DK165004B - Sulfamatderivater og farmaceutiske praeparater indeholdende disse - Google Patents

Sulfamatderivater og farmaceutiske praeparater indeholdende disse Download PDF

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DK165004B
DK165004B DK457784A DK457784A DK165004B DK 165004 B DK165004 B DK 165004B DK 457784 A DK457784 A DK 457784A DK 457784 A DK457784 A DK 457784A DK 165004 B DK165004 B DK 165004B
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sulfamate
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sub
alkyl
hydrogen
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Bruce Eliot Maryanoff
Joseph Francis Gardocki
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Mcneilab Inc
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    • 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
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    • 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
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    • 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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  • Pyrane Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
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Description

i
DK 165004 B
Sulfamater med forskellige strukturer, inklusive sådanne, der afledes af monosaccharider, er beskrevet i referencer såsom N.K.
Kochetkow, et al., i Zhurnal Obshchei Kimii, bind 41, nr. 8, 1866-1871 (1971), bind 42, nr. 12, 2755-2757 (1972) og bind 44, nr. 4, 871-875 5 (1974), og i Doklady Akademii Nauk SSR, bind 216, nr. 1, 97-100 (1974); T. Tsuchiya et al., i Tetrahedron Letters, nr. 36, 3365-3368 (1978); og A.F. Hirsch i Journal of Medicinal Chemistry, 24, 901-903 (1981), samt US-patentskrift nr. 4.075.351.
Det har nu vist sig, at sulfamater med formel (I) 10 Γ~x. .CH,OSO.NHR, ’•VN 111 R, Ri hvori X er 0 eller CH2 og Rj, R2, R3, R4 og Rg er som defineret i det 15 følgende, besidder anti-konvulsivisk aktivitet i pattedyr og derfor er anvendelige til behandling af sygdomstilstande såsom epilepsi og glau-kom. Den foreliggende opfindelse angår hidtil ukendte sulfamater med formlen (I) 2° r,^ch„, (i)
Rj hvori X er CH2 eller oxygen.
25 Rj er hydrogen eller al kyl, og
Rj>, R3, R4 og Rj, uafhængigt af hinanden, er hydrogen eller lavere alkyl og, når X er CH2, er R4 og Rg eventuelt alkengrupper, der tilsammen danner en benzenring og, når X er oxygen, danner R2 og R3 og/eller R4 og Rg eventuelt en methylendioxygruppe med formel (II) 30 (il) R, O- V- 35 hvori
Rg og R^, som er ens eller forskellige, er hydrogen, lavere al kyl eller al kyl, som tilsammen danner en cyclopentyl- eller cyclohexylring. Opfindelsen angår endvidere et farmaceutisk præparat, som er
DK 165004 B
2 ejendommeligt ved det i den kendetegnende del af krav 9 angivne.
Rj er især hydrogen eller al kyl med 1 til 4 carbonatomer såsom methyl, ethyl og isopropyl. I hele beskrivelsen betyder "alkyl" lige-kædede og forgrenede al kyl grupper. Specifikke alkylgrupper for R2, R3, 5 R4, Rg, Rg og Rj omfatter methyl, ethyl, isopropyl og n-propyl. Når X er CHg, kan R4 og Rg kombineres til dannelse af en benzenring, der er fusioneret til den 6-leddede, X-holdige ring, dvs. at R4 og Rg definerer al katrienylgruppen =CH-CH=CH-CH=.
En speciel gruppe forbindelser med formel (I) er sådanne, hvori X 10 er oxygen og både R2 og R3 og R4 og Rg tilsammen danner methyl endioxy-grupper med formel (II), hvori Rg og R7 begge er hydrogen og al kyl eller tilsammen danner en spiro-cyclopentyl- eller cyclohexylring, især, når Rg og R^ begge er al kyl såsom methyl. En anden gruppe forbindelser er sådanne, hvori X er CH2 og R4 og Rg danner en benzenring. En tredje 15 gruppe forbindelser med formel (I) er sådanne, hvori både R2 og R3 er hydrogen.
Forbindelserne med formel (I) kan syntetiseres ved hjælp af følgende fremgangsmåder: a) Omsætning af en alkohol med formlen RCHgOH med et chlorsulfamat 20 med formlen C1S02NH2 eller CISOgNHRj i nærværelse af en base såsom kalium-t-butoxid eller natriumhydrid ved en temperatur på ca. -20 til 25°C og i et opløsningsmiddel såsom toluen, THF eller dimethyl formamid, hvori R har formlen (III) p /"V (III)
25 R,vA
R, R, b) omsætning af en alkohol med formlen RCH20H med sulfurylchlorid med formlen S02C12 i nærværelse af en base såsom triethylamin eller 30 pyridin ved en temperatur på ca. -40 til 25°C i et opløsningsmiddel såsom diethyl ether eller methylenchlorid til dannelse af et chlorsulfat med formi en RCHgOSOgCl.
Chl orsulfatet med formlen RCH20$02C1 kan dernæst omsættes med en amin med formlen RjNH2 ved en temperatur på ca. -40 til 25°C i et opløs-35 ningsmiddel såsom methylenchlorid eller acetonitril til dannelse af en forbindelse med formel (I). Omsætningsbetingelserne for b) er også beskrevet af T. Tsuchiya, et al., i Tet. Letters, nr. 36, side 3365-3368 (1978).
DK 165004 B
3 c) Omsætning af chlorsulfatet RCHgOSOgCl med et metalazid såsom natriumazid i et opløsningsmiddel såsom methylenchlorid eller acetoni-tril giver et azidosulfat med formlen RCHgOSOgN^ som beskrevet af M.
Hedayatul1 ah i Tet. Lett., side 2455-2458 (1975). Az i dosulfatet reduce-5 res dernæst til en forbindelse med formel (I), hvori Rj er hydrogen, ved katalytisk hydrogenering, fx. med et ædelmetal og Hg eller ved opvarmning med kobbermetal i et opløsningsmiddel såsom methanol.
Udgangsforbindelserne med formlen RCHgOH kan fås kommercielt eller som kendt i teknikken. Eksempelvis kan udgangsforbindelser med formlen 10 RCHgOH, hvori både Rg og Rj og R^ og Rg er identiske og har formlen (II), opnås ved fremgangsmåderne ifølge R.F. Brady i Carbohydrate Research, bind 15, side 35-40 (1970), eller ved omsætning af trimethyl-silylenoletheren af en RgCOR^-keton eller -aldehyd med fruktose ved en temperatur på ca. 25°C i et opløsningsmiddel såsom et halogencarbon, fx.
15 methylenchlorid, i nærværelse af en protisk syre såsom saltsyre eller en Lewis-syre såsom zinkchlorid. Trimethylsilylenoletherreaktionen er beskrevet af G. L. Larson et al i J. Org. Chem., bind 38, nr. 22, side 3935 (1973).
Desuden kan carboxylsyrer og aldehyder med formlen RCOOH og RCHO 20 reduceres til forbindelser med formel RCHgOH ved standard-reduktionsteknikker, fx. omsætning med lithiumaluminiumhydrid, natriumborhydrid eller boran-THF-kompleks i et inert opløsningsmiddel såsom diglyme, THF eller toluen ved en temperatur fra ca. 0 til 100°C, fx. som beskrevet af H.O.
House i "Modern Synthetic Reactions", 2. oplag, side 45-144 (1972).
25 Forbindelserne ifølge opfindelsen omfatter forskellige individuelle isomere samt racematerne deraf, fx. de forskellige forbindelser, hvori Rg, Rj, R^ og Rg er bundet i alfa- eller beta-stilling i forhold til den 6-leddede ring, dvs. under og over tegningens plan. Fortrinsvis er methylendioxygruppens (II) oxygener bundet på samme side af den 6-30 leddede ring.
Forbindelserne med formel (I) er nyttige som antikonvulsiviske midler. Den antikonvulsiviske aktivitet af forbindelserne ifølge opfindelsen bestemtes under anvendelse af en standard "maksimal elektrochock-test" (MES). I denne test indikeres aktivitet ved en 35 blokering af den toniske ekstensor-spasme, der frembringes ved påføring af et elektrisk chock til mus via hornhindeelektroder som beskrevet af Swinyard, et al., i J. Pharmacol. Exptl. Therap. 106, 319 (1952), og anføres som % blokering. En nyere beskrivelse af nu-
DK 165004B
4 tidig antikonvulsivisk lægemiddel-screening kan findes i Swinyard, et al., Epilepsia 19, 409 (1978).
Den antikonvulsiviske aktivitet af forbindelser ifølge opfindelsen, der testes iht. Swinyard-metoden (1952), vises i den følgende tabel (I): 5
Tabel (I)
Eksempel Forbindelse MES-test EDgg *(mg/kg, i.p.) 1 /—o 19 5 10 / Vch,oso,nh, _. CH, 2 Ο-,Ο.Ο,ΝΗ, 270 15 . _o CHjOSOjNH, 3 ch>'Z/^Vch‘ 26 CH, CH· 20 J 0^pH,0S0,NHCH, 70% blok ved 200 mg/kgj i p CH, CH» ch2oso,nh, 5' \ / 55
25 K
*Medmindre andet er anført.
30 Til behandling af epilepsi kan der i et voksent gennemsnitsmenneske anvendes en forbindelse med formel (I) i en daglig dosering i området fra ca. 30 til 2000 mg, sædvanligvis i 2 til 4 doser. En enhedsdosis indeholder ca. 10 til 500 mg aktiv bestanddel.
Almindeligvis kan forbindelser med formel (I) anvendes til 35 behandling af epilepsi på en måde, der ligner den, der anvendes med phenytoin. Medicinske aspekter af behandlingen af epilepsi er beskrevet af L.S. Goodman, et al., i "The Pharmacological Basis of Therapeutics", 5. oplag, s. 201-226, Macmillan (1975).
5
Desuden inhiberer forbindelser med formel (I) carbonsyreanhydrase, som vist ved de af S.J. Dodgson. et al., i The Proc. Natl. Acad. Sci., USA, 77, s. 5562-5566 (1980) eller af N. Itada, et al., i The Journal Biol. Chem., 252, s. 3881-3890 (1977) beskrevne fremgangsmåder og er som 5 sådanne anvendelige til behandling af glaukom. Sammenhængen mellem behandling af glaukom og carbonsyreanhydrase-inhibering er beskrevet af A. Stein, et al., i The American Journal of Opthalmology, 95:222-228 (1983). Til behandling af glaukom kan en forbindelse med formel (I) administreres systemisk, fx. ad oral eller parenteral vej som beskrevet 10 nedenfor, eller topisk i øjet som en mineralolieopløsning eller -suspension, eller vandig suspension. Når forbindelsen anvendes systemisk, administreres den i en mængde fra ca. 50 til 500 mg per dag for et voksent gennemsnits-menneske, mens den topiske dosering er ca. 1 til 3 dråber (per øje) af en opløsning eller suspension, der indeholder ca. 1 til 15 5 vægt-% af en forbindelse med formel (I), idet dosen administreres ca.
1 til 4 gange daglig.
Til fremstilling af de farmaceutiske præparater ifølge opfindelsen blandes én eller flere sulfamatforbindel ser med formel (I) grundigt med en farmaceutisk bærer iht. konventionelle farmaceu-20 tiske sammenbland!ngsteknikker, idet bæreren kan være på mange forskellige former i afhængighed af den til administreringen ønskede præparatform, fx. oral, ved suppositorier eller parenteral. Ved fremstilling af præparaterne i oral dosisform kan der anvendes et hvilket som helst af de sædvanlige farmaceutiske medier. Egnede 25 bærere og tilsætningsstoffer for flydende orale præparater som fx suspensioner, elikserer og opløsninger omfatter således vand, gly-koler, olier, alkoholer, smagsstoffer, konserveringsmidler, farvestoffer o.l., for faste orale præparater såsom fx. pulvere, kapsler og tabletter omfatter egnede bærere og tilsætningsstoffer, stivelser, 30 sukkerarter, fortyndere, granuleringsmidler, smøremidler, bindemidler, disintegreringsmidler o.l. P.g.a. den lette administrering udgør tabletter og kapsler den mest fordelagtige orale enhedsdosisform, i hvilket tilfælde der selvfølgelig anvendes faste farmaceutiske bærere. Om ønsket kan tabletter sukkerovertrækkes eller overtræk-35 kes enterisk ved hjælp af standardteknikker. Der kan fremstilles suppositorier, i hvilket tilfælde kakaosmør kan anvendes som bærer.
Ved parenterale præparater omfatter bæreren sædvanligvis sterilt vand, selvom andre bestanddele kan inkluderes, fx med hensigten
DK 165004B
6 såsom at forbedre opløseligheden eller holdbarheden. Der kan også fremstilles injicerbare suspensioner, i hvilket tilfælde der kan anvendes passende flydende bærere, suspensionsmidler o.l.
Det farmaceutiske præparater ifølge opfindelsen vil pr. enheds-5 dosis fx. tabletter, kapsler, pulvere, injektioner, teskefuld, suppositorier o.l. indeholde fra ca. 10 til ca. 500 mg aktiv bestanddel.
De ovennævnte foregående præparater er specielt egnede til anvendelse ved behandling af epilepsi eller epilepsi-symptomer ved hjælp af en fremgangsmåde, der omfatter intern administrering til en 10 patient, der lider af epilepsi-symptomer, idet præparaterne omfatter en effektiv epilepsi-inhiberende mængde af en forbindelse med formel (I).
I de følgende eksempler og i hele beskrivelsen anvendes følgende forkortelser: g (gram), ml (milliliter), cm (centimeter), v/v (volumen til volumen), smp. (smeltepunkt), TLC (tyndtlagskromatografi), NMR 15 (kernemagnetisk resonans), IR (infrarød), DMF (dimethylformamid), THF (tetrahydrofuran) og C, Η, N, etc. (de kemiske symboler for grundstofferne).
Eksempel 1 20 (Tetrahydro-2H-pyran-2-yl)methansulfamat
Til en kold opløsning (-5°C) af tetrahydropyran-2-methanol (2,33 g, 0,02 mol) i DMF (40 ml) sattes 50% olieagtigt natriumhydrid (1,17 g, 0,024 mol som NaH). Efter omrøring i 45 minutter tilsattes sulfamoylchlorid (3,42 g, 0,03 mol) og omrøringen fortsattes i yderi ige-25 re 45 minutter ved -5°C. Reaktionsblandingen hældtes i koldt vand og ekstraheredes med chloroform. Det organiske lag tørredes (Na2S04) og opløsningsmidlerne fjernedes under vakuum, hvilket gav en sirup, der kro-matograferedes på tør kolonne (der elueredes med ethyl acetat:hexan, 4:1 v/v), hvilket gav rent (tetrahydro-2H-pyran-2-yl)methansulfamat som en 30 svagt gul sirup, IR:(CHCl^) 1180 cm"1 og 1370 cm"1 (OSOgNHg).
Eksempel 2 (1-methylcyclohexyl)methansulfamat
Til en kold opløsning (-4°C) af (1-methylcyclohexyl)methanol (6,2 35 g, 0,048 mol) i DMF (90 ml) sattes 50% olieagtigt natriumhydrid (82,81 g, 0,059 mol som NaH). Efter omrøring i 1 time tilsattes sulfamoylchlo-rid (7,82 g, 0,062 mol) og omrøringen fortsattes i yderligere 30 minutter ved -4°C. Reaktionsblandingen hældtes i koldt vand og ekstraheredes
DK 165004 B
7 med toluen. Det organiske lag tørredes (Na2S04) og opløsningsmidlerne fjernedes under vakuum, hvilket gav en sirup, der krystalliserede efter afkøling. Omkrystallisation fra chloroform/ hexan gav rent (1-methyl-cyclohexyljmethansulfamat, smp. 40-42°C.
5
Eksempel 3 2,3:4,5-bi s-0-(1-methyl ethyl i den)-β-O-fruktopyranosesulfamat
Til en kold opløsning (-4°C) af 2,3:4,5-di-0-isopropyliden-/3-fruk-topyranose (75 g, 0,29 mol) i DMF (725 ml) sattes 50% olieagtigt natri -10 umhydrid (16,34 g, 0,34 mol som NaH). Efter omrøring i 90 minutter tilsattes sulfamoylchlorid (54,9 g, 0,48 mol) og omrøringen fortsattes i yderligere 3½ time ved denne temperatur. Reaktionsblandingen hældtes i koldt vand og ekstraheredes med toluen. Det organiske lag tørredes (Na2S04) og opløsningsmidlerne fjernedes under vakuum, hvilket gav en 15 sirup, som øjeblikkeligt krystalliserede. Omkrystallisation fra ethyl -acetat/hexan gav rent 2,3:4,5-bis-0-(l-methylethyliden)-/J-D-fruktopyra-nosesulfamat, smp. 125-126°C.
Eksempel 4 20 2,3:4,5-bi s-0- (1 -methylethyl iden) -jS-D-fruktopyranosemethyl sul famat En opløsning af sulfonylchlorid (93 ml, 1,15 mol) i methylen-chlorid (100 ml) sattes dråbevis til en kold opløsning (-35°C) af 2,3:4,5-di-0-isopropyliden-/3-D-fruktopyranose (150 g, 0,58 mol) i methylenchlorid (400 ml) og pyridin (150 ml). Reaktionsblandingen 25 omrørtes og opvarmedes til stuetemperatur (25°C); den omrørtes i yderligere 2 timer. Opløsningsmidler fjernedes under vakuum. Det resulterende halvfaste stof opløstes i vandfri acetonitril (35 g, 150 ml) og methylamin bobledes igennem. Reaktionsbeholderen lukkedes tæt og opløsningsmidler fjernedes under vakuum. Den resulterende sirup 30 underkastedes væskekromatografi (tør kolonne ethyl acetat: hexan, 4:1), hvilket gav en lysegul sirup, 2,3:4,5-bis-0-(l-methylethyliden)-j3-D-fruktopyranosemethylsul famat, som var homogent ifølge TLC og *H NHR.
Eksempel 5 35 (l,2,3,4-tetrahydro-2-naphthalenyl)methylsulfamsyreester
Til en kold opløsning (-5°) af (l,2,3,4-tetrahydro-2-naphthalenyl)-methanol (7,1 g, 0,044 mol) i DMF (80 ml) sattes 50% olieagtigt natriumhydrid (2,56 g, 0,054 mol som NaH). Efter omrøring i 45 minutter

Claims (10)

1. Sul famater med formlen (I)
15 R ^“^CH.OSO^HR, (I) hvori R|1 Rj X er CH2 eller oxygen. Rj er hydrogen eller al kyl, og
20 R2, Rg, R4 og Rg uafhængigt af hinanden er hydrogen eller lavere alkyl og, når X er CH2, er R^ og Rg eventuelt alkengrupper, der tilsammen danner en benzenring og, når X er oxygen, danner R2 og Rg og/eller R^ og Rg eventuelt en methylendioxygruppe med formel (II)
25 V0_ <U> r{ \>- hvori Rg og Ry, som er ens eller forskellige, er hydrogen, lavere al kyl, eller al kyl som tilsammen danner en cyclopentyl- eller cyclohexylring. 30
2. Sulfamat ifølge krav 1, kendetegnet ved, at X er oxygen og R2 og Rg og R^ og Rg tilsammen danner methylendioxygrupper med formlen (II), hvor Rg og Ry er som defineret ovenfor.
3. Sulfamat ifølge krav 1, kendetegnet ved, at X er CH2 og R^ og Rg er alkengrupper, der tilsammen danner en benzenring. DK 165004B
4. Sulfamat ifølge krav 3, kendetegnet ved, at R2 og Rg er hydrogen.
5. Sulfamat ifølge krav 1, kendetegnet ved, at 5 alkylgruppen for Rj er al kyl med 1 til 4 carbonatomer, den lavere al kyl -gruppe for R2, Rg, R4 og Rg er al kyl med 1 til 3 carbonatomer og den lavere al kyl for Rg og R^ er alkyl med 1 til 3 carbonatomer.
6. Sulfamat ifølge krav 1, kendetegnet ved, at det er ud- 10 valgt fra gruppen bestående af (tetrahydro-2H-pyran-2-yl)methansulfamat, (1-methylcyclohexylJmethansulfamat, 2,3:4,5-bis-0-(l-methyl ethyl i den)-β-ΰ-fruktopyranosesulfamat, 2,3:4,5-bis-0-(l-methyl ethyl i den)-/1-D-fruktopyranosemethy1 sul famat, 15 og (1,2,3,4-tetrahydro-2-napthalenyl)methylsulfamsyreester.
7. Sulfamat ifølge krav 6, kendetegnet ved, at det er 2,3:4,5-bi s-0-(1-methylethyl iden)-β-Ό-fruktopyranosesulfamat. 20
8. Sulfamat ifølge krav 6, kendetegnet ved, at det er (1,2,3,4-tetrahydro-2-naphthalenylJmethylsulfamsyreester.
9. Farmaceutisk præparat, kendetegnet ved, at det 25 omfatter et sulfamat ifølge krav 1 og en farmaceutisk acceptabel bærer.
10. Farmaceutisk præparat ifølge krav 9, kendetegnet ved, at sulfamatet er til stede i en enhedsdosismængde fra ca. 10 til 500 mg sulfamat. 30
DK457784A 1983-09-26 1984-09-25 Sulfamatderivater og farmaceutiske praeparater indeholdende disse DK165004C (da)

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US06/535,475 US4513006A (en) 1983-09-26 1983-09-26 Anticonvulsant sulfamate derivatives

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DK457784A DK457784A (da) 1985-03-27
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DK198191A DK165003C (da) 1983-09-26 1991-12-09 Chlorsulfat
DK199101982A DK173923B1 (da) 1983-09-26 1991-12-09 Azidosulfat

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DK165003B (da) 1992-09-28
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US4513006A (en) 1985-04-23
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