DK153549B - Analogifremgangsmaade til fremstilling af 3-methyl-4-halogen-5-bromethylaminomethylisoxazoler eller farmakologisk acceptable syreadditionssalte deraf - Google Patents
Analogifremgangsmaade til fremstilling af 3-methyl-4-halogen-5-bromethylaminomethylisoxazoler eller farmakologisk acceptable syreadditionssalte deraf Download PDFInfo
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- DK153549B DK153549B DK023187A DK23187A DK153549B DK 153549 B DK153549 B DK 153549B DK 023187 A DK023187 A DK 023187A DK 23187 A DK23187 A DK 23187A DK 153549 B DK153549 B DK 153549B
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- DK
- Denmark
- Prior art keywords
- methyl
- acid addition
- acceptable acid
- pharmacologically acceptable
- preparation
- Prior art date
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- 239000002253 acid Substances 0.000 title claims description 12
- 150000003839 salts Chemical class 0.000 title claims description 10
- 238000000034 method Methods 0.000 title description 6
- 238000002360 preparation method Methods 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims description 20
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 230000036772 blood pressure Effects 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- 150000002545 isoxazoles Chemical class 0.000 description 4
- MVUNGSCTAHNXDF-UHFFFAOYSA-N Cl.CC1=NOC(=C1Cl)CNCBr Chemical compound Cl.CC1=NOC(=C1Cl)CNCBr MVUNGSCTAHNXDF-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- -1 hydrochloric Chemical class 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- FICAQKBMCKEFDI-UHFFFAOYSA-N 3,5-dimethyl-1,2-oxazole Chemical compound CC=1C=C(C)ON=1 FICAQKBMCKEFDI-UHFFFAOYSA-N 0.000 description 1
- VLRGXXKFHVJQOL-UHFFFAOYSA-N 3-chloropentane-2,4-dione Chemical compound CC(=O)C(Cl)C(C)=O VLRGXXKFHVJQOL-UHFFFAOYSA-N 0.000 description 1
- JTJWPHJWCFVTMS-UHFFFAOYSA-N 4-chloro-3,5-dimethyl-1,2-oxazole Chemical compound CC1=NOC(C)=C1Cl JTJWPHJWCFVTMS-UHFFFAOYSA-N 0.000 description 1
- QJSFKHBXZKMSGW-UHFFFAOYSA-N 5-(bromomethyl)-4-chloro-3-methyl-1,2-oxazole Chemical compound CC1=NOC(CBr)=C1Cl QJSFKHBXZKMSGW-UHFFFAOYSA-N 0.000 description 1
- 239000004342 Benzoyl peroxide Substances 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- QMPSJCZMIUUBGV-UHFFFAOYSA-N N-(bromomethyl)-1-(4-chloro-3-methyl-1,2-oxazol-5-yl)methanamine Chemical compound CC1=NOC(=C1Cl)CNCBr QMPSJCZMIUUBGV-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- CJCSPKMFHVPWAR-JTQLQIEISA-N alpha-methyl-L-dopa Chemical compound OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1 CJCSPKMFHVPWAR-JTQLQIEISA-N 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- KGVPNLBXJKTABS-UHFFFAOYSA-N hymexazol Chemical compound CC1=CC(O)=NO1 KGVPNLBXJKTABS-UHFFFAOYSA-N 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000026045 iodination Effects 0.000 description 1
- 238000006192 iodination reaction Methods 0.000 description 1
- 150000002496 iodine Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000011814 protection agent Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- SRVJKTDHMYAMHA-WUXMJOGZSA-N thioacetazone Chemical compound CC(=O)NC1=CC=C(\C=N\NC(N)=S)C=C1 SRVJKTDHMYAMHA-WUXMJOGZSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- 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]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Heart & Thoracic Surgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Cardiology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (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)
- Plural Heterocyclic Compounds (AREA)
Description
i
DK 153549 B
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte isoxazolderi-vater, nærmere betegnet 3-methyl-4-halogen-5-bromethylamino-methylisoxazoler, eller farmakologisk acceptable syread-5 ditionssalte deraf.
Det er kendt, at 3-hydroxy-5-methylisoxazol kan anvendes som plantebeskyttelsesmiddel (Merck index, 9. (1961), side 123). Delvist mættede isoxazolderivater, der anvendes som tumorundertrykkende midler, er beskrevet i Tetrahedron 10 Letters 2549 (1973) og i J. Antib. 2M/ 91 (1975) .
Den foreliggende opfindelse tilvejebringer hidtil ukendte isoxazolderivater med den almene formel (I) CH3 ^ R2 V/ N. X i1) ^0/ ^ CH2NHCH2CH2Br hvori 1*2 står for et halogenatom, eller et farmakologisk accep-20 tabelt syreadditionssalt deraf.
En foretrukket repræsentant for de hidtil ukendte forbindelser med den almene formel (I) er den forbindelse, hvori R2 er chlor, nemlig 3-methyl-4-chlor-5-(bromethylamino--methyl)-isoxazol, og farmakologisk acceptable syreaddi-25 tionssalte, især hydrochloridet, deraf.
Syreadditionssaltene af forbindelserne med den almene formel (I) kan dannes med farmaceutisk acceptable uorganiske eller organiske syrer (f.eks. saltsyre, hydrogenbromidsyre, svovlsyre, phosphorsyre, vinsyre, fumarsyre, maleinsyre 30 eller citronsyre).
Den her omhandlede analogifremgangsmåde er karakteriseret ved, at man omsætter en forbindelse med den almene formel (II) 35
DK 153549 B
2 CH- VY"· 5 ^-0-/\CH2~Br hvori R2 er som defineret ovenfor, med ethylenimin og om ønsket omdanner en således opnået 10 forbindelse med den almene formel (I) til et farmakologisk acceptabelt syreadditionssalt deraf.
Ved fremgangsmåden ifølge den foreliggende opfindelse omsættes en forbindelse med den almene formel (II) med ethylenimin. Reaktionen udføres fortrinsvis i et organisk opløs-15 ningsmiddel (f.eks. acetone). Det foretrækkes at sætte ethy-leniminen til udgangsmaterialet med den almene formel (II) ved en temperatur på *5 - 4-10° C og derefter opvarme reaktionsblandingen til kogepunktet. Slutproduktet omdannes fortrinsvis til dets hydrochlorid ved udfældning med hydro-20 genchlorid.
Forbindelserne med den almene formel (I) kan omdannes på kendt måde til syreadditionssalte, dvs. ved omsætning med ca. 1 molækvivalent af en syre i et egnet opløsningsmiddel. De således opnåede forbindelser kan isoleres ved hjælp 25 af kendte metoder.
På grund af reaktionsevnen af bromatomet i allylstil-ling er forbindelserne med den almene formel (II) meget reaktive og kan anvendes til fremstillingen af forskellige isoxazolderivater.
30 3-Methyl-4-halogen-5-brommethylderivaterne med den almene formel (II) kan fremstilles på følgende måde:
Acetylacetone omsættes med sulfurylchlorid, det således opnåede 3-chloracetylacetone omdannes til 3,5-dimethyl--4-chlorisoxazol ved omsætning med hydroxylamin. Det tilsva-35 rende brom- og iodderivat fremstilles ved bromering eller iodering af 3,5-dimethyl-isoxazol i nærværelsen af salpeter-
DK 153549 B
3 syre. Ved omsætning af 3,5-dimethyl-4-halogen-isoxazol med N-brom-succinimid opnås næsten udelukkende det tilsvarende 3-methyl-4-halogen-5-brommethyl-isoxazol.
De hidtil ukendte forbindelser med formel (I) udviser 5 en stærk og relativ forlænget hypotensiv virkning.
På katte og kaniner opnås en stor formindskelse i blodtrykket med 3-methyl-4-chlor-5-(bromethylamino-methyl) --isoxazolhydrochlorid. På katte resulterer en tyvendedel af LD50-dosen af 3-methyl-4-chlor-5-(bromethyl-aminomethyl)-10 -isoxazolhydrochlorid, bestemt intravenøst på mus, i en 44%'s formindskelse.
Når en tiendedel af u^g-dosen af den samme forbindelse bestemt intravenøst på mus indgives enteralt til bedøvede kaniner, iagttages der en stor og permanent formind-15 skelse i blodtrykket. 30 minutter efter indgivelsen er blodtrykket formindsket med 18%, 90 minutter efter indgivelsen er blodtrykket formindsket med 48%, i forhold til før. Forbindelsen influerer ikke væsentligt på hjertefrekvensen.
Når en tiendedel af LD50-dosen (intravenøst) af L-a-methyl-20 -dopa indgives enteralt, formindskes kaninernes blodtryk med 14% 30 minutter efter indgivelsen og med 37% 90 minutter efter indgivelsen. Dette betyder, at styrken af virkningen af 3-methyl-4-chlor-5- (bromethylamino-methyl) -isoxazolhydrochlorid er af lignende størrelsesorden som virkningen af L-25 -α-methyl-dopa. Fordelen ved de hidtil ukendte forbindelser med formlen (I) er, at de er virksomme, hvadenten de indgives oralt eller intravenøst, medens L-a-methyl-dopa kun er aktivt, når det indgives intravenøst.
Den antiinflammatoriske virkning af de hidtil ukendte 30 forbindelser ifølge den foreliggende opfindelse bestemmes ligeledes. En tiendedel af LDsg-dosen (intravenøst, på mus) indgives rotter, og inhiberingen af ødemet, fremkaldt af lokalindgivelsen af 0,05 ml/3 mg dextran, bestemmes. Med forbindelsen 3-methyl-4-chlor-5- (bromethylamino-methyl) — 35 isoxazol-hydrochlorid opnås herved en inhibering af ødemet på 34%.
DK 153549B
4
Forbindelsen med formlen (I) kan indgå i farmaceutiske præparater, der som aktivt middel indeholder en forbindelse med den almene formel (I) eller et farmaceutisk acceptabelt syreadditionssalt deraf og et egnet indifferent ikke-toksisk, 5 fast eller flydende farmaceutisk bærestof.
Bærestofferne kan være sådanne, som sædvanligvis anvendes i farmacien (f.eks. calciumcarbonat, magnesiumstea-rat, vand, polyalkylenglycol eller stivelse). Ovennævnte farmaceutiske præparater kan formuleres ved hjælp af kendte 10 metoder i fast form (f.eks. tabletter, kapsler, dragées eller stikpiller) eller flydende form (f.eks. opløsninger, suspensioner eller emulsioner).
Den daglige dosis af forbindelserne med den almene formel (I) afhænger af forskellige faktorer (f.eks. den 15 givne forbindelses aktivitet eller patientens tilstand) og bestemmes altid af lægens forordninger.
Den foreliggende opfindelse er illustreret ved hjælp af de følgende eksempler. Eksempel 1 beskriver fremstillingen af de forbindelser med den almene formel (II), der anvendes 20 som udgangsmaterialer.
Eksempel 1
Fremstilling af 3-methvl-4-halogen-5-brommethvl-isoxazoler 0,1 mol af det tilsvarende 3,5-dimethyl-4-halogenis-25 oxazol opløses i 150 ml vandfrit carbontetrachlorid, derefter tilsættes 0,5 g benzoylperoxid, og opløsningen opvarmes til kogepunktet. Derefter tilsættes 0,12 mol N-bromsuccinimid i små portioner i løbet af 1,5 timer, derefter koges blandingen i 4-5 timer. Efter afkøling af opløsningen filtreres det 30 udskilte succinimid fra, og filtratet inddampes. Den resterende sirup er 3-methyl-4-halogen-5-brommethylisoxazol (ca. 90-100%), som kan anvendes uden nogen yderligere rensning.
35
DK 153549 E
5
Eksempel 2
Fremstilling af 3-methvl-4-chlor-5-(bromethvlamino-methvl)--isoxazol-hvdrochlorid 0,35 mol 3-methyl-4-chlor-5-brommethy1-isoxazol op-5 løses i 390 ml vandfri acetone, opløsningen afkøles til *5-—fl0°C, og en opløsning af 19,6 ml ethylenimin i 80 ml vandfri acetone tilsættes under omrøring. Derefter omrøres reaktionsblandingen i 2 timer, afkøles og hældes ud i 1 liter isholdigt vand. Den udskilte, klæbrige masse ekstraheres 10 først med 200 ml, derefter to gange med en samlet mængde på 100 ml ether. Etherfasen skilles fra bundfaldet (8,2 g, smp. 138-141°C), vaskes to gange med 400 ml vand, tørres over magnesiumsulfat, koncentreres til 1/3 af dens tidligere volumen og mættes med vandfrit hydrogenchlorid. Det udskilte 15 produkt filtreres fra og omkrystalliseres fra vandfrit ethanol.
Udbytte: 25%.
Smp.: 164-1660 C.
Analyse 20 Beregnet: C = 33,03%, H = 4,35%, N - 9,66%, Cl = 12,22%,
Cl" = 12,22%, Br = 27,55%.
Fundet: C = 37,87%, H = 4,31%, N = 10,05%, Cl = 12,28%,
Cl” = 12,34%, Br = 27,44%.
Claims (3)
- 5 CH, Ro W N JL (I) ^ CH2NHCH2CH2Br 10 hvori R2 står for et halogenatom, eller farmakologisk acceptable syreadditions salte deraf, kendetegnet ved, at man omsætter en forbindelse med den almene formel (II)
- 15 CIi3 R "x_/ 2 l! { «I) '^0'/\CH2-Br hvori
- 20 R2 er som defineret ovenfor, med ethylenimin og om ønsket omdanner en således opnået forbindelse med den almene formel (I) til et farmakologisk accceptabelt syreadditionssalt deraf.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU63780 | 1980-03-19 | ||
| HU8080637A HU180567B (en) | 1980-03-19 | 1980-03-19 | Method for producing derivatives of isooxazole |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK23187A DK23187A (da) | 1987-01-16 |
| DK153549B true DK153549B (da) | 1988-07-25 |
| DK153549C DK153549C (da) | 1988-12-05 |
Family
ID=10950573
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK122581A DK151012C (da) | 1980-03-19 | 1981-03-18 | Analogifremgangsmaade til fremstilling af 3-methyl-4-halogen-5-aminooxymethyl-isoxazoler eller et syreadditionssalt deraf |
| DK023087A DK151959C (da) | 1980-03-19 | 1987-01-16 | Analogifremgangsmaade til fremstilling af 3-methyl-4-halogenisoxazol-5-yl-methylenoxyguanidin eller farmakologisk acceptable syreadditionssalte deraf |
| DK023187A DK153549C (da) | 1980-03-19 | 1987-01-16 | Analogifremgangsmaade til fremstilling af 3-methyl-4-halogen-5-bromethylaminomethylisoxazoler eller farmakologisk acceptable syreadditionssalte deraf |
Family Applications Before (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK122581A DK151012C (da) | 1980-03-19 | 1981-03-18 | Analogifremgangsmaade til fremstilling af 3-methyl-4-halogen-5-aminooxymethyl-isoxazoler eller et syreadditionssalt deraf |
| DK023087A DK151959C (da) | 1980-03-19 | 1987-01-16 | Analogifremgangsmaade til fremstilling af 3-methyl-4-halogenisoxazol-5-yl-methylenoxyguanidin eller farmakologisk acceptable syreadditionssalte deraf |
Country Status (15)
| Country | Link |
|---|---|
| JP (1) | JPS56158774A (da) |
| BE (1) | BE887954A (da) |
| CA (1) | CA1163631A (da) |
| CH (1) | CH646157A5 (da) |
| DE (1) | DE3110817A1 (da) |
| DK (3) | DK151012C (da) |
| ES (3) | ES501095A0 (da) |
| FI (1) | FI70011C (da) |
| FR (1) | FR2478634A1 (da) |
| GB (1) | GB2075009B (da) |
| HU (1) | HU180567B (da) |
| IT (1) | IT1211010B (da) |
| SE (1) | SE454695B (da) |
| SU (3) | SU1053750A3 (da) |
| YU (1) | YU42560B (da) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2248894T3 (es) * | 1997-04-21 | 2006-03-16 | Dainippon Sumitomo Pharma Co., Ltd. | Derivados de isoxazol. |
| US6100260A (en) * | 1997-04-21 | 2000-08-08 | Sumitomo Pharmaceutical Company, Limited | Isoxazole derivatives |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL302496A (da) * | 1962-12-22 | |||
| US3808221A (en) * | 1971-04-14 | 1974-04-30 | Hoffmann La Roche | Antiandrogenic n-(3,5-dilower alkyl-4-heterocyclic)methyl)phthalimides |
-
1980
- 1980-03-19 HU HU8080637A patent/HU180567B/hu not_active IP Right Cessation
-
1981
- 1981-03-16 BE BE1/10179A patent/BE887954A/fr not_active IP Right Cessation
- 1981-03-17 YU YU689/81A patent/YU42560B/xx unknown
- 1981-03-17 SE SE8101703A patent/SE454695B/sv not_active IP Right Cessation
- 1981-03-18 FR FR8105378A patent/FR2478634A1/fr active Granted
- 1981-03-18 FI FI810838A patent/FI70011C/fi not_active IP Right Cessation
- 1981-03-18 ES ES501095A patent/ES501095A0/es active Granted
- 1981-03-18 IT IT8120395A patent/IT1211010B/it active
- 1981-03-18 CH CH182981A patent/CH646157A5/de not_active IP Right Cessation
- 1981-03-18 DK DK122581A patent/DK151012C/da not_active IP Right Cessation
- 1981-03-18 GB GB8108545A patent/GB2075009B/en not_active Expired
- 1981-03-19 SU SU813261940A patent/SU1053750A3/ru active
- 1981-03-19 DE DE19813110817 patent/DE3110817A1/de not_active Withdrawn
- 1981-03-19 CA CA000373380A patent/CA1163631A/en not_active Expired
- 1981-03-19 JP JP4023281A patent/JPS56158774A/ja active Pending
-
1982
- 1982-04-01 SU SU823416146A patent/SU1158044A3/ru active
- 1982-04-01 SU SU823414099A patent/SU1152518A3/ru active
- 1982-04-16 ES ES511894A patent/ES8401758A1/es not_active Expired
- 1982-04-16 ES ES511895A patent/ES8305340A1/es not_active Expired
-
1987
- 1987-01-16 DK DK023087A patent/DK151959C/da not_active IP Right Cessation
- 1987-01-16 DK DK023187A patent/DK153549C/da not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| BE887954A (fr) | 1981-09-16 |
| FI70011C (fi) | 1986-09-12 |
| DK23187A (da) | 1987-01-16 |
| ES511895A0 (es) | 1983-05-01 |
| DK151959C (da) | 1988-07-11 |
| GB2075009B (en) | 1983-11-30 |
| FI70011B (fi) | 1986-01-31 |
| ES8305340A1 (es) | 1983-05-01 |
| ES8302674A1 (es) | 1983-02-16 |
| DK122581A (da) | 1981-09-20 |
| JPS56158774A (en) | 1981-12-07 |
| FR2478634B1 (da) | 1983-11-10 |
| CA1163631A (en) | 1984-03-13 |
| YU68981A (en) | 1983-10-31 |
| DE3110817A1 (de) | 1982-03-04 |
| IT1211010B (it) | 1989-09-29 |
| GB2075009A (en) | 1981-11-11 |
| DK151012C (da) | 1988-07-04 |
| ES501095A0 (es) | 1983-02-16 |
| IT8120395A0 (it) | 1981-03-18 |
| SU1152518A3 (ru) | 1985-04-23 |
| DK153549C (da) | 1988-12-05 |
| DK23087A (da) | 1987-01-16 |
| FR2478634A1 (fr) | 1981-09-25 |
| SE454695B (sv) | 1988-05-24 |
| YU42560B (en) | 1988-10-31 |
| SU1053750A3 (ru) | 1983-11-07 |
| CH646157A5 (en) | 1984-11-15 |
| DK151012B (da) | 1987-10-12 |
| ES511894A0 (es) | 1984-01-01 |
| HU180567B (en) | 1983-03-28 |
| DK151959B (da) | 1988-01-18 |
| SE8101703L (sv) | 1981-09-20 |
| ES8401758A1 (es) | 1984-01-01 |
| FI810838L (fi) | 1981-09-20 |
| SU1158044A3 (ru) | 1985-05-23 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed |