NL194821C - Farmacologisch actieve catecholderivaten en samenstellingen ervan. - Google Patents

Farmacologisch actieve catecholderivaten en samenstellingen ervan. Download PDF

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Publication number
NL194821C
NL194821C NL8702857A NL8702857A NL194821C NL 194821 C NL194821 C NL 194821C NL 8702857 A NL8702857 A NL 8702857A NL 8702857 A NL8702857 A NL 8702857A NL 194821 C NL194821 C NL 194821C
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Prior art keywords
cyano
dihydroxy
pharmacologically active
nitrophenyl
derivative
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NL8702857A
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English (en)
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NL194821B (nl
NL8702857A (nl
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Orion Yhtymo Oy
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Priority claimed from FI864875A external-priority patent/FI864875A0/fi
Application filed by Orion Yhtymo Oy filed Critical Orion Yhtymo Oy
Publication of NL8702857A publication Critical patent/NL8702857A/nl
Publication of NL194821B publication Critical patent/NL194821B/nl
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    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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 with substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 atoms of the carbocyclic ring
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    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/24—[b,e]-condensed with two six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Description

1 194821
Farmacologisch actieve catecholderivaten en samenstellingen ervan
De uitvinding heeft betrekking op nieuwe, farmacologisch actieve catecholderivaten.
Dergelijke verbindingen zijn bekend uit J. Med. Chem. (1982) 25:258-263, waarin 5-gesubstitueerde 5 3-hydroxy-4-methoxybenzoëzuren (isovanillinezuren) en -benzaldehydes (isovanillines) beschreven als potentiële remmers van catechol O-methyltransferase ["COMT”]. Vermeld wordt, dat de beschreven verbindingen uitstekende substraten zijn voor fenol sulfotransferases. Hierdoor rijst volgens de auteurs de vraag, of de farmacologische of fysiologische effecten van korte duur die gerapporteerd zijn met COMT remmers in vivo, het gevolg zijn van hun effecten op de verzwaveling. Daarom wordt in het artikei gesugge-10 reerd, dat specifieke remmers van COMT die de verzwaveling niet veranderen moeten worden geïdentificeerd.
Thans werd een nieuwe groep catecholderivaten gevonden, met COMT-remmende eigenschappen, welke verbindingen specifiek zijn en een lange werkingsduur in vivo hebben.
De uitvinding heeft derhalve betrekking op nieuwe, farmacologisch actieve catecholderivaten met de 15 algemene formule 1,
RiOv 20 ^ <1>
X
waarbij R, en R2 onafhankelijk van elkaar waterstof, acyl of fenoyl zijn, X halogeen, nitro of cyaan is, en R3 25 een groep met de algemene formule -CH=CR4R5 is, waarin R4 cyaan of acyl is, en Rs cyaan, acyl, alkoxycarbonyl of carboxamido, desgewenst gesubstitueerd met alkyl of hydroxyalkyl, is.
Bij voorkeur past men verbindingen volgens formule 1 toe, waarin R, en R2 beide acyl zijn. Volgens een andere voorkeur past men verbindingen met formule 1 toe, waarin R4 cyaan en R carboxamido, gesubstitueerd door ethyl is.
30 Verbindingen volgens de uitvinding die de voorkeur hebben, omvatten 3-(3,4-dihydroxy-5-nitrobenzyl-ideen)-2,4-pentaandion, N,N-diëthyl-2-cyaan-3-(3,4-dihydroxy-5-nitrofenyl)acrylamide, N-isopropyl-2-cyaan-3-(3,4-dihydroxy-5-nitrofenyl)acrylamide, N,N-dimethyl-2-cyaan-3-(3,4-dihydroxy-5-nitrofenyl)acrylamide en 2-cyaan-3-(3,4-dihydroxy-5-nitrofenyl)acrylamide.
De term ”alkyl” als hier gebruikt, als zodanig of als deel van een andere groep, omvat zowel rechte als 35 vertakte radicalen met maximaal 18 koolstof atomen, bij voorkeur 1-8 en liefst 1-4 koolstof atomen.
Specifieke voorbeelden voor de alkylresten zijn methyl, ethyl, propyl, isopropyl, butyl, t.butyl, pentyl, hexyl, oxtyl, decyl en dodecyl, met inbegrip van de diverse vertakte isomeren daarvan.
De term "acyl” als hier gebruikt, als zodanig of als deel van een andere groep, heeft betrekking op een alkylcarbonyl- of alkenylcarbonylgroep, waarbij de alkyl- en de alkenylgroep zijn als hierboven omschreven. 40 De term "alkenyl” duidt een koolwaterstofgroep aan als hierboven met betrekking tot de term "alkyl" omschreven met ten minste één dubbele koolstof-koolstof-binding. De alkenylresten kunnen maximaal 12, bij voorkeur 2-8 en liefst 2-4 kooistofatomen bevatten.
De uitvinding heeft tevens betrekking op werkwijzen voor de bereiding van verbindingen van formule 1. Volgens de uitvinding kunnen verbindingen van formule 1 bijvoorbeeld aldus worden bereid dat een 45 aldehyde van formule 2 R’°\
50 R2°\=j=/ CH0 PI
X
194821 2 waarin R2 en X zijn als hierboven omschreven, in een base- of zuur-gekatalyseerde reactie wordt gecondenseerd met een verbinding van formule 3 R,4 (3) 5 CH2-R5 met een actieve methyl- of methyleengroep, waarin R4 en R5 zijn als hierboven omschreven.
De verbindingen van formule 2 zijn nieuwe waardevolle tussenverbindingen voor de bereiding van andere waardevolle producten volgens de uitvinding.
Verbindingen van formule 2 waarin X cyaan is kunnen worden bereid uit de overeenkomstige verbindin-10 gen waarin X halogeen, bij voorkeur broom, is, door deze verbindingen bij verhoogde temperatuur (100-200°C) in een polair, aprotisch oplosmiddel, zoals pyridine, N-methylpyrrolidon of N,N-dialkylformamide te laten reageren met cuprocyanide.
Alternatief kunnen de verbindingen van formule 2 waarin X een 5-cyaangroep is worden bereid door het formyleren van 2,3-dihydroxybenzonitril met hexamethyleentetramine.
15 De uitvinding heeft tevens betrekking op farmaceutische preparaten waarin de verbindingen van formule 1 als actief bestanddeel kunnen worden gebruikt. De preparaten kunnen de verbindingen van formule 1 alleen of in combinatie met andere actieve bestanddelen bevatten. Voor de behandeling van de ziekte van Parkinson worden de verbindingen van formule 1 gegeven met levodopa, elk in zijn eigen preparaat of gecombineerd tot één preparaat. Ook kunnen perifere dopa-decarboxylase- (DDC-) remmers aanwezig zijn, 20 zoals carbidopa of benserazide, maar deze zijn niet verplicht.
De verbindingen volgens de uitvinding kunnen in verschillende doseringsvormen worden verschaft voor toediening langs elke geschikte enterale of parenterale weg. De doseringsvormen kunnen volgens bekende principes worden gefabriceerd. Alle farmaceutisch aanvaarde toevoegingen, smeermiddelen, vulstoffen, enz., kunnen worden gebruikt om verschillende eigenschappen van de doseringsvormen te modificeren.
25 Catechol-O-methyltransferase (COMT) katalyseert de overdracht van de methylgroep van S-adenosyl-L-methionine naar een aantal verbindingen met catecholstructuren. Dit enzym is belangrijk bij de extra-neuronale desactivering van catecholaminen en geneesmiddelen met catecholstructuren. COMT is één van de belangrijkste enzymen die een rol spelen bij het metabolisme van catecholaminen. Het is aanwezig in de meeste weefsels, zowel in de periferie als in het centrale zenuwstelsel. De hoogste activiteiten worden 30 aangetroffen in de lever, de darmen en de nieren. COMT is waarschijnlijk aanwezig in oplosbare en membraan-gebonden vormen. De exacte aard van de beide vormen is niet vastgesteld.
Bij de ziekte van Parkinson zijn de dopaminerge neuronen, op de eerste plaats de nigrostriatale neuronen, beschadigd, hetgeen een dopamine-tekort veroorzaakt in de cerebrale basale ganglia. Dit tekort kan worden gecompenseerd door levodopa dat in het centrale zenuwstelsel in dopamine wordt omgezet 35 onder de invloed van DDC.
Tegenwoordig wordt de levodopa-behandeling bijna altijd aangevuld met een perifere DDC-remmer om te vroege dopamine-vorming te remmen en zo de cerebrale levodopa-concentratie te verhogen en de perifere neveneffecten van dopamine te verminderen.
Behalve door DDC wordt levodopa door COMT gemetaboliseerd, dat dit omzet in 3-O-methyldopa 40 (3-OMD). 3-OMD dringt gemakkelijk door de bloedhersenen-barrière heen via een actief transportsysteem. Alleen is het therapeutisch ineffectief en bij concurrentie met levodopa is het nadelig. 3-OMD wordt in weefsels opgeslagen in verband met de lange halfwaardeduur daarvan (ca. 15 uur) in vergelijking met levodopa (ca. 1 uur). Een hoge activiteit van COMT correleert duidelijk met een geringere effectiviteit van levodopa ondanks de aanwezigheid van periferale DDC-inhibitor.
45 Naast monoamine-oxidase (MAO) is COMT een belangrijk enzym, dat aan het amine-metabolisme deelneemt. Door remming van het metabolisme van endogene aminen (dopamine, noradrenaline, adrenaline) in de hersenen verminderen de COMT-remmers de ontleding van deze verbindingen. Derhalve kunnen deze bruikbaar zijn bij de behandeling van depressie.
Door effectieve remming van perifeer COMT leiden COMT-remmers de metabolische route van levodopa 50 in de richting van decarboxylering, waardoor meer dopamine wordt gevormd, hetgeen belangrijk is bij de behandeling van hypertensie en hartfalen.
Onverwacht is waargenomen, dat de verbindingen volgens de uitvinding uiterst effectieve COMT-inhibitoren zijn. Zij openen nieuwe, tot nu toe onbekende mogelijkheden voor de behandeling van de ziekte van Parkinson. Voorts kunnen de verbindingen volgens de uitvinding ook bruikbaar zijn bij de behandeling 55 van depressie en hartfalen, alsmede hypertensie.
De nieuwe COMT-inhibitoren, die de vorming van 3-OMD remmen, kunnen de nadelige effecten van langdurig gebruik van levodopa verminderen. Voorts kunnen de levodopa-doses worden verminderd.
3 194821
Aangetoond is, dat de levodopa-dosis met de helft tot een derde van de dosis kan worden verminderd, die zonder COMT-inhibitor wordt gebruikt. Daar de dosering van levodopa individueel is, is het moeilijk een absolute dosering te geven, maar dagdoses van slechts 25-50 mg worden als voldoende beschouwd om mee te beginnen.
5 Een voorlopige klinische proef met n-butylgallaat, een bekende COMT-remmer, liet zien dat patiënten met de ziekte van Parkinson duidelijk baat hadden bij n-butylgallaat. De studie werd echter niet voortgezet, in verband met de te hoge toxiciteit van n-butylgallaat.
Het COMT-remmende effect van de verbindingen volgens de uitvinding werd getest onder toepassing van de volgende experimentele procedures.
10
Bepaling van de COMT-activiteit in vitro
De in vitro activiteit van COMT werd bepaald in enzym-preparaten geïsoleerd uit de hersenen en de lever van vrouwelijke Han:WIST ratten met een gewicht van ca. 100 g. De ratten werden met kooldioxide gedood en de weefsels werden verwijderd, en bij -80°C opgeslagen voorafgaand aan het bepalen van de enzym-15 activiteit.
Het enzympreparaat werd bereid door het nomogeniseren van de weefsels in 10 mM fosfaatbuffer, pH
7,4 (1 g/10 ml), welke 0,5 mM dithiotreitol bevatte. Het homogenaat werd 20 min. gecentrifugeerd bij 15.000 G. De bovendrijvende vloeistof werd opnieuw gecentrifugeerd gedurende 60 min. bij 100.000 G. Alle procedures werden uitgevoerd bij +4°C. De bovendrijvende vloeistof van de laatste centrifugering (100.000 20 G) werd gebruikt voor het bepalen van de activiteit van oplosbaar COMT-enzym.
De bepaling van ICgo werd uitgevoerd door meting van de COMT-activiteit in diverse geneesmiddelcon-centraties van een reactiemengsel dat het enzympreparaat, 0,4 mM dihydroxybenzoëzuur (substraat), 5 mM magnesiumchloride, 0,2 mM S-adenosyl-L-methionine en COMT-remmer toegevoegd. Het mengsel werd 30 min. bij 37°C geïncubeerd, waarna de reactie werd stopgezet met perchloorzuur en de geprecipiteerde 25 eiwitten werden verwijderd door centrifugeren (4000 G gedurende 10 min.). De activiteit van het enzym werd gemeten door bepaling van de concentratie van 3-methoxy-4-hydroxybenzoëzuur, gevormd uit het substraat van COMT (dihydroxybenzoëzuur) door HPLC onder toepassing van een elektrochemische detector. Chromatografie werd uitgevoerd door injecteren van 20 ul van het monster in een Spherisorb ODS kolom van 4,6 mm x 150 mm (deeltjesgrootte 5 um). De reactieproducten werden uit de kolom geëlueerd 30 met 20% methanol die 0,1 M fosfaat, 20 mM citroenzuur en 0,15 mM EDTA bevatte, pH 3,2, met een stroomsnelheid van 1,5 ml/min. De elektrochemische detector werd ingesteld op 0,9 V tegen een Ag/AgCI-elektrode. De concentratie van het reactieproduct, 3-methoxy-4-hydroxybenzoëzuur, werd vergeleken met de controlemonsters en de monsters die COMT-remmer bevatten. De IC^-waarde is de concentratie die 50% vermindering in COMT-activiteit veroorzaakt.
35
Effect van COMT-remmers in vivo
Mannelijke Han:WIST ratten, gewicht 200-250 g, werden in het experiment gebruikt. De controlegroep kreeg 50 mg/kg carbidopa 30 min. voor levodopa (50 mg/kg). De testgroep kreeg eveneens 50 mg/kg carbidopa 30 min. voor levodopa + COMT-remmer. De geneesmiddelen werden oraal toegediend.
40
Bemonstering
Ongeveer 0,5 ml bloed werd genomen uit de staartslagader. Men liet het monster stollen in ijs. Daarna werd het monster gecentrifugeerd en werd serum afgescheiden. Serum werd bij -80°C opgeslagen tot aan de bepaling van de concentraties aan levodopa en aan metaboliet daarvan 3-OMD.
45
Bepaling van levodopa- en 3-OMD-serumconcentraties
Aan serum (bijvoorbeeld 100 ul) werd een gelijk volume 0,4 M perchloorzuur, 0,1% natriumsulfaat, 0,01% EDTA, dat dihydroxybenzylamine als interne standaard bevatte, toegevoegd. Het monster werd gemengd en in ijs gehouden, waarna de eiwitten werden verwijderd door centrifugeren (4000 G gedurende 10 min.) en 50 de concentraties aan levodopa en 3-OMD werden bepaald door HPLC onder toepassing van een elektrochemische detector. De verbindingen werden gescheiden in een Ultrasphere ODS kolom van 4,6 mm x 150 mm in een elueermiddel dat 4% acetonitril, 0,1 M fosfaatbuffer, 20 mM citroenzuur, 0,15 mM EDTA, 2 mM octylsulfonzuur en 0,2% tetrahydrofolan bevat, pH 2,8. De stroomsnelheid was 2 ml/min. De elektrochemische detector werd ingesteld op +0,8 V tegen een Ag/AgCI-elektrode. De concentraties van de test-55 verbindingen werden bepaald door vergelijken van de hoogte van de pieken met die van de interne standaard. De verhouding werd gebruikt voor het berekenen van de serumconcentraties aan levodopa en 3-OMD bij controleratten en bij die welke COMT-remmer hadden ontvangen.
194821 4
Resultaten
De beste COMT-remmers volgens de uitvinding waren in vitro meer dan 1000 maal zo potent als de meest potente bekende referentieverbinding U-0521 (Tabel A). Deze referentieverbinding is beschreven door A. Reches c.s., Naunyn-Schmiedeberg’s Arch Pharmacology (1982) 320:34-37. 3' 4', dihydroxy-2-methyl 5 propiophenone. Ook bleek dat de oraal toegediende COMT-remmers de vorming van serum-3-OMD (3-O-methyldopa) remden dan U-0521 (Tabel B). Voorts drong de referentieverbinding U-0521 door de bloed-hersenen-barrière heen en remde de thyrosine-hydroxylase-activiteit waardoor de biosynthese van vitaal belangrijke catecholaminen werd geblokkeerd. De verbindingen volgens de uitvinding daarentegen zijn COMT-specifiek en dringen niet in belangrijke mate door de bloed-hersenen-barrière heen.
10
TABEL A
Resultaten in vitro met verbindingen van formule 1, waarin R„ R2l X en R3 de onderstaande betekenis hebben 15 Verbinding van Voorbeeld Ri R2 X ^3 COMT- inhibitie in hersenweefsel (ICen (nM))
20 2 Η H 5-N02 CN
/ CH=C 20 \
CN
25 U-0521 Η Η 5-H CH3 / COCH 6000 \ CH3 30 ---—-- TABEL B In vivo resultaten
Orale dosis (mg/kg) Verbinding 3-OMD-concentratie % van de controle 35 1 uur 5 uur 30 Voorbeeld 2 -96 -89 100 U-0521 -34 -14 40 Figuur 1 toont de 3-OMD-serum-concentraties voor de nieuwe verbinding (volgens Voorbeeld 2) en voor de controleverbinding die geen COMT-remmer bevat. Het proefopzet is dezelfde als voor de bovengenoemde in vivo experimenten. Figuur 2 toont de levodopa-serum-concentraties na dezelfde behandelingen. Deze figuren laten zien dat de verbindingen volgens de uitvinding de biologische beschikbaarheid van levodopa verhogen en de spiegel van de ongewenste metaboliet 3-OMD verlagen. De in serum waargenomen 45 verandering komt tot uiting in de hersenconcentraties aan 3-OMD en levodopa.
Specificiteit van de COMT-remming
De nieuwe verbindingen zijn specifiek COMT-inhibitoren en geen remmers van andere essentiële enzymen. Dit werd aangetoond in, in vitro experimenten die werden uitgevoerd als hierboven beschreven.
50
TABEL C
Verbinding COMT TH DBH DDC MAO-A MAO-B
55 Voorbeeld 2 20 21.000 >50.000 >50.000 >50.000 >50.000 U-0521 6000 24.000 >50.000 >50.000 >50.000 >50.000 5 194621 TH = thyrosine-hydroxylase; DBH = dopamine-B-hydroxylase; MAO-A en -B = monoamine-oxidase-A en -B.
ICgo is de concentratie die 50% van de betreffende enzymactiviteit remt.
De COMT-remmers volgens de uitvinding zijn uiterst specifiek. Zij remmen COMT effectief bij lage 5 concentratie, terwijl de inhibitie van andere enzymen die een rol spelen in het metabolisme van catecholami-nen een 1000 tot 10000 maal zo hoge concentratie vereist. Het verschil in remming van TH en COMT bij de referentieverbinding U-0521 is slechts een factor 4.
Voorbeeld 1 (niet volgens de uitvinding) 10 3,4*Dihydroxy-5,a>-dinitrostyreen
Een oplossing die 3,66 g (0,02 mol) 3,4-dihydroxy-5-nitrobenzaldehyde, 3,66 g (0,06 mol) nitromethaan en 3,31 g ammoniumacetaat in 10 ml absolute ethanol bevatte werd 6 uur verwarmd onder terugvloeiing. Water werd toegevoegd aan het reactiemengsel. Het mengsel werd met zoutzuur aangezuurd en met methyleenchloride geëxtraheerd. Het methyleenchlorideextract werd met water gewassen en het oplosmid-15 del werd onder vacuüm verdampt. Het residu werd gekristalliseerd uit isopropanol, opbrengst 1,9 g (40%), smeltpunt 258-260°C.
Voorbeeld 2 3,4-Dihydroxy-5-nitro-u>,o>-dicyaanstyreen 20 Dezelfde procedure als beschreven in Voorbeeld 1 werd herhaald onder toepassing van 3,0 g 3,4-dihydroxy-5-nitrobenzaldehyde en 3,0 g malonodinitril. Het product werd gekristalliseerd uit methanol/water, opbrengst 1,9 g (50%), smeltpunt 205-209°C.
Voorbeeld 3 25 3-(3,4-Dihydroxy-5-nitrobenzylideen)-2,4-pentaandion
Een oplossing die 1,83 g 3,4-dihydroxy-5-nitrobenzaldehyde en 1,00 g 2,4-pentaandion in 10 ml tetrahydrofuran bevatte werd verzadigd met gasvormig waterstofchloride. Na een nacht staan bij 5°C werd het product afgefiltreerd en gewassen met ether. Opbrengst 1,2 g (50%), smeltpunt 175-178°C.
30 Voorbeeld 4
Ethyl-2-cyaan-3-(3,4-dihydroxy-5-nitrofenyl)acrylaat
De in Voorbeeld 1 beschreven procedure werd herhaald onder toepassing 1,0 g 3,4-dihydroxy-5-nitrobenzaldehyde, 0,9 g ethylcyaanacetaat en 0,15 g ammoniumacetaat in 10 ml ethanol. Opbrengst 0,98 g (57%), smeltpunt 205-210°C.
35
Voorbeeld 5 2-Cyaan-3-(3,4-dihydroxy-5-nitrofenyl)acrylamide
Een oplossing die 1,3 g 3,4-dihydroxy-5-nitrobenzaldehyde, 0,73 g cyaanaceetamide en een katalytische hoeveelheid piperidineacetaat in 40 ml droge ethanol bevatte werd een nacht onder terugvloeiing verwarmd. 40 Het oplosmiddel werd onder vacuüm verdampt en het residu werd geherkristalliseerd uit water/DMF. Opbrengst 0,84 g (48%), smeltpunt 296-298°C.
Voorbeeld 6 N,N-Dimethyl-2-cyaan-3-(3,4-dihydroxy-5-nitrofenyl)acrylamide 45 Een oplossing die 1,83 g 3,4-dihydroxy-5-nitrobenzaldehyde, 1,2 g Ν,Ν-dimethylcyaanaceetamide en een katalytische hoeveelheid piperidineacetaat in 40 ml droge ethanol bevatte werd een nacht onder terugvloeiing verwarmd. Opbrengst 1,1 g (40%), smeltpunt 183-185°C.
Voorbeeld 7 50 N,N-Diëthyl-2-cyaan-3-(3,4-dihydroxy-5-nitrofenyl)acrylamide
De in Voorbeeld 6 beschreven procedure werd herhaald onder toepassing van 1,83 g 3,4-dihydroxy-5-nitrobenzaldehyde en 1,5 g Ν,Ν-diëthylcyaanaceetamide. Opbrengst 2,23 g (73%), smeltpunt 153-156°C.
Voorbeeld 8 55 N-lsopropyl-2-cyaan-3-(3,4-dihydroxy-5-nitrofenyl)acrylamide
De in Voorbeeld 6 beschreven procedure werd herhaald onder toepassing van 1,83 g 3,4-dihydroxy-5-nitrobenzaldehyde en 1,3 g N-isopropylcyaanaceetamide. Opbrengst 1,46 g (50%), smeltpunt 243-245°C.

Claims (11)

194821 6 Voorbeeld 9 Neopentyl-2-cyaan-3-(3,4-dihydroxy-5-nitrofenyl)acrylaat De in Voorbeeld 1 beschreven procedure werd herhaald onder toepassing van 3,4-dihydroxy-5-nitrobenzaldehyde en neopentylcyaanacetaat. Opbrengst 67%, smeltpunt 173-179°C. 5 Voorbeeld 10 N-(3-Hydroxypropyl)-2-cyaan-3-(3,4-dihydroxy-5-nitrofenyl)acrylamide De in Voorbeeld 6 beschreven procedure werd herhaald onder toepassing van N-(3-hydroxypropyl)cyaanaceetamide en 3,4-dihydroxy-5-nitrobenzaldehyde. Opbrengst 52%, smeltpunt 10 223-228°C. Voorbeeld 11 3-(4-Hydroxy-5-nitro-3-pivaloyloxybenzylideen)-2,4-pentaandion Een mengsel dat 2,0 g van het volgens Voorbeeld 3 verkregen product in 5 ml pivaloylchloride werd 15 onder verminderde druk op 100°C verwarmd. De overmaat pivaloylchloride werd onder verminderde druk afgedampt en aan het residu werd ether toegevoegd. Het product werd afgefiltreerd en met ether gewassen. Opbrengst 1,41 g (58%), smeltpunt 143-145°C. 20 Conclusies
1. Farmacologisch actieve catecholderivaten met de algemene formule 1, RiOv 25 _/~\_ RzO—^r3 X 30 met het kenmerk, dat R, en R2 onafhankelijk van elkaar waterstof, acyl of fenoyl zijn, X halogeen, nitro of cyaan is, en R3 een groep met de algemene formule -CH=CR4RS is, waarin
35 R4 cyaan of acyl is, en . R5 cyaan, acyl, alkoxycarbonyl of carboxamide, desgewenst gesubstitueerd met alkyl of hydroxyalkyl, is.
2. Farmacologisch actief catecholderivaat volgens conclusie 1, met het kenmerk, dat het derivaat 3-(3,4-dihydroxy-5-nitrobenzylideen)-2,4-pentaandion is.
3. Farmacologisch actieve catecholderivaten volgens conclusie 1, met het kenmerk, dat R4 cyaan en R5 40 carboxamido, gesubstitueerd door ethyl is.
4. Farmacologisch actief catecholderivaat volgens conclusie 1, met het kenmerk, dat het derivaat N,N-diëthyl-2-cyaan-3-(3,4-dihydroxy-5-nitrofenyl)acrylamide is.
5. Farmacologisch actief catecholderivaat volgens conclusie 1, met het kenmerk, dat het derivaat N-isopropyl-2-cyaan-3-(3,4-dihydroxy-5-nitrofenyl)acrylamide is.
6. Farmacologisch actief catecholderivaat volgens conclusie 1, met het kenmerk, dat het derivaat N,N- dimethyl-2-cyaan-3-(3,4-dihydroxy-5-nitrofenyl)acrylamide is.
7. Farmacologisch actief catecholderivaat volgens conclusie 1, met het kenmerk, dat het derivaat 2-cyaan-3-(3,4-dihydroxy-5-nitrofenyl)acrylamide is.
8. Farmaceutisch preparaat, met het kenmerk, dat dit een verbinding als beschreven in één der conclusies 50 1-7, levodopa en eventueel een perifere decarboxylase remmer omvat, in combinatie met één of meer gebruikelijke dragers en eventueel één of meer gebruikelijke toevoegingen.
9. Farmaceutisch preparaat volgens conclusie 8, met het kenmerk, dat de perifere decarboxylase-remmer carbidopa is.
10. Farmaceutisch preparaat volgens conclusie 8, met het kenmerk, dat de perifere decarboxylase-remmer 55 benzeradine is. * 7 194821
11. Set van twee farmaceutische preparaten, omvattende een farmaceutisch preparaat dat levodopa bevat en een farmaceutisch preparaat dat een verbinding als beschreven in één van de conclusies 1—7 bevat, waarbij één of beide van de genoemde preparaten tevens een perifere decarboxylase-remmer omvat. Hierbij 2 bladen tekening
NL8702857A 1986-11-28 1987-11-27 Farmacologisch actieve catecholderivaten en samenstellingen ervan. NL194821C (nl)

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FI864875A FI864875A0 (fi) 1986-11-28 1986-11-28 Nya farmakologiskt aktiva foereningar, dessa innehaollande kompositioner samt foerfarande och mellanprodukter foer anvaendning vid framstaellning av dessa.
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CS276263B6 (en) 1992-05-13
LV10236B (en) 1995-06-20
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YU2289A (en) 1989-12-31
JPS63170311A (ja) 1988-07-14
SE8704751L (sv) 1988-05-29
AU8187987A (en) 1988-06-02
NO171450C (no) 1993-03-17
PT86236A (en) 1987-12-01
JPH085781B2 (ja) 1996-01-24
DK623087A (da) 1988-05-29
CN1040062C (zh) 1998-10-07
RU2014319C1 (ru) 1994-06-15
NO874966L (no) 1988-05-30
ES2008359A6 (es) 1989-07-16
GB2200109B (en) 1991-07-03
HK75594A (en) 1994-08-12
IT1225762B (it) 1990-11-26
GR871817B (en) 1988-03-24
FR2607493B1 (fr) 1994-08-12
GB8727854D0 (en) 1987-12-31
JP2735834B2 (ja) 1998-04-02
IT8722790A0 (it) 1987-11-27
CS277018B6 (en) 1992-11-18
DK623087D0 (da) 1987-11-27
DE19975025I2 (de) 2000-08-24
CA1289078C (en) 1991-09-17
BE1003279A5 (fr) 1992-02-18
AU621036B2 (en) 1992-03-05
FR2607493A1 (fr) 1988-06-03
BG60407B2 (bg) 1995-02-28
PL152642B1 (en) 1991-01-31
EG18338A (en) 1992-09-30
DE3740383C2 (de) 1997-09-25
LU87050A1 (fr) 1988-05-03
MTP1012B (en) 1988-10-18
AT401053B (de) 1996-06-25
MA21120A1 (fr) 1988-07-01
IE60320B1 (en) 1994-06-29
CN87108011A (zh) 1988-06-08
CS843988A3 (en) 1992-01-15
IS3290A7 (is) 1988-05-29
LV10236A (lv) 1994-10-20
PL269091A1 (en) 1988-12-08
CH685436A5 (de) 1995-07-14
YU48020B (sh) 1996-10-09
NL300136I1 (nl) 2003-12-01
YU47790B (sr) 1996-01-09
NO874966D0 (no) 1987-11-27
US4963590A (en) 1990-10-16
DE3740383A1 (de) 1988-06-01
AR243491A1 (es) 1993-08-31
DK175394B1 (da) 2004-09-20
GB2200109A (en) 1988-07-27
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PT86236B (pt) 1990-11-07
JPS63150237A (ja) 1988-06-22
NL194821B (nl) 2002-12-02
SE503434C2 (sv) 1996-06-17
IS1753B (is) 2000-07-21
ATA312987A (de) 1995-10-15
NZ222729A (en) 1990-04-26
HUT45473A (en) 1988-07-28
SE8704751D0 (sv) 1987-11-27
NL8702857A (nl) 1988-06-16
PH26145A (en) 1992-03-18
CS844088A3 (en) 1992-05-13
CA1334967C (en) 1995-03-28
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YU213587A (en) 1989-06-30

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