NO164897B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE OXAZOLIDINON DERIVATIVES. - Google Patents

ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE OXAZOLIDINON DERIVATIVES. Download PDF

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NO164897B
NO164897B NO862439A NO862439A NO164897B NO 164897 B NO164897 B NO 164897B NO 862439 A NO862439 A NO 862439A NO 862439 A NO862439 A NO 862439A NO 164897 B NO164897 B NO 164897B
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mmol
hours
ether
stirred
oxazolidinone
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Walter Klose
Gerald Kirsch
Andreas Huth
Wolfgang Froehlich
Henry Laurent
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Schering Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F02—COMBUSTION ENGINES; HOT-GAS OR COMBUSTION-PRODUCT ENGINE PLANTS
    • F02B—INTERNAL-COMBUSTION PISTON ENGINES; COMBUSTION ENGINES IN GENERAL
    • F02B1/00—Engines characterised by fuel-air mixture compression
    • F02B1/02—Engines characterised by fuel-air mixture compression with positive ignition
    • F02B1/04—Engines characterised by fuel-air mixture compression with positive ignition with fuel-air mixture admission into cylinder

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
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  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Description

Oppfinnelsen angår en analogifremgangsmåte for fremstilling av terapeutisk aktive oxazolidinonderivater av generell formel Ia The invention relates to an analogue method for the preparation of therapeutically active oxazolidinone derivatives of general formula Ia

hvori Rc- betegner en hydrocarbonrest med to til fire carbon- in which Rc- denotes a hydrocarbon residue with two to four carbon-

atomer. atoms.

Tallrike lignende forbindelser er tidligere kjent. Så- Numerous similar compounds are previously known. So-

ledes er eksempelvis pyrrolidonderivater beskrevet i US patentskrift 4 012 495 og oxazolidinonderivater beskrevet i US patentskrift 4 186 129. Ut fra disse patentskrifter kan thus, for example, pyrrolidone derivatives are described in US patent specification 4 012 495 and oxazolidinone derivatives are described in US patent specification 4 186 129. Based on these patents,

man utlede at disse forbindelser utmerker seg ved en sentral-depressiv, antidopaminerg, antinoziceptiv og antikonvulsiv aktivitet og har enn videre fosfodiesterasehemmende egen- it can be deduced that these compounds are characterized by a central depressant, antidopaminergic, antinociceptive and anticonvulsant activity and furthermore have phosphodiesterase-inhibiting properties

skaper . creates .

Det er nå funnet at forbindelsene av generell formel It has now been found that the compounds of general formula

Ia ved topisk administrering utviser en sterk antiinflam- Ia when administered topically exhibits a strong anti-inflammatory

matorisk aktivitet. matory activity.

Analogifremgangsmåten ifølge oppfinnelsen er kjenne- The analogy method according to the invention is known

tegnet ved at et amin av generell formel characterized by the fact that an amine of general formula

hvori R,, har den ovenfor angitte betydning, kondenseres med en carbonylforbindelse av generell formel V wherein R,, has the above meaning, is condensed with a carbonyl compound of general formula V

hvori X betegner kloratomer, lavere alkoxygrupper eller 1-imidazolyl-rester. wherein X denotes chlorine atoms, lower alkoxy groups or 1-imidazolyl residues.

Denne reaksjonsrekke kan eksempelvis utføres under This series of reactions can, for example, be carried out below

de betingelser som er beskrevet i US patentskrift 4,186,129. the conditions described in US patent 4,186,129.

Den antiinflammatoriske aktivitet av forbindelsene av generell formel Ia ble bestemt ved rotteøretesten ifølge Tonelli (Endocrinol. TT_, 1965, 625 og Proe. Soc. Exp. Med., 159, 1978, 223): Forskjellige konsentrasjoner av prøvesubstans ble løst i en 5 volum% ethanolisk crotonoljeløsning eller dispergert ved 5 minutters behandling i ultralydbad. Pr. konsentrasjon ble 50^ul av denne løsning og substansfrie crotonolje-løsning påført med en 1 ml tuberkulinsprøyte på begge ytre øresider av 10 narkotiserte Wistarrotter (vekt 160 til 200 g). En ubehandlet gruppe tjente som kontroll. 15 timer etter behandlingen ble dyrene avlivet ved behandling med C02~gass, ørene ble avskåret og veiet parvis. The anti-inflammatory activity of the compounds of general formula Ia was determined by the rat ear test according to Tonelli (Endocrinol. TT_, 1965, 625 and Proe. Soc. Exp. Med., 159, 1978, 223): Different concentrations of test substance were dissolved in a 5 volume % ethanolic croton oil solution or dispersed by 5 minute treatment in an ultrasonic bath. Per concentration, 50 µl of this solution and substance-free croton oil solution were applied with a 1 ml tuberculin syringe to both outer ear sides of 10 anesthetized Wistar rats (weight 160 to 200 g). An untreated group served as a control. 15 hours after the treatment, the animals were euthanized by treatment with C02 gas, the ears were cut off and weighed in pairs.

Som mål for den topiske inflammasjonshemmende virkning av testsubstansen ble-den prosentuelle hemning av vekt-økningen fremkalt av crotonolje, bestemt. Den etterfølgende tabell viser de erholdte resultater ved denne test. As a measure of the topical anti-inflammatory effect of the test substance, the percentage inhibition of weight gain induced by croton oil was determined. The following table shows the results obtained in this test.

De angitte resultater viser at forbindelsene av generell formel Ia ved topisk .ad■m tinistrering er vesentlig sterkere antiinflammtorisk virksomme enn de tidligere kjente sammenlignbare substanser 1 og 2. De oppnår nesten virk-ningsintensiteten av sterkt virksomme corticoider slik som hydrocortison-17-butyrat (substans 3). The stated results show that the compounds of general formula Ia when administered topically are significantly more anti-inflammatoryly active than the previously known comparable substances 1 and 2. They almost achieve the intensity of action of highly active corticoids such as hydrocortisone-17-butyrate ( substance 3).

Fremstilling av legemiddelspesialitetene skjer på van-lig måte idet virkestoffet med egnede tilsetninger overføres i den ønskede administreringsform slik som f.eks. løsninger, lotions, salver, kremer eller plastére. I de således formulerte legemidler er virkestoffkonsentrasjonen avhengig av administreringsformen. Ved lotions, kremer og salver anvendes fortrinnsvis en virkestoffkonsentrasjon på 0,01% Preparation of the medicinal specialties takes place in the usual way, as the active substance is transferred with suitable additives in the desired administration form, such as e.g. solutions, lotions, ointments, creams or plasters. In the drugs formulated in this way, the active substance concentration depends on the form of administration. For lotions, creams and ointments, an active substance concentration of 0.01% is preferably used

til 10%. to 10%.

Utførelseseksempler angående syntesen av oxazolidinonderivater av generell formel Ia Embodiments concerning the synthesis of oxazolidinone derivatives of general formula Ia

Eksempel 1 Example 1

3,10 g (15,0 mmol) 3-allyloxy-4-methoxyacetofenon, 2,18 ml (16,4 mmol) trimethylsilylcyanid og 126 mg (0,39 mmol) sinkjodid ble omrørt i 5 timer ved 100°C og i 14 timer ved romtemperatur under argon. Reaksjonsblandingen ble tilsatt 4,6 ml ether, og 0,69 g (18,5 mmol) 1 ithiumaluminiumhydrid i 13,5 ml ether ble dråpevis tilsatt. Etter en omrøringstid på 1 time ved 40°C badtemperatur ble reaksjonsblandingen suksessivt tilsatt 0,7 ml vann, 0,75 ml 4 N natronlut og 2,1 ml vann. Det dannede, faste stoff ble utvasket flere ganger med ether, de forenede etherfaser ble tørket over natriumsulfat, filtrert og inndampet (3,33 g olje). Etter ytterligere tilsetning av 42 mg sinkjodid og 0,73 ml trimethylsilylcyanid ble blandingen omrørt i ytterligere 4 timer ved 100°C. Reaksjonsblandingen ble fortynnet med 3 ml ether og ble dråpevis tilsatt til en suspensjon av 240 mg lithiumaluminiumhydrid i 6 ml ether. Blandingen ble deretter omrørt ved 40°C i 30 minutter hvorpå reaksjonsblandingen ble tilsatt 0,2 ml vann, 0,26 ml 4 N natronlut og 0,8 ml vann. Det dannede, faste stoff ble vasket flere ganger med ether, de forenede etherfaser ble tørket over natriumsulfat, filtrert og inndampet. Det oljeaktige residuum (2,06 g) ble i 31 ml tetrahydrofuran omrørt med 2,11 g (12,4 mmol) carbonyldiimidazol i 20 timer ved romtemperatur. Reaksjonsblandingen ble inndampet i vakuum, residuet ble oppløst i eddikester, den organiske løsning ble vasket med 2 N saltsyre og vann, ble tørket over natriumsulfat, filtrert og inndampet (1,52 g olje). Ved kromatografi på kiselgel med methylenklorid/ether (1:1) ble det erholdt 260 mg 5-methyl-5-(3-allyloxy-4-methoxyfenyl)-2-oxåzolidinon som olje. 3.10 g (15.0 mmol) of 3-allyloxy-4-methoxyacetophenone, 2.18 ml (16.4 mmol) of trimethylsilyl cyanide and 126 mg (0.39 mmol) of zinc iodide were stirred for 5 hours at 100°C and in 14 hours at room temperature under argon. To the reaction mixture was added 4.6 ml of ether, and 0.69 g (18.5 mmol) of 1 lithium aluminum hydride in 13.5 ml of ether was added dropwise. After a stirring time of 1 hour at 40°C bath temperature, 0.7 ml of water, 0.75 ml of 4 N caustic soda and 2.1 ml of water were successively added to the reaction mixture. The solid formed was washed several times with ether, the combined ether phases were dried over sodium sulfate, filtered and evaporated (3.33 g of oil). After further addition of 42 mg of zinc iodide and 0.73 ml of trimethylsilyl cyanide, the mixture was stirred for a further 4 hours at 100°C. The reaction mixture was diluted with 3 ml of ether and was added dropwise to a suspension of 240 mg of lithium aluminum hydride in 6 ml of ether. The mixture was then stirred at 40°C for 30 minutes, after which 0.2 ml of water, 0.26 ml of 4 N caustic soda and 0.8 ml of water were added to the reaction mixture. The solid formed was washed several times with ether, the combined ether phases were dried over sodium sulfate, filtered and evaporated. The oily residue (2.06 g) was stirred in 31 ml of tetrahydrofuran with 2.11 g (12.4 mmol) of carbonyldiimidazole for 20 hours at room temperature. The reaction mixture was evaporated in vacuo, the residue was dissolved in ethyl acetate, the organic solution was washed with 2 N hydrochloric acid and water, was dried over sodium sulfate, filtered and evaporated (1.52 g of oil). Chromatography on silica gel with methylene chloride/ether (1:1) yielded 260 mg of 5-methyl-5-(3-allyloxy-4-methoxyphenyl)-2-oxazolidinone as an oil.

■""H-NMR (CDC13) : S = 1,75 (s, 2H) , 3,63 (s, 2H) , 3,83 (s, 3H) , 4,55 (pseudo d, 2H), 5,10-6,23 (m, 4H), ■""H-NMR (CDCl 3 ) : S = 1.75 (s, 2H), 3.63 (s, 2H), 3.83 (s, 3H), 4.55 (pseudo d, 2H), 5 .10-6.23 (m, 4H),

6,80 (pseudo d, 3H). 6.80 (pseudo d, 3H).

Eksempel 2 Example 2

2,84 g (12,9 mmol) 3-cyclopropylmethoxy-4-methoxyaceto-fenon, 1,87 ml (14,0 mmo]) trimethylsilylcyanid og 109 mg (0,33 mmol) sinkjodid ble omrørt i 5 timer ved 100°C og i 14 timer ved romtemperatur. Etter tilsetning av 4,5 ml ether ble 0,6 g (15,8 mmol) lithiumaluminiumhydrid i 12 ml ether dråpevis tilsatt, og blandingen ble omrørt i 1 time ved 40°C (badtemperatur). Reaksjonsblandingen ble suksessivt tilsatt 0,7 ml vann, 0,75 ml 4 N natronlut og 2,1 ml vann. Det dannede, faste stoff ble vasket flere ganger med ether, de forenede etherfaser ble tørket med natriumsulfat, filtrert og inndampet i vakuum. Residuet (2,31 g olje) ble omrørt med 2,21 g (13,0 mmol) carbonyldiimidazol i 33 ml tetrahydrofuran i 4 timer ved romtemperatur. Den ytterligere opp-arbeidelse fant sted som beskrevet i eksempel 1. Det ble erholdt 558 mg 5-methyl-5-(3-cyclopropylmethoxy-4-methoxy-fenyl)-2-oxazolidinon med smp. 96 til 97°C. 2.84 g (12.9 mmol) of 3-cyclopropylmethoxy-4-methoxyacetophenone, 1.87 ml (14.0 mmo]) of trimethylsilyl cyanide and 109 mg (0.33 mmol) of zinc iodide were stirred for 5 hours at 100° C and for 14 hours at room temperature. After adding 4.5 ml of ether, 0.6 g (15.8 mmol) of lithium aluminum hydride in 12 ml of ether was added dropwise, and the mixture was stirred for 1 hour at 40°C (bath temperature). 0.7 ml of water, 0.75 ml of 4 N caustic soda and 2.1 ml of water were successively added to the reaction mixture. The solid formed was washed several times with ether, the combined ether phases were dried with sodium sulfate, filtered and evaporated in vacuo. The residue (2.31 g of oil) was stirred with 2.21 g (13.0 mmol) of carbonyldiimidazole in 33 ml of tetrahydrofuran for 4 hours at room temperature. The further work-up took place as described in example 1. 558 mg of 5-methyl-5-(3-cyclopropylmethoxy-4-methoxy-phenyl)-2-oxazolidinone with m.p. 96 to 97°C.

Eksempel 3 Example 3

1,63 g (7,8 mmol) 3-propoxy-4-methoxyacetofenon, 1,1 ml (8,5 mmol) trimethylsilylcyanid og 66 mg (0,21 mmol) sinkjodid ble omrørt i 4,5 time ved 100°C og i 14 timer ved romtemperatur. Reaksjonsblandingen ble tilsatt 4,6 ml ether, og 0,36 g (9,6 mmol) lithiumaluminiumhydrid i 7 ml ether ble dråpevis tilsatt. Etter 1 times omrøringstid ved 40°C (badtempeatur) ble reaksjonsblandingen suksessivt tilsatt 1.63 g (7.8 mmol) of 3-propoxy-4-methoxyacetophenone, 1.1 ml (8.5 mmol) of trimethylsilyl cyanide and 66 mg (0.21 mmol) of zinc iodide were stirred for 4.5 hours at 100°C and for 14 hours at room temperature. To the reaction mixture was added 4.6 ml of ether, and 0.36 g (9.6 mmol) of lithium aluminum hydride in 7 ml of ether was added dropwise. After 1 hour of stirring at 40°C (bath temperature) the reaction mixture was successively added

0,4 ml vann, 0,4 ml 4 N natronlut og 1 ml vann. Den videre gjennomføring fant sted analogt med eksempel 1, dog ble det ved den ytterligere tilsetning av reagenser anvendt 20 mg sinkjodid og 0,36 ml trimethylsilylcyanid hhv. 0,1 ml vann, 0,13 ml 4 N natronlut og 0,4 ml vann. For carbonyleringen ble det anvendt 1,19 g (7,0 mmol) carbonyldiimidazol i 17,5 ml tetrahydrofuran. Det ble erholdt 152 mg 5-methyl-5-(4-methoxy-3-propoxyfenyl)-2-oxazolidinon som krystallinsk olje. Omkrystallisering i eddikester ga et smeltepunkt på 78°C. 0.4 ml water, 0.4 ml 4 N caustic soda and 1 ml water. The further implementation took place analogously to example 1, however, in the further addition of reagents, 20 mg of zinc iodide and 0.36 ml of trimethylsilyl cyanide were used respectively. 0.1 ml of water, 0.13 ml of 4 N caustic soda and 0.4 ml of water. For the carbonylation, 1.19 g (7.0 mmol) of carbonyldiimidazole in 17.5 ml of tetrahydrofuran were used. 152 mg of 5-methyl-5-(4-methoxy-3-propoxyphenyl)-2-oxazolidinone were obtained as a crystalline oil. Recrystallization in ethyl acetate gave a melting point of 78°C.

Eksempel 4 Example 4

3,47 g (15,6 mmol) 3-butoxy-4-methoxyacetofenon, 2,26 ml (17,0 mmol) trimethylsilylcyanid og 131 mg (0,91 mmol) sinkjodid ble omrørt i 5 timer ved 100°C og i 14 timer ved romtemperatur. Etter tilsetning av 4,6 ml ether ble 0,73 g (19,2 mmol) lithiumaluminiumhydrid i 14 ml ether dråpevis tilsatt, og blandingen ble omrørt i 1 time ved 40°C (badtemperatur). Den ytterligere gjennomføring fant sted analogt med eksempel 2, dog ble det anvendt 2,18 g (12,8 mmol) carbonyldiimidazol i 32,5 ml tetrahydrofuran. Det ble erholdt 569 mg 5-methyl-5-(3-butoxy-4-methoxyfenyl)-2-oxa-zolidinon med smp. 108-109°C (fra eddikester). 3.47 g (15.6 mmol) of 3-butoxy-4-methoxyacetophenone, 2.26 ml (17.0 mmol) of trimethylsilyl cyanide and 131 mg (0.91 mmol) of zinc iodide were stirred for 5 hours at 100°C and in 14 hours at room temperature. After adding 4.6 ml of ether, 0.73 g (19.2 mmol) of lithium aluminum hydride in 14 ml of ether was added dropwise, and the mixture was stirred for 1 hour at 40°C (bath temperature). The further implementation took place analogously to example 2, however, 2.18 g (12.8 mmol) of carbonyldiimidazole in 32.5 ml of tetrahydrofuran were used. 569 mg of 5-methyl-5-(3-butoxy-4-methoxyphenyl)-2-oxa-zolidinone with m.p. 108-109°C (from vinegar).

Eksempel 5 Example 5

3,01 g (14,5 mmol) 3-isopropyl-4-methoxyacetofenon, 3.01 g (14.5 mmol) 3-isopropyl-4-methoxyacetophenone,

2,1 ml (15,8 mmol) trimethylsilylcyanid og 122 mg (0,38 mmol) sinkjodid ble omrørt under argon i 5 timer ved 100°C og i 14 timer ved romtemperatur. Den ytterligere gjennomføring fant sted analogt med eksempel 1. Det ble erholdt 456 mg 5-methyl-5-(3-isopropoxy-4-methoxyfenyl)-2-oxazolidinon med smp. 67 til 69,5°C. 2.1 ml (15.8 mmol) of trimethylsilyl cyanide and 122 mg (0.38 mmol) of zinc iodide were stirred under argon for 5 hours at 100°C and for 14 hours at room temperature. The further execution took place analogously to example 1. 456 mg of 5-methyl-5-(3-isopropoxy-4-methoxyphenyl)-2-oxazolidinone with m.p. 67 to 69.5°C.

Eksempel 6 Example 6

1,66 g (8,55 mmol) 3-ethoxy-4-methoxyacetofenon ble om-rørt med 1,24 ml (9,3 mmol) trimethylsilylcyanid og 7 2 mg (0,22 mmol) sinkjodid i 5 timer ved 100°C og i 14 timer ved 1.66 g (8.55 mmol) of 3-ethoxy-4-methoxyacetophenone was stirred with 1.24 ml (9.3 mmol) of trimethylsilyl cyanide and 72 mg (0.22 mmol) of zinc iodide for 5 hours at 100° C and for 14 hours at

romtemperatur og under argon. Reaksjonsblandingen ble fortynnet med 2,5 ml ether og ble dråpevis tilsatt til 0,4 g (10,5 mmol) lithiumaluminiumhydrid i 8 ml ether. Etter en omrøringstid på 1 time ved 40°C (badtemperatur) ble reaksjonsblandingen suksessivt tilsatt 0,45 ml vann, 0,45 ml 4 N natronlut og 1,1 ml vann. Det dannede, faste stoff ble utvasket flere ganger med ether, og de forenede etherfaser ble tørket over natriumsulfat, filtrert og inndampet i vakuum. Residuet (1,5 g) ble i 24 ml tetrahyrofuran omrørt med room temperature and under argon. The reaction mixture was diluted with 2.5 ml of ether and was added dropwise to 0.4 g (10.5 mmol) of lithium aluminum hydride in 8 ml of ether. After a stirring time of 1 hour at 40°C (bath temperature), 0.45 ml of water, 0.45 ml of 4 N caustic soda and 1.1 ml of water were successively added to the reaction mixture. The solid formed was washed several times with ether, and the combined ether phases were dried over sodium sulfate, filtered and evaporated in vacuo. The residue (1.5 g) was stirred in 24 ml of tetrahyrofuran

1,61 g (9,5 mmol) carbonyldiimidazol i 4 timer ved romtemperatur. Reaksjonsløsningen ble inndampet, residuet ble løst i eddikester, den organiske løsning ble vasket med 2 N saltsyre og ,vann, tørket over natriumsulfat, filtrert og inndampet (0,8 g olje). Kromatografi på kiselgel med methylenklorid/ether (1:1) ga 370 mg 5-methyl-5-(3-ethoxy-4-methoxy-fenyl)-2-oxazolidinon med smp. 63 til 65°C. 1.61 g (9.5 mmol) of carbonyldiimidazole for 4 hours at room temperature. The reaction solution was evaporated, the residue was dissolved in ethyl acetate, the organic solution was washed with 2 N hydrochloric acid and water, dried over sodium sulfate, filtered and evaporated (0.8 g of oil). Chromatography on silica gel with methylene chloride/ether (1:1) gave 370 mg of 5-methyl-5-(3-ethoxy-4-methoxy-phenyl)-2-oxazolidinone with m.p. 63 to 65°C.

Eksempel 7 Example 7

3,7 g (15,7 mmol) 4-methoxy-3-(3-tetrahydrof uryloxy)-acetofenon, 2,3 ml (17,1 mmol) trimethylsilylcyanid og 134 mg (0,40 mmol) sinkjodid ble omrørt under argon i 5 timer ved 100°C og i 14 timer ved romtemperatur. Den ytterligere gjennomføring fant sted analogt med eksempel 1. Det ble erholdt 600 mg 5-methyl-5-[4-methoxy-3-(3-tetrahydrofuryloxy)-fenyl]-2-oxazolidinon som farveløs olje. 3.7 g (15.7 mmol) of 4-methoxy-3-(3-tetrahydrofuryloxy)-acetophenone, 2.3 ml (17.1 mmol) of trimethylsilyl cyanide and 134 mg (0.40 mmol) of zinc iodide were stirred under argon for 5 hours at 100°C and for 14 hours at room temperature. The further execution took place analogously to example 1. 600 mg of 5-methyl-5-[4-methoxy-3-(3-tetrahydrofuryloxy)-phenyl]-2-oxazolidinone was obtained as a colorless oil.

Eksempel 8 Example 8

500 mg (1,8 mmol) 5-methyl-5-(3-cyclopropylmethoxy-4-methoxyfenyl)-2-oxazolidinon, 113 mg (2,0 mmol) kaliumhydroxyd og 0,15 ml (2,2 mmol) methyljodid ble omrørt i 4 ml tetra-hydrof uran i 4 timer ved romtemperatur. Reaksjonsblandingen ble filtrert, filtratet ble tilsatt 30 ml vann og ble deretter ekstrahert med eddikester. Eddikesterfasen ble vasket med vann, tørket over natriumsulfat, filtrert og inndampet (390 mg gul olje) . Ved PSC-separering med methylenklorid/ ether (1:1) ble det erholdt 212 mg 5-(3-cyclopropylmethoxy-4-methoxyfenyl)-3,5-dimethyl-2-oxazolidinon som olje. 500 mg (1.8 mmol) 5-methyl-5-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-oxazolidinone, 113 mg (2.0 mmol) potassium hydroxide and 0.15 ml (2.2 mmol) methyl iodide were stirred in 4 ml of tetrahydrofuran for 4 hours at room temperature. The reaction mixture was filtered, the filtrate was added to 30 ml of water and was then extracted with acetic acid. The acetate phase was washed with water, dried over sodium sulfate, filtered and evaporated (390 mg yellow oil). By PSC separation with methylene chloride/ether (1:1), 212 mg of 5-(3-cyclopropylmethoxy-4-methoxyphenyl)-3,5-dimethyl-2-oxazolidinone were obtained as an oil.

Eksempel 9 Example 9

500 mg (2,0 mmol) 5-methyl-5-(3-ethoxy-4-methoxyfenyl)-2-oxazolidinon, 125 mg (2,22 mmol) kaliumhydroxyd og 0,167 ml (2,38 mmol) methyljodid ble omrørt i 4 ml tetra-hydrof uran i 4 timer ved romtemperatur. Den ytterligere gjennomføring fant sted analogt med eksempel 8. Det ble erholdt 201 mg 5-(3-ethoxy-4-methoxyfenyl)-3,5-dimethyl-2-oxazolidinon som olje. 500 mg (2.0 mmol) of 5-methyl-5-(3-ethoxy-4-methoxyphenyl)-2-oxazolidinone, 125 mg (2.22 mmol) of potassium hydroxide and 0.167 ml (2.38 mmol) of methyl iodide were stirred in 4 ml of tetrahydrofuran for 4 hours at room temperature. The further operation took place analogously to example 8. 201 mg of 5-(3-ethoxy-4-methoxyphenyl)-3,5-dimethyl-2-oxazolidinone were obtained as an oil.

Eksempel 10 Example 10

500 mg (2,0 mmol) 5-methyl-5-(3-ethoxy-4-methoxyfenyl)-2- oxazolidinon ble først omrørt med 60 mg (2,5 mmol) natriumhydrid i 14 ml dimethylformamid i 30 minutter, og etter tilsetning av 0,29 ml (3,0 mmol) (brommethyl)-cyclopropan omrørt i 17 timer ved romtemperatur. Reaksjonsblandingen ble tilsatt 50 ml vann og ble deretter ekstrahert med eddikester. Eddikesterfasen ble vasket med vann, tørket over natriumsulfat, filtrert og inndampet (766 mg gul olje). 500 mg (2.0 mmol) of 5-methyl-5-(3-ethoxy-4-methoxyphenyl)-2-oxazolidinone was first stirred with 60 mg (2.5 mmol) of sodium hydride in 14 ml of dimethylformamide for 30 minutes, and after addition of 0.29 ml (3.0 mmol) (bromomethyl)-cyclopropane stirred for 17 hours at room temperature. The reaction mixture was added to 50 ml of water and was then extracted with acetic acid. The acetate phase was washed with water, dried over sodium sulfate, filtered and evaporated (766 mg yellow oil).

Ved kromatografi på kiselgel med methylenklorid/ether (1:1) ble det erholdt 4 38 mg 5-methyl-5-(3-ethoxy-4-methoxyfenyl)-3- cyclopropylmethyl-2-oxazolidinon som olje. Chromatography on silica gel with methylene chloride/ether (1:1) gave 438 mg of 5-methyl-5-(3-ethoxy-4-methoxyphenyl)-3-cyclopropylmethyl-2-oxazolidinone as an oil.

Eksempel 11 Example 11

500 mg (1,8 mmol) 5-methyl-5-(3-cyclopropylmethoxy-4-methoxyfenyl)-2-oxazolidinon ble først omrørt med 75 mg (3,1 mmol) natriumhydrid i 17 ml dimethylformamid i 30 minutter, og etter tilsetning av 0,25 ml (2,7 mmol) isopropyl-bromid omrørt i 17 timer ved romtemperatur. Den ytterligere gjennomføring fant sted analogt med eksempel 1. Det ble erholdt 169 mg 5-methyl-5-(3-cyclopropylmethoxy-4-methoxy-fenyl)-3-isopropyl-2-oxazolidinon som olje. 500 mg (1.8 mmol) of 5-methyl-5-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-oxazolidinone was first stirred with 75 mg (3.1 mmol) of sodium hydride in 17 ml of dimethylformamide for 30 minutes, and after addition of 0.25 ml (2.7 mmol) isopropyl bromide stirred for 17 hours at room temperature. The further execution took place analogously to example 1. 169 mg of 5-methyl-5-(3-cyclopropylmethoxy-4-methoxy-phenyl)-3-isopropyl-2-oxazolidinone were obtained as an oil.

Eksempel 12 Example 12

500 mg (1,8 mmol) 5-methyl-5-(3-cyclopropylmethoxy-4-methoxyfenyl)-2-oxazolidinon ble først omrørt med 75 mg (3,1 mmol) natriumhydrid i 17 ml dimethylformamid i 30 minutter, og etter tilsetning av 0,32 ml (2,7 mmol) benzyl- 500 mg (1.8 mmol) of 5-methyl-5-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-oxazolidinone was first stirred with 75 mg (3.1 mmol) of sodium hydride in 17 ml of dimethylformamide for 30 minutes, and after addition of 0.32 ml (2.7 mmol) of benzyl

bromid ble omrørt i 2 timer ved romtemperatur. Den ytterligere gjennomføring fant sted analogt med eksempel 10. Det ble erholdt 348 mg 5-methyl-5-(3-cyclopropylmethoxy-4-methoxyfenyl)-3-benzyl-2-oxazolidinon som olje. bromide was stirred for 2 hours at room temperature. The further execution took place analogously to example 10. 348 mg of 5-methyl-5-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-benzyl-2-oxazolidinone were obtained as an oil.

Claims (1)

Analogifremgangsmåte for fremstilling av terapeutisk aktive oxazolidinonderivater av generell formel IaAnalogous process for the preparation of therapeutically active oxazolidinone derivatives of general formula Ia hvori R,, betegner en hydrocarbonrest med to til fire carbonatomer, karakterisert ved at et amin av generell formel hvori R,, har den ovenfor angitte betydning, kondenseres med en carbonylforbindelse av generell formel V hvori X betegner kloratomer, lavere alkoxygrvipper eller 1-imidazolyl-rester.in which R,, denotes a hydrocarbon residue with two to four carbon atoms, characterized in that an amine of general formula in which R,, has the above-mentioned meaning, is condensed with a carbonyl compound of general formula V in which X denotes chlorine atoms, lower alkoxy groups or 1-imidazolyl -remains.
NO862439A 1984-10-19 1986-06-18 ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE OXAZOLIDINON DERIVATIVES. NO164897C (en)

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US5783591A (en) * 1984-10-19 1998-07-21 Schering Aktiengesellschaft Administration of oxazolidinone and pyrolidinone compounds for the treatment of inflammation
US4681940A (en) * 1985-11-19 1987-07-21 American Home Products Corporation 5-[3-[[2-quinolyl]methoxy]phenyl]-1,3-oxazoles
DE3639225A1 (en) * 1986-11-14 1988-05-19 Schering Ag USE OF 5- (SUBST. PHENYL) -OXAZOLIDINONE DERIATES AS PSYCHOPHARMAKA
HU203330B (en) * 1987-06-10 1991-07-29 Pfizer Process for producing oxazolidin-2-one derivatives and hypoglychemic pharmaceutical compositions containing them
ES2057110T3 (en) * 1988-03-24 1994-10-16 Sankyo Co USE OF ISOXAZOLINONES AS DRUGS WITH ACTION ON THE BRAIN.
DE69128627T2 (en) * 1990-08-03 1998-07-02 Smithkline Beecham Corp TNF INHIBITORS
US5124455A (en) * 1990-08-08 1992-06-23 American Home Products Corporation Oxime-carbamates and oxime-carbonates as bronchodilators and anti-inflammatory agents
US5547979A (en) * 1992-03-30 1996-08-20 Smithkline Beecham TNF inhibition
CN1173818A (en) * 1995-02-10 1998-02-18 舍林股份公司 Pharmaceutical preparations for tumour necrosis factor (TNF) inhibition
DE19540475A1 (en) * 1995-10-20 1997-04-24 Schering Ag Chiral methylphenyloxazolidinones
US6770658B2 (en) * 1998-09-09 2004-08-03 Inflazyme Pharmaceuticals Ltd. Substituted γ-phenyl-Δ-lactams and uses related thereto
MXPA04003516A (en) * 2001-10-16 2004-07-23 Memory Pharm Corp 4-(4-alkoxy-3-hydroxyphenyl)-2-pyrrolidone derivatives as pde-4 inhibitors for the treatment of neurological syndromes.
WO2004098592A1 (en) * 2003-05-06 2004-11-18 Senju Pharmaceutical Co. Ltd. Composition containing oxazolidinone derivative
TW200732313A (en) 2005-12-15 2007-09-01 Astrazeneca Ab Oxazolidinone compounds and their use as metabotropic glutamate receptor potentiators

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