DK152050B - ANALOGY PROCEDURE FOR THE PREPARATION OF OXAZOLOPYRIDINES - Google Patents
ANALOGY PROCEDURE FOR THE PREPARATION OF OXAZOLOPYRIDINES Download PDFInfo
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- DK152050B DK152050B DK284973AA DK284973A DK152050B DK 152050 B DK152050 B DK 152050B DK 284973A A DK284973A A DK 284973AA DK 284973 A DK284973 A DK 284973A DK 152050 B DK152050 B DK 152050B
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- C—CHEMISTRY; METALLURGY
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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
- C07D213/69—Two or more oxygen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- 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]
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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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- C07D213/00—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
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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
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
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- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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Description
DK 152050BDK 152050B
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte oxazolopyridinderivater, hvilke forbindelser har værdifulde antiinf 1 animatoriske, antipyretiske og analgetiske egenskaber.The present invention relates to an analogous process for the preparation of novel oxazolopyridine derivatives which have valuable anti-inflammatory, antipyretic and analgesic properties.
Forbindelserne har den i kravet angivne formel I, hvori R, R"*- og m har den der angivne betydning.The compounds have the formula I according to the claim, wherein R, R "- and m have the meaning given therein.
Fremgangsmåden ifølge opfindelsen er ejendommelig ved det i kravets kendetegnende del anførte.The process according to the invention is characterized by the characterizing part of the claim.
De ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser egner sig til behandling af inflammationer, og de udviser endvidere kraftig analgetisk og antipyretisk aktivitet, således at de kan benyttes til behandling af smerte og feber, som ikke er symptomatisk knyttet til en inflammatorisk lidelse.The compounds of the present invention are suitable for the treatment of inflammation, and they also exhibit potent analgesic and antipyretic activity so that they can be used to treat pain and fever which are not symptomatic of an inflammatory disorder.
Det er kendt at anvende forskellige steroider med antiinflammatorisk aktivitet, men det er også kendt, at sådanne steroider har uønske-It is known to use various steroids with anti-inflammatory activity, but it is also known that such steroids have undesirable effects.
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de sidevirkninger, og der har derfor været et behov for at fremstille antiinflammatoriske midler, der ikke er steroider. Derved er fremkommet nogle få meget effektive og værdifulde midler, som adskiller sig fra steroider og ikke har disses uønskede sidevirkninger og kontraindikationer.the side effects, and there has therefore been a need to produce non-steroidal anti-inflammatory agents. This has resulted in a few very effective and valuable agents that differ from steroids and do not have their undesirable side effects and contraindications.
Ted fremgangsmåden ifølge opfindelsen er tilvejebragt endnu en gruppe hidtil ukendte forbindelser med høj effektivitet som anti-infl animator i ske, antipyretiske og analgetiske midler. Ligesom andre kendte antiinflammatoriske midler er de omhandlede forbindelser inhibitorer for prostaglandin S syntesen.The Ted method of the invention provides yet another group of novel compounds of high efficiency as anti-infl animator in spoon, antipyretic and analgesic agents. Like other known anti-inflammatory agents, the subject compounds are inhibitors of prostaglandin S synthesis.
Forbindelserne er værdifulde til behandling af arthritis og dermatologiske lidelser, der er følsomme for antiinflammatoriske lægemidler. I almindelighed kan de benyttes til et stort antal lidelser, hvor et eller flere af symptomerne er inflammation, feber og smerte. Eksempler på sådanne lidelser er rheumatisk arthritis, osteoarthritis, gigt, infektiøs arthritis, rheumatisk feber og inflammatoriske angreb af øjnene. Forbindelserne udviser også høj analgetisk og antipyretisk aktivitet.The compounds are valuable in the treatment of arthritis and dermatological disorders that are sensitive to anti-inflammatory drugs. Generally, they can be used for a large number of disorders, one or more of the symptoms being inflammation, fever and pain. Examples of such disorders are rheumatic arthritis, osteoarthritis, arthritis, infectious arthritis, rheumatic fever, and inflammatory attacks of the eyes. The compounds also exhibit high analgesic and antipyretic activity.
Til disse formål indgives forbindeiserne oralt, topisk, parenteralt, ved inhalation eller rektalt i doser, der fremstilles på kendt måde ved opblanding i de sædvanlige bærermedier, tilsætningsmidler og fortyndingsmidler. Ted parenteral indgift forstås subkutan injektion, intravenøs, intramuskulær, intrasternal injektion eller infusion. De omhandlede forbindelser kan ikke blot anvendes til behandling af varmblodede dyr, såsom mus, rotter, heste, hunde og katte, men også til behandling af mennesker.For these purposes, the dressings are administered orally, topically, parenterally, by inhalation or rectally in doses prepared in known manner by mixing in the usual carrier media, additives and diluents. Ted parenteral administration is understood as subcutaneous injection, intravenous, intramuscular, intrasternal injection or infusion. The compounds of the present invention can be used not only for the treatment of warm-blooded animals, such as mice, rats, horses, dogs and cats, but also for the treatment of humans.
Farmaceutiske præparater indeholdende den aktive bestanddel kan have form af tabletter, piller, vandige eller olieagtige suspensioner, dispergerbare pulvere eller granulater, emulsioner, hårde eller bløde kapsler, sirupper eller eliksirer. Præparater til oral indgift kan fremstilles på i og for sig kendt måde, idet der kan tilsættes de sædvanlige tilsætningsmidler, såsom sødemidler, aromastoffer, farvestoffer og præserveringsmidler, til opnåelse i af hensigtsmæssige og velsmagende præparater. Tabletterne kan indeholde den aktive bestanddel i blanding med ikke-giftige farmaceutisk acceptable fortyndingsmidler, som er egnede til fremstil-Pharmaceutical compositions containing the active ingredient may take the form of tablets, pills, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs. Compositions for oral administration may be prepared in a manner known per se, the usual additives such as sweeteners, flavorings, dyes and preservatives can be added to obtain convenient and tasty preparations. The tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable diluents suitable for preparation.
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ling af tabletter. Eksempler på sådanne fortyndingsmidler er ealciumcarbonat, natriumcarbonat, lactose, calciumphosphat eller natriumphosphat, granulerings- og disintegreringsmidler, for eksempel majsstivelse eller alginsyre, bindemidler, for eksempel stivelse, gelatine eller acacia, og smøremidler, for eksempel magnesiumstearat, stearinsyre eller talkum. Tabletterne kan om ønsket overtrækkes på kendt måde til opnåelse af præparater med forsinket opløsning og absorption i fordøjelsesorganeme, således at der opnås en virkning i et lasngere tidsrum. Eor eksempel kan der anvendes glycerylmonostearat eller glyceryldistearat som tidsforsinkende materiale.tablets. Examples of such diluents are alkaline carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents, for example corn starch or alginic acid, binders, for example starch, gelatin or acacia, and lubricants, for example magnesium stearate, stearic acid. If desired, the tablets may be coated in known manner to obtain delayed solution and absorption preparations in the digestive organs so as to obtain an effect over a longer period of time. For example, glyceryl monostearate or glyceryl distearate can be used as time-delay material.
Orale præparater kan også indføres i hårde gelatinekapsler, hvori den aktive bestanddel blandes med et inert fast fortyndingsmiddel, for eksempel ealciumcarbonat, calciumphosphat eller kaolin, eller bløde gelatinekapsler, hvori den aktive bestanddel blandes med vand eller et olieagtigt medium, for eksempel jordnøddeolie, flydende paraffin eller olivenolie.Oral preparations may also be introduced into hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, alkaline carbonate, calcium phosphate or kaolin, or soft gelatin capsules in which the active ingredient is mixed with water or an oily medium, for example, peanut oil, liquid paraffin or olive oil.
Vandige suspensioner indeholder den aktive bestanddel i blanding med fortyndingsmidler til fremstilling af vandige suspensioner.Aqueous suspensions contain the active ingredient in admixture with diluents to prepare aqueous suspensions.
Eksempler på sådanne fortyndingsmidler er suspenderingsmidler, såsom natriumcarboxymethylcellulose, methyleellulose, hydroxypropylmethyl-cellulose, natriumalginat, polyvinylpyrrolidon, gummi tragacanth og gummi acacia, dispergerings- og fugtemidler, såsom naturligt forekommende phosphatider, for eksempel lecithin, eller kondensationsprodukter af et alkylenoxid og fedtsyre, for eksempel polyoxyethylen-stearat, eller kondensationsprodukter af ethylenoxid med langkædede alifatiske alkoholer, for eksempel heptadecaethylenoxycetanol, eller kondensationsprodukter af ethylenoxid med partielle estere, der er afledt af fedtsyre og en hexitol, såsom polyoxyethylen-sorbitolmonooleat, eller kondensationsprodukter af ethylenoxid med partielle estere, der er afledt af fedtsyre og hexitolanhydrider, for eksempel polyoxyethylensorbitanmonooleat. De nævnte vandige suspensioner kan også indeholde et eller flere præserveringsmidler, for eksempel ethyl-, n-propyl- og p-hydroxybenzoat, eller et eller flere farvestoffer, et eller flere aromastoffer og et eller flere sødemidler, såsom saccharose eller saccharin.Examples of such diluents are suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, dispersing and wetting agents such as naturally occurring phosphate or humectant, e.g. polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate or condensation products of ethylene oxide of fatty acid and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate. Said aqueous suspensions may also contain one or more preservatives, for example ethyl, n-propyl and p-hydroxybenzoate, or one or more dyes, one or more flavoring agents and one or more sweetening agents such as sucrose or saccharin.
Olieagtige suspensioner kan fremstilles ved suspendering af den ηι.4.4«»Α S π*» μ m T« J *1 λΊ .S λ ara *ι ολΊ ί λOily suspensions may be prepared by suspending the ηι.4.4 «» Α S π * »μ m T« J * 1 λΊ .S λ ara * ι ολΊ ί λ
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olivenolie, sesamolie eller kokosnøddeolie, eller i en mineralolie, såsom flydende paraffin. De olieagtige suspensioner kan indeholde et fortykkelsesmiddel, for eksempel bivoks, hård paraffin eller ce-tyialkohol. Sødemidler, såsom de ovenfor angivne, og aromastoffer kan tilsættes til opnåelse af velsmagende orale præparater. Disse blandinger kan præserveres ved tilsætning af en antioxidant, såsom ascorbinsyre.olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cationic alcohol. Sweeteners such as those listed above and flavorings may be added to give tasty oral preparations. These mixtures can be preserved by the addition of an antioxidant such as ascorbic acid.
Dispergerbare pulvere og granulater, der egner sig til fremstilling af en vandig suspension ved tilsætning af vand, indeholder den aktive bestanddel i blanding med dispergerings- eller fugtemidler, suspenderingsmidler og et eller flere præserveringsmidler. Egnede dispergerings- eller fugtemidler og suspenderingsmidler er nærmere omtalt ovenfor. Der kan tilsættes yderligere fortyndingsmidler, for eksempel sødestoffer, aromastoffer og farvestoffer.Dispersible powders and granules suitable for preparing an aqueous suspension by addition of water contain the active ingredient in admixture with dispersing or wetting agents, suspending agents and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are discussed above. Additional diluents may be added, for example sweeteners, flavorings and dyes.
De omhandlede aktive forbindelser kan om ønsket også indgå i olie- i-vand-emulsioner. Den olieagtige fase kan være en vegetabilsk olie, for eksempel olivenolie eller arachisolie, eller en mineralolie, for eksempel flydende paraffin eller blandinger af disse.The present active compounds may also be included in oil-in-water emulsions if desired. The oily phase may be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures thereof.
Egnede emulgeringsmidler kan være naturligt forekommende gummier, for eksempel gummi acacia eller gummi tragaeanth, naturligt forekommende phosphatider, for eksempel sojabønnelecithin, estere eller partielle estere, afledt af fedtsyre og hexitolanhydrider, for eksempel sorbitanmonooleat, og kondensationsprodukter af de nævnte partielle estere med ethylenoxid, for eksempel polyoxyethylen-sorbitanmonooleat. Emulsionerne kan også indeholde sødemidler og aromastoffer.Suitable emulsifiers may be naturally occurring gums, for example rubber acacia or gum tragaeanth, naturally occurring phosphatides, for example, soybean lecithin, esters or partial esters, derived from fatty acid and hexitol anhydrides, for example, sorbitan monoolide, and condensation products, eg polyoxyethylene sorbitan monooleate. The emulsions may also contain sweeteners and flavorings.
Sirupper og eliksirer kan formuleres med sødemidler, for eksempel glycerol, sorbitol eller saccharose. Sådanne præparater kan også indeholde blødgøringsmidler, præserveringsmidler, aromastoffer og farvestoffer. De farmaceutiske præparater kan forekomme i form af sterile injicerbare præparater, for eksempel en steril injicerbar vandig eller olieholdig suspension. Denne suspension kan formuleres på i og for sig kendt måde under anvendelse af egnede dispergerings- eller fugtemidler og suspenderingsmidler som ovenfor angivet. i Det sterile injicerbare præparat kan også indeholde en steril inji- I carbar opløsning eller suspension i et ikke-giftigt parenteralt j acceptabelt fortyndingsmiddel eller opløsningsmiddel, for eksempel jSyrups and elixirs can be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. Such preparations may also contain plasticizers, preservatives, flavorings and dyes. The pharmaceutical compositions may be in the form of sterile injectable preparations, for example a sterile injectable aqueous or oily suspension. This suspension may be formulated in a manner known per se using suitable dispersing or wetting agents and suspending agents as indicated above. The sterile injectable composition may also contain a sterile injectable solution or suspension in a non-toxic parenteral acceptable diluent or solvent, e.g.
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en opløsning i 1,3-hutandiol. Blandt acceptable bærermedier og opløsningsmidler kan nævnes vand, Ringer*s opløsning og iso-tonisk natriumchloridopløsning. Desuden kan anvendes sterile, ikke-flygtige olier som opløsningsmidler eller suspenderingsmedium. Til dette formål kan anvendes en vilkårlig blandet fikseret olie, herunder syntetiske mono- eller diglycerider. Desuden kan anvendes fedtsyre, såsom oleinsyre, til fremstilling af inhicerba-re tabletter.a solution in 1,3-hutanediol. Among acceptable carriers and solvents are water, Ringer * s solution and isotonic sodium chloride solution. In addition, sterile, non-volatile oils can be used as solvents or suspending medium. For this purpose any mixed fixed oil, including synthetic mono- or diglycerides, may be used. In addition, fatty acid, such as oleic acid, can be used to prepare inducible tablets.
De omhandlede forbindelser kan også indgives i form af suppositorier for rektal indgift af lægemidler. Disse præparater kan fremstilles ved blanding af lægemidlet med et egnet ikke-irriterende fortyndingsmiddel, der er fast ved sædvanlig temperatur, men bliver flydende ved legemstemperaturen, og som derfor vil smelte i rektum til frigivelse af lægemidlet. Sådanne stoffer er kakaosmør og polyethylenglycol.The compounds of the invention may also be administered in the form of suppositories for rectal administration of drugs. These compositions may be prepared by mixing the drug with a suitable non-irritating diluent which is solid at the usual temperature but becomes liquid at the body temperature and which will therefore melt in the drug release rectum. Such substances are cocoa butter and polyethylene glycol.
Til topisk anvendelse kan anvendes cremer,, salver, gelatinøse blandinger, opløsninger eller suspensioner indeholdende det anti-inflammatoriske middel.For topical application, creams, ointments, gelatinous mixtures, solutions or suspensions containing the anti-inflammatory agent may be used.
Dosisstørrelser kan ligge på 0,5 - 140 mg pr. kilogram legemsvægt, og passende doser til voksne patienter er således fra 25 mg - 7 g· Til behandling af inflammation eller til opnåelse af en anti-pyretisk eller analgetisk aktivitet kan benyttes mellem 0,1 og 50 mg af forbindelsen pr. kilogram legemsvægt pr. dag (5 mg til 3,5 g pr. patient pr. dag). Optimale doser ligger mellem 1 mg og 15 mg pr. kilogram legemsvægt pr. dag (50 mg til 1 g pr. patient pr. dag).Dose sizes can range from 0.5 - 140 mg per day. Thus, the appropriate dosages for adult patients are from 25 mg - 7 g. · For the treatment of inflammation or to achieve an anti-pyretic or analgesic activity, between 0.1 and 50 mg of the compound can be used per day. per kilogram of body weight per per day (5 mg to 3.5 g per patient per day). Optimal doses are between 1 mg and 15 mg per day. per kilogram of body weight per per day (50 mg to 1 g per patient per day).
Forholdet mellem den aktive bestanddel og bæremediet kan varieres efter behov. Således kan den aktive bestanddel udgøre mellem 5 og 95 $ af det totale præparat. Enkelte doser kan indeholde fra 25 ®g til 500 mg af den aktive bestanddel.The ratio of the active ingredient to the carrier can be varied as required. Thus, the active ingredient may comprise between 5 and 95 $ of the total composition. Single doses may contain from 25 µg to 500 mg of the active ingredient.
Mængden af stof, der anvendes ved en behandling, afhænger af sygdommens art og patientens tilstand. Således kan alder, legemsvægt, almindelig sundhedstilstand, køn, diæt, indgivelsestidspunkt, indgivelsesvej, udskillelseshastighed, lægemiddel-kombination og sygdommens art og styrke spille en rolle for valg af terapi.The amount of drug used in a treatment depends on the nature of the disease and the condition of the patient. Thus, age, body weight, general health, gender, diet, time of administration, route of administration, rate of excretion, drug combination and nature and disease may play a role in the choice of therapy.
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Forbindelserne fremstilles som nævnt ved fremgangsmåden ifølge opfindelsen* der er ejendommelig ved det i den kendetegnende del af kravet anførte.The compounds are prepared as mentioned by the method according to the invention, which is characterized by the characterizing part of the claim.
Ifølge en hensigtsmæssig udførelsesform for fremgangsmåden ifølge opfindelsen fremstilles forbindelserne ved kondensationscyclisa-tion af en aminohydroxypyridin med en carboxylsyre, et syre-anhydrid eller syrehalogenid med formlen: O 0 R-C-OH, R-C-O- eller halogenid, i overensstemmelse med følgende reaktionsligning: ^ φ z] R1—V N T + ^C-R3-> pi--N i[ // ‘ R3 m I r-if m [I2 0 I afhængighed af kondensationsmidlets art og i nogen grad af den anvendte aminohydroxypyridin kan reaktionen enten betragtes som en ringslutning i et enkelt fælles trin eller som en to trinsproces, der som første trin omfatter dannelsen af et amid efterfulgt af ringslutning af amidet til dannelse af oxazoloringen. I mange tilfælde har det vist sig tilrådeligt og bekvemt at isolere amidmellemproduktet og foretage ringslutningen i et andet særskilt trin.According to a convenient embodiment of the process according to the invention, the compounds are prepared by condensation cyclization of an amino hydroxypyridine with a carboxylic acid, anhydride or acid halide of the formula: O RC-OH, RCO or halide, according to the following reaction equation: ] R1 - VNT + ^ C-R3-> pi - N in [// R3 m I r-if m [I2 0 Depending on the nature of the condensing agent and to some extent on the aminohydroxypyridine used, the reaction can either be considered a cyclization in a single common step or as a two step process comprising as the first step the formation of an amide followed by cyclization of the amide to form the oxazol ring. In many cases, it has been found advisable and convenient to isolate the amide intermediate and make the ring closure in another separate step.
Fremgangsmåden ifølge opfindelsen skal i det efterfølgende illustreres nærmere ved hjælp af nogle udførelseseksempler, hvor de med bogstav nummererede eksempler er eksempler på forbindelser, der ikke er omfattet af,den foreliggende opfindelse.The process according to the invention will be further illustrated in the following with the aid of some exemplary embodiments, the examples of which are numbered by letter being examples of compounds not covered by the present invention.
EKSEMPEL_AEKSEMPEL_A
! 2-Phenyloxazolo[4,5-b]pyridin j i! 2-Phenyloxazolo [4,5-b] pyridine j i
En blanding af 21 g 2-amino-3-hydroxypyridin og 130 g benzoesyre- j i anhydrid opvarmes til dannelse af en smelte og derefter, indtil | blandingen begynder at koge. Efter 10 minutter fjernes varmetil-A mixture of 21 g of 2-amino-3-hydroxypyridine and 130 g of benzoic acid in anhydride is heated to form a melt and then until | the mixture begins to boil. After 10 minutes, heat
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førslen, og efter afkøling i flere minutter hældes smelten i 2 liter benzen. Den dannede opløsning ekstraheres med 4 x 200 ml 2,5 N saltsyre. Denne sure opløsning gøres derefter basisk med natriumhydroxidopløsning. Bundfaldet opsamles og omkrystalliseres af 90 ml absolut ethanol, hvorved fås 12,5 g 2-phenyloxazolo-[4,5-b]pyridin, smp.: 125 - 127° C.and after cooling for several minutes, the melt is poured into 2 liters of benzene. The resulting solution is extracted with 4 x 200 ml 2.5 N hydrochloric acid. This acidic solution is then made basic with sodium hydroxide solution. The precipitate is collected and recrystallized from 90 ml of absolute ethanol to give 12.5 g of 2-phenyloxazolo [4,5-b] pyridine, mp: 125 - 127 ° C.
Ved anvendelse af samme fremgangsmåde som angivet i eksempel A med den ændring, at benzoesyreanhydridet erstattes med en ækvivalent mængde af et anhydrid med formlen: (R-CO^O, fremstilles 2- R-oxazolo[4,5-b]pyridinen som angivet i tabel I i overensstemmelse med følgende ligning:Using the same procedure as in Example A with the change that the benzoic anhydride is replaced by an equivalent amount of an anhydride of the formula: (R-CO 2 O, 2-R-oxazolo [4,5-b] pyridine is prepared as indicated). in Table I according to the following equation:
RV~v ji ·*· <r-oo)2o-> 'J .....RRV ~ v ji · * · <r-oo) 2o-> 'J ..... R
"R " RH2 ^"R" RH 2
Tabel_ITabel_I
Eksempel R1 R _Smp. (°C) 1 H 3-pyridyl 155 - 156Example R1 R _Smp. (° C) 1H 3-pyridyl 155 - 156
EKSEMPEL_BEKSEMPEL_B
2-(2-Eluorphenyl)oxazolo[4,5-b]pyridin2- (2-fluorophenyl) oxazolo [4,5-b] pyridine
En blanding af 5,5 g (0,05 mol) 2-amino-5-hydroxypyridin, 5,6 g (0,04 mol) 2-fluorbenzoesyre og 12 g polyphosphorsyre opvarmes til 175° C og holdes ved denne temperatur i 10 minutter. Efter afkøling hældes lidt af smelten i en blanding af is og vand.A mixture of 5.5 g (0.05 mole) of 2-amino-5-hydroxypyridine, 5.6 g (0.04 mole) of 2-fluorobenzoic acid and 12 g of polyphosphoric acid is heated to 175 ° C and maintained at this temperature for 10 minutes. minutes. After cooling, a little of the melt is poured into a mixture of ice and water.
Efter omrøring til dekomponering af polyphosphorsyren gøres blandingen alkalisk med ammoniumhydroxidopløsning. Det dannede bundfald opsamles og omkrystalliseres af benzen/petroleumsether, hvorved fås 4,0 g 2-(2-fluorphenyl)oxazolo[4,5-b]pyridin, smp.: 126 - 127° C.After stirring to decompose the polyphosphoric acid, the mixture is made alkaline with ammonium hydroxide solution. The precipitate formed is collected and recrystallized from benzene / petroleum ether to give 4.0 g of 2- (2-fluorophenyl) oxazolo [4,5-b] pyridine, mp: 126 - 127 ° C.
Ved anvendelse af fremgangsmåden ifølge eksempel B, idet der i stedet for den anvendte 2-fluorbenzoesyre anvendes en ækvivalent mængde af en benzoesyre med formlen: R~COOH, fremstilles de iUsing the method of Example B, where, instead of the 2-fluorobenzoic acid used, an equivalent amount of a benzoic acid of the formula: R ~ COOH is used.
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tabel II nævnte 2-R-oxazolo[4,5-b]pyridiner i overensstemmelse med følgende ligningsTable II mentioned 2-R-oxazolo [4,5-b] pyridines according to the following equation
>S>0H> S> 0H
R“ L X + R"C00H -* Rm-f- f VrR “L X + R" C00H - * Rm-f- f Fr
2 N2 N
TABEL_IITABEL_II
Reaktions-Eksempel temperatur nr._(fCJ_R* R_Smp. (°C) 2 210 H β-naphthyl 160 - 161 3 190 H 5-n-propylpyrid- 2-on-3-yl 251 - 252 4 200 H styryl 109 - 110 5 200 H 3-nitrophenyl 199 - 201 6 200 H biphenyl 188 - 189 7 145 H benzyl 95 - 97 8 170 H cyclohexyl 95 - 96 9 175 H 2-bromphenyl 60 - 61 10 210 H 4-methylsulfonyl- phenyl 277 - 279 11 175 H pyrid-2-yl 197 - 198 12 210 H pyrid-4-yl 171 - 173 13 180-205 H 2-methylsulfonyl- phenyl 140 - 144 14 180-185 H thiazol-4-yl 215 - 216 15 180-185 H 3-hydroxyphenyl '209 - 210 16 180-185 H 2-methylthio- phenyl 135,5 - 137,5 17 225 H imidazol-4(eller 5)-yl 271 - 272 18 180-185 H 3-methylthio- phenyl 82 - 84 19 180-185 H 2,3-dimethyl- phenyl 72 - 73 20 180-185 H 4-trifluor- methoxyphenyl 139 - 141Reaction Example Temperature No._ (fCJ_R * R_Mp. (° C) 2 210 H β-Naphthyl 160 - 161 3 190 H 5-n-propylpyrid-2-one-3-yl 251 - 252 4 200 H styryl 109 - 110 5 200 H 3-nitrophenyl 199 - 201 6 200 H biphenyl 188 - 189 7 145 H benzyl 95 - 97 8 170 H cyclohexyl 95 - 96 9 175 H 2-bromophenyl 60 - 61 10 210 H 4-methylsulfonyl-phenyl 277 - 279 11 175 H pyrid-2-yl 197 - 198 12 210 H pyrid-4-yl 171 - 173 13 180-205 H 2-methylsulfonyl-phenyl 140 - 144 14 180-185 H thiazol-4-yl 215 - 216 15 180-185 H 3-hydroxyphenyl 209 - 210 16 180-185 H 2-methylthiophenyl 135.5 - 137.5 17 225 H imidazole-4 (or 5) -yl 271 - 272 18 180-185 H 3- methylthiophenyl 82 - 84 19 180-185 H 2,3-dimethylphenyl 72 - 73 20 180-185 H 4-trifluoromethoxyphenyl 139-141
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2-(3-Dimethylaminophenyl)oxazolo[4,5-b3 pyridin EKSEMPEL_212- (3-Dimethylaminophenyl) oxazolo [4,5-b3 pyridine EXAMPLE_21
En blanding af 2,4 g 2-(3-nitrophenyl)oxazolo[4,5-b]pyridin, 6 ml 37 1o formaldehydopløsning, 50 ml eddikesyre og 0,25 g Raney-nik-kel hydrogeneres. Katalysatoren frafiltreres, og filtratet inddampes til tørhed. Remanensen fordeles mellem vandig natriumbi-carbonatopløsning og benzen. Benzenfasen fraskilles, tørres over vandfrit natriumsulfat og inddampes til en olie. Olien optages i methylenchlorid og behandles med tør ether, der er mættet med hydrogenchlorid. Det dannede bundfald opsamles og vaskes med ether, hvorved fås 2-(3-dimethylaminophenyl)oxazolo[4,5-b]-pyridin«2H01, smp.: 208 - 209° C.A mixture of 2.4 g of 2- (3-nitrophenyl) oxazolo [4,5-b] pyridine, 6 ml of 37 l of formaldehyde solution, 50 ml of acetic acid and 0.25 g of Raney nickel is hydrogenated. The catalyst is filtered off and the filtrate is evaporated to dryness. The residue is partitioned between aqueous sodium bicarbonate solution and benzene. The benzene phase is separated, dried over anhydrous sodium sulfate and evaporated to an oil. The oil is taken up in methylene chloride and treated with dry ether saturated with hydrogen chloride. The precipitate formed is collected and washed with ether to give 2- (3-dimethylaminophenyl) oxazolo [4,5-b] pyridine 2H01, mp: 208-209 ° C.
Eksempel 22 2-(3-Aminophenyl)oxazolo[4,5-b]pyridinExample 22 2- (3-Aminophenyl) oxazolo [4,5-b] pyridine
En blanding af 700 mg 2-(3-nitrophenyl)oxazolo[4,5-b]pyridin i 50 ml ethanol hydrogeneres over 150 mg 5 1° palladium-på-carbon-katalysator. Katalysatoren frafiltreres, og opløsningen inddampes til tørhed. Remanensen omkrystalliseres af chloroform-petroleumsether til dannelse af 2-(3-aminophenyl)oxazolo[4,5-b]]- pyridin, smp,: 179 - 180,5° 0·A mixture of 700 mg of 2- (3-nitrophenyl) oxazolo [4,5-b] pyridine in 50 ml of ethanol is hydrogenated over 150 mg of 5 1 ° palladium-on-carbon catalyst. The catalyst is filtered off and the solution is evaporated to dryness. The residue is recrystallized from chloroform-petroleum ether to give 2- (3-aminophenyl) oxazolo [4,5-b]] -pyridine, mp: 179 - 180.5 °
Eksempel 23 2-Benzoyloxazolo[4,5-b]pyridinExample 23 2-Benzoyloxazolo [4,5-b] pyridine
En blanding af 800 mg 2-benzyloxazolo[4,5-b]pyridin, 2,5 g kalium-permanganat, 35 ml vand og 6 dråber 2,5 I natriumhydroxidopløsning opvarmes til 50 - 55° C i 3 timer. Efter afkøling tilsættes svovlsyre til en pH-værdi på ca. 6 og tilstrækkeligt natriumbisulfit til fjernelse af mangandioxid. Det krystallinske bundfald opsamles og omkrystalliseres af ethylacetat til dannelse af 2-benzoyloxazolo[4,5-b]Pyridin, smp.: 151 - 153° C.A mixture of 800 mg of 2-benzyloxazolo [4,5-b] pyridine, 2.5 g of potassium permanganate, 35 ml of water and 6 drops of 2.5 L of sodium hydroxide solution is heated to 50-55 ° C for 3 hours. After cooling, sulfuric acid is added to a pH of approx. 6 and sufficient sodium bisulfite to remove manganese dioxide. The crystalline precipitate is collected and recrystallized from ethyl acetate to give 2-benzoyloxazolo [4,5-b] pyridine, mp: 151 - 153 ° C.
2-( 3-Acetamidophenyl) oxazolo [4, 5-b ]pyridin2- (3-Acetamidophenyl) oxazolo [4,5-b] pyridine
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Eksempel 24Example 24
En opløsning af 0,63 g 2-(3-aminophenyl)oxazolo[4,5-b]pyridin i 10 ml pyridin behandles med 0,35 ml eddikesyreanhydrid under omrøring. Efter omrøring i 72 timer fortyndes blandingen til 50 ml med vand. Efter omrøring i kort tid og afkøling opsamles det dannede bundfald, der vaskes med vand og tørres. Ted omkrystallisation af ethylacetat fås 2-(3-acetamidophenyl)oxazolo[4,5-b]pyridin, smp.: 201,5 - 202,5° C.A solution of 0.63 g of 2- (3-aminophenyl) oxazolo [4,5-b] pyridine in 10 ml of pyridine is treated with 0.35 ml of acetic anhydride with stirring. After stirring for 72 hours, dilute the mixture to 50 ml with water. After briefly stirring and cooling, the formed precipitate is collected, washed with water and dried. Ted recrystallization from ethyl acetate gives 2- (3-acetamidophenyl) oxazolo [4,5-b] pyridine, mp: 201.5 - 202.5 ° C.
Eksempel 25 2-(2-Methylsulfinylphenyl)oxazolo[4,5-b]pyridinExample 25 2- (2-Methylsulfinylphenyl) oxazolo [4,5-b] pyridine
En opløsning af 0,5 g 2-(2-methylthiophenyl)oxazolo[4,5-b]-pyridin i 50 ml acetone behandles med 3 g natriummetaperiodat.A solution of 0.5 g of 2- (2-methylthiophenyl) oxazolo [4,5-b] pyridine in 50 ml of acetone is treated with 3 g of sodium metaperiodate.
Efter omrøring i 72 timer ved stuetemperatur fortyndes blandingen med 30 ml vand. Acetonen afdestilleres, og det dannede bundfald omkrystalliseres til dannelse af 2-(2-methylsulfinylphenyl)-oxazolo[4,5-bJpyridin, smp..: 153,5 - 155,5° C.After stirring for 72 hours at room temperature, the mixture is diluted with 30 ml of water. The acetone is distilled off and the precipitate formed is recrystallized to give 2- (2-methylsulfinylphenyl) oxazolo [4,5-b] pyridine, mp: 153.5 - 155.5 ° C.
Fremgangsmåden ifølge eksempel 25 gentages med 2-(3-methylthio-phenyl)oxazolo[4,5-b]pyridin som udgangsmateriale, hvorved fås 2-(3-methylsulfinylphenyl)oxazolo[4,5-b]pyridin.The procedure of Example 25 is repeated with 2- (3-methylthiophenyl) oxazolo [4,5-b] pyridine as starting material to give 2- (3-methylsulfinylphenyl) oxazolo [4,5-b] pyridine.
Eksempel c 2-(2-Fluorphenyl)oxazolo[5,4-b]pyridinExample c 2- (2-Fluorophenyl) oxazolo [5,4-b] pyridine
Trin A: Præparation af 3-(2-fluorbenzoylamino)-2-pvridonStep A: Preparation of 3- (2-fluorobenzoylamino) -2-pyridone
Til en opløsning af 3,3 g (0,03 mol) 3-amino-2-pyridon i 75 ml pyridin, afkølet på is, sættes portionsvis 6,3 g (0,04 mol) 2-fluorbenzoylchlorid i løbet af 5 minutter. Efter omrøring i 15 timer ved stuetemperatur hældes blandingen i isvand. Eet dannede bundfald opsamles ved filtrering, vaskes med vand og omkrystalliseres af ethanol, hvorved fås 3-(2-fluorbenzoylamino)-2- JTo a solution of 3.3 g (0.03 mole) of 3-amino-2-pyridone in 75 ml of pyridine, cooled on ice, add 6.3 g (0.04 mole) of 2-fluorobenzoyl chloride over 5 minutes. . After stirring for 15 hours at room temperature, the mixture is poured into ice water. An formed precipitate is collected by filtration, washed with water and recrystallized from ethanol to give 3- (2-fluorobenzoylamino) -2- J
o _ i pyridon, smp.; 223 C.o in pyridone, mp .; 223 C.
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Trin Bi Præparation af 2°(2-fluorphenvl)oxazoloΓ5.4—b1pyridinStep Bi Preparation of 2 ° (2-fluorophenyl) oxazolo5.4-b1pyridine
En opløsning af 5,4 g 3-(2-fluorbenzoylamino)-2-pyridon i 55 ml phosphoroxychlorid koges under tilbagesvaling i 5 timer. Overskud af phosphoroxychlorid afdampes, og remanensen behandles med is.A solution of 5.4 g of 3- (2-fluorobenzoylamino) -2-pyridone in 55 ml of phosphorus oxychloride is refluxed for 5 hours. Excess phosphorus oxychloride is evaporated and the residue is treated with ice.
Det dannede bundfald opsamles og omkrystalliseres af hexan-petroleumsether, hvorved fås 3,1 g 2-(2-fluorphenyl)oxazolo-[5,4-b]pyridin, smp.: 119 - 120° G.The precipitate formed is collected and recrystallized from hexane-petroleum ether to give 3.1 g of 2- (2-fluorophenyl) oxazolo [5,4-b] pyridine, mp: 119-120 ° G.
Ved fremgangsmåden ifølge eksempel C, trin A og B, idet der i stedet for 2-fluorbenzoylchlorid anvendes en ækvivalent mængde af et syrechlorid med formlen: R-COC1, fås 3-(R-carbonylamino)- 2-pyridoner og 2-R-oxazolo[5,4-b]pyridiner, der er angivet i tabel III, i overensstemmelse med følgende reaktioner:In the process of Example C, steps A and B, where instead of 2-fluorobenzoyl chloride, is used an equivalent amount of an acid chloride of formula: R-COCl, 3- (R-carbonylamino) -2-pyridones and 2-R oxazolo [5,4-b] pyridines listed in Table III according to the following reactions:
OISLAND
/V*h2 1J^V“/ V * h 2
A + o>R <\XA + o> R <\ X
Η HΗ H
OISLAND
Trxn B POCl^ f jT V*Trxn B POCl ^ f jT V *
N 0 HN 0 H
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Tabel IIITable III
Eksempel R1 R Produktets smeltepunkt (° C)Example R1 R Product melting point (° C)
Trin A Trin BStep A Step B
26 H 2-furyl 252-253 125-127 27· H 2-nitrophenyl 233-235 123-125 28 H 2-cyanophenyl 282 221 29 H 4-nitrophenyl 307 (dek.) 242-243 3C H 4-methylthiophenyl 228-229 157-159 31 H 4-cyanophenyl 258-260 220-221 32 H 3,4-methylendi- 232-234 185/5-187 oxyphenyl 33 H adamantan-l-yl 246-247 70-7126 H 2-furyl 252-253 125-127 27 · H 2-nitrophenyl 233-235 123-125 28 H 2-cyanophenyl 282 221 29 H 4-nitrophenyl 307 (dec.) 242-243 3C H 4-methylthiophenyl 228 229 157-159 31 H 4-cyanophenyl 258-260 220-221 32 H 3,4-methylenedi-232-234 185 / 5-187 oxyphenyl 33 H adamantan-1-yl 246-247 70-71
Eksempel 34 5-Chlor-2-phenyloxazolo[5,4-b ]pyridinExample 34 5-Chloro-2-phenyloxazolo [5,4-b] pyridine
Trin A: Præparation af 5-chlor-3-nitro-2-pyridon 2-Amino-5-chlorpyridin (12,8 g, 0,1 mol) sættes til 50 ml koncentreret svovlsyre. Hertil sættes under omrøring 25 ml koncentreret salpetersyre. Efter at den eksoterme reaktion er overstået afkøles blandingen, som hældes på is. Bundfaldet opsamles og sættes til en blanding af 12 ml koncentreret svovlsyre og 150 ml vand.Step A: Preparation of 5-chloro-3-nitro-2-pyridone 2-Amino-5-chloropyridine (12.8 g, 0.1 mol) is added to 50 ml of concentrated sulfuric acid. To this is added 25 ml of concentrated nitric acid. After the exothermic reaction is over, the mixture is cooled and poured onto ice. The precipitate is collected and added to a mixture of 12 ml of concentrated sulfuric acid and 150 ml of water.
Til denne opløsning, afkølet til 0° C, sættes 7 g natriumnitrit portionsvis, og den dannede blanding henstilles til opvarmning til stuetemperatur. Efter afkøling opsamles bundfaldet, der omkrystalliseres af dimethylformamid/ethanol til dannelse af 5-chlor-3-nitro-2-pyridon, smp.: 225 - 227° C.To this solution, cooled to 0 ° C, is added 7 g of sodium nitrite in portions and the resulting mixture is allowed to warm to room temperature. After cooling, the precipitate is collected, which is recrystallized from dimethylformamide / ethanol to give 5-chloro-3-nitro-2-pyridone, mp: 225 - 227 ° C.
Trin B: Præparation af 5-benzovlamino-5-chlor-2-pyridon 5-Chlor-3-nitro-2-pyridon (5,3 g) hydrogeneres i 225 ml ethanol og 6 ml eddikesyre i nærværelse af 0,6 g 5 °h palladium-på-carbon. Katalysatoren frafiltreres, og filtratet inddampes til tørhed. Remanensen opløses i 75 ml pyridin, afkølet på is, og behandles i løbet af 15 minutter med 4,8 g benzoylchlorid. Isbadet og reaktionsblandingen henstilles til opvarmning til stuetemperatur. jStep B: Preparation of 5-benzoylamino-5-chloro-2-pyridone 5-Chloro-3-nitro-2-pyridone (5.3 g) is hydrogenated in 225 ml of ethanol and 6 ml of acetic acid in the presence of 0.6 g of 5 ° h palladium-on-carbon. The catalyst is filtered off and the filtrate is evaporated to dryness. The residue is dissolved in 75 ml of pyridine, cooled on ice, and treated over 15 minutes with 4.8 g of benzoyl chloride. The ice bath and reaction mixture are allowed to warm to room temperature. j
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Blandingen hældes på 200 g is. Ved fortynding med 500 ml Tand udskilles en olie, der ved vask med vand stivner til dannelse af 4 g fast stof. Den urene 3-benzoylamino-5-chlor-2-pyridon anvendes den direkte i næste trin.The mixture is poured onto 200 g of ice. When diluted with 500 ml of Tooth, an oil is separated which, when washed with water, solidifies to form 4 g of solid. The impure 3-benzoylamino-5-chloro-2-pyridone is used directly in the next step.
Trin 0: Præparation af 5-chlor-2-phenyloxazolor5.4-blpyridinStep 0: Preparation of 5-Chloro-2-phenyloxazolor5,4-blpyridine
En blanding af 2,1 g uren 3-benzoylamino-5-chlor-2-pyridon og 7 g polyphosphorsyre opvarmes i 10 minutter til 140 - 150° C.A mixture of 2.1 g of crude 3-benzoylamino-5-chloro-2-pyridone and 7 g of polyphosphoric acid is heated for 10 minutes to 140 - 150 ° C.
Der tilsættes isvand, bundfaldet opsamles på filter, og det faste stof ekstraheres med varm benzen. Benzenen afdampes, og remanensen optages i ether, filtreres gennem aluminiumoxid og inddampes til tørhed, hvorved fås 300 mg 5-chlor-2-phenyloxazolo[5,4-b]pyridin9 smp.: 150 - 151° C.Ice water is added, the precipitate is collected on filter and the solid is extracted with hot benzene. The benzene is evaporated and the residue is taken up in ether, filtered through alumina and evaporated to dryness to give 300 mg of 5-chloro-2-phenyloxazolo [5,4-b] pyridine 9 mp: 150 - 151 ° C.
Eksempel 35 5-Nitro-2-phenyloxazolo[5,4-b]pyridinExample 35 5-Nitro-2-phenyloxazolo [5,4-b] pyridine
Trin A: Præparation af 3-amino-5-nitro-2-pyridonStep A: Preparation of 3-amino-5-nitro-2-pyridone
En opløsning af 5,5 g 3,5-dinitro-2-pyridon i 200 ml methanol indstilles til en pH-værdi på 8 med ammoniumhydroxid. Ved 60 -65° C sættes langsomt en opløsning af 10,8 g natriumsulfid-nonahydrat i 30 ml vand. Efter 1 time ved 60 - 65° C afdampes opløsningsmidlet, og remanensen ekstraheres med varm benzen og eddikesyre til neutralisering af natriumsaltet. Benzenen afdekanteres og afkøles til dannelse af et bundfald. Ved omkrystallisation af methanol fås 3-amino-5-nitro-2-pyridon, smp.: 200 - 201° 0.A solution of 5.5 g of 3,5-dinitro-2-pyridone in 200 ml of methanol is adjusted to a pH of 8 with ammonium hydroxide. At 60 -65 ° C, slowly dissolve a solution of 10.8 g of sodium sulfide nonahydrate in 30 ml of water. After 1 hour at 60-65 ° C, the solvent is evaporated and the residue is extracted with hot benzene and acetic acid to neutralize the sodium salt. The benzene is decanted and cooled to form a precipitate. Recrystallization from methanol gives 3-amino-5-nitro-2-pyridone, mp: 200 - 201 ° 0.
Trin B: Præparation af 3-benzoylamino-5-nitro-2-pyridonStep B: Preparation of 3-benzoylamino-5-nitro-2-pyridone
En opløsning af 100 mg 3-amino-5-nitro-2-pyridon i 1,5 ml pyridin afkøles og behandles med 200 mg benzoylchlorid. Efter 2 timer tilsættes vand. Den udskilte olie vaskes med vand og udrives med ether. Det dannede stof omkrystalliseres af ethylacetat, hvorved fås 3-benzoylamiho-5-nitro-2-pyridon, smp.: 267 - 268° C.A solution of 100 mg of 3-amino-5-nitro-2-pyridone in 1.5 ml of pyridine is cooled and treated with 200 mg of benzoyl chloride. After 2 hours, water is added. The separated oil is washed with water and triturated with ether. The resulting substance is recrystallized from ethyl acetate to give 3-benzoylamiho-5-nitro-2-pyridone, mp: 267-268 ° C.
I.IN.
14 DK 152050 B14 DK 152050 B
Trin G: Præparation af 5-nitro-2-phenyloxazolor5.4-b]pyridinStep G: Preparation of 5-nitro-2-phenyloxazolor5,4-b] pyridine
En blanding af 300 mg 3-benzoylamino-5-nitro-2-pyridon og 1,5 g polyphosphorsyre opvarmes til 180° C i 15 minutter. Blandingen afkøles, vaskes med is, og bundfaldet opsamles. Bundfaldet opløses i ether, opløsningen filtreres gennem aluminiuinoxid og afdampe s, hvorved fås 5-nitro-2-phenyloxazolo[5,4-b]pyridin, smp.: 219 - 220° C.A mixture of 300 mg of 3-benzoylamino-5-nitro-2-pyridone and 1.5 g of polyphosphoric acid is heated to 180 ° C for 15 minutes. The mixture is cooled, washed with ice and the precipitate is collected. The precipitate is dissolved in ether, the solution is filtered through alumina and evaporated to give 5-nitro-2-phenyloxazolo [5,4-b] pyridine, mp: 219 - 220 ° C.
Eksempel 36 5-Benzoylamino-2-phenyloxazolo[5,4-b ]pyridinExample 36 5-Benzoylamino-2-phenyloxazolo [5,4-b] pyridine
En opløsning af 80 mg 5-amino-2-phenyloxazolo[5,4-b]pyridin i 1 ml pyridin behandles med 0,07 ml benzoylchlorid. Efter henstand i 1 time fortyndes blandingen med isvand. Bundfaldet opsamles og omkrystalliseres af methanol, hvorved fås 5-benzoylamino-2-phenyl-oxazolo[5,4-b]pyridin, smp.: 191 - 192° C.A solution of 80 mg of 5-amino-2-phenyloxazolo [5,4-b] pyridine in 1 ml of pyridine is treated with 0.07 ml of benzoyl chloride. After standing for 1 hour, the mixture is diluted with ice water. The precipitate is collected and recrystallized from methanol to give 5-benzoylamino-2-phenyl-oxazolo [5,4-b] pyridine, mp: 191 - 192 ° C.
Eksempel 37 2,5-Diphenyloxazolo[5 > 4-b]pyridinExample 37 2,5-Diphenyloxazolo [5> 4-b] pyridine
En blanding af 180 mg 5-amino-2-phenyloxazolo[5,4-b]pyridin, 10 ml benzen og 0,2 ml isoamylnitrit koges under tilbagesvaling i 1,5 timer. Den varme opløsning filtreres og inddampes til tørhed. Remanensen ekstraheres med ether, og ekstrakten filtreres gennem aluminiumoxid og inddampes til tørhed. Den krystallinske remanens omkrystalliseres af ethylacetat, hvorved fås 2,5-diphenyloxazolo-[5»4-b]pyridin, smp.: 151 - 152° G.A mixture of 180 mg of 5-amino-2-phenyloxazolo [5,4-b] pyridine, 10 ml of benzene and 0.2 ml of isoamyl nitrite is refluxed for 1.5 hours. The hot solution is filtered and evaporated to dryness. The residue is extracted with ether and the extract is filtered through alumina and evaporated to dryness. The crystalline residue is recrystallized from ethyl acetate to give 2,5-diphenyloxazolo [5 »4-b] pyridine, mp: 151 - 152 ° G.
Eksempel 38 5-Isopropoxycarbonylamino-2-phenyloxazolo[5,4-b]pyridinExample 38 5-Isopropoxycarbonylamino-2-phenyloxazolo [5,4-b] pyridine
En blanding af 300 mg 5-amino-2-phenyloxazolo[5,4-b]pyridin og 3 ml pyridin afkøles på is, og hertil sættes 0,2 ml isopropyl-chlorformiat. Blandingen holdes i et køleskab i 5 dage og fortyndes med is og vand. Bundfaldet opsamles og omkrystalliseres af isopropanol, hvorved fås 5-isopropoxycarbonylamino-2-phenyl-oxazolo[5,4-b]pyridin, smp.: 210 - 211° C.A mixture of 300 mg of 5-amino-2-phenyloxazolo [5,4-b] pyridine and 3 ml of pyridine is cooled on ice, to which is added 0.2 ml of isopropyl chloroformate. The mixture is kept in a refrigerator for 5 days and diluted with ice and water. The precipitate is collected and recrystallized from isopropanol to give 5-isopropoxycarbonylamino-2-phenyl-oxazolo [5,4-b] pyridine, mp 210-121 ° C.
2-(4-Carbamylphenyl)oxazolo[5,4-b]pyridin2- (4-Carbamylphenyl) oxazolo [5,4-b] pyridine
15 DK 152 05 OB15 DK 152 05 OB
Eksempel 39Example 39
En opløsning af 600 mg 2-(4-cyanophenyl)oxazolo[5,4-b]pyridin i 8 ml koncentreret svovlsyre henstilles ved stuetemperatur i 16 timer. Opløsningen hældes på is,' og det hvide bundfald opsamles på filter, hvorved fås 2-(4-carbamylphenyl)oxazolo[5,4-b]pyridin, smp.: 315° C (dek.).A solution of 600 mg of 2- (4-cyanophenyl) oxazolo [5,4-b] pyridine in 8 ml of concentrated sulfuric acid is left at room temperature for 16 hours. The solution is poured onto ice, and the white precipitate is collected on filter to give 2- (4-carbamylphenyl) oxazolo [5,4-b] pyridine, mp: 315 ° C (dec).
Eksempel 40 2-(4-Dimethylaminophenyl)oxazolo[5,4-b]pyridinExample 40 2- (4-Dimethylaminophenyl) oxazolo [5,4-b] pyridine
En blanding af 2,4 g 2-(4-nitrophenyl)oxazolo[5,4-b]pyridin, 7 ml 37 % formaldehydopløsning, 5 ml eddikesyre og 0,25 g Raney-nikkel og 125 ml methanol hydrogeneres. Katalysatoren frafiltreres, og filtratet inddampes til tørhed. Remanensen ekstraheres med vand, og den i vand uopløselige remanens omkrystalliseres af chloroform-petroleumsether til dannelse af 2-(4-dimethylaminophenyl)oxazolo-[5,4-b]pyridin, smp.: 168 - 170° C.A mixture of 2.4 g of 2- (4-nitrophenyl) oxazolo [5,4-b] pyridine, 7 ml of 37% formaldehyde solution, 5 ml of acetic acid and 0.25 g of Raney nickel and 125 ml of methanol is hydrogenated. The catalyst is filtered off and the filtrate is evaporated to dryness. The residue is extracted with water and the water-insoluble residue is recrystallized from chloroform-petroleum ether to give 2- (4-dimethylaminophenyl) oxazolo [5,4-b] pyridine, mp: 168-170 ° C.
Eksempel 41 2-(2-Aminophenyl)oxazolo[5,4-b]pyridinExample 41 2- (2-Aminophenyl) oxazolo [5,4-b] pyridine
En blanding af 700 mg 2-(2-nitrophenyl)oxazolo[5,4-b]pyridin i 50 ml ethanol hydrogeneres over 150 mg 5 f> palladium-på-carbon-katalysator. Katalysatoren frafiltreres, og opløsningsmidlet inddampes til tørhed. Remanensen omkrystalliseres af chloroform-petrol eumsether til dannelse af 2-(2-aminophenyl)oxazolo [5,4-b] - pyridin, smp.: 142 - 144° C.A mixture of 700 mg of 2- (2-nitrophenyl) oxazolo [5,4-b] pyridine in 50 ml of ethanol is hydrogenated over 150 mg of 5 palladium-on-carbon catalyst. The catalyst is filtered off and the solvent is evaporated to dryness. The residue is recrystallized from chloroform-petrol eum ether to give 2- (2-aminophenyl) oxazolo [5,4-b] pyridine, mp: 142 - 144 ° C.
Eksempel 42 2-(2-Benzoylaminophenyl)oxazolo[5,4-b]pyridinExample 42 2- (2-Benzoylaminophenyl) oxazolo [5,4-b] pyridine
En iskold opløsning af 1 g 2-(2-aminophenyl)oxazolo[5,4-b]- pyridin i 15 ml tør pyridin behandles ved langsom tilsætning af 1 g benzoylchlorid. Reaktionsblandingen fortyndes med isvand og omrøres i 10 minutter, og det dannede faste stof opsamles på filter og omkrystalliseres med benzen, hvorved fås 2-(2-benzoyl-aminophenyl)oxazolo[5,4-b]pyridin, smp.: 197 - 198° C.An ice-cold solution of 1 g of 2- (2-aminophenyl) oxazolo [5,4-b] pyridine in 15 ml of dry pyridine is treated by the slow addition of 1 g of benzoyl chloride. The reaction mixture is diluted with ice water and stirred for 10 minutes and the solid formed is collected on filter and recrystallized with benzene to give 2- (2-benzoylaminophenyl) oxazolo [5,4-b] pyridine, mp: 197-198 ° C
5-Chlor-2-(2-fluorphenyl)oxazolo[5,4-b]pyridin5-Chloro-2- (2-fluorophenyl) oxazolo [5,4-b] pyridine
16 DK 152050 B16 DK 152050 B
Eksempel 43Example 43
Trin A: Præparation af 5-chlor-3-(2-fluorbenzoylamino)-2- pyridon__Step A: Preparation of 5-Chloro-3- (2-fluorobenzoylamino) -2-pyridone
En opløsning af 1,7 g 5-chlor-3-nitro-2-pyridon i 75 ml ethanol og 2 ml eddikesyre hydrogeneres over 0,2 g 5 % palladium-på-carbon. Katalysatoren frafiltreres, og opløsningen inddampes til tørhed.A solution of 1.7 g of 5-chloro-3-nitro-2-pyridone in 75 ml of ethanol and 2 ml of acetic acid is hydrogenated over 0.2 g of 5% palladium-on-carbon. The catalyst is filtered off and the solution is evaporated to dryness.
Den tørrede remanens opløses i 30 ml pyridin, afkøles på is og "behandles med 1,6 g 2-fluorbenzoylchlorid i løbet af 5 minutter. Blandingen omrøres ved stuetemperatur i ca. 16 timer og hældes på isvand. Det dannede bundfald opsamles på et filter (1,5 g) og anvendes direkte i næste trin uden rensning.The dried residue is dissolved in 30 ml of pyridine, cooled on ice and treated with 1.6 g of 2-fluorobenzoyl chloride over 5 minutes. The mixture is stirred at room temperature for about 16 hours and poured onto ice water. The precipitate formed is collected on a filter. (1.5 g) and used directly in the next step without purification.
Trin B: Præparation af 5-chlor-2-(2~fluorphenyl)oxazolo- ί5.4-bΊpyridin_Step B: Preparation of 5-Chloro-2- (2-fluorophenyl) oxazolo-5,4-bΊpyridine
En blanding af 1,5 g af ovennævnte amid og 5 ml polyphosphorsyre opvarmes til 160° C i 10 minutter. Efter afkøling sættes blandingen til isvand. Bundfaldet opsamles og ekstraheres med 75 ml varm benzen, og ekstrakten affarves med aktivt kul og inddampes til tørhed. Remanensen opløses i methylenchlorid og filtreres gennem aluminiumoxid, og filteret vaskes med ether. Produktet, 5-chlor-2-(2-fluorphenyl)oxazolo[5,4-b]pyridin, udkrystalliserer af filtratet og har et smeltepunkt på 140 - 141° c.A mixture of 1.5 g of the above amide and 5 ml of polyphosphoric acid is heated to 160 ° C for 10 minutes. After cooling, the mixture is added to ice water. The precipitate is collected and extracted with 75 ml of hot benzene and the extract is decolorized with activated charcoal and evaporated to dryness. The residue is dissolved in methylene chloride and filtered through alumina and the filter is washed with ether. The product, 5-chloro-2- (2-fluorophenyl) oxazolo [5,4-b] pyridine, crystallizes from the filtrate and has a melting point of 140-141 ° C.
Eksempel 44 5-Dimethylamino-2-phenyloxazolo[5,4-b]pyridin 5-Nitro-2-phenyloxazolo[5,4-b]pyridin (1,2 g) i 75 ml methanol, 75 ml benzen, 5 ml eddikesyre og 8 ml 37 % formaldehydopløsning hydrogeneres over 1,5 teskefuld Raney-nikkel. Katalysatoren frafiltreres, og filtratet fortyndes med 10 ml vand og gøres basisk med fast natriumbicarbonat. Blandingen inddampes til tørhed. Remanensen omkrystalliseres af ethylacetat, hvorved fås 5-dimethylamino-2-phenyloxazolo£5,4-b)pyridin, smo.: 127 -129° C.Example 44 5-Dimethylamino-2-phenyloxazolo [5,4-b] pyridine 5-Nitro-2-phenyloxazolo [5,4-b] pyridine (1.2 g) in 75 ml methanol, 75 ml benzene, 5 ml acetic acid and 8 ml of 37% formaldehyde solution are hydrogenated over 1.5 teaspoons of Raney nickel. The catalyst is filtered off and the filtrate is diluted with 10 ml of water and made basic with solid sodium bicarbonate. The mixture is evaporated to dryness. The residue is recrystallized from ethyl acetate to give 5-dimethylamino-2-phenyloxazolo [5,4-b) pyridine, m.p .: 127-129 ° C.
17 DK 152050 B17 DK 152050 B
Eksempel 45 5- Methoxy-6-methyl-2-phenyloxazolo[5,4-b]pyridinExample 45 5- Methoxy-6-methyl-2-phenyloxazolo [5,4-b] pyridine
Trin Å: Præparation af 5-methoxy-2-methvl-6-nitropyridinStep A: Preparation of 5-methoxy-2-methyl-6-nitropyridine
Til en iskold blanding af 3 ml koncentreret svovlsyre og 3 ml rygende salpetersyre sættes 0,5 g 3-methoxy-2-methylpyridin i løbet af 5 minutter. Efter spontan opvarmning til stuetempera» tur opvarmes blandingen til 55 - 60° C i 6 timer. Blandingen afkøles og sættes til 35 ml isvand. Efter omrøring i 2 timer op-samles bundfaldet, der tørres, hvorved fås 3-methoxy-2-methyl=6~ nitropyridin, smp.: 99 - 100,5° C.To an ice-cold mixture of 3 ml of concentrated sulfuric acid and 3 ml of smoking nitric acid is added 0.5 g of 3-methoxy-2-methylpyridine over 5 minutes. After spontaneous heating to room temperature, the mixture is heated to 55 - 60 ° C for 6 hours. The mixture is cooled and added to 35 ml of ice water. After stirring for 2 hours, the precipitate which is dried is collected to give 3-methoxy-2-methyl = 6-nitropyridine, mp: 99-100.5 ° C.
Trin Bs Præparation af 6-amino-5-methoxy-2-methylpyridin 3-Methoxy-2-methyl-6-nitropyridin (0,317 g) i 20 ml methanol, hydrogeneres over 0,1 g 5 1° palladium-på-carbon. Katalysatoren frafiltreres, og filtratet inddampes til tørhed, hvorved fås 6- amino-3-methoxy-2-methylpyridin, der anvendes direkte i næste trin.Step Bs Preparation of 6-amino-5-methoxy-2-methylpyridine 3-Methoxy-2-methyl-6-nitropyridine (0.317 g) in 20 ml of methanol is hydrogenated over 0.1 g of 5 1 ° palladium-on-carbon. The catalyst is filtered off and the filtrate is evaporated to dryness to give 6- amino-3-methoxy-2-methylpyridine, which is used directly in the next step.
Trin 0: Præparation af 5-methoxy-6-methyl-2-pyridonStep 0: Preparation of 5-methoxy-6-methyl-2-pyridone
Til en iskold blanding af 0,2 ml koncentreret svovlsyre, 2,0 ml vand og 138 mg 6-amino-3“methoxy-2-methylpyridin sættes en opløsning af 75 mg natriumnitrit i 1 ml vand, Ben kolde opløsning henstilles til opvarmning ved stuetemperatur i løbet af 18 timer. Blandingen fortyndes med lidt vand og gøres basisk med fast na-triumbicarbonat. Blandingen ekstraheres med methylenchlorid, og ekstrakten inddampes til tørhed, hvorved fås 120 mg 5-methoxy- 6-methyl-2-pyridon, der anvendes direkte i næste trin.To an ice-cold mixture of 0.2 ml of concentrated sulfuric acid, 2.0 ml of water and 138 mg of 6-amino-3 ”methoxy-2-methylpyridine is added a solution of 75 mg of sodium nitrite in 1 ml of water. Bone cold solution is allowed to warm at room temperature over 18 hours. The mixture is diluted with a little water and made basic with solid sodium bicarbonate. The mixture is extracted with methylene chloride and the extract is evaporated to dryness to give 120 mg of 5-methoxy-6-methyl-2-pyridone, which is used directly in the next step.
Trin D: Præparation af 5-methoxv-6-methyl-5-nitro-2-pyridonStep D: Preparation of 5-methoxy-6-methyl-5-nitro-2-pyridone
Til en blanding af 4,2 g 5-methoxy-6-methyl-2-pyridon i 50 ml iskold koncentreret svovlsyre sættes 2,5 ml koncentreret salpetersyre dråbevis ved ca. 5° C i løbet af 60 minutter. Omrøringen i kulden fortsættes i 18 timer. Blandingen sættes til ca, 700 g is under omrøring. Efter ca. 30 minutter opsamles bundfaldet9 der vaskes med vand og tørres, hvorved fås 3,7 g 5-methoxy-6-methyl-3-nitro-2-pyridon, der anvendes direkte i næste trin.To a mixture of 4.2 g of 5-methoxy-6-methyl-2-pyridone in 50 ml of ice-cold concentrated sulfuric acid, add 2.5 ml of concentrated nitric acid dropwise at ca. 5 ° C over 60 minutes. Stirring in the cold is continued for 18 hours. The mixture is added to about 700 g of ice with stirring. After approx. 30 minutes, the precipitate is collected9, washed with water and dried to give 3.7 g of 5-methoxy-6-methyl-3-nitro-2-pyridone, which is used directly in the next step.
18 DK 152050 B18 DK 152050 B
Trin E: Præparation af 3-benzoylamino-5-methoxy-6-methyl-2- pyridon_ 5-Methoxy-6-methyl-3-nitro-2-pyridon (1,84 g) i 100 ml methanol hydrogeneres over 0,3 g 5 $ palladium-på-carbon-katalysator. Katalysatoren frafiltreres, og filtratet inddampes til tørhed. Remanensen opløses i 15 ml pyridin og "behandles i kulden med 1,2 ml benzoylchlorid. Efter henstand i 18 timer på is fortyndes blandingen med vand. Bundfaldet opsamles og omkrystalliseres af ethanol. Det dannede stof ekstraheres flere gange med ether, og det uopløselige stof omkrystalliseres af ethanol, hvorved fås 3-benzoylamino-5-methoxy-6-methyl-2-pyridon, smp.: 247 - 248° C.Step E: Preparation of 3-benzoylamino-5-methoxy-6-methyl-2-pyridone-5-Methoxy-6-methyl-3-nitro-2-pyridone (1.84 g) in 100 ml of methanol is hydrogenated over 0.3 g $ 5 palladium-on-carbon catalyst. The catalyst is filtered off and the filtrate is evaporated to dryness. The residue is dissolved in 15 ml of pyridine and treated in the cold with 1.2 ml of benzoyl chloride. After standing for 18 hours on ice, the mixture is diluted with water. The precipitate is collected and recrystallized from ethanol. The resulting substance is extracted several times with ether and the insoluble matter. is recrystallized from ethanol to give 3-benzoylamino-5-methoxy-6-methyl-2-pyridone, mp: 247 - 248 ° C.
Trin B: Præparation af 5-methoxy-6-methyl-2-phenyloxazolo- Γ5.4-b]pyridin_Step B: Preparation of 5-methoxy-6-methyl-2-phenyloxazolo- [5,4-b] pyridine
En blanding af 200 mg 3-benzoylamino-5-methoxy-6-methyl-2-pyridon og 3 ml phosphoroxychlorid opvarmes på dampbad i 20 timer. Blandingen inddampes til tørhed, og remanensen optages i ether, gøres basisk med ammoniumhydroxid og fortyndes med vand. Etheren fraskilles, og den vandige fase ekstraheres 3 gange med ether. De forenede etherfaser tørres og inddampes til tørhed, hvorved fås 5-methoxy~6-methyl-2-phenyloxazolo[5,4-bjpyridin, smp.: 167- 168° C.A mixture of 200 mg of 3-benzoylamino-5-methoxy-6-methyl-2-pyridone and 3 ml of phosphorus oxychloride is heated on a steam bath for 20 hours. The mixture is evaporated to dryness and the residue is taken up in ether, basified with ammonium hydroxide and diluted with water. The ether is separated and the aqueous phase is extracted 3 times with ether. The combined ether phases are dried and evaporated to dryness to give 5-methoxy-6-methyl-2-phenyloxazolo [5,4-b] pyridine, mp: 167-168 ° C.
Eksempel 46 2-(2-Cyanophenyl)oxazolo[4,5-b]pyridinExample 46 2- (2-Cyanophenyl) oxazolo [4,5-b] pyridine
En blanding af 2,8 g 2-(2-bromphenyl)oxazolo[4,5-b]pyridin, 1,6 g cuprocyanid og 15 ml N-methylpyrrolidinon afluftes ved gen-nembobling af nitrogen gennem blandingen i 5 minutter. Den opvarmes dernæst til 175° C på oliebad og holdes ved denne temperatur i 5 timer under en nitrogenatmosfære, hvorefter der afkøles til stuetemperatur. Reaktionsblandingen behandles med 75 ml 10 io ammoniumhydroxid, og det dannede bundfald udfældes. Bundfaldet ekstraheres med 100 ml kogende methylenchlorid, og methylen-chloridet afdampes. Remanensen omkrystalliseres af methylenchlorid, hvorved fås 2-(2-cyanophenyl)oxazolo[4,5-b]pyridin, smp.: 166 - 167° C.A mixture of 2.8 g of 2- (2-bromophenyl) oxazolo [4,5-b] pyridine, 1.6 g of cuprocyanide and 15 ml of N-methylpyrrolidinone is deaerated by re-bubbling nitrogen through the mixture for 5 minutes. It is then heated to 175 ° C on an oil bath and kept at this temperature for 5 hours under a nitrogen atmosphere, after which it is cooled to room temperature. The reaction mixture is treated with 75 ml of 10 µm ammonium hydroxide and the precipitate formed precipitates. The precipitate is extracted with 100 ml of boiling methylene chloride and the methylene chloride is evaporated. The residue is recrystallized from methylene chloride to give 2- (2-cyanophenyl) oxazolo [4,5-b] pyridine, mp: 166 - 167 ° C.
19 DK 152050 B19 DK 152050 B
Farmakologiske forsøgPharmacological trials
Den efterfølgende tabel viser den fordelagtige virkning af forbindelserne fremstillét ved fremgangsmåden ifølge opfindelsen i sammenligning med den kendte forbindelse indomethacin.The following table shows the beneficial effect of the compounds produced by the process of the invention in comparison with the known compound indomethacin.
TABELTABLE
ID50 mus p.g. MaveblødningID50 mouse p.g. Gastrointestinal Bleeding
Syntnétaseprøve (læsioner på (cyclooxygenase- Perforeret 2 mm og derover inhibering) tarm, sår i diameter) _^ug/ml_ mg/kg__mg/kg_ άοηSynthesis test (lesions on (cyclooxygenase-Perforated 2 mm and beyond inhibition) intestine, ulcer diameter) _ µg / ml_ mg / kg__mg / kg_ άοη
RR
2-F 3 4/5 ved 256 2-CN - 0/5 ved 256 2,6-F2 15 0/5 ved 256 3/5 ved 2562-F 3 4/5 at 256 2-CN - 0/5 at 256 2.6-F2 15 0/5 at 256 3/5 at 256
Orø'1"·Orø'1 "·
RR
2-F 3 0/5 ved 512 2-CN 14 0/5 ved 256 INDOMETHACIN 10 5/5 ved 2,42-F 3 0/5 at 512 2-CN 14 0/5 at 256 INDOMETHACIN 10 5/5 at 2.4
Claims (4)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK357175A DK138456B (en) | 1972-06-14 | 1975-08-06 | Analogous process for the preparation of oxazolo (4,5-b) pyridines. |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US26289872A | 1972-06-14 | 1972-06-14 | |
| US26289872 | 1972-06-14 | ||
| BE147896A BE819177R (en) | 1972-06-14 | 1974-08-26 | OXAZOLO- AND THIAZOLOPYRIDINES |
| BE147896 | 1974-08-26 |
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| Publication Number | Publication Date |
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| DK152050B true DK152050B (en) | 1988-01-25 |
| DK152050C DK152050C (en) | 1988-07-18 |
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| DK284973A DK152050C (en) | 1972-06-14 | 1973-05-24 | ANALOGY PROCEDURE FOR THE PREPARATION OF OXAZOLOPYRIDINES |
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| JP (1) | JPS5943475B2 (en) |
| AR (1) | AR208500A1 (en) |
| AT (1) | AT333277B (en) |
| AU (1) | AU472528B2 (en) |
| BE (2) | BE800868A (en) |
| CA (1) | CA1019741A (en) |
| CS (1) | CS178889B2 (en) |
| DD (1) | DD105237A5 (en) |
| DE (1) | DE2330109A1 (en) |
| DK (1) | DK152050C (en) |
| FI (1) | FI57417C (en) |
| FR (1) | FR2187356B1 (en) |
| GB (1) | GB1421619A (en) |
| LU (1) | LU67786A1 (en) |
| NL (1) | NL184836C (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2527321A1 (en) * | 1975-06-19 | 1976-12-23 | Merck & Co Inc | 2-(Substd phenyl) oxazolo (4,5-b) pyridines - topical anti-inflammatories with very low systemic activity |
| JPS527992A (en) * | 1975-07-04 | 1977-01-21 | Merck & Co Inc | Oxazolo *4*55b* pyridines |
| NL187021C (en) * | 1975-07-15 | 1991-05-01 | Merck & Co Inc | PROCESS FOR THE PREPARATION OF A PHARMACEUTICAL PREPARATION WITH ANTI-INFLAMMATORY ACTION, AND A METHOD FOR PREPARING ANTI-INFLAMMATIC ACTIVITY 2-PHENYL-OXAZOLO-PID-BIDANE. |
| US4011326A (en) * | 1975-07-29 | 1977-03-08 | Merck & Co., Inc. | 2-Substituted oxazolo[4,5-b]pyridine anti-inflammatory agents |
| US4753673A (en) * | 1977-07-22 | 1988-06-28 | The Dow Chemical Company | Trifluoromethyl pyridinyloxyphenoxy and pyridinylthiophenoxy propanoic acids and propanols and derivatives thereof and methods of herbicidal use |
| DE2862490D1 (en) * | 1977-08-12 | 1988-04-21 | Ici Plc | Phenoxypyridine compound |
| JPS5461182A (en) * | 1977-10-20 | 1979-05-17 | Ishihara Sangyo Kaisha Ltd | 2-phenoxy-5-trifluoromethylpyridine compounds |
| JPS5461183A (en) * | 1977-10-21 | 1979-05-17 | Ishihara Sangyo Kaisha Ltd | 2-substituted-5-trifluoromethyl pyridine compounds |
| EP0003877B1 (en) * | 1978-02-15 | 1988-02-03 | Imperial Chemical Industries Plc | Herbicidal derivatives of 2-(4(2-pyridyloxy)phenoxy)propane, processes for preparing them, and herbicidal compositions containing them |
| JPS55130840U (en) * | 1979-03-12 | 1980-09-16 | ||
| JPS55124763A (en) * | 1979-03-19 | 1980-09-26 | Ishihara Sangyo Kaisha Ltd | 5-trifluoromethyl-2-pyridone derivative |
| GB8333514D0 (en) * | 1983-12-16 | 1984-01-25 | Erba Farmitalia | Tetrahydrothiazolo(5 4-c)pyridine derivatives |
| FR2652085A1 (en) * | 1989-09-20 | 1991-03-22 | Science Organisation | NEW PROCESS FOR THE SYNTHESIS OF OXAZOLOPYRIDINE DERIVATIVES |
| US6172074B1 (en) * | 1996-11-11 | 2001-01-09 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Imidazopyridines and oxazolopyridines |
| US6232320B1 (en) | 1998-06-04 | 2001-05-15 | Abbott Laboratories | Cell adhesion-inhibiting antiinflammatory compounds |
| SK18542000A3 (en) * | 1998-06-04 | 2001-12-03 | Abbott Laboratories | Cell adhesion-inhibiting anti-inflammatory compounds |
| EP1181296A1 (en) * | 1999-06-03 | 2002-02-27 | Abbott Laboratories | Cell adhesion-inhibiting antiinflammatory compounds |
| AU2002216649A1 (en) * | 2000-10-31 | 2002-05-15 | Lynn Bonham | Benzoxazole lpaat- beta inhibitors and uses thereof |
| US8093401B2 (en) | 2005-08-04 | 2012-01-10 | Sirtris Pharmaceuticals, Inc. | Sirtuin modulating compounds |
| CA2617557A1 (en) * | 2005-08-04 | 2007-02-15 | Sirtris Pharmaceuticals, Inc. | Benzimidazole derivatives as sirtuin modulators |
| US7855289B2 (en) | 2005-08-04 | 2010-12-21 | Sirtris Pharmaceuticals, Inc. | Sirtuin modulating compounds |
| US8088928B2 (en) | 2005-08-04 | 2012-01-03 | Sirtris Pharmaceuticals, Inc. | Sirtuin modulating compounds |
| TW200916472A (en) | 2007-06-20 | 2009-04-16 | Sirtris Pharmaceuticals Inc | Sirtuin modulating compounds |
| EP2320891B1 (en) * | 2008-08-29 | 2013-10-09 | Treventis Corporation | Butyrylcholinesterase ligands as diagnostic tools and treatment for deseases of the nervous system |
| WO2010071853A1 (en) | 2008-12-19 | 2010-06-24 | Sirtris Pharmaceuticals, Inc. | Thiazolopyridine sirtuin modulating compounds |
| BR112012007237A2 (en) * | 2009-09-30 | 2019-09-24 | Sumitomo Chemical Co | composition and method for controlling arthropod pests |
| BR112013006016A2 (en) * | 2010-09-15 | 2016-06-07 | Hoffmann La Roche | azabenzothiazole compounds, compositions and methods of use |
| CN103261170B (en) | 2010-12-24 | 2016-08-24 | 住友化学株式会社 | Fused heterocyclic compound and the purposes for Pest control thereof |
| WO2015200650A1 (en) * | 2014-06-25 | 2015-12-30 | Epizyme, Inc. | Substituted benzene and 6,5-fused bicyclic heteroaryl compounds |
| EP3227302B1 (en) | 2014-12-02 | 2018-07-11 | Bayer CropScience AG | Bicyclic compounds as pest controllers |
| US10399966B2 (en) | 2016-01-21 | 2019-09-03 | University Of Washington | Compounds for treatment of trypanosomes and neurological pathogens and uses thereof |
| JP7430486B2 (en) * | 2016-07-07 | 2024-02-13 | 保土谷化学工業株式会社 | Compounds with benzazole ring structure and organic electroluminescent devices |
-
1973
- 1973-03-12 AR AR248527A patent/AR208500A1/en active
- 1973-05-22 FI FI1657/73A patent/FI57417C/en active
- 1973-05-24 DK DK284973A patent/DK152050C/en not_active IP Right Cessation
- 1973-05-25 SE SE7307412A patent/SE401675B/en unknown
- 1973-05-30 NL NLAANVRAGE7307582,A patent/NL184836C/en not_active IP Right Cessation
- 1973-06-04 ZA ZA00733760A patent/ZA733760B/en unknown
- 1973-06-04 AU AU56511/73A patent/AU472528B2/en not_active Expired
- 1973-06-05 CA CA173,275A patent/CA1019741A/en not_active Expired
- 1973-06-08 AT AT508673A patent/AT333277B/en active
- 1973-06-11 GB GB2763273A patent/GB1421619A/en not_active Expired
- 1973-06-12 CS CS7300004243A patent/CS178889B2/en unknown
- 1973-06-12 DD DD171559A patent/DD105237A5/xx unknown
- 1973-06-13 LU LU67786A patent/LU67786A1/xx unknown
- 1973-06-13 BE BE132231A patent/BE800868A/en not_active IP Right Cessation
- 1973-06-13 DE DE2330109A patent/DE2330109A1/en not_active Withdrawn
- 1973-06-13 FR FR7321443A patent/FR2187356B1/fr not_active Expired
- 1973-06-14 JP JP48066453A patent/JPS5943475B2/en not_active Expired
-
1974
- 1974-08-26 BE BE147896A patent/BE819177R/en not_active IP Right Cessation
-
1976
- 1976-04-14 SE SE7604385A patent/SE432767B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| AT333277B (en) | 1976-11-10 |
| BE800868A (en) | 1973-12-13 |
| FR2187356B1 (en) | 1977-01-28 |
| FI57417C (en) | 1980-08-11 |
| FI57417B (en) | 1980-04-30 |
| DD105237A5 (en) | 1974-04-12 |
| NL184836C (en) | 1989-11-16 |
| LU67786A1 (en) | 1973-08-16 |
| CA1019741A (en) | 1977-10-25 |
| ATA508673A (en) | 1976-03-15 |
| SE401675B (en) | 1978-05-22 |
| JPS4961195A (en) | 1974-06-13 |
| NL184836B (en) | 1989-06-16 |
| DK152050C (en) | 1988-07-18 |
| SE432767B (en) | 1984-04-16 |
| SE7604385L (en) | 1976-04-14 |
| DE2330109A1 (en) | 1974-01-03 |
| AU5651173A (en) | 1974-12-05 |
| GB1421619A (en) | 1976-01-21 |
| JPS5943475B2 (en) | 1984-10-22 |
| FR2187356A1 (en) | 1974-01-18 |
| CS178889B2 (en) | 1977-10-31 |
| AU472528B2 (en) | 1976-05-27 |
| ZA733760B (en) | 1975-01-29 |
| AR208500A1 (en) | 1977-02-15 |
| BE819177R (en) | 1975-02-26 |
| NL7307582A (en) | 1973-12-18 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed |