NO151362B - Analogifremgangsmaate til fremstilling av terapeutisk aktive urinstoffderivater - Google Patents

Analogifremgangsmaate til fremstilling av terapeutisk aktive urinstoffderivater Download PDF

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NO151362B
NO151362B NO801965A NO801965A NO151362B NO 151362 B NO151362 B NO 151362B NO 801965 A NO801965 A NO 801965A NO 801965 A NO801965 A NO 801965A NO 151362 B NO151362 B NO 151362B
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phenyl
trifluoromethyl
chloro
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Hans-Joachim Kabbe
Erich Klauke
Hans Peter Krause
Mithat Mardin
Ruediger Sitt
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Bayer Ag
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Description

Oppfinnelsen vedrører analogifremgangsmåten til fremstilling av terapeutisk aktive urinstoffderivater.
Noen urinstoffderivater er allerede kjent (sml. DOS 1.443. 560, US-patent 3.335.142, 3.856.952 og 3.903.130). Disse kjente urinstoffderivater er det likeledes omtalt noen bio-logiske virkninger. De kan f. eks. anvendes som herbizider, bakterizider, fungizider og fortilsetningsstoffer. Deres virkning på fettstoffskiftet, spesielt deres lipidabsorbsjonshemmende virkning er tidligere ikke kjent.
Oppfinnelsen vedrører følgelig analogifremgangsmåte til fremstilling av terapeutisk aktive urinstoffderivater med den generelle formel
hvori
(I) når R betyr 3-klor-4-trifluormetyl-fenyl, betyr
R 4 en rest fra gruppen 4-fluor-fenyl, 3-klor-4-trifluormetyl-fenyl, 3-cyanofenyl, 3-trifluormetyl-fenyl og 3-trifluormetoksy-fenyl,
(II) nar R 3 betyr 3-trifluormetyl-fenyl, betyr R4 en rest fra gruppen 3-klor-4-trifluormetylmerkapto-fenyl, 3-trifluor-metylmerkapto-fenyl og 4-klor-3-trifluormetyl-fenyl, eller (III) når R3 betyr 3-trifluormetoksy-fenyl, betyr R4 en rest fra gruppen 3-trifluormetylmerkapto-fenyl, 4-klor-3-trifluormetyl-fenyl, 4-trifluormetyl-fenyl og 4-tri fluormetoksy-fenyl, eller (IV) når R3 betyr 3-cyanofenyl, betyr R4 en rest fra gruppen 3- trifluor-metylmerkapto-fenyl, 4-klor-3-trifluormetyl-fenyl, 3-trifluormetyl-fenyl, 4-trifluormetyl-fenyl og 4- trifluormetoksy-fenyl.
Overraskende viser urinstoffderivatene med den generelle formel I en sterk lipidabsorbsjonshemmende virkning. Men kjennskap til teknikkens stand kunne det ikke ventes at forbindelser av denne stoffklasse kunne anvendes som lipidab-sorbs jonshemmende virksomme stoffer. Deres allerede kjente anvendelse som fortilsetningsstoffer i dyrehold og deres bakterizide virkning lot vente at etter deres applikasjon legemet forsterket opptar næringsmidler, hvilket fører til den i dyrehold ønskede vektsøkning. Lipidabsorbsjonshemme-virkningen av den herav resulterende mulighet til å anvende urinstoffderivater som tilleggsstoff ved næringsmidler, resp. ved applikasjon av tilsvarende legemiddelformuleringer å hemme.^lipidabsorbsjonen fra næringsmidler er overvinnelse av en fra teknikkens stand resulterende fordom.
Anvendelsen av urinstoffderivatene ved behandling av hyperlipemi muliggjør behandling også av slike pasienter som over-for allerede kjente lipidabsorbsjonshemmere viser uforenlig-het eller tilvenning. Den førstegangs anvendelse av urin-stof f derivatene som virksomme stoffer ved behandling av hyperlipemi er således en berikelse av farmasien.
Urinstoffderivatene med den generelle formel I fremstilles på i og for seg kjent måte, idet
a) et amin med den generelle formel II
hvori
R 4har ovennevnte betydning, omsettes med en forbindelse med den generelle formel III
hvori
R^ har den angitte betydning,
i et inert organisk oppløsningsmiddel ved temperaturer mellom 20°C og 120°C eller
b) et amin med den generelle formel II
hvori
R 4 har ovennevnte betydning, omsettes med klormaursyrefenylester med formel IV
ved temperaturer mellom 0 og 25°C og de derved dannede fenylkarbamidsyreestere med den generelle formel V omsettes direkte eller etter isolering med et amin med den generelle formel VI
2 3
hvori R og R har ovennevnte betydning, i et inert organisk oppløsningsmiddel ved temperaturer mellom 20°C og 200°C.
Ved de ovennevnte fremgangsmåtevarianter a) og b), kan aminene med den generelle formel (II) resp. den generelle formel (VI) hver gang anvendes alternativt når betydningen av R resp. av R 3 er gitt på • forhå•nd i den eventuelle reaksjonsdeltager.
Fremstillingen av de nye forbindelsene fra de med den generelle formel (I) definerte stoffklasse foregår likeledes etter i og for seg kjente metoder, ifølge de ovennevnte fremgangsmåtevarianter a) til b), idet de som utgangsstoffer anvendte iso-cyanatderivater, aminer og fenylkarbamidsyreestere med de generelle formler (III), (IV) og (VI) er kjent eller kan fremstilles etter kjente metoder (sml. R. Wagner et al., Synthetic Organic Chem. Wiley, New York, (1953), side 640, 645, 653).
Urinstoffderivatene ifølge formel (I) viser en fordelaktig hemming av lipidabsorbsjonen hos mennesker og dyr. Ved opp-tak av fettholdig næring fører de til en mindre elementær hyperlipami, ved samtidig hemming av cholesterolabsorbsjon, således at de spesielt kan anvendes til behandling av fett-stoff skiftef or styrrelser som f. eks. hyperlipoproteinami, atherosklerose eller adipositas.
Påvisningen av den fordelaktige virkning lar seg vise på følgende forsøksanordning på rotter: For frembingelse av en elementær hyperlipemi får en gruppe rotter 2,5 ml/kg olivenolje pr. os administrert (kontrollgruppe) . En tilsvarende gruppe av andre rotter får samtidig med olivenolje-applikasjonen det virksomme stoff som sus-pensjon i tragangslim administrert med sluksonde. En ytter-ligere kontrollgruppe av rotter får bare applisert tragant-slim.
2 timer etter applikasjon av olivenolje bestemmes konsen-trasjonen av serumtriglycerider i alle tre rottegrupper
(Metode: J. Ziegenhorst, Klin. Chem. 21, (1975) 1627). To timer etter fettapplikasjonen viser de bare med olivenolje behandlede rotter (gruppe 1) i forhold til rottene uten fett-applikas jon (gruppe 3) en tydelig økning av serumtriglycerider. Med denne økning, som er satt lik 100 %, sammenlignet den forminskede serumtriglyceridøkning av de med virkomt stoff og olivenolje behandlede dyr (gruppe). Det ble funnet,, at allerede mindre doseringer av urinstoffderivater ifølge formel (I) be-virker en signifikant senkning av serumtriglyceridene. Ved siden av den sterke lipidabsorbsjonshemmende virkning viser forbindelsene også en utpreget god tålbarhet.
Farmasøytiske tilberedninger, kan ved siden av ikke-toksiske inerte farmasøytiske egnede bærestoffer inneholde en eller flere forbindelser av ovennevnte formel eller bestå av en eller flere forbindelser av ovennevnte formler, samt frem-gangsmåter til fremstilling av disse tilberedninger.
De virksomme stoffer eller de farmasøytiske tilberedninger
kan appliseres oralt, parenteralt, fortrinnsvis oralt.
Generelt har det såvel i human- som også i veterinær-medisinen vist seg som fordelaktig å applisere det eller de virksomme stoffer i mengder fra ca. 1,0 til ca. 500, fortrinnsvis 5 til 100 mg/kg legemsvekt pr. 24 timer, fordelt på 1 til 6 administreringer, niemlig før og/eller under og/ eller etter måltidet. En enkeltinngivning inneholder det eller de virksomme stoffer, fortrinnsvis i mengder fra ca. 1 til ca. 100 mg/kg legemsvekt. Det kan imidlertid være nødvendig å avvike fra de nevnte doseringer, nemlig avhengig-het av type og legemsvekt av objektet som skal behandles, sykdommens type og tyngde, typen av tilberedning og applikasjon av legemidlet, samt tidsrommet, resp. intervallet innen hvilket administreringen foregår. Således kan det i noen tilfelle være tilstrekkelig å komme ut med mindre enn ovennevnte mengde virksomt stoff, mens i andre tilfelle ovennevnte virksomme stoffmengde må overskrides. Fastleggelse av den hver gang nødvendige optimale dosering og applikasjons-type av det virksomme stoff kan lett foregå av enhver fagmann på grunn av hans fagkunnskaper.
Eksempel 1 (Variant a)
0,05 mol 2-klor-5-trifluormetylanilin oppløses i 30 ml tetrahydrofuran og utrøres med en oppløsning av 0,05 mol 3-klor-4-trifluormetylfenylisocyanat i 30 ml tetrahydrofuran. Reaksjonsblandingen oppvarmes til 50°C, idet det faller ut N-2-klor-5-trifluormetylfenyl-N'-3-klor-4-trifluormetylfenyl-urinstoff.
Sm.p. 210-212°C, utbytte: 82 % av det teoretiske.
Eksempel 2 (variant b)
En oppløsning av 0,5 mol p-fluoranilin i 300 ml diklor-benzen og 70 ml (0,5 mol) trietylamin blandes med 0,5 mol klormaursyrefenylester under avkjøling (0-10°C). Reaksjonsblandingen hensettes deretter 24 timer ved værelsestempera-tur. Man frasuger dannet trietylamin-hydroklorid og blander filtratet med 0,5 mol 3-klor-4-trifluormetylanilin. Reak-sjonsoppløsningen oppvarmes 6 timer ved 180°C, oppløs-ningsmidlet fjernes under vakuum og residuet kokes ut i 250 ml eter og frasuges igjen. Man får N-4-fluorfenyl-N'-3-klor-4-trifluormetyl-fenylurinstoff av sm.p. 212 til 212°C. Utbytte: 67 % av det teoretiske.

Claims (1)

  1. Analogifremgangsmåte til fremstilling av terapeutisk aktive urinstoffderivater med den generelle formel hvori (I) når R_ betyr 3-klor-4-trifluormetyl-fenyl, betyr R4 en rest fra gruppen 4-fluor-fenyl, 3-klor-4-trifluormetyl-fenyl, 3-cyanofenyl, 3-trifluormetyl-fenyl og 3-trifluormetoksy-fenyl, (II) når R^ betyr 3-trifluormetyl-fenyl, betyr R4 en rest fra gruppen 3-klor-4-trifluormetylmerkapto-fenyl, 3-trifluor-metylmerkapto-fenyl og 4-klor-3-trifluor-i metyl-fenyl, eller (III) når R3 betyr 3-trifluormetoksy-fenyl, betyr R^ en rest fra gruppen 3-trifluormetylmerkapto-fenyl, 4-klor-3-trifluormetyl-fenyl, 4-trifluormetyl-fenyl og 4-tri-
    ) fluormetoksy-fenyl, eller (IV) når R3 betyr 3-cyanofenyl, betyr R4 en rest fra gruppen 3-trifluor-metylmerkapto-fenyl, 4-klor-3-trifluormetyl-fenyl, 3-trifluormetyl-fenyl, 4-trifluormetyl-fenyl og 4-trifluormetoksy-fenyl,karakterisert ved at a) et amin med den generelle formel II hvori R^ har den ovennevnte betydning, omsettes med en forbindelse med den generelle formel III hvori 3 R har ovennevnte betydning, i et inert organisk oppløsningsmiddel ved temperaturer mellom
    20°C og 120°C, eller b). et amin med den generelle formel II
    hvori
    R<4> har den ovennevnte betydning,
    omsettes med klormaursyrefenylester med formel IV
    ved temperaturer mellom 0°C og 25°C og de derved dannede fenylkarbamidsyreestere med den generelle formel V
    omsettes direkte eller etter isolering med et amin med den generelle formel VI
    hvori
    R 3 har ovennevnte betydning, i et inert organisk oppløsnings-middel ved temperaturer mellom 20°C og 200°C.
NO801965A 1979-07-14 1980-06-30 Analogifremgangsmaate til fremstilling av terapeutisk aktive urinstoffderivater. NO151362C (no)

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DE19792928485 DE2928485A1 (de) 1979-07-14 1979-07-14 Verwendung von harnstoffderivaten als arzneimittel bei der behandlung von fettstoffwechselstoerungen

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NO801965L NO801965L (no) 1981-01-15
NO151362B true NO151362B (no) 1984-12-17
NO151362C NO151362C (no) 1985-03-27

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DE (1) DE2928485A1 (no)
DK (1) DK302480A (no)
ES (1) ES493327A0 (no)
IL (1) IL60555A0 (no)
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US4405644A (en) 1983-09-20
NO151362C (no) 1985-03-27
DK302480A (da) 1981-01-15
ZA804180B (en) 1981-07-29
ES493327A0 (es) 1981-05-16
EP0022958A1 (de) 1981-01-28
NO801965L (no) 1981-01-15
DE2928485A1 (de) 1981-01-29
AU544252B2 (en) 1985-05-23
IL60555A0 (en) 1980-09-16

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