PL78370B1 - - Google Patents

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PL78370B1
PL78370B1 PL1970142516A PL14251670A PL78370B1 PL 78370 B1 PL78370 B1 PL 78370B1 PL 1970142516 A PL1970142516 A PL 1970142516A PL 14251670 A PL14251670 A PL 14251670A PL 78370 B1 PL78370 B1 PL 78370B1
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lower alkyl
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optionally substituted
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substituted lower
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    • 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
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
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    • C07C39/18—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring monocyclic with unsaturation outside the aromatic ring
    • C07C39/19—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring monocyclic with unsaturation outside the aromatic ring containing carbon-to-carbon double bonds but no carbon-to-carbon triple bonds
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    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D239/26—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 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
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    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
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    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00Ā -Ā C07D463/00 in which the condensed system contains two hetero rings
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more Pā€”C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4056—Esters of arylalkanephosphonic acids

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Description

Uprawniony z patentu: Dr Karl Thomae GmbH, Biberach n/Riss, (Republika Federalna Niemiec) SposĆ³b wytwarzania nowych 6-arylo-2-aminoalkoksystyroli Przedmiotem wynalazku jest sposĆ³b wytwarzania nowych arylo-2-aminoal'kotasystyroli o wzorze ogĆ³lĀ¬ nym 1, w ktĆ³rym Ar oznacza grupe fenylowa, gruĀ¬ pe 2- lub 3- lub 4-pirydylowa, ewentualnie podstaĀ¬ wiona nizsza grupe alkilowa, grupe 2-chinolilowa lub 2-pirazynylowa, ewentualnie podstawiona nizsza grupe alkilowa, grupe pirymidylowa ewentualnie podstawiona nizsza grupe alkilowa, grupe benzimi- dazolilowa, ewentualnie podstawiona atomem chloĀ¬ rowca lub nizsza grupa alkilowa lub grupa trĆ³j- fluorometylowa, grupe 2-furylowa *lub 2-tienylowa, grupe 5-izoksazolilowa, ewentualnie podstawiona nizsza grupa alkilowa lub grupa fenylowa, grupe 5-(l,2,4-oksadiazolilowa) ewentualnie podstawiona nizsza grupa alkilowa, RĀ± i R2, R4 i R5, moga byc takie same lub rĆ³zne i oznaczaja atomy wodoru lub nizsze grupy alkilowe, R3 oznacza atom wodoru lub nizsza grupe alkoksylowa, R6 i R7 moga byc takie same lub rĆ³zne i oznaczaja atomy wodoru lub nizsze grupy alkilowe, alkenylowe, hydroksyalkilo- we, alkoksyalkilowe lub grupy aralkilowe, przy czym reszty R6 i R7 lacznie ze znajdujacym sie miedzy nimi atomem azotu moga rĆ³wniez tworzyc nasycony, monocykliczny, heterocykliczny 5ā€”7 czloĀ¬ nowy pierscien, ewentualnie zawierajacy jeszcze atom tlenu lub dalszy atom azotu, a n oznacza liczbe 0 lub 1, jak rĆ³wniez ich fizjologicznie doĀ¬ puszczalnych soli addycyjnych z nieorganicznymi lub organicznymi kwasami.Nowe zwiazki o wzorze 1 wytwarza sie przez 10 15 25 30 odszczepienie wody od zwiazkĆ³w o wzorze ogĆ³lnym 2? w ktĆ³rym Ar, RĀ± do R7 oraz n maja wyzej poĀ¬ dane znaczenie. Odszczepienie wody nastepuje za pomoca odpowiednich do tego celu srodkĆ³w, np. za pomoca kwasu fosforowego, kwasĆ³w polifosforo- wych,* kwasu fosforowego z pieciotlenkiem fosforu lub kwasu siarkowego; jako szczegĆ³lnie odpowiedni okazal sie 85% kwas fosforowy. Reakcja przebiega w podwyzszonych temperaturach, korzystnie w zaĀ¬ kresie temperatur 70ā€”130Ā°C.Zwiazki o wzorze 1 powstaja na ogĆ³L jako mieĀ¬ szaniny ich izomerĆ³w cis i trans. Jezeli symbole Rt i R2 oznaczaja atomy wodoru, tĆ³ powstaja glĆ³wĀ¬ nie zwiazki trans. Zwiazki cis i trans daja sie rozdzielic przez frakcjonowana krystalizacje, zwlaszĀ¬ cza ich soli, np. chlorowodorkĆ³w.Zwiazki o wtzorze 1 mozna w znany sposĆ³b przeĀ¬ prowadzic w ich sole addycyjne z kwasami za poĀ¬ moca nieorganicznych lub organicznych kwasĆ³w.Jezeli Ar oznacza pierscien heterocykliczny zawieĀ¬ rajacy azot, to mozliwe jest dzieki stopniowej neuĀ¬ tralizacji przylaczenie protonu tylko do zasadowego atomu azotu lancucha bocznego. Jezeli do wytworzeĀ¬ nia soli stosuje sie nadmiar kwasu, to otrzymuje sie rĆ³wniez sole przez przylaczenie protonu do atoĀ¬ mĆ³w azotu pierscieni heterocyklicznych. Jako kwasy nadaja sie szczegĆ³lnie: kwas solny, kwas bromowo- dorowy, kwas siarkowy, kwas fosforowy, kwas wiĀ¬ nowy, kwas p-toluenosulfonowy.Zwiazki o wzorze ogĆ³lnym 2, sluzace jako sub- 78 3703 stancje wyjsciowe otrzymuje sie przez kondensacje zwiazku o wzorze ogĆ³lnym 3 z estrem o wzorze ogĆ³lnym 4 prowadzaca do ketonu o wzorze ogĆ³lnym 5, np. z udzialem lamidku sodowego w roztworze toluenu i redukcje ketonu o wzorze ogĆ³lnym 5 za pomoca kompleksowych wodorkĆ³w, np. borowodorĀ¬ ku sodowego lub katalitycznie uaktywnionego woĀ¬ doru do alkoholu o wzorze ogĆ³lnym 2. We wzorach 3ā€”5 symbole B,Ā± do R7 oraz n maja wyzej podane znaczenia, a R9 oznacza grupe alkilowa.Zwiazki o wzorze ogĆ³lnym 1 posiadaja cenne wlasciwosci farmakologiczne. Dzialaja one zwlaszcza analgetycznie, nie posiadajac przy tym ubocznego dzialania morfiny, a ponadto wykazuja dobre dziaĀ¬ lanie uspakajajace i zwalniaja napiecie miesni.Dla dzialania fizjologicznego istotne znaczenie ma budowa czasteczki zwiazku o wzorze 1, a zwlaszcza obecnosc zasadowego lancucha bocznego przy piersĀ¬ cieniu benzenowym w polozeniu orto do grupy wiĀ¬ nylowej. Tak wiec np. znane izomeryczne 4-amino- alkoksystyrole [Cavallini i inni. II Farmaco, Ed Sci. 9, 405ā€”415 (1954) oraz Montegazza i inni, Arch. intern, pharmacodyn 103, 371ā€”309] w ogĆ³le nie sa aktywne analgetycznie. Wedlug danych literaturoĀ¬ wych wykazuja one dzialanie antynikotynowe i an- tyhistaminowe.Zwiazki o wzorze ogĆ³lnym 1 badano na dzialanie analgetyczne metoda goracej plyty wedlug Chen i Beckmanna, Science, 113, 1951, strona 631. PoddaĀ¬ no przy tym bĆ³lowi wywolanemu skutkiem dzialaĀ¬ nia podwyzszonej temperatury myszy po 10 w gruĀ¬ pie na goracej plycie o temperaturze 56Ā°C. ZwieĀ¬ rzeta uzyte do prĆ³by reagowaly na nia normalnie w ciagu 20 sekunld. Amalgetyczne dzialanie okresloĀ¬ no wedlug procentu zwierzat niereagujacych na bĆ³l przy okreslonej dawce zwiazku o wzorze 1 w ciagu 50 sekund. Wartosc ED50 przedstawia przy tym dawke, przy ktĆ³rej podaniu 50% myszek nie reagoĀ¬ walo na bĆ³l. Substancje aktywne podawano do przewodu pokarmowego. Nowe zwiazki sa tylko nieĀ¬ znacznie toksyczne. Ostra toksycznosc oznaczono na myszkach. Myszkom w grupach po 10 wprowadzono do przewodu pokarmowego substancje aktywna przy wzrastajacych dawkach. Wartosc LD50 odpowiada dawce, przy podaniu ktĆ³rej 50% myszek padalo w ciagu 14 dni (obliczono z uzyskanych wartosci wedlug metody Lichtfielda i Wilcoxona).Nizej zestawione zwiazki dzialaja szczegĆ³lnie silĀ¬ nie analgetycznie: monochlorowodorek 2-[2-(2-dwumetyloaminoetoksy)- -styrylo] -pirazyny, monochlorowodorek 2-[2-(2-dwumetyloaminoetoksy)- -styrylo] -chinoliny, monochlorowodorek 2-[2-(2-dwumetyloaminoetoksy)- -styrylo] -6-metylopirydyny, monochlorowodorek 2-[2-(2-dwumetyloaminoetoksy)- -styrylo]-pirydyny, chlorowodorek 5- {[2-dwumetyloamino(-etoksy]- -styrylo} -3-metyloizoksazolu, chlorowodorek 5- {[2-dwumetyloamino(-etoksy]- -styrylo} -3-fenyloizoksazolu, dwuchlorowodorek 2-i[2-(2-dwumetyloaminoetoksy) - -styrylo]-1-metylobenzimidazolu, chlorowodorek 2- (dwumetyloaminoetoksy)-stylbenu, 78 370 4 chlorowodorek 2-[2-(2-dwumetyloaminoetoksy)- -styrylo] -furanu, chlorowodorek 2- [2- (2-dwumetyloaminoetoksy)- -styrylo] -tiofenu, 5 monochlorowodorek 1-(2-dwumetyloaminoetoksyfe- nylo) -2-pirydylo-2)-propenu-1, dwuchlorowodorek 2-[2-(2-metyloaminoetoksy)- -styrylo]-pirydyny oraz dwuchlorowodorek 2-[2-(2-morfolinoetoksy)-styrylo]- io -pirydyny.Przy podaniu myszom do przewodu pokarmowego zwiazki o wzorze 1 maja ED5o = 10ā€”60 mg/kg myĀ¬ szy. Toksycznosc substancji jest niewielka, tak wiec np. wartosci LD50 wynosza 500ā€”800 mg/kg myszy 15 dla nastepujacych substancji: dwuchlorowodorek 2-[2-(2-dwumetyloaminoetoksy) - -styrylo]-1-metylobenzimidazolu, chlorowodorek 2-(2-dwuime1;yloaminoetoksy)-stylbeĀ¬ nu, dwuchlorowodorek 2-[2-(2-morfolinoetoksy)-sty- 20 rylo]-pirydyny oraz chlorowodorek 2-[2-(2-dwumetyloaminoetoksy) - -styrylo]-6-metylopirydyny.Nastepujace przyklady blizej wyjasniaja wynalaĀ¬ zek nie ograniczajac jego zakresu: Przyklad I. 20,2 g l-pirazynylo-2-(2-dwume- tyloaminoetoksy-fenylo)-etanolu-2 miesza sie z 60 ml 85% kwasu fosforowego, przy czym mieszanine ogrzewa sie do temperatury 70Ā°C. Potem ogrzewa 30 sie w ciagu 1 godziny do temperatury 110Ā°C, po oziebieniu rozpuszcza sie w 300 ml wody, zobojetnia i wysyca weglanem potasowym. Ekstrahuje sie wyĀ¬ tworzony produkt reakcji trzykrotnie po 50 ml eteĀ¬ ru, osusza nad bezwodnym weglanem potasowym 35 i przesacza przez wegiel. Pozostalosc po odparowaĀ¬ niu destyluje sie pod zmniejszonym cisnieniem.Otrzymuje sie 13,25 g (co odpowiada 70,2% wydajĀ¬ nosci teoretycznej), jasnozĆ³ltego oleju, o temperaĀ¬ turze wrzenia przy 0,01 mm Hg 143ā€”150Ā°C. Olej 40 rozpuszcza sie w 250 ml acetonu i ostroznie zadaje tylko taka iloscia roztworu gazowego chlorowodoru w acetonie, aby nastapilo zĆ³lte zabarwienie. Po oziebieniu w lazni z lodem wydzielaja sie biale krysztaly, ktĆ³rych ilosc jeszcze sie powieksza przez 45 domieszanie 150 ml eteru. Po odsaczeniu i wysuĀ¬ szeniu otrzymuje sie 13,9 g (co odpowiada 88,2% wydajnosci teoretycznej w stosunku do tworzacego sie chlorowodorku) monochlorowodorku 2-[2-(2- dwumetyloaminoetoksy)-styrylo]-pirazyny, o tempe- eA raturze topnienia 194ā€”195Ā°C. 5U l-(pirazynylo-2)-2-(2-dwumetyloaminoetoksyfeny- lo)-etanol-2 stosowany jako produkt wyjsciowy, nie destylujacy zĆ³lty olej, jednolity w chromatogramie cienkowarstwowym, otrzymuje sie z ketonu(pirazy- 55 nylo-2)-(2-dwumetyloaminoetoksyfenylowego) (nie destylujacy olej, tworzy krystaliczny enolan litowy) przez redukcje borowodorkiem sodowym; potrzebny do tego keton otrzymuje sie z 2-metylopirazyny i estru metylowego kwasu 2-dwumetyloaminoeto- 60 ksybenzoesowego przez kondensacje za pomoca amidku sodowego w toluenie.Analogicznie do sposobu opisanego w przykladzie I wytworzono nastepujace substancje.Przyklad II. Z l-(chinolilo-2)-2-(2-dwumety- 65 loaminoetoksyfenylo)-etanolu-2. zĆ³ltego nie destylu-5 Jacego oleju, jednolitego w chromatogramie cienkoĀ¬ warstwowym, wytwarza sie monochlorowodorek r2-[2-(2-dwumetyloaminoetoksy)-styrylo] -chinoliny o temperaturze topnienia 188Ā°C z wydajnoscia 87%.Przyklad III. Z l-(6-metylopirydylo)-2-(o- -dwumetyloaminoetoksyfenylo)-etanolu-2 (jasnozĆ³l- te krysztaly o temperaturze topnienia 228Ā°C) otrzyĀ¬ muje sie monochlorowodorek 2-[2-(2-dwumetyloamiĀ¬ noetoksy)-styrylo]-6-metylopirydyny, o temperaturze topnienia 200Ā°C z wydajnoscia 20%.Przyklad IV. Z l-(4,6-dwumetylopirydylo-2)-2- - (o-dwumetyloaminoetoksyfenylo) -etanolu-2 (jasno- -zĆ³lty, nie destylujacy olej, jednolity w chromatoĀ¬ gramie cienkowarstwowym) wytwarza sie dwuchlo- rowodorek 2- [2- (2-dwumetyloaminoetoksy)-styrylo]- -4,6-dwumetylopirydyny, o temperaturze topnienia 177Ā°C, z wydajnoscia 81%.Przyklad V. Z l-(2-pirydylo)-2-(2-dwumety loĀ¬ aminoetoksyfenylo)-etanolu-2, oleju zĆ³ltego, nie deĀ¬ stylujacego, jednolitego w chromatogramie cienkoĀ¬ warstwowym, wytwarza sie monochlorowodorek 2-[2-(2-dwumetyloaminoetoksy)-styrylo] -pirydyny, o temperaturze topnienia 183Ā°C, z wydajnoscia 88%.Przyklad VI. Z l-(5-metylopirazynylo-2)-2- - (2-dwumetyloaminoetoksyfenylo)-etanolu-2, oleju bezbarwnego, nie destylujacego, jednolitego w chro- mlatogramie cienkowarstwowym, wytwiarza sie dwu- *chlorowodorek !2-[2- (2-dwumetyloaminoetoksy)-styĀ¬ rylo]-5^metylopirazymy-2, zywicowata, biala subĀ¬ stancje, jednolita w chromatogramie cienkowarsĀ¬ twowym, z wydajnoscia 65%.Przyklad VII. Z l-(4-metylopirydymidylo-6)- ā€”2-(2-dwumetyloaminoetoksyfenylo) -etanolu-2, nie destylujacego klarowanego zĆ³ltego oleju, jednolitego w chromatogramie cienkowarstwowym, wytwarza sie 6- [2- (2-dwumetyloaminoetoksy)-styrylo]-4-mety- lopirymidyne, o temperaturze topnienia 234Ā°C, z wyĀ¬ dajnoscia 87%. PL PL PLPatent proprietor: Dr. Karl Thomae GmbH, Biberach n / Riss, (Federal Republic of Germany). Method for the preparation of new 6-aryl-2-aminoalkoxystyroles. where Ar is a phenyl group, a 2- or 3- or 4-pyridyl group, an optionally substituted lower alkyl group, a 2-quinolyl or 2-pyrazinyl group, an optionally substituted lower alkyl group, a pyrimidyl group, an optionally substituted lower alkyl group, a benzimidazolyl group, optionally substituted with a halogen atom or a lower alkyl group or a trifluoromethyl group, a 2-furyl * or 2-thienyl group, a 5-isoxazolyl group, an optionally substituted lower alkyl group or a phenyl group, a 5- (1) group , 2,4-oxadiazolyl) optionally substituted lower alkyl group, R Ā± and R2, R4 and R5, may be the same or different and represent hydrogen atoms or lower alkyl groups, R3 is hydrogen or lower alk oxyl, R6 and R7 can be the same or different and represent hydrogen atoms or lower alkyl, alkenyl, hydroxyalkyl, alkoxyalkyl or aralkyl groups, where the residues R6 and R7 including the nitrogen atom between them can also form a saturated, a monocyclic heterocyclic 5-7 membered ring, optionally containing an oxygen atom or a further nitrogen atom, and n is a number 0 or 1, as well as their physiologically acceptable addition salts with inorganic or organic acids. by cleavage of water from compounds of general formula 2 wherein Ar, R 6 to R 7 and n are as defined above. The water is separated off by suitable means, for example with phosphoric acid, polyphosphoric acids, * phosphoric acid with phosphorus pentoxide or sulfuric acid; 85% phosphoric acid has proved to be particularly suitable. The reaction takes place at elevated temperatures, preferably in the temperature range 70-130 Ā° C. The compounds of formula I are generally formed as mixtures of their cis and trans isomers. If the symbols Rt and R2 represent hydrogen atoms, then mainly trans compounds are formed. The cis and trans compounds can be separated by fractionated crystallization, in particular by their salts, e.g. A heterocyclic ring containing nitrogen, it is possible, due to the gradual neutralization, to attach a proton only to the basic nitrogen atom of the side chain. If an excess of acid is used in the preparation of the salt, salts are also obtained by attaching a proton to the nitrogen atoms of the heterocyclic rings. The following are particularly suitable as acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, tartaric acid, p-toluenesulfonic acid. of general formula III with an ester of general formula IV to a ketone of general formula V, e.g. with sodium lamide in a toluene solution, and reduction of the ketone of general formula V with complex hydrides, e.g. sodium borohydride or catalytically activated hydrogen to alcohol of general formula 2. In Formulas 3-5 the symbols B, Ā± to R7 and n have the above meanings and R9 represents an alkyl group. Compounds of general formula I have valuable pharmacological properties. They work especially analgesically, without the side effect of morphine, and moreover, they have a good sedative effect and relieve muscle tension. ortho to the vinyl group. Thus, for example, the known isomeric 4-amino-alkoxystyroles [Cavallini et al. II Farmaco, Ed Sci. 9, 405-415 (1954) and Montegazza et al., Arch. intern, pharmacodyn 103, 371-309] are not analgetically active at all. According to the literature, they show anti-smoking and antihistamine effects. Compounds of general formula 1 were tested for analgesic action by the hot plate method according to Chen and Beckmann, Science, 113, 1951, page 631. The elevated temperature of 10 mice per group was placed on a hot plate at 56 Ā° C. The animals used in the trial responded normally within 20 seconds. The amalgesic effect was determined according to the percentage of animals not responding to pain at a given dose of a compound of formula I within 50 seconds. The ED50 value here represents the dose at which 50% of the mice had no pain response when administered. The active substances were administered to the gastrointestinal tract. The new compounds are only slightly toxic. Acute toxicity was determined in the mice. In groups of 10 mice, the active substance was introduced into the gastrointestinal tract at increasing doses. The LD50 value corresponds to the dose at which 50% of the mice died within 14 days (calculated from the values obtained according to the Lichtfield and Wilcoxon method). The compounds listed below are particularly analgesic: 2- [2- (2-dimethylaminoethoxy) monohydrochloride - -styryl] -pyrazine, 2- [2- (2-dimethylaminoethoxy) -styryl] -quinoline monohydrochloride, 2- [2- (2-dimethylaminoethoxy) -styryl] -6-methylpyridine monohydrochloride, 2- [2- (2-dimethylaminoethoxy) -styryl] -pyridine, 5- {[2-dimethylamino (-ethoxy] -styryl} -3-methylisoxazole hydrochloride, 5- {[2-dimethylamino (-ethoxy] -styryl} - hydrochloride) 3-phenylisoxazole, 2-i [2- (2-dimethylaminoethoxy) -styryl] -1-methylbenzimidazole dihydrochloride, 2- (dimethylaminoethoxy) -stilbene hydrochloride, 78 370 4 2- [2- (2-dimethylaminoethoxy) - - hydrochloride styryl] furan, 2- [2- (2-dimethylaminoethoxy) -styryl] -thiophene hydrochloride, 1- (2-dimethylaminoethoxyphenyl) -2-pi monohydrochloride ridyl-2) -propene-1, 2- [2- (2-methylaminoethoxy) -styryl] -pyridine dihydrochloride, and 2- [2- (2-morpholinoethoxy) -styryl] - and -pyridine dihydrochloride. of the gastrointestinal tract, compounds of formula May 1 ED 50 = 10-60 mg / kg of mice. The toxicity of the substance is low, so e.g. LD50 values are 500-800 mg / kg of mice 15 for the following substances: 2- [2- (2-dimethylaminoethoxy) -styryl] -1-methylbenzimidazole hydrochloride, 2- (2- dimethylaminoethoxy) styrene, 2- [2- (2-morpholinoethoxy) styryl] -pyridine dihydrochloride and 2- [2- (2-dimethylaminoethoxy) styryl] -6-methylpyridine hydrochloride. The following examples explain the invention without limiting its scope: heated to 70 Ā° C. Then it is heated within 1 hour to 110 Ā° C, after cooling it is dissolved in 300 ml of water, neutralized and saturated with potassium carbonate. The resulting reaction product is extracted three times with 50 ml of ether, dried over anhydrous potassium carbonate and filtered over coal. The evaporation residue is distilled under reduced pressure. The yield is 13.25 g (corresponding to 70.2% of theory) of a light yellow oil, boiling at 0.01 mm Hg 143-150 Ā° C. The oil 40 is dissolved in 250 ml of acetone and only carefully treated with just enough of a solution of hydrogen chloride gas in acetone until a yellow color appears. After cooling in an ice bath, white crystals are released, the number of which is further increased by mixing 150 ml of ether. After filtering off and drying, 13.9 g (corresponding to 88.2% of theory, with respect to the hydrochloride formed) of 2- [2- (2-dimethylaminoethoxy) styryl] -pyrazine monohydrochloride, mp 194-195 Ā° C. 5U 1- (pyrazinyl-2) -2- (2-dimethylaminoethoxyphenyl) -ethanol-2 used as starting product, non-distilling yellow oil, uniform in thin layer chromatogram, obtained from ketone (pyrazin-2-nyl-2) - (2-dimethylaminoethoxyphenyl) (non-distilling oil, forms crystalline lithium enolate) by reduction with sodium borohydride; the ketone required for this is obtained from 2-methylpyrazine and 2-dimethylaminoethoxybenzoic acid methyl ester by condensation with sodium amide in toluene. The following materials were prepared analogously to the procedure described in Example 1. Example II. From 1- (quinolyl-2) -2- (2-dimethylaminoethoxyphenyl) -ethanol-2. A yellow, non-distilled oil, uniform in the thin layer chromatogram, is prepared r2- [2- (2-dimethylaminoethoxy) styryl] quinoline monohydrochloride having a melting point of 188 Ā° C, a yield of 87%. Example III. 2- [2- (2-Dimethylaminoethoxy) monohydrochloride is obtained from 1- (6-methylpyridyl) -2- (o-dimethylaminoethoxyphenyl) -ethanol-2 (light yellow crystals, m.p. 228 Ā° C) -styryl] -6-methylpyridine, mp 200 Ā° C, yield 20%. Example IV. 2- [ 2- (2-dimethylaminoethoxy) styryl] -4,6-dimethylpyridine, m.p. 177 Ā° C, yield 81%. Aminoethoxyphenyl) -ethanol-2, a yellow oil, non-distilling, uniform in the thin-layer chromatogram, the preparation of 2- [2- (2-dimethylaminoethoxy) styryl] -pyridine monohydrochloride, m.p. 183 Ā° C, yield: 88%. Example VI. From 1- (5-methylpyrazinyl-2) -2- (2-dimethylaminoethoxyphenyl) -ethanol-2, a colorless, non-distilling oil, uniform in the thin-layer chromatogram, di- * hydrochloride! 2- [2- ( 2-Dimethylaminoethoxy) styryl] -5-methylpyrazine-2, gummy, white solid, uniform in thin layer chromatogram, yield 65%. Example VII. From 1- (4-methylpyridimidyl-6) -2- (2-dimethylaminoethoxyphenyl) -ethanol-2, non-distilling clarified yellow oil, uniform in the thin-layer chromatogram, 6- [2- (2-dimethylaminoethoxy) -styryl] is prepared -4-methylpyrimidine, mp 234 Ā° C., yield 87%. PL PL PL

Claims (3)

1. Zastrzezenia patentowe 1. SposĆ³b wytwarzania nowych P-arylo-2-amino- -alkoksystyroli o wzorze ogĆ³lnym 1, w ktĆ³rym Ar ^oznacza grupe fenylowa, grupe 2- lub 3- lub 4-piry- * 370 6 dylowa, ewentualnie podstawiona nizsza grupa alkiĀ¬ lowa, grupe ,2-chinolinowa lub 2-pirazynylowa, ewentualnie podstawiona nizsza grupa alkilowa, t grupe pirymidylowa ewentualnie podstawiona niz- 5 sza grupa alkilowa, grupe 2-benzimidazolilowa ewentualnie podstawiona atomem chlorowca lub nizsza grupa alkilowa lub grupa trĆ³jfluorometylowa, grupe 2-furylowa lub 2-tienylowa, grupe 5-izoksa- zolilowa ewentualnie podstawiona nizsza grupa al- 10 kilowa lub grupa fenylowa, 5-(l,2,4-oksadiazolilowa) ewentualnie podstawiona nizsza grupa alkilowa, Ru R2, R4 i R5, moga byc jednakowe lub rĆ³zne i oznaĀ¬ czaja atomy wodoru lub nizsze grupy alkilowe, R8 oznacza atom wodoru lub nizsza grupe alkoksylowa, 2. 15. R6 i R7, moga byc jednakowe lub rĆ³zne i oznaczaja atomy wodoru lub nizsze grupy alkilowe, alkeny- lowe, hydroksyalkilowe, alkoksyalkilowe lub grupy aralkilowe, przy czym R6 i R7 lacznie ze znajdujaĀ¬ cym sie miedzy nimi atomem azotu moga rĆ³wniez 20 tworzyc nasycony, monocykliczny, heterocykliczny 5-7 czlonowy pierscien, ewentualnie zawierajacy jeszcze atom tlenu lub dalszy atom azotu, a n oznaĀ¬ cza liczbe 0 lub 1, jak rĆ³wniez ich fizjologicznie dopuszczalnych soli addycyjnych z nieorganicznymi .25 lub organicznymi kwasami, znamienny tym, ze ze zwiazku o wzorze ogĆ³lnym 2, w ktĆ³rym Ar, Rx do R7 i n maja podane wyzej znaczenia, odszczepia sie wode za pomoca srodkĆ³w odciagajacych wode w (podwyzszonej temperaturze i ewentualnie pow- 30 stala mieszanine izomerĆ³w cis i trans rozdziela sie nastepnie przez frakcjonowana krystalizacje i/lub otrzymany zwiazek o wzorze li przeprowadza sie w sĆ³l addycyjna z nieorganicznym lub organicznym kwasem. 351. Claims 1. A method for the preparation of new P-aryl-2-amino-alkoxystroles of general formula I, in which Ar1 is a phenyl group, a 2- or 3- or 4-pyrrolyl group, optionally substituted lower alkyl group, 2-quinoline or 2-pyrazinyl group, optionally substituted lower alkyl group, t pyrimidyl group optionally substituted lower alkyl group, 2-benzimidazolyl group optionally substituted with halogen or lower alkyl group or trifluoromethyl group, 2-furyl or 2-thienyl, 5-isoxazolyl optionally substituted lower alkyl or phenyl, 5- (1,2,4-oxadiazolyl) optionally substituted lower alkyl, Ru R2, R4 and R5 may be the same or different and represent hydrogen atoms or lower alkyl groups, R8 is hydrogen or lower alkoxy, 2. 15. R6 and R7, may be the same or different and represent hydrogen atoms or lower alkyl groups, alkenes- low, hydroxyalkyl These, alkoxyalkyl or aralkyl groups, whereby R6 and R7 together with the nitrogen atom therebetween can also form a saturated monocyclic heterocyclic 5-7 membered ring, optionally further containing an oxygen atom or a further nitrogen atom, either a total of 0 or 1, as well as their physiologically acceptable addition salts with inorganic .25 or organic acids, characterized in that, with the compound of general formula II, in which Ar, Rx to R7 and n are as defined above, the water is separated by The water attractants are then separated at (elevated temperature and possibly the resulting mixture of cis and trans isomers by fractionated crystallization and / or the obtained compound of formula I into an addition salt with an inorganic or organic acid). 35 2. SposĆ³b wedlug zastrz. 1, znamienny tym, ze jako srodek odciagajacy wode stosuje sie kwas fosĀ¬ forowy, kwasy polifosforowe, pieciotlenek fosforu i kwas fosforowy lub kwas siarkowy.2. The method according to p. The process of claim 1, wherein phosphoric acid, polyphosphoric acids, phosphorus pentoxide, and phosphoric acid or sulfuric acid are used as the water extractant. 3. SposĆ³b wedlug zastrz. 1, znamienny tym, ze 49 w przypadku otrzymania mieszaniny izomerĆ³w cis i trans pojedyncze skladniki rozdziela sie od siebie przez frakcjonowana krystalizacje ich chlorowoĀ¬ dorkĆ³w.KI. 12q,14/04 78 370 MKP C07c 43/20 0-CH-CH-(CH2)n-N: I I R4 Rs WZƓR 1 *7 OH r3 Ar-CH-C-fjY R1 R2 O-CH-CH-Cd-UL-N^ 6 II 2n ^R7 R4 R5 WZƓR 2 Ar-CH, I 2 , WZƓR 3 RQOOC ^T R. \ / 0-CH-CH-(CHJn-N I I 2n R4 R5 WZƓR 4 /R6 XR, o-ch-ch-cchj-n: ii 2 n R4 R5 , WZƓR 5 Zaklady Typograficzne LĆ³dz, zam. 233/75 ā€” 110 egz. ^R. ERRATA Strona 1, w tekscie: TwĆ³rcy wynalazku jest: Willi Diedener powinno byc: Willi Diederen Cena 10 zl PL PL PL3. The method according to p. A process as claimed in claim 1, characterized in that when a mixture of cis and trans isomers is obtained, the individual components are separated from each other by fractionated crystallization of their hydrochlorides. 12q, 14/04 78 370 MKP C07c 43/20 0-CH-CH- (CH2) nN: II R4 Rs FORMULA 1 * 7 OH r3 Ar-CH-C-fjY R1 R2 O-CH-CH-Cd-UL -N ^ 6 II 2n ^ R7 R4 R5 FORMULA 2 Ar-CH, I 2, FORMULA 3 RQOOC ^ T R. \ / 0-CH-CH- (CHJn-N II 2n R4 R5 FORMULA 4 / R6 XR, o- ch-ch-cchj-n: ii 2 n R4 R5, MODEL 5 Zaklady Typograficzne LĆ³dz, Zam. 233/75 - 110 copies. ^ R. ERRATA Page 1, in the text: The inventors are: Willi Diedener should be: Willi Diederen Price PLN 10 PL PL PL
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JPS6045632B2 (en) * 1978-03-09 1985-10-11 äø‰č±åŒ–å­¦ę Ŗ式会ē¤¾ Ļ‰-aminoalkoxystilbenes and their acid addition salts
DE2818765A1 (en) 1978-04-28 1979-11-08 Basf Ag AMINO DERIVATIVES OF 2-METHYL-5- (2-HYDROXYSTYRENE) -1,3,4-THIADIAZOLE
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JPS5629548A (en) * 1979-08-16 1981-03-24 Mitsubishi Chem Ind Ltd Omega-aminoalkoxystilbenes and their acid addition salts
DE2943406A1 (en) 1979-10-26 1981-05-07 Basf Ag, 6700 Ludwigshafen AMINO DERIVATIVES OF 2-METHYL-5- (2-HYDROXYSTYRYL) -1,3,4-THIADIAZOL
DE2943405A1 (en) * 1979-10-26 1981-05-07 Basf Ag, 6700 Ludwigshafen NEW AMINO DERIVATIVES OF 5- (2-HYDROXYSTYRYL) -ISOXAZOLE
DE3006809A1 (en) * 1980-02-23 1981-09-24 Basf Ag, 6700 Ludwigshafen 2 - ((3-AMINO-2-HYDROXY-PROPOXY) -STYRYL) -ISOXAZOLES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM
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JPS5113150B1 (en) 1976-04-26
RO58861A2 (en) 1975-06-30
IE34634L (en) 1971-02-05
IE34634B1 (en) 1975-07-09
DE1939809B2 (en) 1978-04-13
NO135243C (en) 1977-03-09
IL35047A (en) 1973-05-31
GB1307436A (en) 1973-02-21
NL7011590A (en) 1971-02-09
CS170533B2 (en) 1976-08-27
DE1939809C3 (en) 1979-01-11
CS170535B2 (en) 1976-08-27
RO57794A (en) 1975-06-15
ES382426A1 (en) 1972-11-16
BG18599A3 (en) 1975-02-25
DK139717C (en) 1979-09-17
AT301565B (en) 1972-09-11
FR2068463B1 (en) 1974-08-30
FR2068463A1 (en) 1971-08-27
JPS5113148B1 (en) 1976-04-26
SU439965A3 (en) 1974-08-15
BG17951A3 (en) 1974-03-05
FI54912C (en) 1979-04-10
CH548981A (en) 1974-05-15
JPS5113147B1 (en) 1976-04-26
RO57548A (en) 1975-02-15
AT303055B (en) 1972-11-10
CS170536B2 (en) 1976-08-27
ES382429A1 (en) 1972-11-16

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