DK151012B - Analogifremgangsmaade til fremstilling af 3-methyl-4-halogen-5-aminooxymethyl-isoxazoler eller et syreadditionssalt deraf - Google Patents
Analogifremgangsmaade til fremstilling af 3-methyl-4-halogen-5-aminooxymethyl-isoxazoler eller et syreadditionssalt deraf Download PDFInfo
- Publication number
- DK151012B DK151012B DK122581AA DK122581A DK151012B DK 151012 B DK151012 B DK 151012B DK 122581A A DK122581A A DK 122581AA DK 122581 A DK122581 A DK 122581A DK 151012 B DK151012 B DK 151012B
- Authority
- DK
- Denmark
- Prior art keywords
- methyl
- acid addition
- addition salt
- aminooxymethyl
- isoxazoles
- Prior art date
Links
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
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Heart & Thoracic Surgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Cardiology (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
151012 o
Det er kendt, at 3-hydroxy-5-methylisoxazol kan anvendes som plantebeskyttelsesmiddel (Merck index, 9.
(1961), side 123). Delvis mættede isoxazolderivater, der anvendes som tumorundertrykkende midler, er beskrevet i 5 Tetrahedron Letters 2549 (1973) og i J. Antib. 28A, 91 (1975).
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte 3-methyl- . -4-halogen-.5-aminooxymethyl-isoxazoler med den almene 10 formel (I)
CH, R
"W
N II
15 ^ O CH2ONH2 hvori R2 står for et halogenatom, eller et farmaceutisk acceptabelt syreadditionssalt deraf.
Disse forbindelser med formel (I) er nyttige til 20 anvendelse som farmaceutika, da de har hypotensiv, antiphlo-gistisk og antipyretisk virkning. Til forskel fra kendte forbindelser kan de tillige indgives såvel oralt som intravenøst.
Foretrukne repræsentanter for de hidtil ukendte 25 forbindelser med den almene formel (I) er de, hvori R2 er chlor.
Syreadditionssaltene af forbindelserne med den almene formel (I) kan dannes med farmaceutisk acceptable uorganiske eller organiske syrer (f.eks. saltsyre, hydro-30 genbromidsyre, svovlsyre, phosphorsyre, vinsyre, fumarsyre, maleinsyre eller citronsyre) .
Den her omhandlede analogifremgangsmåde er karakteriseret ved, at man omsætter en forbindelse med den almene formel (Id) 35
O
2 151012 CH3 R2 XX^/V)
II
o hvori R2 er som defineret ovenfor, med hydrazinhydrat og om øn-10 sket omdanner en således opnået forbindelse med den almene formel (I) til et farmaceutisk acceptabelt syreadditions-salt deraf.
Ved fremgangsmåden ifølge den foreliggende opfindelse omsættes en forbindelse med den almene formel (Id) 15 med hydrazinhydrat. Reaktionen udføres i et organisk opløsningsmiddel. Chlorerede carbonhydrider (f.eks. dichlormethan, dichlorethan eller chloroform) anvendes fortrinsvis til dette formål. Reaktionens temperatur kan varieres fra ca. 20°C til reaktionsblandingens kogepunkt. Slutproduktet kan for-20 trinsvis omdannes til dets hydrochlorid med saltsyre.
De hidtil ukendte forbindelser fremstillet ved fremgangsmåden ifølge den foreliggende opfindelse udviser en stærk hypotensiv virkning, og visse af forbindelserne udøver også antiphlogistiske og antipyretiske virkninger.
25 Når en tiendedel af LD^g-dosen af 3-methyl-4- -brom-5-aminooxymethyl-isoxazol bestemt intravenøst på mus indgives intravenøst til bedøvede katte, iagttages der en stor hypotensiv virkning med kort varighed. Fordelen ved de hidtil ukendte forbindelser fremstillet ifølge opfindelsen 30 er., at de er virksomme, hvad enten de indgives oralt eller intravenøst, medens L-a-methyl-dopa kun er aktivt, når det indgives intravenøst.
Den antiinflammatoriske virkning af de hidtil ukendte forbindelser fremstillet ifølge den foreliggende opfindel-35 se bestemmes ligeledes. En tiendedel af LD^g-dosen (intravenøst, på mus) indgives rotter, og inhiberingen af ødemet, fremkaldt af lokalindgivelse af (0,05 ml/3 mg dextran, bestemmes.
Herved opnås med det i eksemplet beskrevne chlorderivat en inhibe- 3 151012
O
ring af ødemet på 38%.
De fremstillede forbindelser anvendes i farmaceutiske præparater, der som aktivt middel indeholder en forbindelse med den almene formel (I) eller et farmaceutisk 5 acceptabelt syreadditionssalt deraf og et egnet indifferent ikke-toksisk, fast eller flydende farmaceutsk bærestof.
Bærestofferne kan være sådanne, som sædvanligvis anvendes i farmacien (f.eks. calciumcarbonat, magnesiumstea-rat, vand, polyalkylenglycol eller stivelse). Ovennævnte 10 farmaceutiske præparater kan formuleres ved hjælp af kendte 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 15 formel (I) afhænger af forskellige faktorer (f.eks. den givne forbindelses aktivitet, patientens tilstand, etc.) og bestemmes altid af lægens forordninger.
Den foreliggende opfindelse er illustreret ved hjælp af det følgende eksempel.
20
Eksempel
Fremstilling af 3-methyl-4-chlor(brom)-5-aminooxymethyl--isoxazolhydrochlorid 25 0,14 mol 3-methyl-4-chlor(brom)-5-(phthalimido- -oxymethyl)-isoxazol opløses i 500 ml vandfrit dichlormethan eller dichlorethan, derefter tilsættes 60 g 98%'s hydrazinhydrat, og opløsningen omrøres ved stuetemperatur i 16-20 timer. Det fraskilte phthaloyl-hydrazid opløses, vaskes 30 med dichlorethan,- og filtratet, som er kombineret med vaskevæsken, inddampes. Remanensen opløses i 200 ml vandfri ether, opløsningen tørres over magnesiumsulfat, koncentreres til 1/3 af den tidligere vægt og mættes med vandfrit hydrogen-chlorid. Det udskilte produkt filtreres fra, vaskes med 35 vandfri ether og omkrystalliseres.
151012 4
O
Chlorderivat:
Udbytte: 87%
Smp.ϊ 198-200°C
Omkrystallisation: fra vandfrit ethanol.
5 Analyse:
Beregnet: C = 30,17%, H = 4,05%, N = 14,08%, Cl = 17,81%^
Cl" = 17,81%.
Fundet: C = 30,02%, H = 3,99%, N = 14,06%, Cl = 17,77%;
Cl" = 17,78.
10
Bromderivat:
Udbytte: 8 3 %
Smp.: 180-182°C
15 Omkrystallisation: fra vandfrit ethanol.
Analyse:
Beregnet: C = 24,66%, H = 3,11%, N = 11,5%, Cl" = 14,56%,
Br = 32,80%.
Fundet: C = 25,11%, H = 3,08%, N = 11,37%, Cl" = 14,50%^ 20 Br = 32,72%.
Fremstilling af udgangsmaterialet 3-methyl-4-chlor(brom)--5-(phthalimido-oxymethyl)-isoxazol 0,1 mol 3-methyl-4-chlor(brom)-5-brommethyl-isoxazol 25 opløses i 120 ml vandfrit N,N-dimethylformamid, derefter tilsættes 0,11 mol N-hydroxy-phthalimid og 0,11 mol tri-ethylaminjog blandingen holdes på et vandbad, der er opvarmet til 100°C. Derefter afkøles den, fortyndes med vand.og de udskilte krystaller filtreres fra, vaskes med koldt 30 vand og omkrystalliseres.
Chlorderivat:
Udbytte: 89%
Smp.: 152-153°C
35 Omkrystallisation: fra ethanol
Analyse:
Beregnet: C = 53,54%, H = 3,10%, N = 9,57%, Cl= 12,11%. Fundet: C = 53,08%, H = 2,99%, N = 9,58%, Cl = 12,15%.
5 151012
O
Bromderivat:
Udbytte: 90%
Snip.: 154-156°C.
Omkrystallisation: fra ethanol/vand.
5 Analyse:
Beregnet: C = 46,31%, H = 2,59%, N = 8,31%, Br = 23,7%. Fundet: C = 47,0%, . H = 2,59%, N = 8,25%, Br = 23,67%.
Claims (1)
- O 151012 Patentkrav . Analogifremgangsmåde til fremstilling af 3-methyl--4-halogen-5-aminooxymethyl-isoxazoler med den almene formel (X) 5 CH R9 _/2 ii in N 1 CH2ONH2 10 hvori R2 står for et halogenatom, eller et farmaceutisk acceptabelt syreadditionssalt deraf, kendetegnet ved, at man omsætter en forbindelse med den almene formel (Id) 15 CH3 R XoX ch2-o-/^Y^ <Id> 20 II o hvori R2 er som defineret ovenfor, med hydrazinhydrat og 25 om ønsket omdanner en således opnået forbindelse med den almene formel (I) til et farmaceutisk acceptabelt syreadditionssalt deraf.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU8080637A HU180567B (en) | 1980-03-19 | 1980-03-19 | Method for producing derivatives of isooxazole |
| HU63780 | 1980-03-19 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK122581A DK122581A (da) | 1981-09-20 |
| DK151012B true DK151012B (da) | 1987-10-12 |
| DK151012C DK151012C (da) | 1988-07-04 |
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 After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| 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 |
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 |
|---|---|---|---|---|
| ATE309228T1 (de) * | 1997-04-21 | 2005-11-15 | Sumitomo Pharma | Isoxazolderivate |
| 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 SE SE8101703A patent/SE454695B/sv not_active IP Right Cessation
- 1981-03-17 YU YU689/81A patent/YU42560B/xx unknown
- 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 GB GB8108545A patent/GB2075009B/en not_active Expired
- 1981-03-18 DK DK122581A patent/DK151012C/da not_active IP Right Cessation
- 1981-03-18 FI FI810838A patent/FI70011C/fi not_active IP Right Cessation
- 1981-03-18 FR FR8105378A patent/FR2478634A1/fr active Granted
- 1981-03-18 ES ES501095A patent/ES501095A0/es active Granted
- 1981-03-19 SU SU813261940A patent/SU1053750A3/ru active
- 1981-03-19 JP JP4023281A patent/JPS56158774A/ja active Pending
- 1981-03-19 CA CA000373380A patent/CA1163631A/en not_active Expired
- 1981-03-19 DE DE19813110817 patent/DE3110817A1/de not_active Withdrawn
-
1982
- 1982-04-01 SU SU823416146A patent/SU1158044A3/ru active
- 1982-04-01 SU SU823414099A patent/SU1152518A3/ru active
- 1982-04-16 ES ES511895A patent/ES8305340A1/es not_active Expired
- 1982-04-16 ES ES511894A patent/ES8401758A1/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 |
|---|---|
| SE454695B (sv) | 1988-05-24 |
| GB2075009B (en) | 1983-11-30 |
| ES8302674A1 (es) | 1983-02-16 |
| CA1163631A (en) | 1984-03-13 |
| SU1152518A3 (ru) | 1985-04-23 |
| FI70011B (fi) | 1986-01-31 |
| JPS56158774A (en) | 1981-12-07 |
| FI70011C (fi) | 1986-09-12 |
| SE8101703L (sv) | 1981-09-20 |
| YU68981A (en) | 1983-10-31 |
| DK151959C (da) | 1988-07-11 |
| DK151959B (da) | 1988-01-18 |
| BE887954A (fr) | 1981-09-16 |
| ES511895A0 (es) | 1983-05-01 |
| ES511894A0 (es) | 1984-01-01 |
| DK122581A (da) | 1981-09-20 |
| FR2478634A1 (fr) | 1981-09-25 |
| DE3110817A1 (de) | 1982-03-04 |
| SU1158044A3 (ru) | 1985-05-23 |
| DK153549C (da) | 1988-12-05 |
| GB2075009A (en) | 1981-11-11 |
| DK151012C (da) | 1988-07-04 |
| IT8120395A0 (it) | 1981-03-18 |
| DK153549B (da) | 1988-07-25 |
| DK23187A (da) | 1987-01-16 |
| FI810838L (fi) | 1981-09-20 |
| ES8305340A1 (es) | 1983-05-01 |
| ES501095A0 (es) | 1983-02-16 |
| CH646157A5 (en) | 1984-11-15 |
| SU1053750A3 (ru) | 1983-11-07 |
| YU42560B (en) | 1988-10-31 |
| ES8401758A1 (es) | 1984-01-01 |
| FR2478634B1 (da) | 1983-11-10 |
| HU180567B (en) | 1983-03-28 |
| DK23087A (da) | 1987-01-16 |
| IT1211010B (it) | 1989-09-29 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed |