PL165357B1 - Sposób wytwarzania nowych pochodnych mocznika PL PL - Google Patents

Sposób wytwarzania nowych pochodnych mocznika PL PL

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Publication number
PL165357B1
PL165357B1 PL90291470A PL29147090A PL165357B1 PL 165357 B1 PL165357 B1 PL 165357B1 PL 90291470 A PL90291470 A PL 90291470A PL 29147090 A PL29147090 A PL 29147090A PL 165357 B1 PL165357 B1 PL 165357B1
Authority
PL
Poland
Prior art keywords
compounds
cholesterol
formula
urea derivatives
methylthio
Prior art date
Application number
PL90291470A
Other languages
English (en)
Other versions
PL291470A1 (en
Inventor
Peter A Mccarthy
Frederick J Walker
Ernest S Hamanaka
George Chang
Thien Truong
Original Assignee
Pfizer
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pfizer filed Critical Pfizer
Publication of PL291470A1 publication Critical patent/PL291470A1/xx
Publication of PL165357B1 publication Critical patent/PL165357B1/pl

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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
    • C07D213/70—Sulfur atoms
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—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
    • C07D215/16—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 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
    • C07D215/18—Halogen atoms or nitro radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
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Abstract

Sposób wytwarzania nowych pochod- nych mocznika o wzorze przedstawionym na rysunku, w którym R1 oznacza tri(C1 -C4)- alkoksyfenyl,(C1 -C4)alkilo-di(C1 -C4)alkilotio- pirydynyl, (C1 -C4)alkilo-di(C1 -C4)alkilotio- pirymidynyl, a R17 i R18 oznaczaja grupe (C4-C8)alkilowa lub grupe (C1 -C6)alkilofenylo- metylowa i ich sole, znamienny tym, ze drugo- rzedowa amine o wzorze N H R17R18, w którym R1 7 i R1 8 maja wyzej podane znaczenie, pod- daje sie reakcji ze zwiazkiem o wzorze R1 NCO, w którym R1 ma wyzej podane znaczenie. Wzór 1 PL PL

Description

Przedmiotem wynalazku jest sposób wytwarzania nowych pochodnych mocznika, mających zastosowanie jako składniki leków przeznaczonych do hamowania absorpcji cholesterolu w jelitach, obniżania poziomu cholesterolu w surowicy i odwracania procesu arteriosklerozy. Wytwarzane związki są inhibitorami acylo-koenzymu A: acylotransferazy cholesterolowej (ACAT).
Cholesterol konsumowany wraz z pożywieniem (cholesterol pokarmowy) jest absorbowany w postaci wolnego cholesterolu przez komórki śluzówki jelita cienkiego. Tam zachodzi jego estryfikacja, w której pośredniczy enzym ACTA, po czym wnika do cząstek znanych jako chylomikrony i przechodzi do krwioobiegu. Chylomikrony są cząstkami, do których „pakowany jest cholesterol pokarmowy i za pośrednictwem których wprowadzany jest do krwioobiegu. Przez hamowanie działania ACTA związki wytwarzane sposobem według wynalazku, zapobiegają absorpcji cholesterolu pokarmowego w jelitach, obniżając przez to poziom cholesterolu w surowicy. Są zatem użyteczne w zapobieganiu arteriosklerozie, atakom serca i udarom.
Poprzez hamowanie aktywności ACTA, związki wytwarzane sposobem według wynalazku umożliwiają usuwanie cholesterolu ze ścian naczyń krwionośnych. Działanie to sprawia, że związki te są użyteczne do spowolniania lub odwracania procesu arteriosklerozy, jak również do zapobiegania atakom serca i udarom.
Inne inhibitory ACTA są ujawnione w opisach patentowych Stanów Zjednoczonych Ameryki nr nr 4716 175 i 4743 605 (powstały z podziału patentu nr 4 716 175) oraz w publikacjach europejskich zgłoszeń patentowych nr nr EP 0242 610, 0245687 oraz 0252524. Niektóre moczniki i tiomoczniki wykazujące aktywność jako środki hamujące sklerozę naczyń krwionośnych są opisane w opisie patentowym Stanów Zjednoczonych Ameryki nr4 623 662.
Przedmiotem wynalazku jest sposób wytwarzania nowych pochodnych mocznika o wzorze przedstawionym na rysunku, w którym R1 oznacza tri(C1-C 4)alkoksyfenyl, (C1-C 4)alkilo-di(C1C4)alkilotiopirydynyl, (C1-C4)alkilo-di-(C1-C4)alkilotiopirymidynyl, a Rv i Rw oznaczają grupę (C 4-C8)alkilową lub grupę (C1-C6)alkilofenylometylową.
Sposób według wynalazku polega na poddaniu drugorzędowej aminy o wzorze NHR^R^, w którym R17 i Rw mają wyżej podane znaczenie, reakcji ze związkiem o wzorze R1NCO, w którym R1 ma wyżej podane znaczenie. Otrzymany produkt w razie potrzeby przekształca się w sól.
Korzystnymi związkami wytwarzanymi zgodnie z wynalazkiem są te, w których R1 oznacza grupę 2,4,6-trójmetoksyfenylową, 2-metylo-4,6-dwu(metylotio)pirymidyn-5-ylową i 6-metylo-2,4-dwumetylotio/pirydyn-3-ylową.
Kompozycje farmaceutyczne zawierające omawiane związki są przeznaczone do hamowania aktywności enzymu ACAT, hamowania jelitowej absorpcji cholesterolu, odwracania lub spowolniania procesu arteriosklerozy i obniżania stężenia cholesterolu w surowicy ssaków, również ludzi. Kompozycje zawierają taką ilość związku czynnego lub dopuszczalnej w farmacji soli tego związku, która skutecznie hamuje aktywność enzymu ACTA lub absorpcję jelitową cholesterolu, odwraca lub spowalnia proces arteriosklerozy i obniża stężenie cholesterolu w surowicy a ponadto zawiera dopuszczalny w technologii farmaceutycznej nośnik.
165 357
Przykładami dopuszczalnych w technologii farmaceutycznej soli addycyjnych otrzymanych związków z kwasami są sole utworzone z kwasem solnym, p-toluenosulfonowym, fumarowym, cytrynowym, bursztynowym, salicylowym, szczawiowym, bromowodorowym, fosforowym, metanosulfonowym, winowym, dwutoluilowinowym i migdałowym.
Pochodne mocznika wytwarza się jak wspomniano w reakcji drugorzędowej aminy o wzorze NHR17R18 ze związkiem o wzorze R1NCO. Reakcję prowadzi się zazwyczaj w temperaturze otoczenia w rozpuszczalniku węglowodorowym, takim jak heksan. Drugorzędowe aminy o wzorze NHR17r18 można wytwarzać różnymi metodami znanymi w chemii, na przykład według sposobu podanego w „Vogel's Textbook of Practical Organic Chemistry, Longman Inc., New York, str. 564 - 575 (4 wyd. 1978).
Nowe związki otrzymane sposobem według wynalazku i ich dopuszczalne w farmacji sole są użyteczne jako inhibitory acylo-koenzymu A: acylotransferazy cholesterolowej (ACAT). Związki te hamują jelitową absorpcję cholesterolu u ssaków i są użyteczne do leczenia wysokiego poziomu cholesterolu w surowicy ssaków, w tym również ludzi. Leczenie to dotyczy zarówno zapobiegania jak i obniżania wysokiego poziomu cholesterolu we krwi. Związki te mogą być podawane osobom wymagającym leczenia wieloma konwencjonalnymi drogami podawania, doustnie, parenteralnie lub miejscowo. W zasadzie, związki te będą podawane doustnie lub parenteralnie, w dawkach od 0,5 do około 30 mg/kg wagi ciała pacjenta/dzień, korzystnie w dawkach od około 0,08 do 5 mg/kg. Dla dorosłego człowieka o średniej wadze (70 kg) zazwyczaj stosowana dawka będzie zatem wynosić od około 3,5 do około 2000 mg dziennie. Pewne różnice w dawkowaniu będą jednak niezbędne, w zależności od stanu zdrowia leczonego pacjenta i aktywności zastosowanego związku. W każdym przypadku, osoba odpowiedzialna za leczenie określi odpowiednią dawkę dla danego pacjenta.
Związek czynny lub dopuszczalną w farmacji sól tego związku można podawać jako czysty związek lub w połączeniu z dopuszczalnymi w technologii farmaceutycznej nośnikami, w dawce pojedynczej lub w dawkach podzielonych. Odpowiednimi nośnikami farmaceutycznymi są tu obojętne, stałe rozcieńczalniki lub napełniacze, sterylne roztwory wodne oraz różne rozpuszczalniki organiczne. Wytworzone kompozycje farmaceutyczne podaje się dogodnie w różnych formach dawkowania, takich jak tabletki, proszki, pastylki, syropy, roztwory injekcyjne i podobne. Jeśli to potrzebne, takie kompozycje farmaceutyczne mogą zawierać środki pomocnicze, takie jak cytrynian sodowy, węglan wapniowy czy fosforan wapniowy, jak również różne środki rozsadzające, takie jak skrobię, kwas alginowy oraz niektóre kompleksy krzemianów oraz środki wiążące, takie jak poliwinylopirolidon, sacharozę, żelatynę lub gumę akacjową. Ponadto, do celów tabletkowania często stosuje się środki poślizgowe, takie jak stearynian magnezowy, laurylo-siarczan sodowy i talk. Stałe kompozycje o podobnym składzie można również stosować do napełniania miękkich i twardych kapsułek żelatynowych. Korzystnymi środkami pomocniczymi stosowanymi w tym przypadku są laktoza lub cukier mlekowy oraz glikole polistyrenowe o wysokim ciężarze cząsteczkowym. Przy przygotowaniu związków wodnych lub eliksirów do podawania doustnego łączy się podstawowy składnik czynny z różnymi środkami słodzącymi lub zapachowymi, substancjami barwnymi lub barwnikami i tam, gdzie to potrzebne, ze środkami emulgującymi lub suspendującymi oraz z rozcieńczalnikami, takimi jak woda, etanol, glikol propylenowy, gliceryna i ich kombinacje.
Do celów podawania parenteralnego stosuje się roztwory związku czynnego lub dopuszczalnej w farmacji soli tego związku w oleju sezamowym lub arachidowym, w wodnym roztworze glikolu propylenowego lub w sterylnym roztworze wodnym. Takie roztwory wodne powinny być odpowiednie do potrzeb, właściwie buforowane a ciekły rozcieńczalnik powinien być uprzednio doprowadzany do izotoniczności odpowiednią ilością soli fizjologicznej lub glukozy. Rioztwory te są przeznaczone zwłaszcza do podawania dożylnego, domięśniowego, podskórnego i dootrzewnowego. Stosowane w tego typu formach sterylne media wodne są łatwo osiągalne znanymi standardowymi technikami.
Aktywność związków wytwarzanych sposobem według wynalazku jako inhibitorów ACAR można oznaczyć różnymi standardowymi testami biologicznymi lub farmakologicznymi. Przykładowo dla oznaczenia aktywności hamującej ACTA stosuje się następującą procedurę. Enzym ACAT oznacza się w mikrosomach wyizolowanych ze szczurów rasy Spraque-Dawley karmionych
165 357 specjalną paszą według metody Bilheimer'a J. T. (Meth. Enzymol., 111, str. 286 - 293, 1985) z niewielkimi modyfikacjami. Przed użyciem mikrosomy z wątroby preparuje się przez wirowanie różnicowe i przemycie buforem do oznaczeń. Oznaczana mieszanina zawierała 25gl BSA (40 mg/ml), 30/g roztworu mikrosomów z wątroby szczura (100 gg mikrosomalnego białka), 20 gl buforu do oznaczeń (0,1 M K2PO4 1,0 mM zredukowanego glutationu, pH 7,4), 20gg cholesterolu w 100gl 0,6 procentowego Tritenu WR-1339 w buforze do oznaczeń i 5 gl roztworu badanego związku rozpuszczonego w 100 procentowym DMSO (całkowita objętość - 180 pl). Mieszaninę tę inkubowano przez 30 minut w temperaturze 37°C. Reakcję inicjowano przez dodanie 20 pl 14COleile-CoA (100 pM, 2000dpm/nmol) i kontynuowano przez 15 minut w temperaturze 37CC. Reakcję zatrzymywano przez dodanie 1 ml EtOH. Lipidy ekstrahowano do 4 ml heksanu. Ilość 5 ml tego ekstraktu suszono w atmosferze azotu i zawieszano w 100pl chloroformu. Ilość 50pml zawiesiny chloroformowej nakraplano na aktywowaną ciepłem płytkę TLC i rozwijano w układzie: heksan : eter dietylowy : kwas octowy (85:15:1 objętościowo). Radioaktywność wprowadzoną do estrów cholesterolu oznacza się ilościowo w analizatorze liniowym TLC Bertholda LB2842. Aktywność hamująca ACTA wyliczono w stosunku do próby kontrolnej z DMSO.
Aktywność omawianych związków w hamowaniu jelitowej absorpcji cholesterolu można oznaczać metodą opisaną przez Melchoir'a i Harwell'a (J. Lipid. Res., 26, 306 - 315 (1985)).
Sposób według wynalazku zilustrowany jest następującymi przykładami. Temperatury topnienia nie są korygowane. Pomiarów widm protonowego rezonansu magnetycznego jądrowego (1HNMR) i magnetycznego rezonansu jądrowego C15 (C^NMR) dokonywano w roztworach w deuterochloroformie (CDCI3) a pozycje pików wyrażano w częściach na milion (ppm) w dół od tetrametylosilanu (TMS). Kształty pików oznaczono następująco: s - singlet, d - dublet, t - triplet, q - kwartet, m - multiplet, br - szeroki, c - złożony.
Przykład I. N-(2,4,6-Trójmetoksyfenylo)-N'-[4-(3-metylobutylo)fenylometylo]-N'-heptylomocznik.
Mieszaninę 209 mg (1 milimol) 2,4,6-trójmetoksyfenyloizocyjanianu, 275 mg N-heptylo-4-(3metylobutylo)benzyloaminy i 10 ml chlorku metylenowego miesza się w temperaturze pokojowej przez dobę. Następnie mieszaninę reakcyjną zatęża się pod zmniejszonym ciśnieniem. Po chromatografii na 100g żelu krzemionkowego z eluowaniem układem: heksan-octan etylowy (1:1) uzyskuje się 320 mg produktu (66% wydajności).
1HNMR (CDCI3): δ 0,81 - 0,96 (c) i 0,92 (d) (całość 9K), 1,27 (c, 9H), 1,44 - 1,68 (c, 4H), 2,6 (t, 2H), 3,33 (t, 2H), 3,75 (s, 6H), 3,77 (s, 3H), 4,55 (s, 2H), 5,55 (s, 1H), 6,11 (s, 2H), 7,15 (d, 2H), 7,24 (d, 2H). IR (CHCI3): 1654 cm'\
Przykład II. N-(2,4,6-Trójmetoksyfenylo)-N'-[4-(2,2-dimetylopropylo)fenylo]-N-heptylomocznik.
Tytułowy związek wytwarza się w sposób opisany w przykładzie I, stosując 760 mg (3,63 milimola) 2,4,6-trójmetoksyfenyloizocyjanianu, 1,0 g (3,63 milimola) N-heptylo-4-(2,2-dimetylopropylo)benzyloaminy i 20 ml chlorku metylenowego. Uzyskuje się 1,25 g produktu (71% wydajności).
Ή NMR (CDCl3): δ 0,82 - 0,95 (c) i 0,89 (s) (całość 12H), 1,27 (c, 8H), 1,61 (c, 2H), 2,48 (s, 2H), 3,34 (t, 2H), 3,76 (s, 6H), 3,78 (s, 3H), 4,57 (s, 2H), 5,59 (s, 1H), 6,12 (s, 2H), 7,1 (d, 2H), 7,23 (d, 2H). IR (CHCl3): 1657 cm!
Przykład III. N'-[2,4-dwu(metylotio)-6-metylopirymidyn-3-ylo]-N-[4-(3-metylobutylo)benzylo]-N-cykloheptylomocznik.
A. Izocyjanian 2,4-dwu(metylotio)-6-metylopirydyn-3-ylo.
Roztwór 800 mg (4 milimoli) 2,4-dwu(metylotio)-3-amino-6-metylopirydyny i 0,4 ml (2,3 milimoli) chloromrówczanu trójchlorometylu w 20 ml bezwodnego dioksanu ogrzewa się przez noc w temperaturze wrzenia pod chłodnicą zwrotną. Mieszaninę reakcyjną chłodzi się i sączy, a przesącz odparowuje się w próżni do sucha, otrzymując 730 mg tytułowego związku (81% wydajności) jako zabarwionego brązowo ciała stałego.
B. N'-[2,4-dwu(metylotio)-6-metylopirydyn-3-ylo]-N-[4-(3-metylobutylo)benzylo]-N-cykloheptylomocznik.
Roztwór 135 mg (0,6 milimola) izocyjanianu z przykładu IIIA i 164 mg (0,6 milimoli) N-cykloheptylo-4-(3-metylobutylo)benzyloaminy w 15 ml chlorku metylenu ogrzewa się przez noc
165 357 w atmosferze azotu, w temperaturze wrzenia pod chłodnicą zwrotną. Mieszaninę reakcyjną chłodzi się do temperatury pokojowej i odparowuje w próżni. Pozostałość chromatografuje się na 200 g żelu krzemionkowego, eluuje się 7:3 heksanem/octanem etylu, otrzymuje się 140 mg (32% wydajności) tytułowego związku jako prawie białego ciała stałego.
1HNMR (CDCls): δ 0,92 (d, 6H), 1,39- 1,74 (c, 13H), 1,98 (m,2H), 2,37 (s, 3H), 2,44 (s,6H),
2.59 (t, 2H), 4,37 (m, 1H), 4,50 (s, 2H), 5,47 (s, 1H), 6,57 (s, 1H), 7,18 (d, 2H), 7,32 (d, 2H).
IR (CHCla): 1921, 2853, 1650, 1560, 1469 cm’1.
W analogiczny sposób do sposobu postępowania z przykładu III otrzymano związki:
N'-[2,4-dwu(metylotio)-6-metylopirydyn-3-ylo]-N-[/4-(2,2-d\wimetylopropylo)benzylo]-N-cykloheptylomocznik. 70% wydajności.
1H NMR (CDCls): δ 0,88 (s, 9H), 1,39 -1,74 (c, 10H), 1,99 (m, 2H), 2,33 (s, 3H), 2,44 (2s, 6 H), 2,48 (s, 2H), 4,38 (m, 1H), 4,52 (s, 2H), 5,46 (s, 1H), 6,57 (s, 1H), 7,13 (d, 2H), 7,31 (d, 2H).
IR (CHCI3): 2922, 2853, 1651, 1561, 1470 cm.
N'-[2-metylo-4,6-dwu(metylotio)pirymidyn-5-ylo]-N-[4-(3-metylobutylo)benzylo]-N-cykloheptylomocznik. 72% wydajności.
1H NMR (CDCI3): δ 0,92 (d, 6 H), 1,40 - 1,75 (c, 13H), 1,98 (m, 2H), 2,44 (s, 6 H), 2,55 (s, 3H),
2.60 (t, 2H), 4,37 (m, 1H), 4,51 (s, 2H), 5,37 (s, 1H), 7,20 (d, 2H), 7,31 (d, 2H).
IR (CHCI3): 2920, 2853, 1651, 1467 cm'1.
N'-[2-metylo-4,6-dwu(metylotio)pirymidyn-5-ylo]-N-[4-(2,2-dwumetylopropylo)benzylo--N-cykloheptylomocznik. 70% wydajności.
1H NMR (CDCI3): δ 0,87 (t, 3H), 1,21-1,82 (c, 24H), 2,28 (m, 2H), 2,51 (s, 6 H), 6,69 (s, 1H), 8,64 (s, 1H).
IR (CHCla): 2922, 2850, 1682, 1452, 1405, 1358 cm'1.
N'-[2-metylo-4,6-dwu(metylotio)pirymidyn-5-ylo]-N-[4-(3-metylobutylo)benzylo]-N-heptylomocznik. 43% wydajności.
1H NMR (CDCI3): δ 0,86 (m), 0,92 (d) (całkowity 9H), 1,20 - 1,72 (d, 13H), 2,47 (s, 6 H), 2,57 (s), 2,60 (t), (całkowity 5H), 3,34 (t, 2H), 4,56 (s, 2H), 5,51 (s, 1H), 7,15 (d, 2H), 7,24 (d, 2H).
IR (CHCl3): 2920, 2850, 1659, 1468, 1415 cm'1.
N'-[-,4-dwu(metylotio)-6-metylopiΓydyn-3-ylo--N-[4-(3-metylobutylo)benzylo--N-heptylomocznik. 32% wydajności.
1HNMR (CDCl3): δ 0,87 (m), 0,92 (d) (całkowity 9H), 1,19 -1,72 (c, 13H), 2,37 (s, 3H), 2,46 (s, 3H), 2,48 (s, 3H), 2,59 (t, 2H), 3,34 (t, 2H), 4,58 (s, 2H), 5,61 (s, 1H), 6,61 (s, 1H), 7,17 (d, 2H), 7,27 (d, 2H).
IR (CDCI3): 2922, 2852, 1656, 1558, 1467 cm'1.
Wzór 1
Departament Wydawnictw UP RP. Nakład 90 egz. Cena 10 000 zł

Claims (1)

  1. Zastrzeżenie patentowe
    Sposób wytwarzania nowych pochodnych mocznika o wzorze przedstawionym na rysunku, w którym R1 oznacza tri(C1-C4)alkoksyfenyl, (C1-C4)alkilo-di(C1-C4)alkilotiopirydynyl, (C1-C4)alkilo-di(C1-C4)alkilotiopirymidynyl, a R17 i Rw oznaczają grupę (C4-Ca)alkilową lub grupę (C1-C6)alkilofenylometylową i ich sole, znamienny tym, że drugorzędową aminę o wzorze NHR R , w którym R 1 R mają wyżej podane znaczenie, poddaje się reakcji ze związkiem o wzorze R1NCO, w którym R1 ma wyżej podane znaczenie.
PL90291470A 1989-09-15 1990-09-14 Sposób wytwarzania nowych pochodnych mocznika PL PL PL165357B1 (pl)

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ZA907346B (en) 1992-05-27
DE69018908T2 (de) 1995-08-24
PL291470A1 (en) 1992-07-13
CA2025301C (en) 2001-10-16
KR910006233A (ko) 1991-04-27
DE69032981D1 (de) 1999-04-08
JPH03120243A (ja) 1991-05-22
PL165370B1 (pl) 1994-12-30
EP0609960A1 (en) 1994-08-10
AU652345B2 (en) 1994-08-25
CN1050183A (zh) 1991-03-27
AU6255390A (en) 1991-04-18
ATE177082T1 (de) 1999-03-15
KR930011303B1 (ko) 1993-11-29
GR3029826T3 (en) 1999-06-30
JPH0825974B2 (ja) 1996-03-13
IE903336A1 (en) 1991-04-10
PL291472A1 (en) 1992-07-13
IE66324B1 (en) 1995-12-27
DD298092A5 (de) 1992-02-06
IL110321A0 (en) 1994-10-21
IL95610A (en) 1994-12-29
DE69032981T2 (de) 1999-07-08
EP0609960B1 (en) 1999-03-03
PL291471A1 (en) 1992-06-26
NZ235323A (en) 1993-02-25
NO904022L (no) 1991-03-18
FI111362B (fi) 2003-07-15
WO1991004027A1 (en) 1991-04-04
HUT70027A (en) 1995-09-28
DE69018908D1 (de) 1995-06-01
EP0418071A3 (en) 1992-03-25
IL110324A0 (en) 1994-10-21
ES2071033T3 (es) 1995-06-16
EP0418071B1 (en) 1995-04-26
NO904022D0 (no) 1990-09-14
ES2127878T3 (es) 1999-05-01
PT95310A (pt) 1991-05-22
HU9302945D0 (en) 1993-12-28
ATE121730T1 (de) 1995-05-15
FI904537A0 (fi) 1990-09-14
MX22406A (es) 1994-01-31
IL95610A0 (en) 1991-06-30
DK0609960T3 (da) 1999-09-27
EG19358A (en) 1994-12-30
PT95310B (pt) 1997-06-30
DK0418071T3 (da) 1995-09-04
EP0418071A2 (en) 1991-03-20
CA2025301A1 (en) 1991-03-16

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