NO793473L - Fremgangsmaate til fremstilling av terapeutisk virksomme fenylalkylaminer - Google Patents

Fremgangsmaate til fremstilling av terapeutisk virksomme fenylalkylaminer

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Publication number
NO793473L
NO793473L NO793473A NO793473A NO793473L NO 793473 L NO793473 L NO 793473L NO 793473 A NO793473 A NO 793473A NO 793473 A NO793473 A NO 793473A NO 793473 L NO793473 L NO 793473L
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Norway
Prior art keywords
acid
compounds
formula
acid addition
procedure
Prior art date
Application number
NO793473A
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English (en)
Inventor
Bernard Leon Zenitz
Original Assignee
Sterling Drug Inc
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Publication date
Priority claimed from US05/641,511 external-priority patent/US4069256A/en
Publication of NO793473L publication Critical patent/NO793473L/no
Application filed by Sterling Drug Inc filed Critical Sterling Drug Inc

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—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
    • C07D213/06—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 containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/16—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 containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—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
    • C07D207/04—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 no double bonds between ring members or between ring members and non-ring members
    • C07D207/06—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 no double bonds between ring members or between ring members and non-ring members with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—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
    • C07D207/18—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 one double bond between ring members or between a ring member and a non-ring member
    • C07D207/20—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 one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • 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
    • C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/12—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with only hydrogen atoms attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • 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
    • C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • 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
    • C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/16—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D295/04—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
    • C07D295/08—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 substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—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 substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D295/04—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
    • C07D295/10—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 substituted by doubly bound oxygen or sulphur atoms
    • C07D295/112—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 substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D295/04—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
    • C07D295/12—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 substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—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 substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings 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
    • C07D309/10—Oxygen atoms
    • C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Description

Foreliggende oppfinnelse angår en fremgangsmåte til fremstilling av fenyl-lavere-alkylaminer som kan brukes som anti-inflammatoriske midler.
Mange typer organiske forbindelser kan brukes som anti-inflammatoriske midler, men mange slike midler er sure,
dette gjelder f.eks. a-(3-benzoylfenyl)propionsyre, vanligvis kjent som ketoprofen (britisk patent nr. 1.164.585). Slike sure midler er ofte irriterende, og de kan i visse tilfeller fremkalle mavesår når de tilføres oralt. Det er således et stort behov for anti-inflammatoriske midler som ikke er irriterende på mavens slimhinner, f.eks. forbindelser med en basisk aminfunksjon. Skjønt det i den kjemiske litteratur er beskrevet en rekke amin-substituerte forbindelser med anti-inflammatorisk aktivitet [se f.eks. US-patentene 3.770.748 og 3.803.127, (N-fenylpolymetyleniminer), US-patentene 3.772.311 og 3.773.772, (polymetylenimino-lavere-alkanoylpyrazoler), US-patent 3.773.944, (1-[3-aminopropyl]ftalaner), US-patent 3.801.594, (3-amino-lavere-alkylindoler), US-patent 3.810.985, (4-anilino-l,3,5-triaziner) og fransk patent 1.549.342, (4-[benzoylfenylmetyl]-morfoliner)], så er det ingen slike basiske forbindelser kommersielt tilgjengelige, og ingen er kjent for å være under-
søkt av farmakologer for mulig kommersiell utvikling. Man har derfor stadig vært på jakt etter et effektivt ikke-surt, anti-inf lammatorisk middel som kan utvikles kommersielt.
Foreliggende oppfinnelse angår forbindelser méd formel:
hvor gruppen representerer representerer lavere-alkyl eller hvor gruppen
representerer hydrogen.
Med begrepene lavere alkyl forstås mettede, enverdige, allfatiske radikaler, slik som forgrenede radikaler med fra 1-4 karbonatomer, f.eks. metyl, etyl, propyl, isopropyl, butyl, sek-butyl og isobutyl.
Forbindelser med formel Ia hvor/C=X representerer
fremstilles ved å omsette ét 3-(fenyl-CO)-fenyl-CHR_-halogenid med formel XIII med morfolin, ifølge reaksjonsskjemaet: hvor R~har samme betydning som angitt ovenfor og Hal er halogen. Reaksjonen utføres ved å omsette en oppløsning av halogenider med et molart overskudd av morfolin ved romtemperatur i et.inert organisk oppløsningsmiddel, f.eks. metanol, etanol, isopropanol eller DMF, hvorav det sistnevnte oppløsningsmiddel er det fore-trukne. Forbindelser med formel Ia hvor gruppen representerer fremstilles fra de tilsvarende forbindelser hvor
representerer C=0 ved å omdanne sistnevnte til oksimet
(ved oppvarming av sistnevnte med hydroksylamin i et inert organisk oppløsningsmiddel, f.eks. en lavere alkanol) og redusere oksimet til aminet med natrium i en lavere alkanol.
De nye forbindelser fremstilt ifølge foreliggende oppfinnelse er forbindelsene med formel Ia, samt deres syreaddisjonssalter. Forbindelser med formel Ia i fri baseform kan om-
dannés til syreaddisjonssaltformen ved å reagere basen med en
j syre. På lignende måte kan den frie base regenereres fra syre-addis jonssaltet på vanlig måte, dvs. at man behandler saltene med en kald, svak vandig base, f.eks. alkalimetallkarbonater og alkalimetallbikarbonater. De således regenererte baser kan igjen omsettes med samme eller forskjellig syre hvoretter man får et annet syreaddisjonssalt. Alle de nye baser og alle deres syreaddisjonssalter er således lett omdannbare til hverandre.
Formel Ia omfatter således ikke bare selve basene med nevnte formel, men også representerer alle forbindelser med nevnte formel enten det er i form av en fri base eller i form
av et syreaddisjonssalt. Man har funnet at både basene og deres syreaddisjonssalter har de farmakologiske aktiviteter som er mer detaljert beskrevet nedenfor. Denne aktivitet kan utnyttes for farmasøytiske formål enten ved at man anvender de frie baser som sådan eller'deres syreaddisjonssalter, dvs. ved hjelp av syrer hvis anioner er uskadelige for dyreorganismer i effektive doser slik at man oppnår deønskede effekter uten at nevnte anioner frembringer bivirkninger.
Når man ønsker å utnytte de farmakologiske aktiviteter til de fremstilte forbindelser, er det foretrukket å bruke farmasøytisk akseptable salter. Skjønt vann-uoppløselighet, høy toksisitet og mangel av krystallinsk karakter kan gjøre noen spesielle salttyper uegnede eller mindre ønskelige for bruk i et gitt farmasøytisk tilfelle, så kan vann-uoppløselig eller toksiske salter omdannes til de tilsvarende farmasøytisk akseptable baser ved å dekomponere saltet med en vandig base slik det er forklart ovenfor, eller alternativt kan det omdannes til farmasøytisk akseptable syreaddisjonssalter ved en dobbelt de-komponeringsreaksjon som innbefatter anionet, f.eks. ved ioneut-bytting.
Foruten at de kan brukes for farmasøytiske formål, kan saltene brukes for å karakterisere eller identifisere derivater av de frie baser eller for å isolere eller å lense slike baser. Som alle andre syreaddisjonssalter kan slike rensningssalt-derivater hvis det er ønskelig, brukes for å regenererte de farmasøytisk akseptable frie baser ved at nevnte salter rea-geres med vandig base eller alternativt kan basen omdannes til farmasøytisk akseptable syreaddisjonssalter ved ioneutbytnings-
metoder.
Det fremgår av det foregående at alle syreaddisjonssalter av de nye baser er brukbare og verdifulle forbindelser uansett hvorvidt de er oppløselige, toksiske, eller har en uegnet fysisk form for de rent farmasøytiske formål, og alle forbindelser inngår således i oppfinnelsen.
Egenskapene til de fremstilte forbindelser ligger i basene eller de kationiske former av de nye N-{3-[R^-(fenyl)-C(=X)]-fenyl^lavere-alkyl}morfoliner og ikke i en spesiell syre-gruppe eller syreanion som er forbundet med saltformene av disse forbindelser, og disse syregrupper og anioner er i seg selv hverken nye eller kritiske og kan følgelig innbefatte ethvert syreanion eller syrelignende stoff som. er i stand til å danne salter med basene. I vandige oppløsninger vil således baseformen eller et vannoppløselig syreaddisjonssalt av forbindelser med formel I både ha en vandig protonert kation eller ammoniumion.
Passende syreaddisjonssalter er således de som er fremstilt av forskjellige syrer, slik som maursyre, eddiksyre, isosmørsyre, alfa-merkaptopropionsyre, eplesyre, fumarsyre, rav-syre, succinaminsyre, vinsyre, sitronsyre, melkesyre, benzoe-syre, 4-metoksybenzosyre, ftalsyre, antranilinsyre, 1-naftalen-karboksylsyre, kanelsyre, cykloheksankarboksylsyre, mandelsyre, tropinsyre, krontonsyre, acetylendikarboksylsyre, sorbinsyre, 2-furankarboksylsyre, kolinsyre, pyrenkarboksylsyre, 2-pyridin-karboksylsyre, 3-indoleddiksyre, kininsyre, sulfaminsyre, metansulfonsyre, isetioninsyre, benzensulfonsyre, p-toluensulfon-syre, benzensulfinsyre, butylarsonsyre, dietylfosfonsyre, p-amino-fenylarsinsyre, fenylstibninsyre, fenylfosforsyre, metylfosfinsyre, fenylfosfinsyre, flussyre, saltsyre, hydrobromsyre, hydrojodsyre, perklorsyre, salpetersyre, svovelsyre, fosforsyre, blåsyre, fosforvolframsyre, molybdensyre, fosformolybdensyre, pyrofosfor-syre, arsensyre, pikrinsyr.e, pikroloninsyre, barbitursyre, bortri-fluorid og lignende.
Syreaddisjonssaltene kan fremstilles ved å omsette den frie base og syren i et organisk oppløsningsmiddel hvoretter man isolerer saltet direkte eller ved å konsentrere oppløsningen.
På grunn av tilstedeværelsen av et asymmetrisk senter, forbindelser med formel Ia, dvs. det karbonatom som er til-støtende til fenylringen til hvilket R^-gruppen er knyttet eller karbonatomer i ^CHN^-gruppen, så vil forbindelser med formel Ia eksistere i stereokjemiske isomere former som alle inngår i foreliggende oppfinnelse. Hvis det er ønskelig, kan man-isolere eller fremstille en spesiell stereokjemisk form, noe som kan gjøres ved at man bruker i seg selv kjente fremgangsmåter.
I standard farmakologiske prøver har man funnet at forbindelser med formel Ia har meget verdifull anti-inflammatorisk aktivitet og kan følgelig brukes som anti-inflammatoriske midler. Den anti-inflammatoriske aktivitet ble bestemt ved å bruke
(1) hemmingen av karrageenin-indusert fotødemprøve som i alt
vesentlig er beskrevet av Van Arman et al., J. Pharmacol, Exptl. Therap. 150, 328 (1965) modifisert av Winter et al., Proe. Soc. Exp. Biol. og Med. 111, 544 (1962) og (2) en modifikasjon av hemmingen av hjelpemiddel-indusert arthritisprøven som er beskrevet av Pierson, J. Chronic Diseases 16, 863 (1963) og Glenn et al., Am. J. Vet. Res. 26, 1180 (1965),
Forbindelser med formel. Ia kan fremstilles slik at de kan opparbeides i enhetsdoseformer for tabletter eller kapsler for oral tilførsel, enten alene eller i kombinasjon med egnet fortynningsmidler, slik som kalsiumkarbonat, stivelse, laktose, talkum, magnesiumstearat, gummi acacia og lignende. Videre kan forbindelsen opparbeides for oral tilførsel i vandig alkohol, glykol eller oljeoppløsninger eller i olje-vannemulsjoner på samme måte som man gjør i vanlig farmasøytisk industri.
Foreliggende forbindelsers molekylstruktur ble bestemt på basis av studier over spektra i infrarødt, ultrafiolett, samt kjernemagnetiske spektra, og bekreftet ved at det var en overens-stemmelse mellom beregnet og funnet verdi for de forskjellige elementer i forbindelsene.
Følgende eksempler illustrerer oppfinnelsen. Alle smeltepunkter er ukorrigerte.
Eksempel 1
En blanding av 28,62 g (0,09 mol) 4-(3-benzoylfenyl)metyl-morfolinhydroklorid og 9,6 3 g (0,14 mol) hydroksylaminhydroklorid i 35 ml 95% etanol og 27 ml vann, ble behandlet under omrøring med 21,68 g (0,54 mol) pulverformig natriumhydroksyd og blandingen ble tilbakeløpskokt i 1/2 time. Blandingen ble deretter avkjølt,
fortynnet med vann og ekstrahert flere ganger med benzen. Benzenekstraktene ga ved fordampning til tørrhet, et fast
materiale som ble omkrystallisert fra benzen/heksan til 13,9 g 4-(3-benzoylfenyl)metylmorfolinoksim (smp. 145-167°C).
Eksempel 2
En oppløsning av 8,12 g (0,027 mol) 4-(3-benzoylfenyl)-metyl-morfolinoksim i absolutt etanol, ble brakt til tilbakeløps-koking og behandlet med 6,45 g (0,28 mol) natriummetall tilsatt i små biter. Tilbakeløpskoking ble fortsatt inntil alt natrium var oppløst og oppløsningen ble deretter avkjølt, fortynnet med vann, surgjort med fortynnet saltsyre, inndampet til et volum på ca. 100 ml i vakuum og deretter ekstrahert med dietyleter. De organiske ekstrakter ble inndampet til tørrhet, en metanol-oppløsning av resten ble behandlet med eterholdig hydrogenklorid og oppløsningen inndampet til tørrhet, hvilket ga 8,3 g 4-{[3-(a-aminobenzyl)fenyl]metyl}morfolindihydrokloridmonohydrat, smp. 270-274°C.
Eksempel 3
En oppløsning av 11,0 g (0,126 mol) morfolin i 24 ml dimetylformamid ble omrørt ved hjelp av ytre avkjøling i et vann-bad og behandlet iløpet av 10 minutter med en oppløsning av 17,35 g (0,06 mol) 1-(3-bénzoylfenyl)-1-brometan i 24 ml dimetylformamid. Etter at tilsetningen var fullstendig, ble blandingen omrørt i ytterligere 1 time ved romtemperatur. Den ble deretter filtrert, filteret vasket med eter og filtratet helt over i 125 ml vann og blandingen ekstrahert to ganger med eter. Isolering av produktet i form av en fri base fra eterekstraktene på vanlig måte gå 14,8 g av et oljeaktig produkt som ble kromato-grafert på aluminiumoksyd idet man som elueringsmiddel brukte en 1:1 eter/heksanoppløsning, og dette ga 12 g av 4-[l-(3-benzoylfenyl)etyl]morfolin som en blekt gul olje.
Analyse:
Beregnet for C19<H>21N02: C 77,26; H 7,17; N 4,74
Funnet: C 76,95; H 7,11; N 4,61.
Biologiske prøveresultater
Nevnte N-{3-[F^-(fenyl)-C(=X)]-fenyl-lavere-alkyl}-morfoliner med formel Ia er blitt prøvet i de kjente karragenin-ødem (CE) og hjelpemiddel arthritis (AA) prøver, og man fant at de hadde anti-inflammatorisk aktivitet. De oppnådde resul-tater angitt som prosenthemming.ved en dose uttrykt i millimol (yM)/kg kroppsvekt, er angitt i tabell A nedenfor. For sammen- lignende formål har man også oppgitt data som ble oppnådd i en karrageeninødemprøve med en referanseforbindelse (angitt "Ref."), dvs. 4-[(3-benzoylfenyl)metyl]morfolin, beskrevet i fransk patent 1.549.342. Alle data ble oppnådd ved oral tilførsel.

Claims (1)

  1. Fremgangsmåte for fremstilling av terapeutisk virksomme forbindelser med formelen:
    hvor gruppen
    representerer
    og R, representerer lavere alkyl, eller hvor gruppen
    representerer
    og R3representerer hydrogen, samt farmasøytisk akseptable syreaddisjonssalter derav,karakterisert vedat man: a) fremstiller en forbindelse
    representerer
    og R, representerer lavere alkyl, ved å omsette en forbindelse med formelen: med morfolin, eller b) fremstiller en forbindelse
    representerer
    og R-. er hydrogen, ved å redusere med natrium i en lavere alkanol en forbindelse med formel Ia hvor X er og R-. er hydrogen, og, om ønsket, omdanner et således fremstilt syreaddisjonssalt til et annet syreaddisjonssalt.
NO793473A 1975-01-20 1979-10-29 Fremgangsmaate til fremstilling av terapeutisk virksomme fenylalkylaminer NO793473L (no)

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US54255375A 1975-01-20 1975-01-20
US05/641,511 US4069256A (en) 1975-01-20 1975-12-17 Anti-inflammatory phenyl-lower-alkylamines

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NO760169A NO142907C (no) 1975-01-20 1976-01-19 Analogifremgangsmaate til fremstilling av terapeutisk virksomme fenylalkylaminer
NO793447A NO143902C (no) 1975-01-20 1979-10-26 Fenyl-lavere alkanoylaminer for bruk til fremstilling av terapeutisk virksomme fenyl-lavere-alkylaminer
NO793473A NO793473L (no) 1975-01-20 1979-10-29 Fremgangsmaate til fremstilling av terapeutisk virksomme fenylalkylaminer

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NO793447A NO143902C (no) 1975-01-20 1979-10-26 Fenyl-lavere alkanoylaminer for bruk til fremstilling av terapeutisk virksomme fenyl-lavere-alkylaminer

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ES (2) ES444437A1 (no)
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FR (2) FR2297614A1 (no)
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US4308382A (en) * 1975-01-20 1981-12-29 Sterling Drug Inc. 4-[[3-[α-Aminobenzyl]phenyl]methyl]morpholine and 4-[-[3-benzoylphenyl]ethyl]morpholine
EP0052311A1 (en) * 1980-11-19 1982-05-26 Sterling Drug Inc. 1-((Benzoylphenyl) - lower-alkyl) piperidines and carbinol analogs and preparation thereof
US4339576A (en) 1980-11-19 1982-07-13 Sterling Drug Inc. Anti-asthmatic, anti-allergic, anti-cholinergic, bronchodilator and anti-inflammatory 1-[(benzoylphenyl)-lower-alkyl]piperidines and analogs thereof
US4396765A (en) 1981-08-24 1983-08-02 Sterling Drug Inc. Amino-1-[(halophenyl)-lower-alkyl]piperidines
MXPA00007394A (es) * 1998-01-29 2003-08-01 Viropharma Inc Compuestos, composiciones y metodos para tratar o evitar infeccion de neumovirus y enfermedades asociadas.
US6495580B1 (en) 1998-01-29 2002-12-17 Viropharma Incorporated Compounds, compositions and methods for treating or preventing pneumovirus infection and associated diseases
US8202896B2 (en) 2002-08-09 2012-06-19 Microdose Therapeutx, Inc. Compounds, compositions and methods for treating or preventing pneumovirus infection and associated diseases
US8119672B2 (en) 2002-08-09 2012-02-21 Microdose Therapeutx, Inc. Compounds, compositions and methods for treating or preventing pneumovirus infection and associated diseases

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GB1508391A (en) 1978-04-26
AR221467A1 (es) 1981-02-13
NO143902B (no) 1981-01-26
PT64718B (fr) 1977-06-03
CH619924A5 (en) 1980-10-31
SE7910737L (sv) 1979-12-28
JPS51125364A (en) 1976-11-01
ATA304378A (de) 1979-06-15
NL7600566A (nl) 1976-07-22
ES458807A1 (es) 1978-03-01
FI760112A (no) 1976-07-21
DK19176A (da) 1976-07-21
NO143902C (no) 1981-05-06
GB1508392A (en) 1978-04-26
NO142907B (no) 1980-08-04
AT354454B (de) 1979-01-10
CH619923A5 (en) 1980-10-31
ES444437A1 (es) 1977-10-01
AU503063B2 (en) 1979-08-23
MX3819E (es) 1981-07-30
NO760169L (no) 1976-07-21
CH618677A5 (en) 1980-08-15
FR2320294A1 (fr) 1977-03-04
PT64718A (fr) 1976-02-01
FR2297614A1 (fr) 1976-08-13
CH612920A5 (en) 1979-08-31
DE2601923A1 (de) 1976-07-22
NO142907C (no) 1980-11-12
FR2320294B1 (no) 1980-09-19
CA1053251A (en) 1979-04-24
IL55523A0 (en) 1978-12-17
IL48863A0 (en) 1976-03-31
NO793447L (no) 1976-07-21
IL48863A (en) 1979-11-30
FR2297614B1 (no) 1979-07-20
SE7600505L (sv) 1976-09-02
AU1047876A (en) 1977-07-28

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