DK151013B - Analogifremgangsmaade til fremstilling af 5-methyl-isoxazol-4-carboxylsyreanilider - Google Patents
Analogifremgangsmaade til fremstilling af 5-methyl-isoxazol-4-carboxylsyreanilider Download PDFInfo
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- DK151013B DK151013B DK248376AA DK248376A DK151013B DK 151013 B DK151013 B DK 151013B DK 248376A A DK248376A A DK 248376AA DK 248376 A DK248376 A DK 248376A DK 151013 B DK151013 B DK 151013B
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- 238000000034 method Methods 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title claims description 6
- VQBXUKGMJCPBMF-UHFFFAOYSA-N 5-methyl-1,2-oxazole-4-carboxylic acid Chemical compound CC=1ON=CC=1C(O)=O VQBXUKGMJCPBMF-UHFFFAOYSA-N 0.000 title 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- -1 methylenedioxy group Chemical group 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 150000008065 acid anhydrides Chemical class 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- ZYEWRBNSDKQNSJ-UHFFFAOYSA-N 5-methyl-n-phenyl-1,2-oxazole-4-carboxamide Chemical class O1N=CC(C(=O)NC=2C=CC=CC=2)=C1C ZYEWRBNSDKQNSJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
- WFPDGMINSGBGKC-UHFFFAOYSA-N acetic acid;n-phenylacetamide Chemical compound CC(O)=O.CC(=O)NC1=CC=CC=C1 WFPDGMINSGBGKC-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 230000003110 anti-inflammatory effect Effects 0.000 description 6
- FZERHIULMFGESH-UHFFFAOYSA-N N-phenylacetamide Chemical compound CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 150000002545 isoxazoles Chemical class 0.000 description 5
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 229960002895 phenylbutazone Drugs 0.000 description 4
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- SCYGGCAQZFJGRF-UHFFFAOYSA-N n-(3,4-dichlorophenyl)acetamide Chemical compound CC(=O)NC1=CC=C(Cl)C(Cl)=C1 SCYGGCAQZFJGRF-UHFFFAOYSA-N 0.000 description 3
- 208000009386 Experimental Arthritis Diseases 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 230000001760 anti-analgesic effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- RIFXXMYHOTWSEC-UHFFFAOYSA-N n-(3,4-dichlorophenyl)-5-methyl-1,2-oxazole-4-carboxamide Chemical compound O1N=CC(C(=O)NC=2C=C(Cl)C(Cl)=CC=2)=C1C RIFXXMYHOTWSEC-UHFFFAOYSA-N 0.000 description 2
- 239000003791 organic solvent mixture Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001562 ulcerogenic effect Effects 0.000 description 2
- ZEONKMXUCHNYRN-UHFFFAOYSA-N 2-(3,5-dimethyl-1,2-oxazol-4-yl)acetic acid Chemical compound CC1=NOC(C)=C1CC(O)=O ZEONKMXUCHNYRN-UHFFFAOYSA-N 0.000 description 1
- IJEUISLJVBUNRE-UHFFFAOYSA-N 3,5-dimethyl-1,2-oxazole-4-carboxylic acid Chemical compound CC1=NOC(C)=C1C(O)=O IJEUISLJVBUNRE-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Natural products CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 238000011785 NMRI mouse Methods 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000003555 analeptic effect Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 229940051881 anilide analgesics and antipyretics Drugs 0.000 description 1
- 150000003931 anilides Chemical class 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 210000005069 ears Anatomy 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000011694 lewis rat Methods 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N n-propyl alcohol Natural products CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 210000002445 nipple Anatomy 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 atoms of the carbocyclic ring
- C07D317/66—Nitrogen atoms not forming part of a nitro radical
-
- 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
-
- 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
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pain & Pain Management (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
151013 o
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af 5-methyl-isoxazol-4-carb-oxylsyreanilider med den almene formel I
5 CONH- / f|-( r2 (I) N ]_ CH, „1 1 2 hvori R og R er ens eller forskellige og betyder methyl, der 10 eventuelt er substitueret med 1-3 ens eller forskellige halogenatomer, eller betyder halogen eller nitro, eller
1 12 R betyder hydrogen, idet dog, når R betyder hydrogen, R
o xkke kan betyde methyl, i hvilket tilfælde R dog desuden betyder phenoxy, der eventuelt er substitueret én 1 2
15 gang med halogen, eller hvori R og R sammen betyder en methylendioxygruppe, hvilken fremgangsmåde er ejendommelig ved, at et aceteddikesyreanilid med formlen II
CH^-C0-CHo-C0NH- /\\ 20 3 2 (ii) R1 1 2 hvori R og R har ovennævnte betydninger, opvarmes med en orthomyresyreester med formlen III 25 HC(OR)3 (III)
hvori R betyder C1_4-alkyl, og med et syreanhydrid, og det således fremstillede 2-alkoxymethylenaceteddikesyre-30 anilid med formlen IV
0HrC0-5-00NH-^Q\ (Iy) H^^OR T^R2 35 R1
O
2 151013 1 2 hvori R, R og R har ovennævnte betydninger, isoleres og derefter behandles med hydroxylamin i et organisk opløsningsmiddel .
Der foretrækkes forbindelser med formlen I, hvori 1 2 5 R betyder hydrogen, og R betyder halogen, såsom fluor, chlor eller brom, eller en CF^-gruppe.
Der foretrækkes endvidere forbindelser med form-1 2 len I, hvori R og R er ens eller forskellige og betyder halogen, såsom fluor, chlor eller brom, eller en CF^-grup-10 pe.
Der foretrækkes endvidere forbindelser med formlen 1 2 I, hvori R betyder methyl, og R betyder halogen, såsom fluor, chlor eller brom.
Yderligere foretrækkes en forbindelse med formlen 1 2 15 I, hvori R og R tilsammen danner en 3,4-methylendioxy--gruppe.
Der anvendes hensigtsmæssigt mindst den ækvimolæ-re mængde orthomyresyreester HC(0R)3, hvori R betyder C-^_^-alkyl, fortrinsvis methyl eller ethyl, og hensigts-20 mæssigt et dobbelt til firedobbelt molært overskud af et syreanhydrid, hensigtsmæssigt et aliphatisk syreanhydrid med 4-6 carbonatomer, fortrinsvis acetanhydrid. Blandingen opvarmes i almindelighed i 30 minutter til 3 timer til en temperatur mellem 80° og 150°C, fortrinsvis til 25 blandingens kogetemperatur, hvorefter det således fremstillede 2-alkoxymethylenaceteddikesyreanilid med den almene formel IV isoleres og derpå behandles med en hensigtsmæssigt mindst ækvimolær mængde hydroxylamin i et organisk opløsningsmiddel eller en opløsningsmiddelblan-30 ding, fortrinsvis methyl-, ethyl-, propyl- eller isopro-pylalkohol, eventuelt under tilsætning af op til 2 volumendele, fortrinsvis op til 1 volumendel, vand pr. 1 volumendel organisk opløsningsmiddel, ved en temperatur mellem 0° og 100°C, fortrinsvis mellem 10° og 50°C.
35 De som udgangsmateriale til fremstilling af de her
O
3 151013 omhandlede forbindelser med formlen I nødvendige 2-alkoxy-methylenaceteddikesyreanilider med formlen IV er hidtil ukendte.
Kun fremstillingen af det ifølge den foreliggende 5 ansøgning ikke anvendte 2-ethoxymethylenaceteddikesyreani- lid af aceteddikesyreanilid, orthomyresyretriethylester og acetanhydrid er beskrevet af G. Kempter, W. Schmidt og H. Dost, Chem. Ber. £8, 955-961 (1965).
De hidtil ukendte 2-ethoxymethylenaceteddikesyre- 10 anilider er anført i tabel I.
Isoxazolerne med formlen I fremstillet ifølge den foreliggende opfindelse er hidtil ukendte. Kun tre analo- 1 2 ge isoxazoler, hvori R og R" betyder hydrogen, eller 1 2 R betyder hydrogen, og- R betyder 2-CHg eller 4-CHg, 15 er beskrevet af F.B. Dains og E.L. Griffin, J. Am. Chem.
Soc. _35, 959-976 (1913) . Disse kendte forbindelser har imidlertid ingen praktisk udnyttelige, antiinflammatori-ske eller analgetiske egenskaber.
Fra dansk patentskrift nr. 54.063 kendes 3- og/el-20 ler 5-methylsubstituerede isoxazol-4-carboxylsyredialkyl- amider, der er analeptisk virksomme. Fra dansk patentskrift nr. 58.785 kendes 3,5-dimethylisoxazol-4-eddikesyre- og -4-propionsyredialkylamider med analeptisk virkning. Endvidere kendes der fra dansk patentskrift nr. 58.903 en 25 fremgangsmåde til fremstilling af substituerede amider af 3,5-dimethylisoxazol-4-carboxylsyre. Disse kendte forbindelser har imidlertid i lighed med de ovennævnte kendte forbindelser ingen antiinflammatorisk virkning.
Reaktionstrinnet fra en forbindelse med formlen 30 IV til fremgangsmådeprodukterne med formlen I er overraskende. Det omfatter cycliseringen af de let tilgængelige 2-ethoxymethylenaceteddikesyreanilider med hydroxyl-amin til isoxazolerne med formlen I, der allerede ved stuetemperatur forløber i udbytter mellem 90 og 100%.
35 De hidtil ukendte fremgangsmådeprodukter med form-
O
151013 4 len I er sammenfattet i tabel II.
De her omhandlede forbindelser med formlen I udviser stærke antiinflammatoriske og analgetiske egenskaber.
En sammenligning med antiinflammatorisk virksomme stof-5 fer viser, at det kendte phenylbutazon ganske vist har en Omtrent lige så kraftig antiinflammatorisk virkning, men er væsentlig mere toksisk. I sammenligning med kendte, antiinflammatorisk virksomme stoffer med ca. samme toksicitet, er forbindelserne fremstillet ifølge opfindelsen me-10 re virksomme. De overgår desuden phenylbutazon med hensyn til analgetisk virkning. De har en væsentlig svagere ulcerogen bivirkning end phenylbutazon.
Som det endvidere fremgår af tabel III nedenfor, udviser de ifølge opfindelsen fremstillede isoxazoler en 15 gunstigere akut toksicitet, og de udviser en ringere akut gastrisk ulcerogenitet, der ved denne lægemiddelgruppe er en også hos mennesker typisk optrædende bivirkning.
Afgørende for den terapeutiske fordel af de ifølge opfindelsen fremstillede isoxazoler er især deres sto-20 re afstand mellem den antiinflammatorisk virksomme dosis og den dosis, der udløser bivirkninger eller toksicitet, hvilket fremgår tydeligt af de i tabel III nedenfor anførte terapeutiske indekser.
Den antiinflammatoriske virkning påvises på adju-25 vans-arthritis hos rotter (pearson, C.M. og Wood, F.D.,
Arthrit. Rheumat. 2^, (1959) , 440) , og den analgetiske virkning ved et Writhing-forsøg med mus (Sigmund, E. et al., Proc. Sco. Exp. Biol. Med. 95^ (1957), 729).
ED^Q-værdierne bestemmes grafisk i et sandsynlig-30 hedsnet. Ved Writhing-forsøget defineres ED5Q-værdien ved den præparatdosis, der i forhold til kontrollen nedsætter antallet af sløjfebevægelser med 50%. Ved adjuvans--arthritis-forsøget tjener den på 17. dagen efter begyndelsen af præparatindgiften i forhold til kontrolgruppen 35 iagttagne hæmning af de sekundære læsioner på dyrenes ører,
O
5 151013 pøter og hale til bedømmelse af virkningen. Som ED^-vaer-di gælder den dosis, der formindsker disse læsioner med 50% i forhold til kontrolgruppen.
Til undersøgelse af den ulcerogene aktivitet ind-5 gives prøvesubstanserne oralt til hanrotter af en Sprague--Dawley-stamme, der har fastet i 18 timer, og 24 timer derefter undersøges dyrenes mave-tarmområde for ulcera.
Ved den akutte toksicitetsundersøgelse ifølge Litchfield og Wilcoxon (Litchfield, J.T. og Wilcoxon, F.W., J. Phar-10 macol. exp. Ther. 96^ (1949) , 99) foretages bestemmelsen af LD^Q-værdierne på han- eller hun-N.M.R.I.-mus eller på Wi-star-Lewis-hunrotter.
De konstaterede værdier for nogle forbindelser med formlen I og de kendte forbindelser indomethacin og phe-15 nylbutazon er angivet i nedenstående tabel III.
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O
7 151013
Fremstillingseksempel 1 a) 2-Ethoxymethylenaceteddikesyre-3,4-dichloranilid med formlen IV_ 246 g, 1,0 mol, aceteddikesyre-3,4-dichloranilid 5 med formlen II koges under tilbagesvaling i 1,5 timer med 166 g, 1,12 mol, orthomyresyretriethylester med formlen III og 302 g, 2,97 mol, acetanhydrid. Efter afkøling til stuetemperatur fraskilles de udfældede krystaller ved sugning og vaskes med en blanding af 1 volumendel benzen 10 og 2 volumendele benzin.
Udbyttet udgør 251 g 2-ethoxymethylenaceteddike-syre-3,4-dichloranilid svarende til 83% af det teoretiske.
Smeltepunkt efter omkrystallisation fra benzen: 15 125-126°C.
Analyse for 0^83.3^2^3 molekylvægt 302,15 Beregnet: C = 51,7%, H = 4,3%, N = 4,6%
Fundet: C = 51,8%, H = 4,1%, N = 4,5%.
De i tabel I anførte forbindelser fremstilles ana-20 logt hermed.
Ved godt opløselige 2-ethoxymethylenaceteddikesy-reanilider skal reaktionsblandingen eventuelt koncentreres destillativt.
25 b) 5-Methyl-isoxazol-4-carboxylsyre-3,4-dichloranilid med formlen I_ 7,65 g, 0,11 mol, hydroxylaminhydrochlorid opløses i 30 ml vand, blandes med en iskold opløsning af 4,4 g, 0,11 mol, natriumhydroxid i 20 ml vand og fortyndes med 30 150 ml methanol. Derpå tilsættes der 30,2 g, 0,1 mol, af det ifølge a) fremstillede 2-ethoxymethylenaceteddikesyre--3,4-dichloranilid, og der omrøres i ca. 4 timer ved stuetemperatur. Blandingen afkøles til +5°C, krystallerne fraskilles ved sugning, og der vaskes med vand. Efter tørring 35 i luften fås der farveløse krystaller.
O
151013 8
Udbyttet udgør 26,4 g 5-methyl-isoxazol-4-carboxyl-syre-3,4-dichloranilid svarende til 97,5% af det teoretiske.
Smeltepunkt efter omkrystallisation fra methanol: 5 146°C.
Analyse for ciiH8C^2N202 molekylvægt 271,1 Beregnet: C = 48,7%, H = 3,0%, N = 10,3%
Fundet: C = 48,6%, H = 3,0%, N = 10,2%
De i tabel II anførte forbindelser fremstilles ana-10 logt hermed.
O
9 151013
Tabel I
Mellemprodukter med formlen IV:
Nr.__Smp. (°C) 5 1 H 2-Cl 95-96 2 H 3-Cl 98 3 H 4-Cl 139,5 4 2-Cl 4-Cl 127 5 2-Cl 5-Cl 146 10 6 3-Cl 4-Cl 125-126 7 3-Cl 5-Cl 131 8 H 3-Br 118 9 H 4-Br 124 10 H 4-F 127 15 11 H 3-CF3 84 12 3-CF3 5_CF3 111 13 H 4-NO2 160-162 14 2_CH3 4-CH3 105 15 3,4-0. 136-137 20 _0>CH2 16 2-CH3 3-C1 129 17 2-CH3 4-C1 128 18 2_CH3 5-C1 141 14 2-CF., 4-Cl 108
25 J
20 H 4-0--Cl 78-79 21 H 4-°~{C))~Br 88 30 22 2-Br 5-Br 140 23 3-Cl 4_CH3 120 24 H 3-J 148 25 2-OH 3 5-Br 140-141 27 3"CH3 4"Br 123 35 28 H 3-F 109,5 10 151013 o
Tabel I (fortsat)
Nr.__R^_Smp. (°C) 29 2_CH3 3-F 124-125 5 30 3-Cl 4-F 110,5-111,5 31 3-CF3 4-C1 115,5 32 2-F 5“CF3 139,5-140 33 H 4-J 148,5-149 10
Tabel II
5-Methyl-isoxazol-4-carboxy1-syreanilider med formlen I
Nr._R^_R^_Smp. (°C) 15 1 H 2-C1 111-112 2 H 3-Cl 106-107 3 H 4-Cl 151 4 2-Cl 4-Cl 120-121 5 2-Cl 5-Cl 122 20 6 3-Cl 4-Cl 146 7 3-Cl 5-Cl 182-183 8 H 3-Br 122 9 H 4-Br 162-163 10 H 4-F 117-118 25 11 H 3-CF3 119-120 12 3_CF3 5“CF3 176 13 H 4-NO2 190-191 14 2_CH3 4_CH3 160-161 15 3,4-0. 125-126 30 _0>2 16 2-CH3 3-Cl 158-159 17 2-CB3 4-Cl 147-148 18 2_CH3 5-Cl 127-128 19 2-CFo 4-Cl 133-134 35 -5
O
11 151013
Tabel II (fortsat)
Nr.__Smp. (°C) 5 20 H 4-0-^0)-01 137-138 21 H 4-0-^Q^-Br 138 22 2-Br 5-Br 171-173 10 23 3-C1 4_CH3 149-150 24 H 3-J 148-149 25 2-CH3 5-Br 138-139 26 ‘ 3-CH3 4-Br 130-131 28 H 3-F 122 15 29 2_CH3 3-F 142 30 3-Cl 4-F 123-124 31 3-CF3 4-Cl 161-161,5 32 2-F 5_CF3 107-108 33 H 4-J 173-173,5 20 -
Claims (1)
- O 151013 Patentkrav. Analogifremgangsmåde til fremstilling af 5-methyl--isoxazol-4-carboxylsyreanilider med den almene formel 5 r-Y0""^ N L il ’CH-r R 10 υ 3 1 2 hvori R og R er ens eller forskellige og betyder methyl, der eventuelt er substitueret med 1-3 ens eller forskellige halogenatomer, eller betyder halogen eller nitro, eller R1 betyder hydrogen, idet dog, når R^ betyder hydrogen, 15. ikke kan betyde methyl/ i hvilket tilfælde R dog desuden betyder phenoxy, der eventuelt er substitueret én gang 1 2 med halogen, eller hvori R og R sammen betyder en methy-lendioxygruppe, kendetegnet ved, at et aceted-dikesyreanilid med formlen II 20 CVC.-CV™, ^ (ni R1 1 2 25 hvori R og R har ovennævnte betydninger, opvarmes med en orthomyresyreester med formlen III HC(0R)3 (III) 30 hvori R betyder C^^-alkyl, og med et syreanhydrid, og det således fremstillede 2-alkoxymethylenaceteddikesyre-anilid med formlen IV CH,-C0-C-C0NH- \ (IV) 35. sK H V0R 17 R R1 O 151013 1 2 hvori R, R og R har ovennævnte betydninger, isoleres og derefter behandles med hydroxylamin i et organisk opløsningsmiddel .
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2524959 | 1975-06-05 | ||
| DE2524959A DE2524959C2 (de) | 1975-06-05 | 1975-06-05 | 5-Methyl-isoxazol-4-carbonsäureanilide, Verfahren zu ihrer Herstellung, diese Verbindungen enthaltende Mittel |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK248376A DK248376A (da) | 1976-12-06 |
| DK151013B true DK151013B (da) | 1987-10-12 |
| DK151013C DK151013C (da) | 1988-03-07 |
Family
ID=5948292
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK248376A DK151013C (da) | 1975-06-05 | 1976-06-04 | Analogifremgangsmaade til fremstilling af 5-methyl-isoxazol-4-carboxylsyreanilider |
Country Status (15)
| Country | Link |
|---|---|
| US (1) | US4087535A (da) |
| JP (1) | JPS5938230B2 (da) |
| AT (1) | AT349007B (da) |
| BE (1) | BE842689A (da) |
| CA (1) | CA1076584A (da) |
| CH (1) | CH603608A5 (da) |
| DK (1) | DK151013C (da) |
| ES (1) | ES448386A1 (da) |
| FR (1) | FR2313052A1 (da) |
| GB (1) | GB1547452A (da) |
| IE (1) | IE43136B1 (da) |
| IT (1) | IT1063592B (da) |
| LU (1) | LU75077A1 (da) |
| MX (1) | MX3144E (da) |
| NL (1) | NL178596C (da) |
Families Citing this family (34)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2654797A1 (de) * | 1976-12-03 | 1978-06-08 | Hoechst Ag | Verfahren zur herstellung von isoxazolderivaten |
| JPS54102196U (da) * | 1977-12-28 | 1979-07-18 | ||
| DE2854439A1 (de) * | 1978-12-16 | 1980-07-03 | Hoechst Ag | Ein isoxazolderivat, verfahren zu seiner herstellung, diese verbindung enthaltende mittel und verwendung |
| IL60269A (en) * | 1979-06-11 | 1983-12-30 | Ciba Geigy | Alpha-carbamoyl-pyrrolpropionitriles,their preparation and pharmaceutical compositions containing them |
| DE2940189A1 (de) * | 1979-10-04 | 1981-04-16 | Basf Ag, 6700 Ludwigshafen | Isoxazolylcarbonsaeureanilide, verfahren zu ihrer herstellung und ihre verwendung als fungizide |
| FR2538806B1 (fr) * | 1982-12-30 | 1986-02-21 | Bago Sa Labor | Composes phenyl-3 methyl isoxazole-5 carboxy-4 anilides substitues, actifs therapeutiquement contre l'inflammation et la douleur |
| JPS6398092A (ja) * | 1986-10-14 | 1988-04-28 | 富士電機株式会社 | 金券用カ−ド残金精算装置 |
| US4935434A (en) * | 1988-01-26 | 1990-06-19 | Bristol-Myers Company | Antiarthritic isoxazole-4-carboxamides |
| US5583150A (en) * | 1989-08-18 | 1996-12-10 | Alcon Laboratories, Inc. | 5-methyl-isoxazole-4-carboxylic acid anilides and 2-hydroxyethylidene-cyano acetic anilides for the treatment of ocular diseases |
| DD297328A5 (de) | 1989-08-18 | 1992-01-09 | �������@���������k���Kk�� | 5-methyl-isoxalol-4-carbonsaeureanilide und 2 hydroxyethyliden-cyanoessigsaeureanilide zur behandlung von augenerkrankungen |
| US5001124A (en) * | 1990-02-02 | 1991-03-19 | Syntex (U.S.A.) Inc. | 4-isoxazolecarboxamide derivatives |
| US5108999A (en) * | 1990-02-02 | 1992-04-28 | Syntex (U.S.A.) Inc. | 4-isoxazolecarboxamide derivatives |
| DE59010701D1 (de) * | 1990-05-18 | 1997-05-22 | Hoechst Ag | Isoxazol-4-carbonsäureamide und hydroxyalkyliden-cyanessigsäureamide, diese verbindungen enthaltende arzneimittel und deren verwendung |
| US6133301A (en) * | 1991-08-22 | 2000-10-17 | Aventis Pharma Deutschland Gmbh | Pharmaceuticals for the treatment of rejection reactions in organ transplantations |
| DE4127737A1 (de) * | 1991-08-22 | 1993-02-25 | Hoechst Ag | Arzneimittel zur behandlung von abstossungsreaktionen bei organverpflanzungen |
| GB9320299D0 (en) * | 1993-10-01 | 1993-11-17 | Roussel Lab Ltd | Isoxazole derivatives |
| US5610173A (en) * | 1994-01-07 | 1997-03-11 | Sugen, Inc. | Formulations for lipophilic compounds |
| US6335356B1 (en) | 1994-01-07 | 2002-01-01 | Sugen, Inc. | Method of treating a patient by parenteral administration of a lipophilic compound |
| US5700823A (en) * | 1994-01-07 | 1997-12-23 | Sugen, Inc. | Treatment of platelet derived growth factor related disorders such as cancers |
| US5624946A (en) * | 1994-07-05 | 1997-04-29 | Williams; James | Use of leflunomide to control and reverse chronic allograft rejection |
| US5721277A (en) * | 1995-04-21 | 1998-02-24 | Sugen, Inc. | Compounds and methods for inhibiting hyper-proliferative cell growth |
| US6331555B1 (en) | 1995-06-01 | 2001-12-18 | University Of California | Treatment of platelet derived growth factor related disorders such as cancers |
| US6316479B1 (en) | 1997-05-19 | 2001-11-13 | Sugen, Inc. | Isoxazole-4-carboxamide compounds active against protein tryosine kinase related disorders |
| DK0987256T3 (da) * | 1997-08-08 | 2002-02-11 | Aventis Pharma Gmbh | Krystalform af N-(4-trifluormethylphenyl)-5-methylisoxazol-4-carboxylsyreamid |
| US7691890B2 (en) | 1998-03-11 | 2010-04-06 | James W. Williams | Anti-viral uses of leflunomide products |
| EP1169036B1 (en) * | 1998-03-11 | 2008-01-02 | James W. Williams | Anti-viral uses of leflunomide products |
| US20050255071A1 (en) * | 1998-12-10 | 2005-11-17 | Aventis Pharma Deutschland Gmbh | Preparation having improved therapeutic breadth comprising nucleotide synthesis inhibitors |
| WO2002080897A1 (en) | 2001-04-05 | 2002-10-17 | Aventis Pharmaceuticals Inc. | Use of (z)-2-cyano-3-hydroxy-but-2-enoic acid-(4'-trifluoromethylphenyl)-amide for treating multiple sclerosis |
| GB0123571D0 (en) * | 2001-04-05 | 2001-11-21 | Aventis Pharm Prod Inc | Use of (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4'-trifluoromethylphenyl)-amide for treating multiple sclerosis |
| US20050158371A1 (en) * | 2002-02-12 | 2005-07-21 | Sumitomo Pharmaceuticals Co., Ltd. | Novel external agent |
| ATE399165T1 (de) * | 2003-09-12 | 2008-07-15 | Rigel Pharmaceuticals Inc | Chinolinverbindungen und deren verwendungen |
| EP1781637A1 (en) * | 2004-06-29 | 2007-05-09 | Rigel Pharmaceuticals, Inc. | 2-substituted quinoline compounds and their uses as inhibitors of the ige receptor signaling cascade |
| US20060024376A1 (en) * | 2004-07-30 | 2006-02-02 | The University Of Chicago | Methods and compositions for reducing toxicity associated with leflunomide treatment |
| JOP20190207A1 (ar) | 2017-03-14 | 2019-09-10 | Actelion Pharmaceuticals Ltd | تركيبة صيدلانية تشتمل على بونيسيمود |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK54063C (da) * | 1935-02-22 | 1937-12-27 | Hoffmann La Roche | Fremgangsmaade til Fremstilling af dialkylsubstituerede Amider af Isoksazolkarbonsyrer. |
| DK58785C (da) * | 1938-01-18 | 1941-06-23 | Hoffmann La Roche | Fremgangsmaade til Fremstilling af substituerede Amider af Isoksazolkarbonsyrernes Homologe. |
| DK58903C (da) * | 1940-02-27 | 1941-08-04 | Hoffmann La Roche | Fremgangsmaade til Fremstilling af substituerede Amider af 3,5-Dimetyl-isoksazol-karbonsyre-(4). |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE634286C (de) * | 1935-02-23 | 1936-08-26 | Hoffmann La Roche & Co Akt Ges | Verfahren zur Herstellung dialkylsubstituierter Amide von Isoxazolcarbonsaeuren |
| US2126329A (en) * | 1936-03-20 | 1938-08-09 | Hoffmann La Roche | Amide derivatives of isoxazole carboxylic acids |
| US2288863A (en) * | 1940-02-27 | 1942-07-07 | Hoffmann La Roche | Process for the manufacture of substituted amides of 3,5-dimethylisoxazole-4-carboxylic acid |
-
1976
- 1976-05-31 NL NLAANVRAGE7605841,A patent/NL178596C/xx not_active IP Right Cessation
- 1976-05-31 ES ES448386A patent/ES448386A1/es not_active Expired
- 1976-06-02 CH CH696276A patent/CH603608A5/xx not_active IP Right Cessation
- 1976-06-03 IT IT23923/76A patent/IT1063592B/it active
- 1976-06-03 US US05/692,306 patent/US4087535A/en not_active Expired - Lifetime
- 1976-06-03 LU LU75077A patent/LU75077A1/xx unknown
- 1976-06-04 GB GB23185/76A patent/GB1547452A/en not_active Expired
- 1976-06-04 AT AT413776A patent/AT349007B/de not_active IP Right Cessation
- 1976-06-04 MX MX000270U patent/MX3144E/es unknown
- 1976-06-04 JP JP51065476A patent/JPS5938230B2/ja not_active Expired
- 1976-06-04 CA CA254,134A patent/CA1076584A/en not_active Expired
- 1976-06-04 DK DK248376A patent/DK151013C/da not_active IP Right Cessation
- 1976-06-04 IE IE1202/76A patent/IE43136B1/en unknown
- 1976-06-04 FR FR7617038A patent/FR2313052A1/fr active Granted
- 1976-06-08 BE BE167707A patent/BE842689A/xx not_active IP Right Cessation
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK54063C (da) * | 1935-02-22 | 1937-12-27 | Hoffmann La Roche | Fremgangsmaade til Fremstilling af dialkylsubstituerede Amider af Isoksazolkarbonsyrer. |
| DK58785C (da) * | 1938-01-18 | 1941-06-23 | Hoffmann La Roche | Fremgangsmaade til Fremstilling af substituerede Amider af Isoksazolkarbonsyrernes Homologe. |
| DK58903C (da) * | 1940-02-27 | 1941-08-04 | Hoffmann La Roche | Fremgangsmaade til Fremstilling af substituerede Amider af 3,5-Dimetyl-isoksazol-karbonsyre-(4). |
Also Published As
| Publication number | Publication date |
|---|---|
| BE842689A (fr) | 1976-12-08 |
| DK151013C (da) | 1988-03-07 |
| LU75077A1 (da) | 1977-03-09 |
| GB1547452A (en) | 1979-06-20 |
| US4087535A (en) | 1978-05-02 |
| FR2313052B1 (da) | 1979-09-28 |
| NL178596C (nl) | 1986-04-16 |
| IE43136L (en) | 1976-12-05 |
| CH603608A5 (da) | 1978-08-31 |
| DK248376A (da) | 1976-12-06 |
| CA1076584A (en) | 1980-04-29 |
| AT349007B (de) | 1979-03-12 |
| NL7605841A (nl) | 1976-12-07 |
| IT1063592B (it) | 1985-02-11 |
| FR2313052A1 (fr) | 1976-12-31 |
| JPS5938230B2 (ja) | 1984-09-14 |
| MX3144E (es) | 1980-05-09 |
| JPS527960A (en) | 1977-01-21 |
| ES448386A1 (es) | 1978-04-16 |
| IE43136B1 (en) | 1980-12-31 |
| ATA413776A (de) | 1978-08-15 |
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Legal Events
| Date | Code | Title | Description |
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| PUP | Patent expired |