NO177262B - Analogifremgangsmåte for fremstilling av terapeutisk aktive, O-substituerte oximer - Google Patents
Analogifremgangsmåte for fremstilling av terapeutisk aktive, O-substituerte oximer Download PDFInfo
- Publication number
- NO177262B NO177262B NO891970A NO891970A NO177262B NO 177262 B NO177262 B NO 177262B NO 891970 A NO891970 A NO 891970A NO 891970 A NO891970 A NO 891970A NO 177262 B NO177262 B NO 177262B
- Authority
- NO
- Norway
- Prior art keywords
- ethyl
- oxime
- methanone
- formula
- carboxypiperidin
- Prior art date
Links
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- 150000002923 oximes Chemical class 0.000 claims abstract description 25
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 11
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- 239000001257 hydrogen Substances 0.000 claims abstract description 9
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- 125000003118 aryl group Chemical group 0.000 claims abstract description 3
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- 238000000034 method Methods 0.000 claims description 22
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- 239000011780 sodium chloride Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
Classifications
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- C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
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- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/78—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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Description
Foreliggende oppfinnelse vedrører fremstilling av nye O-substituerte oximer og salter derav for anvendelse ved klinisk behandling av unormal funksjon i y-aminosmørsyre-neurotrans-misj onssystemet.
I de senere år er det blitt utført mye farmakologisk forskning vedrørende y-aminosmørsyre (heretter betegnet GABA), som er en hemmende neurotransmitter i sentralnervesystemet til pattedyr.
Hemmingen av GABA-gjenopptak resultererer i økning
i tilgjengeligheten av denne hemmende neurotransmitter i synapsespalten, noe som fører til økt GABA-erg aktivitet.
Økt GABA-erg aktivitet kan være nyttig i behandlingen av f.eks. angst, smerte og epilepsi, samt muskel- og bevegelses-sykdommer (se f.eks. Progress in Medicinal Chemistry, 22 (1985), s. 68-112 (redigert av G.P. Ellis og G.B. West, Elsevier Science Publishers, B.V.).
F.eks. piperidin-3-carboxylsyre (nipecotinsyre) er en velkjent og sterk hemmer for GABA-gjennopptak fra synapsespalten og inn i presynaptiske nerveender og gliaceller. Ettersom den er en forholdsvis polar forbindelse og derfor
ute av stand til å krysse blod/hjerne-barrieren har piperidin-3-carboxylsyre selv ikke funnet noen praktisk anvendelighet som et legemiddel.
I US patentskrifter nr. 4.383.999 og 4.514.414, og i europeiske patentsøknader nr. 86903274 og 87300064 er noen derivater av N-(4,4-disubstituert-3-buten-l-yl)-azahetero-cykliske carboxylsyrer påberopt som hemmere for GABA-opptak. Videre er det i europeisk patentsøknad nr. 86115478.9 påberopt at l-aryloxyalkylpyridin-3-carboxylsyrer også er hemmere for GABA-gjenopptak.
Ifølge J. Pharm. Exp. Therap. 228 (1984), s. 109,
er N-(4,4-difenyl-3-buten-l-yl)nipecotinsyre (betegnet SK&F 89976A), N-(4,4-difenyl-3-buten-l-y)guvacin (betegnet SK&F 100330A), N-(4,4-difenyl-3-buten-l-yl)homo-3-prolin (betegnet SK&F 100561) og N-(4-fenyl)-4-(2-thienyl)-3-buten-l-yl)nipecotinsyre (betegnet SK&F 100604J) orale hemmere for GABA-opptak. Disse dataene er oppsummert i Epilepsi Res. 1 (1987), s. 77-93.
Guvacin er 1,2,5,6-tetrahydro-pyridin-3-carboxylsyre og homo-(3-prolin er pyrrolidin-3-eddiksyre.
Foreliggende oppfinnelse vedrører en analogifremgangsmåte for fremstilling av nye, terapeutisk aktive, 0-substituerte oximer hvor O-substituenten inneholder enten et derivat av pyridin-3-carboxylsyre (nipecotinsyre) eller av en annen GABA-mimetisk, cyklisk aminosyrerest med den generelle formel II. Forbindelsene fremstilt ifølge oppfinnelsen har den generelle formel I
hvorR<1>og R<2>, uavhengig av hverandre, er en aromatisk rest valgt fra gruppen bestående av imidazolyl, fenyl, pyridinyl, pyrrolyl, thienyl og 1,2,4-triazolyl, idet hver ring eventuelt er substituert med én, to eller tre substituenter valgt fra gruppen bestående av laverealkoxy, azido, halogen, hydroxy, laverealkyl, nitro og trifluormethyl;R<3>er hydrogen eller laverealkyl; n og m er hele tall fra 0 til 2;R<4>er en cyklisk aminosyrerest med den generelle formel II
hvor R<5>er hydrogen; R<6>er hydrogen, eller R<5>er sammen medR<6>en ytterligere binding; og X er NH2eller R<9>, hvor R<9>er hydroxy eller alkoxy, samt farmasøytisk akseptable syreaddisjonssalter derav, og når R<9>er hydroxy, farmasøytisk akseptable metallsalter og eventuelt substituerte ammoniumsalter derav„
Analogifremgangsmåten er kjennetegnet ved at
a) et oxim med formel V
hvor A er som definert ovenfor, omsettes med en
forbindelse med formel VI
hvorR<3>, R<4>, n og m er som definert ovenfor, og Y er en uttredende gruppe, eller
b) et oxim med formel ,V
hvor A er som definert ovenfor, alkyleres med en
forbindelse med formel VII
hvor Y er en uttredende gruppe, Z er en mindre labil gruppe og R<3>, n og m er som definert ovenfor, hvoretter det erholdte mellomprodukt med formel VIII
hvor A, R<3>, n og m og Z er som definert ovenfor, omsettes med R<4>H, hvor R<4>er en aminosyre eller
et aminosyrederivat, hvoretter
den erholdte forbindelse, om ønsket, omdannes til et farma-søytisk akseptabelt syreaddisjonssalt derav eller eventuelt et farmasøytisk akseptabelt metallsalt eller eventuelt substituert ammoniumsalt derav.
Forbindelsene med formel I har en større lipofilisi-tet, og derved en større tilgjengelighet for hjernen, samt en langt høyere affinitet til GABA-opptaksetene sammenlignet med opphavs-aminosyrene, og de har derfor interessante og nyttige farmakologiske egenskaper.
Det er blitt vist at de nye forbindelsene med den generelle formel I utviser hemmende egenskaper med hensyn til GABA-gjenopptak og har nyttige farmakologiske egenskaper på sentralnervesystemet, dvs. at de forårsaker en selektiv økning i GABA-erg aktivitet. Forbindelser med formel I kan anvendes til å behandle f.eks. smerte, angst, epilepsi og visse muskel- og bevegeIsessykdommer. De kan også finne bruk som sedativer og hypnotika.
I formel I er minst én av ringene R<1>og R<2>, som er like eller forskjellige, og som eventuelt kan være substituert, fortrinnsvis valgt fra gruppen bestående av fenyl, pyridinyl, pyrrolyl, thienyl og 1,2,4-triazolyl, mest foretrukket fra gruppen bestående av fenyl, pyrrolyl og thienyl.
I definisjonen av R<1>og R<2>er imidazolyl 2-imidazolyl, 4-imidazolyl eller 5-imidazolyl; pyrimidyl er 2-pyrimidyl, 4-pyrimidyl eller 5-pyrimidyl; pyrrolyl er 2-pyrrolyl; thienyl er 2-thienyl eller 3-thienyl og 1,2,4-triazolyl er l,2,4-triazol-3-yl eller 1,2,4-triazol-5-yl.
Substituentene som eventuelt er valgt for ringene R<1>og/eller R<2>er fortrinnsvis laverealkoxy, azido, halogen, hydroxy, laverealkyl eller trifluormethyl, mest foretrukket laverealkoxy, halogen eller laverealkyl. Uttrykket halogen betegner i denne sammenheng fluor, klor, brom og jod, fortrinnsvis fluor, kor og brom, og mest foretrukket fluor og klor.
R3 er fortrinnsvis hydrogen, methyl eller ethyl, mest foretrukket er R<3>hydrogen.
Fortrinnsvis er n + m = 0, 1 eller 2, mest foretrukket er n + m = 1.
X er fortrinnsvis R<9>.
R 9 er hydroxy eller alkoxy, fortrinnsvis er R 9 hydroxy, methoxy eller ethoxy; mest foretrukket er R<9>hydroxy.
I definisjonen av forbindelsene med formel I betegner uttrykket laverealkyl når det brukes alene, med mindre annet er angitt, en alkylgruppe med ikke mer enn 4 carbonatomer, f.eks. methyl, ethyl, propyl, isopropyl, cyclopropyl eller tert.-butyl, idet de foretrukne grupper er methyl, ethyl og cyclopropyl. Når det brukes i kombinasjoner som alkoxy, alkylthio og alkylamino, betegner uttrykket "laverealkyl" likeledes en alkylgruppe med ikke mer enn 4 carbonatomer, fortrinnsvis methyl og ethyl, slik at de foretrukne kombinasjoner er henholdsvis methoxy, ethoxy, methylthio, ethylthio, methylamino og ethylamino.
Eksempler på bestemte og foretrukne forbindelser med formel I er de følgende:
(R)-difenylamino-0[2-(3-carboxypiperidin-l-yl)-ethyl]oxim (1)
(R)-(2-methylfenyl)-(3-methyl-2-thienyl)methanon-0[2-(3-carboxypiperidin-l-yl) ethyl ]oxim-hydroklorid (2)
(R)-bis(3-methyl-2-thienyl)methanon-O-[2-(3-carboxypiperidin-l-yl) ethyl ]-hydroklorid (3)
(R)-(2-ethylfenyl)-(3-methyl-2-thienyl)methanon-O-[2-(3-carboxypiperidin-l-yl) ethyl ]oxim-hydroklorid (4)
(R)-(3-methyl-2-thienyl)-(2-thienyl)methanon-O-[2-(3-carboxypiperidin-l-yl) ethyl] -oxim (5)
(R)-(2-methylfenyl)-(3-methyl-2-thienyl)methanon-O-[2-(3-carboxypiperidin-l-yl) ethyl ]oxim-hydroklorid (10)
Difenylmethanon-O-[2-(3-carboxypiperidin-l-yl)ethyl]oxim-hydroklorid (25)
(2-Methylfenyl)-(3-methyl-2-thienyl)methanon-O-[2-(3-carboxypiperidin-l^yl)ethyl]oxim-hydroklorid (26)
Difenylmethanon-O-[2-(3-carboxy-l,2,5,6-tetrahydropyridin-1-yl)ethyl]oxim (45)
(2-Methylfenyl)fenylmethanon-O-[2-(3-carboxy-l,2,5,6-tetra-hydropyridin-l-yl)ethyl]oxim-hydroklorid (50)
(3-Fluorfenyl)-(2-methylfenyl)methanon-O-[2-(3-carboxy-l,2,5,6-tetrahydropyridin-l-yl)ethyl]oxim-hydroklorid (51)
(R)-bis(4-fluor-2-methylfenyl)methanon-O-[2-(carboxypiperidin-l-yl)ethyl]oxim-hydroklorid (53)
(2,4-Diklorfenyl)-(3-methyl-2-thienyl)methanon-O-[2-(3-car-boxy-l, 2,5,6-tetrahydropyridin-l-yl)ethyl]oxim-hydroklorid
(58)
Bis(2-methylfenyl)methanon-O-[2-(3-carboxy-l,2,5,6-tetra-hydropyridin-l-yl) ethyl]oxim-hydroklorid (64)
(2-Klorfenyl)feny1-methanon-O-[2-(3-carboxycarbonyl-l,2,5,6-tetrahydropyridin-l-yl)ethyljoxim-hydroklorid (76)
og farmasøytisk akseptable syreaddisjonssalter og metallsalter og eventuelt alkylerte ammoniumsalter derav.
Forbindelsene med formel I kan foreligge som geome-triske og optiske isomerer, og alle isomerer og blandinger derav er inkludert her. Isomerer kan separeres ved hjelp av standardmetoder, slik som kromatografiske teknikker eller fraksjonell krystallisasjon av salter med optisk aktive syrer eller baser.
Farmasøytisk akseptable syreaddisjonssalter av forbindelser av formel I omfatter de som er avledet fra uorga-niske eller organiske syrer, slik som saltsyre, hydrobrom-syre, svovelsyre, fosforsyre, eddiksyre, melkesyre, malein-syre, fthalsyre og fumarsyre.
Forbindelsene med den generelle formel I fremstilles ved hjelp av de følgende vanlige fremgangsmåter:
Fremgangsmåte a;
Et oxim med formel V, hvor A er som definert ovenfor, omsettes med en forbindelse med formel VI, hvor R 3 , R 4, n og m er som definert ovenfor, og Y er en egnet uttredende gruppe, slik som halogen eller-p-toluen-sulfonat. Denne om-setning kan utføres i et polart, inert oppløsningsmiddel, f.eks. aceton, ethanol eller N,N-dimethylformamid, i nærvær av en base, f.eks. kaliumcarbonat eller natriumhydrid, ved en temperatur opp til tilbakestrømningstemperatur i 1 - 72 timer.
Fremgangsmåte b;
Et oxim med formel V, hvor A er som definert ovenfor, alkyleres med en forbindelse med formel VII, hvor Y er en egnet reaktiv uttredende gruppe, slik som brom eller p-toluen-sulfonat, og Z er en mindre labil gruppe, f.eks. klor (eller alternativt en slik gruppe som ethoxy som kan omdannes til en reaktiv uttredende gruppe), og R 3, n og m er som definert ovenfor. Denne reaksjonen kan utføres i et egnet oppløsnings-middel, f.eks. aceton, ethanol eller N,N-dimethylformamid,
i nærvær av en base, f.eks. kaliumcarbonat eller natriumhydrid, ved en temperatur opp til tilbakestrømningstempera-tur i 1 - 72 timer.
Produktet VIII fra denne reaksjonen hvor A, R 3, n, m og Z er som definert ovenfor, omsettes med R 4 H, hvor R 4 er en aminosyre eller et aminosyrederivat som angitt ovenfor. Denne alkyleringsreaksjonen kan utføres i et inert oppløs-ningsmiddel, slik som aceton, i nærvær av en base, f.eks. kaliumcarbonat, og en katalysator, f.eks. et alkalimetall-jodid, ved en temperatur opp til tilbakestrømningstemperatur i 1 - 96 timer.
Under visse omstendigheter kan det være nødvendig å beskytte f.eks. carboxylgruppene i mellomproduktene som brukes ved fremgangsmåtene ovenfor (f.eks. RH, V eller VI) med egnede beskyttelsesgrupper. I tilfeller hvor A inneholder en aminogruppe kan denne beskyttes ved acylering, og i tilfellene hvor A og/eller R 4 inneholder en hydroxylgruppe, kan denne beskyttes f.eks. ved acylering eller med ether-dannelse. Carboxylsyregruppen i R 4 kan f.eks. forestres. Inn-føring og fjerning av slike grupper er beskrevet "Protec-
tive Groups in Organic Chemistry", J.F.M. McOrnie utg. (New York, 1973).
Forbindelser med formel V kan fremstilles ved å om-sette vedkommende keton eller aldehyd med hydroxylamin (eller hydrokloridet derav) i et slikt oppløsningsmiddel som ethanol eller pyridin (se f.eks. W.E. Bachmann, Org. Syn., (1967) 70; W.G. Honey et al., J. Pharm. Sei., 66 (1977), s. 1602-1606; S. Rossi et al., Farm. Ed. Sei., 24 (1969), s. 685-703 eller P.L. Huerta et al., J. Pharm. Sei., 66 (1977), s. 1120-4.
Forbindelser med formel VI kan fremstilles ved om-setning av vedkommende aminosyre (R 4H) beskytter f.eks. ethyl-esteren, med en 2-haloethanol, f.eks. 2-bromethanol, i nærvær av en base, f.eks. triethylamin eller et alkalimetallcarbonat. Oppløsningsmidlet kan passende være ethanol, aceton, methyl-ethylketon eller N,N-dimethylformamid. Dette etterfølges av halogenering med et egnet halogeneringsmiddel i et inert oppløsningsmiddel ved tilbakestrømningstemperatur i 0,5 - 24 timer. Oppløsningsmidlet kan passende være toluen og haloge-neringsmidlet kan f.eks. være thionylklorid.
Farmakologiske metoder
Den in vitro hemming av [ H]-GABA-opptak ble fastlagt hovedsakelig ved hjelp av metoden til Fjalland (Acta Pharma-col. Toxicol., 42 /1978), s. 73-76). •
Corticalvev fra Wistar-rotte av hannkjønn ble forsik-tig homogenisert for hånd under anvendelse av en glass-teflon-homogenisator i 10 volumdeler 0,32 M sucrose. Inkubasjon ble utført i en 40 mM Tris-HCl-buffer (pH 7,5 ved 30°C) inne-holdende 120 nM NaCl, 9,2 nM KC1, 4 mM MgS04, 2,3 mM CaCl2og 10 mM glukose, i 60 minutter ved 30°C. Ligandkonsentrasjon var 0,2 nM.
Verdier for hemming av GABA-opptak for noen forbindelser fremstilt ifølge oppfinnelsen er oppført nedenunder.
Oppnådde resultater - hemming av [ 3H]-GABA-opptak
Forbindelser med formel I er anvendbare fordi de har farmakologisk virkning på mennesker. Forbindelsene med formel I er særlig nyttige som hemmede for GABA-opptak.
For de ovenfor nevnte indikasjoner vil doseringen variere avhengig av den forbindelse med formel I som anevndes, av administråsjonsmåten og av den ønskede behandling. Gene-relt oppnåes imidlertid tilfredsstillende resultater med en dose fra ca. 0,5 mg til ca. 1000 mg, fortrinnsvis fra 1 mg til-ca. 500 mg, av forbindelser med formel I, passende gitt fra 1 til 5 ganger daglig, eventuelt i en form med langvarig frigjørelse. Vanligvis omfatter doseringsformene som er egnet for oral administrering, fra ca. 0,5 mg til ca. 1000 mg, fortrinnsvis fra ca. 1 mg til ca. 500 mg, av forbindelsene med formel I blandet med en farmasøytisk bærer eller fortynner. Ingen toksiske virkninger er blitt observert.
Forbindelsene med formel I kan administreres i form av farmasøytisk akseptabel syreaddisjonssalt, eller når det er mulig, som et metall- eller laverealkylammoniumsalt. Slike saltformer gir omtrent den samme størrelsesorden på aktivi-teten som formene med fri base.
De fremstilte forbindelser kan anvendes i form av farmasøytiske preparater som omfatter en forbindelse med formel I eller et farmasøytisk akseptabelt salt derav, og vanligvis inneholder slike preparater også en farmasøytisk bærer eller fortynner. Preparatene kan fremstilles ved hjelp av vanlige teknikker eller foreligger i vanlige former, f.eks. kapsler eller tabletter.
Den farmasøytiske bærer som anvendes, kan være en van-lig fast eller flytende bærer. Eksempler på faste bærere er laktose, terra alba, sucrosé, talkum, gelatin, agar, pectin, akasie, magnesiumstearat og stearinsyre. Eksempler på flytende bærere er sirup, peanøttolje, olivenolje og vann.
Likeledes kan bæreren eller fortynningsmidlet omfatte hvilket som helst tidsforsinkende materiale som er kjent innen teknikken, slik som glycerylmonostearat eller glyceryl-distearat, alene eller blandet med en voks.
Dersom det anvendes en fast bærer for oral administrering, kan preparatet tabletteres, plasseres i en hard gelatinkapsel i pulver- eller pelletform, eller i form av en rund, flat pastill. Mengden av fast bærer vil variere over et bredt område, men vil vanligvis være fra ca. 25 mg til ca. lg. Dersom det brukes en flytende "Toærer, kan preparater foreligge i form av en sirup, emulsjon, bløt gelatinkapsel eller steril injiserbar væske, slik som en vandig eller ikke-vandig flytende suspensjon.
De farmasøytiske preparater kan lages ved å følge de vanlige teknikkene innen den farmasøytiske industri, deri-blant blanding, granulering og pressing, eller avvekslende blanding og oppløsning av bestanddelene ettersom hva som er passende for å gi det ønskede sluttprodukt.
Administreringsveien kan være hvilken som helst vei som effektivt transporterer den aktive forbindelse til det rette eller ønskede sted, slik som oral eller parenteral, idet den orale vei er foretrukket.
Trekkene som er beskrevet ovenfor og i eksemplene og
i kravene nedenunder, kan både hver for seg og i hvilken som helst kombinasjon være av avgjørende betydning for reali-sering av oppfinnelsen i forskjellige former.
Fremgangsmåten for fremstilling av forbindelser med formel I og preparater som inneholder disse er ytterligere illustrert i eksemplene nedenunder. Eksemplene illustrerer noen foretrukne utførelsesformer.
Nedenunder står tic for tynnsjiktkromatografi, THF er tetrahydrofuran, DMF er N,N-dimethylformamid, og sm.p. er smeltepunkt. Strukturen til forbindelsene er bekreftet ved hjelp av NMR og elementæranalyse. Når smeltepunkter er angitt, er disse ukorrigerte. Forbindelser som anvendes som ut-gangsmaterialer er enten kjente forbindelser eller forbindelser som lett kan fremstilles ved hjelp av fremgangsmåter som er kjent per se. Kolonnekromatografi ble utført under anvendelse av teknikken beskrevet av W. C. Still et al., J. Org. Chem., 43 (1978), s. 2923-2925 på "Kieselgel 60" (Art. 9385) silikagel.
Eksempel 1 ( Fremgangsmåte A): (R) -Difenylmethanon-O-[2- (3-carboxypiperidin- 1-yl) ethyl]oxim
100 g (0,64 mol) av (R)-enantiomeren av ethylnipeco-tat (A.M. Akkerman et al., Ree. Trav. Chim., 70 (1951), s. 899; G. Bettoni et al., Gazz. "Chim. Ital., 102 (1972), s. 189) ble blandet i 300 ml tørr aceton med 4,98 g (0,68 mol) 2-
bromethanol, 176,91 g (1,28 mol)' tørket, pulverisert kaliumcarbonat og 21,58 g (0,13 mol) kaliumjodid. Reaksjonsblandingen ble omrørt ved værelsetemperatur i 18 timer og ved til-bakestrømning i 24 timer. Filtrering og inndamping av filtratet ga en olje som ble renset ved destillasjon under vakuum (110 - 115°C, 0,1 mmHg), utbytte 72,17 g (56%). Tic,
rf 0,20 (Si02; diklormethan/methanol 19/1).
19,86 g (0,099 mol) av den ovenfor nevnte alkohol ble oppløst i 125 ml toluen. En oppløsning av 14,16 (0,119 mol) thionylklorid i 50 ml toluen ble tilsatt dråpevis og reaksjonsblandingen omrørt ved værelsetemperatur i 2 timer. Avkjøling i et isbad etterfulgt av filtrering ga (R)-N-(2-klorethyl)-nipecotinsyreesteren som et fast stoff. En prøve ble rekrystallisert fra 2-propanol, sm.p. 187,5-194,5°C.
Til 2,56 g (10 mmol) av det ovenfor nevnte esterhydro-klorid ble det tilsatt 5,53 g (40 mmol) tørket, pulverisert kaliumcarbonat, 200 ml aceton og 3,94 g (20 mmol) benzofenonoxim. Suspensjonen ble oppvarmet ved tilbakestrømning i 6 timer, avkjølt og filtrert. Oppløsningsmidlet ble fjernet fra filtratet under vakuum, hvorved man fikk en rest. 100 ml vann og 100 ml ethylacetat ble innført. Vannsjiktet ble fraskilt og ytterligere ekstrahert med 2 x 100 ml ethylacetat. De kombinerte organiske ekstrakter ble tørket (MgSO^) og inndampet, hvorved man fikk 6,2 g av en brun olje. Denne oljen ble renset med "flash"-kromatografi under eluering med cyclohexan/ ethylacetat (5/1), hvorved man fikk 2,66 g (70%) av (R)-difenylmethanon-O-[2-(ethoxycarbonylpiperidin-l-yl)ethyl]oximet som en gummi, tic,rf 0,067 (Si02/cyclohexan/ethylacetat 5/1).
2,66 g (6,99 mmol) av den ovenfor nevnte ester ble oppløst i 100 ml ethanol og 6,99 ml 10M natriumhydroxydopp-løsning ble innført. Etter 2 timer ved værelsetemperatur ble oppløsningen avkjølt i et isbad og OH ble regulert til 3 med 4 N saltsyre. Ekstraksjon med 3 x 50 ml diklormethan, tørking (MgSO^) av de kombinerte fraksjoner og inndamping ga 1,3 g (53%) av tittelforbindelsen som et hydrokloridhydrat, sm.p. 241 - 242°C.
Ved hjelp av den generélle fremgangsmåten ovenfor ble de følgende oximderivater fremstilt: Eksempel 2
(R) -£-Methylfenyl)-(3-methyl-2-thienyl)methanon-O-[2-(3-carboxypiperidin- l- yl) ethyl] oxim- hydroklorid
Tic, rf 0,30 (Si02, diklormethan/methanol 1/1).
Eksempel 3
(R)-Bis(3-methyl-2-thienyl)methanon-O-[2-(3-carboxypiperidin-1- y1) ethyl] oxim- hydroklorid
Sm.p. 45°C.
Eksempel 4
(R)-(2-Ethylfenyl)-(3-methyl-2-thienyl)methanon-O-[2-(3-carboxypiperidin- l- yl) ethyl] oxim- hydroklorid
Smp. 202 — 203°C (aceton)".
Eksempel 5
(R)-(3-Methyl-2-thienyl)-(2-thienyl)methanon-O-[2-(3-carboxypiperidin- l- yl) ethyl] oxim
Sm.p. 210 - 216°C.
Eksempel 6
(R)-(3-Methoxyfenyl)-(3-methyl-2-thienyl)methanon-0-[2-(3-carboxypiperidin- l- yl) ethyl ] oxim- hydroklor id
Tic, rf 0,3 (Si02, diklormethan/methanol 1/1).
Eksempel 7
(R) - (,2-Methylfenyl) - (l-methyl-2-pyrrolyl) methanon-O- [ 2- (3-carboxypiperidin- l- y1) ethyl] oxim
Tic, rf 0,29 (Si02, diklormethan/methanol 1/1).
Eksempel 8
(R)-(l-Ethyl-2-pyrrolyl)fenylmethanon-O-[2-(3-carboxypiperidin- l- yl) ethyl] oxim- hydroklorid
Sm.p. 221,5 - 225°C.
Eksempel 9
(R) - (3-Methoxyfenyl) -(4-methyib-2-thienyl) methanon-O-[ 2- (3-carboxypiperidin- l- y1) ethyl] oxim- hydroklorid
Tic, rf 0,31 (S<i>02, diklormethan/methanol 1/1).
Eksempel" 10
(R)-(2-Methylfenyl)-(3-methyl-2-thienyl)methanon-O-[2-(3-carboxypiperidin- l- yl) ethyl] oxim- hydroklorid
Tic, rf 0,32 (Si02, diklormethan/methanol 1/1).
Eksempel 11
(R)-(2-Methyl-l,2,4-triazol-3-yl)-(2-thienyl)methanon-O-[ 2-( 3- carboxypiperidin- l- yl) ethyl] oxim- hydroklorid
Tic, rf 0,90 (snudd'fase', Whatman KCl 8F, methanol/ vann 4/1).
Eksempel 12
(R)-(2-Methyl-l,2,4-triazol-3-yl)-(2-thienyl)methanon-O-[ 2-( 3- carboxypiperidin- l- yl) ethyl] oxim- hydroklorid
Tic, rf 0,90 (snudd fase, Whatman KCl 8F, methanol/ vann 4/1).
Eksempel 13
(R)-(3-Azidofenyl)-(3-methyl-2-thienyl)methanon-O-[2-(3-carboxypiperidin- l- yl) ethyl] oxim- hydroklorid
Tic, rf 0,20 (Si02, methanol).
Eksempel 14
(R)-(2-Methylfenyl)-(3-methy1-2-thienyl)methanon-O-[2-(3-ethoxycarbonylpiperidin- l- yl) ethyl] oxim
Tic, rf 0,35 (Si02, cyclohexan/ethylacetat 1/1).
Eksempel 15
(R)-(2-Azidofenyl)fenylmethanon-O-[2-(3-carboxypiperidin-l-yl) ethyl] oxim- hydroklorid
Tic, rf 0,14 (Si02, diklormethan/methanol 1/1).
Eksempel 16
( S)-Difenylmethanon-O-[2-(3-carboxypiperidin-l-yl)ethyl]-oxim- hydroklorid
Tic, rf 0,38 (Si02, diklormethan/methanol 1/1).
Eksempel 17
(R)-Bis(3-ethyl-2-thienyl)methanon-O-[2-(3-carboxypiperidin-1- yl) ethyl] oxim- hydroklorid
Tic, rf 0,30 (Si02, diklormethan/methanol 1/1).
Eksempel 18
(R)-(2,4-Diklorfenyl)-(3-methyl-2-thienyl)methanon-O-[2-(3-carboxypiperidin- l- yl) ethyl] oxim- hydroklorid
Tic, rf 0,52 (Si02,'diklormethan/methanol 1/1).
Eksempel 19
(R)-(3-Methoxyfenyl)fenylmethanon-O-C2-(3-carboxypiperidin-1- yl) ethyl] oxim- hydroklorid
Sm.p. 180 - 185°C.
Eksempel 20
(R)-(3-Methoxyfenyl)-(2-methoxyfenyl)methanon-O-[2-(3-carboxypiperidin- l- yl) ethyl] oxim- hydroklorid
Sm.p. 185 - 190°C.
Eksempel 21
(R)-Bis(4-klor-2-methylfenyl)methanon-O-[2-(3-carboxypiperidin- l- yl) ethyl] oxim- hydroklorid
Sm.p. 230 - 232°C.
Eksempel 22
(R)-(2-Methylfenyl)-(3-methyl-2-thienyl)methanon-O-[2-(3-ethoxycarbonylpiperidin- l- yl) ethyl] oxim- hydroklorid
Sm.p. 124 - 125,5°C.
Eksempel 23
(R)-(4-Klor-2-methylfenyl)-(3-methyl-2-thienyl)methanon-O-[ 2-( 3- carboxypiperidin- l- yl) ethyl] oxim- hydroklorid
Sm.p. 170 - 175°C.
Eksempel 24
(R)-Bis(2-methylfenyl)methanon-O-[2-(3-carboxypiperidin-l-yl)-ethyl] oxim- hydroklorid
Tic, rf 0,49 (Si02, diklormetahn/methanol 1/1).
Ved å bruke (R,.S) -N- (2-klorethyl) nipecotinsyre-ethyl-ester som utgangsmateriale ble de følgende (R, S) -enantio-
mere blandinger fremstilt (ifølge fremgangsmåte A, eksempel 1) »
Eksempel 25
Difenylmethanon-O-[2-(3-carboxypiperidin-l-yl)ethyl]oxim-hydroklorid
Sm.p. 234 - 235°C.
Eksempel 26
(2-Methylfenyl)-(3-methyl-2-thienyl)methanon-O-[2-(3-carboxypiperidin- l- yl) ethyl] oxim- hydroklorid
Tic, rf 0,30 (Si02, diklormethan/methanol 1/1).
Eksempel 27
(l-Methyl-2-imidazolyl)fenylmethanon-O-[2-(3-carboxypiperidin-1- y 1) ethyl ] oxim
Tic, rf 0,07 (Si02, methanol/diklormethan 1/1).
Eksempel 2 8
Fenyl-(2-pyridyl)methanon-O-[2-(3-carboxypiperidin-l-yl)ethyl]-oxim- hydroklorid
Sm.p. 61 - 63°C.
Eksempel 29
Fenyl-(2-pyrrolyl)methanon-O-[2-(3-carboxypiperidin-l-yl)-ethyl] oxim- hydroklorid
Sm.p. 172,5 - 176°C.
Eksempel 30
Bis(4-klorfenyl)methanon-O-[2-(3-carboxypiperidin-l-yl)ethyl]-oxim- hydroklorid
Tic, rf 0,25 (Si02, diklormethan/methanol 1/1).
Eksempel 31
(3-Azidofenyl)fenylmethanon-O-[2-(3-carboxypiperidin-l-yl)-ethyl ] oxim- hydroklor id
Tic, rf 0,30 (Si02 methanol).
Eksempel 32
(4-Fluorfenyl)fenylmethanon-O-[2-(3-carboxypiperidin-l-yl)-ethyl] oxim- hydroklorid
Tic, rf 0,35 (Si02, diklormethan/methanol 1/1).
Eksempel 33
(2-Klorfenyl)fenylmethanon-O-[2-(3-carboxypiperidin-l-yl)-ethyl] oxim- hydroklorid
Tic, rf. 0,35 (Si02; diklormethan/methanol 1/1).
Eksempel 34
(4-Klor-2-methylfenyl)-(2-methylfenyl)methanon-O-[2-(3-carboxypiperidin- l- y 1) ethyl] oxim- hydroklorid
Tic, rf 0,33 (Si02, diklormethan/methanol 1/1).
Eksempel 35
(3-Azidofenyl)fenylmethanon-0-[2-(3-carboxypiperidin-l-yl)-ethyl] oxim- hydroklorid
Tic, rf 0,30 (Si02, methanol).
Eksempel 36
(3-Nitrofenyl)fenylmethanon-O-[2-(3-carboxypiperidin-l-yl)-ethyl] oxim- hydroklorid
Tic, rf 0,30 (Si02, methanol).
Eksempel 37
Bis(2-hydroxyfenyl)-methanon-O-[2-(3-carboxypiperidin-l-yl)-ethyl] oxim- hydroklorid
Sm.p. 215 - 220°C (ikke rekrystallisert).
Eksempel 38
Bis(3-methoxyfenyl)-methanon-O-[2-(3-carboxypiperidin-l-yl-ethy1] oxim- hydroklorid
Tic, rf 0,31 (Si02, diklormethan/methanol 1/1).
Eksempel 40
(2,4-Diklorfenyl)-(3-methyl-2-thienyl)methanon-O-[2-(3-carboxypiperidin- l- yl) ethyl] oxim- hydroklorid
TlC, rf<0>,<30>(SiO„ 4.^/4-^ i
2, diklormethan/methanol 1/1).
Eksempel 41
(2-Methylfenyl)-(3-methylfenyl)methanon-O-[2-(3-carboxypiperidin- l- yl) ethyl] oxim- hydroklorid
Sm.p. 174 - 176°C.
Eksempel 42
(2-Methylfenyl)-(3-methyl-2-thienyl)methanon-O-[2-(3-carboxypiperidin- l- yl) ethyl] oxim- hydroklorid
Sm.p. 209 - 211°C.
Eksempel 43
(3-Hydroxyfenyl)fenylmethanon-0-[2-(3-carboxypiperidin-l-yl) ethyl] oxim- hydroklorid
Tic, rf 0,40 (Si02, methanol).
Eksempel 44
Bis(2-methylfenyl)methanon-O-[2-(3-carboxypiperidin-l-yl)-1- methylethy1] oxim- hemihydroklorid
Tic, rf 0,52 (snudd fase, Whatman KCl 8F, methanol/ vann 4/1).
Eksempel 45 ( Fremgangsmåte B) :
Difenylmethanon- 0-[2-(3-carboxy-l,2,5,6-tetrahydropyri-din- l- yl)- ethyl] oxim
3,94 g (20 mmol) benzofenonoxim, 28,7 g (200 mmol) l-brom-2-klorethan og 5,53 g (80 mmol) tørket, pulverisert kaliumcarbonat i 60 ml aceton ble varmet opp ved tilbake-strømning i 72 timer. Reaksjonsblandingen ble avkjølt og filtrert, og filtratet inndampet til en oljeaktig rest som ble renset ved "flash"-kromatografi (eluering med heptan/ ethylacetat 19/1), hvorved man fikk 3,82 g (73%) difenylmethanon-(0)-(2-klorethyl)oxim som en olje, tic, rf 0,36 (Si02, heptan/ethylacetat 9/1) .
1,309 g (5 mmol) av det ovenfor nevnte klorethyloxim ble oppløst i 25 ml aceton og 1,776 g (10 mmol) guvacin-methylesterhydroklorid, 2,073 g (15 mmol) pulverisert, tørket kaliumcarbonat og 0,75""g: (5 mmol) kaliumjodid ble innført. Reaksjonsblandingen ble varmet opp ved tilbake-
strømning i 18 timer og avkjølt". Filtrering og inndamping av filtratet ga en olje som ble renset ved "flash"-kroma-tografi på silikagel under eluering med cyclohexan/ethylacetat (2/1), hvorved man fikk 0,87 g (48%) difenylmethanon-O- [2-(3-methoxycarbonyl-l,2,5,6-tetrahydropyridin-l-yl)-ethyl]oxim som en gummi, tic, rf 0,30 (Si02, heptan/ethylacetat 1/1). Det ble også isolert 0,66 g (50%) av utgangs-difenylmethanon-O-(2-haloethyl)oximet.
0,81 g (2,39 mmol) av déhovenfor nevnte methylester ble oppløst i 25 ml ethanol og 2,39 ml 10 N natriumhydroxyd-oppløsning ble tilsatt. Oppløsningen ble omrørt ved værelsetemperatur i 4 timer og surgjort til pH 2 med 2 N saltsyre. Væsken ble ekstrahert med 3 x 50 ml diklormethan og de kombinerte organiske ekstrakter ble tørket (MgS04). Inndamping av oppløsningsmidlet ga en gummi som ble frysetørket, hvorved man fikk 0,825 g (89%) av tittelforbindelsen som et hemihydroklorid. Tic, rf 0,40 (Si02, diklormethan/methanol 1/1). Funnet: C: 65,6; H: 6,3; N: 7,05; Cl: 4,9.<C>21<H>22N2°3*1/HC1*H2° krever C: 65,2; H: 6,4; N: 7,2;
Cl: 4,6%.
Ved hjelp av den ovenfor angitte generelle fremgangsmåte (aksempel 45,Fremgangsmåte B) ble de følgende oximderivater fremstilt: Eksempel 46
Bis(3-methyl-2-thienyl)methanon-O-[2-(3-carboxy-l,2,5,6-tetrahydropyridin- l- y1) ethyl] oxim- hydroklorid
Sm.p. 79 - 80°C.
Eksempel 47
(S)-Bis(3-methyl-2-thienyl)methanon-O<1>[2-(3-carboxypiperidin- l- yl) ethyl] oxim- hydroklorid
Sm.p. 168 - 169°C.
Eksempel 48
(S)-(2-Methylfenyl)-(3-methyl-2-thienyl)methanon-O-[2-(3-carboxypiperidin- l- y1) ethyl] oxim- hydroklorid
Tic, rf 0,30 (Si02,diklormethan/methanol 1/1).
Eksempel 49
(3-Methyl-2-thienyl)-(2-thienyl)methanon-O-[ 2-(3-carboxy-1/ 2, 5, 6- tetrahydropyridin- l- yl) ethyl] oxim- hydroklorid
Tic, rf 0,8 (snudd fase, Whatman KLc 8F, methanol/ vann 4/1).
Eksempel 50
(2-Methylfenyl)fenylmethanon-O-[ -2-(3-carboxy-l,2,5,6-tetra-hydropyridin- l- y1) ethyl] oxim- hydroklorid
Tic, rf 0,49 (Si02, diklormethan/methanol 1/1).
Eksempel 51
(3-Fluorfenyl)-(2-methylfenyl)methanon-O-[ 2-(3-carboxy-1, 2, 5, 6- tetrahydropyridin- l- yl) ethyl] oxim- hydroklorid
Sm.p. 219 - 223°C.
Eksempel 52
(R)-Bis(4-fluor-2-methylfenyl)methanon-[2-(3-ethoxycarbonyl-piperidin- l- yl) ethyl ] oxim- hydroklorid
Sm.p. 102 - 103°C.
Eksempel 53
(R)-Bis(4-fluor-2-methylfenyl)methanon-O-[2-(3-carboxypiperidin- l- yl) ethyl] oxim- hydroklorid
Sm.p. 181 - 182°C.
Eksempel 54
(2-Methylfenyl)-(3-methyl-2-thienyl)methanon-O-[2-(3-ethoxy-carbonyl-1,2,5,6-tetrahydropyridin-l-yl)ethyl]oxim-hydroklorid
Sm.p. 116 - 117°C.
Eksempel 55
(2-Methylfenyl)-(3-methyl-2-thienyl)methanon-O-[2-(3-car-boxy- 1, 2, 5, 6- tetrahydropyridin- l- yl) ethyl] oxim- hydroklorid Sm.p. 204 - 207°C.
Eksempel 56
Bis(4-fluor-2-methylfenyl)methanon-O-[2-(3-ethoxycarbonyl-1, 2, 5, 6- tetrahydropyridin- l- yl) ethyl] oxim- hydroklorid
Sm.p. 157 - 159°C.
Eksempel 57
Bis(4-fluor-2-methylfenyl)methanon-O-[2-(3-carboxy-l,2,5,6-tetrahydropyridin- l- yl) ethyl] oxim- hydroklorid
Sm.p. 241 - 244°C.
Eksempel 58
(2,4-Diklorfenyl)-(3-methyl-2-thienyl)methanon-O-[2-(3-car-boxy- 1, 2, 5, 6- tetrahydropyridin- l- yl) ethyl] oxim- hydroklorid
Tic, rf 0,76 (snudd fase, Whatman JC1 8F, methanol/ vann 4/1).
Eksempel 59
(2-Klorfenyl)-(2-methylfenyl)methanon-O-[2-(3-carboxy-1, 2, 5, 6- tetrahydropyridin- l- yl) ethyl] oxim- hydroklorid
Sm.p. 152 - 155°C.
Eksempel 60
(2-Methylfenyl)-(3-trifluormethylfenyl)methanon-O-[2-(3-car-boxy- 1, 2, 5, 6- tetrahydropyridin- l- yl) ethyl] oxim- hydroklorid
Sm.p. 205 - 207°C.
Eksempel 61
(R)-(2-Methylfenyl)-(3-trifluormethylfenyl)methanon-O-[2-(3-carboxypiperidin- l- y) ethyl] oxim- hydroklorid
Sm.p. 156 - 158°C.
Eksempel 62
E/Z-2-(2-Methylfenyl)-2-(2-methyl-4-trifluormethylfenyl)-acetaldehyd-0-[2-(3-carboxy-l,2,5,6-tetrahydropyridin-l-yl)-ethyl] oxim- hydroklorid
Sm.p. 195 - 200°C.
Eksempel 63
(S)-(2-Methylfenyl)-(3-methyl-2-thienyl)methanon-O-[2-(3-ethoxycarbonylpiperidin- l- yl) ethyl] oxim- hydroklorid
Rlc, rf 0,35 (Si02, cyclohexan/ethylacetat 1/1).
Eksempel 64
Bis(2-methylfenyl)methanon-O-[2-(3-carboxy-l,2,5,6-tetra-hydropyridin- l- yl) ethyl] oxim- hydroklorid
Sm.p. 214 - 218,5°Cf.
Eksempel 65
(S)-Bis(2-methylfenyl)methanon-O-[2-(3-carboxypiperidin-l-yl) ethyl] oxim- hydroklorid
Rlc, rf 0,39 (Si02, diklormethan/methanol 1/1).
Eksempel 66
Difenylmethanon-O-[2-(3-aminocarbonylpiperidin-l-yl)ethyl]-oxim
Tic, rf 0,41 (Si02, diklormethan/methanol 9/1).
Eksempel 67
(4-Klor-2-methylfenyl)-(2-methylfenyl)methanon-O-[2-(3-carbo-xy- 1, 2, 5, 6- tetrahydropyridin- l- yl) ethyl] oxim- hydroklorid
Tic, rf 0,45 (Si02, diklormethan/methanol 1/1).
Eksempel 68
(2-Klorfenyl)fenylmethanon-O-[2-(3-carboxy-l,2,5,6-tetra-hydropyridin- l- y1) ethyl] oxim- hydroklorid
Sm.p. 198,5 - 200°C.
Eksempel 69
(2-Thienyl)fenylmethanon-O-[2-(3-carboxy-l,2,5,6-tetrahydro-pyridin- l- yl) ethyl] oxim- hydroklorid
Tic, rf 0,63 (Si02, diklormethan/methanol 1/1).
Eksempel 70
(3-Klorfenyl)-(2-methylfenyl)methanon-O-[2-(3-carboxy-l,2,5,6-tetrahydropyridin- l- yl) ethyl] oxim- hydroklorid
Sm.p. 223°C (dek.).
Eksempel 71
(3-Methoxyfenyl)fenylmethanon-O-[2-(3-carboxy-l,2,5,6-tetra-hydropyridin- l- yl) ethyl] oxim- hydroklorid
Sm.p. 140 - 145°C.
Eksempel 72
(3-Methoxyfenyl)-(2-methylfenyl)methanon-O-[2-(3-carboxy-1, 2, 5, 6- tetrahydropyridin- l- yl) ethyl] oxim- hydroklorid
Sm.p. 190 - 195°C.
Eksempel 73
(4-Fluor-2-methylfenyl)-(2-methylfenyl)methanon-O-[2-(3-car-boxy- 1, 2, 5, 6- tetrahydropyridin- l- yl) ethyl] oxim- hydroklorid
Sm.p. 205 - 213°C.
Eksempel 74
Difenylmethanon-O-[2-(3-ethoxycarbonyl-l,2,5,6-tetrahydro-pyridin- l- y1) ethyl] oxim- hydroklorid
Sm.p. 110 - 116°C (toluen/cyclohexan).
Eksempel 75
(2-Fluorfenyl)-(2-methylfenyl)methanon-O-[2-(3-carboxy-1, 2, 5, 6- tetrahydropyridin- l- yl) ethyl] oxim- hydroklorid
Sm.p. 195 - 196°C.
Eksempel 7 6
(2-Klorfenyl)fenylmethanon-O-[2-(3-ethoxycarbonyl-l,2,5,6-tetrahydropyridin- l- yl) ethyl] oxim- hydroklorid
Tic, rf 0,25 (Si02, cyclohexan/ethylacetat 1/1).
Eksempel 77
Bis(2-methylfenyl)methanon-O-[2-(3-ethoxycarbonyl-l,2,5,6-tetrahydropyridin- l- yl) ethyl] oxim- hydroklorid
Sm.p. 163 - 164,5°C (toluen/cyclohexan).
Eksempel 7 8
(4-Klor-2-methylfenyl)-(3-metEyl-2-thienyl)methanon-O-C2-(3-carboxy- 1, 2, 5, 6- tetrahydropyridin- l- yl) ethyl] oxim- hydroklorid Sm.p. 213 - 216°C.
Eksempel 79
(4-Fluor^-2-methylfenyl)-(3-methy1-2-thienyl)methanon-O-[2-(3-carboxy-l,2,5,6-tetrahydropyridin-l-yl)ethyl]oxim-hydroklorid
Sm.p. 165 - 169°C.
Eksempel 80
(3,4-Diklorfenyl)-(2-methylfenyl)methanon-O-[2-(3-carboxy-1, 2, 5, 6- tetrahydropyridin- l- yl) ethyl] oxim- hydroklorid
Sm.p. 258 - 260°C.
Eksempel 81
Bis(2-ethylfenyl)methanon-O-[2-(3-carboxy-l,2,5,6-tetrahydro-pyridin- l- y1) ethyl] oxim- hydroklorid
Sm.p. 130 - 135°C.
Eksempel 82 ( Fremgangsmåte A)
(R,S)-Difenylmethanon-O-[3-(3-carboxypiperidin-l-yl)-propyl]-oxim- hydroklorid
15,72 g (100 mmol) (R,S)-ethylnipecotat ble blandet
i 120 ml tørr aceton med 20,85 g (150 mmol) 3-brom-l-propanol og 20,73 g (150 mmol) tørket, pulverisert kaliumcarbonat. Reaksjonsblandingen ble varmet opp ved tilbakestrømning i
3 timer, avkjølt og filtrert. Filtratet ble inndampet til 32,8 g av en olje som ble oppløst i diklormethan. Til denne oppløsning ble det innført 30,45 g (112,5 mmol) fosfortri-bromid dråpevis mens tilbakestrømning ble opprettholdt under tilsetningen, og da tilsetningen var fullstendig, ble til-bakestrømning fortsatt i 2,5 timer. Etter avkjøling ble 30 ml tørr methanol tilsatt og blandingen ble helt over i en blanding av 250 ml mettet natriumbicarbonatoppløsning og 250 ml vann. Diklormethansjiktet ble fraskilt og vannsjiktet ble ekstrahert med 2 x 150 ml ethylacetat. De sammenslåtte organiske ekstrakter ble tørket over MgSO^og inndampet til en olje som ble renset ved hjelp av "flash"-kromatografi. Eluering med cyclohexan/tetrahydrofuran 3/1 ga 7,85 g (28%) N-(3-brompropyl)-nipecotinsyre-^éthylester som et voksaktig fast stoff. Funnet: C: 43,7; H: 7,9; N: 4,7. C^H^BrNO^
0,2 H20 krever C: 46,9; H: 7,2"; N: 4,9%.
Denne forbindelse ble brukt til å alkylere benzofenonoxim som redegjort for i eksempel 1, og den etterfølgende ester ble hydrolysert, hvorved man fikk 0,5 g (52% fra N-(3-brompropyl)-nipecotinsyre-ethylester) av tittelforbindelsen som et gummiaktig fast stoff, tic, rf 0,70 (snudd fase, Whatman KCl 8F, methanol/vann 8/2).
Ved å bruke (R)-N-(2-bromethyl)-nipecotinsyre-ethyl-ester-hydrobromid og et 2/2-diarylacetaldehydoxim som ut-gangsmaterialer ble følgende forbindelser fremstilt (ifølge fremgangsmåte A, eksémpel 1): Eksempel 83
E/Z-(R)-2,2-Difenylacetaldehyd-0-[2-(3-carboxypiperidin-1- y1) ethyl] oxim- hydroklorid
rf 0,34 (Si02, diklormethan/methanol 1/1).
Eksempel 84
E/Z-(R)-2-(2-Methylfenyl)-2-fenylacetaldehyd-O-[2-(3-carboxypiperidin- l- yl) ethyl] oxim- hydroklorid
rf 0,40 (Si02, diklormethan/methanol 1/1).
Eksempel 85
E/Z-(R)-2-(2-Methylfenyl)-2-(2-methyl-4-trifluormethylfenyl)-acetaldehyd-0-[2-(3-carboxypiperidin-l-yl)ethyl]oxim-hydroklorid
Sm.p. 190 - 200°C.
Fremstilling av kapsler
De ovenfor angitte bestanddeler ble grundig blandet
og plassert i harde gelatinkapsler. Slike kapsler administreres oralt 1-5 daglig i individer som trenger behandling.
Fremstilling av tabletter
Oximet blandes grundig med to tredjedeler av maisstiv-elsen og det granuleres. De oppnådde granuler tørkes, blandes med de gjenværende bestanddeler og presses til tabletter.
De således fremstilte kapsler eller tabletter administreres oralt. På samme måte kan det anvendes andre oximer med formel I.
Claims (1)
- Analogifremgangsmåte for fremstilling av terapeutisk aktive, O-substituerte oximer med den generelle formel Ihvor R<1>og R<2>, uavhengig av hverandre, er en aromatisk rest valgt fra gruppen bestående av imidazolyl, fenyl, pyridinyl, pyrrolyl, thienyl og 1,2,4-triazolyl, idet hver ring eventuelt er substituert med én, to ellex tre substituenter valgt fra gruppen bestående av laverealkoxy, azido, halogen, hydroxy, laverealkyl, nitro og trifluormethyl; R<3>er hydrogen eller laverealkyl; n og m er hele tall fra 0 til 2; R<4>er en cyklisk aminosyrerest med den generelle formel II hvor R<5>er hydrogen; R<6>er hydrogen, eller R<5>er sammen medR<6>en ytterligere binding; og X er NH2eller R<9>, hvor R<9>er hydroxy eller alkoxy, samt farmasøytisk akseptable syreaddisjonssalter derav, og nar R<9>er hydroxy, farmasøytisk akseptable metallsalter og eventuelt substituerte ammoniumsalter derav,karakterisert vedat a) et oxim med formel Vhvor A er som definert ovenfor, omsettes med en forbindelse med formel VIhvorR<3>,R<4>, n og m er som definert ovenfor, og Y er en uttredende gruppe, eller b) et oxim med formel Vhvor A er som definert ovenfor, alkyleres med en forbindelse med formel VIIhvor Y er en uttredende gruppe, Z er en mindre labil gruppe og R3, n og m er som definert ovenfor, hvoretter det erholdte mellomprodukt med formel VIIIhvor A, R<3>, n og m og Z er som definert ovenfor, omsettes med R<4>H, hvor R4 er en aminosyre eller et aminosyrederivat:, hvoretter den erholdte forbindelse, om ønsket, omdannes til et farma-søytisk akseptabelt syreaddisjonssalt derav eller eventuelt et farmasøytisk akseptabelt metallsalt eller eventuelt substituert ammoniumsalt derav.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DK270488A DK270488D0 (da) | 1988-05-18 | 1988-05-18 | Hidtil ukendte o-substituerede ketoximer |
Publications (4)
Publication Number | Publication Date |
---|---|
NO891970D0 NO891970D0 (no) | 1989-05-16 |
NO891970L NO891970L (no) | 1989-11-20 |
NO177262B true NO177262B (no) | 1995-05-08 |
NO177262C NO177262C (no) | 1995-08-16 |
Family
ID=8114842
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO891970A NO177262C (no) | 1988-05-18 | 1989-05-16 | Analogifremgangsmåte for fremstilling av terapeutisk aktive, O-substituerte oximer |
Country Status (18)
Country | Link |
---|---|
US (1) | US5039685A (no) |
EP (1) | EP0342635B1 (no) |
JP (1) | JP2824661B2 (no) |
KR (1) | KR900018058A (no) |
AT (1) | ATE110064T1 (no) |
AU (1) | AU622178B2 (no) |
CA (1) | CA1337123C (no) |
DE (1) | DE68917517T2 (no) |
DK (1) | DK270488D0 (no) |
ES (1) | ES2058383T3 (no) |
FI (1) | FI93955C (no) |
IE (1) | IE66016B1 (no) |
IL (1) | IL90313A0 (no) |
NO (1) | NO177262C (no) |
NZ (1) | NZ229136A (no) |
PH (1) | PH26373A (no) |
PT (1) | PT90607B (no) |
ZA (1) | ZA893733B (no) |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK704488D0 (da) * | 1988-12-19 | 1988-12-19 | Novo Industri As | Nye n-substituerede azaheterocykliske carboxylsyrer |
JP2765876B2 (ja) * | 1988-10-24 | 1998-06-18 | 科研製薬株式会社 | ピリジルケトオキシムエーテル誘導体 |
DK93791D0 (da) * | 1991-05-17 | 1991-05-17 | Novo Nordisk As | Nye heterocykliske carboxylsyrer |
EP0767174A1 (de) * | 1991-11-21 | 1997-04-09 | Ciba-Geigy Ag | Neue Aminoalkanphosphinsäuren und ihre Salze |
TW266206B (no) * | 1993-04-28 | 1995-12-21 | Takeda Pharm Industry Co Ltd | |
DK74393D0 (da) * | 1993-06-23 | 1993-06-23 | Novo Nordisk As | Novel heterocyclic chemistry |
DK74493D0 (da) * | 1993-06-23 | 1993-06-23 | Novo Nordisk As | Novel heterocyclic chemistry |
US5962449A (en) | 1995-04-07 | 1999-10-05 | Novo Nordisk A/S | Tricyclic compounds in treating hyperalgesic conditions and NIDDM |
EP0802187B1 (en) * | 1996-04-15 | 2000-02-16 | Takeda Chemical Industries, Ltd. | Hydroxypyridine derivatives, their production and their pharmaceutical use |
AU3104097A (en) * | 1996-06-27 | 1998-01-14 | Ciaran Regan | Use of nipecotic acid or guvacine derivatives for the manufacture of a medicament for the treatment of postischemic neurodegenerative disorders |
WO2000041728A1 (fr) * | 1999-01-12 | 2000-07-20 | Takeda Chemical Industries, Ltd. | Compositions pour le traitement de la miction frequente et de l'incontinence d'urine |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4235931A (en) * | 1967-04-05 | 1980-11-25 | Duphar International Research B.V. | Compounds having pharmacological properties |
FR2162312B1 (no) * | 1971-12-10 | 1975-02-07 | Buzas Andre | |
FR2248033B1 (no) | 1973-10-19 | 1977-03-11 | Cerpha | |
US4207319A (en) * | 1973-10-19 | 1980-06-10 | Albert Rolland S.A. | Thienyl or furyl phenyl O-hetero amino alkyl oximes and use thereof |
US4148911A (en) * | 1977-07-08 | 1979-04-10 | Societe Anonyme Dite Albert Rolland S.A. | Method of treating respiratory disorders |
DE2851387A1 (de) * | 1977-11-28 | 1979-06-07 | Degussa | Aminoaethyloxime mit mindestens einem thienylrest und verfahren zu deren herstellung |
AU532700B2 (en) * | 1979-04-02 | 1983-10-13 | Sumitomo Chemical Company, Limited | Diphenylalkanoether |
JPS5626863A (en) * | 1979-08-13 | 1981-03-16 | Sumitomo Chem Co Ltd | Novel diphenylalkanone oxime derivative |
US4722930A (en) * | 1980-03-01 | 1988-02-02 | John Wyeth And Brother Limited | 3-benzoyl-1-[(oxo or thioheteroaryl-ylalkyl)-piperid-4-yl]ureas and derivatives |
US4514414A (en) * | 1982-10-25 | 1985-04-30 | Smithkline Beckman Corporation | N-Substituted pyrrolidineacetic acids and their esters |
FI864246A (fi) * | 1985-11-08 | 1987-05-09 | Warner Lambert Co | N-substituerade 3-piperidin- eller 3-pyridinkarboxylsyror samt deras derivat. |
IL81179A (en) * | 1986-01-07 | 1992-02-16 | Novo Nordisk As | N-phenylbutenyl substituted azaheterocyclic carboxylic acids,their preparation and pharmaceutical compositions comprising them |
-
1988
- 1988-05-18 DK DK270488A patent/DK270488D0/da not_active Application Discontinuation
-
1989
- 1989-05-05 PH PH38628A patent/PH26373A/en unknown
- 1989-05-10 US US07/350,151 patent/US5039685A/en not_active Expired - Fee Related
- 1989-05-11 IE IE153389A patent/IE66016B1/en not_active IP Right Cessation
- 1989-05-16 IL IL90313A patent/IL90313A0/xx not_active IP Right Cessation
- 1989-05-16 NZ NZ229136A patent/NZ229136A/en unknown
- 1989-05-16 AU AU34845/89A patent/AU622178B2/en not_active Ceased
- 1989-05-16 NO NO891970A patent/NO177262C/no not_active IP Right Cessation
- 1989-05-17 CA CA000599974A patent/CA1337123C/en not_active Expired - Fee Related
- 1989-05-17 AT AT89108850T patent/ATE110064T1/de not_active IP Right Cessation
- 1989-05-17 DE DE68917517T patent/DE68917517T2/de not_active Expired - Fee Related
- 1989-05-17 EP EP89108850A patent/EP0342635B1/en not_active Expired - Lifetime
- 1989-05-17 ES ES89108850T patent/ES2058383T3/es not_active Expired - Lifetime
- 1989-05-18 KR KR1019890006609A patent/KR900018058A/ko not_active Application Discontinuation
- 1989-05-18 PT PT90607A patent/PT90607B/pt not_active IP Right Cessation
- 1989-05-18 FI FI892388A patent/FI93955C/fi not_active IP Right Cessation
- 1989-05-18 ZA ZA893733A patent/ZA893733B/xx unknown
- 1989-05-18 JP JP1123007A patent/JP2824661B2/ja not_active Expired - Lifetime
Also Published As
Publication number | Publication date |
---|---|
NO891970D0 (no) | 1989-05-16 |
ATE110064T1 (de) | 1994-09-15 |
DK270488D0 (da) | 1988-05-18 |
IE66016B1 (en) | 1995-11-29 |
FI892388A (fi) | 1989-11-19 |
EP0342635A1 (en) | 1989-11-23 |
PH26373A (en) | 1992-06-01 |
IE891533L (en) | 1989-11-18 |
FI892388A0 (fi) | 1989-05-18 |
EP0342635B1 (en) | 1994-08-17 |
AU622178B2 (en) | 1992-04-02 |
FI93955C (fi) | 1995-06-26 |
ZA893733B (en) | 1990-02-28 |
NO891970L (no) | 1989-11-20 |
NO177262C (no) | 1995-08-16 |
DE68917517T2 (de) | 1994-12-15 |
CA1337123C (en) | 1995-09-26 |
FI93955B (fi) | 1995-03-15 |
PT90607A (pt) | 1989-11-30 |
DE68917517D1 (de) | 1994-09-22 |
JPH0217158A (ja) | 1990-01-22 |
IL90313A0 (en) | 1989-12-15 |
US5039685A (en) | 1991-08-13 |
AU3484589A (en) | 1989-11-23 |
ES2058383T3 (es) | 1994-11-01 |
PT90607B (pt) | 1995-03-01 |
KR900018058A (ko) | 1990-12-20 |
NZ229136A (en) | 1992-01-29 |
JP2824661B2 (ja) | 1998-11-11 |
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