PL90632B1 - - Google Patents

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PL90632B1
PL90632B1 PL1974171913A PL17191374A PL90632B1 PL 90632 B1 PL90632 B1 PL 90632B1 PL 1974171913 A PL1974171913 A PL 1974171913A PL 17191374 A PL17191374 A PL 17191374A PL 90632 B1 PL90632 B1 PL 90632B1
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    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/32—Sulfur atoms
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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
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/48—Aldehydo radicals
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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
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C07D213/66—One oxygen atom attached in position 3 or 5 having in position 3 an oxygen atom and in each of the positions 4 and 5 a carbon atom bound to an oxygen, sulphur, or nitrogen atom, e.g. pyridoxal
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—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 with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/36—One oxygen atom
    • C07D263/42—One oxygen atom attached in position 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/58—Pyridine rings

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  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

Przedmiotem wynalazku jest sposób wytwarzania nowych merkaptoalkilopirydyn o wzorze 1, ewentualnie w postaci ich farmaceutycznie dopuszczalnych soli. Zwiazki te maja zastosowanie w leczeniu goscca stawowego i pokrewnych chorób zapalnych.Srodki przeciwzapalno-przeciwbólowo-przeciwgoraczkowe nie bedace steroidami, takie jak aspiryna oraz wiele nowych leków bedacych w stadium ich klinicznej oceny, sa przede wszystkim efektywne w objawowym leczeniu jedynie ostrych objawów.Nowe merkaptoalkilopirydyny bedace przedmiotem niniejszego wynalazku maja w powaznym stopniu dzialanie przeciwgosccowe.Sposób wedlug ^ wynalazku polega na tym, ze zwiazek o wztfrze 2 poddaje sie dzialaniu srodka utleniajacego, po czym otrzymany produkt o wzorze 1 ewentualnie przeprowadza sie w sól.Korzystnie sposób wedlug wynalazku prowadzi sie traktujac zwiazek o wzorze 2 nadtlenkiem wodoru, w wodnym roztworze, w temperaturze 0-15°C.Jako srodki utleniajace mozna tez stosowac nadkwasy takie jak kwas m-nadchlorobenzoesowy. kwas nadoctowy, nadftalowy, podchloryn sodu lubjod. * - W celu leczniczym zwiazki wytwarzane sposobem wedlug wynalazku mozna podawac doustnie .lokalnie poza jelitowo, przez inhalacje lub doodbytniczo w dawkach jednostkowych kompozycji zawierajacych konwen¬ cjonalne farmaceutycznie nietoksyczne nosniki, srodki pomocnicze oraz podloza. Terminpozajelitowe, stosowa¬ ny tutaj, oznacza injekcje podskórne, dozylne, domiesniowe, domostkowe i dostawowe oraz wlewikL Oprócz dzialania leczniczego na zwierzeta cieplokrwiste, takie jak myszy, króle.konie, psy koty itp., zwiazki te sa równiez efektywne w leczeniu ludzi.Kompozycje farmaceutyczne zawierajace jako skladnik aktywny zwiazki wytwarzane sposobem wedlug wynalazku moga byc wytwarzane w postaci odpowiedniej do podawania doustnego, na przyklad jako tabletki,2 90632 kolaczki, pastylki romboidalna, zawiesiny wodne lub olejowe, proszki dyspergujaca sie lub granulki, emulsje kapsulki twarde lub miekkie oraz syropy lub eliksiry. Kompozycje przeznaczone do podawania doustnego mozna wytworzyc jedna ze znanych fachowcom metod wytwarzania takich kompozycji farmaceutycznych i kompozycje te moga zawierac jeden lub wiecej srodków wybranych sposród grupy obejmujacej srodki slodzace. srodki smakowe, barwiace oraz konserwujace wcelg nadania lekowi wygladu farmaceutyku i dobrych wlasnosci smakowych. Tabletki zawieraja srodek aktywny z domieszka typowych nietoksycznych i dopuszczalnych farmaceutycznie srodków pomocniczych, takich jak na przyklad obojetne rozcienczalniki, takie jak weglan wapnia, weglan sodu, laktoza, fosforan wapnia lub fosforan sodu, srodki granulujace lub dyspergujace.jak skrobia kukurydziana lub kwas alginowy, srodki wiazace, jak skrobia, zelatyna lub guma arabska oraz srodki smarne jak stearynian magnezu, kwas stearowy lub talk. Tabletki moga byc niepowlekane lub tez mozna je powlekac znanymi metodami celem zapobiegania ich rozpadaniu sie i absorpcji w przewodzie pokarmowym, a wiec aby uzyskac zalozone dzialanie przez dluzszy okres czasu. Na przyklad, mozna stosowac taka substancje przedluzajaca czas dzialania, jak monostearynian gliceryny lub dwustearynian gliceryny. r^. r^—Kompozycje do stosowania doustnego moga takze miec postac twardych kapsulek zelatynowych WlctórycrP^cladnik aktywny zmieszany jest z obojetnym stalym rozcienczalnikiem, na przyklad z weglanem wapnia, forforanem wapnia lub kaolinem, badz tez w postaci miekkich kapsulek zelatynowych, w których ^^^^ekladcykjifctywny zmieszany jest z woda lub srodowiskiem olejowym, na przyklad olejem arachidowym, - *'-* 'cleKlymfr-pfrafinami lub oliwa.Zawiesiny wodne zawieraja skladnik aktywny zmieszany z srodkami pomocniczymi i odpowiednimi do wytwarzania zawiesin wodnych. Takie srodki'pomocnicze obejmuja srodki suspendujace, na przyklad sól sodowa, karboksymetylocelulozy, metyloceluloze, hydroksypropylometyloceluloze. alginian sodu, poliwinylopirolidon, tragakant i gume arabska, srodki dyspergujace lub zwilzajace, jakimi moga byc wystepujace w przyrodzie fosfatydy, na przyklad lecytyna lub produkty kondensacji tlenków alkilenów z kwasami tluszczowymi, na przyklad stearynian polioksyetylenowy, badz tez produkty kondensacji tlenku etylenu z dlugolancuchowymi alkoholami alifatycznymi, na przyklad stearynian polioksyetylenowy. badz tez produkty kondensacji tlenku etylenu z dlugolancuchowymi alkoholami alifatycznymi, na przyklad heptadekaetylenooksyetanol lub produkty kondensacji tlenku etylenu z czesciowymi estrami kwasów tluszczowych i heksytolu, jak na przyklad polioksy- . etylenowany monooleinian' sorbrtolu, lub tez produkty kondensacji tlenku etylenu z czesciowymi estrami kwasów tluszczowych i bezwodników heksytoli, na przyklad monoleinian polioksyetylenowany sorbitanu. Te zawiesiny wodne moga takze zawierac jeden lub wieksza liczbe srodków konswerwujacych na przyklad parahydroksybenzoesanu etylu lub n-propylu, jeden lub wieksza liczbe srodków barwiacych, jeden lub wieksza liczbe srodków smakowych oraz jeden lub wieksza liczbe srodków slodzacych, takich jak sacharoza lub sacharyna.Zawiesine olejowa mozna wytwarzac przez wytwarzanie zawiesiny skladnika aktywnego woleju roslin¬ nym, na przyklad arachidowym, oliwie, oleju sezamowym lub kokosowym,badz tez woleju mineralnym, takim jak ciekle parafiny. Zawiesiny oleiste moga zawierac srodek zageszczajacy, na przyklad wosk pszczeli, twarde parafiny lub alkohol cetylowy. Do zawiesiny dodawac mozna srodki slodzace, taki jak przytoczone wyzej .oraz inne srodki smakowe celem nadania przyjemnego smaku preparatowi. Kompozycje te mozna konserwowac przez dodatek antyutleniaczy, takich jak kwasaskorbinowy.. • Dyspergujace sie proszki oraz granulki odpowiednie do wytwarzania zawiesin wodnych przez dodanie wody zawieraja skladnik aktywny zmieszany ze srodkiem dyspergujacym lub zwilzajacym, srodek suspendujacy, oraz jeden lub wieksza liczbe srodków konserwujacych. Dodawac równiez mozna inne srodki pomocnicze .takie jak srodki slodzace, smakowe i barwiace.Kompozycje farmaceutyczne wedlug wynalazku moga miec równiez postac emulsji olejowo-wodnych.Faza olejowa moze byc olej roslinny, na przyklad oliwa lub olej arachidowy lub tez olej mineralny.na przyklad ciekle parafiny lub tez mieszaniny tych substancji. Odpowiednimi srodkami emulgujacymi moga byc wystepuja¬ ce w przyrodzie gumy, takie jak guma arabska lub tragakant wystepujace w przyrodzie fosfatydy takie jak lecytyna z soji, oraz estry lub czesciowo estry pochodzace od kwasów tluszczowych i bezwodników heksytoli, na przyklad monooleinian sorbitanu oraz produkty kondensacji takich czesciowych estrów z tlenkiem etylenu, na przyklad polioksyetylenowany monooleinian sorbitanu. Emulsje takie moga równfez zawierac srodki slodzace i smakowe.Syropy i eliksiry mozna wytwarzac z zastosowaniem srodków slodzacych, na przyklad gliceryny, sorbrtolu lub sacharozy. Takie kompozycje moga równiez zawierac srodki konserwujace, smakowe, barwiace i srodki lagodzace. Kompozycje farmaceutyczne moga miec równiez postac sterylnych preparatów do injekeji, na przyklad sterylnych zawiesin wodnych lub oleistych do injekcjL Zawiesiny takie mozna wytwarzac znanymi fachowcom metodami przy zastosowaniu odpowiednich wspomnianych wczesniej* srodków dyspergujacych,90 632 3 zwilzajacych i suspendujacych. Sterylne preparaty do injekcji moga. miec takze postac sterylnych roztworów lub zawiesin nietoksycznych pozajelitowo dopuszczalnych rozcienczalników lub rozpuszczalników, na przyklad w postaci roztworów w butandiolu-1,3. Wsród tych dopuszczalnych podlozy i rozpuszczalników, które mozna stosowac sa woda, roztwór Ringer a i izotoniczny roztwór chlorku sodu. Ponadto, równiez czesto stosuje sie jako rozpuszczalnik lub srodowisko dla zawiesiny sterylne nielotne oleje. Do tego celu stosów?c mozna dowolny lagodny nielotny olej, wlaczajac w to równiez syntetyczne mono- i dwuglicerydy Ponadto, kwasy tluszczowe takie jak kwas oleinowy, znajduja równiez zastosowanie przy wytwarzaniu preparatów do injekcji.Zwiazki otrzymane sposobem wedlug wynalazku mozna takze podawac w postaci czopków wprowadzajac lek doodbytniczo. Takie kompozycje mozna wytwarzac przez zmieszanie leku z odpowiednim niepodrazmajacym srodkiem pomocniczym, który jest staly w temperaturze otoczenia lecz ciekly w temperaturze panujacej w odbycie i wiec topi sie w odbytnicy uwalniajac lek. Takimi substancjami sa maslo kakaowe i glikole polietylenowe.Do stosowania miejscowego wytwarza sie kremy, masci, galarety, roztwory lub zawiesiny.itp zawierajace srodki przeciwzapalne.Dawki rzedu 0,5 mg-140 mg na kilogram wagi ciala i dzien sa uzyteczne w leczeniu wspomnianych wyzej schorzen. (25 mg do 7 g dziennie na przecietnego pacjenta). Na przyklad stany zapalne efektywnie leczy sie i obserwuje sie dzialanie przeciwbólowe i przeciwgoraczkowe przy podawaniu od okolo 0,1 do 50 mg zwiazku na kilogram wagi ciala i dzien (od 5 mg do 3,5 g dziennie na pacjenta). Korzystnie wysoce efektywne wyniki uzyskuje sie przy podawaniu od okolo 1 mg do 15 mg na kilogram wagi ciala dziennie omawianych srodków (50 mg —1 g dziennie na pacjenta).Ilosc skladnika aktywnego, która mozna polaczyc z substancja nosnikowa w celu wytworzenia pojedyn¬ czej dawki (dawki jednostkowej) zalezy od leczonego pacjenta oraz sposobu podawania leku. Na przyklad/ kompozycje przeznaczone do doustnego podawania ludziom moga zawierac 5 mg-5 g skladnika aktywnego polaczonego z odpowiednia i dogodna iloscia substancji nosnikowej, której ilosc moze zawierac od okolo 5 do okolo 95% calkowitej masy kompozycji. Dawka jednostkowa zawiera zwykle od okolo 25 mg do okolo 500 mg skladnika aktywnego.Nalezy jednak rozumiec, ze poszczególne dawki dla róznych pacjentów beda zalezne od wielu czynników, wlaczajac w to aktywnosc szczególnego stosowanego zwiazku, wiek, wage, ogólny stan zdrowia, plec, diete, czas podawania i sposób podawania, szybkosc wydzielania, polaczenia z innymi lekami oraz stan rozwoju choroby poddawanej leczeniu.Przyklad I. Wytwarzanie dwusiarczku bis-(2-metylo-3-hydroksy-5-winy1o-4-pirydylometylu).Chlorowodorek 2-metylo-3-hydroksy-4-merkaptometylo-5-winylopirydyny (4,36 g) rozpuszczono w 40 ml wody w temperaturze 2°—7°C w atmosferze azotu. Do roztworu tego dodano wciagu 2 minut 2,0 ml 30% nadtlenku wodoru utrzymujac jednoczesnie temperature 2°-7°C. Po 30 minutowym mieszaniu w tej tempera¬ turze mieszanine przesaczono, a przesacz mieszano pod azotem, wciagu 10 minut z nadmiarem nasyconego roztworu dwuweglanu sodowego w temperaturze 2°C. Mieszanine szybko przesaczono a osad na saczku przemyto 2 X 40 ml acetonitrylu. Stala substancje wysuszono nad pieciotlenkiem fosforu otrzymujac dwusiar¬ czek bis(2-metylo-3-hydroksy-5-winylo-4^irydylometylu) o temperaturze topnienia powyzej 300°C. Temperatu¬ ra topnienia jednowodziariu 178°-180°C.Przyklad II. Wytwarzanie jednowodzianu siarczanu dwusiarczku bis-(2-metylo-3-hydroksy-5-winylo- •4-pirydylornetylu).Do roztworu 6,1 g 95,6% kwasu siarkowego w 100 ml wody w 35°C dodano mieszajac 10,0 g dwusiarczku bis-(2rmetylo-3-hydroksy-5-winylo-4-pirydylornetylo). Roztwór ogrzewano do 90°C do otrzymania przezroczyste¬ go jaskrawo zóltego roztworu. Nastepnie roztwór ochlodzono powoli do 0-5°C i pozostawiono na 1 godzine Osad odfiltrowano, przemyto 2 X 3 ml lodowatej wody i wysuszono w temperaturze pokojowej pod próznia uzyskujac 11,05 g (84%) jednowodzianu siarczanu dwusiarczku bis-<2-metylo-3-hydroksy-5-winylo-4i)irydylo- metylu).* PL PL PLThe invention relates to a process for the preparation of the novel mercaptoalkylpyridines of the formula I, optionally in the form of their pharmaceutically acceptable salts. These compounds have applications in the treatment of gynecological rheumatism and related inflammatory diseases. Non-steroidal anti-inflammatory, analgesic and antipyretic agents, such as aspirin, and many new drugs in their clinical evaluation stage, are primarily effective in the symptomatic treatment of only acute symptoms. New mercaptoalkylpyridines The method according to the invention consists in treating the compound with an oxidizing agent and then optionally converting the product of the formula I obtained into a salt. the compound of formula II with hydrogen peroxide in aqueous solution at 0-15 ° C. Peracids such as m-perchlorobenzoic acid can also be used as oxidizing agents. peracetic acid, perphthalic acid, sodium hypochlorite or iodine. For therapeutic purposes, the compounds of the invention may be administered orally, locally parenterally, by inhalation or rectally in unit doses of compositions containing conventional pharmaceutically non-toxic carriers, adjuvants and vehicles. The term parenteral as used herein means subcutaneous, intravenous, intramuscular, intrasternal and intra-articular injections and infusion. In addition to its therapeutic effect on warm-blooded animals such as mice, kings, horses, dogs, cats, etc., these compounds are also effective in treating humans. pharmaceuticals containing as active ingredient the compounds according to the invention can be prepared in a form suitable for oral administration, for example as tablets, 2 90632 colics, rhomboid lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules and syrups or elixirs. Compositions for oral administration may be prepared by any of the methods known to those skilled in the art for preparing such pharmaceutical compositions, and the compositions may contain one or more agents selected from the group consisting of sweetening agents. Flavoring, coloring and preserving agents to give the drug the appearance of a pharmaceutical and good taste properties. The tablets contain the active agent in admixture with conventional non-toxic and pharmaceutically acceptable auxiliaries such as, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating or dispersing agents, such as corn starch or alginic acid, binders such as starch, gelatin or acacia; and lubricants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known methods to prevent their disintegration and absorption in the gastrointestinal tract, thus obtaining the intended action over an extended period of time. For example, substances extending the duration of action may be used, such as glycerin monostearate or glycerin distearate. r ^. r ^ —Compositions for oral use may also take the form of hard gelatine capsules. The active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or in the form of soft ^ gelatine capsules The eclyclicfactive is mixed with water or an oily environment, for example peanut oil, - * '- *' cleKlymfr-pfrafinami or olive oil. Aqueous suspensions contain the active ingredient mixed with auxiliary agents and suitable for the preparation of aqueous suspensions. Such adjuvants include suspending agents, for example sodium salt, carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose. sodium alginate, polyvinylpyrrolidone, tragacanth and gum arabic, dispersing or wetting agents such as naturally occurring phosphatides, e.g. lecithin or condensation products of alkylene oxides with fatty acids, e.g. for example polyoxyethylene stearate. or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadekaethyleneoxyethanol, or condensation products of ethylene oxide with partial fatty acid esters of hexitol, such as polyoxyethylene. ethoxylated sorbitan monooleate, or the condensation products of ethylene oxide with partial fatty acid esters of hexitol anhydrides, for example polyoxyethylene sorbitan monoleate. These aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl parahydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents such as sucrose or oleic saccharin. can be prepared by suspending the active ingredient of a vegetable oil, for example peanut oil, olive oil, sesame or coconut oil, or a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffins or cetyl alcohol. Sweetening agents, such as those listed above, and other flavoring agents may be added to the suspension to impart a pleasant taste to the preparation. These compositions may be preserved by the addition of antioxidants such as ascorbic acid. Dispersible powders and granules suitable for the preparation of aqueous suspensions by the addition of water contain the active ingredient mixed with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Other adjuvants such as sweetening, flavoring and coloring agents may also be added. The pharmaceutical compositions according to the invention may also be in the form of oil-water emulsions. The oily phase may be a vegetable oil, for example olive oil or peanut oil, or also a mineral oil, for example liquid paraffins or mixtures of these substances. Suitable emulsifying agents may be naturally occurring gums, such as gum arabic or tragacanth, naturally occurring phosphatides such as soybean lecithin, and esters or partially esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monooleates and condensation products of such compounds. esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. Such emulsions may also contain sweetening agents and flavoring. Syrups and elixirs may be prepared with the use of sweetening agents, for example glycerin, sorbrtol or sucrose. Such compositions may also contain preservatives, flavors, colorants and soothing agents. The pharmaceutical compositions may also be in the form of sterile injectable preparations, for example sterile aqueous or oleaginous suspensions for injection. Such suspensions can be prepared by methods known to those skilled in the art using the appropriate dispersing, wetting and suspending agents mentioned above. Sterile injectable preparations can. also take the form of sterile solutions or suspensions of non-toxic parenterally acceptable diluents or solvents, for example in the form of solutions in 1,3-butanediol. Among these acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are also often used as a solvent or medium for suspensions. Any mild non-volatile oil may be used for this purpose, including synthetic mono- and diglycerides. In addition, fatty acids such as oleic acid also find use in the preparation of injectables. The compounds of the invention may also be administered in the form of suppositories. introducing the drug rectally. Such compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ambient temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the drug. Such substances are cocoa butter and polyethylene glycols. For topical use, creams, ointments, jellies, solutions or suspensions are made, etc. containing anti-inflammatory agents. Doses of 0.5 mg-140 mg per kilogram body weight and daily are useful in the treatment of the above-mentioned ailments. (25 mg to 7 g per day for an average patient). For example, inflammation is effectively treated, and its analgesic and antipyretic effect is observed when administering from about 0.1 to 50 mg of the compound per kilogram of body weight and per day (from 5 mg to 3.5 g per patient per day). Preferably, highly effective results are obtained with administration of from about 1 mg to 15 mg per kg body weight per day of the agents in question (50 mg -1 g per day per patient). Amount of active ingredient which may be combined with a carrier substance to produce a single dose. (unit dose) depends on the treated patient and the method of administration. For example, compositions intended for oral administration to humans may contain 5 mg-5 g of active ingredient combined with an appropriate and convenient amount of carrier material which may contain from about 5 to about 95% of the total weight of the composition. A unit dose will normally contain from about 25 mg to about 500 mg of active ingredient; however, it should be understood that the different dosages for different patients will depend on many factors, including the activity of the particular compound being used, age, weight, general health, back, and diet. , time of administration and method of administration, rate of excretion, combination with other drugs, and the state of development of the disease being treated. Example I. Preparation of bis- (2-methyl-3-hydroxy-5-wine-1--4-pyridylmethyl) disulfide. 2-Methyl hydrochloride -3-hydroxy-4-mercaptomethyl-5-vinylpyridine (4.36 g) was dissolved in 40 ml of water at 2 ° -7 ° C under nitrogen atmosphere. To this solution was added 2.0 ml of 30% hydrogen peroxide within 2 minutes while maintaining the temperature at 2 ° -7 ° C. After stirring for 30 minutes at this temperature, the mixture was filtered and the filtrate was stirred under nitrogen for 10 minutes with an excess of saturated sodium bicarbonate solution at 2 ° C. The mixture was filtered quickly and the filter cake was washed with 2 X 40 ml acetonitrile. The solids were dried over phosphorus pentoxide to give bis (2-methyl-3-hydroxy-5-vinyl-4-iridylmethyl) disulfide with a melting point above 300 ° C. The melting point of monohydrate is 178 ° -180 ° C. Example II. Preparation of bis- (2-methyl-3-hydroxy-5-vinyl- • 4-pyridylmethyl) sulfate disulfide monohydrate. To a solution of 6.1 g of 95.6% sulfuric acid in 100 ml of water at 35 ° C was added with stirring 10.0 g of bis- (2-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl) disulfide. The solution was heated to 90 ° C. until a clear bright yellow solution was obtained. The solution was then cooled slowly to 0-5 ° C and left for 1 hour The precipitate was filtered off, washed with 2 X 3 ml of ice water and dried at room temperature under vacuum to give 11.05 g (84%) bis- <2-methyl disulfide monohydrate -3-hydroxy-5-vinyl-4i) iridylmethyl). * PL PL PL

Claims (2)

1. Zastrzezenia patentowe 1. Sposób wytwarzania nowych merkaptoalkilopirydyn o wzorze 1, ewentualnie w postaci ich farmaceuty¬ cznie dopuszczalnych soli, znamienny tym, ze zwiazek o wzorze 2 poddaje sie dzialaniu srodka utleniajacego po czym otrzymany produkt o wzorze 1 ewentualnie przeprowadza sie wsól. '1. Claims 1. A process for the preparation of the new mercaptoalkylpyridines of the formula I, optionally in the form of their pharmaceutically acceptable salts, characterized in that the compound of the formula II is treated with an oxidizing agent and the resulting product of the formula I is optionally bred. ' 2. Sposób wedlug zastrz. 1, z n a m i e n n y tym, ze zwiazek o wzorze 2 poddaje sie dzialaniu nadtlenku wodoru, w wodnym roztworze, w temperaturze 0—15°C,90 632 O II CN X o II CM "I O (N L UJ X o to CH 2" XT CH,' -N J Wzór 1 CH2SH H CH3" "N Wzór 2 Prac. Poligraf. UP PRL naklad 120+18 Cena 10 zl PL PL PL2. The method according to p. The process of claim 1, characterized in that the compound of formula II is treated with hydrogen peroxide in aqueous solution at a temperature of 0-15 ° C, 90 632 O II CN X o II CM "IO (NL UJ X is CH 2" XT CH , '-NJ Pattern 1 CH2SH H CH3 "" N Pattern 2 Printing works UP PRL circulation 120 + 18 Price PLN 10 PL PL PL
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