(minszollnyl) -4" C 3 ", 4 »-mföi;h;yl,rmülos:ybenayl) razin.5. 1 - C 4 "- (minszollnyl) -4" C 3 ", 4» -mföi; h; yl, rmülos: ybenayl) razin. 6. "«{2! «Ohinseoliriyl)-4-C3"
perazin,6. "« {2 ! «Ohinseoliriyl) -4-C3"
perazine, 109817/2200 bad original109817/2200 bad original U)
7. 1 - C 2' -H'j-&hyl«45 -ehln aaclinyl) -4-=· C 3ρ?, 4^-Ώβ fe "λ flU)
7. 1 - C 2 '-H'j- & hyl «4 5 -ehln aaclinyl) -4- = · C 3 ρ? , 4 ^ -Ώβ fe "λ fl 3. 1 - (3' «Pyraßlnyl )~4~ C 3 }?, 4"-£i®-e^IiiM3. 1 - (3 '"Pyraßinyl) ~ 4 ~ C 3 }? , 4 "- £ i® -e ^ IiiM 9» Me Additionssalze, bescndera die physiologisch vejr^rSg» lichaii Salsa, άατ in Aen .Ansprüchen 1-8 böänspruiclitera ?©rbind?xngen, mit Mineral säur 011 imd orgasii molten Säuren.9 »Me addition salts, bescndera the physiologically vejr ^ rSg» lichaii salsa, άατ in Aen. Claims 1-8 böänspruiclitera? © rbind? Xngen, with mineral acid 011 imd orgasii molten acids. 10» Verfahren ssur Herstellung clar Yerbiadun^aii iiaoh Anspruch 1 ψ öadiircii gskeunagichnet, dass man sin HalogeMsriirat der allgeiüöinen Formel II10 »Process ssur production clar Yerbiadun ^ aii iiaoh claim 1 ψ öadiircii gskeunagichnet that one sin HalogeMsriirat of the general formula II Het «■ Z, (II) Het «■ Z, (II) wobei 2 Chlor odsr Brom und Hat einen vorö*sehe.3i(i ge ten Hest bedeutet, lalt 1-(3!l»4i-Mei*hyleiidio.iiybensyl)-piperazin der Formel IIIwhere 2 is chlorine or bromine and has a proposed.3i (i ge th hest means lalt 1- (3 ! l »4 i -Mei * hyleiidio.iiybensyl) -piperazine of the formula III CHC - N IHCH C - N IH Verfahren :.iach Aaaprach 10$ dadurch gekimriaisicjhnöts dans man cliu Um-setauitig in eirasm polaren lössmigßiaitbeli, a^ege·» w-illi.Lt aus llkohöleii R;it lioben Sleriepmik^öj:, od&r arumatJ-; sahen jimiden, odar ainesa ni(ih*cpolar©n Lüaungu-ni'üfcalp aw=- gewählt aus aromati.3che:a Kohlonwaösersto.ffe.^» bei Seatpe·=- raturöii yon 80 -» 14O0O in Segt^mfart einaia AkKöptorn für dis im Verlauf der Ε-satt: bimi g'öb.i.ldete Säure t Procedure: .iach Aaaprach $ 10 thereby gekimriaisicjhnöts dans man cliu Um-setauitig in eirasm polar loessmigßiaitbeli, a ^ ege · »w-illi.Lt from llkohöleii R; it lioben Sleriepmik ^ öj :, od & r arumatJ-; saw jimiden, odar ainesa ni (ih * cpolar © n Lüaungu-ni'üfcalp aw = - chosen from aromatic: a Kohlonwaösersto.ffe. ^ »at Seatpe · = - raturöii yon 80 -» 14O 0 O in Segt ^ mfart einaia AkKöptorn for dis in the course of Ε-satt: bimi g'öb.i.ldete acid t Verfahren nach Anspifuch 10 ur.ii 11, dadurch gekmjnKal daea aiiüi als SaiAreakia-ap boj? ein. Alkali-Method according to Anspifuch 10 ur.ii 11, thereby gekmjnKal daea aiiüi as SaiAreakia-ap boj? a. Alkali- 109817/220 0 8AO ORIGINAL109817/220 0 8AO ORIGINAL — ! I-! I. tsrt.läre organieeras Base ods:? einen Über« iS<mosuliötI1;u:ler1;G:ii j?;Lpe:caz±:i£i der Fo.r III Tui^tsrt.läre organieeras Base ods :? an about « iS <mosuliötI1; u: ler1; G: ii j?; Lpe: caz ±: i £ i der Fo.r III Tui ^ 10 9817/220010 9817/2200 BAD OR(GiNALBAD OR (GiNAL
DE19681809225 1967-11-15 1968-11-15 New heterocyclic compounds and processes for their preparation Pending DE1809225A1 (en)

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US3859438A (en) * 1971-07-08 1975-01-07 Boehringer Sohn Ingelheim Pharmaceutical compositions containing an n-(1-bicyclic aryl-propyl-2)-n-bicyclic aryl-piperazine and method of use
GB1369379A (en) * 1972-04-07 1974-10-09 Science Union & Cie Benzodioxole derivatives and processes for preparing them
US4166852A (en) * 1974-08-09 1979-09-04 Produits Chimiques Ugine Kuhlmann Piperazino-pyrimidines and their use as spasmolytic agents
OA06083A (en) * 1977-11-09 1981-06-30 Science Union & Cie Ste Franca New disubstituted piperazines, their preparation processes and pharmaceutical compositions containing them.
FR2519986A1 (en) * 1982-01-21 1983-07-22 Adir NOVEL BENZODIOXINE DERIVATIVES, PROCESSES FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS COMPRISING SAME
CH651027A5 (en) * 1982-11-12 1985-08-30 Sandoz Ag HETEROCYCLIC COMPOUNDS, THEIR PRODUCTION AND USE.
ES2062940B1 (en) * 1993-03-11 1995-06-16 Vita Invest Sa GASTROCINETIC AGENT, PROCESS FOR ITS PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN IT.
ES2063700B1 (en) * 1993-04-28 1995-07-16 Vita Invest Sa ACTIVE AGENT ON THE CENTRAL NERVOUS SYSTEM, PROCESS FOR ITS PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN IT.
US20070219213A1 (en) * 2004-05-20 2007-09-20 Soares Romeiro Luiz A Use of Adrenergic N-Phenylpiperazine Antagonists, Pahrmaceutical Compositions Containning Them, and Methods of Preparing Them
MA41169A (en) * 2014-12-17 2017-10-24 Acraf WIDE-SPECTRUM ANTIBACTERIAL COMPOUNDS

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E77 Valid patent as to the heymanns-index 1977