NO133669B - - Google Patents

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NO133669B
NO133669B NO4295/70A NO429570A NO133669B NO 133669 B NO133669 B NO 133669B NO 4295/70 A NO4295/70 A NO 4295/70A NO 429570 A NO429570 A NO 429570A NO 133669 B NO133669 B NO 133669B
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pyridone
methyl
mixture
preparation
compounds
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NO4295/70A
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Norwegian (no)
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NO133669C (en
Inventor
B E Witzel
T-Y Shen
P M Graham
R L Clark
A A Pessolano
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Merck & Co Inc
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Publication of NO133669C publication Critical patent/NO133669C/no

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    • 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
    • C07D213/64—One oxygen atom attached in position 2 or 6
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    • 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
    • C07D213/61—Halogen atoms or nitro radicals
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    • 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
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    • 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
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
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    • 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
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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    • 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
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    • 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
    • C07D213/04—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
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
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    • C07—ORGANIC CHEMISTRY
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    • 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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)

Description

Foreliggende oppfinnelse angår en analogifremgangsmåte ved fremstilling av en ny gruppe terapeutisk aktive substituerte aminopyridoner, som er nyttige ved behandling av inflammasjon og som også oppviser sterk analgetisk og antipyretisk aktivitet. The present invention relates to an analogous method for the production of a new group of therapeutically active substituted aminopyridones, which are useful in the treatment of inflammation and which also exhibit strong analgesic and antipyretic activity.

De nye pyridoner som fremstilles ifølge oppfinnelsen, har strukturformelen: The new pyridones produced according to the invention have the structural formula:

hvor R <1> er lavere alkyl, R <2>er hydrogen eller lavere alkanoyl, og 3 where R <1> is lower alkyl, R <2> is hydrogen or lower alkanoyl, and 3

R er lavere alkanoyl. R is lower alkanoyl.

Forbindels ene med formel I fremstilles ifølge oppfinnelsen Compound one with formula I is produced according to the invention

ved at en forbindelse av den generelle formel: in that a compound of the general formula:

hvor R<1> er som ovenfor angitt, reduseres under samtidig eller på-følgende acylering. where R<1> is as indicated above, is reduced during simultaneous or subsequent acylation.

Fra Chemical Abstraets J50, 2576, er det kjent å frem- From Chemical Abstracts J50, 2576, it is known to produce

stille 3(5)-amino-, 5-acetamido- og 5-benzamido-l-methyl-2(lH)-pyridon, men intet er angitt om slike forbindelsers aktivitet. quiet 3(5)-amino-, 5-acetamido- and 5-benzamido-1-methyl-2(1H)-pyridone, but nothing is indicated about the activity of such compounds.

I motsetning til foreliggende fremgangsmåteforbindelser har disse kjente forbindelser en methylgruppe i 1-stilling. In contrast to the present process compounds, these known compounds have a methyl group in the 1-position.

Fra DOS 1.810.822 er det kjent å fremstille pyridoner som From DOS 1,810,822 it is known to prepare pyridones which

er substituert med en carbocyclisk eller heterocyclisk aryl- is substituted with a carbocyclic or heterocyclic aryl-

gruppe og eventuelt andre substituenter, og som angis å ha anti-inf lammas jonsvirkning og være fri for bivirkninger. Foreligg- group and possibly other substituents, and which are stated to have anti-inflammation effect and to be free of side effects. exist-

ende fremgangsmåteforbindelser har ingen slik arylsubstituent på pyridonringen, og har, foruten antiinflammatorisk, også analgetisk og antipyretisk aktivitet. end method compounds have no such aryl substituent on the pyridone ring, and have, in addition to anti-inflammatory, also analgesic and antipyretic activity.

De substituerte pyridoner som fremstilles ifølge oppfinnelsen, har en høy grad av antiinflammatorisk, analgetisk og antipyretisk aktivitet. De er verdifulle ved behandlingen av arthritiske og dermatologiske lidelser eller lignende tilstander som er responsive til antiinflammatoriske droger. Generelt kan de anvendes for en lang rekke tilstander-hvor én eller flere av symp-tomene på inflammasjon, feber og smerte viser seg. Innbefattet i denne kategori er lidelser som rheumatoid arthritis, osteo arthritis, gikt, smittsom arthritis og rheumatisk feber. Som nevnt ovenfbr, har fremgangsmåteforbindelsene også en nyttig grad av analgetisk og antipyretisk aktivitet. The substituted pyridones produced according to the invention have a high degree of anti-inflammatory, analgesic and antipyretic activity. They are valuable in the treatment of arthritic and dermatological disorders or similar conditions responsive to anti-inflammatory drugs. In general, they can be used for a wide range of conditions - where one or more of the symptoms of inflammation, fever and pain appear. Included in this category are disorders such as rheumatoid arthritis, osteo arthritis, gout, infectious arthritis and rheumatic fever. As mentioned above, the process compounds also have a useful degree of analgesic and antipyretic activity.

For disse formål kan fremgangsmåteforbindelsene administreres oralt, lokalt, parenteralt, ved inhaleringsspray eller rektalt i formuleringer inneholdende konvensjonelle ikke-giftige farmasøytisk godtagbare bærere, hjelpestoffer og væsker. Uttrykket parenteralt er her anvendt for å innbefatte subcutane injeksjoner, intravenøs, intramuskulær, intrasternal injeksjon eller infusjonsmetoder„ Foruten til behandling av varmblodige dyr som mus, rotter, hester, hunder, katter, etc;, er fremgangsmåteforbindelsene virksomme ved. behandling av mennesker. For these purposes, the method compounds can be administered orally, topically, parenterally, by inhalation spray or rectally in formulations containing conventional non-toxic pharmaceutically acceptable carriers, excipients and liquids. The term parenteral is used here to include subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion methods. In addition to the treatment of warm-blooded animals such as mice, rats, horses, dogs, cats, etc., the process compounds are effective at. treatment of people.

De farmasøytiske preparater inneholdende den aktive bestanddel kan være i en form egnet for oral anvendelse, f.eks. som tab-letter., pastiller, vandige eller oljesuspensjoner, dispergerbare pulvere eller korn, emulsjoner, hårde eller myke kapsler eller siruper eller eliksirer. Preparater beregnet på oral anvendelse kan fremstilles på i og for seg kjent vis. Tabletter.kan være ubelagte eller de kan være belagt ved kjente metoder for å sinke oppbryt-ningen og absorbsjonen i fordøyelseskanalen og derved frembringe en protrahert virkning over en lengre periode. The pharmaceutical preparations containing the active ingredient can be in a form suitable for oral use, e.g. as tablets, lozenges, aqueous or oil suspensions, dispersible powders or grains, emulsions, hard or soft capsules or syrups or elixirs. Preparations intended for oral use can be prepared in a manner known per se. Tablets can be uncoated or they can be coated by known methods to slow down the breakdown and absorption in the digestive tract and thereby produce a prolonged effect over a longer period.

Preparater for oral anvendelse kan også være i form av hårde gelatinkapsler hvori den aktive bestanddel er blandet med et inert fast fortynningsmiddel, eller som myke gelatinkapsler hvor den aktive bestanddel er blandet med vann eller et oljemedium. Preparations for oral use can also be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium.

Vandige suspensjoner inneholder de aktive forbindelser i blanding med hjelpestoffer egnet for fremstilling av vandige suspensjoner. Aqueous suspensions contain the active compounds in a mixture with excipients suitable for the production of aqueous suspensions.

Oljesuspensjoner kan være formulert ved å suspendere den aktive forbindelse i en vegetabilsk olje. Oil suspensions may be formulated by suspending the active compound in a vegetable oil.

Dispergerbare pulvere og korn egnet for fremstilling av en vandig suspensjon ved tilsetning av vann har den aktive bestanddel i blanding med et dispergerings- eller fuktemiddel, suspensjons-middel og ett eller flere konserveringsmidler. Dispersible powders and grains suitable for producing an aqueous suspension by adding water have the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.

De farmasøytiske preparater med fremgangsmåteforbindelsene kan også være i form av olje-i-vannemulsjoner. The pharmaceutical preparations with the process compounds can also be in the form of oil-in-water emulsions.

Siruper og eliksirer kan være formulert med søtemidler. De farmasøytiske preparater kan også være i form av et sterilt injiser-bart preparat f.eks. som en steril injiserbar vandig eller oljesus-pensjon. Det sterile injiserbare preparat kan også være en steril injiserbar oppløsning eller suspensjon i et ikke-giftig parenteralt godtagbart fortynningsmiddel eller oppløsningsmiddel f.eks. som en oppløsning i 1,3-butandiol. Blant de godtagbare medier og oppløs - ningsmidler som kan anvendes, er vann, Ringer's oppløsning og iso-tonisk natriumkloridoppløsning. Dessuten anvendes sterile, ikke-flyktige oljer konvensjonelt som oppløsnings- eller suspensjons - medium. Syrups and elixirs may be formulated with sweeteners. The pharmaceutical preparations can also be in the form of a sterile injectable preparation, e.g. as a sterile injectable aqueous or oil suspension. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent e.g. as a solution in 1,3-butanediol. Among the acceptable media and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, non-volatile oils are conventionally used as dissolution or suspension medium.

For lokal anvendelse anvendes kremer, salver, geléer, oppløs-ninger eller suspensjoner, etc., inneholdende de antiinflammatoriske midler. For local application, creams, ointments, jellies, solutions or suspensions, etc., containing the anti-inflammatory agents are used.

Doser av størrelsesorden 20 mg til 7 g pr. dag er nyttige ved behandling av de ovennevnte lidelser. Eksempelvis behandles inflammasjon effektivt og antipyretisk og .analgetisk aktivitet gir seg tilkjenne ved administrasjon av fra 0,3 - lOO mg fremgangs-måtef o-rbindelse pr . kg legemsvekt pr. dag. Fra 2 mg til 5 mg j>r. kg legemsvekt og særlig fra 4 mg til 20 mg/kg pr. dag gir meget effektive resultater. Doses of the order of 20 mg to 7 g per day are useful in treating the above disorders. For example, inflammation is effectively treated and antipyretic and analgesic activity is manifested by administration of from 0.3 - 100 mg of the method of procedure per . kg body weight per day. From 2 mg to 5 mg per year. kg body weight and in particular from 4 mg to 20 mg/kg per day gives very effective results.

Mengden av aktiv bestanddel som kan kombineres med bærér-materialene for å danne en enkelt doseform, vil variere avhengig av den vert som behandles, og administrasjonsmåten. Eksempelvis kan et preparat beregnet på oral administrasjon til mennesker inneholde fra 5 mg til 5 Q aktiv bestanddel opparbeidet med en passende og bekvem mengde bærermateriale som kan variere fra 5 til 95% av totalpreparatet. Enhetsdoseformer vil i alminnelighet inneholde mellom 25 mg og 500 mg aktiv bestanddel. The amount of active ingredient that can be combined with the carrier materials to form a single dosage form will vary depending on the host being treated and the mode of administration. For example, a preparation intended for oral administration to humans may contain from 5 mg to 5 Q active ingredient prepared with a suitable and convenient amount of carrier material which may vary from 5 to 95% of the total preparation. Unit dosage forms will generally contain between 25 mg and 500 mg of active ingredient.

Den spesifikke dosemengde for en spesiell pasient vil imidler-tid avhenge av en rekke faktorer innbefattende aktiviteten av den spesielle forbindelse som anvendes, alderen, legemsvekten, den alminnelige helsetilstand, kjønn, diett, administrasjonstid, admin-istras jonsvei, utskillelseshastighet, drogekombinasjon og graden av den spesielle lidelse som behandles. The specific dosage amount for a particular patient will, however, depend on a number of factors including the activity of the particular compound used, age, body weight, general state of health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the degree of the particular disorder being treated.

En bekvem måte for å fremstille fremgangsmåteforbindelsene, som illustrert i det følgende prosesskjema, innbefatter generelt oxydasjon av et pyridin (A) til det tilsvarende N-oxyd (F). N-oxydef kan overføres til 2-[lH]-pyridonet ved oppvarmning med laverealkansyreanhydrid, hvilket fører til dannelsen av 2-acyloxy-pyridinet, som ved sur, nøytral eller basisk hydrolyse gir 2-[lH]-pyridon (E). Nitrering av pyridonet (E) vil resultere i det til-svarende nitropyridon (II). Nitropyridonet (II) kan fremstilles på en alternativ måte ved aminering av pyridinet (A) for å danne aminopyridinet (B) . Aminopyridinet (B) kan enten nitreres for å danne et amino-nitropyridin (C) som så diazoteres til nitropyridonet (II) eller alternativt overføres aminopyridinet til pyridonet (E) og nitreres så for å danne nitropyridinet (II), som er utgangsmateri-alet ved foreliggende fremgangsmåte. Reduksjon av nitropyridonet (II) vil føre til dannelsen av aminopyridonet (H) ifølge oppfinnelsen, idet dette aminopyridon (H) ved samtidig acylering ifølge oppfinnelsen overføres til de substituerte aminopyridoner (I). A convenient way to prepare the process compounds, as illustrated in the following process scheme, generally involves oxidation of a pyridine (A) to the corresponding N-oxide (F). N-oxydef can be transferred to the 2-[lH]-pyridone by heating with lower alkanoic anhydride, leading to the formation of the 2-acyloxy-pyridine, which on acid, neutral or basic hydrolysis yields 2-[lH]-pyridone (E). Nitration of the pyridone (E) will result in the corresponding nitropyridone (II). The nitropyridone (II) can be prepared in an alternative way by amination of the pyridine (A) to form the aminopyridine (B). The aminopyridine (B) can either be nitrated to form an amino-nitropyridine (C) which is then diazotized to the nitropyridone (II) or alternatively the aminopyridine is transferred to the pyridone (E) and then nitrated to form the nitropyridine (II), which is the starting material by the present method. Reduction of the nitropyridone (II) will lead to the formation of the aminopyridone (H) according to the invention, as this aminopyridone (H) is transferred to the substituted aminopyridones (I) by simultaneous acylation according to the invention.

r-*- t og R er som ovenfor angitt. r-*- t and R are as stated above.

Eksempel Example

Fremstilling av utqanqsmaterialer Production of output materials

A. Fremstilling av 2- amino- 4- methylpyridin A. Preparation of 2-amino-4-methylpyridine

Til en omrørt suspensjon av friskt fremstilt natriumamid (fra 24 g natrium) i 90 ml dimethylanilin (fremstilt ved fremgangs-måten i Organic Reactions, Vol. I) tilsettes 0,8 mol 4-methylpyridin, og den dannede blanding oppvarmes langsomt til ca. 155°C. Efter at hydrogenutviklingen er avtatt betraktelig, får reaksjonen lov til å fortsette i 5 timer og derpå avkjøles. Blandingen spaltes med l6o ml 5%-ig natriumhydroxydoppløsriing og ekstraheres med benzen. Benzenekstraktene tørres, inndampes i vakuum og det oljeaktige residuum krystalliseres fraksjonert fra ether-petrol-ether., hvilket gir 2-amino-4-methylpyridin. To a stirred suspension of freshly prepared sodium amide (from 24 g of sodium) in 90 ml of dimethylaniline (prepared by the method in Organic Reactions, Vol. I) is added 0.8 mol of 4-methylpyridine, and the resulting mixture is slowly heated to approx. 155°C. After hydrogen evolution has subsided considerably, the reaction is allowed to continue for 5 hours and then cooled. The mixture is split with 160 ml of 5% sodium hydroxide solution and extracted with benzene. The benzene extracts are dried, evaporated in vacuo and the oily residue fractionally crystallized from ether-petrol-ether., which gives 2-amino-4-methylpyridine.

B. Fremstillingen av 2- amino- 4- methyl- 3- nitropyridi- B. The preparation of 2- amino- 4- methyl- 3- nitropyridi-

Til en isavkjølt, omrørt blanding av 0,19 mol 2-amino-4-methylpyridinet fra trinn A i 120 ml konsentrert svovelsyre tilsettes 15»2 ml konsentrert salpetersyre i 30 ml svovelsyre i løpet av 1,3 timer, idet temperaturen av blandingen holdes under 6°C. Efter oppvarmning til værelsetemperatur oppvarmes blandingen langsomt til 92°C, holdes i 3 timer ved denne temperatur, avkjøles og tilsettes så til 2 liter is. Blandingen gjøres så basisk med konsentrert ammoniumhydroxyd. Den erholdte blanding ekstraheres med kloroform, kloroformen fjernes i vakuum og residuet damp-' destilleres. Destillatet oppsamles inntil destillasjonskolben er fri for de mere flyktige isomerer. Ekstraksjon av destillatet med methylenklorid gir 2-amino-4-methyl-3-nitxopyridin. To an ice-cooled, stirred mixture of 0.19 mol of the 2-amino-4-methylpyridine from step A in 120 ml of concentrated sulfuric acid, 15.2 ml of concentrated nitric acid in 30 ml of sulfuric acid are added over the course of 1.3 hours, while the temperature of the mixture is maintained below 6°C. After heating to room temperature, the mixture is slowly heated to 92°C, held for 3 hours at this temperature, cooled and then added to 2 liters of ice. The mixture is then made basic with concentrated ammonium hydroxide. The resulting mixture is extracted with chloroform, the chloroform is removed in vacuo and the residue is steam-distilled. The distillate is collected until the distillation flask is free of the more volatile isomers. Extraction of the distillate with methylene chloride gives 2-amino-4-methyl-3-nitxopyridine.

C. Fremstilling av 4-methyl-3-nitro-2-[lH]-pyridon C. Preparation of 4-methyl-3-nitro-2-[1H]-pyridone

Til en omrørt oppløsning av 0,032 mol 2-amino-4-methy1-3-nitropyridin fra trinn B i en blanding av 9 ml svovelsyre og 90 ml vann ved 5° C tilsettes en konsentrert vandig oppløsning av 2,4 g (0,022 mol) natriumnitrit mens temperaturen holdes under 10°C ved utvendig kjøling. Blandingen får lov til å oppvarmes til værelsetemperatur, oppvarmes til 45°C, avkjøles, filtreres, og det opp-samlede produkt vaskes med "vann og tørres, hvorved man får 4-methyl-3-nitro-2-[lH]-pyridon. Omkrystallisasjon gir det rene materiale. To a stirred solution of 0.032 mol of 2-amino-4-methyl-3-nitropyridine from step B in a mixture of 9 ml of sulfuric acid and 90 ml of water at 5° C is added a concentrated aqueous solution of 2.4 g (0.022 mol) sodium nitrite while the temperature is kept below 10°C by external cooling. The mixture is allowed to warm to room temperature, warmed to 45°C, cooled, filtered, and the collected product washed with water and dried to give 4-methyl-3-nitro-2-[1H]-pyridone Recrystallization gives the pure material.

Fremstilling av sluttprodukt Production of final product

D. Fremstilling av 3-acetamido-4-methyl-2-[lH]-pyridon og N-(4~D. Preparation of 3-acetamido-4-methyl-2-[1H]-pyridone and N-(4~

methyl- 2-[ lH]- pyridon- 3- yl)- acetimid methyl-2-[1H]-pyridon-3-yl)-acetimide

En blanding av 3,0 g (0,02 mol) 4-methyl-3-nitro-2-[lH]-pyridon, 100 ml eddiksyreanhy.drid, 0,5 ml eddiksyre og 1,0 g 5%-ig palladium-på-carbon omsettes i en hydrogenatmosfære (2,8 kg/cm 2) ved værelsetemperatur. Da den teoretiske mengde hydrogen var opp-tatt, ble blandingen filtrert og konsentrert i vakuum til ca. 10 g. Oljen ble så tilsatt til 50 ml isvann, omrørt over natten og den vandige blanding inndampet i vakuum til en tykk olje som størknet ved triturering med ether under dannelse av et hvitt, fast stoff. Fraksjonert omkrystallisasjon fra aceton ga acetatet, 3-acetamido-4-methyl-2-[lH]-pyridon med smeltepunkt 218-220,5°C, og imidet, N-(4-methyl-2-[lH]-pyridon-3-yl)-acetimid, smeltepunkt 159-163°C. A mixture of 3.0 g (0.02 mol) 4-methyl-3-nitro-2-[1H]-pyridone, 100 ml acetic anhydride, 0.5 ml acetic acid and 1.0 g 5% palladium -on-carbon is reacted in a hydrogen atmosphere (2.8 kg/cm 2 ) at room temperature. When the theoretical amount of hydrogen had been absorbed, the mixture was filtered and concentrated in vacuum to approx. 10 g. The oil was then added to 50 ml of ice water, stirred overnight and the aqueous mixture evaporated in vacuo to a thick oil which solidified by trituration with ether to form a white solid. Fractional recrystallization from acetone gave the acetate, 3-acetamido-4-methyl-2-[lH]-pyridone, m.p. 218-220.5°C, and the imide, N-(4-methyl-2-[lH]-pyridone- 3-yl)-acetimide, melting point 159-163°C.

Claims (1)

Analogifremgangsmåte ved fremstilling av terapeutisk aktive forbindelser av den generelle formel:Analogous method for the preparation of therapeutically active compounds of the general formula: 1 2 hvor R er lavere alkyl, R er hydrogen eller lavere alkanoyl,. og Ru 3 er lavere alkanoyl, karakterisert ved at en forbindelse av den generelle formel: hvor R er som ovenfor angitt, reduseres under samtidig eller på-følgende acylering.1 2 where R is lower alkyl, R is hydrogen or lower alkanoyl,. and Ru 3 is lower alkanoyl, characterized in that a compound of the general formula: where R is as indicated above, is reduced during simultaneous or subsequent acylation.
NO4295/70A 1969-11-12 1970-11-11 NO133669C (en)

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US4467087A (en) * 1973-05-03 1984-08-21 Smith Kline & French Laboratories Limited 1,2,4-Triazines
US4035374A (en) * 1973-05-03 1977-07-12 Smith Kline & French Laboratories Limited Imidazolyl alkylaminopyridone and pyridinethione compounds
US4260744A (en) * 1973-05-03 1981-04-07 Smith Kline & French Laboratories Limited Pharmacologically active compounds
US4578459A (en) * 1973-05-03 1986-03-25 Smithkline & French Laboratories Limited Heterocyclic alkylaminoheterocycles
DE3106460A1 (en) * 1980-03-03 1982-01-28 Sandoz-Patent-GmbH, 7850 Lörrach 2 (1H) -PYRIDINONE DERIVATIVES, THEIR PRODUCTION AND THE PHARMACEUTICAL PREPARATIONS CONTAINING THE SAME
US4371537A (en) * 1981-08-13 1983-02-01 The Dow Chemical Company Sulfur-substituted phenoxypyridines having antiviral activity
US4412077A (en) * 1982-03-15 1983-10-25 Sterling Drug Inc. Process for preparing 5-(lower-alkanoyl)-6-(lower-alkyl)-2(1H)-pyridinone
US4524149A (en) * 1982-03-15 1985-06-18 Sterling Drug Inc. 5-Alkanoyl-6-alkyl-2(1H)-pyridinones, their preparation and their cardiotonic use
US4451469A (en) * 1982-12-16 1984-05-29 Sterling Drug Inc. Selected 6-alkyl-and 4,6-dialkyl-2(1H)-pyridinones as cardiotonics
US4681873A (en) * 1985-07-29 1987-07-21 Warner-Lambert Company 4-amino-3-halo-2-pyridinone nucleoside and nucleotide compounds
US5164506A (en) * 1988-12-14 1992-11-17 Bayer Aktiengesellschaft Substituted 2-pyridones and pyrid-2-thiones compounds
US5032602A (en) * 1988-12-14 1991-07-16 Bayer Aktiengesellschaft Inhibiting HMG-CoA reductase with novel substituted 2-pyridones and pyrid-2-thiones
US5308854A (en) * 1990-06-18 1994-05-03 Merck & Co., Inc. Inhibitors of HIV reverse transcriptase
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KR100901931B1 (en) 2002-02-14 2009-06-10 파마시아 코포레이션 Substituted Pyridinones as Modulators of P38 MAP Kinase
AU2007202607B2 (en) * 2002-02-14 2008-12-18 Pharmacia Corporation Substituted Pyridinones as Modulators of p38 MAP Kinase
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