NO144149B - Analogifremgangsmaate ved fremstilling av terapeutisk aktivt bis-(2-methyl-3-hydroxy-4-hydroxymethyl-pyrid-5-yl-methyl)-carbodithioat - Google Patents

Analogifremgangsmaate ved fremstilling av terapeutisk aktivt bis-(2-methyl-3-hydroxy-4-hydroxymethyl-pyrid-5-yl-methyl)-carbodithioat Download PDF

Info

Publication number
NO144149B
NO144149B NO742042A NO742042A NO144149B NO 144149 B NO144149 B NO 144149B NO 742042 A NO742042 A NO 742042A NO 742042 A NO742042 A NO 742042A NO 144149 B NO144149 B NO 144149B
Authority
NO
Norway
Prior art keywords
methyl
pyrid
hydroxymethyl
hydroxy
formula
Prior art date
Application number
NO742042A
Other languages
English (en)
Other versions
NO144149C (no
NO742042L (no
Inventor
Tsung-Ying Shen
Howard Jones
Dennis Michael Mulvey
Conrad Peter Dorn
Original Assignee
Merck & Co Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck & Co Inc filed Critical Merck & Co Inc
Publication of NO742042L publication Critical patent/NO742042L/no
Publication of NO144149B publication Critical patent/NO144149B/no
Publication of NO144149C publication Critical patent/NO144149C/no

Links

Classifications

    • 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
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C07D213/66—One oxygen atom attached in position 3 or 5 having in position 3 an oxygen atom and in each of the positions 4 and 5 a carbon atom bound to an oxygen, sulphur, or nitrogen atom, e.g. pyridoxal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • 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
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/26—Radicals substituted by halogen atoms or nitro radicals
    • 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
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/32—Sulfur atoms
    • 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
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • 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
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • 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
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • 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
    • C07D213/89—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 with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D327/00—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D327/02—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms one oxygen atom and one sulfur atom
    • 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
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D497/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D497/04—Ortho-condensed systems

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Rheumatology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Pain & Pain Management (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Description

Foreliggende oppfinnelse angår analogifremgangsmåter
ved fremstilling av et nytt, terapeutisk aktivt bis-(2-methyl-3-hydroxy-4-hydroxymethyl-pyrid-5-yl-methyl)-carbodithioat med strukturformelen:
og hydrater og syreaddisjonssalter derav, hvilke forbindelser har anvendbarhet ved behandling av rheumatoid arthritis.
De farmasøytisk godtagbare addisjonssalter innbefatter
dem som fremstilles fra mineral- og organiske syrer som vanlig anvendes i farmasien, som saltsyre, hydrogenbromid, svovelsyre, salpetersyre, maleinsyre, fumarsyre, vinsyre eller ravsyre.
Andre salter som er innbefattet under oppfinnelsen, er alkali-metallsaltene av mercaptangruppen og toverdige metallkomplekser fra mercaptogruppen med metaller som kalsium eller magnesium.
Til tross for utstrakt antiinflammatorisk forskning
i de siste tyve år, er det fremdeles et åpenbart behov for et effektivt og godt tolererbart middel for behandling av rheumatoid arthritis. Konvensjonelle ikke-steroide, anti-inf lammatorisk-analgetisk-antipyretiske midler, som acetyl-
salicylsyre, og mange eksperimentelle nye dro-
ger under klinisk evaluering, er virksomme til å gi symptomatisk lindring bare for det akutte syndrom, men er ikke istand til å endre forløpet av sykdommen. Som følge av dette har de anti-rheumatiske virkninger av to gamle remedier, gull og D-penicillamin, til tross for deres potensielle bivirkninger, oppnådd fornyet interesse i de siste par år. Den kliniske virksomhet av begge dro-ger ble bekreftet ved velkontrollerte multi-centerkliniske under-søkelser. Flere rheumatologer har uttrykt den mening at en bedre D-penicillamin-lignende forbindelse ville være et verdifullt bidrag til medisinen på dette viktige felt. Det er derfor en viktig er-kjennelse at mange av de kjente mercaptomethyl-pyridiner og de nye mercaptomethyl-pyridiner som fremstilles ved foreliggende oppfinnelse, har en viktig grad av anti-rheumatoid arthritis-aktivitet.
For disse formål kan fremgangsmåteforbindelsen admini-streres oralt, lokalt, parenteralt, ved inhaleringsspra/ eller rec-talt i enhetsdosepreparater inneholdende konvensjonelle ikke-giftige farmasøytisk godtagbare bærer, hjelpestoffer og medier. Uttrykket parenteral er her anvendt for å innbefatte subcutane injeksjoner, intravenøs, intramuskulær, intrasternal injeksjon, intraartikulære eller infusjonsmetoder. Foruten til behandling av varmblodige dyr som mus, rotter, hester, hunder, katter, marsvin, kaniner etc, er fremgangsmåteforbindelsene virksomme ved behandling av mennesker.
Dosemengder av størrelsesorden 1 mg til 140 mg pr. kg legemsvekt pr. dag er nyttige ved behandling av de ovenfor angitte tilstander. I alminnelighet ligger en effektiv dose i området 5 - 50 mg pr. kg legemsvekt pr. dag.
Det vil imidlertid forståes at den spesifikke dosestørrel-se for en spesiell pasient vil avhenge av en rekke faktorer innbe-fattende aktiviteten av den spesielle forbindelse som anvendes, al-der, legemsvekt, alminnelig helsetilstand, kjønn, diett, administra-sjonstid, administrasjonsvei, utskillelseshastighet, drogekombina-sjon og graden av den spesielle sykdom som underkastes terapi.
Virkning av fremgangsmåteforbindelsen på lymfokin-indusert inflammasjon hos marsvin
Grupper på 4 marsvin ble dosert p.o. med fremgangsmåteforbindelsen på nulltidspunktet i mengder på 30 mg/kg eller 90 mg/kg. Hvert dyr fikk en annen dose av den aktive forbindelse i samme mengde 17 timer senere. 1 time efter den annen dose av den aktive forbindelse fikk hvert dyr intradermalt lymfokin, og størrelsen av erytemet på injeksjonsstedet ble målt ved 22 timer.
Resultat; Både sulfatsaltet av bis-(3-hydroxy-4-hydroxymethyl-2-methyl-pyrid-5-yl-methyl)-carbodithionat og dihydrokloridsaltet viste en virkning sammenlignbar med 5-mercaptopyridoxin ved ca. 1/3 av dosen i dette forsøk.
Forbindelsen som fremstilles ifølge oppfinnelsen, har formelen:
og fremstilles ved at:
(a) 2-methyl-3-hydroxy-4-hydroxymethyl-5-mercaptomethylpyridin behandles med p-nitrofenylklorformiat eller fosgen i et aprotisk oppløsningsmiddel som tetrahydrofuran ved 0 - 10°C i 1 - 3 timer fulgt av oppvarmning til 20 - 50°C;
(b) en forbindelse med formelen:
hydrolyseres med fortynnet mineralsyre ved 20 - 50°C i 1 - 5 timer, hvor R-^g og R2o' som er -^^e eller forskjellige, er hydrogen, en syrelabil beskyttende gruppe, som tetrahydropyranyl, eller R^g og R^ q danner sammen en gruppe med formelen: hvor R^ og , som er like eller forskjellige, er hydrogen, C^_2-alkyl eller fenyl; og R^^ er =0 eller =N-R^g, hvor R^g er hydrogen, fenyl eller ^-alkyl, med det forbehold at når R^ er =0, er ikke R-^g og R^ q begge hydrogen; (c) en forbindelse med formelen: eller
behandles med et oxydasjonsmiddel som kaliumpermanganat, salpetersyre, kvikksølv(II)-oxyd eller lignende, ved værelsetemperatur i 1-3 timer;
(d) en forbindelse med formelen:
behandles med mineralsyre under langsom oppvarmning til 80 - 100°C, hvor R^g og R2Q er som tidligere angitt,
og, om ønskes, omdannes de erholdte forbindelser med formel (I)
til deres syreaddisjonssalter eller hydrater, eller et erholdt syreaddisjonssalt overføres til den frie base:.
Eksempel 1
S, S'- bis-( 3- hydroxy- 4- hydroxymethyl- 2- methyl- pyrid- 5- yl- methyl)-carbodithioat- dihydroklorid- monohydrat
Trinn A: Fremstilling av S,S'-bis-(2,2,8-trimethyl-4H-m-dioxino-[ 4, 5- c]- pyrid- 5- yl- methyl)- carbodithioat
Til en isavkjølt oppløsning av 4,5 g 5-mercaptomethyl-2,2,8-trimethyl-4H-m-dioxino-[4,5-c]-pyridin i 50 ml tørr pyridin ble tilsatt dråpevis 10 ml av en 12,5%-ig oppløsning av fosgen i benzen. Reaksjonsblandingen fikk lov til å anta værelsetemperatur og ble omrørt i 3 timer, hvorefter den ble inndampet i vakuum. Residuet ble ekstrahert mellom benzen og mettet natrium-bicarbonatoppløsning. Benzenskiktet ble fraskilt, vasket med vann, tørret over natriumsulfat og inndampet i vakuum. Residuet ble kromatografert på 250 g silicagel. Eluering med ether ga 3,59 g S,S'-bis-(2,2,8-trimethyl-4H-m-dioxino-[4,5-c]-pyrid-5-yl-methyl-carbodithioat, smp. 88 - 90°C.
Trinn B: Fremstilling av S,S<1->bis-(3-hydroxy-4-hydroxymethyl-2-methyl-pyrid-5-yl-methyl)-carbodithioat-dihydroklorid-monohydrat
En oppløsning av 0,2 g S,S<1->bis-(2,2,8-trimethyl-4H-m-dioxino-[4,5-c]-pyrid-5-yl-methyl-carbodithioat i 0,9 ml iskold konsentrert saltsyre ble omrørt koldt i 5 minutter hvorefter den ble fortynnet til 2,5 ml med methanol. Avkjøling i is-aceton ga et krystallinsk bunnfall som ble frafiltrert, hvorved man fikk
0,120 g S,S<1->bis-(3-hydroxy-4-hydroxymethyl-2-methyl-pyrid-5-yl-methyl)-carbodithioat-dihydroklorid-monohydrat, smp. 125 - 130°C.
Eksempel 2
Bis-[ 2- methyl- 3- hydroxy- 4- hydroxymethyl- pyrid- 5- yl- methylthio]-carbonat
En oppløsning av 0,1 mol 5-mercaptopyridoxin i 100 ml tørr tetrahydrofuran omrøres ved 0 - 5°C mens 0,1 mol 1-nitrofenylklorformiat i 10 ml tørr tetrahydrofuran tilsettes i løpet av 1 time. Efter ytterligere 1 time inndampes oppløsningen ved 10°C til 10 ml. Hvis nødvendig kan p-nitrofenylmonothiocarbonatet av 5-mercaptopyridoxin-mellomproduktet isoleres ved filtrering på dette trinn.
Alternativt kan ytterligere 0,1 mol 5-mercaptopyridoxin tilsettes før inndampning, og tetrahydrofuranoppløsningen oppvarmes til 40°C. Inndampning fulgt av ekstrahering av dithio-carbonatet i 3 x 100 ml ethylacetat fra mettet vandig natriumbicarbonat følges av tørring av det organiske skikt over magnes-iumsulfat. Det organiske skikt filtreres og inndampes til tørr-het. Råproduktet kromatograferes på en silicagelkolonne 50 mm x 60 cm under anvendelse av oppløsninger av methylenklorid-methanol som elueringsmiddel, hvorved man får bis-[2-methyl-3-hydroxy-4-hydroxymethyl-pyrid-5-yl-methylthio]-carbonat.
Eksempel 3
Bis-[ 2- methyl- 3- hydroxy- 4- hydroxymethyl- pyrid- 5- yl- methylthio]-carbonat
Til 0,05 mol ammoniumdithiocarbamat i 300 ml 75%-ig ethanol tilsettes 0,1 mol 5-klormethyl-2,2,8-trimethyl-4H-m-dioxino-[4,5-c]-pyridin (fra tilsvarende hydroklorid + natriumbicarbonat). Reaksjonsblandingen kokes under tilbakeløp i 2 timer, avkjøles, til værelsetemperatur og syres med saltsyre. Efter 3 timer ved værelsetemperatur inndampes reaksjonsblandingen, og residuet taes opp mellom ether-benzen og overskudd av mettet natriumbicarbonat. Det organiske skikt fraskilles, vaskes godt med vann, tørres og inndampes, hvilket gir bis-[2-methyl-3-hydroxy-4-hydroxymethyl-pyrid-5-yl-methylthio]-carbonat.
Eksempel 4
Bis-[ 2- methyl- 3- hydroxy- 4- hydroxymethyl- pyrid- 5- yl- methylthio]-carbonat
Til 0,2 mol natriumhydrid i tørt dimethylformamid under nitrogen tilsettes under, avkjøling 0,2 mol 5-mercaptomethyl-2,2,8-trimethyl-4H-m-dioxino-[4,5-c]-pyridin i dimethylformamid. Bland-ingen omrøres i 15 minutter efter at utviklingen av hydrogen er opphørt. Der tilsettes så 0,1 mol fenylisonitril-diklorid. Reaksjonsblandingen omrøres ved værelsetemperatur over natten og inndampes så i vakuum. Residuet omrøres i 3 timer ved værelsetemperatur i fortynnet saltsyre. Behandling med mettet natriumbicarbonat gir så bis-[2-methyl-3-hydroxy-4-hydroxymethyl-pyrid-5-yl-methylthio]-carbonat.
Eksempel 5
Bis-[ 2- methyl- 3- hydroxy- 4- hydroxymethyl- pyrld- 5- yl- methylthio]-carbonat
Til 0,1 mol natriummethoxyd i 150 ml ethanol tilsettes
0,1 mol.5-mercaptomethyl-2,2,8-trimethyl-4H-m-dioxino-[4,5-c]-pyridin. Efter 15 minutter fjernes'ethanolen ved inndampning i vakuum. Til det gjenværende natriummercaptid tilsettes 0,05 mol difenylcarbonat, og den dannede masse oppvarmes på dampbad i 1 time. Efter avkjøling til værelsetemperatur tilsettes en blanding av benzen-ether og fortynnet natriumhydroxyd. Det organiske skikt fraskilles, vaskes godt med vann, tørres og inndampes, hvorved man får bis-[2-methyl-3-hydroxy-4-hydroxymethyl-pyrid-5-yl-methylthio]-carbonat.
Eksempel 6
Bis - [ 2- methyl- 3- hydroxy- 4- hydroxymethyl-- pyrid- 5- yl- methylthio] - carbonat
Til 0,4 mol kvikksølv(II)-oxyd som er'suspendert ved kraftig omrøring i 200 ml vann, tilsettes - 0, 22 mol bis-(2,2,8-trimethyl-4H-m-dioxino-[4,5-c]-pyrid-5-yl-methylthio)-thiocarbonat i 100 ml eddiksyreanhydrid.- Reaksjonsblandingen omrøres ved værelsetemperatur- i .1 time og ekstraheres med ether-benzen (1:1). Det organiske skikt fraskilles, vaskes med mettet natriumbicarbonat-oppløsning, vann, og tørres over natriumsulfat hvorved man får bis-(2,2,8-trimethyl-4H-m-dioxino-[4,5-c]-pyrid-5-yl-methylthio)-carbonat. Syrehydrolyse under vanlige betingelser gir bis-[2-methyl-3-hydroxy-4-hydroxymethyl-pyrid-5-yl-methylthio]-carbonat.
Alternativt kan isopropylidengruppen hydrolyseres først fulgt av oxydasjon av thiocarbonatgruppen til carbonatet og derved oppnå det samme resultat.
Eksempel 7
Bis - [ 2^ m' ethyl- 3- hydroxy- 4- hydroxymethyl- pyrid- 5- yl- methylthio] - carbonat
Eh blanding av 0,1 mol 2,2,8-trimethyl-4H-m-dioxino-[4,5-c]-pyrid-5-yl-methylthiocyanat og 5 ml svovelsyre oppvarmes langsomt på dampbad. En kraftig utvikling av carbondioxyd.finner sted. Efter at gassutviklingen er opphørt, helles reaksjonsblandingen på is og omrøres i 3 timer ved værelsetemperatur. Denne blanding helles så i en blanding av ether-benzen og overskudd av natriumbicarbonatoppløsning. Det organiske skikt fraskilles, vaskes godt med vann, tørres og inndampes, hvorved man får bis-[2-methyl-3-hydroxy-4-hydroxymethyl-pyrid-5-yl-methylthio]-carbonat.

Claims (1)

  1. Analogifremgangsmåte ved fremstilling av den terapeutisk aktive forbindelse med formelen:
    og hydrater og syreaddisjonssalter derav,karakterisert ved at: (a) 2-methyl-3-hydroxy-4-hydroxymethyl-5-mercaptomethylpyri-din behandles med p-nitrofenylklorformiat eller fosgen, eller (b) en forbindelse med formelen: behandles med en mineralsyre, idet r og I^q som er like eller forskjellige, er hydrogen, en syrelabil beskyttende gruppe eller R^g og R^q danner sammen en gruppe med formelen: hvor R^ og R^, som er like eller forskjellige, er hydrogen, C, ,-alkyl eller fenyl, og R^ er =0 eller =N-R^g, hvor R^g er hydrogen, fenyl eller C^_.j-alkyl, med det forbehold at når R-^y er =0, er ikke både R^g og R2q hydrogen, eller (c) en forbindelse med formelen: (d) en forbindelse med formelen: hvor R^g og R^q er som ovenfor angitt, behandles med mineralsyre, og, om ønskes, omdannes de erholdte forbindelser med formel (I) til deres syreaddisjonssalter eller hydrater, eller et erholdt syreaddisjonssalt overføres til den frie base.
NO742042A 1973-06-15 1974-06-06 Analogifremgangsmaate ved fremstilling av terapeutisk aktivt bis-(2-methyl-3-hydroxy-4-hydroxymethyl-pyrid-5-yl-methyl)-carbodithioat NO144149C (no)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US36877473A 1973-06-15 1973-06-15
US05/470,231 US3971797A (en) 1973-06-15 1974-05-16 S,S'-bis(pyridylmethyl)-carbonodithioates

Publications (3)

Publication Number Publication Date
NO742042L NO742042L (no) 1975-05-05
NO144149B true NO144149B (no) 1981-03-23
NO144149C NO144149C (no) 1981-07-01

Family

ID=27004328

Family Applications (1)

Application Number Title Priority Date Filing Date
NO742042A NO144149C (no) 1973-06-15 1974-06-06 Analogifremgangsmaate ved fremstilling av terapeutisk aktivt bis-(2-methyl-3-hydroxy-4-hydroxymethyl-pyrid-5-yl-methyl)-carbodithioat

Country Status (21)

Country Link
US (1) US3971797A (no)
JP (3) JPS5032180A (no)
AR (1) AR203749A1 (no)
BG (1) BG24408A3 (no)
CA (1) CA1037956A (no)
CH (4) CH613951A5 (no)
DD (1) DD113001A5 (no)
DE (2) DE2428409C3 (no)
DK (1) DK148595C (no)
ES (1) ES427277A1 (no)
FI (1) FI58775C (no)
FR (2) FR2233057B1 (no)
GB (2) GB1466295A (no)
IE (1) IE39467B1 (no)
IL (1) IL44998A (no)
LU (1) LU70342A1 (no)
NL (2) NL185841C (no)
NO (1) NO144149C (no)
PH (1) PH10366A (no)
RO (2) RO71434A (no)
SE (1) SE411346B (no)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4061759A (en) * 1975-05-19 1977-12-06 Merck & Co., Inc. Ethenyl and ethynyl mercaptoalkyl pyridines
CH655110A5 (de) * 1982-09-03 1986-03-27 Otsuka Pharma Co Ltd Carbostyrilderivate, verfahren zu deren herstellung und arzneimittel, welche diese enthalten.
GB2266887B (en) * 1992-05-15 1996-04-17 British Tech Group Substituted pyridines,their preparation and pharmaceutical use
KR100235976B1 (ko) * 1992-05-15 1999-12-15 말콤 카터, 리차드 케이쓰 퍼시 치환된 피리딘 화합물,이것들의 제조방법 및 약제학적 사용방법
GB201718148D0 (en) * 2017-11-02 2017-12-20 Ipotts Ltd Hair cutting comb
GB2603007B (en) * 2021-01-26 2023-01-11 Pickuls Gizmo Ltd A hair cutting guide

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3515726A (en) * 1968-10-16 1970-06-02 Olin Mathieson 2,2'-bis(pyridyl-n-oxide) dithiolcarbonates and trithiocarbonates

Also Published As

Publication number Publication date
FI58775B (fi) 1980-12-31
DE2428409C3 (de) 1979-08-09
AR203749A1 (es) 1975-10-15
SE411346B (sv) 1979-12-17
CH634302A5 (de) 1983-01-31
RO70852A (ro) 1981-08-17
DD113001A5 (no) 1975-05-12
NO144149C (no) 1981-07-01
LU70342A1 (no) 1975-03-27
AU7004174A (en) 1975-12-18
JPS5387363A (en) 1978-08-01
US3971797A (en) 1976-07-27
NL7407618A (no) 1974-12-17
CH618428A5 (no) 1980-07-31
DK303274A (no) 1975-02-10
FI58775C (fi) 1981-04-10
GB1466295A (en) 1977-03-02
FR2233057A1 (no) 1975-01-10
IE39467B1 (en) 1978-10-11
SE7407296L (no) 1974-12-16
NL185841C (nl) 1990-08-01
FR2233056B1 (no) 1977-10-28
CH613951A5 (no) 1979-10-31
NL7407616A (no) 1974-12-17
PH10366A (en) 1977-01-18
BG24408A3 (en) 1978-02-10
NL185841B (nl) 1990-03-01
RO71434A (ro) 1981-08-17
FI168574A (no) 1974-12-16
GB1466386A (en) 1977-03-09
FR2233056A1 (no) 1975-01-10
JPS5032181A (no) 1975-03-28
CA1037956A (en) 1978-09-05
CH610305A5 (no) 1979-04-12
DE2428409B2 (de) 1978-11-30
DK148595C (da) 1986-01-27
JPS5032180A (no) 1975-03-28
JPS5747189B2 (no) 1982-10-07
DE2428409A1 (de) 1975-01-09
DK148595B (da) 1985-08-12
NO742042L (no) 1975-05-05
IL44998A (en) 1977-10-31
FR2233057B1 (no) 1978-03-24
ES427277A1 (es) 1976-09-16
IL44998A0 (en) 1974-09-10
IE39467L (en) 1974-12-15
DE2428294A1 (de) 1975-01-09

Similar Documents

Publication Publication Date Title
US2918408A (en) Anti-spasmodic compositions specific for treating spasm of the colon
EP0532528A1 (en) Derivatives of hydroxy and alkoxy pyridines
UA43841C2 (uk) Імідазопіридини та фармацевтична композиція на їх основі
CZ284896A3 (en) Novel hydroxypyridinones, process of their preparation and pharmaceutical composition in which such hydroxypyridinones are comprised
NO133669B (no)
NO144149B (no) Analogifremgangsmaate ved fremstilling av terapeutisk aktivt bis-(2-methyl-3-hydroxy-4-hydroxymethyl-pyrid-5-yl-methyl)-carbodithioat
US3910922A (en) Novel trifluoromethyl-quinolines
EP0087629B1 (en) Antiinflammatory and/or analgesic 2,3-diaryl-5-halo thiophenes
DE2360550A1 (de) Indenylaethyltetrazole, -sulfonsaeuren und -phosphorsaeuren
US3127401A (en) Z-benzyl-j
SI9300349A (sl) Substitunirani piridinil-2 propeonati in njihovi homologi
EP0282077A2 (en) Pyridyloxy derivatives
JPH07252260A (ja) 新規チエノチアジン誘導体、その製造方法及びその使用方法
US4071630A (en) 1-Substituted-amino-3-(4-furo[3,2-c]pyridinyloxy)-2-propanols
US3775479A (en) Amine compounds
NO118975B (no)
GB1598628A (en) Guanidine derivatives
Gadekar et al. Synthesis and biological activity of pyridoxine analogs
JPS6353984B2 (no)
CN113582953B (zh) 一种盐酸胺碘酮关键中间体的制备方法
US3856909A (en) Novel quinolines in the treatment of pain and inflammation
US4259335A (en) 1-Methyl-4-piperidinol esters of 4-quinolinylamino benzoates and antiinflammatory and analgesic compositions and methods employing them
US3787578A (en) Method of treating helminthiasis
NO121344B (no)
US3806513A (en) Alpha-substituted indolizine propionic acid and its salts