NO170280B - Analogifremgangsmaate for fremstilling av terapeutisk aktive sulfamatderivater - Google Patents
Analogifremgangsmaate for fremstilling av terapeutisk aktive sulfamatderivater Download PDFInfo
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- NO170280B NO170280B NO843836A NO843836A NO170280B NO 170280 B NO170280 B NO 170280B NO 843836 A NO843836 A NO 843836A NO 843836 A NO843836 A NO 843836A NO 170280 B NO170280 B NO 170280B
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- 238000000034 method Methods 0.000 title claims abstract description 8
- 238000002360 preparation method Methods 0.000 title claims description 3
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical class NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 title abstract description 4
- 230000001225 therapeutic effect Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 7
- -1 methylenedioxy group Chemical group 0.000 claims description 7
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 239000012312 sodium hydride Substances 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- YUMNNMSNSLHINV-UHFFFAOYSA-N chloro sulfamate Chemical compound NS(=O)(=O)OCl YUMNNMSNSLHINV-UHFFFAOYSA-N 0.000 claims description 2
- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical compound OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 claims 1
- 239000001961 anticonvulsive agent Substances 0.000 abstract description 5
- 206010015037 epilepsy Diseases 0.000 abstract description 5
- 230000001773 anti-convulsant effect Effects 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 4
- 229960003965 antiepileptics Drugs 0.000 abstract description 3
- 239000000543 intermediate Substances 0.000 abstract 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000006188 syrup Substances 0.000 description 6
- 235000020357 syrup Nutrition 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 208000010412 Glaucoma Diseases 0.000 description 4
- 229960002737 fructose Drugs 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 3
- QAHVHSLSRLSVGS-UHFFFAOYSA-N sulfamoyl chloride Chemical compound NS(Cl)(=O)=O QAHVHSLSRLSVGS-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 102000003846 Carbonic anhydrases Human genes 0.000 description 2
- 108090000209 Carbonic anhydrases Proteins 0.000 description 2
- LKDRXBCSQODPBY-VRPWFDPXSA-N D-fructopyranose Chemical compound OCC1(O)OC[C@@H](O)[C@@H](O)[C@@H]1O LKDRXBCSQODPBY-VRPWFDPXSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- XTHPWXDJESJLNJ-UHFFFAOYSA-M chlorosulfate Chemical compound [O-]S(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-M 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- CVZHVPDGAGIDDX-UHFFFAOYSA-N oxan-2-yl n-methylsulfamate Chemical compound CNS(=O)(=O)OC1CCCCO1 CVZHVPDGAGIDDX-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- UUBPRIUBEQJUQL-UHFFFAOYSA-N (1-methylcyclohexyl)methanol Chemical compound OCC1(C)CCCCC1 UUBPRIUBEQJUQL-UHFFFAOYSA-N 0.000 description 1
- QWBRAALMTSQLEN-UHFFFAOYSA-N 1,1-dimethylcyclohexane;sulfamic acid Chemical compound NS(O)(=O)=O.CC1(C)CCCCC1 QWBRAALMTSQLEN-UHFFFAOYSA-N 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 1
- 241000906446 Theraps Species 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940125681 anticonvulsant agent Drugs 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- FIYXUOWXHWJDAM-UHFFFAOYSA-N methyl sulfamate Chemical compound COS(N)(=O)=O FIYXUOWXHWJDAM-UHFFFAOYSA-N 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960002036 phenytoin Drugs 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
- C07H9/02—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing only oxygen as ring hetero atoms
- C07H9/04—Cyclic acetals
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D309/06—Radicals substituted by oxygen atoms
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Ophthalmology & Optometry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Pain & Pain Management (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Saccharide Compounds (AREA)
- Pyrane Compounds (AREA)
- Pyridine Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Medicinal Preparation (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Polymers With Sulfur, Phosphorus Or Metals In The Main Chain (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Hydrogenated Pyridines (AREA)
Description
Sulfamater med forskjellige strukturer, inkludert de som er avledet fra monosakkarider, er beskrevet i referanser som N.K. Kochetkov et al i "Zhurnal Obshchei Kimii", Vol. 41, nr. 8, 1866 til 1871 (1971), Vol. 42, nr. 12, 2755 til 2757 (1972) og Vol. 44, nr. 4, 871 til 875 (1974) og i "Doklady Akademi! Nauk SSR", Vol. 216, nr. 1, 97 til 100
(1974); T. Tsuchiya et al., i "Tetrahedron Letters", nr. 36, 3365 til 3368 (1978); og A.F. Hirsch i "Journal of Medicinal Chemistry", 24, 901 til 903 (1981) og US-PS 4.075.351.
Det er nu funnet at sulfamater som beskrevet nedenfor har antikonvulsiv virkning i pattedyr og således er brukbare for behandling av sykdomstilstander som epilepsi og glaukom. I henhold til dette angår foreliggende oppfinnelse en analogifremgangsmåte for fremstilling av terapeutisk aktive forbindelser med formel (I).
der
X er CH2 eller oksygen;
R-L er hydrogen eller C^_4-alkyl;
R2 er hydrogen- eller G^.^-alkyl og R3, R4 og R5 uavhengig er hydrogen og, når X er oksygen, R 2 og R3 og R4 og R5 sammen kan være en metylendioksygruppe med formel (II):
De ovenfor angitte forbindelser med formel (I) kan frem-stilles ved:
a) Omsetning av en alkohol med formelen RCHgOH der R er en del med den generelle formel (III):
R2, R3, R4 og R5 har den ovenfor angitte betydning, med et klorsulfamat med formelen C1S02NH2 eller C1S02NHR1, der R} har den ovenfor angitte betydning, i nærvær av en base som
o
natriumhydrid ved en temperatur on til +25 C og i et oppløsningsmiddel som toluen, TEF eller dimetylformamid;
eller
b) omsetning av en forbindelse med formel RCHgOH der R har den ovenfor angitte betydning med sulfurylklorid med
formel SO2SI2 i nærvær av en base som pyrridin ved en temperatur av -40 til +25°C i et oppløsningsmiddel som metylenklorid for å oppnå et klorsulfat med formelen RCHgOSOgCl der R har den ovenfor angitte betydning som deretter omsettes med metylamin.
Klorsulfatet "med formelen RCH2OSO2 kan så omsettes med et amin med formelen R1NH2 ved en temperatur av ca -40 til +25°C i et oppløsningsmiddel slik som metylenklorid eller acetonitril for å oppnå en forbindelse med formel (I). Omsetnings-betingelsene for reaksjonen b) er også beskrevet av T. Tsuchiya et al i "Tet. Letters", nr. 36, side 3365 til 3368
(1978).
Utgangsmaterialene med formel RCHgOH kan oppnås kommer-sielt eller kjente i denne teknikk. For eksempel kan utgangsmaterialer med formel RCH20H der både R2 og Rg og R4 og Rg er identiske og har formel (II), oppnås ved den fremgangsmåte som beskrives av R.F. Brady i "Carbohydrate Research" Vol. 15, side 35 til 40 (1970) eller ved omsetning av trimetylsilylenoleteren av et R^CORy keton eller -aldehyd med fruktose ved en temperatur av ca. 25°C i et oppløs-ningsmiddel som et halogenkarbon, for eksempel metylenklorid, i nærvær av en protisk syre som saltsyre eller en Lewis-syre som sinkklorid. Trimetylsilylenoleter-reaksjonen er beskrevet av G.L. Larson et al. i "J. Org. Chem. Vol. 38, nr. 22, side 3935 (1973).
Videre kan karboksylsyrer og -aldehydsyrer med formelen RC00H og RCHO reduseres til forbindelser med formelen RCHgOH ved standardreduksjonsteknikker, for eksempel omsetning med litiumaluminiumhydrid, natriumborhydrid eller boran-THF-kompleks i et inert oppløsningsmiddel som diglym, THF eller toluen, ved en temperatur av ca. 0 til 100°C, for eksempel slik som beskrevet av H.O. House i "Modern Synthetic Reactions", 2nd Ed., sidene 45 til 144 (1972). Forbindelsene ifølge oppfinnelsen inkluderer i forskjellige individuelle isomerer så vel som rasemater derav, for eksempel de forskjellige a- og g<->bindinger, for eksempel over og under tegningsplanet, for Rg, Rg, R^ og Rg i den 6-leddede ring. Fortrinnsvis er oksygen i metylendioksygruppen (II) bundet på samme side av den 6-leddede ring.
Forbindelsene med formel (I) er brukbare som antikonvulsive midler. Den antikonvulsive virkning av de angjeldende forbindelser ble bestemt ved bruk av en standard "maksimal elektrosjokkprøve" (MES). I denne prøve indikeres aktivi-teten ved en blokk av den toniske ekstensorsammentrekning forårsaket ved pålegning av et elektrisk sjokk til mus via kornealelektroder som beskrevet av Swinyard et al. i "J. Pharmacol. Exptl. Therap." 106, 319 (1952), og notert som #-blokkering. En nyere beskrivelse av dagens antikonvulsiv medikamentbedømmelse er gitt i Swinyard et al. i "Epilepsia 19", 409, (1978).
Den antikonvulsive aktivitet av forbindelsene ifølge oppfinnelsen som prøves ifølge Swinyards metode av 1952 er vist i den følgende tabell I:
* Hvis ikke annet er sagt ;For behandling av epilepsi kan en forbindelse med formel (I) benyttes i en daglig dosering innen området ca. 30 til 2000 mg, vanligvis i 2 til 4 oppdelte doser, for et gjen-nomsnittlig voksent menneske. En enhetsdose ville inneholde ca. 10 til 500 mg av aktiv bestanddel. ;Generelt kan forbindelser med formel (I) benyttes ved behandling av epilepsi i en måte tilsvarende den som benyttes for fenytoin. Medisinske aspekter ved behandlingen av epilepsi er beskrevet av L.S. Goodman et al. i "The Phar-macological Basis of Therapeutics", 5th Ed., sidene 201 til 226, Macmillan (1975). ;Videre er forbindelser med formel (I) inhibitorer for karbonisk anhydrase som bestemt ved de metoder som er beskrevet av S.J. Dodgson et al. i "Proe. Nati. Åcad. Sei.", USA, 77, sidene 5562 til 5566 (1980) eller av N. Itada et al. i "Journal Biol. Chem.", 252, sidene 3881 til 3890 (1977) og er som sådanne brukbare ved behandling av galukom. Forbindelsen mellom behandlingen av glaukom og karbonisk anhydraseinhibering er beskrevet av A. Stein et al. i "American Journal of Opthalmology", 95:222-228 (1983). For behandling av galukom kan en forbindelse med formel (I) inngis systemisk, for eksempel ad oral eller parenteral vei som beskrevet nedenfor, eller topisk i øyet i en mineral-oljeoppløsning eller -suspensjon, eller en vandig suspensjon. Brukt systemisk vil forbindelsen inngis i en megde på ca. 50 til 500 mg pr. dag for et midlere voksent menneske, mens den topiske dose ville være ca. 1 til 3 dråper (pr. øye) av en oppløsning eller suspensjon inneholdende 1 til 5 vekt-# av en forbindelse med formel (I) der dosen inngis ca. 1 til 4 ganger daglig. ;Eksempel 1 ;( Tetrahydro- 2H- pyran- 2- yl) metansulfamat ;Til en -5°C kold oppløsning av tetrahydropran-2-metanol (2,33 g, 0,02 mol) i 40 ml dimetylformamid ble det satt 50$ oljeform i natriumhydrid (1,17 g, 0,024 mol som NaH). Efter omrøring i 45 min. ble sulfamoylklorid (3,42 g, 0,03 mol) tilsatt og omrøringen fortsatt i ytterligere 45 min. ved ;-5°C. Reaks jonsblandingen ble helt i koldt vann og ekstrahert med kloroform. Det organiske sjikt ble tørket (NagS04) og oppløsningsmidlene fjernet under vakuum for derved å oppnå en sirup som ble tørrklonnekromatografert (eluert med etylacetat:heksan, 4:1 volum/volum) for å gi ;ren (tetrahydro-2H-pyran-2-yl) metansulfamat som en blekgul sirup IE:(CHC13) 1180 cm<-1> og 1370 cm<-1> (OSOgNHg). ;Eksempel 2 ;( 1- metylcykloheksyl) metansulfamat) ;Til en -4°C kold oppløsning av (1-metylcykloheksyl)metanol (6,2 g, 0,048 mol) i 90 ml DMF ble det satt 50#-ig oljeaktig natriumhydrid (2,81 g, 0,059 mol som NaE). Etter omrøring i 1 time ble sulfamoylklorid (7,82 g, 0,062 mol) tilsatt og omrøringen fortsatt i ytterligere 30 min. ved -4°C. Reaksjonsblandinger ble helt i koldt vann og ekstrahert med toluen. Det organiske sjikt ble tørket (Na2S04) og oppløsningsmidlene fjernet under vakuum for derved å gi en sirup som krystalliserte ved avkjøling. Omkrystallisering fra kloroform/heksan ga rent (1-metylcykloheksylMetan-sulfamat med smeltepunkt 40°-42°C. ;Eksempel 3 ;( 2. 3:4. 5- bis- 0-( 1- metyletyliden)- g- D- fruktopyranosesulfamat) ;Til en -4°C kold oppløsning av 2,3:4,5-di-O-isopropyl-iden-beta-fruktopyranose (75 g, 0,29 mol) i 725 ml DMF ble det satt 50^-ig oljeaktig natriumhydrid (16,34 g, 0,34 mol som NaH). Efter omrøringen i 90 min. ble sulfamoylklorid (54,9 g, 0,48 mol) tilsatt og omrøringen fortsatt i ytterligere 3,5 timer ved denne temperatur. Reaksjonsblandingen ble helt i koldt vann og ektrahert med toluen. Det organiske sjikt ble tørket (Na2S04) og oppløsningsmidlene fjernet under vakuum hvorved det ble oppnådd en sirup som umiddelbart krystalliserte. Omkrystallisering fra etylace-tat/heksan ga ren 2,3:4,5-bis-0(1-metyletyliden)-p<->D-fruktopyranosesulfamat, med smeltepunkt 125°C-126°C. ;Eksempel 4 ;2. 3;4. 5- bis- 0-( 1- metyletyliden)- p- D- fruktopyranosesulfamat ;En oppløsning av sulfonylklorid (93 ml , 1,15 mol) i 100 ml metylenklorid ble tilsatt dråpevis til en -35°C kold oppløsning av 2,3:4,5-di-O-isopropyliden-p<->D-fruktopyranose (150 g, 0,58 mol) i 400 ml metylenklorid og 150 ml pyridin. Reaksjonsblandingen ble omrørt og oppvarmet til rom-temperatur, 25°C, og ble så omrørt i ytterligere 2 timer. Oppløsningsmidlene ble fjernet under vakuum. Det resulterende halveis faste materialet ble oppløst i vannfri acetonitril (35 g, 150 ml) og metylamin ble boblet inn. Reaksjonsblandingene ble korket tett til og oppløsningsmid-lene fjernet under vakuum. Den resulterende sirup ble underkastet væskekromatografi (tørrkolonne; etylace-tat:heksan 4:1) hvorved man oppnådde en lett gul sirup 2 ,3:4 ,5-bis-0-(l-metyletyliden ) -p-D-f ruktopyranose )me-tylsulfamat, som var homogent ved TLC og *H NMR.
Claims (1)
- Analogifremgangsmåte for fremstilling av terapeutisk aktiv forbindelse med formel (I):hvoriX er CH£ eller oksygen;Ri er hydrogen eller C^_4-alkyl; ogR2 er hydrogen eller C^_4-alkyl,R3, R4 og R5 uavhengig er hydrogen og, når X er oksygen, R2 og R3 og R4 og R5 sammen kan være en metylendioksygruppe med den følgende formel (II):karakterisert ved: a) omsetning av en alkohol med formelen RCH2OH der R er endel med den generelle formel (III):derR2, R3, R4 og R5 har den ovenfor angitte betydning, med et klorsulfamat med formelen C1S02NH2 eller CISO2NHR1, der har den ovenfor angitte betydning, i nærvær av en base som natriumhydrid ved en temperatur av -20 til +25"C og i et oppløsningsmiddel som toluen, THF eller dimetylformamid; eller b) omsetning av en forbindelse med formel RCH2OH der R har den ovenfor angitte betydning med sulfurylklorid med formel SO2SI2 i nærvær av en base som pyrridin ved en temperatur av -40 til +25°C i et oppløsningsmiddel som metylenklorid for å oppnå et klorsulfat med formelen RCH2OSO2CI der R har den ovenfor angitte betydning som derefter omsettes med metylamin.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/535,475 US4513006A (en) | 1983-09-26 | 1983-09-26 | Anticonvulsant sulfamate derivatives |
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| Publication Number | Publication Date |
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| NO843836L NO843836L (no) | 1985-03-27 |
| NO170280B true NO170280B (no) | 1992-06-22 |
| NO170280C NO170280C (no) | 1992-09-30 |
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|---|---|---|---|
| NO843836A NO170280C (no) | 1983-09-26 | 1984-09-25 | Analogifremgangsmaate for fremstilling av terapeutisk aktive sulfamatderivater |
| NO1997004C NO1997004I1 (no) | 1983-09-26 | 1997-05-09 | Topiramat |
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| Application Number | Title | Priority Date | Filing Date |
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| NO1997004C NO1997004I1 (no) | 1983-09-26 | 1997-05-09 | Topiramat |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3997585A (en) * | 1974-12-30 | 1976-12-14 | Ortho Pharmaceutical Corporation | Aliphatic sulfamates |
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1983
- 1983-09-26 US US06/535,475 patent/US4513006A/en not_active Expired - Lifetime
-
1984
- 1984-09-10 NZ NZ209494A patent/NZ209494A/en unknown
- 1984-09-24 CA CA000463864A patent/CA1241951A/en not_active Expired
- 1984-09-25 DK DK457784A patent/DK165004C/da not_active IP Right Cessation
- 1984-09-25 KR KR1019840005883A patent/KR920001775B1/ko not_active IP Right Cessation
- 1984-09-25 ZA ZA847550A patent/ZA847550B/xx unknown
- 1984-09-25 IE IE2444/84A patent/IE57684B1/en not_active IP Right Cessation
- 1984-09-25 HU HU843621A patent/HU194540B/hu unknown
- 1984-09-25 AT AT84306512T patent/ATE36149T1/de active
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- 1984-09-25 JP JP59198772A patent/JPS60109558A/ja active Granted
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- 1984-09-25 FI FI843765A patent/FI79095C/fi not_active IP Right Cessation
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- 1992-07-21 JP JP4214693A patent/JPH05331132A/ja active Pending
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1997
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