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
    • C07D213/30—Oxygen atoms
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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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
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • 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
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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 C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07F9/28—Phosphorus compounds with one or more P—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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  • Pyridine Compounds (AREA)
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Description

Uprawniony z patentu: Dr Karl Thomae GmbH, Biberach n/Riss, (Republika Federalna Niemiec) Sposób wytwarzania nowych 6-arylo-2-aminoalkoksystyroli Przedmiotem wynalazku jest sposób wytwarzania nowych arylo-2-aminoal'kotasystyroli o wzorze ogól¬ nym 1, w którym Ar oznacza grupe fenylowa, gru¬ pe 2- lub 3- lub 4-pirydylowa, ewentualnie podsta¬ 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 chlo¬ rowca lub nizsza grupa alkilowa lub grupa trój- 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, R± i R2, R4 i R5, moga byc takie same lub rózne i oznaczaja atomy wodoru lub nizsze grupy alkilowe, R3 oznacza atom wodoru lub nizsza grupe alkoksylowa, R6 i R7 moga byc takie same lub rózne 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 równiez tworzyc nasycony, monocykliczny, heterocykliczny 5—7 czlo¬ nowy pierscien, ewentualnie zawierajacy jeszcze atom tlenu lub dalszy atom azotu, a n oznacza liczbe 0 lub 1, jak równiez ich fizjologicznie do¬ puszczalnych soli addycyjnych z nieorganicznymi lub organicznymi kwasami.Nowe zwiazki o wzorze 1 wytwarza sie przez 10 15 25 30 odszczepienie wody od zwiazków o wzorze ogólnym 2? w którym Ar, R± do R7 oraz n maja wyzej po¬ dane znaczenie. Odszczepienie wody nastepuje za pomoca odpowiednich do tego celu srodków, np. za pomoca kwasu fosforowego, kwasów polifosforo- wych,* kwasu fosforowego z pieciotlenkiem fosforu lub kwasu siarkowego; jako szczególnie odpowiedni okazal sie 85% kwas fosforowy. Reakcja przebiega w podwyzszonych temperaturach, korzystnie w za¬ kresie temperatur 70—130°C.Zwiazki o wzorze 1 powstaja na ogóL jako mie¬ szaniny ich izomerów cis i trans. Jezeli symbole Rt i R2 oznaczaja atomy wodoru, tó powstaja glów¬ nie zwiazki trans. Zwiazki cis i trans daja sie rozdzielic przez frakcjonowana krystalizacje, zwlasz¬ cza ich soli, np. chlorowodorków.Zwiazki o wtzorze 1 mozna w znany sposób prze¬ prowadzic w ich sole addycyjne z kwasami za po¬ moca nieorganicznych lub organicznych kwasów.Jezeli Ar oznacza pierscien heterocykliczny zawie¬ rajacy azot, to mozliwe jest dzieki stopniowej neu¬ tralizacji przylaczenie protonu tylko do zasadowego atomu azotu lancucha bocznego. Jezeli do wytworze¬ nia soli stosuje sie nadmiar kwasu, to otrzymuje sie równiez sole przez przylaczenie protonu do ato¬ mów azotu pierscieni heterocyklicznych. Jako kwasy nadaja sie szczególnie: kwas solny, kwas bromowo- dorowy, kwas siarkowy, kwas fosforowy, kwas wi¬ nowy, kwas p-toluenosulfonowy.Zwiazki o wzorze ogólnym 2, sluzace jako sub- 78 3703 stancje wyjsciowe otrzymuje sie przez kondensacje zwiazku o wzorze ogólnym 3 z estrem o wzorze ogólnym 4 prowadzaca do ketonu o wzorze ogólnym 5, np. z udzialem lamidku sodowego w roztworze toluenu i redukcje ketonu o wzorze ogólnym 5 za pomoca kompleksowych wodorków, np. borowodor¬ ku sodowego lub katalitycznie uaktywnionego wo¬ doru do alkoholu o wzorze ogólnym 2. We wzorach 3—5 symbole B,± do R7 oraz n maja wyzej podane znaczenia, a R9 oznacza grupe alkilowa.Zwiazki o wzorze ogólnym 1 posiadaja cenne wlasciwosci farmakologiczne. Dzialaja one zwlaszcza analgetycznie, nie posiadajac przy tym ubocznego dzialania morfiny, a ponadto wykazuja dobre dzia¬ 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 piers¬ cieniu benzenowym w polozeniu orto do grupy wi¬ nylowej. Tak wiec np. znane izomeryczne 4-amino- alkoksystyrole [Cavallini i inni. II Farmaco, Ed Sci. 9, 405—415 (1954) oraz Montegazza i inni, Arch. intern, pharmacodyn 103, 371—309] w ogóle nie sa aktywne analgetycznie. Wedlug danych literaturo¬ wych wykazuja one dzialanie antynikotynowe i an- tyhistaminowe.Zwiazki o wzorze ogólnym 1 badano na dzialanie analgetyczne metoda goracej plyty wedlug Chen i Beckmanna, Science, 113, 1951, strona 631. Podda¬ no przy tym bólowi wywolanemu skutkiem dziala¬ nia podwyzszonej temperatury myszy po 10 w gru¬ pie na goracej plycie o temperaturze 56°C. Zwie¬ rzeta uzyte do próby reagowaly na nia normalnie w ciagu 20 sekunld. Amalgetyczne dzialanie okreslo¬ no wedlug procentu zwierzat niereagujacych na ból przy okreslonej dawce zwiazku o wzorze 1 w ciagu 50 sekund. Wartosc ED50 przedstawia przy tym dawke, przy której podaniu 50% myszek nie reago¬ walo na ból. Substancje aktywne podawano do przewodu pokarmowego. Nowe zwiazki sa tylko nie¬ 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 której 50% myszek padalo w ciagu 14 dni (obliczono z uzyskanych wartosci wedlug metody Lichtfielda i Wilcoxona).Nizej zestawione zwiazki dzialaja szczególnie sil¬ 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 = 10—60 mg/kg my¬ szy. Toksycznosc substancji jest niewielka, tak wiec np. wartosci LD50 wynosza 500—800 mg/kg myszy 15 dla nastepujacych substancji: dwuchlorowodorek 2-[2-(2-dwumetyloaminoetoksy) - -styrylo]-1-metylobenzimidazolu, chlorowodorek 2-(2-dwuime1;yloaminoetoksy)-stylbe¬ nu, dwuchlorowodorek 2-[2-(2-morfolinoetoksy)-sty- 20 rylo]-pirydyny oraz chlorowodorek 2-[2-(2-dwumetyloaminoetoksy) - -styrylo]-6-metylopirydyny.Nastepujace przyklady blizej wyjasniaja wynala¬ 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 70°C. Potem ogrzewa 30 sie w ciagu 1 godziny do temperatury 110°C, po oziebieniu rozpuszcza sie w 300 ml wody, zobojetnia i wysyca weglanem potasowym. Ekstrahuje sie wy¬ tworzony produkt reakcji trzykrotnie po 50 ml ete¬ ru, osusza nad bezwodnym weglanem potasowym 35 i przesacza przez wegiel. Pozostalosc po odparowa¬ niu destyluje sie pod zmniejszonym cisnieniem.Otrzymuje sie 13,25 g (co odpowiada 70,2% wydaj¬ nosci teoretycznej), jasnozóltego oleju, o tempera¬ turze wrzenia przy 0,01 mm Hg 143—150°C. Olej 40 rozpuszcza sie w 250 ml acetonu i ostroznie zadaje tylko taka iloscia roztworu gazowego chlorowodoru w acetonie, aby nastapilo zólte zabarwienie. Po oziebieniu w lazni z lodem wydzielaja sie biale krysztaly, których ilosc jeszcze sie powieksza przez 45 domieszanie 150 ml eteru. Po odsaczeniu i wysu¬ 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 194—195°C. 5U l-(pirazynylo-2)-2-(2-dwumetyloaminoetoksyfeny- lo)-etanol-2 stosowany jako produkt wyjsciowy, nie destylujacy zólty 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. zóltego nie destylu-5 Jacego oleju, jednolitego w chromatogramie cienko¬ warstwowym, wytwarza sie monochlorowodorek r2-[2-(2-dwumetyloaminoetoksy)-styrylo] -chinoliny o temperaturze topnienia 188°C z wydajnoscia 87%.Przyklad III. Z l-(6-metylopirydylo)-2-(o- -dwumetyloaminoetoksyfenylo)-etanolu-2 (jasnozól- te krysztaly o temperaturze topnienia 228°C) otrzy¬ muje sie monochlorowodorek 2-[2-(2-dwumetyloami¬ noetoksy)-styrylo]-6-metylopirydyny, o temperaturze topnienia 200°C z wydajnoscia 20%.Przyklad IV. Z l-(4,6-dwumetylopirydylo-2)-2- - (o-dwumetyloaminoetoksyfenylo) -etanolu-2 (jasno- -zólty, nie destylujacy olej, jednolity w chromato¬ gramie cienkowarstwowym) wytwarza sie dwuchlo- rowodorek 2- [2- (2-dwumetyloaminoetoksy)-styrylo]- -4,6-dwumetylopirydyny, o temperaturze topnienia 177°C, z wydajnoscia 81%.Przyklad V. Z l-(2-pirydylo)-2-(2-dwumety lo¬ aminoetoksyfenylo)-etanolu-2, oleju zóltego, nie de¬ stylujacego, jednolitego w chromatogramie cienko¬ warstwowym, wytwarza sie monochlorowodorek 2-[2-(2-dwumetyloaminoetoksy)-styrylo] -pirydyny, o temperaturze topnienia 183°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)-sty¬ rylo]-5^metylopirazymy-2, zywicowata, biala sub¬ stancje, jednolita w chromatogramie cienkowars¬ twowym, z wydajnoscia 65%.Przyklad VII. Z l-(4-metylopirydymidylo-6)- —2-(2-dwumetyloaminoetoksyfenylo) -etanolu-2, nie destylujacego klarowanego zóltego oleju, jednolitego w chromatogramie cienkowarstwowym, wytwarza sie 6- [2- (2-dwumetyloaminoetoksy)-styrylo]-4-mety- lopirymidyne, o temperaturze topnienia 234°C, z wy¬ 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 ± 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 ° 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, ± 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 ° 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 ° C. Then it is heated within 1 hour to 110 ° 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 ° 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 ° 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 ° 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 ° C) -styryl] -6-methylpyridine, mp 200 ° C, yield 20%. Example IV. 2- [ 2- (2-dimethylaminoethoxy) styryl] -4,6-dimethylpyridine, m.p. 177 ° 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 ° 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 ° C., yield 87%. PL PL PL

Claims (3)

1. Zastrzezenia patentowe 1. Sposób wytwarzania nowych P-arylo-2-amino- -alkoksystyroli o wzorze ogólnym 1, w którym Ar ^oznacza grupe fenylowa, grupe 2- lub 3- lub 4-piry- * 370 6 dylowa, ewentualnie podstawiona nizsza grupa alki¬ 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 trójfluorometylowa, 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 rózne i ozna¬ czaja atomy wodoru lub nizsze grupy alkilowe, R8 oznacza atom wodoru lub nizsza grupe alkoksylowa, 2. 15. R6 i R7, moga byc jednakowe lub rózne i oznaczaja atomy wodoru lub nizsze grupy alkilowe, alkeny- lowe, hydroksyalkilowe, alkoksyalkilowe lub grupy aralkilowe, przy czym R6 i R7 lacznie ze znajduja¬ cym sie miedzy nimi atomem azotu moga równiez 20 tworzyc nasycony, monocykliczny, heterocykliczny 5-7 czlonowy pierscien, ewentualnie zawierajacy jeszcze atom tlenu lub dalszy atom azotu, a n ozna¬ cza liczbe 0 lub 1, jak równiez ich fizjologicznie dopuszczalnych soli addycyjnych z nieorganicznymi .25 lub organicznymi kwasami, znamienny tym, ze ze zwiazku o wzorze ogólnym 2, w którym Ar, Rx do R7 i n maja podane wyzej znaczenia, odszczepia sie wode za pomoca srodków odciagajacych wode w (podwyzszonej temperaturze i ewentualnie pow- 30 stala mieszanine izomerów cis i trans rozdziela sie nastepnie przez frakcjonowana krystalizacje i/lub otrzymany zwiazek o wzorze li przeprowadza sie w sól 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. Sposób wedlug zastrz. 1, znamienny tym, ze jako srodek odciagajacy wode stosuje sie kwas fos¬ 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. Sposób wedlug zastrz. 1, znamienny tym, ze 49 w przypadku otrzymania mieszaniny izomerów cis i trans pojedyncze skladniki rozdziela sie od siebie przez frakcjonowana krystalizacje ich chlorowo¬ dorków.KI. 12q,14/04 78 370 MKP C07c 43/20 0-CH-CH-(CH2)n-N: I I R4 Rs WZÓR 1 *7 OH r3 Ar-CH-C-fjY R1 R2 O-CH-CH-Cd-UL-N^ 6 II 2n ^R7 R4 R5 WZÓR 2 Ar-CH, I 2 , WZÓR 3 RQOOC ^T R. \ / 0-CH-CH-(CHJn-N I I 2n R4 R5 WZÓR 4 /R6 XR, o-ch-ch-cchj-n: ii 2 n R4 R5 , WZÓR 5 Zaklady Typograficzne Lódz, zam. 233/75 — 110 egz. ^R. ERRATA Strona 1, w tekscie: Twórcy 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 Lódz, 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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AT302345B (en) 1972-10-10
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BG20095A3 (en) 1975-10-30
RO57794A (en) 1975-06-15
CH548367A (en) 1974-04-30
NO135243B (en) 1976-11-29
BG17952A3 (en) 1974-03-05
IL35047A (en) 1973-05-31
IE34634L (en) 1971-02-05
FR2068463A1 (en) 1971-08-27
DK139717C (en) 1979-09-17
IL35047A0 (en) 1970-10-30
NL7011590A (en) 1971-02-09
CS170535B2 (en) 1976-08-27

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